Successful treatment of calcific uraemic arteriolopathy with bisphosphonates
Tratamiento eficaz de la arteriolopatía urémica calcificante con bifosfonatos
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Torregrosa, Carlos Eduardo Duran, Carlos E. Durán, Xoana Barros, Miquel Blasco, Marta Arias, Aleix Cases, Josep Maria Campistol, Josep M. Campistol" "autores" => array:10 [ 0 => array:4 [ "nombre" => "Jose-Vicente" "apellidos" => "Torregrosa" "email" => array:1 [ 0 => "vtorre@clinic.ub.es" ] "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "affa" ] ] ] 1 => array:4 [ "nombre" => "José V." "apellidos" => "Torregrosa" "email" => array:1 [ 0 => "vtorre@clinic.ub.es" ] "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "affb" ] ] ] 2 => array:3 [ "nombre" => "Carlos Eduardo" "apellidos" => "Duran" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "affa" ] ] ] 3 => array:3 [ "nombre" => "Carlos E." 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"apellidos" => "Campistol" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "affb" ] ] ] ] "afiliaciones" => array:2 [ 0 => array:3 [ "entidad" => "Nefrologia, Hospital Clínic Barcelona, Barcelona, Spain, " "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "affa" ] 1 => array:3 [ "entidad" => "Servicio de Nefrología, Hospital Clínic, Barcelona, " "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "affb" ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Tratamiento eficaz de la arteriolopatía urémica calcificante con bifosfonatos" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:8 [ "identificador" => "fig4" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "figura" => array:1 [ 0 => array:4 [ "imagen" => "11137_16025_29392_en_f2_11137.jpg" "Alto" => 954 "Ancho" => 1004 "Tamanyo" => 237388 ] ] "descripcion" => array:1 [ "en" => "Serum creatinine values in kidney transplant patients after administering bisphosphonates" ] ] ] "textoCompleto" => "<p class="elsevierStylePara"><span class="elsevierStyleBold">INTRODUCTION</span></p><p class="elsevierStylePara"> </p><p class="elsevierStylePara">Calcific uraemic arteriolopathy (CUA), also known as calciphylaxis, is a rare but potentially life-threatening condition that almost exclusively affects patients with chronic kidney disease (CKD). The incidence of CUA among dialysis patients has been estimated at 1% annually, with a prevalence rate as high as 4%. CUA is a crippling<span class="elsevierStyleBold"> </span>disease with a mortality rate of 60%-80%; the main cause of death is sepsis.<span class="elsevierStyleSup">1,2</span> Despite the fact that medial calcification in large vessels is very common in CKD patients, small vessel calcification is rare. The skin’s vulnerability to CUA is probably due to its proximity to external forces, such as changes in temperature and pressure. CUA is characterised by progressive calcification of small blood vessels and the development of ischaemic necrosis of skin and soft tissues.</p><p class="elsevierStylePara">Given the rareness of CUA, treatment is often based on results from individual cases. Traditional treatment suggestions include debridement of necrotic tissue, antibiotic treatment to prevent or treat infection, nutritional support, correction of biochemical parameters,<span class="elsevierStyleSup">2</span> parathyroidectomy, cinacalcet, sodium thiosulphate (STS) and bisphosphonates.<span class="elsevierStyleSup">3-13</span> Bisphosphonates inhibit osteoclasts and bone resorption and are used in treating osteoporosis, Paget's disease, multiple myeloma, and tumour-induced hypercalcaemia. In animal studies, bisphosphonates have been shown to have a beneficial effect on the prevention of arterial calcification.<span class="elsevierStyleSup">3</span> Because of these recent observations, bisphosphonates were recently introduced as CUA treatment, with good results.