Cystinosis in adult and adolescent patients: Recommendations for the comprehensive care of cystinosis

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] 10 => array:3 [ "nombre" => "Manel" "apellidos" => "Perelló" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "j" "identificador" => "aff0050" ] ] ] 11 => array:3 [ "nombre" => "Guillem Pintos" "apellidos" => "Morell" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "k" "identificador" => "aff0055" ] ] ] 12 => array:3 [ "nombre" => "Roser" "apellidos" => "Torra" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "l" "identificador" => "aff0060" ] ] ] 13 => array:3 [ "nombre" => "Anna Vila" "apellidos" => "Santandreu" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] ] ] 14 => array:3 [ "nombre" => "Ana" "apellidos" => "Güell" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "m" "identificador" => "aff0065" ] ] ] 15 => array:3 [ "nombre" => "Grupo" "apellidos" => "T-CiS.bcn" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "n" "identificador" => "aff0070" ] ] ] ] "afiliaciones" => array:14 [ 0 => array:3 [ "entidad" => "Servicio de Nefrología Pediátrica, Hospital Universitari Vall d’Hebron, Grupo Renaltube, Redinren, Barcelona, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Servicio de Nefrología Pediátrica, Hospital San Joan de Déu, Barcelona, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Servicio de Nefrología Pediátrica, Hospital Universitari Vall d’Hebron, Barcelona, Spain" "etiqueta" => "c" "identificador" => "aff0015" ] 3 => array:3 [ "entidad" => "Servicio de Farmacia, Hospital Universitari Vall d’Hebron, Barcelona, Spain" "etiqueta" => "d" "identificador" => "aff0020" ] 4 => array:3 [ "entidad" => "Servicio de Neurología, Hospital Universitari Vall d’Hebron, Barcelona, Spain" "etiqueta" => "e" "identificador" => "aff0025" ] 5 => array:3 [ "entidad" => "Servicio Bioquímica y Genética Molecular. Sección de Errores Congénitos del Metabolismo. Hospital Universitari Clínic. IDIBAPS y CIBERER, Barcelona, Spain" "etiqueta" => "f" "identificador" => "aff0030" ] 6 => array:3 [ "entidad" => "Servicio de Endocrinología y Nutrición, Hospital Universitari Clínic, Barcelona, Spain" "etiqueta" => "g" "identificador" => "aff0035" ] 7 => array:3 [ "entidad" => "Servicio de Oftalmología, Hospital Universitari Vall d’Hebron, Barcelona, Spain" "etiqueta" => "h" "identificador" => "aff0040" ] 8 => array:3 [ "entidad" => "Servicio de Nefrología y Trasplante Renal, Hospital Universitari Clínic, Barcelona, Spain" "etiqueta" => "i" "identificador" => "aff0045" ] 9 => array:3 [ "entidad" => "Servicio de Nefrología, Hospital Universitari Vall d’Hebron, Barcelona, Spain" "etiqueta" => "j" "identificador" => "aff0050" ] 10 => array:3 [ "entidad" => "Unidad de Nefrología Pediátrica, Hospital Universitari Germans Trias i Pujol, Badalona, Barcelona, Spain" "etiqueta" => "k" "identificador" => "aff0055" ] 11 => array:3 [ "entidad" => "Servicio de Nefrología, Fundació Puigvert, AIRG-E, Redinren, Barcelona, Spain" "etiqueta" => "l" "identificador" => "aff0060" ] 12 => array:3 [ "entidad" => "Product affairs, Orphan Europe - Recordati Group, Spain" "etiqueta" => "m" "identificador" => "aff0065" ] 13 => array:3 [ "entidad" => "TCiS.bcn: Working group for multidisciplinary care and transition from paediatric to adult units in cystinosis, Barcelona, Spain" "etiqueta" => "n" "identificador" => "aff0070" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author: Gema Ariceta, Servicio de Nefrología Pediátrica. Hospital Universitari Vall d’Hebron. Grupo Renaltube. Redinren, Pg/ Vall d’Hebron 119-129, 08034 Barcelona, Spain. Tel.: 934893082." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Cistinosis en pacientes adolescentes y adultos: recomendaciones para la atención integralde la cistinosis" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1183 "Ancho" => 1817 "Tamanyo" => 162844 ] ] "descripcion" => array:1 [ "en" => "Clinical manifestations of cystinosis in patients not treated with cysteamine. CKD: chronic kidney disease, ESRD: end stage renal disease, RRT: renal replacement therapy." ] ] ] "textoCompleto" => "IntroductionCystinosis is a rare systemic lysosomal storage disease which, if not treated, leads to end-stage kidney failure in the first decade of life.<a class="elsevierStyleCrossRef" href="#bib0635">1</a> Its natural history has been transformed thanks to the development of kidney transplantation (KTx) in children<a class="elsevierStyleCrossRef" href="#bib0640">2</a> and the availability of specific treatment with cysteamine, a drug therapy that should be maintained throughout the patient's lifetime.<a class="elsevierStyleCrossRef" href="#bib0645">3</a> As a consequence, patient survival has increased from the first decade of life to beyond the fourth decade and cystinosis has passed from paediatrics to adult medicine.<a class="elsevierStyleCrossRef" href="#bib0650">4</a>The control of cystinosis is complex owing to its severity and multisystemic nature, and the requirement of treatment with several drugs with a very strict dosage schedule. Early diagnosis, prompt cysteamine administration and treatment adherence influence morbidity and prognosis.<a class="elsevierStyleCrossRefs" href="#bib0655">5,6</a> Nevertheless, adherence to therapy, which is usually good in children, tends to wane in teenagers and adults.<a class="elsevierStyleCrossRef" href="#bib0665">7</a> Furthermore, when patients reach adult age, they are usually transferred from the paediatric expert centre to a local hospital with limited experience in cystinosis, while the systemic manifestations continue to progress and the disease becomes more complex.<a class="elsevierStyleCrossRef" href="#bib0670">8</a> This phenomenon is seen in other chronic renal diseases that debut in paediatric patients<a class="elsevierStyleCrossRef" href="#bib0675">9</a> and highlights the need to implement transition strategies and promote patient self-care.<a class="elsevierStyleCrossRef" href="#bib0680">10</a>The current cystinosis count in Spain comprises 56 patients treated and followed up at 22 hospitals. Approximately 50% are adults and 16% adolescents; 57% are kidney transplant recipients.<a class="elsevierStyleCrossRef" href="#bib0665">7</a>The working group for the care and transition of cystinosis in Barcelona (T-CiS.bcn) has assembled a group of experts in the disease to establish, as a first step, recommendations for the comprehensive care of cystinosis and the transition of adolescents to adult-care units in our country. This consensus document presents a support tool for health care professionals both involved in and interested in cystinosis. It is focused on reducing disease impact, improving quality of life and prolonging survival, in accordance with the guidelines of the International Society of Nephrology (ISN) and the International Paediatric Nephrology Association (IPNA).<a class="elsevierStyleCrossRef" href="#bib0680">10</a> At a later date, the T-CiS.bcn group plans to create a coordinated model of transition from paediatric to adult care services which will cover the specific needs of cystinosis.EtiopathogenesisCystinosis is a hereditary autosomal recessive disease caused by mutations with loss of function of the CTNS gene (chromosome 17p13), which encodes for cystinosin.<a class="elsevierStyleCrossRef" href="#bib0685">11</a> Cystinosin is a specific transmembrane protein for the transport of cystine from the lysosome to cell cytoplasm.<a class="elsevierStyleCrossRef" href="#bib0690">12</a> Its absence causes progressive deposits of intralysosomal cystine, the main diagnostic marker of the disease<a class="elsevierStyleCrossRef" href="#bib0635">1</a>. Its annual incidence is estimated at 1/100,000–200,000 newborns, while the population prevalence is 1–9/1,000,000.<a class="elsevierStyleCrossRef" href="#bib0695">13</a> The most frequent mutation in the CTNS gene is a deletion of 57Kb<a class="elsevierStyleCrossRef" href="#bib0700">14</a> which is also observed in 34% of patients in the Spanish population.<a class="elsevierStyleCrossRef" href="#bib0705">15</a>The amino acid cysteine oxidises inside the lysosome and forms cystine. In patients with cystinosis, there is an accumulation of cystine that precipitates in crystal form in all the cells of the organism, particularly in renal and ocular tissue.<a class="elsevierStyleCrossRef" href="#bib0710">16</a> The increase in the lysosomal concentration of cystine is associated with increased cellular apoptosis, oxidative stress and alterations in the metabolism of glutathione and arachidonic acid.<a class="elsevierStyleCrossRefs" href="#bib0715">17–19</a> Other pathogenic mechanisms involved are inflammatory<a class="elsevierStyleCrossRef" href="#bib0730">20</a> and “endoplasmic reticulum stress”, which finally lead to cell death.<a class="elsevierStyleCrossRefs" href="#bib0735">21,22</a>SymptomsCystinosis is a multisystemic disease<a class="elsevierStyleCrossRef" href="#bib0745">23</a> with the kidneys and eyes being the first organs to be affected. Three clinical forms have been described: infantile nephropathic cystinosis (OMIM#219800), the most serious subtype, which debuts early on; juvenile nephropathic cystinosis (OMIM#219900), a less severe subtype, which debuts in childhood or later; and adult non-nephropathic cystinosis (OMIM#219750), with exclusively ocular involvement.<a class="elsevierStyleCrossRef" href="#bib0750">24</a> Nonetheless, in clinical practice, two main subtypes are defined: nephropathic cystinosis that debuts in early childhood with severe Fanconi syndrome (representing 95% of all cases) and late-onset non-nephropathic cystinosis, which appears in young patients or adults with renal and/or ocular involvement (representing <5% of affected patients). In some patients, ocular involvement can precede renal manifestations by several years.<a class="elsevierStyleCrossRef" href="#bib0755">25</a>Renal diseaseFanconi syndromeTypical clinical symptoms include the appearance of severe Fanconi syndrome with evolution to chronic kidney disease (CKD) (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>). Tubulopathy characteristically becomes evident in the second semester of life after a symptom-free interval.<a class="elsevierStyleCrossRef" href="#bib0750">24</a> Affected newborns are apparently normal, although it is possible to detect urinary alterations (alkalineurine with glycosuria and/or proteinuria) very early preceding symptoms.<a class="elsevierStyleCrossRef" href="#bib0760">26</a> Cystinosis is the most frequent cause of inherited Fanconi syndrome<a class="elsevierStyleCrossRef" href="#bib0750">24</a> and should be considered in the initial differential diagnosis in newborns. Nonetheless, cases have been described of cystinotic patients who debuted with atypical symptoms not suggestive of Fanconi syndrome but of distal tubulopathy, such as nephrogenic diabetes insipidus or Batter syndrome. Thus, the diagnosis of cystinosis should be considered in all newborns with complex tubulopathy, particulary if growth is affected and the patient is anorexic.<a class="elsevierStyleCrossRef" href="#bib0635">1</a> The differential diagnosis should contemplate the possibility of secondary proximal tubulopathy.<a class="elsevierStyleCrossRefs" href="#bib0765">27,28</a> The severity of Fanconi syndrome associated with cystinosis requires rigorous treatment that is frequently very complex (<a class="elsevierStyleCrossRef" href="#tbl0020">Table 1</a>).<elsevierMultimedia ident="fig0005"></elsevierMultimedia><elsevierMultimedia ident="tbl0020"></elsevierMultimedia>Chronic kidney diseaseAfter the age of two, if no specific treatment is administered, glomerular involvement progress with a drop in the glomerular filtration rate (GFR) and an increase in plasma creatinine starting at the age of 4 to 6, which evolves to advanced CKD.<a class="elsevierStyleCrossRef" href="#bib0635">1</a> Concurrently, Fanconi syndrome usually remits and, consequently, it is possible to reduce water/electrolyte supplements (<a class="elsevierStyleCrossRef" href="#tbl0020">Table 1</a>). In the absence of specific pharmacological treatment (cysteamine), mean age at the onset of end-stage renal disease (ESRD) is 9.2 years. In more contemporary series including patients who received early treatment with cysteamine, there is a significant delay in evolution to ESRD at the age of 13.5 which has been attributed to better patient control by physicians. Furthermore, in cases with very early diagnosis and treatment, there is a growing percentage of patients who remain in predialysis after adolescence.<a class="elsevierStyleCrossRef" href="#bib0660">6</a>There are also forms of attenuated or late-onset cystinosis that debut in adolescence or in young adults, such as glomerular disease and proteinuria without Fanconi syndrome, although occasionally signs suggestive of proximal tubulopathy are observed. Usually, patients also present ocular manifestations of the disease that can be nearly asymptomatic<a class="elsevierStyleCrossRef" href="#bib0755">25</a> (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>).Although renal biopsy is not necessary for diagnosis, it demonstrates non-specific lesions of glomerulosclerosis and other more characteristic signs such as irregularities on the brush border of proximal tubule cells, swan neck deformity and, occasionally, deposits of cystine crystals and giant multinucleated podocytes.<a class="elsevierStyleCrossRefs" href="#bib0640">2,16,24</a>DialysisThe renal replacement therapy (RRT) of choice in cystinosis is the kidney transplantation (KTx) since the disease does not recur in kidney grafts. In many cases, however, the limitation of organs or delayed diagnosis results in the start of dialysis. According to the NAPRTCS register, 1.4% of patients <18 years of age who initiated chronic dialysis had cystinosis.<a class="elsevierStyleCrossRef" href="#bib0780">30</a> On the other hand, in the European ESPN/ERA-EDTA Registry, 0.9% of patients <20 years of age and 0.1% of patients >20 years with RRT had cystinosis. In Europe, peritoneal dialysis (PD) was the most frequent initial treatment modality (39.6%), followed by preventive KTx (35.1%). Some 17.9% of patients received haemodialysis (HD).<a class="elsevierStyleCrossRef" href="#bib0655">5</a>Fanconi syndrome can persist after the start of dialysis, which influences the dietetic prescription for water, patient diet and the possible need to administer other medications such as phosphorus chelates. Although the urinary loss of saline and polyuria usually decrease in advanced CKD, the patient may continue to need water/electrolyte supplements and carnitine (<a class="elsevierStyleCrossRef" href="#tbl0020">Table 1</a>). On rare occasions, the severity of Fanconi syndrome justifies nephrectomy of the native kidneys.<a class="elsevierStyleCrossRef" href="#bib0785">31</a> Moreover, many cystinotic patients on dialysis characteristically present extrarenal involvement requiring the integrated intervention of other specialists (see section on extrarenal involvement), which can be a challenge for nephrologists when treating their patients.<a class="elsevierStyleCrossRef" href="#bib0790">32</a>Kidney transplantationAs previously stated, the RRT of choice in cystinosis is KTx. Since graft cells do not carry the lysosomal defect, the disease does not recur in the transplanted organ. However, it is possible to observe interstitial deposits of cystine crystals, which represent leukocytes of the recipient and have no pathological significance.<a class="elsevierStyleCrossRef" href="#bib0735">21</a> Family-donor transplantation is also curative, and heterozygous carriers of the CTNS mutation can be appropriate donors since they do not have the disease.<a class="elsevierStyleCrossRefs" href="#bib0650">4,6,33</a>Indirect data from cystinotic patients with advanced kidney failure and international registries suggest that preventive kidney transplantation would be beneficial in this disease, particularly when a living donor is available<a class="elsevierStyleCrossRef" href="#bib0650">4</a> thereby avoiding the need for dialysis.<a class="elsevierStyleCrossRef" href="#bib0655">5</a> Thus, the indication for kidney transplantation is established when the GFR is <20ml/min/1.73m2, which would be somewhat earlier than in other kidney diseases.<a class="elsevierStyleCrossRef" href="#bib0635">1</a>In the United States (USRDS2013), mean age of patients with cystinosis at the first KTx is 13.8 years (range: 2 to 24), which has not changed in recent decades; 32.4% underwent preventive KTx.<a class="elsevierStyleCrossRef" href="#bib0800">34</a> Similarly data from the European Registry (ESPN/ERA-EDTA Registry) show a similar percentage of 35.1% predialysis transplantations, a much higher percentage than in other nephropathies (17.1%).<a class="elsevierStyleCrossRef" href="#bib0655">5</a> Eighty-five percent of all the cystinotic patients in RRT were kidney transplant recipients. Regarding the type of donor, 54% of patients in the US received a living and 46% a deceased donor organ.<a class="elsevierStyleCrossRef" href="#bib0800">34</a> Similarly, in Europe 48.9% received a living donor transplant.<a class="elsevierStyleCrossRef" href="#bib0655">5</a>It is worthy of mention that the duration of functioning kidney grafts in cystinotic patients is longer than that observed in the population of recipients transplanted for other causes.<a class="elsevierStyleCrossRefs" href="#bib0655">5,35</a>Extrarenal diseaseThe longer survival and better prognosis of patients with cystinosis have resulted in better understanding of the multiple organ involvement in this disease<a class="elsevierStyleCrossRefs" href="#bib0650">4,6,32,36</a> (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>).Ocular involvementEye involvement is intrinsic to cystinosis. The presence of cystine crystals in the cornea is a diagnostic criterion for this disease,<a class="elsevierStyleCrossRef" href="#bib0815">37</a> although its absence before the age of 12 months may not rule it out.<a class="elsevierStyleCrossRef" href="#bib0635">1</a>Cystine deposits in the cornea are one of the earliest manifestations of cystinosis (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>). Although no crystals are present at birth, they can be observed in children who are only a few months old.<a class="elsevierStyleCrossRef" href="#bib0635">1</a> Initially, they are deposited in the superficial layers of the peripheral cornea, but progressively begin to affect all the layers and entire extension of the cornea. If left untreated, corneal crystal deposits progress inexorably, increasing with age, resulting in photophobia, which can be quite incapacitating, and in abnormal corneal sensitivity. In time, this condition leads to recurrent corneal erosions and stromal oedema, which can reduce visual acuity. Reports also exist of calcium deposition in Bowman's membrane or band keratopathy, which affect vision when situated in the visual axis.<a class="elsevierStyleCrossRef" href="#bib0815">37</a>Crystals are also deposited in other ocular structures such us the conjunctiva, anterior chamber, iris, ciliary body, choroid and retina. Retinal involvement causes degeneration of the photoreceptors, mainly the rods, thereby altering the peripheral visual field and night vision, although central vision may also be reduced. Less frequently, there have been reports of posterior synechiae, adherence of the iris to the anterior lens capsule and neovascularisation of the peripheral cornea.<a class="elsevierStyleCrossRefs" href="#bib0820">38,39</a> Furthermore, tear production is reduced, causing dry eye, and neuro-ophthalmological manifestations (papilledema and ophthalmoplegia) are observed secondary to the increased intracranial pressure reported in this disease.<a class="elsevierStyleCrossRef" href="#bib0650">4</a> In late-onset disease, the presence of crystals might not be detected until adulthood.<a class="elsevierStyleCrossRef" href="#bib0755">25</a>Growth and development: mineral-bone involvementFailure to thrive is a classic clinical symptom of cystinosis and frequently is the reason for an early consultation.<a class="elsevierStyleCrossRef" href="#bib0810">36</a> The underlying mechanism is multifactorial, although it is related to Fanconi syndrome severity. The concurrence of metabolic acidosis, hyponutrition, increased gastrointestinal and renal losses and CKD lead to delayed growth that can be very severe.<a class="elsevierStyleCrossRefs" href="#bib0830">40,41</a> Similarly, patients present endocrine alterations (see endocrine involvement section) and, infrequently, primary growth hormone (GH) deficiency.<a class="elsevierStyleCrossRef" href="#bib0840">42</a>Patients with inadequate treatments usually have shorter stature.<a class="elsevierStyleCrossRef" href="#bib0810">36</a> Classically, the adult height reported in patients with suboptimal treatment is 144cm and weight 45kg (25cm and 25kg below the normal population average, respectively).<a class="elsevierStyleCrossRef" href="#bib0650">4</a> The most recent series with better therapeutic control reported less retarded growth<a class="elsevierStyleCrossRef" href="#bib0670">8</a> and a favourable impact of treatment on growth regulation mechanisms.<a class="elsevierStyleCrossRef" href="#bib0845">43</a> Nevertheless, nowadays 27% of transplanted cystinotic patients and 44% of those on dialysis continue to be shorter than average.<a class="elsevierStyleCrossRef" href="#bib0655">5</a>Early GH administration improves height and weight, although the therapeutic response is usually lower than that observed in CKD due to other causes, despite optimum disease control. GH is an essential therapeutic tool in this disease, for its impact on longitudinal growth and its anabolic effect.<a class="elsevierStyleCrossRefs" href="#bib0830">40,44</a> Patients with cystinosis develop a characteristic metabolic bone disease caused by different factors: bone deposits of cystine crystals, mineral deficiency, renal rickets<a class="elsevierStyleCrossRef" href="#bib0750">24</a> and CKD per se.<a class="elsevierStyleCrossRef" href="#bib0855">45</a> Bone anomalies attributed to copper deficiency, possibly secondary to Fanconi syndrome have also been described.<a class="elsevierStyleCrossRef" href="#bib0860">46</a> It is therefore common to detect osteopenia, especially in transplant recipients, related also to other endocrine alterations of the disease (see endocrine involvement section) and potentially to the treatment.<a class="elsevierStyleCrossRefs" href="#bib0745">23,47</a> Some patients have bone fragility and a higher risk of fractures.<a class="elsevierStyleCrossRef" href="#bib0790">32</a>Endocrine involvementEndocrine manifestations are caused by destruction of the affected glands due to cystine deposits; their incidence and age at appearance are associated with the establishment of specific treatment with cysteamine.<a class="elsevierStyleCrossRef" href="#bib0845">43</a>Primary hypothyroidism is the most frequent endocrine complication;<a class="elsevierStyleCrossRef" href="#bib0745">23</a> it is progressive and requires chronic treatment with levothyroxine.<a class="elsevierStyleCrossRefs" href="#bib0635">1,4</a> Diabetes mellitus (DM) is characterised by a progressive alteration in insulin secretion,<a class="elsevierStyleCrossRef" href="#bib0870">48</a> with negative immunology, and requires treatment with insulin.<a class="elsevierStyleCrossRef" href="#bib0640">2</a> It is observed in transplant recipients who receive corticosteroids.<a class="elsevierStyleCrossRef" href="#bib0745">23</a> In males, cystinosis causes primary hypogonadism and infertility is a constant.<a class="elsevierStyleCrossRefs" href="#bib0650">4,49</a> In females, however, neither hypogonadism nor infertility are prevalent, and affected patients can thus have children,<a class="elsevierStyleCrossRef" href="#bib0880">50</a> although the risk of prematurity is increased.<a class="elsevierStyleCrossRef" href="#bib0885">51</a>Cardiovascular involvementThe appearance of dyslipidemia and vascular calcification due to cystinosis and CKD are considered increased cardiovascular risk factors.<a class="elsevierStyleCrossRefs" href="#bib0745">23,32,41</a> 42% of patients develop arterial hypertension, usually post-transplantation. Aortic aneurysms and coronary vessels involvement, as well as cardiomyopathy associated with cystine crystals deposits in the myocardium have also been reported.<a class="elsevierStyleCrossRef" href="#bib0810">36</a> In adult patients, screening for ischaemic heart disease is recommended.<a class="elsevierStyleCrossRef" href="#bib0650">4</a>Neurological involvementCystinosis is associated with alterations in cerebral structure and increased cystine levels in different areas of the nervous system and muscle tissue.<a class="elsevierStyleCrossRefs" href="#bib0650">4,6,32,52</a> In general, neurological complications worsen the prognosis of the disease:<ul class="elsevierStyleList" id="lis0040"><li class="elsevierStyleListItem" id="lsti0125">•Progressive ischaemic myopathy<a class="elsevierStyleCrossRefs" href="#bib0650">4,32,53</a> is predominantly distal and begins in the hands; loss of muscle mass is also observed with later ventilator capacity impairment and swallowing difficulties. Some authors attribute muscle weakness in these patients to carnitine deficiency.<a class="elsevierStyleCrossRefs" href="#bib0750">24,28,29</a></li><li class="elsevierStyleListItem" id="lsti0130">•Central nervous system (CNS) involvement<a class="elsevierStyleCrossRefs" href="#bib0650">4,31</a> is mainly observed in patients with suboptimal treatment with cysteamine:<ul class="elsevierStyleList" id="lis0045"><li class="elsevierStyleListItem" id="lsti0135">–Acute presentation: epilepsy, stroke, encephalopathy, cephalalgia<a class="elsevierStyleCrossRefs" href="#bib0900">54–57</a></li><li class="elsevierStyleListItem" id="lsti0140">–Subacute/progressive presentation: intracranial hypertension, cerebral atrophy, ataxia, pyramidalism, gait disorders, basal and periventricular lymph node calcifications, demyelination of white matter, mental deterioration<a class="elsevierStyleCrossRefs" href="#bib0920">58–66</a></li></ul></li><li class="elsevierStyleListItem" id="lsti0145">•Neurocognitive alterations:<a class="elsevierStyleCrossRefs" href="#bib0965">67–73</a> in cystinotic patients, a specific profile of alterations in visual-motor integration, visual memory, maintained attention, planning, motor processing speed and arithmetic calculation have been described. Consequently, they account for a significant incidence of social difficulties that could explain the behavioural phenotype in some patients. Intelligence is usually normal.</li></ul>Early detection of neurological complications in cystinosis facilitates better therapeutic strategies, reduces the number of hospitalisations and improves quality of life. The participation of a neurologist will help to evaluate the functional capacity of patients and detect earlier the neurological manifestations that can affect autonomy in basic daily life activities.<a class="elsevierStyleCrossRefs" href="#bib0670">8,31,32,55</a>MiscellaneousThe ubiquity of cystinosis is demonstrated by its non-specific symptoms e.g. gastrointestinal and other disorders such as heat intolerance and hypophoresis. Similarly, the systemic nature of the disease explains the progressive appearance of other clinical symptoms secondary to the deposition of cystine crystals in different organs and systems, as detailed below (Fig. 1):<ul class="elsevierStyleList" id="lis0050"><li class="elsevierStyleListItem" id="lsti0030">•Digestive system<a class="elsevierStyleCrossRef" href="#bib1000">74</a>:<ul class="elsevierStyleList" id="lis0020"><li class="elsevierStyleListItem" id="lsti0035">–Nausea, vomiting, epigastralgia, anorexia</li><li class="elsevierStyleListItem" id="lsti0040">–Increased gastrin secretion (associated with taking cysteamine)</li><li class="elsevierStyleListItem" id="lsti0045">–Decreased salivation</li><li class="elsevierStyleListItem" id="lsti0050">–Mechanical swallowing difficulties</li><li class="elsevierStyleListItem" id="lsti0055">–Delayed gastric emptying and intestinal and intestinal dysmotility</li><li class="elsevierStyleListItem" id="lsti0060">–Intestinal pseudo-obstruction</li><li class="elsevierStyleListItem" id="lsti0065">–Intestinal inflammatory disease</li></ul></li><li class="elsevierStyleListItem" id="lsti0070">•Liver<a class="elsevierStyleCrossRefs" href="#bib0790">32,75</a>:<ul class="elsevierStyleList" id="lis0025"><li class="elsevierStyleListItem" id="lsti0075">–Regenerative nodular hyperplasia without liver failure</li><li class="elsevierStyleListItem" id="lsti0080">–Non-cirrhotic portal hypertension with hypersplenism</li><li class="elsevierStyleListItem" id="lsti0085">–Cholestasis</li><li class="elsevierStyleListItem" id="lsti0090">–Hypercholesterolemia</li></ul></li><li class="elsevierStyleListItem" id="lsti0095">•Skin<a class="elsevierStyleCrossRefs" href="#bib0635">1,76</a>:<ul class="elsevierStyleList" id="lis0030"><li class="elsevierStyleListItem" id="lsti0100">–Hypopigmentation of skin and hair due to altered melanogenesis</li><li class="elsevierStyleListItem" id="lsti0105">–Altered sweating and intolerance to heat</li></ul></li><li class="elsevierStyleListItem" id="lsti0110">•Bone marrow<a class="elsevierStyleCrossRef" href="#bib0650">4</a>:<ul class="elsevierStyleList" id="lis0035"><li class="elsevierStyleListItem" id="lsti0115">–Anaemia</li><li class="elsevierStyleListItem" id="lsti0120">–Coagulopathy due to dysfunctional platelets</li></ul></li></ul>DiagnosisThe clinical diagnosis of cystinosis is symptom-based and is confirmed by biochemical and molecular diagnosis.Clinical diagnosisGuiding signs are early-onset of severe Fanconi syndrome and the detection of corneal crystals. As the disease progresses, systemic involvement may be observed (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>). However, in patients with less severe forms, renal involvement is restricted to proteinuria and CKD. Occasionally, corneal crystals in adult patients with CKD of unknown aetiology lead to the diagnosis of cystinosis.<a class="elsevierStyleCrossRef" href="#bib0755">25</a> Kidney biopsy, while not a requirement for the diagnosis of cystinosis, can be useful in these atypical presentations.<a class="elsevierStyleCrossRefs" href="#bib0640">2,16,24,32</a>General biochemical diagnosisThis diagnosis is based on the detection of water/electrolyte disorders, affected acid-base balance and eventually renal function, which are all prototypical of Fanconi syndrome.<a class="elsevierStyleCrossRefs" href="#bib0750">24,28,29</a>Specific biochemical diagnosisThis involves the detection of elevated white blood cells (WBC) cystine levels.<a class="elsevierStyleCrossRef" href="#bib1015">77</a> Currently High Performance Liquid Chromatography–Tandem Mass Spectrometry (HPLC-MS/MS) in granulocytes is used as it is a more sensitive technique.<a class="elsevierStyleCrossRefs" href="#bib1020">78,79</a>The reference values are:<ul class="elsevierStyleList" id="lis0055"><li class="elsevierStyleListItem" id="lsti0150">•healthy individual: ≤0.5nmol 1/2 cystine/mg protein (values >0.5 may have diagnostic significance, and it is recommended to repeat the determination)</li><li class="elsevierStyleListItem" id="lsti0155">•affected individual without treatment: >1nmol 1/2 cystine/mg protein (usually >2)</li><li class="elsevierStyleListItem" id="lsti0160">•individual treated with good therapeutic control: ≤1 nmol 1/2 cystine/mg protein</li></ul>Normal WBC cystine levels in newborns do not completely rule out the diagnosis. Therefore, in cases where cystinosis is highly suspected, a second test is recommended 3–6 months after the first study when the results are not conclusive<a class="elsevierStyleCrossRef" href="#bib1025">79</a> (<a class="elsevierStyleCrossRef" href="#tbl0030">Table 2</a>).<elsevierMultimedia ident="tbl0030"></elsevierMultimedia>Molecular diagnosisCystinosis is confirmed by the detection of homozygous or compound heterozygous mutations in the CTNS gene. More than 100 different mutations have been reported and the most frequent one is the ∼57kb deletion affecting the first 10 exons, especially in patients of Northern European descent. Specific mutations turn into an absence of protein or a probably non-functional truncated protein<a class="elsevierStyleCrossRefs" href="#bib0685">11,12,14,15,80</a> (<a class="elsevierStyleCrossRef" href="#tbl0030">Table 2</a>).Genetic counsellingSince cystinosis is an autosomal recessive disease, the probability of a family with one affected child having another with cystinosis is 25%.<a class="elsevierStyleCrossRef" href="#bib1035">81</a> In this case, genetic counselling includes information on prenatal diagnostic techniques and embryo selection.<a class="elsevierStyleCrossRefs" href="#bib1040">82,83</a> The probability of a woman with cystinosis having an affected child is very low, except in consanguineous families or endogamous populations. Males with cystinosis are universally sterile.<a class="elsevierStyleCrossRef" href="#bib0875">49</a>Genetic counselling usually includes information on patient associations<a class="elsevierStyleCrossRefs" href="#bib1050">84–86</a> and institutional strategies in rare diseases.<a class="elsevierStyleCrossRef" href="#bib1065">87</a>TreatmentSymptomatic treatment of kidney involvementThe aim of treatment (<a class="elsevierStyleCrossRef" href="#tbl0020">Table 1</a> & <a class="elsevierStyleCrossRef" href="#sec0210">Annex 1</a>) is to control Fanconi syndrome, its complications and other factors involved in kidney failure progression.<a class="elsevierStyleCrossRefs" href="#bib0750">24–28</a> In ESRD, promoting KTx is a priority. Regardless of kidney involvement, all patients should receive specific treatment with cysteamine for the prevention and therapeutic control of the systemic disease.Treatment of CKD should follow international guidelines.<a class="elsevierStyleCrossRefs" href="#bib1070">88–90</a> In transplanted patients, minimising or avoiding corticosteroids use is recommended.<a class="elsevierStyleCrossRef" href="#bib0745">23</a>Specific treatment with cysteamineOral cysteamineThe specific treatment for all clinical forms of cystinosis is oral cysteamine. Cysteamine depletes lysosomal cystine content by forming disulphide cysteine–cysteamine complexes able to exit the lysosomes by means of the alternative lysine channel, and the remaining cysteine via a cysteine carrier.<a class="elsevierStyleCrossRefs" href="#bib0645">3,19,91</a>The first specific pharmacological treatment for cystinosis is Cystagon® (oral cysteamine bitartrate in hard capsules), the only authorised therapy in Spain<a class="elsevierStyleCrossRefs" href="#bib1090">92–94</a>. A new formula in hard gastro-resistant capsules has recently been approved for cysteamine.<a class="elsevierStyleCrossRefs" href="#bib1095">93–96</a>Therapeutic benefitsOral cysteamine should be initiated at the time of diagnosis and continued lifelong. When compliance is consistent, cysteamine is able to deplete up to 95% of cellular cystine deposits.<a class="elsevierStyleCrossRef" href="#bib0940">62</a> The reduction in these deposits correlates with cystinosis severity.<a class="elsevierStyleCrossRef" href="#bib0790">32</a> It has been demonstrated that cysteamine prolongs the life of the patient, while delaying kidney disease progression and the need for renal replacement therapy.