Marcella Greco

Risk Factors for Cyclosporin A Nephrotoxicity in Children with Steroid-Dependant Nephrotic Syndrome

BACKGROUND AND OBJECTIVES Cyclosporin A (CsA) is a well-established treatment for steroid-dependent nephrotic syndrome (SDNS) that may, however, cause chronic ischemic renal lesions. The objective of the study was to assess the prevalence of CsA nephrotoxicity (CsAN) in protocol biopsies of children with SDNS. DESIGN, SETTINGS, PARTICIPANTS, & MEASUREMENTS From 1990 through 2008, we performed 71 renal biopsies in 53 patients with SDNS. The mean CsA C2 levels were 466 +/- 134 ng/ml, and the mean duration of treatment was 4.7 +/- 2.0 yr before biopsy (range 2.9 to 12.7 yr). RESULTS CsAN was observed in 22 (31%) of 71 renal biopsies. Of these, 11 corresponded to isolated vascular or tubular lesions, and 11 corresponded to combined vascular and tubular lesions. The majority of CsAN lesions were mild (17 of 22). In no cases were lesions graded as severe. By regression analysis, CsAN was positively associated with the use of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) and with hyperuricemia and negatively associated with minimal-change lesions. By multivariate analysis, only association with the use of ACEIs or ARBs retained significance. Stratification of the population according to CsA C2 levels showed increased risk for CsAN for C2 levels >600 ng/ml. CONCLUSIONS Mild to moderate CsAN occurs in approximately one third of patients who have SDNS and are treated with CsA for >3 yr. Our data suggest that patients who require high dosages of CsA or treatment for hypertension, in particular when ACEIs/ARBs are used, are at higher risk for CsAN.

Acute tubulointerstitial nephritis occurring with 1-year lapse in identical twins

We report monozygotic female twins who developed acute tubulointerstitial nephritis, with identical histological features and similar clinical symptoms, 1 year apart. Both patients presented with acute renal failure; only one developed bilateral uveitis after the onset of the nephritis.

Mutational spectrum of the CTNS gene in Italy

Classic nephropathic or infantile cystinosis (NC) is an autosomal recessive disorder; the gene coding for the integral membrane protein cystinosin, which is responsible for membrane transport of cystine (CTNS), was cloned. Mutation analysis of the CTNS gene of Caucasian patients revealed a common 57-kb deletion, and several other mutations spread throughout the entire gene. In the present study, we report the CTNS mutations identified in 42 of 46 Italian families with NC. The percentage of mutations characterized in this study is 86%. The mutational spectrum of the Italian population is different from that of populations of North European origin: the 57-kb deletion is present in a lower percentage, while the splicing mutations represent 30% of mutation detected in our sample. In all, six novel mutations have been identified, and the origin of one recurrent mutation has been traced.

Copper deficiency in patients with cystinosis with cysteamine toxicity

OBJECTIVES To assess whether copper deficiency plays a role in the recently described cysteamine toxicity in patients with cystinosis, and to examine whether polymorphisms in copper transporters, lysyl oxidase, and/or type I procollagen genes could be responsible for the occurrence of cysteamine toxicity in a small subset of patients with cystinosis. STUDY DESIGN Thirty-six patients with cystinosis were included: 22 with Fanconi syndrome (including 7 with cysteamine toxicity), 12 after renal transplantation, 1 receiving hemodialysis, and 1 with ocular cystinosis. Serum copper and ceruloplasmin levels and urinary copper/creatinine ratio were measured. Genes ATP7A and CTR1 (encoding copper transporters), LOX (encoding lysyl oxidase), and COL1A1 and COL1A2 (encoding type I procollagen) were analyzed in patients with (n = 6) and without (n = 5) toxicity. Fibroblast (pro)collagen synthesis was compared in patients with (n = 3) and those without (n = 2) cysteamine toxicity. RESULTS All 22 patients with Fanconi syndrome had increased urinary copper excretion. Serum copper and ceruloplasmin levels were decreased in 9 patients, including all 7 patients with cysteamine toxicity. No specific sequence variations were associated with toxicity. All fibroblasts exhibited normal (pro)collagen synthesis. CONCLUSION Patients with cystinosis with cysteamine toxicity demonstrate copper deficiency. This can cause decreased activity of lysyl oxidase, the enzyme that generates the aldehydes required for collagen cross-linking. Thus, copper supplementation might prevent cysteamine toxicity.

Controversies and research agenda in nephropathic cystinosis: conclusions from a “Kidney Disease: Improving Global Outcomes” (KDIGO) Controversies Conference

Nephropathic cystinosis is an autosomal recessive metabolic, lifelong disease characterized by lysosomal cystine accumulation throughout the body that commonly presents in infancy with a renal Fanconi syndrome and, if untreated, leads to end-stage kidney disease (ESKD) in the later childhood years. The molecular basis is due to mutations in CTNS, the gene encoding for the lysosomal cystine-proton cotransporter, cystinosin. During adolescence and adulthood, extrarenal manifestations of cystinosis develop and require multidisciplinary care. Despite substantial improvement in prognosis due to cystine-depleting therapy with cysteamine, no cure of the disease is currently available. Kidney Disease: Improving Global Outcomes (KDIGO) convened a Controversies Conference on cystinosis to review the state-of-the-art knowledge and to address areas of controversies in pathophysiology, diagnostics, monitoring, and treatment in different age groups. More importantly, promising areas of investigation that may lead to optimal outcomes for patients afflicted with this lifelong, systemic disease were discussed with a research agenda proposed for the future.