<span class="elsevierStyleSup">9-13</span> After undertaking preliminary studies, our unit began using bisphosphonates in 2002 as a treatment alternative for all patients with CUA. We present our series of CUA cases since 2002, all of which were successfully treated with bisphosphonates.</p><p class="elsevierStylePara"> </p><p class="elsevierStylePara"><span class="elsevierStyleBold">MATERIAL AND METHOD</span></p><p class="elsevierStylePara"> </p><p class="elsevierStylePara"><span class="elsevierStyleBold">Study population</span></p><p class="elsevierStylePara"> </p><p class="elsevierStylePara">Prospective study of the 8 patients diagnosed with CUA in our unit between 2002 and 2010. They included 4 men and 4 women with a mean age of 61±7 years. Five were on haemodialysis (3 following kidney graft loss) with time on dialysis ranging between 2 and 20 years. The other 3 had functioning kidney grafts (durations between 1 and 5 years). Demographic characteristics and risk factors are summarised in Table 1, and initial laboratory results are summarised in Table 2.</p><p class="elsevierStylePara">Relevant data: Previous history of high calcium-phosphorous product in 5 patients (75-157mg<span class="elsevierStyleSup">2</span>/dl<span class="elsevierStyleSup">2</span>), previous history of severe secondary hyperparathyroidism (>800pg/ml) in 6 patients (4 had undergone parathyroidectomy), history of high cumulative doses of steroids in 5 patients, and 6 patients undergoing treatment with dicoumarin derivatives (Sintrom<span class="elsevierStyleSup">®</span>) for a number of reasons (heart valve, atrial fibrillation or severe vascular access thrombosis problems). Only one patient had hepatitis C (HCV) and none were diabetic or obese. All of the patients had purple ulcerous skin lesions with a necrotic centre, erythematous edges and <span class="elsevierStyleItalic">livedo reticularis</span> in the entire area. The lesions were located on the inner thighs in 6 patients and in the tibial area in 3 patients (one had lesions in both locations). Diagnosis was based on clinical suspicion and a confirmatory biopsy was performed in 6 patients.</p><p class="elsevierStylePara"><span class="elsevierStyleBold"> </span></p><p class="elsevierStylePara"><span class="elsevierStyleBold">Treatment with bisphosphonates </span></p><p class="elsevierStylePara"> </p><p class="elsevierStylePara">All patients were treated with bisphosphonates. The first (patient 1) received oral alendronate 70mg/week; 4 patients (patients 2, 3, 4 and 5) received oral risedronate 35mg/week, and the last 3 (patients 6, 7 and 8) received intravenous ibandronate 6mg (1 dose) followed by a second 3mg dose after 15 days, followed by oral ibandronate 150mg/month during 6 months.</p><p class="elsevierStylePara">In patients on dicoumarin treatment, we decided to maintain the anticoagulant therapy for two reasons: to prevent thrombosis-related problems and determine whether the effect on calciphylaxis was due to the bisphosphonates alone.</p><p class="elsevierStylePara"> </p><p class="elsevierStylePara"><span class="elsevierStyleBold">Follow-up</span></p><p class="elsevierStylePara"> </p><p class="elsevierStylePara">In all patients, bisphosphonate treatment was maintained until all lesions had healed completely during at least 6 months. During the follow-up period, blood values of calcium, phosphorous, alkaline phosphatase and intact parathyroid hormone (iPTH) (Diasorin<span class="elsevierStyleSup">®</span>) were measured monthly.</p><p class="elsevierStylePara">In the last 3 patients who received a second dose of ibandronate at 15 days, calcium levels were also measured prior to administrating that dose. Renal function was also measured in the patients with functioning allografts.