<a class="elsevierStyleCrossRefs" href="#bib0655">5,97</a> Similarly, it reduces the severity and frequency of extrarenal complications.<a class="elsevierStyleCrossRef" href="#bib0790">32</a> Prognosis of the disease is directly related to early treatment and its duration. Even when cystinosis diagnosis is delayed, cysteamine has demonstrated clinical benefits.<a class="elsevierStyleCrossRefs" href="#bib0650">4,6,98</a> Although Fanconi syndrome is not usually reversible with cysteamine,<a class="elsevierStyleCrossRef" href="#bib0725">19</a> in some isolated cases of prenatal diagnosis the beginning of cysteamine therapy within the first weeks of life prevented the appearance of tubulopathy.<a class="elsevierStyleCrossRefs" href="#bib1125">99,100</a>Cystagon®: dosage, administration and treatment monitoringTreatment is based on the depletion of lysosomal cystine content which, in clinical practice, means the reduction of WBC cystine levels, with an optimal therapeutic goal <1nmol hemicystine/mg of protein. The decrease in those WBC cysteine levels correlates with plasma cysteamine concentrations for the 6 hours following Cystagon® dose, being minimum at ∼2h after the drug is taken and returning to baseline (pre-dose) 6h later. This explains the need to take the drug every 6h, overnight dose included<a class="elsevierStyleCrossRefs" href="#bib1135">101,102</a> (<a class="elsevierStyleCrossRef" href="#tbl3">Table 3</a>).<elsevierMultimedia ident="tbl3"></elsevierMultimedia>Monitoring of WBC cysteine levels at the start of treatment and monthly after changes in the prescribed dosage is recommended. In patients with maintained cystine levels, follow-up controls are recommended every 6 months. Similarly, in an individualised manner, the frequency of monitoring should be increased in case of significant clinical changes such as KTx and dialysis<a class="elsevierStyleCrossRefs" href="#bib1015">77,78,79</a> (<a class="elsevierStyleCrossRef" href="#tbl0030">Table 2</a>).Oral treatment in special situationsChronic kidney disease, dialysis and transplantationSince there is no correlation between GFR and plasma cysteamine levels, it is not necessary to adjust the dosage to renal function; instead, the prescribed dosage should be adjusted to the quantification of WBC cystine levels. Adjustments for Fanconi syndrome are also unnecessary.<a class="elsevierStyleCrossRefs" href="#bib0660">6,103</a>Pregnancy and breastfeedingAlthough data is insufficient, reproductive toxicity and teratogenic effects of cysteamine have been observed in animals.<a class="elsevierStyleCrossRef" href="#bib1150">104</a> Its use is therefore contraindicated during pregnancy, particularly in the first trimester. Family planning is recommended in women of childbearing age. Furthermore, cysteamine administration should be avoided during breastfeeding.Cysteamine eye dropsSpecific treatment of ocular involvement in cystinosis requires, in addition to oral cysteamine, the use of cysteamine eye drops. The ophthalmological therapeutic strategy<a class="elsevierStyleCrossRefs" href="#bib0790">32,37</a> makes a distinction between:Corneal involvementCystine crystal deposits should be treated with topical cysteamine since the cornea is an avascular structure and, consequently, oral medication is not effective for the cornea.<a class="elsevierStyleCrossRefs" href="#bib0815">37,38,105,106</a> The recommended prescription is shown in <a class="elsevierStyleCrossRef" href="#tbl3">Table 3</a>. Viscous formulae are being developed to achieve longer contact of cysteamine with the ocular surface and be able to reduce the frequency of instillations with equal efficacy.<a class="elsevierStyleCrossRefs" href="#bib1165">107,108</a>Involvement of non-corneal structuresOral cysteamine is effective in the retina and other ocular structures. The incidence of retinopathies has decreased with the systemic use of cysteamine. The frequency and severity of non-corneal manifestations are directly related to compliance with oral cysteamine treatment, and the risk of important vision loss may arise if systemic treatment is not correctly followed.<a class="elsevierStyleCrossRefs" href="#bib0825">39,109</a>Compliance with specific cysteamine treatmentThe World Health Organization (WHO) defines compliance as the degree to which patient behaviour follows the recommendations of medical professionals.<a class="elsevierStyleCrossRef" href="#bib1180">110</a>The impact of non-adherence in cystinosis results in poorer prognosis and faster progression of the renal and extrarenal disease in patients who are non-compliant compared with those who are.<a class="elsevierStyleCrossRefs" href="#bib0655">5,6,97</a>Information on adherence in patients with cystinosis is limited, although monitoring WBC cystine levels is able to detect non-compliant patients.<a class="elsevierStyleCrossRefs" href="#bib1015">77,79</a> Other studies have confirmed adequate adherence to Cystagon® in children patients which wanes significantly in adolescents and adults.<a class="elsevierStyleCrossRefs" href="#bib0665">7,8</a> Nonetheless, in groups of highly motivated patients, only 8% had compliance problems.<a class="elsevierStyleCrossRef" href="#bib1185">111</a>In cystinosis, risk factors for non-compliance with cysteamine therapy include: dosage schedules, problems with tolerance, side effects and the requirements of several medications for the control of the clinical manifestations of the disease. Moreover, other risk factors which are not exclusive to cystinosis are: limited knowledge of the disease, lack of motivation, inadequate transition of patients to adult care units and impact of the disease on quality of life.<a class="elsevierStyleCrossRefs" href="#bib0665">7,9,10</a>Nevertheless, suboptimal treatment compliance is not a phenomenon restricted to cystinosis. Recent studies report that 52 to 67% of adult kidney transplant recipients do not correctly follow prescribed immunosuppressant treatment, which increases the probability of graft loss.<a class="elsevierStyleCrossRefs" href="#bib1190">112,113</a> These percentages are similar to those published in patients with cystinosis in our population,<a class="elsevierStyleCrossRef" href="#bib0665">7</a> which may indicate the coexistence of scenarios in common with CKD. Therefore, in order to improve adherence in cystinotic patients, the recommended strategy is to correct risk factors for non-compliance and promote patient self-care, similar to the strategies used successfully in adult kidney transplant recipients<a class="elsevierStyleCrossRefs" href="#bib1200">114–119</a> (<a class="elsevierStyleCrossRef" href="#tbl0035">Table 4</a>).<elsevierMultimedia ident="tbl0035"></elsevierMultimedia>Recommendations for the follow-up and treatment of patients with cystinosisT-CiS.bcn group members, after an exhaustive review of medical literature and based on our clinical practice with patients, have stablished recommendations for the multidisciplinary care and connected transition from paediatric to adult-care units in cystinosis. Our aim was to provide support tools and medical advice to health care professionals involved and interested in the care of cystinosis.These recommendations are presented in <a class="elsevierStyleCrossRefs" href="#tbl0035">Tables 4–8</a>.<elsevierMultimedia ident="tbl0040"></elsevierMultimedia><elsevierMultimedia ident="tbl0045"></elsevierMultimedia><elsevierMultimedia ident="tbl0050"></elsevierMultimedia><elsevierMultimedia ident="tbl0055"></elsevierMultimedia>Conflict of interestThe authors have no conflicts of interest to declare." "textoCompletoSecciones" => array:1 [ "secciones" => array:12 [ 0 => array:3 [ "identificador" => "xres577021" "titulo" => "Abstract" "secciones" => array:5 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Introduction" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Objective" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Methods" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Results" ] 4 => array:2 [ "identificador" => "abst0025" "titulo" => "Conclusions" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec593648" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres577020" "titulo" => "Resumen" "secciones" => array:5 [ 0 => array:2 [ "identificador" => "abst0030" "titulo" => "Introducción" ] 1 => array:2 [ "identificador" => "abst0035" "titulo" => "Objetivo" ] 2 => array:2 [ "identificador" => "abst0040" "titulo" => "Método" ] 3 => array:2 [ "identificador" => "abst0045" "titulo" => "Resultados" ] 4 => array:2 [ "identificador" => "abst0050" "titulo" => "Conclusiones" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec593649" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Etiopathogenesis" ] 6 => array:3 [ "identificador" => "sec0015" "titulo" => "Symptoms" "secciones" => array:3 [ 0 => array:3 [ "identificador" => "sec0185" "titulo" => "Renal disease" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "sec0025" "titulo" => "Fanconi syndrome" ] 1 => array:2 [ "identificador" => "sec0030" "titulo" => "Chronic kidney disease" ] 2 => array:2 [ "identificador" => "sec0035" "titulo" => "Dialysis" ] 3 => array:2 [ "identificador" => "sec0040" "titulo" => "Kidney transplantation" ] ] ] 1 => array:3 [ "identificador" => "sec0190" "titulo" => "Extrarenal disease" "secciones" => array:5 [ 0 => array:2 [ "identificador" => "sec0050" "titulo" => "Ocular involvement" ] 1 => array:2 [ "identificador" => "sec0055" "titulo" => "Growth and development: mineral-bone involvement" ] 2 => array:2 [ "identificador" => "sec0060" "titulo" => "Endocrine involvement" ] 3 => array:2 [ "identificador" => "sec0065" "titulo" => "Cardiovascular involvement" ] 4 => array:2 [ "identificador" => "sec0070" "titulo" => "Neurological involvement" ] ] ] 2 => array:2 [ "identificador" => "sec0075" "titulo" => "Miscellaneous" ] ] ] 7 => array:3 [ "identificador" => "sec0080" "titulo" => "Diagnosis" "secciones" => array:5 [ 0 => array:2 [ "identificador" => "sec0085" "titulo" => "Clinical diagnosis" ] 1 => array:2 [ "identificador" => "sec0090" "titulo" => "General biochemical diagnosis" ] 2 => array:2 [ "identificador" => "sec0095" "titulo" => "Specific biochemical diagnosis" ] 3 => array:2 [ "identificador" => "sec0100" "titulo" => "Molecular diagnosis" ] 4 => array:2 [ "identificador" => "sec0105" "titulo" => "Genetic counselling" ] ] ] 8 => array:3 [ "identificador" => "sec0110" "titulo" => "Treatment" "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0115" "titulo" => "Symptomatic treatment of kidney involvement" ] 1 => array:3 [ "identificador" => "sec0120" "titulo" => "Specific treatment with cysteamine" "secciones" => array:6 [ 0 => array:3 [ "identificador" => "sec0125" "titulo" => "Oral cysteamine" "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0130" "titulo" => "Therapeutic benefits" ] 1 => array:2 [ "identificador" => "sec0135" "titulo" => "Cystagon: dosage, administration and treatment monitoring" ] ] ] 1 => array:3 [ "identificador" => "sec0140" "titulo" => "Oral treatment in special situations" "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0145" "titulo" => "Chronic kidney disease, dialysis and transplantation" ] 1 => array:2 [ "identificador" => "sec0150" "titulo" => "Pregnancy and breastfeeding" ] ] ] 2 => array:2 [ "identificador" => "sec0195" "titulo" => "Cysteamine eye drops" ] 3 => array:2 [ "identificador" => "sec0160" "titulo" => "Corneal involvement" ] 4 => array:2 [ "identificador" => "sec0165" "titulo" => "Involvement of non-corneal structures" ] 5 => array:2 [ "identificador" => "sec0170" "titulo" => "Compliance with specific cysteamine treatment" ] ] ] ] ] 9 => array:2 [ "identificador" => "sec0175" "titulo" => "Recommendations for the follow-up and treatment of patients with cystinosis" ] 10 => array:2 [ "identificador" => "sec0180" "titulo" => "Conflict of interest" ] 11 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec593648" "palabras" => array:6 [ 0 => "Cystinosis" 1 => "Cysteamine" 2 => "Fanconi syndrome" 3 => "White blood cell (WBC) cystine levels" 4 => "Transition" 5 => "Adherence" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec593649" "palabras" => array:6 [ 0 => "Cistinosis" 1 => "Cisteamina" 2 => "Síndrome de Fanconi" 3 => "Cistina intraleucocitaria" 4 => "Transición" 5 => "Adherencia" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:3 [ "titulo" => "Abstract" "resumen" => "IntroductionCystinosis is a rare systemic lysosomal storage disease that mainly affects the kidney and the eye. Renal replacement therapy is started in patients with cystinosis during the first decade of life in the absence of treatment. The prognosis of cystinosis depends on early diagnosis and the prompt start of and good compliance with cysteamine treatment. Kidney disease progression, extra-renal complications and shorter life expectancy are more pronounced in patients who do not adhere to treatment. ObjectiveThe aim of this work was to establish recommendations for the comprehensive care of cystinosis and facilitate patient transition from paediatric to adult medicine, based on clinical experience. The goal is to reduce the impact of the disease and improve prognosis and patient quality of life. MethodsBibliographic research and consensus meetings with a multidisciplinary professional team of clinical experts in cystinosis (T-CiS.bcn group) from 5 hospitals in Barcelona. ResultsThis consensus document gathers specific recommendations for the diagnosis, treatment and multidisciplinary care of cystinotic patients in the following areas: nephrology, dialysis, kidney transplantation, ophthalmology, endocrinology, neurology, laboratory, genetic counselling, nursing and pharmacy. ConclusionsGuidelines for the comprehensive care of cystinosis provide a support tool for health professionals who look after these patients. They are based on the following main pillars: (a) a multidisciplinary approach; (b) appropriate disease monitoring and control of white blood cell (WBC) cystine levels; (c) the importance of adherence to cysteamine treatment; and (d) the promotion of patient self-care by means of disease education programmes. All these recommendations will lead us, in a second phase, to create a coordinated model of transition from paediatric to adult care services which will cover the specific needs of cystinosis." "secciones" => array:5 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Introduction" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Objective" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Methods" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Results" ] 4 => array:2 [ "identificador" => "abst0025" "titulo" => "Conclusions" ] ] ] "es" => array:3 [ "titulo" => "Resumen" "resumen" => "IntroducciónLa cistinosis es una enfermedad lisosomal minoritaria de expresión sistémica con especial afectación renal y oftalmológica, en la que los pacientes inician terapia renal sustitutiva en la primera década de la vida en ausencia de tratamiento. El pronóstico de la cistinosis depende del diagnóstico precoz, la pronta instauración del tratamiento con cisteamina y el buen cumplimiento terapéutico. La progresión de la enfermedad renal y de las complicaciones extrarrenales y una menor supervivencia, son más acentuadas en pacientes no adherentes. ObjetivoEl objetivo de este trabajo fue la elaboración de unas recomendaciones para la atención integral de la cistinosis y la transición del adolescente a la medicina del adulto, basadas en la experiencia clínica, con el fin de reducir el impacto de la enfermedad y mejorar la calidad de vida y el pronóstico del paciente. MétodoBúsqueda bibliográfica y reuniones de consenso de un equipo multidisciplinar de expertos en la práctica clínica con pacientes afectos de cistinosis (Grupo T-CiS.bcn), procedentes de 5 hospitales localizados en Barcelona. ResultadosEl documento recoge recomendaciones específicas y necesarias para el diagnóstico, tratamiento y seguimiento multidisciplinar de la cistinosis en las siguientes áreas: nefrología, diálisis, trasplante renal, oftalmología, endocrinología, neurología, laboratorio, consejo genético, enfermería y farmacia. ConclusionesDisponer de un documento de referencia para la atención integral de la cistinosis constituye una herramienta de soporte para los profesionales de la salud que asisten a estos pacientes. Los principales pilares en los que se sustenta son: a) el enfoque multidisciplinar, b) la adecuada monitorización de la enfermedad y control de los niveles de cistina intraleucocitarios, c) la importancia de la adherencia al tratamiento con cisteamina y d) la promoción del autocuidado del paciente mediante programas de educación en la enfermedad. Todo ello conducirá, en una segunda fase, a la elaboración de un modelo de transición coordinado entre los servicios de pediatría y de adultos que contemple las necesidades específicas de la cistinosis." "secciones" => array:5 [ 0 => array:2 [ "identificador" => "abst0030" "titulo" => "Introducción" ] 1 => array:2 [ "identificador" => "abst0035" "titulo" => "Objetivo" ] 2 => array:2 [ "identificador" => "abst0040" "titulo" => "Método" ] 3 => array:2 [ "identificador" => "abst0045" "titulo" => "Resultados" ] 4 => array:2 [ "identificador" => "abst0050" "titulo" => "Conclusiones" ] ] ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "Please cite this article as: Ariceta G, Camacho JA, Fernández-Obispo M, Fernández-Polo A, Gamez J, García-Villoria J, et al. Cistinosis en pacientes adolescentes y adultos: recomendaciones para la atención integralde la cistinosis. Nefrologia. 2015;35:304–321." ] ] "apendice" => array:1 [ 0 => array:1 [ "seccion" => array:2 [ 0 => array:4 [ "apendice" => "<elsevierMultimedia ident="tbl0015"></elsevierMultimedia>" "etiqueta" => "ANNEX 1.a" "titulo" => "Supplements, drugs and pharmaceutical formulations prescribed in cystinosis" "identificador" => "sec0210" ] 1 => array:4 [ "apendice" => "<elsevierMultimedia ident="tbl0010"></elsevierMultimedia>" "etiqueta" => "Annex 1.b" "titulo" => "Supplements, drugs and pharmaceutical formulations prescribed in cystinosis" "identificador" => "sec0205" ] ] ] ] "multimedia" => array:11 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1183 "Ancho" => 1817 "Tamanyo" => 162844 ] ] "descripcion" => array:1 [ "en" => "Clinical manifestations of cystinosis in patients not treated with cysteamine. CKD: chronic kidney disease, ESRD: end stage renal disease, RRT: renal replacement therapy." ] ] 1 => array:7 [ "identificador" => "tbl0020" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "leyenda" => "ACEi/ARB: inhibitors of the renin-angiotensin system." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Therapeutic aims \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Treatment \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry " rowspan="2" align="left" valign="top">Preserve water balance by replacing losses</td><td class="td" title="table-entry " align="left" valign="top">Replace water loss according to need (between 1.5 and 6L/day), either orally or by nasogastric tube or gastrostomy, if needed. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Reduce polyuria: oral indomethacin (1–3mg/kg/day) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " rowspan="3" align="left" valign="top">Preserve electrolyte balance by replacing losses</td><td class="td" title="table-entry " align="left" valign="top">Potassium (between 2 and 10mEq/kg/day) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">ClNa (1–2mEq/kg/day, with progressive increase in dosage) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Phosphorus (between 1 and 4g/day) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="middle">Neutralise acidosis (maintain normal blood pH and serum bicarbonate between 22 and 24mEq/L) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Bicarbonate or citrate at an initial dose of 1–2mEq/kg/day, with progressive increase in dosage \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Nutritional support \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Nutritional assessment with appropriate caloric supplementation according to age and kidney function \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " rowspan="4" align="left" valign="top">Treatment of bone mineral disease</td><td class="td" title="table-entry " align="left" valign="top">Cholecalciferol \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Calcium supplements \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Active vitamin D (1 Alpha-vitamin D, Calcitriol, Paricalcitol, others) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Growth hormone (if indicated) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " rowspan="2" align="left" valign="top">Others</td><td class="td" title="table-entry " align="left" valign="top">Carnitine<a class="elsevierStyleCrossRef" href="#bib0775">29</a> (100mg/kg/día) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">ACEi/ARB antiproteinuric agents (assess tolerance) \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab942052.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Symptomatic treatment of renal disease in cystinosis.<a class="elsevierStyleCrossRefs" href="#bib0635">1,24,29,31</a>" ] ] 2 => array:7 [ "identificador" => "tbl0030" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " colspan="2" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Requirements for WBC cystine level monitoring<a class="elsevierStyleCrossRefs" href="#bib1015">77–79</a></th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry " rowspan="5" align="left" valign="top">Sampling conditions</td><td class="td" title="table-entry " align="left" valign="top">No fasting required \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">In treated patients, blood extraction should be made 6h post-cysteamine dose \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Collect within lithium or sodium heparin tube \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Ship immediately to the laboratory: it should be processed into 24 hours post-sampling \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Keep at room temperature \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " rowspan="2" align="left" valign="top">Minimum volume</td><td class="td" title="table-entry " align="left" valign="top">For patients <10kg body weight: 6mL blood \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">For patients ≥10kg body weight: 10mL blood \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " rowspan="4" align="left" valign="top" style="border-bottom: 2px solid black">RECOMMENDATIONS for monitoring WBC cystine levels</td><td class="td" title="table-entry " align="left" valign="top">At the start of Cystagon® treatment \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Monthly after dose adjustments \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Every 6 months in stable patients \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top" style="border-bottom: 2px solid black">Increase frequency in cases of significant clinical changes (Transplantation and Dialysis) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="left" valign="top">Reference Laboratory in Spain</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="left" valign="top">Hospital Clínic de Barcelona</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="left" valign="top">Servicio de Bioquímica y Genética Molecular. Sección de Errores Congénitos del Metabolismo</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="left" valign="top">Dra. Judit García Villoria: jugarcia@clinic.ub.es</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="left" valign="top">Tfn. 93 227 56 00 Ext. 7585</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="left" valign="top">C/ Mejía Lequerica s/n. Edificio Helios III. Planta baja. 08028 Barcelona, Spain.</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="left" valign="top" style="border-bottom: 2px solid black"></td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="center" valign="top" style="border-bottom: 2px solid black">Requirements for the molecular diagnosis ofCTNSgene<a class="elsevierStyleCrossRefs" href="#bib0690">12,13,15,80</a></td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="left" valign="top">Genetic testing of patient and family</td></tr><tr title="table-row"><td class="td" title="table-entry " rowspan="2" align="left" valign="top">Sample</td><td class="td" title="table-entry " align="left" valign="top">2–3mL blood in EDTA at room temperature \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">DNA at room temperature \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="left" valign="top">Prenatal testing</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Sample \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">DNA from cultured amniocytes or chorionic villi sampling \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="left" valign="top">Prior identification of the disease-causing mutations in parents and in index case</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="left" valign="top">Previous appointment with the laboratory is essential</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="left" valign="top">Reference Laboratory in Spain</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="left" valign="top">Hospital Clínic de Barcelona</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="left" valign="top">Servicio de Bioquímica y Genética Molecular. Sección de Errores Congénitos del Metabolismo</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="left" valign="top">Dra. MªJosep Coll: mjcoll@clinic.ub.es</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="left" valign="top">Tfn. 93 227 9341</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="left" valign="top">C/ Mejía Lequerica s/n. Edificio Helios III. Planta baja. 08028 Barcelona, Spain.</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab942060.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Biochemical diagnosis and WBC cystine level monitoring. Molecular diagnosis (www.orpha.net)." ] ] 3 => array:7 [ "identificador" => "tbl3" "etiqueta" => "Table 3" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " colspan="3" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Oral Cysteamine – Cystagon®<a class="elsevierStyleCrossRefs" href="#bib0785">31,47,92–94,102</a></th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry " colspan="3" align="left" valign="top">Dosage</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">By age \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="center" valign="top">Children ≤12 years \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="center" valign="top">Patients >12 years \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="3" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Recommended dosage \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="center" valign="top">by body surface area (g/m2/day) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="center" valign="top">if weight > 50 Kg \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="3" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">(Dosage should be divided 4 times daily) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="center" valign="top">1.30g/m2/day \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="center" valign="top">2g/day \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="3" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " rowspan="2" align="left" valign="top">Starting dosage</td><td class="td" title="table-entry " colspan="2" align="center" valign="top">1/4 to 1/6 of the recommended dosage</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="center" valign="top">Increase gradually over 4–6 weeks to avoid intolerance**</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="3" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="middle">Dosage adjustments \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " colspan="2" align="center" valign="top">Raise if adequate tolerance and WB C cystine level is greater than > 1nmol ½ cystine/mg protein</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="3" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " rowspan="2" align="left" valign="top">Maximum dosage</td><td class="td" title="table-entry " colspan="2" align="center" valign="top">1.95g/m2/day</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="center" valign="top">Overdosing is not recommended since it does not improve the prognosis and is associated with adverse effects<a class="elsevierStyleCrossRef" href="#bib0865">47</a></td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Renal insufficiency \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " colspan="2" align="center" valign="top">No dose adjustment required</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="3" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " rowspan="12" align="left" valign="top">RECOMMENDATIONS for appropriate dosage</td><td class="td" title="table-entry " colspan="2" align="center" valign="top">Treatment should be initiated under the supervision of a physician experienced in the treatment of cystinosis</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="center" valign="top">4 doses per day; every 6 hours; night dose included</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="center" valign="top">Adjust the dose according to WBC cystine levels</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="center" valign="top">Hard capsules should not be administered to children under the age of 6 years owing to risk of aspiration</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="center" valign="top">If needed, open the capsules and sprinkle the content on food</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="center" valign="top">Cysteamine powder could be mixed with milk, potatoes and other starch-based products. Avoid acidic drinks.</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="center" valign="top">CYSTAGON® should be restarted after renal transplant to prevent non-renal complications</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="3" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " rowspan="13" align="left" valign="top">Side effects</td><td class="td" title="table-entry " colspan="2" align="center" valign="top">Gastrointestinal disorders due to gastric acid hypersecretion</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="center" valign="top">RECOMMENDATIONS for improving gastrointestinal tolerability:</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="center" valign="top">Concomitant administration of proton pump inhibitors<a class="elsevierStyleCrossRef" href="#bib1140">102</a></td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="center" valign="top">Administer with meals or immediately afterwards. Intake is recommended with food such as milk, potatoes or other starchy foods<a class="elsevierStyleCrossRefs" href="#bib1090">92–94</a></td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="center" valign="top">Characteristic body odour and halitosis</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="center" valign="top">RECOMMENDATIONS for improving halitosis: mentholated pills<a class="elsevierStyleCrossRef" href="#bib0785">31</a></td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="center" valign="top">Other adverse reactions refer to SMPC<a class="elsevierStyleCrossRefs" href="#bib1090">92–94</a></td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="3" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " rowspan="3" align="left" valign="top">Drug interactions</td><td class="td" title="table-entry " colspan="2" align="center" valign="top">No interaction studies have been conducted</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="center" valign="top">Can be administered in conjunction with electrolytic or mineral supplements, vitamin D analogues, tyrosine or immunosuppressive drugs</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="3" align="left" valign="top" style="border-bottom: 2px solid black"></td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="3" align="center" valign="top" style="border-bottom: 2px solid black">Cysteamine eye drops<a class="elsevierStyleCrossRefs" href="#bib0815">37–39,105–109</a></td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="3" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Eye drops \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " colspan="2" align="center" valign="top">0.55% cysteamine solution (see Annex 1)</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Dose \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " colspan="2" align="center" valign="top">1 drop/eye</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Dosage \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " colspan="2" align="center" valign="top">10–12 instillations/day</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab942054.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Specific treatment with cysteamine." ] ] 4 => array:7 [ "identificador" => "tbl0035" "etiqueta" => "Table 4" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Identify risk factors that affect adherence and apply corrective measures when possible: \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Intrinsic patient and socio-economic factors \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Disease-related factors \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Treatment-related factors \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Healthcare system organisation barriers \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Identify and assign a “Patient health Coordinator” \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Promote patient education and treatment support: \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Implement disease education programmes \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Establish treatment programmes: easy to follow with support measures for compliance \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Use questionnaires to detect non-compliance \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Follow-up of appointments and absences \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Develop patient support programmes involving family members, friends and patient associations \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Create a multidisciplinary medical team \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Implement protocols for transition to adult care \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab942051.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Recommendations for improving treatment compliance.<a class="elsevierStyleCrossRefs" href="#bib0665">7,9,10,114–119</a>" ] ] 5 => array:7 [ "identificador" => "tbl0040" "etiqueta" => "Table 5" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "leyenda" => "In any clinical situation, it is necessary to administer specific cystinosis treatment with oral cysteamine to maintain recommended WBC cystine levels <1nmol hemicystine/mg protein and cysteamine eye drops to eliminate corneal deposits (see <a class="elsevierStyleCrossRef" href="#tbl3">Table 3</a>)." