A new gel formulation of topical cysteamine for the treatment of corneal cystine crystals in cystinosis: the Cystadrops OCT-1 study.

OBJECTIVE: To establish the safety and efficacy of a new gel formulation of cysteamine hydrochloride (CH) eye drops, for the treatment of corneal complications of nephropathic cystinosis. DESIGN: Open label dose response clinical trial. PARTICIPANTS: Eight patients with infantile nephropathic cystinosis including 4 children, 3 adolescents, and 1 adult (mean age at inclusion, 12.1 ± 4.6 years) treated with CH 0.1% eye drops. INTERVENTION: Patients were treated, in both eyes, with the control CH 0.1% eye drop formulation on average 4 times daily for one month and then switched to Cystadrops® at the same dose frequency. Based on clinical ocular findings, the dose regimen was adapted at D30 and D90 in order to decrease the frequency of instillation. After D90, this dose frequency was maintained, except in cases of crystal density worsening. Patients had a follow-up visit every 6 months during 48 months. MAIN OUTCOME MEASURES: Safety assessment consisted of adverse event and serious adverse event monitoring and recording at each visit. For the efficacy study, the primary endpoint was the corneal cystine crystal density measured with an in vivo confocal microscopy (IVCM) score. RESULTS: All patients completed the study. During the 4-year study period, neither serious adverse events nor significant adverse events related to the study drug were reported. After switching to Cystadrops®, the IVCM total score decreased from baseline to D90 by a mean of 28.6 ± 17.5% (p<0.001). From D90 to M48, the IVCM total score remained stable and significantly decreased as compared to that at D1 despite a reduced dose regimen from D90. At M48, the mean IVCM total score was 8.13 ± 4.15, decreased by a mean 29.9 ± 26.29% from D1 (p = 0.001), with a reduced number of instillations compared to that at D1. The IVCM total score and photophobia were significantly correlated (p = 0.04). CONCLUSION: This study provides evidence that Cystadrops® gel is superior to the CH 0.1% formulation in terms of efficacy and has a good safety profile over a long follow-up period.

In vivo reflectance confocal microscopy of the skin: a noninvasive means of assessing body cystine accumulation in infantile cystinosis.

BACKGROUND: Patients with infantile nephropathic cystinosis have progressive accumulation of cystine in tissues leading to delayed extrarenal complications. No simple tool is available to evaluate the level of body cystine accumulation. OBJECTIVE: We sought to determine the value of in vivo reflectance confocal microscopy of the skin in patients with infantile nephrogenic cystinosis. METHODS: Nine patients and control subjects were recruited for this study. Images were acquired by means of a near-infrared reflectance confocal laser scanning microscope. RESULTS: Scattered bright particles within the papillary dermis were observed in all patients but not in control subjects. The density of particles ranged from numerous (+++) to very few (+/-) and their distribution was heterogeneous. Electron microscopy confirmed that these particles corresponded to cystine crystal deposits within dermal fibroblasts. The density of cystine crystals within the dermis was greater in older patients, in patients with a high leukocyte cystine concentration, and with delayed cysteamine therapy. There was no correlation between the density of cystine deposits and renal disease or hypopigmentation but high levels of deposition occurred in association with extrarenal manifestations. LIMITATIONS: This is a preliminary study on a small sample of patients. Repeated examination and longer follow-up is necessary. CONCLUSION: In vivo reflectance confocal microscopy of the skin appears to be a noninvasive means of assessing body cystine accumulation in infantile cystinosis and could be used as a complementary marker of treatment response in addition to leukocyte cystine measurement.

Cystinosin is a melanosomal protein that regulates melanin synthesis.