</p><p class="elsevierStylePara"><span class="elsevierStyleBold"> </span></p><p class="elsevierStylePara"><span class="elsevierStyleBold">RESULTS</span></p><p class="elsevierStylePara"> </p><p class="elsevierStylePara">In all cases, skin lesions stopped progressing after administration of bisphosphonates. After 2-4 weeks, the edges began healing and the size of the wound diminished. Gradual decrease in pain was recorded after 2-5 days. The decrease in pain and wound size was noted more quickly in patients treated with intravenous bisphosphonates. No other drugs were used (vitamin D, cinacalcet, phosphate binders) and previous treatment and dialysis regimes were not modified.</p><p class="elsevierStylePara">After follow-up periods ranging between 1 and 9 years, there have been no recurrences in any of the patients or death. After administration of bisphosphonates, no significant changes were reported in blood calcium and phosphorus levels in any of the cases (Figure 1). Similarly, there were no changes in iPTH or alkaline phosphatase. In patients with a functioning kidney transplant, renal function remained stable (Figure 2). The treatment was well tolerated in all cases and no relevant adverse effects were observed.</p><p class="elsevierStylePara"> </p><p class="elsevierStylePara"><span class="elsevierStyleBold">DISCUSSION</span></p><p class="elsevierStylePara"> </p><p class="elsevierStylePara">CUA develops mainly in patients with stage 3-4 CKD, in both dialysis and transplant patients. The incidence of CUA seems to have increased in recent years; the reason for this is unknown, but it could be due to better record-keeping. It occurs in up to 4% of patients on dialysis.<span class="elsevierStyleSup">1,2</span></p><p class="elsevierStylePara">CUA should be suspected in the presence of very painful, necrotic cutaneous ulcers in a patient with long-standing CKD. In the beginning other cutaneous manifestations are present, such as indurated plaques or <span class="elsevierStyleItalic">livedo reticularis, </span><span class="elsevierStyleItalic">sometimes accompanied by palpable deposits of subcutaneous calcium.</span> These lesions are usually located proximal (trunk) or distal (limbs), especially along the inner thigh.<span class="elsevierStyleSup">1</span></p><p class="elsevierStylePara">Simple high-sensitivity x-ray can reveal calcification of small blood vessels, but the diagnostic gold standard is still a skin biopsy of the lesions, despite the risk of spreading the ulcer. The typical histological finding is calcification of the small blood vessels with intimal proliferation and intravascular thrombosis, sometimes associated with panniculitis.<span class="elsevierStyleSup">1</span> Von Kossa staining can also reveal perivascular calcium deposits. Risk factors for developing CUA include: age (patients tend to be younger), female sex, high body mass index, diabetes mellitus, longer time on dialysis, high blood levels of calcium, phosphates, calcium-phosphorus product, alkaline phosphatase and PTH. Some authors have described a potential association with HCV, and another important risk factor is being treated with high doses of steroids or with warfarin (acenocoumarol).<span class="elsevierStyleSup">1,2</span></p><p class="elsevierStylePara">Our series includes equal numbers of men and women, dialysis patients with very different treatment durations, and kidney transplant recipients. There was only one patient with HCV and none of the patients were obese or diabetic. Elevated blood values of calcium, phosphorus and iPTH were found in 1 patient, 2 patients and 1 patient, respectively. It is true, however, that most had a history of very high calcium-phosphorus product levels. On the other hand, most of our patients were being treated with steroids and acenocoumarol.</p><p class="elsevierStylePara">When CUA is diagnosed, priority treatment alternatives include normalising hypercalcaemia and hyperphosphataemia and avoiding intake of vitamin D and calcium salts. Topical treatment and beginning empirical antibiotic treatment may also be helpful.<span class="elsevierStyleSup">1,2</span> In patients with high PTH levels, parathyroidectomy was suggested as a good alternative, but results have been contradictory and risk of mortality may increase after surgery.