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Recommendations for dialysis<a class="elsevierStyleCrossRefs" href="#bib0660">6,103</a> \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Promote preventive KTx as an initial method of RRT in patients with advanced CKD \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Monitor residual urine volume and urinary saline loss to adapt the dialysis prescription and avoid excessive ultrafiltration \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Maintain the general treatment of Fanconi syndrome and adapt the diet in an individual manner \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Carefully monitor extrarenal involvement on a multidisciplinary basis \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Oral and ophthalmological cysteamine treatment must be maintained \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top" style="border-bottom: 2px solid black">Cysteamine dosage should not be adjusted to glomerular filtration rate (see Specific Treatment with Cysteamine section) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="center" valign="top" style="border-bottom: 2px solid black">Recommendations for kidney transplantation<a class="elsevierStyleCrossRefs" href="#bib0650">4–6,33,88–90</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Prior to waiting list inclusion \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Promote preventive kidney transplantation when the glomerular filtrate ≤20mL/min/1.73 m2 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Living or deceased donor \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Evaluate the associated Fanconi syndrome (residual diuresis – can be very high – saline loss, rickets, tubular acidosis, carnitine deficiency) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Monitor WBC cystine levels and optimise treatment with cysteamine (oral and ophthalmological) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Assess possible systemic involvement and its impact on the transplant (hypothyroidism, diabetes, cardiovascular disease, bone disease, swallowing disorders) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Prescribe fluids and individualised diet. Assess phosphate, potassium, bicarbonate and carnitine supplement requirements \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Pre-transplant and peri-transplant \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Avoid volume depletion before and during surgery (intensive endovenous fluid therapy to guarantee normovolaemia, including potassium and bicarbonate supplements) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Immunosuppression according to hospital protocol \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Temporary suspension of cysteamine treatment \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Immediately post-transplant \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Administer fluid therapy and sufficient electrolytes to maintain adequate water/electrolyte balance and good control of residual Fanconi syndrome \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Monitor the possible appearance of diabetes. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Immunosuppression therapy according to hospital protocol \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Continued post-transplant care \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Reintroduce cysteamine once the patient and graft are stable, approximately 3–4 weeks post-transplantation, at increasing doses up to therapeutic doses \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Monitor WBC cystine levels \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Immunosuppression following hospital protocol; promote reduction in and/or suspension of corticosteroids \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Controls and follow-up in accordance with recommendations and clinical guidelines \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Maintain ophthalmological treatment with cysteamine and stimulate treatment compliance \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Assess possible systemic involvement and its impact on transplantation. Promote and standardise a multidisciplinary health care plan for cystinosis \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab942059.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Recommendations for follow-up of patients on renal replacement therapy (RRT): dialysis (D) and transplantation (TxR)." ] ] 6 => array:7 [ "identificador" => "tbl0045" "etiqueta" => "Table 6" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:3 [ "leyenda" => "ERG: electroretinogram; GH: growth hormone; VA: visual acuity." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Test \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Ocular structure \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Frequency \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Observations \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Slit lamp biomicroscopy \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Study of the cornea and rest of anterior segment \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Annual \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Intraocular pressure measurement \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Rule out ocular hypertension \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Annual \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " rowspan="2" align="left" valign="top">Dilated fundus examination</td><td class="td" title="table-entry " rowspan="2" align="left" valign="top">Assess optic disc and retinal pigmentation</td><td class="td" title="table-entry " align="left" valign="top">Annual \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " rowspan="2" align="left" valign="top">Urgent: if the patient reports severe loss of VA (uncommon)</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">In patients with GH, do a baseline assessment and after 4 months to detect intracranial hypertension<a class="elsevierStyleCrossRef" href="#bib1230">120</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Photopic and scotopic ERG \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Functionality of rods and cones \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Only if patient reports altered night vision or abnormal retinal examination \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="4" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " rowspan="3" align="left" valign="top" style="border-bottom: 2px solid black">Equipment</td><td class="td" title="table-entry " colspan="3" align="left" valign="top">Slit lamp<a class="elsevierStyleCrossRef" href="#tblfn0045">*</a></td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="3" align="left" valign="top">Tonometer</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="3" align="left" valign="top" style="border-bottom: 2px solid black">Indirect ophthalmoscope</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="4" align="left" valign="top">In any clinical situation, specific cystinosis treatment is required with oral cysteamine to maintain recommended WBC cystine levels <1nmol hemicystine/mg protein and cysteamine eye drops to eliminate corneal deposits (See <a class="elsevierStyleCrossRef" href="#tbl3">Table 3</a>).</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab942053.png" ] ] ] "notaPie" => array:1 [ 0 => array:3 [ "identificador" => "tblfn0045" "etiqueta" => "*" "nota" => "Very sensitive for diagnosing cystine crystals in the cornea, but less useful for patient follow-up since the quantification of crystals is rather subjective. It is therefore interesting to record detailed data at each examination on the distribution of crystals in the cornea, specifying whether the deposition is only peripheral or diffuse and whether they are located in the epithelium, stroma and/or endothelium." ] ] ] "descripcion" => array:1 [ "en" => "Recommendations for ophthalmological follow-up.<a class="elsevierStyleCrossRefs" href="#bib0650">4,37–39,105–109,120</a>" ] ] 7 => array:7 [ "identificador" => "tbl0050" "etiqueta" => "Table 7" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "leyenda" => "25OHD3: 25-hydroxycholecalciferol (calcifediol); FSH: follicle-stimulating hormone; GH: growth hormone; HbA1c: glycated haemoglobin; IGF-1: insulin-like growth factor 1; IGFBP3: insulin-like growth factor-binding protein 3; LH: luteinising hormone; PTH: parathyroid hormone; rGH: recombinant growth hormone; SHBG: sex hormone-binding globulin; T: testosterone; T4: free thyroxine; TG: triglycerides; TSH: thyroid-stimulating hormone." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Disorder \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Complementary studies \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Frequency \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Treatment \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Observations \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry " rowspan="2" align="left" valign="top">Hypothyroidism</td><td class="td" title="table-entry " align="left" valign="top">TSH, T4L, Anti-thyroid Ab/Imaging study not necessary \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">At diagnosis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " rowspan="2" align="left" valign="top">Levothyroxine</td><td class="td" title="table-entry " rowspan="2" align="left" valign="top">Initiate treatment when TSH > 10 mIU/L/if there are symptoms, consider initiating with TSH, 5–10 mIU/L</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">TSH, T4L \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Routine follow-up: Quarterly for dosage adjustments/annual, if TSH is normal \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="5" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " rowspan="7" align="left" valign="top">Diabetes Mellitus</td><td class="td" title="table-entry " align="left" valign="top">Glycaemia, HbA1c (optional: c-peptide) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Diagnosis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " rowspan="3" align="left" valign="top">Insulin</td><td class="td" title="table-entry " rowspan="7" align="left" valign="top">If pancreatic reserve is sufficient, consider single daily dose of slow-release insulin</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">If symptoms of polyuria-polydypsia: laboratory tests with ionogram, venous blood gases and ketonuria \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Glycaemia, HbA1c \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Quarterly or biannual follow-up, according to clinical criteria/annual, if no symptoms \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Lipid profile: total cholesterol, LDL, HDL and TG \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Annual \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Dyslipidaemia treatment \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Funduscopy \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Annual \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">According to ophthalmologist criteria \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Pain and vibration sensitivity \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Annual \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Education to prevent lesions \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Examination feet and pulse \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Annual \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="5" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " rowspan="12" align="left" valign="top">Impaired longitudinal growth</td><td class="td" title="table-entry " align="left" valign="top">Nutritional assessment \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">According to clinical criteria \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Optimise nutrition \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Consider supplements and referral to nutritionist \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Height and weight \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">At each visit \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Until bone maturity \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">See Fanconi syndrom section \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Treatment of Fanconi syndrome \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Bone age \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Diagnosis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">r-GH \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " rowspan="3" align="left" valign="top">In pubescent patients, rule out hypogonadism/in transplant recipients, consider withdrawal or reduction of corticosteroids</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">GH, IGF-1, IGFBP-3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">If no kidney failure: GH secretion studies \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Bone age, IGF-1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Annual follow-up \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Funduscopy \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Before initiating GH and after 3–4 months under treatment \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Intracranial hypertension secondary to GH usually occurs at the start of treatment (mean: 3–4 months) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Urgent if headache or reduced vision \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Calcium, phosphorus, alkaline phosphatase, 25OH·D3, PTH \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Annual \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Vitamin D, if deficiency \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Rule out rickets and vitamin D nutritional deficiency \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Calcitriol, if kidney failure \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Bone mineral density \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">In adulthood; to be assessed according to results. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">If there is osteoporosis, consider specific treatment \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="5" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " rowspan="3" align="left" valign="top">Hypogonadism</td><td class="td" title="table-entry " align="left" valign="top">Physical exam: sexual maturation and secondary sexual characteristics \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">At each visit \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">During puberty period until complete maturity \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Testosterone, SHBG, LH, FSH+assessment of thyroid function (see above) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Diagnosis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Daily testosterone replacement therapy (TRT): Topical (if panic to injections), or IM (if compliance problems) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">If low testosterone with normal LH and FSH levels: MRI of pituitary \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">T, LH, FSH \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Annual follow-up \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="5" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " rowspan="2" align="left" valign="top" style="border-bottom: 2px solid black">Fertility</td><td class="td" title="table-entry " align="left" valign="top">Semen analysis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Diagnosis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Infertility is a constant feature in affected males \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top" style="border-bottom: 2px solid black">Consider high-risk pregnancy \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top" style="border-bottom: 2px solid black">Suspend oral cysteamine during gestation \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="5" align="left" valign="top">In any clinical situation, specific cystinosis treatment is required with oral cysteamine treatment to maintain recommended WBC cystine levels <1nmol hemicystine/mg protein and topical cysteamine to eliminate corneal deposits.</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab942055.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Recommendations for the follow-up and treatment of endocrine system involvement.<a class="elsevierStyleCrossRefs" href="#bib0650">4,5,32,48,49,121</a>" ] ] 8 => array:7 [ "identificador" => "tbl0055" "etiqueta" => "Table 8" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "leyenda" => "MRI: magnetic resonance imaging, CPAP: Continuous Positive Airway Pressure, BIPAP: biphasic positive airway pressure." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Disorder \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Evaluation \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Complementary studies \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Frequency \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Treatment \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Observations \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry " rowspan="5" align="left" valign="top">Motor functions of the skeletal muscles<a class="elsevierStyleCrossRefs" href="#bib0650">4,52,53</a></td><td class="td" title="table-entry " align="left" valign="top">Degree of muscle atrophy/disease progression/degree of disability \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">MRC scale \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Annual \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Rehabilitation \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Use validate instruments \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Quantitative determinations of hand muscle strength (Jamar dynamometer, Martin vigorimeter and Jamar Hydraulic Pinch Gauge) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Annual \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Electromyography \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">According to clinical criteria \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Muscle MRI \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">According to clinical criteria \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Muscle biopsy \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">According to clinical criteria \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="6" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " rowspan="2" align="left" valign="top">Orofacial motor function (language) and swallowing<a class="elsevierStyleCrossRefs" href="#bib0920">58,122,123</a></td><td class="td" title="table-entry " align="left" valign="top">Facial and bulbar muscles: strength and range of movement of lips, tongue, soft palate, jaw and facial muscles in phonation, articulation, swallowing, breathing and expressions \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Focused physical examination \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Annual \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Reeducation if early signs of dysphagia are detected to prevent bronchoaspirates \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Video fluoroscopy \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">According to clinical criteria \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Objective: to asses different phases of swallowing and movement of food bolus within the oral cavity and its passage through the esophagus \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="6" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " rowspan="3" align="left" valign="top">Respiratory muscle function<a class="elsevierStyleCrossRef" href="#bib1250">124</a></td><td class="td" title="table-entry " align="left" valign="top">Presence of dyspnoea, apnoea and/or snoring during sleep, morning headaches, daytime hypersomnia, decreased coughing capacity or increased anomalies in expectoration \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Spirometry \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Annual \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Symptomatic respiratory physiotherapy, ventilatory support (CPAP/BIPAP) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Especially in patients with swallowing disorders, risk of bronchoaspirtion or who present symptoms of neuromuscular respiratory insufficiency \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Oxygen saturation Arterial blood gas \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Annual \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Polysomnography \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Annual \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="6" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Central nervous system<a class="elsevierStyleCrossRefs" href="#bib0900">54–57,59–68,125,126</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Signs of involvement (headache, episodes of unconsciousness, poor school performance, decline in cognitive functions, behavioural alterations, etc.) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Focused physical examinationNeurophysiological studiesNeuroimaging \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">AnnualAccording to clinical criteriaAccording to clinical criteria \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Directed at underlying disorder \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Complementary tests if anomalies are detected \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="6" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top" style="border-bottom: 2px solid black">Neurocognitive alterations<a class="elsevierStyleCrossRefs" href="#bib0975">69–73</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top" style="border-bottom: 2px solid black">Neuropsychological examination \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top" style="border-bottom: 2px solid black">Specific evaluation questionnaires for overall cognitive performance, attention and executive functions, language, memory; perceptive, visuospatial and visuoconstructive functions; voluntary cognitive motor control \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top" style="border-bottom: 2px solid black">Annual \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top" style="border-bottom: 2px solid black">Directed to underlying disorder \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top" style="border-bottom: 2px solid black">Adapted to patient's age (school children and adults) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="6" align="left" valign="top">In any clinical situation, specific cystinosis treatment is required with oral cysteamine treatment to maintain recommended WBC cystine levels <1nmol hemicystine/mg protein and topical cysteamine to eliminate corneal deposits.</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab942056.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Recommendations for the follow-up and treatment of neurological involvement.<a class="elsevierStyleCrossRefs" href="#bib0650">4,52–73,122–126</a>" ] ] 9 => array:5 [ "identificador" => "tbl0015" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => false "mostrarDisplay" => true "tabla" => array:2 [ "leyenda" => "cap.: capsules, *: magistral formulation." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Drug \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Brand name/Product \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Content \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry " colspan="3" align="center" valign="top" style="border-bottom: 2px solid black">Alkaline supplements</td></tr><tr title="table-row"><td class="td" title="table-entry " rowspan="6" align="left" valign="top">Sodium bicarbonate</td><td class="td" title="table-entry " align="left" valign="top">Sodium bicarbonate Torres Muñoz 500mg (30 cap.) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">500 mg/comp. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Sodium bicarbonate Torres Muñoz 60 g; 200 g; 750 g (powder) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Sodium bicarbonate Serra 180 g (powder) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Sodium bicarbonate Viviar 210 g; 250 g; 500 g (powder) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Sodium bicarbonate NM 1 g; 2 g (sachet) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1g/sachet; 2g/sachet \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">*Sodium bicarbonate 1M (8,4%) solución oral \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1mEq/mL \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Sodium citrate \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">*Bicitra oral solution \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1mEq Bicarbonate/mL; 1mEq Na/mL; 0.5mmolcitrate/mL \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " rowspan="2" align="left" valign="top" style="border-bottom: 2px solid black">Potassium citrate</td><td class="td" title="table-entry " align="left" valign="top">*Polycitra oral solution \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2mEq Bicarbonate; 1mEq Na/mL; 1mEq K/mL; 1mmolCitrate/mL \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top" style="border-bottom: 2px solid black">*Polycitra LC with phosphrous-oral solution \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top" style="border-bottom: 2px solid black">2mEq Bicarbonate; 1mEq Na/mL; 1mEq K/mL; 1mmolCitrate/mL; 0.6mmolP/mL \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="3" align="center" valign="top" style="border-bottom: 2px solid black">Potassium supplements</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Potassium ascorbate \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Boi-K (20 effervescents tablets) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1mEq K/tablet \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Bok-K Aspártico (20 effervescents tablets) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">25mEq K/tablet \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Potassium chloride \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Potasion 600 mg (60 cap.s) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">8mEq K/tablet \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top" style="border-bottom: 2px solid black">Potassium glucoheptonate \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top" style="border-bottom: 2px solid black">Potasion 1,32 g/5 mL (125 mL; 250 mL) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top" style="border-bottom: 2px solid black">1mEq K/mL \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="3" align="center" valign="top" style="border-bottom: 2px solid black">Phosphorus supplements</td></tr><tr title="table-row"><td class="td" title="table-entry " rowspan="4" align="left" valign="top" style="border-bottom: 2px solid black">Sodium Phosphate</td><td class="td" title="table-entry " align="left" valign="top">*Phosphorus oral solution or Joulie Solution \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1mmol P/ml (30.9mg P/ml) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Phosphate Sandoz 500mg (100 cap.) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">16.1mmol P/comp (500mg P/comp.) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Sodium Phosphate monobase NM (100 sachets) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">26mmol P/sobre (800mg P/sachet) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top" style="border-bottom: 2px solid black">*Polycitra LC with phosphrous-oral solution \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top" style="border-bottom: 2px solid black">2mEq Bicarbonate; 1mEq Na/mL; 1mEq K/mL; 1mmol Citrate/mL; 0.6mmol P/mL) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="3" align="center" valign="top" style="border-bottom: 2px solid black">Others</td></tr><tr title="table-row"><td class="td" title="table-entry " rowspan="3" align="left" valign="top">Carnitine</td><td class="td" title="table-entry " align="left" valign="top">Carnicor 1.5g/5mL (40mL oral solution) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">300mg/mL carnitine \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Carnicor 1g drinkable vials (10mL) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">100mg/mL carnitine \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Secabiol 300mg/mL (40mL oral solution) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">300mg/mL carnitine \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " rowspan="5" align="left" valign="top">Indomethacin</td><td class="td" title="table-entry " align="left" valign="top">Artinovo 25mg (30 cap.) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">25mg indomethacin \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Flogoter 25mg (40 cap.) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">25mg indomethacin \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Inacid 25mg (30 cap.) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">25mg indomethacin \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Indonilo 25mg (24 cap.) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">25mg indomethacin \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">*Indomethacin 2mg/mL oral solution \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2mg indomethacin \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Cysteamine \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">*Cysteamine 0.55% eye drop solution \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0.55% cysteamine \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab942058.png" ] ] ] ] ] 10 => array:5 [ "identificador" => "tbl0010" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => false "mostrarDisplay" => true "tabla" => array:2 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " colspan="3" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Compounded formulations</th></tr><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Liquid formulation \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Component \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Amount \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry " rowspan="2" align="left" valign="top">Sodium bicarbonate 1M (8.4%) oral solution<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a></td><td class="td" title="table-entry " align="left" valign="top">Sodium bicarbonate \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">8.4g \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Sterile distilled water (qs) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">100mL \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " rowspan="4" align="left" valign="top">Bicitra oral solution<a class="elsevierStyleCrossRef" href="#tblfn0010">b</a></td><td class="td" title="table-entry " align="left" valign="top">Sodium, citrate 2H2O (Tri-) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">10g \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Monohydrated citric acid \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">6.7g \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Simple syrup with preservatives \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">50mL \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Sterile distilled water \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">40mL \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " rowspan="5" align="left" valign="top">Polycitra oral solution<a class="elsevierStyleCrossRef" href="#tblfn0010">b</a></td><td class="td" title="table-entry " align="left" valign="top">Potassium, citrate H2O (Tri-) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">11g \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Sodium, citrate 2H2O (Tri-) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">10g \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Monohydrate citric acid \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">6.7g \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Simple syrup with preservatives \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">50mL \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Sterile distilled water \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">38mL \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " rowspan="8" align="left" valign="top">Polycitra LC with phosphorus, oral solution<a class="elsevierStyleCrossRef" href="#tblfn0015">c</a></td><td class="td" title="table-entry " align="left" valign="top">Sodium hydrogenophosphate-12 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1.4g \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Phosphoric acid 85% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1.4mL \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Sterile distilled water \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">32mL \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Potassium, citrate H2O \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">11g \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Sodium, citrate \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">10g \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Monohydrate citric acid \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">6.7g \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Simple syrup (qs) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">100mL \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Orange extract \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1 drop \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " rowspan="4" align="left" valign="top">Indomethacin 2 mg/mL oral solution<a class="elsevierStyleCrossRefs" href="#tblfn0020">d,e,f,g</a></td><td class="td" title="table-entry " align="left" valign="top">Indomethacin \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0.2g \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Ethyl alcohol \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0.7mL \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Sterile distilled water \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0.3mL \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Simple syrup+Nipagin/nipasol \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">100mL \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " rowspan="3" align="left" valign="top">Phosphates, oral solution (Joulie solution)<a class="elsevierStyleCrossRef" href="#tblfn0010">b</a></td><td class="td" title="table-entry " align="left" valign="top">Phosphoric acid 85% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">5.45g \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Disodium phosphate 12 H2O (di) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">18.72g \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Sterile distilled water (qs) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">100mL \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " rowspan="3" align="left" valign="top">Cysteamine 0.55% eye drop solution<a class="elsevierStyleCrossRef" href="#tblfn0040">h</a></td><td class="td" title="table-entry " align="left" valign="top">Benzalkonium chloride \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0.045g \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Sodium chloride 0.9% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">225mL \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Cysteamine hydrochloride \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1.2375g \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] 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Cistinosis en pacientes adolescentes y adultos: recomendaciones para la atención integralde la cistinosis

