Typical clinical symptoms include the appearance of severe Fanconi syndrome with evolution to chronic kidney disease (CKD) (Fig. 1). Tubulopathy characteristically becomes evident in the second semester of life after a symptom-free interval.24 Affected newborns are apparently normal, although it is possible to detect urinary alterations (alkalineurine with glycosuria and/or proteinuria) very early preceding symptoms.26 Cystinosis is the most frequent cause of inherited Fanconi syndrome24 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.1 The differential diagnosis should contemplate the possibility of secondary proximal tubulopathy.27,28 The severity of Fanconi syndrome associated with cystinosis requires rigorous treatment that is frequently very complex (Table 1).

Fig. 1.

Clinical manifestations of cystinosis in patients not treated with cysteamine. CKD: chronic kidney disease, ESRD: end stage renal disease, RRT: renal replacement therapy.

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After 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.1 Concurrently, Fanconi syndrome usually remits and, consequently, it is possible to reduce water/electrolyte supplements (Table 1). 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.6

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 asymptomatic25 (Fig. 1).

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.2,16,24

The 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.30 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).5

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 (Table 1). On rare occasions, the severity of Fanconi syndrome justifies nephrectomy of the native kidneys.31 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.32

As 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.21 Family-donor transplantation is also curative, and heterozygous carriers of the CTNS mutation can be appropriate donors since they do not have the disease.4,6,33

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 available4 thereby avoiding the need for dialysis.5 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.1

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.34 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%).5 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.34 Similarly, in Europe 48.9% received a living donor transplant.5

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.5,35

Eye involvement is intrinsic to cystinosis. The presence of cystine crystals in the cornea is a diagnostic criterion for this disease,37 although its absence before the age of 12 months may not rule it out.1

Cystine deposits in the cornea are one of the earliest manifestations of cystinosis (Fig. 1). Although no crystals are present at birth, they can be observed in children who are only a few months old.1 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.37

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.38,39 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.4 In late-onset disease, the presence of crystals might not be detected until adulthood.25

Failure to thrive is a classic clinical symptom of cystinosis and frequently is the reason for an early consultation.36 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.40,41 Similarly, patients present endocrine alterations (see endocrine involvement section) and, infrequently, primary growth hormone (GH) deficiency.42

Patients with inadequate treatments usually have shorter stature.36 Classically, the adult height reported in patients with suboptimal treatment is 144cm and weight 45kg (25cm and 25kg below the normal population average, respectively).4 The most recent series with better therapeutic control reported less retarded growth8 and a favourable impact of treatment on growth regulation mechanisms.43 Nevertheless, nowadays 27% of transplanted cystinotic patients and 44% of those on dialysis continue to be shorter than average.5

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.40,44 Patients with cystinosis develop a characteristic metabolic bone disease caused by different factors: bone deposits of cystine crystals, mineral deficiency, renal rickets24 and CKD per se.45 Bone anomalies attributed to copper deficiency, possibly secondary to Fanconi syndrome have also been described.46 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.23,47 Some patients have bone fragility and a higher risk of fractures.32

Endocrine 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.43

Primary hypothyroidism is the most frequent endocrine complication;23 it is progressive and requires chronic treatment with levothyroxine.1,4 Diabetes mellitus (DM) is characterised by a progressive alteration in insulin secretion,48 with negative immunology, and requires treatment with insulin.2 It is observed in transplant recipients who receive corticosteroids.23 In males, cystinosis causes primary hypogonadism and infertility is a constant.4,49 In females, however, neither hypogonadism nor infertility are prevalent, and affected patients can thus have children,50 although the risk of prematurity is increased.51

The appearance of dyslipidemia and vascular calcification due to cystinosis and CKD are considered increased cardiovascular risk factors.23,32,41 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.36 In adult patients, screening for ischaemic heart disease is recommended.4

Cystinosis is associated with alterations in cerebral structure and increased cystine levels in different areas of the nervous system and muscle tissue.4,6,32,52 In general, neurological complications worsen the prognosis of the disease:

• •

  Progressive ischaemic myopathy4,32,53 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.24,28,29

• •

  Central nervous system (CNS) involvement4,31 is mainly observed in patients with suboptimal treatment with cysteamine:

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    Acute presentation: epilepsy, stroke, encephalopathy, cephalalgia54–57

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    Subacute/progressive presentation: intracranial hypertension, cerebral atrophy, ataxia, pyramidalism, gait disorders, basal and periventricular lymph node calcifications, demyelination of white matter, mental deterioration58–66

• •

  Neurocognitive alterations:67–73 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.

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.8,31,32,55

The 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.3,19,91

The first specific pharmacological treatment for cystinosis is Cystagon® (oral cysteamine bitartrate in hard capsules), the only authorised therapy in Spain92–94. A new formula in hard gastro-resistant capsules has recently been approved for cysteamine.93–96

Specific treatment of ocular involvement in cystinosis requires, in addition to oral cysteamine, the use of cysteamine eye drops. The ophthalmological therapeutic strategy32,37 makes a distinction between:

Cystine 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.37,38,105,106 The recommended prescription is shown in Table 3. 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.107,108

Oral 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.39,109

The World Health Organization (WHO) defines compliance as the degree to which patient behaviour follows the recommendations of medical professionals.110

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.5,6,97

Information on adherence in patients with cystinosis is limited, although monitoring WBC cystine levels is able to detect non-compliant patients.77,79 Other studies have confirmed adequate adherence to Cystagon® in children patients which wanes significantly in adolescents and adults.7,8 Nonetheless, in groups of highly motivated patients, only 8% had compliance problems.111

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.7,9,10

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.112,113 These percentages are similar to those published in patients with cystinosis in our population,7 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 recipients114–119 (Table 4).