<span class="elsevierStyleSup">1,2</span> Cinacalcet has been shown to be beneficial in some cases of CUA with secondary hyperparathyroidism, generally in combination with other treatments, such as hyperbaric oxygen and sodium thiosulphate (STS).<span class="elsevierStyleSup">4,8</span> Some cases of good response to hyperbaric treatment have been described, but this treatment is always combined with other alternatives.<span class="elsevierStyleSup">7</span></p><p class="elsevierStylePara">STS recently emerged as an interesting treatment option after publication of a few isolated cases and two clinical series with promising results.<span class="elsevierStyleSup">8</span> This compound seems to play a role in dissolving calcium deposits within tissues through the formation of soluble calcium thiosulphate complexes, and it may also act as an antioxidant to combat endothelial dysfunction. The most recent series, published in 2011, describes the use of STS in 6 patients. Authors reported pain relief and lesion healing in 4 patients, but 3 patients (including 2 of the 4 who responded to treatment) died less than 1 year after diagnosis.<span class="elsevierStyleSup">8</span> In addition, most of them had received at least 1 dose of IV pamidronate in the same month or the month prior to beginning STS treatment, and 2 patients were treated with cinacalcet. Only 1 of the patients did not develop adverse effects (vomiting or metabolic acidosis).</p><p class="elsevierStylePara">Another possible treatment alternative is the use of bisphosphonates, which are pyrophosphate analogues that are widely used in treating osteoporosis. The pyrophosphate (PPi) is a potent inhibitor of calcium and circulates in the bloodstream at levels that are high enough to prevent hydroxyapatite formation. It therefore serves as an endogenous calcification inhibitor.<span class="elsevierStyleSup">14,15</span> In particular, production of PPi by vascular smooth muscle cells may be an important defence mechanism against calcification of the vascular media. PPi has been shown to inhibit calcification of the arterial media in rats intoxicated<span class="elsevierStyleBold"> </span>with vitamin D.<span class="elsevierStyleSup">16</span> The effect of PPi is limited by its rapid <span class="elsevierStyleItalic">in vivo </span>hydrolysis. Bisphosphonates are non-hydrolysable PPi analogues which are able to inhibit vascular calcification at much lower doses.<span class="elsevierStyleSup">15</span> In recent years, bisphosphonates have been used in isolated cases as treatment for CUA, with a good response and good tolerance.<span class="elsevierStyleSup">9-13,17</span></p><p class="elsevierStylePara">At the pharmacological level, bisphosphonates inhibit hydroxyapatite crystallisation or reabsorption <span class="elsevierStyleItalic">in vitro,</span> depending on their concentration.<span class="elsevierStyleSup">15,18</span> It has been suggested that the same effect could occur <span class="elsevierStyleItalic">in vivo</span>. These compounds also inhibit the transformation of osteoclast precursors into mature cells. Some authors state that the similarity between smooth muscle cells and osteogenic-like cells could favour binding of bisphosphonates to the vascular wall, which would prevent ossification. Other studies have also shown that bisphosphonates reduce macrophage activity on a local level,<span class="elsevierStyleSup">19</span> and decrease secretion of pro-inflammatory cytokines.<span class="elsevierStyleSup">20</span></p><p class="elsevierStylePara">The administration of diphosphonate ethane-1-hydroxy-1, 1-diphosphonate and dichloromethylene diphosphonate reduced CUA lesions in rats, but its mechanism of action is still not well understood. Ibandronate, a potent inhibitor of arterial calcification, has been shown to be effective for decreasing and preventing vascular calcification in uraemic rats.