Gema Aricetaa,

Corresponding author

gariceta@vhebron.net
gariceta@bilbaodigital.net

Corresponding author: Gema Ariceta, Servicio de Nefrología Pediátrica. Hospital Universitari Vall d’Hebron. Grupo Renaltube. Redinren, Pg/ Vall d’Hebron 119-129, 08034 Barcelona, Spain. Tel.: 934893082.

, Juan Antonio Camachob, Matilde Fernández-Obispoc, Aurora Fernández-Polod, Josep Gameze, Judit García-Villoriaf, Enrique Lara Monteczumac, Pere Leyesg, Nieves Martín-Beguéh, Federico Oppenheimeri, Manel Perellój, Guillem Pintos Morellk, Roser Torral, Anna Vila Santandreub, Ana Güellm, Grupo T-CiS.bcnn

a Servicio de Nefrología Pediátrica, Hospital Universitari Vall d’Hebron, Grupo Renaltube, Redinren, Barcelona, Spain

b Servicio de Nefrología Pediátrica, Hospital San Joan de Déu, Barcelona, Spain

c Servicio de Nefrología Pediátrica, Hospital Universitari Vall d’Hebron, Barcelona, Spain

d Servicio de Farmacia, Hospital Universitari Vall d’Hebron, Barcelona, Spain

e Servicio de Neurología, Hospital Universitari Vall d’Hebron, Barcelona, Spain

f Servicio Bioquímica y Genética Molecular. Sección de Errores Congénitos del Metabolismo. Hospital Universitari Clínic. IDIBAPS y CIBERER, Barcelona, Spain

g Servicio de Endocrinología y Nutrición, Hospital Universitari Clínic, Barcelona, Spain

h Servicio de Oftalmología, Hospital Universitari Vall d’Hebron, Barcelona, Spain

i Servicio de Nefrología y Trasplante Renal, Hospital Universitari Clínic, Barcelona, Spain

j Servicio de Nefrología, Hospital Universitari Vall d’Hebron, Barcelona, Spain

k Unidad de Nefrología Pediátrica, Hospital Universitari Germans Trias i Pujol, Badalona, Barcelona, Spain

l Servicio de Nefrología, Fundació Puigvert, AIRG-E, Redinren, Barcelona, Spain

m Product affairs, Orphan Europe - Recordati Group, Spain

n TCiS.bcn: Working group for multidisciplinary care and transition from paediatric to adult units in cystinosis, Barcelona, Spain