Cystinosis is a rare autosomal recessive disease characterized by cystine crystal accumulation leading to multiorgan dysfunctions and caused by mutation in CTNS. CTNS encodes cystinosin, a cystine/H(+) symporter that exports cystine out of the lysosomes. Patients with cystinosis frequently exhibit blond hair and fair complexion, suggesting an alteration in melanogenesis. However, the pigmentation singularities of these patients have not been studied, and the role of cystinosin in melanogenesis has remained unknown. In our study, a clinical evaluation of 27 patients with cystinosis showed that 44% had a cutaneous pigmentation dilution compared to their relatives. Analysis of the hair melanin content in these patients by HPLC demonstrated a 50% decrease in eumelanin (4360 vs. 9360 ng/mg), and a 2-fold increase in pheomelanin (53 vs. 20 ng/mg), the yellow/red pigments. Cystinosin-deficient mice also showed a 4-fold increase in hair pheomelanin content. In vitro studies showed that cystinosin was located at melanosomes. CTNS silencing led to a 75% reduction of melanin synthesis that was caused by a degradation of tyrosinase by lysosomal proteases. Our results objectify the pigmentation defect in patients with cystinosis. We also identify the role of CTNS in melanogenesis and add a new gene to the list of the genes involved in the control of skin and hair pigmentation.

Cysteamine therapy delays the progression of nephropathic cystinosis in late adolescents and adults.

Nephropathic cystinosis is a multisystem autosomal recessive disease caused by cystine accumulation, which is usually treated by oral cysteamine. In order to determine long-term effects of this therapy, we enrolled 86 adult patients (mean age 26.7 years) diagnosed with nephropathic cystinosis, 75 of whom received cysteamine. Therapy was initiated at a mean age of 9.9 years with a mean duration of 17.4 years. By last follow-up, 78 patients had end-stage renal disease (mean age 11.1 years), 62 had hypothyroidism (mean age 13.4), 48 developed diabetes (mean age 17.1 years), and 32 had neuromuscular disorders (mean age 23.3 years). Initiating cysteamine therapy before 5 years of age significantly decreased the incidence and delayed the onset of end-stage renal disease, and significantly delayed the onset of hypothyroidism, diabetes, and neuromuscular disorders. The development of diabetes and hypothyroidism was still significantly delayed, however, in patients in whom therapy was initiated after 5 years of age, compared with untreated patients. The life expectancy was significantly improved in cysteamine-treated versus untreated patients. Thus, cysteamine decreases and delays the onset of complications and improves life expectancy in cystinosis. Hence, cysteamine therapy should be introduced as early as possible during childhood and maintained lifelong.

In vivo confocal microscopy and anterior segment optical coherence tomography analysis of the cornea in nephropathic cystinosis.

OBJECTIVE: To analyze the corneas of patients with nephropathic cystinosis using in vivo confocal microscopy (IVCM) and anterior segment optical coherence tomography (AS-OCT). DESIGN: Prospective case series. PARTICIPANTS: Sixteen eyes of 8 patients with nephropathic cystinosis aged 8 to 21 years. METHODS: The ophthalmologic evaluation included best-corrected visual acuity, evaluation of photophobia (0-4), slit-lamp biomicroscopy analysis, intraocular pressure measurement, evaluation of crystal density using a slit-lamp-based scoring of the cornea, as well as AS-OCT and IVCM analysis. MAIN OUTCOME MEASURES: The depth of crystal deposition (DCD) in the central cornea and the central cornea thickness (CCT) were assessed using AS-OCT and IVCM. The IVCM images were evaluated for crystal density in each corneal layer and an IVCM score was calculated for each eye. RESULTS: All eyes had corneal crystal deposits, with a mean slit-lamp photography score of 2.90+/-0.13 (range, 2.75-3.00). Using AS-OCT, corneal crystals were observed in all eyes. These crystals appeared as hyperreflective punctuate deposits, predominantly observed within the anterior stroma. Measured with AS-OCT, the mean depth of DCD in the central cornea was 291.40+/-81.42 microm (range, 200-531 microm); the mean CCT was 543.47+/-29.62 microm. Using IVCM, the crystals appeared as spindle, needle-shaped, and fusiform hyperreflective bodies measuring from 1 to 175 microm in length and 1 to 30 microm in thickness. Except for the endothelium, randomly oriented crystals were observed in all corneal layers, with the greatest density observed within the anterior stroma. Measured with IVCM, the mean DCD was 426.07+/-88.19 microm (range, 284-531 microm); the mean CCT was 531.87+/-34.77 microm. There was no significant difference between the CCT measurements obtained with IVCM and with AS-OCT (mean difference, 11.31 microm; P = 0.07). Nevertheless, the DCD was significantly higher with IVCM than with AS-OCT (mean difference, 126.25 microm; P<0.0001). CONCLUSIONS: In patients with nephropathic cystinosis, IVCM could precisely quantify the density of crystals within the central cornea. Anterior segment OCT and IVCM should be used in further studies evaluating crystal deposition in patients with nephropathic cystinosis. FINANCIAL DISCLOSURE(S): The authors have no proprietary or commercial interest in any materials discussed in this article.