<span class="elsevierStyleSup">3</span> It decreases calcium levels and reduces the ability of mineral deposits to form and grow on the arterial wall. This is probably due to its ability to inhibit the production of pro-inflammatory cytokines.</p><p class="elsevierStylePara">Nitrogen-containing bisphosphonates such as ibandronate can inhibit enzymes of the mevalonate pathway, thereby preventing the biosynthesis of isoprenoid compounds, including farnesyl pyrophosphate.<span class="elsevierStyleSup">22</span> Farnesyl pyrophosphate is necessary in post-translational modification of proteins, such as <span class="elsevierStyleItalic">GTP-binding proteins</span> (for example, Ras, Rho and Rac),<span class="elsevierStyleSup">23</span> which may be involved in the genetic expression of the OPG-RANKL complex. This may be one of the explanations for the proven effect of bisphosphonates on OPG generation, and for their contribution to healing extraosseous calcification.<span class="elsevierStyleSup">24</span></p><p class="elsevierStylePara">In our patients, we observed rapid improvement of pain at the lesions after beginning treatment with bisphosphonates, regardless of the type of bisphosphonate used. However, the effect was perceived more quickly with intravenous administration, which suggests an effect on the mobilisation of calcium salts in soft tissues. No significant decreases in hypercalcaemia were observed in any of our cases. However, given the potential risk of hypocalcaemia during treatment with bisphosphonates, we recommend measuring calcium levels 7-15 days after administering the dose.</p><p class="elsevierStylePara">In recent years (with the last 3 patients) we decided to use intravenous ibandronate as it appears to be the safest type of bisphosphonate, despite renal clearance being 50% of total clearance. No negative effects on renal function have been described. Ibandronate does not affect renal tubule cells and it does not interfere with renal tubular reabsorption or glomerular filtration.<span class="elsevierStyleSup">25</span></p><p class="elsevierStylePara">We are aware of the medical community’s concerns regarding the use of bisphosphonates in patients with advanced CKD, and which are mostly founded on the potential risk of causing or worsening adynamic bone disease. However, we decided to use this treatment for 2 basic reasons. Firstly, the bone-binding capacity<span class="elsevierStyleBold"> </span>of bisphosphonates is known to be related to remodelling activity, and in the presence of adynamic bone disease, bisphosphonates would therefore be deposited in very small quantities. The second and more important reason is that calciphylaxis is a life-threatening disease, and we prefer to run the risk of worsening a possible case of adynamic bone disease if it means reducing the morbidity and mortality rates for CUA.</p><p class="elsevierStylePara">In conclusion, bisphosphonates may be a new, attractive treatment alternative for CUA treatment. Based on our experience, we recommend initial administration of an intravenous dose of bisphosphonate, preferably ibandronate, in patients with a suspected case of CUA. Treatment may then be continued depending on the definitive diagnosis or patient progress. We must keep in mind that CUA is potentially fatal, and it must be treated with all the means at our disposal, including suppression of calcium salts, vitamin D and analogues, dicoumarin derivatives and precipitating factors, and by early administration of bisphosphonates or STS.</p><p class="elsevierStylePara"> </p><p class="elsevierStylePara"><span class="elsevierStyleBold">Conflicts of interest</span></p><p class="elsevierStylePara"> </p><p class="elsevierStylePara">The authors affirm that they have no conflicts of interest related to the content of this article.