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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Cystinosis is a rare systemic lysosomal storage disease which&#44; if not treated&#44; leads to end-stage kidney failure in the first decade of life&#46;<a class="elsevierStyleCrossRef" href="#bib0635"><span class="elsevierStyleSup">1</span></a> Its natural history has been transformed thanks to the development of kidney transplantation &#40;KTx&#41; in children<a class="elsevierStyleCrossRef" href="#bib0640"><span class="elsevierStyleSup">2</span></a> and the availability of specific treatment with cysteamine&#44; a drug therapy that should be maintained throughout the patient&#39;s lifetime&#46;<a class="elsevierStyleCrossRef" href="#bib0645"><span class="elsevierStyleSup">3</span></a> As a consequence&#44; patient survival has increased from the first decade of life to beyond the fourth decade and cystinosis has passed from paediatrics to adult medicine&#46;<a class="elsevierStyleCrossRef" href="#bib0650"><span class="elsevierStyleSup">4</span></a></p><p id="par0405" class="elsevierStylePara elsevierViewall">The control of cystinosis is complex owing to its severity and multisystemic nature&#44; and the requirement of treatment with several drugs with a very strict dosage schedule&#46; Early diagnosis&#44; prompt cysteamine administration and treatment adherence influence morbidity and prognosis&#46;<a class="elsevierStyleCrossRefs" href="#bib0655"><span class="elsevierStyleSup">5&#44;6</span></a> Nevertheless&#44; adherence to therapy&#44; which is usually good in children&#44; tends to wane in teenagers and adults&#46;<a class="elsevierStyleCrossRef" href="#bib0665"><span class="elsevierStyleSup">7</span></a> Furthermore&#44; when patients reach adult age&#44; they are usually transferred from the paediatric expert centre to a local hospital with limited experience in cystinosis&#44; while the systemic manifestations continue to progress and the disease becomes more complex&#46;<a class="elsevierStyleCrossRef" href="#bib0670"><span class="elsevierStyleSup">8</span></a> This phenomenon is seen in other chronic renal diseases that debut in paediatric patients<a class="elsevierStyleCrossRef" href="#bib0675"><span class="elsevierStyleSup">9</span></a> and highlights the need to implement transition strategies and promote patient self-care&#46;<a class="elsevierStyleCrossRef" href="#bib0680"><span class="elsevierStyleSup">10</span></a></p><p id="par0410" class="elsevierStylePara elsevierViewall">The current cystinosis count in Spain comprises 56 patients treated and followed up at 22 hospitals&#46; Approximately 50&#37; are adults and 16&#37; adolescents&#59; 57&#37; are kidney transplant recipients&#46;<a class="elsevierStyleCrossRef" href="#bib0665"><span class="elsevierStyleSup">7</span></a></p><p id="par0415" class="elsevierStylePara elsevierViewall">The working group for the care and transition of cystinosis in Barcelona &#40;T-CiS&#46;bcn&#41; has assembled a group of experts in the disease to establish&#44; as a first step&#44; recommendations for the comprehensive care of cystinosis and the transition of adolescents to adult-care units in our country&#46; This consensus document presents a support tool for health care professionals both involved in and interested in cystinosis&#46; It is focused on reducing disease impact&#44; improving quality of life and prolonging survival&#44; in accordance with the guidelines of the International Society of Nephrology &#40;ISN&#41; and the International Paediatric Nephrology Association &#40;IPNA&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0680"><span class="elsevierStyleSup">10</span></a> At a later date&#44; the T-CiS&#46;bcn group plans to create a coordinated model of transition from paediatric to adult care services which will cover the specific needs of cystinosis&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Etiopathogenesis</span><p id="par0020" class="elsevierStylePara elsevierViewall">Cystinosis is a hereditary autosomal recessive disease caused by mutations with loss of function of the <span class="elsevierStyleItalic">CTNS</span> gene &#40;chromosome 17p13&#41;&#44; which encodes for cystinosin&#46;<a class="elsevierStyleCrossRef" href="#bib0685"><span class="elsevierStyleSup">11</span></a> Cystinosin is a specific transmembrane protein for the transport of cystine from the lysosome to cell cytoplasm&#46;<a class="elsevierStyleCrossRef" href="#bib0690"><span class="elsevierStyleSup">12</span></a> Its absence causes progressive deposits of intralysosomal cystine&#44; the main diagnostic marker of the disease<a class="elsevierStyleCrossRef" href="#bib0635"><span class="elsevierStyleSup">1</span></a>&#46; Its annual incidence is estimated at 1&#47;100&#44;000&#8211;200&#44;000 newborns&#44; while the population prevalence is 1&#8211;9&#47;1&#44;000&#44;000&#46;<a class="elsevierStyleCrossRef" href="#bib0695"><span class="elsevierStyleSup">13</span></a> The most frequent mutation in the <span class="elsevierStyleItalic">CTNS</span> gene is a deletion of 57<span class="elsevierStyleHsp" style=""></span>Kb<a class="elsevierStyleCrossRef" href="#bib0700"><span class="elsevierStyleSup">14</span></a> which is also observed in 34&#37; of patients in the Spanish population&#46;<a class="elsevierStyleCrossRef" href="#bib0705"><span class="elsevierStyleSup">15</span></a></p><p id="par0420" class="elsevierStylePara elsevierViewall">The amino acid cysteine oxidises inside the lysosome and forms cystine&#46; In patients with cystinosis&#44; there is an accumulation of cystine that precipitates in crystal form in all the cells of the organism&#44; particularly in renal and ocular tissue&#46;<a class="elsevierStyleCrossRef" href="#bib0710"><span class="elsevierStyleSup">16</span></a> The increase in the lysosomal concentration of cystine is associated with increased cellular apoptosis&#44; oxidative stress and alterations in the metabolism of glutathione and arachidonic acid&#46;<a class="elsevierStyleCrossRefs" href="#bib0715"><span class="elsevierStyleSup">17&#8211;19</span></a> Other pathogenic mechanisms involved are inflammatory<a class="elsevierStyleCrossRef" href="#bib0730"><span class="elsevierStyleSup">20</span></a> and &#8220;endoplasmic reticulum stress&#8221;&#44; which finally lead to cell death&#46;<a class="elsevierStyleCrossRefs" href="#bib0735"><span class="elsevierStyleSup">21&#44;22</span></a></p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Symptoms</span><p id="par0030" class="elsevierStylePara elsevierViewall">Cystinosis is a multisystemic disease<a class="elsevierStyleCrossRef" href="#bib0745"><span class="elsevierStyleSup">23</span></a> with the kidneys and eyes being the first organs to be affected&#46; Three clinical forms have been described&#58; infantile nephropathic cystinosis &#40;OMIM&#35;219800&#41;&#44; the most serious subtype&#44; which debuts early on&#59; juvenile nephropathic cystinosis &#40;OMIM&#35;219900&#41;&#44; a less severe subtype&#44; which debuts in childhood or later&#59; and adult non-nephropathic cystinosis &#40;OMIM&#35;219750&#41;&#44; with exclusively ocular involvement&#46;<a class="elsevierStyleCrossRef" href="#bib0750"><span class="elsevierStyleSup">24</span></a> Nonetheless&#44; in clinical practice&#44; two main subtypes are defined&#58; nephropathic cystinosis that debuts in early childhood with severe Fanconi syndrome &#40;representing 95&#37; of all cases&#41; and late-onset non-nephropathic cystinosis&#44; which appears in young patients or adults with renal and&#47;or ocular involvement &#40;representing &#60;5&#37; of affected patients&#41;&#46; In some patients&#44; ocular involvement can precede renal manifestations by several years&#46;<a class="elsevierStyleCrossRef" href="#bib0755"><span class="elsevierStyleSup">25</span></a></p><span id="sec0185" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Renal disease</span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Fanconi syndrome</span><p id="par0035" class="elsevierStylePara elsevierViewall">Typical clinical symptoms include the appearance of severe Fanconi syndrome with evolution to chronic kidney disease &#40;CKD&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46; Tubulopathy characteristically becomes evident in the second semester of life after a symptom-free interval&#46;<a class="elsevierStyleCrossRef" href="#bib0750"><span class="elsevierStyleSup">24</span></a> Affected newborns are apparently normal&#44; although it is possible to detect urinary alterations &#40;alkalineurine with glycosuria and&#47;or proteinuria&#41; very early preceding symptoms&#46;<a class="elsevierStyleCrossRef" href="#bib0760"><span class="elsevierStyleSup">26</span></a> Cystinosis is the most frequent cause of inherited Fanconi syndrome<a class="elsevierStyleCrossRef" href="#bib0750"><span class="elsevierStyleSup">24</span></a> and should be considered in the initial differential diagnosis in newborns&#46; Nonetheless&#44; cases have been described of cystinotic patients who debuted with atypical symptoms not suggestive of Fanconi syndrome but of distal tubulopathy&#44; such as nephrogenic diabetes insipidus or Batter syndrome&#46; Thus&#44; the diagnosis of cystinosis should be considered in all newborns with complex tubulopathy&#44; particulary if growth is affected and the patient is anorexic&#46;<a class="elsevierStyleCrossRef" href="#bib0635"><span class="elsevierStyleSup">1</span></a> The differential diagnosis should contemplate the possibility of secondary proximal tubulopathy&#46;<a class="elsevierStyleCrossRefs" href="#bib0765"><span class="elsevierStyleSup">27&#44;28</span></a> The severity of Fanconi syndrome associated with cystinosis requires rigorous treatment that is frequently very complex &#40;<a class="elsevierStyleCrossRef" href="#tbl0020">Table 1</a>&#41;&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><elsevierMultimedia ident="tbl0020"></elsevierMultimedia></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Chronic kidney disease</span><p id="par0040" class="elsevierStylePara elsevierViewall">After the age of two&#44; if no specific treatment is administered&#44; glomerular involvement progress with a drop in the glomerular filtration rate &#40;GFR&#41; and an increase in plasma creatinine starting at the age of 4 to 6&#44; which evolves to advanced CKD&#46;<a class="elsevierStyleCrossRef" href="#bib0635"><span class="elsevierStyleSup">1</span></a> Concurrently&#44; Fanconi syndrome usually remits and&#44; consequently&#44; it is possible to reduce water&#47;electrolyte supplements &#40;<a class="elsevierStyleCrossRef" href="#tbl0020">Table 1</a>&#41;&#46; In the absence of specific pharmacological treatment &#40;cysteamine&#41;&#44; mean age at the onset of end-stage renal disease &#40;ESRD&#41; is 9&#46;2 years&#46; In more contemporary series including patients who received early treatment with cysteamine&#44; there is a significant delay in evolution to ESRD at the age of 13&#46;5 which has been attributed to better patient control by physicians&#46; Furthermore&#44; in cases with very early diagnosis and treatment&#44; there is a growing percentage of patients who remain in predialysis after adolescence&#46;<a class="elsevierStyleCrossRef" href="#bib0660"><span class="elsevierStyleSup">6</span></a></p><p id="par0425" class="elsevierStylePara elsevierViewall">There are also forms of attenuated or late-onset cystinosis that debut in adolescence or in young adults&#44; such as glomerular disease and proteinuria without Fanconi syndrome&#44; although occasionally signs suggestive of proximal tubulopathy are observed&#46; Usually&#44; patients also present ocular manifestations of the disease that can be nearly asymptomatic<a class="elsevierStyleCrossRef" href="#bib0755"><span class="elsevierStyleSup">25</span></a> &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46;</p><p id="par0430" class="elsevierStylePara elsevierViewall">Although renal biopsy is not necessary for diagnosis&#44; it demonstrates non-specific lesions of glomerulosclerosis and other more characteristic signs such as irregularities on the brush border of proximal tubule cells&#44; swan neck deformity and&#44; occasionally&#44; deposits of cystine crystals and giant multinucleated podocytes&#46;<a class="elsevierStyleCrossRefs" href="#bib0640"><span class="elsevierStyleSup">2&#44;16&#44;24</span></a></p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Dialysis</span><p id="par0055" class="elsevierStylePara elsevierViewall">The renal replacement therapy &#40;RRT&#41; of choice in cystinosis is the kidney transplantation &#40;KTx&#41; since the disease does not recur in kidney grafts&#46; In many cases&#44; however&#44; the limitation of organs or delayed diagnosis results in the start of dialysis&#46; According to the NAPRTCS register&#44; 1&#46;4&#37; of patients &#60;18 years of age who initiated chronic dialysis had cystinosis&#46;<a class="elsevierStyleCrossRef" href="#bib0780"><span class="elsevierStyleSup">30</span></a> On the other hand&#44; in the European ESPN&#47;ERA-EDTA Registry&#44; 0&#46;9&#37; of patients &#60;20 years of age and 0&#46;1&#37; of patients &#62;20 years with RRT had cystinosis&#46; In Europe&#44; peritoneal dialysis &#40;PD&#41; was the most frequent initial treatment modality &#40;39&#46;6&#37;&#41;&#44; followed by preventive KTx &#40;35&#46;1&#37;&#41;&#46; Some 17&#46;9&#37; of patients received haemodialysis &#40;HD&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0655"><span class="elsevierStyleSup">5</span></a></p><p id="par0435" class="elsevierStylePara elsevierViewall">Fanconi syndrome can persist after the start of dialysis&#44; which influences the dietetic prescription for water&#44; patient diet and the possible need to administer other medications such as phosphorus chelates&#46; Although the urinary loss of saline and polyuria usually decrease in advanced CKD&#44; the patient may continue to need water&#47;electrolyte supplements and carnitine &#40;<a class="elsevierStyleCrossRef" href="#tbl0020">Table 1</a>&#41;&#46; On rare occasions&#44; the severity of Fanconi syndrome justifies nephrectomy of the native kidneys&#46;<a class="elsevierStyleCrossRef" href="#bib0785"><span class="elsevierStyleSup">31</span></a> Moreover&#44; many cystinotic patients on dialysis characteristically present extrarenal involvement requiring the integrated intervention of other specialists &#40;see section on extrarenal involvement&#41;&#44; which can be a challenge for nephrologists when treating their patients&#46;<a class="elsevierStyleCrossRef" href="#bib0790"><span class="elsevierStyleSup">32</span></a></p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Kidney transplantation</span><p id="par0065" class="elsevierStylePara elsevierViewall">As previously stated&#44; the RRT of choice in cystinosis is KTx&#46; Since graft cells do not carry the lysosomal defect&#44; the disease does not recur in the transplanted organ&#46; However&#44; it is possible to observe interstitial deposits of cystine crystals&#44; which represent leukocytes of the recipient and have no pathological significance&#46;<a class="elsevierStyleCrossRef" href="#bib0735"><span class="elsevierStyleSup">21</span></a> Family-donor transplantation is also curative&#44; and heterozygous carriers of the CTNS mutation can be appropriate donors since they do not have the disease&#46;<a class="elsevierStyleCrossRefs" href="#bib0650"><span class="elsevierStyleSup">4&#44;6&#44;33</span></a></p><p id="par0440" class="elsevierStylePara elsevierViewall">Indirect data from cystinotic patients with advanced kidney failure and international registries suggest that preventive kidney transplantation would be beneficial in this disease&#44; particularly when a living donor is available<a class="elsevierStyleCrossRef" href="#bib0650"><span class="elsevierStyleSup">4</span></a> thereby avoiding the need for dialysis&#46;<a class="elsevierStyleCrossRef" href="#bib0655"><span class="elsevierStyleSup">5</span></a> Thus&#44; the indication for kidney transplantation is established when the GFR is &#60;20<span class="elsevierStyleHsp" style=""></span>ml&#47;min&#47;1&#46;73<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span>&#44; which would be somewhat earlier than in other kidney diseases&#46;<a class="elsevierStyleCrossRef" href="#bib0635"><span class="elsevierStyleSup">1</span></a></p><p id="par0445" class="elsevierStylePara elsevierViewall">In the United States &#40;USRDS2013&#41;&#44; mean age of patients with cystinosis at the first KTx is 13&#46;8 years &#40;range&#58; 2 to 24&#41;&#44; which has not changed in recent decades&#59; 32&#46;4&#37; underwent preventive KTx&#46;<a class="elsevierStyleCrossRef" href="#bib0800"><span class="elsevierStyleSup">34</span></a> Similarly data from the European Registry &#40;ESPN&#47;ERA-EDTA Registry&#41; show a similar percentage of 35&#46;1&#37; predialysis transplantations&#44; a much higher percentage than in other nephropathies &#40;17&#46;1&#37;&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0655"><span class="elsevierStyleSup">5</span></a> Eighty-five percent of all the cystinotic patients in RRT were kidney transplant recipients&#46; Regarding the type of donor&#44; 54&#37; of patients in the US received a living and 46&#37; a deceased donor organ&#46;<a class="elsevierStyleCrossRef" href="#bib0800"><span class="elsevierStyleSup">34</span></a> Similarly&#44; in Europe 48&#46;9&#37; received a living donor transplant&#46;<a class="elsevierStyleCrossRef" href="#bib0655"><span class="elsevierStyleSup">5</span></a></p><p id="par0450" class="elsevierStylePara elsevierViewall">It is worthy of mention that the duration of functioning kidney grafts in cystinotic patients is longer than that observed in the population of recipients transplanted for other causes&#46;<a class="elsevierStyleCrossRefs" href="#bib0655"><span class="elsevierStyleSup">5&#44;35</span></a></p></span></span><span id="sec0190" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Extrarenal disease</span><p id="par0085" class="elsevierStylePara elsevierViewall">The longer survival and better prognosis of patients with cystinosis have resulted in better understanding of the multiple organ involvement in this disease<a class="elsevierStyleCrossRefs" href="#bib0650"><span class="elsevierStyleSup">4&#44;6&#44;32&#44;36</span></a> &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46;</p><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Ocular involvement</span><p id="par0090" class="elsevierStylePara elsevierViewall">Eye involvement is intrinsic to cystinosis&#46; The presence of cystine crystals in the cornea is a diagnostic criterion for this disease&#44;<a class="elsevierStyleCrossRef" href="#bib0815"><span class="elsevierStyleSup">37</span></a> although its absence before the age of 12 months may not rule it out&#46;<a class="elsevierStyleCrossRef" href="#bib0635"><span class="elsevierStyleSup">1</span></a></p><p id="par0455" class="elsevierStylePara elsevierViewall">Cystine deposits in the cornea are one of the earliest manifestations of cystinosis &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46; Although no crystals are present at birth&#44; they can be observed in children who are only a few months old&#46;<a class="elsevierStyleCrossRef" href="#bib0635"><span class="elsevierStyleSup">1</span></a> Initially&#44; they are deposited in the superficial layers of the peripheral cornea&#44; but progressively begin to affect all the layers and entire extension of the cornea&#46; If left untreated&#44; corneal crystal deposits progress inexorably&#44; increasing with age&#44; resulting in photophobia&#44; which can be quite incapacitating&#44; and in abnormal corneal sensitivity&#46; In time&#44; this condition leads to recurrent corneal erosions and stromal oedema&#44; which can reduce visual acuity&#46; Reports also exist of calcium deposition in Bowman&#39;s membrane or band keratopathy&#44; which affect vision when situated in the visual axis&#46;<a class="elsevierStyleCrossRef" href="#bib0815"><span class="elsevierStyleSup">37</span></a></p><p id="par0460" class="elsevierStylePara elsevierViewall">Crystals are also deposited in other ocular structures such us the conjunctiva&#44; anterior chamber&#44; iris&#44; ciliary body&#44; choroid and retina&#46; Retinal involvement causes degeneration of the photoreceptors&#44; mainly the rods&#44; thereby altering the peripheral visual field and night vision&#44; although central vision may also be reduced&#46; Less frequently&#44; there have been reports of posterior synechiae&#44; adherence of the iris to the anterior lens capsule and neovascularisation of the peripheral cornea&#46;<a class="elsevierStyleCrossRefs" href="#bib0820"><span class="elsevierStyleSup">38&#44;39</span></a> Furthermore&#44; tear production is reduced&#44; causing dry eye&#44; and neuro-ophthalmological manifestations &#40;papilledema and ophthalmoplegia&#41; are observed secondary to the increased intracranial pressure reported in this disease&#46;<a class="elsevierStyleCrossRef" href="#bib0650"><span class="elsevierStyleSup">4</span></a> In late-onset disease&#44; the presence of crystals might not be detected until adulthood&#46;<a class="elsevierStyleCrossRef" href="#bib0755"><span class="elsevierStyleSup">25</span></a></p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Growth and development&#58; mineral-bone involvement</span><p id="par0105" class="elsevierStylePara elsevierViewall">Failure to thrive is a classic clinical symptom of cystinosis and frequently is the reason for an early consultation&#46;<a class="elsevierStyleCrossRef" href="#bib0810"><span class="elsevierStyleSup">36</span></a> The underlying mechanism is multifactorial&#44; although it is related to Fanconi syndrome severity&#46; The concurrence of metabolic acidosis&#44; hyponutrition&#44; increased gastrointestinal and renal losses and CKD lead to delayed growth that can be very severe&#46;<a class="elsevierStyleCrossRefs" href="#bib0830"><span class="elsevierStyleSup">40&#44;41</span></a> Similarly&#44; patients present endocrine alterations &#40;see endocrine involvement section&#41; and&#44; infrequently&#44; primary growth hormone &#40;GH&#41; deficiency&#46;<a class="elsevierStyleCrossRef" href="#bib0840"><span class="elsevierStyleSup">42</span></a></p><p id="par0465" class="elsevierStylePara elsevierViewall">Patients with inadequate treatments usually have shorter stature&#46;<a class="elsevierStyleCrossRef" href="#bib0810"><span class="elsevierStyleSup">36</span></a> Classically&#44; the adult height reported in patients with suboptimal treatment is 144<span class="elsevierStyleHsp" style=""></span>cm and weight 45<span class="elsevierStyleHsp" style=""></span>kg &#40;25<span class="elsevierStyleHsp" style=""></span>cm and 25<span class="elsevierStyleHsp" style=""></span>kg below the normal population average&#44; respectively&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0650"><span class="elsevierStyleSup">4</span></a> The most recent series with better therapeutic control reported less retarded growth<a class="elsevierStyleCrossRef" href="#bib0670"><span class="elsevierStyleSup">8</span></a> and a favourable impact of treatment on growth regulation mechanisms&#46;<a class="elsevierStyleCrossRef" href="#bib0845"><span class="elsevierStyleSup">43</span></a> Nevertheless&#44; nowadays 27&#37; of transplanted cystinotic patients and 44&#37; of those on dialysis continue to be shorter than average&#46;<a class="elsevierStyleCrossRef" href="#bib0655"><span class="elsevierStyleSup">5</span></a></p><p id="par0470" class="elsevierStylePara elsevierViewall">Early GH administration improves height and weight&#44; although the therapeutic response is usually lower than that observed in CKD due to other causes&#44; despite optimum disease control&#46; GH is an essential therapeutic tool in this disease&#44; for its impact on longitudinal growth and its anabolic effect&#46;<a class="elsevierStyleCrossRefs" href="#bib0830"><span class="elsevierStyleSup">40&#44;44</span></a> Patients with cystinosis develop a characteristic metabolic bone disease caused by different factors&#58; bone deposits of cystine crystals&#44; mineral deficiency&#44; renal rickets<a class="elsevierStyleCrossRef" href="#bib0750"><span class="elsevierStyleSup">24</span></a> and CKD <span class="elsevierStyleItalic">per se</span>&#46;<a class="elsevierStyleCrossRef" href="#bib0855"><span class="elsevierStyleSup">45</span></a> Bone anomalies attributed to copper deficiency&#44; possibly secondary to Fanconi syndrome have also been described&#46;<a class="elsevierStyleCrossRef" href="#bib0860"><span class="elsevierStyleSup">46</span></a> It is therefore common to detect osteopenia&#44; especially in transplant recipients&#44; related also to other endocrine alterations of the disease &#40;see endocrine involvement section&#41; and potentially to the treatment&#46;<a class="elsevierStyleCrossRefs" href="#bib0745"><span class="elsevierStyleSup">23&#44;47</span></a> Some patients have bone fragility and a higher risk of fractures&#46;<a class="elsevierStyleCrossRef" href="#bib0790"><span class="elsevierStyleSup">32</span></a></p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Endocrine involvement</span><p id="par0120" class="elsevierStylePara elsevierViewall">Endocrine manifestations are caused by destruction of the affected glands due to cystine deposits&#59; their incidence and age at appearance are associated with the establishment of specific treatment with cysteamine&#46;<a class="elsevierStyleCrossRef" href="#bib0845"><span class="elsevierStyleSup">43</span></a></p><p id="par0475" class="elsevierStylePara elsevierViewall">Primary hypothyroidism is the most frequent endocrine complication&#59;<a class="elsevierStyleCrossRef" href="#bib0745"><span class="elsevierStyleSup">23</span></a> it is progressive and requires chronic treatment with levothyroxine&#46;<a class="elsevierStyleCrossRefs" href="#bib0635"><span class="elsevierStyleSup">1&#44;4</span></a> Diabetes mellitus &#40;DM&#41; is characterised by a progressive alteration in insulin secretion&#44;<a class="elsevierStyleCrossRef" href="#bib0870"><span class="elsevierStyleSup">48</span></a> with negative immunology&#44; and requires treatment with insulin&#46;<a class="elsevierStyleCrossRef" href="#bib0640"><span class="elsevierStyleSup">2</span></a> It is observed in transplant recipients who receive corticosteroids&#46;<a class="elsevierStyleCrossRef" href="#bib0745"><span class="elsevierStyleSup">23</span></a> In males&#44; cystinosis causes primary hypogonadism and infertility is a constant&#46;<a class="elsevierStyleCrossRefs" href="#bib0650"><span class="elsevierStyleSup">4&#44;49</span></a> In females&#44; however&#44; neither hypogonadism nor infertility are prevalent&#44; and affected patients can thus have children&#44;<a class="elsevierStyleCrossRef" href="#bib0880"><span class="elsevierStyleSup">50</span></a> although the risk of prematurity is increased&#46;<a class="elsevierStyleCrossRef" href="#bib0885"><span class="elsevierStyleSup">51</span></a></p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">Cardiovascular involvement</span><p id="par0130" class="elsevierStylePara elsevierViewall">The appearance of dyslipidemia and vascular calcification due to cystinosis and CKD are considered increased cardiovascular risk factors&#46;<a class="elsevierStyleCrossRefs" href="#bib0745"><span class="elsevierStyleSup">23&#44;32&#44;41</span></a> 42&#37; of patients develop arterial hypertension&#44; usually post-transplantation&#46; Aortic aneurysms and coronary vessels involvement&#44; as well as cardiomyopathy associated with cystine crystals deposits in the myocardium have also been reported&#46;<a class="elsevierStyleCrossRef" href="#bib0810"><span class="elsevierStyleSup">36</span></a> In adult patients&#44; screening for ischaemic heart disease is recommended&#46;<a class="elsevierStyleCrossRef" href="#bib0650"><span class="elsevierStyleSup">4</span></a></p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0140">Neurological involvement</span><p id="par0135" class="elsevierStylePara elsevierViewall">Cystinosis is associated with alterations in cerebral structure and increased cystine levels in different areas of the nervous system and muscle tissue&#46;<a class="elsevierStyleCrossRefs" href="#bib0650"><span class="elsevierStyleSup">4&#44;6&#44;32&#44;52</span></a> In general&#44; neurological complications worsen the prognosis of the disease&#58;<ul class="elsevierStyleList" id="lis0040"><li class="elsevierStyleListItem" id="lsti0125"><span class="elsevierStyleLabel">&#8226;</span><p id="par0480" class="elsevierStylePara elsevierViewall">Progressive ischaemic myopathy<a class="elsevierStyleCrossRefs" href="#bib0650"><span class="elsevierStyleSup">4&#44;32&#44;53</span></a> is predominantly distal and begins in the hands&#59; loss of muscle mass is also observed with later ventilator capacity impairment and swallowing difficulties&#46; Some authors attribute muscle weakness in these patients to carnitine deficiency&#46;<a class="elsevierStyleCrossRefs" href="#bib0750"><span class="elsevierStyleSup">24&#44;28&#44;29</span></a></p></li><li class="elsevierStyleListItem" id="lsti0130"><span class="elsevierStyleLabel">&#8226;</span><p id="par0485" class="elsevierStylePara elsevierViewall">Central nervous system &#40;CNS&#41; involvement<a class="elsevierStyleCrossRefs" href="#bib0650"><span class="elsevierStyleSup">4&#44;31</span></a> is mainly observed in patients with suboptimal treatment with cysteamine&#58;<ul class="elsevierStyleList" id="lis0045"><li class="elsevierStyleListItem" id="lsti0135"><span class="elsevierStyleLabel">&#8211;</span><p id="par0490" class="elsevierStylePara elsevierViewall">Acute presentation&#58; epilepsy&#44; stroke&#44; encephalopathy&#44; cephalalgia<a class="elsevierStyleCrossRefs" href="#bib0900"><span class="elsevierStyleSup">54&#8211;57</span></a></p></li><li class="elsevierStyleListItem" id="lsti0140"><span class="elsevierStyleLabel">&#8211;</span><p id="par0495" class="elsevierStylePara elsevierViewall">Subacute&#47;progressive presentation&#58; intracranial hypertension&#44; cerebral atrophy&#44; ataxia&#44; pyramidalism&#44; gait disorders&#44; basal and periventricular lymph node calcifications&#44; demyelination of white matter&#44; mental deterioration<a class="elsevierStyleCrossRefs" href="#bib0920"><span class="elsevierStyleSup">58&#8211;66</span></a></p></li></ul></p></li><li class="elsevierStyleListItem" id="lsti0145"><span class="elsevierStyleLabel">&#8226;</span><p id="par0500" class="elsevierStylePara elsevierViewall">Neurocognitive alterations&#58;<a class="elsevierStyleCrossRefs" href="#bib0965"><span class="elsevierStyleSup">67&#8211;73</span></a> in cystinotic patients&#44; a specific profile of alterations in visual-motor integration&#44; visual memory&#44; maintained attention&#44; planning&#44; motor processing speed and arithmetic calculation have been described&#46; Consequently&#44; they account for a significant incidence of social difficulties that could explain the behavioural phenotype in some patients&#46; Intelligence is usually normal&#46;</p></li></ul></p><p id="par0505" class="elsevierStylePara elsevierViewall">Early detection of neurological complications in cystinosis facilitates better therapeutic strategies&#44; reduces the number of hospitalisations and improves quality of life&#46; The participation of a neurologist will help to evaluate the functional capacity of patients and detect earlier the neurological manifestations that can affect autonomy in basic daily life activities&#46;<a class="elsevierStyleCrossRefs" href="#bib0670"><span class="elsevierStyleSup">8&#44;31&#44;32&#44;55</span></a></p></span></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0145">Miscellaneous</span><p id="par0165" class="elsevierStylePara elsevierViewall">The ubiquity of cystinosis is demonstrated by its non-specific symptoms e&#46;g&#46; gastrointestinal and other disorders such as heat intolerance and hypophoresis&#46; Similarly&#44; the systemic nature of the disease explains the progressive appearance of other clinical symptoms secondary to the deposition of cystine crystals in different organs and systems&#44; as detailed below &#40;Fig&#46; 1&#41;&#58;<ul class="elsevierStyleList" id="lis0050"><li class="elsevierStyleListItem" id="lsti0030"><span class="elsevierStyleLabel">&#8226;</span><p id="par0170" class="elsevierStylePara elsevierViewall">Digestive system<a class="elsevierStyleCrossRef" href="#bib1000"><span class="elsevierStyleSup">74</span></a>&#58;<ul class="elsevierStyleList" id="lis0020"><li class="elsevierStyleListItem" id="lsti0035"><span class="elsevierStyleLabel">&#8211;</span><p id="par0175" class="elsevierStylePara elsevierViewall">Nausea&#44; vomiting&#44; epigastralgia&#44; anorexia</p></li><li class="elsevierStyleListItem" id="lsti0040"><span class="elsevierStyleLabel">&#8211;</span><p id="par0180" class="elsevierStylePara elsevierViewall">Increased gastrin secretion &#40;associated with taking cysteamine&#41;</p></li><li class="elsevierStyleListItem" id="lsti0045"><span class="elsevierStyleLabel">&#8211;</span><p id="par0185" class="elsevierStylePara elsevierViewall">Decreased salivation</p></li><li class="elsevierStyleListItem" id="lsti0050"><span class="elsevierStyleLabel">&#8211;</span><p id="par0190" class="elsevierStylePara elsevierViewall">Mechanical swallowing difficulties</p></li><li class="elsevierStyleListItem" id="lsti0055"><span class="elsevierStyleLabel">&#8211;</span><p id="par0195" class="elsevierStylePara elsevierViewall">Delayed gastric emptying and intestinal and intestinal dysmotility</p></li><li class="elsevierStyleListItem" id="lsti0060"><span class="elsevierStyleLabel">&#8211;</span><p id="par0200" class="elsevierStylePara elsevierViewall">Intestinal pseudo-obstruction</p></li><li class="elsevierStyleListItem" id="lsti0065"><span class="elsevierStyleLabel">&#8211;</span><p id="par0205" class="elsevierStylePara elsevierViewall">Intestinal inflammatory disease</p></li></ul></p></li><li class="elsevierStyleListItem" id="lsti0070"><span class="elsevierStyleLabel">&#8226;</span><p id="par0210" class="elsevierStylePara elsevierViewall">Liver<a class="elsevierStyleCrossRefs" href="#bib0790"><span class="elsevierStyleSup">32&#44;75</span></a>&#58;<ul class="elsevierStyleList" id="lis0025"><li class="elsevierStyleListItem" id="lsti0075"><span class="elsevierStyleLabel">&#8211;</span><p id="par0215" class="elsevierStylePara elsevierViewall">Regenerative nodular hyperplasia without liver failure</p></li><li class="elsevierStyleListItem" id="lsti0080"><span class="elsevierStyleLabel">&#8211;</span><p id="par0220" class="elsevierStylePara elsevierViewall">Non-cirrhotic portal hypertension with hypersplenism</p></li><li class="elsevierStyleListItem" id="lsti0085"><span class="elsevierStyleLabel">&#8211;</span><p id="par0225" class="elsevierStylePara elsevierViewall">Cholestasis</p></li><li class="elsevierStyleListItem" id="lsti0090"><span class="elsevierStyleLabel">&#8211;</span><p id="par0230" class="elsevierStylePara elsevierViewall">Hypercholesterolemia</p></li></ul></p></li><li class="elsevierStyleListItem" id="lsti0095"><span class="elsevierStyleLabel">&#8226;</span><p id="par0235" class="elsevierStylePara elsevierViewall">Skin<a class="elsevierStyleCrossRefs" href="#bib0635"><span class="elsevierStyleSup">1&#44;76</span></a>&#58;<ul class="elsevierStyleList" id="lis0030"><li class="elsevierStyleListItem" id="lsti0100"><span class="elsevierStyleLabel">&#8211;</span><p id="par0240" class="elsevierStylePara elsevierViewall">Hypopigmentation of skin and hair due to altered melanogenesis</p></li><li class="elsevierStyleListItem" id="lsti0105"><span class="elsevierStyleLabel">&#8211;</span><p id="par0245" class="elsevierStylePara elsevierViewall">Altered sweating and intolerance to heat</p></li></ul></p></li><li class="elsevierStyleListItem" id="lsti0110"><span class="elsevierStyleLabel">&#8226;</span><p id="par0250" class="elsevierStylePara elsevierViewall">Bone marrow<a class="elsevierStyleCrossRef" href="#bib0650"><span class="elsevierStyleSup">4</span></a>&#58;<ul class="elsevierStyleList" id="lis0035"><li class="elsevierStyleListItem" id="lsti0115"><span class="elsevierStyleLabel">&#8211;</span><p id="par0255" class="elsevierStylePara elsevierViewall">Anaemia</p></li><li class="elsevierStyleListItem" id="lsti0120"><span class="elsevierStyleLabel">&#8211;</span><p id="par0260" class="elsevierStylePara elsevierViewall">Coagulopathy due to dysfunctional platelets</p></li></ul></p></li></ul></p></span></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0150">Diagnosis</span><p id="par0265" class="elsevierStylePara elsevierViewall">The clinical diagnosis of cystinosis is symptom-based and is confirmed by biochemical and molecular diagnosis&#46;</p><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0155">Clinical diagnosis</span><p id="par0270" class="elsevierStylePara elsevierViewall">Guiding signs are early-onset of severe Fanconi syndrome and the detection of corneal crystals&#46; As the disease progresses&#44; systemic involvement may be observed &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46; However&#44; in patients with less severe forms&#44; renal involvement is restricted to proteinuria and CKD&#46; Occasionally&#44; corneal crystals in adult patients with CKD of unknown aetiology lead to the diagnosis of cystinosis&#46;<a class="elsevierStyleCrossRef" href="#bib0755"><span class="elsevierStyleSup">25</span></a> Kidney biopsy&#44; while not a requirement for the diagnosis of cystinosis&#44; can be useful in these atypical presentations&#46;<a class="elsevierStyleCrossRefs" href="#bib0640"><span class="elsevierStyleSup">2&#44;16&#44;24&#44;32</span></a></p></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0160">General biochemical diagnosis</span><p id="par0275" class="elsevierStylePara elsevierViewall">This diagnosis is based on the detection of water&#47;electrolyte disorders&#44; affected acid-base balance and eventually renal function&#44; which are all prototypical of Fanconi syndrome&#46;<a class="elsevierStyleCrossRefs" href="#bib0750"><span class="elsevierStyleSup">24&#44;28&#44;29</span></a></p></span><span id="sec0095" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0165">Specific biochemical diagnosis</span><p id="par0280" class="elsevierStylePara elsevierViewall">This involves the detection of elevated white blood cells &#40;WBC&#41; cystine levels&#46;<a class="elsevierStyleCrossRef" href="#bib1015"><span class="elsevierStyleSup">77</span></a> Currently High Performance Liquid Chromatography&#8211;Tandem Mass Spectrometry &#40;HPLC-MS&#47;MS&#41; in granulocytes is used as it is a more sensitive technique&#46;<a class="elsevierStyleCrossRefs" href="#bib1020"><span class="elsevierStyleSup">78&#44;79</span></a></p><p id="par0510" class="elsevierStylePara elsevierViewall">The reference values are&#58;<ul class="elsevierStyleList" id="lis0055"><li class="elsevierStyleListItem" id="lsti0150"><span class="elsevierStyleLabel">&#8226;</span><p id="par0515" class="elsevierStylePara elsevierViewall">healthy individual&#58; &#8804;0&#46;5<span class="elsevierStyleHsp" style=""></span>nmol 1&#47;2 cystine&#47;mg protein &#40;values &#62;0&#46;5 may have diagnostic significance&#44; and it is recommended to repeat the determination&#41;</p></li><li class="elsevierStyleListItem" id="lsti0155"><span class="elsevierStyleLabel">&#8226;</span><p id="par0520" class="elsevierStylePara elsevierViewall">affected individual without treatment&#58; &#62;1<span class="elsevierStyleHsp" style=""></span>nmol 1&#47;2 cystine&#47;mg protein &#40;usually &#62;2&#41;</p></li><li class="elsevierStyleListItem" id="lsti0160"><span class="elsevierStyleLabel">&#8226;</span><p id="par0525" class="elsevierStylePara elsevierViewall">individual treated with good therapeutic control&#58; &#8804;1 nmol 1&#47;2 cystine&#47;mg protein</p></li></ul></p><p id="par0530" class="elsevierStylePara elsevierViewall">Normal WBC cystine levels in newborns do not completely rule out the diagnosis&#46; Therefore&#44; in cases where cystinosis is highly suspected&#44; a second test is recommended 3&#8211;6 months after the first study when the results are not conclusive<a class="elsevierStyleCrossRef" href="#bib1025"><span class="elsevierStyleSup">79</span></a> &#40;<a class="elsevierStyleCrossRef" href="#tbl0030">Table 2</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0030"></elsevierMultimedia></span><span id="sec0100" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0170">Molecular diagnosis</span><p id="par0305" class="elsevierStylePara elsevierViewall">Cystinosis is confirmed by the detection of homozygous or compound heterozygous mutations in the <span class="elsevierStyleItalic">CTNS</span> gene&#46; More than 100 different mutations have been reported and the most frequent one is the &#8764;57<span class="elsevierStyleHsp" style=""></span>kb deletion affecting the first 10 exons&#44; especially in patients of Northern European descent&#46; Specific mutations turn into an absence of protein or a probably non-functional truncated protein<a class="elsevierStyleCrossRefs" href="#bib0685"><span class="elsevierStyleSup">11&#44;12&#44;14&#44;15&#44;80</span></a> &#40;<a class="elsevierStyleCrossRef" href="#tbl0030">Table 2</a>&#41;&#46;</p></span><span id="sec0105" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0175">Genetic counselling</span><p id="par0310" class="elsevierStylePara elsevierViewall">Since cystinosis is an autosomal recessive disease&#44; the probability of a family with one affected child having another with cystinosis is 25&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib1035"><span class="elsevierStyleSup">81</span></a> In this case&#44; genetic counselling includes information on prenatal diagnostic techniques and embryo selection&#46;<a class="elsevierStyleCrossRefs" href="#bib1040"><span class="elsevierStyleSup">82&#44;83</span></a> The probability of a woman with cystinosis having an affected child is very low&#44; except in consanguineous families or endogamous populations&#46; Males with cystinosis are universally sterile&#46;<a class="elsevierStyleCrossRef" href="#bib0875"><span class="elsevierStyleSup">49</span></a></p><p id="par0535" class="elsevierStylePara elsevierViewall">Genetic counselling usually includes information on patient