Complement factor H deficiency and posttransplantation glomerulonephritis with isolated C3 deposits.

We report the first cases of atypical hemolytic and uremic syndrome associated with complement factor H (CFH) deficiency in native kidneys and glomerulonephritis with isolated C3 deposits after kidney transplantation. Two boys developed atypical hemolytic and uremic syndrome at 16 and 11 months of age, associated with low C3 and CFH levels. Both rapidly progressed to end-stage renal failure and received a kidney transplant. Patient 1 had combined CFH and complement factor I (CFI) heterozygous mutations and a membrane cofactor protein (gene symbol, CD46) gene polymorphism. Five years posttransplantation, an allograft biopsy specimen showed numerous mesangial and extramembranous C3 deposits, although the patient had no biological sign of glomerulopathy. Nine years after transplantation, he was well with stable kidney function. Patient 2, who had a homozygous CFH mutation, developed glomerulonephritis with isolated C3 deposits 5 months after kidney transplantation while he was treated for early recurrence of hemolytic anemia. Four years later, the second kidney transplant biopsy specimen showed recurrence of thrombotic microangiopathy. Six years posttransplantation, kidney function was stable and complete blood cell count was normal with regular plasma therapy. These observations suggest that constitutional dysregulation of the alternative pathway is associated with a wide spectrum of kidney diseases, and glomerulonephritis with isolated C3 deposits and thrombotic microangiopathy may be different expressions of the same condition. Several factors could influence the disease, such as degree of CFH haploinsufficiency and other complement alternative pathway regulator abnormalities, such as a membrane cofactor protein polymorphism.

Prognosis of autosomal dominant polycystic kidney disease diagnosed in utero or at birth.

The use of prenatal ultrasonography has resulted in increased numbers of fetuses being diagnosed with autosomal dominant polycystic kidney disease (ADPKD), but the long-term prognosis is still not well-known. Between 1981 and 2006 we followed 26 consecutive children with enlarged hyperechoic kidneys detected between the 12th week of pregnancy and the first day of life (Day 1) as well as one affected parent. Three other fetuses were excluded following the termination of the pregnancy. The mother was the transmitting parent in 16 of the 26 children (ns, p=0.1). Clinical features that presented during follow-up were oligoamnios (5/26), neonatal pneumothorax (3/26), pyelonephritis (5/26), gross hematuria (2/26), hypertension (5/26), proteinuria (2/26) and chronic renal insufficiency (CRI) (2/26). At the last follow-up (mean duration of follow-up: 76 months; range: 0.5-262 months), 19 children (mean age: 5.5 years) were asymptomatic, five (mean age: 8.5 years) had hypertension, two (mean age: 9.7 years) had proteinuria and two (mean age: 19 years) had CRI. Children presenting enlarged kidneys postnatally tended to have more clinical manifestations than their counterparts who did not. Of 25 siblings of the patients, seven had renal cysts; these were detected during childhood in five siblings and in utero in two siblings. In conclusion, prognosis is favourable in most children with prenatal ADPKD, at least during childhood. The sex of the transmitting parent is not a risk factor of prenatal ADPKD. A high proportion of siblings develop early renal cysts. Abnormalities visualized by ultrasonography appear to be associated to more clinical manifestations.