</p><p class="elsevierStylePara"><a href="grande/11137_16025_29389_en_t1_11137.jpg" class="elsevierStyleCrossRefs"><img src="11137_16025_29389_en_t1_11137.jpg" alt="Baseline demographic characteristics and risk factors"></img></a></p><p class="elsevierStylePara">Table 1. Baseline demographic characteristics and risk factors</p><p class="elsevierStylePara"><a href="grande/11137_16025_29390_en_t2_11137.jpg" class="elsevierStyleCrossRefs"><img src="11137_16025_29390_en_t2_11137.jpg" alt="Baseline laboratory values"></img></a></p><p class="elsevierStylePara">Table 2. Baseline laboratory values</p><p class="elsevierStylePara"><a href="grande/11137_16025_29391_en_f1_11137.jpg" class="elsevierStyleCrossRefs"><img src="11137_16025_29391_en_f1_11137.jpg" alt="Serum Ca and P values after administering bisphosphonates"></img></a></p><p class="elsevierStylePara">Figure 1. Serum Ca and P values after administering bisphosphonates</p><p class="elsevierStylePara"><a href="grande/11137_16025_29392_en_f2_11137.jpg" class="elsevierStyleCrossRefs"><img src="11137_16025_29392_en_f2_11137.jpg" alt="Serum creatinine values in kidney transplant patients after administering bisphosphonates"></img></a></p><p class="elsevierStylePara">Figure 2. Serum creatinine values in kidney transplant patients after administering bisphosphonates</p>" "pdfFichero" => "P1-E536-S3491-A11137-EN.pdf" "tienePdf" => true "PalabrasClave" => array:2 [ "es" => array:6 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec438319" "palabras" => array:1 [ 0 => "Bifosfonatos" ] ] 1 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec438321" "palabras" => array:1 [ 0 => "Calcifilaxis" ] ] 2 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec438323" "palabras" => array:1 [ 0 => "Trasplante renal" ] ] 3 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec438325" "palabras" => array:1 [ 0 => "Enfermedad renal crónica" ] ] 4 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec438327" "palabras" => array:1 [ 0 => "Hiperparatiroidismo secundario" ] ] 5 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec438329" "palabras" => array:1 [ 0 => "Arteriolopatía urémica calcificante" ] ] ] "en" => array:6 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec438320" "palabras" => array:1 [ 0 => "Bisphosphonates" ] ] 1 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec438322" "palabras" => array:1 [ 0 => "Calciphylaxis" ] ] 2 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec438324" "palabras" => array:1 [ 0 => "Kidney transplantation" ] ] 3 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec438326" "palabras" => array:1 [ 0 => "Chronic kidney disease" ] ] 4 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec438328" "palabras" => array:1 [ 0 => "Secondary hyperparathyroidism" ] ] 5 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec438330" "palabras" => array:1 [ 0 => "Calcific uraemic arteriolopathy" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "es" => array:1 [ "resumen" => "<p class="elsevierStylePara"><span class="elsevierStyleBold">Antecedentes y objetivos:</span> La arteriolopatía urémica calcificante (CUA) o calcifilaxis es una enfermedad rara pero potencialmente mortal que afecta casi exclusivamente a pacientes con enfermedad renal crónica. Para su tratamiento se han empleado diferentes alternativas con resultados irregulares, siendo los bifosfonatos una de ellas. Desde 2002 iniciamos en nuestra Unidad el tratamiento con bifosfonatos en todos los pacientes con diagnóstico de CUA. <span class="elsevierStyleBold">Material y métodos:</span> Se recogieron prospectivamente, entre 2002 y 2010, ocho pacientes (cuatro hombres, cinco en diálisis y tres con trasplante renal funcionante) con CUA tratados con bifosfonatos. El diagnóstico se realizó por sospecha clínica y biopsia de confirmación. Cinco pacientes con antecedentes de producto calcio-fósforo elevado, seis con antecedentes de hormona paratiroidea elevada (> 800 pg/ml), cuatro paratiroidectomizados, cinco con elevada dosis acumulada de esteroides y seis recibiendo dicumarínicos. Ningún paciente presentaba obesidad ni diabetes mellitus. <span class="elsevierStyleBold">Resultados: </span>En todos los casos se constató disminución de sintomatología (dolor) a los pocos días y regresión de las lesiones entre 2 a 4 semanas tras iniciar los bifosfonatos, sin cambios en los valores séricos de calcio y fósforo. La mejoría fue más rápida en los que recibieron ibandronato intravenoso. Todos se mantuvieron en tratamiento con bifosfonatos durante al menos 6 meses, hasta que las heridas se curaron completamente. No se han observado recurrencias tras un seguimiento de entre 1 y 9 años. La función renal se mantuvo estable en los pacientes trasplantados. El tratamiento fue bien tolerado y no se observaron efectos adversos. <span class="elsevierStyleBold">Conclusiones: </span>Los bifosfonatos podrían constituir una alternativa nueva y atractiva para el tratamiento de la CUA.</p>" ] "en" => array:1 [ "resumen" => "<p class="elsevierStylePara"><span class="elsevierStyleBold">Background and objectives:</span> Calcific uraemic arteriolopathy (CUA), also known as calciphylaxis, is a rare but life-threatening condition that almost exclusively affects patients with chronic kidney disease. Several therapies have been employed to treat this disease but with irregular results. We report a prospective case series of eight patients diagnosed with CUA in our unit between 2002 and 2010. <span class="elsevierStyleBold">Material and method:</span> The series consisted of eight patients with CUA (including 4 men, 5 dialysis patients and 3 with functioning allografts) who were treated with bisphosphonates. The diagnosis was by clinical suspicion and a confirmatory biopsy. Five patients had a previous history of high calcium-phosphorus product, 6 had a history of high parathyroid hormone levels (>800pg/ml), 4 had undergone parathyroidectomy, 5 had a history of high cumulative doses of steroids, and 6 patients were under dicoumarin treatment. None of the patients were obese or had diabetes mellitus. <span class="elsevierStyleBold">Results:</span> In all patients, progression of skin lesions stopped between 2 to 4 weeks after starting bisphosphonate therapy, with no changes in blood levels of calcium and phosphate. Improvement in pain and lesions was faster in patients receiving intravenous ibandronate. All of these patients remained on bisphosphonate treatment for at least 6 months until the wounds healed completely. No recurrences have been observed after follow-up periods between 1 and 9 years. Renal function remained stable in transplant recipients. The treatment was well tolerated and no adverse effects were observed. <span class="elsevierStyleBold">Conclusions:</span> Bisphosphonates could be a new and attractive alternative to treat CUA.</p>" ] ] "multimedia" => array:4 [ 0 => array:8 [ "identificador" => "fig1" "etiqueta" => "Tab. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "figura" => array:1 [ 0 => array:4 [ "imagen" => "11137_16025_29389_en_t1_11137.jpg" "Alto" => 754 "Ancho" => 2162 "Tamanyo" => 558117 ] ] "descripcion" => array:1 [ "en" => "Baseline demographic characteristics and risk factors" ] ] 1 => array:8 [ "identificador" => "fig2" "etiqueta" => "Tab. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "figura" => array:1 [ 0 => array:4 [ "imagen" => "11137_16025_29390_en_t2_11137.jpg" "Alto" => 511 "Ancho" => 2149 "Tamanyo" => 360911 ] ] "descripcion" => array:1 [ "en" => "Baseline laboratory values" ] ] 2 => array:8 [ "identificador" => "fig3" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "figura" => array:1 [ 0 => array:4 [ "imagen" => "11137_16025_29391_en_f1_11137.jpg" "Alto" => 1166 "Ancho" => 988 "Tamanyo" => 273557 ] ] "descripcion" => array:1 [ "en" => "Serum Ca and P values after administering bisphosphonates" ] ] 3 => array:8 [ "identificador" => "fig4" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "figura" => array:1 [ 0 => array:4 [ "imagen" => "11137_16025_29392_en_f2_11137.jpg" "Alto" => 954 "Ancho" => 1004 "Tamanyo" => 237388 ] ] "descripcion" => array:1 [ "en" => "Serum creatinine values in kidney transplant patients after administering bisphosphonates" ] ] ] "bibliografia" => array:2 [ "titulo" => "Bibliography" "seccion" => array:1 [ 0 => array:1 [ "bibliografiaReferencia" => array:25 [ 0 => array:3 [ "identificador" => "bib1" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Rogers NM, Coates PT. 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 6 | 11 | 17 |