associations<a class="elsevierStyleCrossRefs" href="#bib1050"><span class="elsevierStyleSup">84&#8211;86</span></a> and institutional strategies in rare diseases&#46;<a class="elsevierStyleCrossRef" href="#bib1065"><span class="elsevierStyleSup">87</span></a></p></span></span><span id="sec0110" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0180">Treatment</span><span id="sec0115" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0185">Symptomatic treatment of kidney involvement</span><p id="par0315" class="elsevierStylePara elsevierViewall">The aim of treatment &#40;<a class="elsevierStyleCrossRef" href="#tbl0020">Table 1</a> &#38; <a class="elsevierStyleCrossRef" href="#sec0210">Annex 1</a>&#41; is to control Fanconi syndrome&#44; its complications and other factors involved in kidney failure progression&#46;<a class="elsevierStyleCrossRefs" href="#bib0750"><span class="elsevierStyleSup">24&#8211;28</span></a> In ESRD&#44; promoting KTx is a priority&#46; Regardless of kidney involvement&#44; all patients should receive specific treatment with cysteamine for the prevention and therapeutic control of the systemic disease&#46;</p><p id="par0540" class="elsevierStylePara elsevierViewall">Treatment of CKD should follow international guidelines&#46;<a class="elsevierStyleCrossRefs" href="#bib1070"><span class="elsevierStyleSup">88&#8211;90</span></a> In transplanted patients&#44; minimising or avoiding corticosteroids use is recommended&#46;<a class="elsevierStyleCrossRef" href="#bib0745"><span class="elsevierStyleSup">23</span></a></p></span><span id="sec0120" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0190">Specific treatment with cysteamine</span><span id="sec0125" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0195">Oral cysteamine</span><p id="par0325" class="elsevierStylePara elsevierViewall">The specific treatment for all clinical forms of cystinosis is oral cysteamine&#46; Cysteamine depletes lysosomal cystine content by forming disulphide cysteine&#8211;cysteamine complexes able to exit the lysosomes by means of the alternative lysine channel&#44; and the remaining cysteine via a cysteine carrier&#46;<a class="elsevierStyleCrossRefs" href="#bib0645"><span class="elsevierStyleSup">3&#44;19&#44;91</span></a></p><p id="par0545" class="elsevierStylePara elsevierViewall">The first specific pharmacological treatment for cystinosis is Cystagon<span class="elsevierStyleSup">&#174;</span> &#40;oral cysteamine bitartrate in hard capsules&#41;&#44; the only authorised therapy in Spain<a class="elsevierStyleCrossRefs" href="#bib1090"><span class="elsevierStyleSup">92&#8211;94</span></a>&#46; A new formula in hard gastro-resistant capsules has recently been approved for cysteamine&#46;<a class="elsevierStyleCrossRefs" href="#bib1095"><span class="elsevierStyleSup">93&#8211;96</span></a></p><span id="sec0130" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0200">Therapeutic benefits</span><p id="par0335" class="elsevierStylePara elsevierViewall">Oral cysteamine should be initiated at the time of diagnosis and continued lifelong&#46; When compliance is consistent&#44; cysteamine is able to deplete up to 95&#37; of cellular cystine deposits&#46;<a class="elsevierStyleCrossRef" href="#bib0940"><span class="elsevierStyleSup">62</span></a> The reduction in these deposits correlates with cystinosis severity&#46;<a class="elsevierStyleCrossRef" href="#bib0790"><span class="elsevierStyleSup">32</span></a> It has been demonstrated that cysteamine prolongs the life of the patient&#44; while delaying kidney disease progression and the need for renal replacement therapy&#46;<a class="elsevierStyleCrossRefs" href="#bib0655"><span class="elsevierStyleSup">5&#44;97</span></a> Similarly&#44; it reduces the severity and frequency of extrarenal complications&#46;<a class="elsevierStyleCrossRef" href="#bib0790"><span class="elsevierStyleSup">32</span></a> Prognosis of the disease is directly related to early treatment and its duration&#46; Even when cystinosis diagnosis is delayed&#44; cysteamine has demonstrated clinical benefits&#46;<a class="elsevierStyleCrossRefs" href="#bib0650"><span class="elsevierStyleSup">4&#44;6&#44;98</span></a> Although Fanconi syndrome is not usually reversible with cysteamine&#44;<a class="elsevierStyleCrossRef" href="#bib0725"><span class="elsevierStyleSup">19</span></a> in some isolated cases of prenatal diagnosis the beginning of cysteamine therapy within the first weeks of life prevented the appearance of tubulopathy&#46;<a class="elsevierStyleCrossRefs" href="#bib1125"><span class="elsevierStyleSup">99&#44;100</span></a></p></span><span id="sec0135" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0205">Cystagon<span class="elsevierStyleSup">&#174;</span>&#58; dosage&#44; administration and treatment monitoring</span><p id="par0340" class="elsevierStylePara elsevierViewall">Treatment is based on the depletion of lysosomal cystine content which&#44; in clinical practice&#44; means the reduction of WBC cystine levels&#44; with an optimal therapeutic goal &#60;1<span class="elsevierStyleHsp" style=""></span>nmol hemicystine&#47;mg of protein&#46; The decrease in those WBC cysteine levels correlates with plasma cysteamine concentrations for the 6 hours following Cystagon<span class="elsevierStyleSup">&#174;</span> dose&#44; being minimum at &#8764;2<span class="elsevierStyleHsp" style=""></span>h after the drug is taken and returning to baseline &#40;pre-dose&#41; 6<span class="elsevierStyleHsp" style=""></span>h later&#46; This explains the need to take the drug every 6<span class="elsevierStyleHsp" style=""></span>h&#44; overnight dose included<a class="elsevierStyleCrossRefs" href="#bib1135"><span class="elsevierStyleSup">101&#44;102</span></a> &#40;<a class="elsevierStyleCrossRef" href="#tbl3">Table 3</a>&#41;&#46;</p><elsevierMultimedia ident="tbl3"></elsevierMultimedia><p id="par0550" class="elsevierStylePara elsevierViewall">Monitoring of WBC cysteine levels at the start of treatment and monthly after changes in the prescribed dosage is recommended&#46; In patients with maintained cystine levels&#44; follow-up controls are recommended every 6 months&#46; Similarly&#44; in an individualised manner&#44; the frequency of monitoring should be increased in case of significant clinical changes such as KTx and dialysis<a class="elsevierStyleCrossRefs" href="#bib1015"><span class="elsevierStyleSup">77&#44;78&#44;79</span></a> &#40;<a class="elsevierStyleCrossRef" href="#tbl0030">Table 2</a>&#41;&#46;</p></span></span><span id="sec0140" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0210">Oral treatment in special situations</span><span id="sec0145" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0215">Chronic kidney disease&#44; dialysis and transplantation</span><p id="par0350" class="elsevierStylePara elsevierViewall">Since there is no correlation between GFR and plasma cysteamine levels&#44; it is not necessary to adjust the dosage to renal function&#59; instead&#44; the prescribed dosage should be adjusted to the quantification of WBC cystine levels&#46; Adjustments for Fanconi syndrome are also unnecessary&#46;<a class="elsevierStyleCrossRefs" href="#bib0660"><span class="elsevierStyleSup">6&#44;103</span></a></p></span><span id="sec0150" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0220">Pregnancy and breastfeeding</span><p id="par0355" class="elsevierStylePara elsevierViewall">Although data is insufficient&#44; reproductive toxicity and teratogenic effects of cysteamine have been observed in animals&#46;<a class="elsevierStyleCrossRef" href="#bib1150"><span class="elsevierStyleSup">104</span></a> Its use is therefore contraindicated during pregnancy&#44; particularly in the first trimester&#46; Family planning is recommended in women of childbearing age&#46; Furthermore&#44; cysteamine administration should be avoided during breastfeeding&#46;</p></span></span><span id="sec0195" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0225">Cysteamine eye drops</span><p id="par0555" class="elsevierStylePara elsevierViewall">Specific treatment of ocular involvement in cystinosis requires&#44; in addition to oral cysteamine&#44; the use of cysteamine eye drops&#46; The ophthalmological therapeutic strategy<a class="elsevierStyleCrossRefs" href="#bib0790"><span class="elsevierStyleSup">32&#44;37</span></a> makes a distinction between&#58;</p></span><span id="sec0160" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0230">Corneal involvement</span><p id="par0365" class="elsevierStylePara elsevierViewall">Cystine crystal deposits should be treated with topical cysteamine since the cornea is an avascular structure and&#44; consequently&#44; oral medication is not effective for the cornea&#46;<a class="elsevierStyleCrossRefs" href="#bib0815"><span class="elsevierStyleSup">37&#44;38&#44;105&#44;106</span></a> The recommended prescription is shown in <a class="elsevierStyleCrossRef" href="#tbl3">Table 3</a>&#46; Viscous formulae are being developed to achieve longer contact of cysteamine with the ocular surface and be able to reduce the frequency of instillations with equal efficacy&#46;<a class="elsevierStyleCrossRefs" href="#bib1165"><span class="elsevierStyleSup">107&#44;108</span></a></p></span><span id="sec0165" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0235">Involvement of non-corneal structures</span><p id="par0370" class="elsevierStylePara elsevierViewall">Oral cysteamine is effective in the retina and other ocular structures&#46; The incidence of retinopathies has decreased with the systemic use of cysteamine&#46; The frequency and severity of non-corneal manifestations are directly related to compliance with oral cysteamine treatment&#44; and the risk of important vision loss may arise if systemic treatment is not correctly followed&#46;<a class="elsevierStyleCrossRefs" href="#bib0825"><span class="elsevierStyleSup">39&#44;109</span></a></p></span><span id="sec0170" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0240">Compliance with specific cysteamine treatment</span><p id="par0375" class="elsevierStylePara elsevierViewall">The World Health Organization &#40;WHO&#41; defines compliance as the degree to which patient behaviour follows the recommendations of medical professionals&#46;<a class="elsevierStyleCrossRef" href="#bib1180"><span class="elsevierStyleSup">110</span></a></p><p id="par0560" class="elsevierStylePara elsevierViewall">The impact of non-adherence in cystinosis results in poorer prognosis and faster progression of the renal and extrarenal disease in patients who are non-compliant compared with those who are&#46;<a class="elsevierStyleCrossRefs" href="#bib0655"><span class="elsevierStyleSup">5&#44;6&#44;97</span></a></p><p id="par0565" class="elsevierStylePara elsevierViewall">Information on adherence in patients with cystinosis is limited&#44; although monitoring WBC cystine levels is able to detect non-compliant patients&#46;<a class="elsevierStyleCrossRefs" href="#bib1015"><span class="elsevierStyleSup">77&#44;79</span></a> Other studies have confirmed adequate adherence to Cystagon<span class="elsevierStyleSup">&#174;</span> in children patients which wanes significantly in adolescents and adults&#46;<a class="elsevierStyleCrossRefs" href="#bib0665"><span class="elsevierStyleSup">7&#44;8</span></a> Nonetheless&#44; in groups of highly motivated patients&#44; only 8&#37; had compliance problems&#46;<a class="elsevierStyleCrossRef" href="#bib1185"><span class="elsevierStyleSup">111</span></a></p><p id="par0570" class="elsevierStylePara elsevierViewall">In cystinosis&#44; risk factors for non-compliance with cysteamine therapy include&#58; dosage schedules&#44; problems with tolerance&#44; side effects and the requirements of several medications for the control of the clinical manifestations of the disease&#46; Moreover&#44; other risk factors which are not exclusive to cystinosis are&#58; limited knowledge of the disease&#44; lack of motivation&#44; inadequate transition of patients to adult care units and impact of the disease on quality of life&#46;<a class="elsevierStyleCrossRefs" href="#bib0665"><span class="elsevierStyleSup">7&#44;9&#44;10</span></a></p><p id="par0575" class="elsevierStylePara elsevierViewall">Nevertheless&#44; suboptimal treatment compliance is not a phenomenon restricted to cystinosis&#46; Recent studies report that 52 to 67&#37; of adult kidney transplant recipients do not correctly follow prescribed immunosuppressant treatment&#44; which increases the probability of graft loss&#46;<a class="elsevierStyleCrossRefs" href="#bib1190"><span class="elsevierStyleSup">112&#44;113</span></a> These percentages are similar to those published in patients with cystinosis in our population&#44;<a class="elsevierStyleCrossRef" href="#bib0665"><span class="elsevierStyleSup">7</span></a> which may indicate the coexistence of scenarios in common with CKD&#46; Therefore&#44; in order to improve adherence in cystinotic patients&#44; the recommended strategy is to correct risk factors for non-compliance and promote patient self-care&#44; similar to the strategies used successfully in adult kidney transplant recipients<a class="elsevierStyleCrossRefs" href="#bib1200"><span class="elsevierStyleSup">114&#8211;119</span></a> &#40;<a class="elsevierStyleCrossRef" href="#tbl0035">Table 4</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0035"></elsevierMultimedia></span></span></span><span id="sec0175" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0245">Recommendations for the follow-up and treatment of patients with cystinosis</span><p id="par0580" class="elsevierStylePara elsevierViewall">T-CiS&#46;bcn group members&#44; after an exhaustive review of medical literature and based on our clinical practice with patients&#44; have stablished recommendations for the multidisciplinary care and connected transition from paediatric to adult-care units in cystinosis&#46; Our aim was to provide support tools and medical advice to health care professionals involved and interested in the care of cystinosis&#46;</p><p id="par0585" class="elsevierStylePara elsevierViewall">These recommendations are presented in <a class="elsevierStyleCrossRefs" href="#tbl0035">Tables 4&#8211;8</a>&#46;</p><elsevierMultimedia ident="tbl0040"></elsevierMultimedia><elsevierMultimedia ident="tbl0045"></elsevierMultimedia><elsevierMultimedia ident="tbl0050"></elsevierMultimedia><elsevierMultimedia ident="tbl0055"></elsevierMultimedia></span><span id="sec0180" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0250">Conflict of interest</span><p id="par0400" class="elsevierStylePara elsevierViewall">The authors have no conflicts of interest to declare&#46;</p></span></span>"
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            0 => "Cystinosis"
            1 => "Cysteamine"
            2 => "Fanconi syndrome"
            3 => "White blood cell &#40;WBC&#41; cystine levels"
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            0 => "Cistinosis"
            1 => "Cisteamina"
            2 => "S&#237;ndrome de Fanconi"
            3 => "Cistina intraleucocitaria"
            4 => "Transici&#243;n"
            5 => "Adherencia"
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        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Introduction</span><p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">Cystinosis is a rare systemic lysosomal storage disease that mainly affects the kidney and the eye&#46; Renal replacement therapy is started in patients with cystinosis during the first decade of life in the absence of treatment&#46; The prognosis of cystinosis depends on early diagnosis and the prompt start of and good compliance with cysteamine treatment&#46; Kidney disease progression&#44; extra-renal complications and shorter life expectancy are more pronounced in patients who do not adhere to treatment&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Objective</span><p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">The aim of this work was to establish recommendations for the comprehensive care of cystinosis and facilitate patient transition from paediatric to adult medicine&#44; based on clinical experience&#46; The goal is to reduce the impact of the disease and improve prognosis and patient quality of life&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Methods</span><p id="spar0075" class="elsevierStyleSimplePara elsevierViewall">Bibliographic research and consensus meetings with a multidisciplinary professional team of clinical experts in cystinosis &#40;T-CiS&#46;bcn group&#41; from 5 hospitals in Barcelona&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Results</span><p id="spar0080" class="elsevierStyleSimplePara elsevierViewall">This consensus document gathers specific recommendations for the diagnosis&#44; treatment and multidisciplinary care of cystinotic patients in the following areas&#58; nephrology&#44; dialysis&#44; kidney transplantation&#44; ophthalmology&#44; endocrinology&#44; neurology&#44; laboratory&#44; genetic counselling&#44; nursing and pharmacy&#46;</p></span> <span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Conclusions</span><p id="spar0085" class="elsevierStyleSimplePara elsevierViewall">Guidelines for the comprehensive care of cystinosis provide a support tool for health professionals who look after these patients&#46; They are based on the following main pillars&#58; &#40;a&#41; a multidisciplinary approach&#59; &#40;b&#41; appropriate disease monitoring and control of white blood cell &#40;WBC&#41; cystine levels&#59; &#40;c&#41; the importance of adherence to cysteamine treatment&#59; and &#40;d&#41; the promotion of patient self-care by means of disease education programmes&#46; All these recommendations will lead us&#44; in a second phase&#44; to create a coordinated model of transition from paediatric to adult care services which will cover the specific needs of cystinosis&#46;</p></span>"
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        "resumen" => "<span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Introducci&#243;n</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">La cistinosis es una enfermedad lisosomal minoritaria de expresi&#243;n sist&#233;mica con especial afectaci&#243;n renal y oftalmol&#243;gica&#44; en la que los pacientes inician terapia renal sustitutiva en la primera d&#233;cada de la vida en ausencia de tratamiento&#46; El pron&#243;stico de la cistinosis depende del diagn&#243;stico precoz&#44; la pronta instauraci&#243;n del tratamiento con cisteamina y el buen cumplimiento terap&#233;utico&#46; La progresi&#243;n de la enfermedad renal y de las complicaciones extrarrenales y una menor supervivencia&#44; son m&#225;s acentuadas en pacientes no adherentes&#46;</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Objetivo</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">El objetivo de este trabajo fue la elaboraci&#243;n de unas recomendaciones para la atenci&#243;n integral de la cistinosis y la transici&#243;n del adolescente a la medicina del adulto&#44; basadas en la experiencia cl&#237;nica&#44; con el fin de reducir el impacto de la enfermedad y mejorar la calidad de vida y el pron&#243;stico del paciente&#46;</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">M&#233;todo</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">B&#250;squeda bibliogr&#225;fica y reuniones de consenso de un equipo multidisciplinar de expertos en la pr&#225;ctica cl&#237;nica con pacientes afectos de cistinosis &#40;Grupo T-CiS&#46;bcn&#41;&#44; procedentes de 5 hospitales localizados en Barcelona&#46;</p></span> <span id="abst0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Resultados</span><p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">El documento recoge recomendaciones espec&#237;ficas y necesarias para el diagn&#243;stico&#44; tratamiento y seguimiento multidisciplinar de la cistinosis en las siguientes &#225;reas&#58; nefrolog&#237;a&#44; di&#225;lisis&#44; trasplante renal&#44; oftalmolog&#237;a&#44; endocrinolog&#237;a&#44; neurolog&#237;a&#44; laboratorio&#44; consejo gen&#233;tico&#44; enfermer&#237;a y farmacia&#46;</p></span> <span id="abst0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Conclusiones</span><p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Disponer de un documento de referencia para la atenci&#243;n integral de la cistinosis constituye una herramienta de soporte para los profesionales de la salud que asisten a estos pacientes&#46; Los principales pilares en los que se sustenta son&#58; a&#41; el enfoque multidisciplinar&#44; b&#41; la adecuada monitorizaci&#243;n de la enfermedad y control de los niveles de cistina intraleucocitarios&#44; c&#41; la importancia de la adherencia al tratamiento con cisteamina y d&#41; la promoci&#243;n del autocuidado del paciente mediante programas de educaci&#243;n en la enfermedad&#46; Todo ello conducir&#225;&#44; en una segunda fase&#44; a la elaboraci&#243;n de un modelo de transici&#243;n coordinado entre los servicios de pediatr&#237;a y de adultos que contemple las necesidades espec&#237;ficas de la cistinosis&#46;</p></span>"
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        "nota" => "<p class="elsevierStyleNotepara" id="npar0010">Please cite this article as&#58; Ariceta G&#44; Camacho JA&#44; Fern&#225;ndez-Obispo M&#44; Fern&#225;ndez-Polo A&#44; Gamez J&#44; Garc&#237;a-Villoria J&#44; et al&#46; Cistinosis en pacientes adolescentes y adultos&#58; recomendaciones para la atenci&#243;n integralde la cistinosis&#46; Nefrologia&#46; 2015&#59;35&#58;304&#8211;321&#46;</p>"
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            "etiqueta" => "ANNEX 1&#46;a"
            "titulo" => "Supplements&#44; drugs and pharmaceutical formulations prescribed in cystinosis"
            "identificador" => "sec0210"
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            "etiqueta" => "Annex 1&#46;b"
            "titulo" => "Supplements&#44; drugs and pharmaceutical formulations prescribed in cystinosis"
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          "en" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Clinical manifestations of cystinosis in patients not treated with cysteamine&#46; CKD&#58; chronic kidney disease&#44; ESRD&#58; end stage renal disease&#44; RRT&#58; renal replacement therapy&#46;</p>"
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                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Therapeutic aims&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Treatment&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " rowspan="2" align="left" valign="top">Preserve water balance by replacing losses</td><td class="td" title="table-entry  " align="left" valign="top">Replace water loss according to need &#40;between 1&#46;5 and 6<span class="elsevierStyleHsp" style=""></span>L&#47;day&#41;&#44; either orally or by nasogastric tube or gastrostomy&#44; if needed&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Reduce polyuria&#58; oral indomethacin &#40;1&#8211;3<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;day&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " rowspan="3" align="left" valign="top">Preserve electrolyte balance by replacing losses</td><td class="td" title="table-entry  " align="left" valign="top">Potassium &#40;between 2 and 10<span class="elsevierStyleHsp" style=""></span>mEq&#47;kg&#47;day&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">ClNa &#40;1&#8211;2<span class="elsevierStyleHsp" style=""></span>mEq&#47;kg&#47;day&#44; with progressive increase in dosage&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Phosphorus &#40;between 1 and 4<span class="elsevierStyleHsp" style=""></span>g&#47;day&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="middle">Neutralise acidosis &#40;maintain normal blood pH and serum bicarbonate between 22 and 24<span class="elsevierStyleHsp" style=""></span>mEq&#47;L&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Bicarbonate or citrate at an initial dose of 1&#8211;2<span class="elsevierStyleHsp" style=""></span>mEq&#47;kg&#47;day&#44; with progressive increase in dosage&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Nutritional support&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Nutritional assessment with appropriate caloric supplementation according to age and kidney function&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " rowspan="4" align="left" valign="top">Treatment of bone mineral disease</td><td class="td" title="table-entry  " align="left" valign="top">Cholecalciferol&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Calcium supplements&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Active vitamin D &#40;1 Alpha-vitamin D&#44; Calcitriol&#44; Paricalcitol&#44; others&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Growth hormone &#40;if indicated&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " rowspan="2" align="left" valign="top">Others</td><td class="td" title="table-entry  " align="left" valign="top">Carnitine<a class="elsevierStyleCrossRef" href="#bib0775"><span class="elsevierStyleSup">29</span></a> &#40;100<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;d&#237;a&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">ACEi&#47;ARB antiproteinuric agents &#40;assess tolerance&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
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          "en" => "<p id="spar0100" class="elsevierStyleSimplePara elsevierViewall">Symptomatic treatment of renal disease in cystinosis&#46;<a class="elsevierStyleCrossRefs" href="#bib0635"><span class="elsevierStyleSup">1&#44;24&#44;29&#44;31</span></a></p>"
        ]
      ]
      2 => array:7 [
        "identificador" => "tbl0030"
        "etiqueta" => "Table 2"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "tabla" => array:1 [
          "tablatextoimagen" => array:1 [
            0 => array:2 [
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                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " colspan="2" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Requirements for WBC cystine level monitoring<a class="elsevierStyleCrossRefs" href="#bib1015"><span class="elsevierStyleSup">77&#8211;79</span></a></th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " rowspan="5" align="left" valign="top"><span class="elsevierStyleItalic">Sampling conditions</span></td><td class="td" title="table-entry  " align="left" valign="top">No fasting required&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">In treated patients&#44; blood extraction should be made 6<span class="elsevierStyleHsp" style=""></span>h post-cysteamine dose&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Collect within lithium or sodium heparin tube&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Ship immediately to the laboratory&#58; it should be processed into 24 hours post-sampling&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Keep at room temperature&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " rowspan="2" align="left" valign="top"><span class="elsevierStyleItalic">Minimum volume</span></td><td class="td" title="table-entry  " align="left" valign="top">For patients &#60;10<span class="elsevierStyleHsp" style=""></span>kg body weight&#58; 6<span class="elsevierStyleHsp" style=""></span>mL blood&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">For patients &#8805;10<span class="elsevierStyleHsp" style=""></span>kg body weight&#58; 10<span class="elsevierStyleHsp" style=""></span>mL blood&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " rowspan="4" align="left" valign="top" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">RECOMMENDATIONS for monitoring WBC cystine levels</span></td><td class="td" title="table-entry  " align="left" valign="top">At the start of Cystagon&#174; treatment&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Monthly after dose adjustments&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Every 6 months in stable patients&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top" style="border-bottom: 2px solid black">Increase frequency in cases of significant clinical changes &#40;Transplantation and Dialysis&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleBold">Reference Laboratory in Spain</span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Hospital Cl&#237;nic de Barcelona</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Servicio de Bioqu&#237;mica y Gen&#233;tica Molecular&#46; Secci&#243;n de Errores Cong&#233;nitos del Metabolismo</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Dra&#46; Judit Garc&#237;a Villoria&#58; jugarcia&#64;clinic&#46;ub&#46;es</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Tfn&#46; 93 227 56 00 Ext&#46; 7585</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>C&#47; Mej&#237;a Lequerica s&#47;n&#46; Edificio Helios III&#46; Planta baja&#46; 08028 Barcelona&#44; Spain&#46;</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top" style="border-bottom: 2px solid black"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="center" valign="top" style="border-bottom: 2px solid black"><span class="elsevierStyleBold">Requirements for the molecular diagnosis of</span><span class="elsevierStyleItalic"><span class="elsevierStyleBold">CTNS</span></span><span class="elsevierStyleBold">gene</span><a class="elsevierStyleCrossRefs" href="#bib0690"><span class="elsevierStyleSup">12&#44;13&#44;15&#44;80</span></a></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleItalic"><span class="elsevierStyleBold">Genetic testing of patient and family</span></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " rowspan="2" align="left" valign="top">Sample</td><td class="td" title="table-entry  " align="left" valign="top">2&#8211;3<span class="elsevierStyleHsp" style=""></span>mL blood in EDTA at room temperature&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">DNA at room temperature&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleItalic"><span class="elsevierStyleBold">Prenatal testing</span></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Sample&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">DNA from cultured amniocytes or chorionic villi sampling&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Prior identification of the disease-causing mutations in parents and in index case</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Previous appointment with the laboratory is essential</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleBold">Reference Laboratory in Spain</span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Hospital Cl&#237;nic de Barcelona</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Servicio de Bioqu&#237;mica y Gen&#233;tica Molecular&#46; Secci&#243;n de Errores Cong&#233;nitos del Metabolismo</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Dra&#46; M&#170;Josep Coll&#58; mjcoll&#64;clinic&#46;ub&#46;es</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Tfn&#46; 93 227 9341</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>C&#47; Mej&#237;a Lequerica s&#47;n&#46; Edificio Helios III&#46; Planta baja&#46; 08028 Barcelona&#44; Spain&#46;</td></tr></tbody></table>
                  """
              ]
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                0 => "xTab942060.png"
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        "descripcion" => array:1 [
          "en" => "<p id="spar0110" class="elsevierStyleSimplePara elsevierViewall">Biochemical diagnosis and WBC cystine level monitoring&#46; Molecular diagnosis &#40;<span class="elsevierStyleInterRef" id="intr0005" href="http://www.orpha.net/">www&#46;orpha&#46;net</span>&#41;&#46;</p>"
        ]
      ]
      3 => array:7 [
        "identificador" => "tbl3"
        "etiqueta" => "Table 3"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "tabla" => array:1 [
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " colspan="3" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Oral Cysteamine &#8211; Cystagon&#174;<a class="elsevierStyleCrossRefs" href="#bib0785"><span class="elsevierStyleSup">31&#44;47&#44;92&#8211;94&#44;102</span></a></th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="left" valign="top"><span class="elsevierStyleItalic">Dosage</span></td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>By age&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="center" valign="top"><span class="elsevierStyleBold">Children &#8804;12 years</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="center" valign="top"><span class="elsevierStyleBold">Patients &#62;12 years</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Recommended dosage&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="center" valign="top"><span class="elsevierStyleBold">by body surface area</span> &#40;g&#47;m<span class="elsevierStyleSup">2</span>&#47;day&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="center" valign="top"><span class="elsevierStyleBold">if weight &#62; 50 Kg</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">&#40;Dosage should be divided 4 times daily&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="center" valign="top"><span class="elsevierStyleBold">1&#46;30</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleBold">g&#47;m</span><span class="elsevierStyleSup"><span class="elsevierStyleBold">2</span></span><span class="elsevierStyleBold">&#47;day</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="center" valign="top"><span class="elsevierStyleBold">2</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleBold">g&#47;day</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " rowspan="2" align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Starting dosage</td><td class="td" title="table-entry  " colspan="2" align="center" valign="top">1&#47;4 to 1&#47;6 of the recommended dosage</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="center" valign="top">Increase gradually over 4&#8211;6 weeks to avoid intolerance&#42;&#42;</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="middle"><span class="elsevierStyleHsp" style=""></span>Dosage adjustments&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " colspan="2" align="center" valign="top">Raise if adequate tolerance and WB C cystine level is greater than <span class="elsevierStyleBold">&#62; 1</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleBold">nmol &#189; cystine&#47;mg protein</span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " rowspan="2" align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleBold">Maximum dosage</span></td><td class="td" title="table-entry  " colspan="2" align="center" valign="top"><span class="elsevierStyleBold">1&#46;95</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleBold">g&#47;m</span><span class="elsevierStyleSup">2</span>&#47;day</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="center" valign="top"><span class="elsevierStyleItalic"><span class="elsevierStyleBold">Overdosing</span> is not recommended since it does not improve the prognosis and is associated with adverse effects</span><a class="elsevierStyleCrossRef" href="#bib0865"><span class="elsevierStyleSup">47</span></a></td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Renal insufficiency&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " colspan="2" align="center" valign="top">No dose adjustment required</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " rowspan="12" align="left" valign="top"><span class="elsevierStyleItalic">RECOMMENDATIONS for appropriate dosage</span></td><td class="td" title="table-entry  " colspan="2" align="center" valign="top">Treatment should be initiated under the supervision of a physician experienced in the treatment of cystinosis</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="center" valign="top"><span class="elsevierStyleBold">4 doses per day&#59; every 6 hours&#59; night dose included</span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="center" valign="top">Adjust the dose according to WBC cystine levels</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="center" valign="top">Hard capsules should not be administered to children under the age of 6 years owing to risk of aspiration</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="center" valign="top">If needed&#44; open the capsules and sprinkle the content on food</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="center" valign="top">Cysteamine powder could be mixed with milk&#44; potatoes and other starch-based products&#46; Avoid acidic drinks&#46;</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="center" valign="top">CYSTAGON&#174; should be restarted after renal transplant to prevent non-renal complications</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " rowspan="13" align="left" valign="top"><span class="elsevierStyleItalic">Side effects</span></td><td class="td" title="table-entry  " colspan="2" align="center" valign="top">Gastrointestinal disorders due to gastric acid hypersecretion</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="center" valign="top"><span class="elsevierStyleItalic">RECOMMENDATIONS for improving gastrointestinal tolerability&#58;</span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="center" valign="top"><span class="elsevierStyleItalic">Concomitant administration of proton pump inhibitors</span><a class="elsevierStyleCrossRef" href="#bib1140"><span class="elsevierStyleSup">102</span></a></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="center" valign="top"><span class="elsevierStyleItalic">Administer with meals or immediately afterwards&#46; Intake is recommended with food such as milk&#44; potatoes or other starchy foods</span><a class="elsevierStyleCrossRefs" href="#bib1090"><span class="elsevierStyleSup">92&#8211;94</span></a></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="center" valign="top">Characteristic body odour and halitosis</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="center" valign="top"><span class="elsevierStyleItalic">RECOMMENDATIONS for improving halitosis&#58; mentholated pills</span><a class="elsevierStyleCrossRef" href="#bib0785"><span class="elsevierStyleSup">31</span></a></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="center" valign="top">Other adverse reactions refer to SMPC<a class="elsevierStyleCrossRefs" href="#bib1090"><span class="elsevierStyleSup">92&#8211;94</span></a></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " rowspan="3" align="left" valign="top"><span class="elsevierStyleItalic">Drug interactions</span></td><td class="td" title="table-entry  " colspan="2" align="center" valign="top">No interaction studies have been conducted</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="center" valign="top">Can be administered in conjunction with electrolytic or mineral supplements&#44; vitamin D analogues&#44; tyrosine or immunosuppressive drugs</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="left" valign="top" style="border-bottom: 2px solid black"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="center" valign="top" style="border-bottom: 2px solid black"><span class="elsevierStyleBold">Cysteamine eye drops</span><a class="elsevierStyleCrossRefs" href="#bib0815"><span class="elsevierStyleSup">37&#8211;39&#44;105&#8211;109</span></a></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Eye drops&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " colspan="2" align="center" valign="top">0&#46;55&#37; cysteamine solution <span class="elsevierStyleItalic">&#40;see Annex 1&#41;</span></td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Dose&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " colspan="2" align="center" valign="top"><span class="elsevierStyleBold">1 drop&#47;eye</span></td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Dosage&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " colspan="2" align="center" valign="top"><span class="elsevierStyleBold">10&#8211;12 instillations&#47;day</span></td></tr></tbody></table>
                  """
              ]
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                0 => "xTab942054.png"
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        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0115" class="elsevierStyleSimplePara elsevierViewall">Specific treatment with cysteamine&#46;</p>"
        ]
      ]
      4 => array:7 [
        "identificador" => "tbl0035"
        "etiqueta" => "Table 4"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "tabla" => array:1 [
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">Identify risk factors that affect adherence and apply corrective measures when possible&#58;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Intrinsic patient and socio-economic factors&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Disease-related factors&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Treatment-related factors&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Healthcare system organisation barriers&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">Identify and assign a &#8220;Patient health Coordinator&#8221;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">Promote patient education and treatment support&#58;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Implement disease education programmes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Establish treatment programmes&#58; easy to follow with support measures for compliance&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Use questionnaires to detect non-compliance&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Follow-up of appointments and absences&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">Develop patient support programmes involving family members&#44; friends and patient associations</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">Create a multidisciplinary medical team</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">Implement protocols for transition to adult care</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
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                0 => "xTab942051.png"
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        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0120" class="elsevierStyleSimplePara elsevierViewall">Recommendations for improving treatment compliance&#46;<a class="elsevierStyleCrossRefs" href="#bib0665"><span class="elsevierStyleSup">7&#44;9&#44;10&#44;114&#8211;119</span></a></p>"
        ]
      ]
      5 => array:7 [
        "identificador" => "tbl0040"
        "etiqueta" => "Table 5"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "tabla" => array:2 [
          "leyenda" => "<p id="spar0130" class="elsevierStyleSimplePara elsevierViewall">In any clinical situation&#44; it is necessary to administer specific cystinosis treatment with oral cysteamine to maintain recommended WBC cystine levels &#60;1<span class="elsevierStyleHsp" style=""></span>nmol hemicystine&#47;mg protein and cysteamine eye drops to eliminate corneal deposits &#40;see <a class="elsevierStyleCrossRef" href="#tbl3">Table 3</a>&#41;&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Recommendations for dialysis<a class="elsevierStyleCrossRefs" href="#bib0660"><span class="elsevierStyleSup">6&#44;103</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Promote preventive KTx as an initial method of RRT in patients with advanced CKD&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Monitor residual urine volume and urinary saline loss to adapt the dialysis prescription and avoid excessive ultrafiltration&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Maintain the general treatment of Fanconi syndrome and adapt the diet in an individual manner&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Carefully monitor extrarenal involvement on a multidisciplinary basis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Oral and ophthalmological cysteamine treatment must be maintained&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top" style="border-bottom: 2px solid black">Cysteamine dosage should not be adjusted to glomerular filtration rate &#40;see Specific Treatment with Cysteamine section&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="center" valign="top" style="border-bottom: 2px solid black">Recommendations for kidney transplantation<a class="elsevierStyleCrossRefs" href="#bib0650"><span class="elsevierStyleSup">4&#8211;6&#44;33&#44;88&#8211;90</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">Prior to waiting list inclusion</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Promote preventive kidney transplantation when the glomerular filtrate &#8804;20<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#47;1&#46;73 m<span class="elsevierStyleSup">2</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Living or deceased donor&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Evaluate the associated Fanconi syndrome &#40;residual diuresis &#8211; can be very high &#8211; saline loss&#44; rickets&#44; tubular acidosis&#44; carnitine deficiency&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Monitor WBC cystine levels and optimise treatment with cysteamine &#40;oral and ophthalmological&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Assess possible systemic involvement and its impact on the transplant &#40;hypothyroidism&#44; diabetes&#44; cardiovascular disease&#44; bone disease&#44; swallowing disorders&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Prescribe fluids and individualised diet&#46; Assess phosphate&#44; potassium&#44; bicarbonate and carnitine supplement requirements&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">Pre-transplant and peri-transplant</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Avoid volume depletion before and during surgery &#40;intensive endovenous fluid therapy to guarantee normovolaemia&#44; including potassium and bicarbonate supplements&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Immunosuppression according to hospital protocol&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Temporary suspension of cysteamine treatment&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">Immediately post-transplant</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Administer fluid therapy and sufficient electrolytes to maintain adequate water&#47;electrolyte balance and good control of residual Fanconi syndrome&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Monitor the possible appearance of diabetes&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Immunosuppression therapy according to hospital protocol&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">Continued post-transplant care</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Reintroduce cysteamine once the patient and graft are stable&#44; approximately 3&#8211;4 weeks post-transplantation&#44; at increasing doses up to therapeutic doses&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Monitor WBC cystine levels&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Immunosuppression following hospital protocol&#59; promote reduction in and&#47;or suspension of corticosteroids&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Controls and follow-up in accordance with recommendations and clinical guidelines&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Maintain ophthalmological treatment with cysteamine and stimulate treatment compliance&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Assess possible systemic involvement and its impact on transplantation&#46; Promote and standardise a multidisciplinary health care plan for cystinosis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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        "descripcion" => array:1 [
          "en" => "<p id="spar0125" class="elsevierStyleSimplePara elsevierViewall">Recommendations for follow-up of patients on renal replacement therapy &#40;RRT&#41;&#58; dialysis &#40;D&#41; and transplantation &#40;TxR&#41;&#46;</p>"
        ]
      ]
      6 => array:7 [
        "identificador" => "tbl0045"
        "etiqueta" => "Table 6"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "tabla" => array:3 [
          "leyenda" => "<p id="spar0145" class="elsevierStyleSimplePara elsevierViewall">ERG&#58; electroretinogram&#59; GH&#58; growth hormone&#59; VA&#58; visual acuity&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Test&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Ocular structure&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Frequency&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Observations&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Slit lamp biomicroscopy&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Study of the cornea and rest of anterior segment&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Annual&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Intraocular pressure measurement&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Rule out ocular hypertension&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Annual&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " rowspan="2" align="left" valign="top">Dilated fundus examination</td><td class="td" title="table-entry  " rowspan="2" align="left" valign="top">Assess optic disc and retinal pigmentation</td><td class="td" title="table-entry  " align="left" valign="top">Annual&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " rowspan="2" align="left" valign="top">Urgent&#58; if the patient reports severe loss of VA &#40;uncommon&#41;</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">In patients with GH&#44; do a baseline assessment and after 4 months to detect intracranial hypertension<a class="elsevierStyleCrossRef" href="#bib1230"><span class="elsevierStyleSup">120</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Photopic and scotopic ERG&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Functionality of rods and cones&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Only if patient reports altered night vision or abnormal retinal examination&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="4" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " rowspan="3" align="left" valign="top" style="border-bottom: 2px solid black">Equipment</td><td class="td" title="table-entry  " colspan="3" align="left" valign="top">Slit lamp<a class="elsevierStyleCrossRef" href="#tblfn0045"><span class="elsevierStyleSup">&#42;</span></a></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="left" valign="top">Tonometer</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="left" valign="top" style="border-bottom: 2px solid black">Indirect ophthalmoscope</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="4" align="left" valign="top">In any clinical situation&#44; specific cystinosis treatment is required with oral cysteamine to maintain recommended WBC cystine levels &#60;1<span class="elsevierStyleHsp" style=""></span>nmol hemicystine&#47;mg protein and cysteamine eye drops to eliminate corneal deposits &#40;See <a class="elsevierStyleCrossRef" href="#tbl3">Table 3</a>&#41;&#46;</td></tr></tbody></table>
                  """
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              "identificador" => "tblfn0045"
              "etiqueta" => "&#42;"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Very sensitive for diagnosing cystine crystals in the cornea&#44; but less useful for patient follow-up since the quantification of crystals is rather subjective&#46; It is therefore interesting to record detailed data at each examination on the distribution of crystals in the cornea&#44; specifying whether the deposition is only peripheral or diffuse and whether they are located in the epithelium&#44; stroma and&#47;or endothelium&#46;</p>"
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          "en" => "<p id="spar0135" class="elsevierStyleSimplePara elsevierViewall">Recommendations for ophthalmological follow-up&#46;<a class="elsevierStyleCrossRefs" href="#bib0650"><span class="elsevierStyleSup">4&#44;37&#8211;39&#44;105&#8211;109&#44;120</span></a></p>"
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        "etiqueta" => "Table 7"
        "tipo" => "MULTIMEDIATABLA"
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        "tabla" => array:2 [
          "leyenda" => "<p id="spar0180" class="elsevierStyleSimplePara elsevierViewall">25OHD3&#58; 25-hydroxycholecalciferol &#40;calcifediol&#41;&#59; FSH&#58; follicle-stimulating hormone&#59; GH&#58; growth hormone&#59; HbA1c&#58; glycated haemoglobin&#59; IGF-1&#58; insulin-like growth factor 1&#59; IGFBP3&#58; insulin-like growth factor-binding protein 3&#59; LH&#58; luteinising hormone&#59; PTH&#58; parathyroid hormone&#59; rGH&#58; recombinant growth hormone&#59; SHBG&#58; sex hormone-binding globulin&#59; T&#58; testosterone&#59; T4&#58; free thyroxine&#59; TG&#58; triglycerides&#59; TSH&#58; thyroid-stimulating hormone&#46;</p>"
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                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Disorder&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Complementary studies&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Frequency&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Treatment&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Observations&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " rowspan="2" align="left" valign="top">Hypothyroidism</td><td class="td" title="table-entry  " align="left" valign="top">TSH&#44; T4L&#44; Anti-thyroid Ab&#47;Imaging study not necessary&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">At diagnosis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " rowspan="2" align="left" valign="top">Levothyroxine</td><td class="td" title="table-entry  " rowspan="2" align="left" valign="top">Initiate treatment when TSH &#62; 10 mIU&#47;L&#47;if there are symptoms&#44; consider initiating with TSH&#44; 5&#8211;10 mIU&#47;L</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">TSH&#44; T4L&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Routine follow-up&#58; Quarterly for dosage adjustments&#47;annual&#44; if TSH is normal&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="5" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " rowspan="7" align="left" valign="top">Diabetes Mellitus</td><td class="td" title="table-entry  " align="left" valign="top">Glycaemia&#44; HbA1c &#40;optional&#58; c-peptide&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Diagnosis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " rowspan="3" align="left" valign="top">Insulin</td><td class="td" title="table-entry  " rowspan="7" align="left" valign="top">If pancreatic reserve is sufficient&#44; consider single daily dose of slow-release insulin</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">If symptoms of polyuria-polydypsia&#58; laboratory tests with ionogram&#44; venous blood gases and ketonuria&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Glycaemia&#44; HbA1c&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Quarterly or biannual follow-up&#44; according to clinical criteria&#47;annual&#44; if no symptoms&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Lipid profile&#58; total cholesterol&#44; LDL&#44; HDL and TG&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Annual&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Dyslipidaemia treatment&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Funduscopy&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Annual&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">According to ophthalmologist criteria&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Pain and vibration sensitivity&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Annual&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Education to prevent lesions&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Examination feet and pulse&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Annual&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="5" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " rowspan="12" align="left" valign="top">Impaired longitudinal growth</td><td class="td" title="table-entry  " align="left" valign="top">Nutritional assessment&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">According to clinical criteria&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Optimise nutrition&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Consider supplements and referral to nutritionist&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Height and weight&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">At each visit&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Until bone maturity&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">See Fanconi syndrom section&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Treatment of Fanconi syndrome&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Bone age&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Diagnosis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">r-GH&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " rowspan="3" align="left" valign="top">In pubescent patients&#44; rule out hypogonadism&#47;in transplant recipients&#44; consider withdrawal or reduction of corticosteroids</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">GH&#44; IGF-1&#44; IGFBP-3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">If no kidney failure&#58; GH secretion studies&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Bone age&#44; IGF-1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Annual follow-up&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Funduscopy&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Before initiating GH and after 3&#8211;4 months under treatment&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Intracranial hypertension secondary to GH usually occurs at the start of treatment &#40;mean&#58; 3&#8211;4 months&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Urgent if headache or reduced vision&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Calcium&#44; phosphorus&#44; alkaline phosphatase&#44; 25OH&#183;D3&#44; PTH&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Annual&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Vitamin D&#44; if deficiency&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Rule out rickets and vitamin D nutritional deficiency&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Calcitriol&#44; if kidney failure&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Bone mineral density&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">In adulthood&#59; to be assessed according to results&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">If there is osteoporosis&#44; consider specific treatment&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="5" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " rowspan="3" align="left" valign="top">Hypogonadism</td><td class="td" title="table-entry  " align="left" valign="top">Physical exam&#58; sexual maturation and secondary sexual characteristics&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">At each visit&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">During puberty period until complete maturity&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Testosterone&#44; SHBG&#44; LH&#44; FSH<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>assessment of thyroid function &#40;see above&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Diagnosis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Daily testosterone replacement therapy &#40;TRT&#41;&#58; Topical &#40;if panic to injections&#41;&#44; or IM &#40;if compliance problems&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">If low testosterone with normal LH and FSH levels&#58; MRI of pituitary&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">T&#44; LH&#44; FSH&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Annual follow-up&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="5" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " rowspan="2" align="left" valign="top" style="border-bottom: 2px solid black">Fertility</td><td class="td" title="table-entry  " align="left" valign="top">Semen analysis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Diagnosis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Infertility is a constant feature in affected males&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top" style="border-bottom: 2px solid black">Consider high-risk pregnancy&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top" style="border-bottom: 2px solid black">Suspend oral cysteamine during gestation&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="5" align="left" valign="top">In any clinical situation&#44; specific cystinosis treatment is required with oral cysteamine treatment to maintain recommended WBC cystine levels &#60;1<span class="elsevierStyleHsp" style=""></span>nmol hemicystine&#47;mg protein and topical cysteamine to eliminate corneal deposits&#46;</td></tr></tbody></table>
                  """
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          "en" => "<p id="spar0150" class="elsevierStyleSimplePara elsevierViewall">Recommendations for the follow-up and treatment of endocrine system involvement&#46;<a class="elsevierStyleCrossRefs" href="#bib0650"><span class="elsevierStyleSup">4&#44;5&#44;32&#44;48&#44;49&#44;121</span></a></p>"
        ]
      ]
      8 => array:7 [
        "identificador" => "tbl0055"
        "etiqueta" => "Table 8"
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        "tabla" => array:2 [
          "leyenda" => "<p id="spar0175" class="elsevierStyleSimplePara elsevierViewall">MRI&#58; magnetic resonance imaging&#44; CPAP&#58; Continuous Positive Airway Pressure&#44; BIPAP&#58; biphasic positive airway pressure&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Disorder&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Evaluation&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Complementary studies&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Frequency&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Treatment&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Observations&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " rowspan="5" align="left" valign="top">Motor functions of the skeletal muscles<a class="elsevierStyleCrossRefs" href="#bib0650"><span class="elsevierStyleSup">4&#44;52&#44;53</span></a></td><td class="td" title="table-entry  " align="left" valign="top">Degree of muscle atrophy&#47;disease progression&#47;degree of disability&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">MRC scale&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Annual&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Rehabilitation&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Use validate instruments&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Quantitative determinations of hand muscle strength &#40;Jamar dynamometer&#44; Martin vigorimeter and Jamar Hydraulic Pinch Gauge&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Annual&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Electromyography&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">According to clinical criteria&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Muscle MRI&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">According to clinical criteria&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Muscle biopsy&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">According to clinical criteria&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="6" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " rowspan="2" align="left" valign="top">Orofacial motor function &#40;language&#41; and swallowing<a class="elsevierStyleCrossRefs" href="#bib0920"><span class="elsevierStyleSup">58&#44;122&#44;123</span></a></td><td class="td" title="table-entry  " align="left" valign="top">Facial and bulbar muscles&#58; strength and range of movement of lips&#44; tongue&#44; soft palate&#44; jaw and facial muscles in phonation&#44; articulation&#44; swallowing&#44; breathing and expressions&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Focused physical examination&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Annual&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Reeducation if early signs of dysphagia are detected to prevent bronchoaspirates&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Video fluoroscopy&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">According to clinical criteria&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Objective&#58; to asses different phases of swallowing and movement of food bolus within the oral cavity and its passage through the esophagus&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="6" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " rowspan="3" align="left" valign="top">Respiratory muscle function<a class="elsevierStyleCrossRef" href="#bib1250"><span class="elsevierStyleSup">124</span></a></td><td class="td" title="table-entry  " align="left" valign="top">Presence of dyspnoea&#44; apnoea and&#47;or snoring during sleep&#44; morning headaches&#44; daytime hypersomnia&#44; decreased coughing capacity or increased anomalies in expectoration&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Spirometry&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Annual&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Symptomatic respiratory physiotherapy&#44; ventilatory support &#40;CPAP&#47;BIPAP&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Especially in patients with swallowing disorders&#44; risk of bronchoaspirtion or who present symptoms of neuromuscular respiratory insufficiency&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Oxygen saturation Arterial blood gas&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Annual&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Polysomnography&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Annual&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="6" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Central nervous system<a class="elsevierStyleCrossRefs" href="#bib0900"><span class="elsevierStyleSup">54&#8211;57&#44;59&#8211;68&#44;125&#44;126</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Signs of involvement &#40;headache&#44; episodes of unconsciousness&#44; poor school performance&#44; decline in cognitive functions&#44; behavioural alterations&#44; etc&#46;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Focused physical examinationNeurophysiological studiesNeuroimaging&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">AnnualAccording to clinical criteriaAccording to clinical criteria&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Directed at underlying disorder&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Complementary tests if anomalies are detected&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="6" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top" style="border-bottom: 2px solid black">Neurocognitive alterations<a class="elsevierStyleCrossRefs" href="#bib0975"><span class="elsevierStyleSup">69&#8211;73</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top" style="border-bottom: 2px solid black">Neuropsychological examination&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top" style="border-bottom: 2px solid black">Specific evaluation questionnaires for overall cognitive performance&#44; attention and executive functions&#44; language&#44; memory&#59; perceptive&#44; visuospatial and visuoconstructive functions&#59; voluntary cognitive motor control&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top" style="border-bottom: 2px solid black">Annual&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top" style="border-bottom: 2px solid black">Directed to underlying disorder&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top" style="border-bottom: 2px solid black">Adapted to patient&#39;s age &#40;school children and adults&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="6" align="left" valign="top">In any clinical situation&#44; specific cystinosis treatment is required with oral cysteamine treatment to maintain recommended WBC cystine levels &#60;1<span class="elsevierStyleHsp" style=""></span>nmol hemicystine&#47;mg protein and topical cysteamine to eliminate corneal deposits&#46;</td></tr></tbody></table>
                  """
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          "en" => "<p id="spar0165" class="elsevierStyleSimplePara elsevierViewall">Recommendations for the follow-up and treatment of neurological involvement&#46;<a class="elsevierStyleCrossRefs" href="#bib0650"><span class="elsevierStyleSup">4&#44;52&#8211;73&#44;122&#8211;126</span></a></p>"
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          "leyenda" => "<p id="spar0095" class="elsevierStyleSimplePara elsevierViewall">cap&#46;&#58; capsules&#44; &#42;&#58; magistral formulation&#46;</p>"
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            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Drug&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Brand name&#47;Product&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Content&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="center" valign="top" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic"><span class="elsevierStyleBold">Alkaline supplements</span></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " rowspan="6" align="left" valign="top">Sodium bicarbonate</td><td class="td" title="table-entry  " align="left" valign="top">Sodium bicarbonate Torres Mu&#241;oz 500mg &#40;30 cap&#46;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">500 mg&#47;comp&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Sodium bicarbonate Torres Mu&#241;oz 60 g&#59; 200 g&#59; 750 g &#40;powder&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Sodium bicarbonate Serra 180 g &#40;powder&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Sodium bicarbonate Viviar 210 g&#59; 250 g&#59; 500 g &#40;powder&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Sodium bicarbonate NM 1 g&#59; 2 g &#40;sachet&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1<span class="elsevierStyleHsp" style=""></span>g&#47;sachet&#59; 2<span class="elsevierStyleHsp" style=""></span>g&#47;sachet&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">&#42;Sodium bicarbonate 1M &#40;8&#44;4&#37;&#41; soluci&#243;n oral&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1<span class="elsevierStyleHsp" style=""></span>mEq&#47;mL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Sodium citrate&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#42;Bicitra oral solution&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1<span class="elsevierStyleHsp" style=""></span>mEq Bicarbonate&#47;mL&#59; 1<span class="elsevierStyleHsp" style=""></span>mEq Na&#47;mL&#59; 0&#46;5<span class="elsevierStyleHsp" style=""></span>mmol<span class="elsevierStyleHsp" style=""></span>citrate&#47;mL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " rowspan="2" align="left" valign="top" style="border-bottom: 2px solid black">Potassium citrate</td><td class="td" title="table-entry  " align="left" valign="top">&#42;Polycitra oral solution&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2<span class="elsevierStyleHsp" style=""></span>mEq Bicarbonate&#59; 1<span class="elsevierStyleHsp" style=""></span>mEq Na&#47;mL&#59; 1<span class="elsevierStyleHsp" style=""></span>mEq K&#47;mL&#59; 1<span class="elsevierStyleHsp" style=""></span>mmol<span class="elsevierStyleHsp" style=""></span>Citrate&#47;mL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top" style="border-bottom: 2px solid black">&#42;Polycitra LC with phosphrous-oral solution&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top" style="border-bottom: 2px solid black">2<span class="elsevierStyleHsp" style=""></span>mEq Bicarbonate&#59; 1<span class="elsevierStyleHsp" style=""></span>mEq Na&#47;mL&#59; 1<span class="elsevierStyleHsp" style=""></span>mEq K&#47;mL&#59; 1<span class="elsevierStyleHsp" style=""></span>mmol<span class="elsevierStyleHsp" style=""></span>Citrate&#47;mL&#59; 0&#46;6<span class="elsevierStyleHsp" style=""></span>mmol<span class="elsevierStyleHsp" style=""></span>P&#47;mL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="center" valign="top" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic"><span class="elsevierStyleBold">Potassium supplements</span></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Potassium ascorbate&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Boi-K &#40;20 effervescents tablets&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1<span class="elsevierStyleHsp" style=""></span>mEq K&#47;tablet&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Bok-K Asp&#225;rtico &#40;20 effervescents tablets&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">25<span class="elsevierStyleHsp" style=""></span>mEq K&#47;tablet&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Potassium chloride&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Potasion 600 mg &#40;60 cap&#46;s&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">8<span class="elsevierStyleHsp" style=""></span>mEq K&#47;tablet&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top" style="border-bottom: 2px solid black">Potassium glucoheptonate&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top" style="border-bottom: 2px solid black">Potasion 1&#44;32 g&#47;5 mL &#40;125 mL&#59; 250 mL&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top" style="border-bottom: 2px solid black">1<span class="elsevierStyleHsp" style=""></span>mEq K&#47;mL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="center" valign="top" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic"><span class="elsevierStyleBold">Phosphorus supplements</span></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " rowspan="4" align="left" valign="top" style="border-bottom: 2px solid black">Sodium Phosphate</td><td class="td" title="table-entry  " align="left" valign="top">&#42;Phosphorus oral solution or Joulie Solution&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1<span class="elsevierStyleHsp" style=""></span>mmol P&#47;ml &#40;30&#46;9<span class="elsevierStyleHsp" style=""></span>mg P&#47;ml&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Phosphate Sandoz 500mg &#40;100 cap&#46;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">16&#46;1<span class="elsevierStyleHsp" style=""></span>mmol P&#47;comp &#40;500<span class="elsevierStyleHsp" style=""></span>mg P&#47;comp&#46;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Sodium Phosphate monobase NM &#40;100 sachets&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">26<span class="elsevierStyleHsp" style=""></span>mmol P&#47;sobre &#40;800<span class="elsevierStyleHsp" style=""></span>mg P&#47;sachet&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top" style="border-bottom: 2px solid black">&#42;Polycitra LC with phosphrous-oral solution&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top" style="border-bottom: 2px solid black">2<span class="elsevierStyleHsp" style=""></span>mEq Bicarbonate&#59; 1<span class="elsevierStyleHsp" style=""></span>mEq Na&#47;mL&#59; 1<span class="elsevierStyleHsp" style=""></span>mEq K&#47;mL&#59; 1<span class="elsevierStyleHsp" style=""></span>mmol Citrate&#47;mL&#59; 0&#46;6<span class="elsevierStyleHsp" style=""></span>mmol P&#47;mL&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="center" valign="top" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic"><span class="elsevierStyleBold">Others</span></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " rowspan="3" align="left" valign="top">Carnitine</td><td class="td" title="table-entry  " align="left" valign="top">Carnicor 1&#46;5<span class="elsevierStyleHsp" style=""></span>g&#47;5<span class="elsevierStyleHsp" style=""></span>mL &#40;40<span class="elsevierStyleHsp" style=""></span>mL oral solution&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">300<span class="elsevierStyleHsp" style=""></span>mg&#47;mL carnitine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Carnicor 1<span class="elsevierStyleHsp" style=""></span>g drinkable vials &#40;10<span class="elsevierStyleHsp" style=""></span>mL&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">100<span class="elsevierStyleHsp" style=""></span>mg&#47;mL carnitine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Secabiol 300<span class="elsevierStyleHsp" style=""></span>mg&#47;mL &#40;40<span class="elsevierStyleHsp" style=""></span>mL oral solution&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">300<span class="elsevierStyleHsp" style=""></span>mg&#47;mL carnitine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " rowspan="5" align="left" valign="top">Indomethacin</td><td class="td" title="table-entry  " align="left" valign="top">Artinovo 25<span class="elsevierStyleHsp" style=""></span>mg &#40;30 cap&#46;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">25<span class="elsevierStyleHsp" style=""></span>mg indomethacin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Flogoter 25<span class="elsevierStyleHsp" style=""></span>mg &#40;40 cap&#46;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">25<span class="elsevierStyleHsp" style=""></span>mg indomethacin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Inacid 25<span class="elsevierStyleHsp" style=""></span>mg &#40;30 cap&#46;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">25<span class="elsevierStyleHsp" style=""></span>mg indomethacin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Indonilo 25<span class="elsevierStyleHsp" style=""></span>mg &#40;24 cap&#46;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">25<span class="elsevierStyleHsp" style=""></span>mg indomethacin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">&#42;Indomethacin 2<span class="elsevierStyleHsp" style=""></span>mg&#47;mL oral solution&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2<span class="elsevierStyleHsp" style=""></span>mg indomethacin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Cysteamine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#42;Cysteamine 0&#46;55&#37; eye drop solution&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;55&#37; cysteamine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " colspan="3" align="center" valign="top" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">Compounded formulations</span></th></tr><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Liquid formulation&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Component&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Amount&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " rowspan="2" align="left" valign="top">Sodium bicarbonate 1M &#40;8&#46;4&#37;&#41; oral solution<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a></td><td class="td" title="table-entry  " align="left" valign="top">Sodium bicarbonate&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">8&#46;4<span class="elsevierStyleHsp" style=""></span>g&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Sterile distilled water &#40;qs&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">100<span class="elsevierStyleHsp" style=""></span>mL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " rowspan="4" align="left" valign="top">Bicitra oral solution<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a></td><td class="td" title="table-entry  " align="left" valign="top">Sodium&#44; citrate 2H<span class="elsevierStyleInf">2</span>O &#40;Tri-&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">10<span class="elsevierStyleHsp" style=""></span>g&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Monohydrated citric acid&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">6&#46;7<span class="elsevierStyleHsp" style=""></span>g&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Simple syrup with preservatives&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">50<span class="elsevierStyleHsp" style=""></span>mL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Sterile distilled water&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">40<span class="elsevierStyleHsp" style=""></span>mL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " rowspan="5" align="left" valign="top">Polycitra oral solution<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a></td><td class="td" title="table-entry  " align="left" valign="top">Potassium&#44; citrate H<span class="elsevierStyleInf">2</span>O &#40;Tri-&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">11<span class="elsevierStyleHsp" style=""></span>g&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Sodium&#44; citrate 2H<span class="elsevierStyleInf">2</span>O &#40;Tri-&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">10<span class="elsevierStyleHsp" style=""></span>g&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Monohydrate citric acid&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">6&#46;7<span class="elsevierStyleHsp" style=""></span>g&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Simple syrup with preservatives&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">50<span class="elsevierStyleHsp" style=""></span>mL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Sterile distilled water&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">38<span class="elsevierStyleHsp" style=""></span>mL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " rowspan="8" align="left" valign="top">Polycitra LC with phosphorus&#44; oral solution<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">c</span></a></td><td class="td" title="table-entry  " align="left" valign="top">Sodium hydrogenophosphate-12&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#46;4<span class="elsevierStyleHsp" style=""></span>g&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Phosphoric acid 85&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#46;4<span class="elsevierStyleHsp" style=""></span>mL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Sterile distilled water&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">32<span class="elsevierStyleHsp" style=""></span>mL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Potassium&#44; citrate H<span class="elsevierStyleInf">2</span>O&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">11<span class="elsevierStyleHsp" style=""></span>g&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Sodium&#44; citrate&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">10<span class="elsevierStyleHsp" style=""></span>g&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Monohydrate citric acid&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">6&#46;7<span class="elsevierStyleHsp" style=""></span>g&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Simple syrup &#40;qs&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">100<span class="elsevierStyleHsp" style=""></span>mL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Orange extract&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1 drop&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " rowspan="4" align="left" valign="top">Indomethacin 2 mg&#47;mL oral solution<a class="elsevierStyleCrossRefs" href="#tblfn0020"><span class="elsevierStyleSup">d&#44;e&#44;f&#44;g</span></a></td><td class="td" title="table-entry  " align="left" valign="top">Indomethacin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;2<span class="elsevierStyleHsp" style=""></span>g&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Ethyl alcohol&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;7<span class="elsevierStyleHsp" style=""></span>mL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Sterile distilled water&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;3<span class="elsevierStyleHsp" style=""></span>mL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Simple syrup<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>Nipagin&#47;nipasol&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">100<span class="elsevierStyleHsp" style=""></span>mL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " rowspan="3" align="left" valign="top">Phosphates&#44; oral solution &#40;Joulie solution&#41;<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a></td><td class="td" title="table-entry  " align="left" valign="top">Phosphoric acid 85&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">5&#46;45<span class="elsevierStyleHsp" style=""></span>g&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Disodium phosphate 12 H<span class="elsevierStyleInf">2</span>O &#40;di&#41;&nbsp;\t\t\t\t\t\t\n
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Article information