| 2024 October | 57 | 48 | 105 |
| 2024 September | 62 | 25 | 87 |
| 2024 August | 65 | 54 | 119 |
| 2024 July | 49 | 26 | 75 |
| 2024 June | 65 | 38 | 103 |
| 2024 May | 81 | 45 | 126 |
| 2024 April | 62 | 41 | 103 |
| 2024 March | 49 | 16 | 65 |
| 2024 February | 40 | 44 | 84 |
| 2024 January | 35 | 29 | 64 |
| 2023 December | 38 | 33 | 71 |
| 2023 November | 40 | 41 | 81 |
| 2023 October | 61 | 29 | 90 |
| 2023 September | 44 | 30 | 74 |
| 2023 August | 41 | 11 | 52 |
| 2023 July | 45 | 34 | 79 |
| 2023 June | 27 | 21 | 48 |
| 2023 May | 55 | 33 | 88 |
| 2023 April | 32 | 22 | 54 |
| 2023 March | 45 | 21 | 66 |
| 2023 February | 54 | 18 | 72 |
| 2023 January | 33 | 30 | 63 |
| 2022 December | 55 | 28 | 83 |
| 2022 November | 68 | 33 | 101 |
| 2022 October | 39 | 28 | 67 |
| 2022 September | 52 | 37 | 89 |
| 2022 August | 59 | 56 | 115 |
| 2022 July | 31 | 41 | 72 |
| 2022 June | 66 | 31 | 97 |
| 2022 May | 51 | 27 | 78 |
| 2022 April | 34 | 66 | 100 |
| 2022 March | 61 | 57 | 118 |
| 2022 February | 52 | 52 | 104 |
| 2022 January | 70 | 35 | 105 |
| 2021 December | 66 | 48 | 114 |
| 2021 November | 55 | 39 | 94 |
| 2021 October | 266 | 46 | 312 |
| 2021 September | 243 | 36 | 279 |
| 2021 August | 62 | 45 | 107 |
| 2021 July | 69 | 40 | 109 |
| 2021 June | 163 | 27 | 190 |
| 2021 May | 49 | 36 | 85 |
| 2021 April | 79 | 43 | 122 |
| 2021 March | 53 | 55 | 108 |
| 2021 February | 42 | 29 | 71 |
| 2021 January | 37 | 15 | 52 |
| 2020 December | 32 | 19 | 51 |
| 2020 November | 41 | 15 | 56 |
| 2020 October | 31 | 20 | 51 |
| 2020 September | 33 | 20 | 53 |
| 2020 August | 47 | 14 | 61 |
| 2020 July | 43 | 22 | 65 |
| 2020 June | 30 | 14 | 44 |
| 2020 May | 65 | 19 | 84 |
| 2020 April | 32 | 19 | 51 |
| 2020 March | 48 | 16 | 64 |
| 2020 February | 45 | 22 | 67 |
| 2020 January | 87 | 27 | 114 |
| 2019 December | 67 | 52 | 119 |
| 2019 November | 52 | 26 | 78 |
| 2019 October | 50 | 20 | 70 |
| 2019 September | 41 | 28 | 69 |
| 2019 August | 41 | 22 | 63 |
| 2019 July | 30 | 22 | 52 |
| 2019 June | 56 | 17 | 73 |
| 2019 May | 40 | 21 | 61 |
| 2019 April | 92 | 61 | 153 |
| 2019 March | 47 | 32 | 79 |
| 2019 February | 42 | 22 | 64 |
| 2019 January | 44 | 35 | 79 |
| 2018 December | 159 | 45 | 204 |
| 2018 November | 369 | 20 | 389 |
| 2018 October | 214 | 19 | 233 |
| 2018 September | 286 | 16 | 302 |
| 2018 August | 73 | 31 | 104 |
| 2018 July | 87 | 21 | 108 |
| 2018 June | 108 | 23 | 131 |
| 2018 May | 200 | 17 | 217 |
| 2018 April | 220 | 13 | 233 |
| 2018 March | 222 | 11 | 233 |
| 2018 February | 85 | 9 | 94 |
| 2018 January | 105 | 10 | 115 |
| 2017 December | 81 | 9 | 90 |
| 2017 November | 117 | 14 | 131 |
| 2017 October | 309 | 11 | 320 |
| 2017 September | 176 | 7 | 183 |
| 2017 August | 78 | 14 | 92 |
| 2017 July | 199 | 19 | 218 |
| 2017 June | 96 | 9 | 105 |
| 2017 May | 61 | 13 | 74 |
| 2017 April | 81 | 11 | 92 |
| 2017 March | 218 | 12 | 230 |
| 2017 February | 257 | 14 | 271 |
| 2017 January | 135 | 13 | 148 |
| 2016 December | 84 | 8 | 92 |
| 2016 November | 119 | 9 | 128 |
| 2016 October | 141 | 9 | 150 |
| 2016 September | 167 | 12 | 179 |
| 2016 August | 278 | 20 | 298 |
| 2016 July | 226 | 18 | 244 |
| 2016 June | 145 | 0 | 145 |
| 2016 May | 148 | 0 | 148 |
| 2016 April | 158 | 0 | 158 |
| 2016 March | 107 | 0 | 107 |
| 2016 February | 121 | 0 | 121 |
| 2016 January | 122 | 0 | 122 |
| 2015 December | 131 | 0 | 131 |
| 2015 November | 123 | 0 | 123 |
| 2015 October | 102 | 0 | 102 |
| 2015 September | 87 | 0 | 87 |
| 2015 August | 78 | 0 | 78 |
| 2015 July | 79 | 0 | 79 |
| 2015 June | 44 | 0 | 44 |
| 2015 May | 91 | 0 | 91 |
| 2015 April | 9 | 0 | 9 |
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