ISSN: 20132514
Original language: English

DOI:10.1016/j.nefroe.2015.06.010

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Year/Month	Html	Pdf	Total

2024 November	11	8	19
2024 October	105	72	177
2024 September	120	53	173
2024 August	123	102	225
2024 July	84	55	139
2024 June	111	76	187
2024 May	109	57	166
2024 April	107	72	179
2024 March	128	51	179
2024 February	87	64	151
2024 January	58	38	96
2023 December	78	54	132
2023 November	79	60	139
2023 October	99	44	143
2023 September	64	41	105
2023 August	52	51	103
2023 July	78	42	120
2023 June	111	56	167
2023 May	101	50	151
2023 April	82	41	123
2023 March	135	55	190
2023 February	100	49	149
2023 January	109	54	163
2022 December	153	55	208
2022 November	82	39	121
2022 October	131	59	190
2022 September	77	62	139
2022 August	103	62	165
2022 July	97	68	165
2022 June	117	54	171
2022 May	126	56	182
2022 April	188	63	251
2022 March	131	61	192
2022 February	107	57	164
2022 January	84	57	141
2021 December	201	57	258
2021 November	184	59	243
2021 October	382	69	451
2021 September	99	25	124
2021 August	124	38	162
2021 July	129	43	172
2021 June	139	44	183
2021 May	282	42	324
2021 April	211	34	245
2021 March	101	52	153
2021 February	110	38	148
2021 January	100	39	139
2020 December	70	42	112
2020 November	97	33	130
2020 October	57	27	84
2020 September	67	32	99
2020 August	76	19	95
2020 July	97	26	123
2020 June	90	28	118
2020 May	119	36	155
2020 April	79	33	112
2020 March	102	43	145
2020 February	240	46	286
2020 January	133	59	192
2019 December	124	57	181
2019 November	132	43	175
2019 October	109	39	148
2019 September	123	42	165
2019 August	78	35	113
2019 July	66	30	96
2019 June	69	42	111
2019 May	76	44	120
2019 April	115	63	178
2019 March	73	35	108
2019 February	65	37	102
2019 January	73	53	126
2018 December	244	58	302
2018 November	528	32	560
2018 October	117	30	147
2018 September	99	19	118
2018 August	70	18	88
2018 July	78	13	91
2018 June	92	19	111
2018 May	112	14	126
2018 April	95	12	107
2018 March	59	12	71
2018 February	43	18	61
2018 January	57	8	65
2017 December	54	9	63
2017 November	75	16	91
2017 October	64	13	77
2017 September	60	10	70
2017 August	58	11	69
2017 July	66	14	80
2017 June	71	12	83
2017 May	58	19	77
2017 April	74	18	92
2017 March	66	21	87
2017 February	102	26	128
2017 January	43	30	73
2016 December	81	6	87
2016 November	200	38	238
2016 October	169	31	200
2016 September	306	18	324
2016 August	404	25	429
2016 July	323	39	362
2016 June	199	0	199
2016 May	241	0	241
2016 April	249	0	249
2016 March	228	0	228
2016 February	194	0	194
2016 January	141	0	141
2015 December	185	0	185
2015 November	172	0	172
2015 October	170	0	170
2015 September	248	0	248
2015 August	150	0	150
2015 July	42	0	42

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