Rapid Response to Cyclosporin A and Favorable Renal Outcome in Nongenetic Versus Genetic Steroid-Resistant Nephrotic Syndrome

Abstract

Background and objectives: Treatment of congenital nephrotic syndrome (CNS) and steroid-resistant nephrotic syndrome (SRNS) is demanding, and renal prognosis is poor. Numerous causative gene mutations have been identified in SRNS that affect the renal podocyte. In the era of high-throughput sequencing techniques, patients with nongenetic SRNS frequently escape the scientific interest. We here present the long-term data of the German CNS/SRNS Follow-Up Study, focusing on the response to cyclosporin A (CsA) in patients with nongenetic versus genetic disease.

Design, setting, participants, & measurements: Cross-sectional and longitudinal clinical data were collected from 231 patients with CNS/SRNS treated at eight university pediatric nephrology units with a median observation time of 113 months (interquartile range, 50-178). Genotyping was performed systematically in all patients.

Results: The overall mutation detection rate was high at 57% (97% in CNS and 41% in SRNS); 85% of all mutations were identified by the analysis of three single genes only (NPHS1, NPHS2, and WT1), accounting for 92% of all mutations in patients with CNS and 79% of all mutations in patients with SRNS. Remission of the disease in nongenetic SRNS was observed in 78% of patients after a median treatment period of 2.5 months; 82% of nongenetic patients responded within 6 months of therapy, and 98% of patients with nongenetic SRNS and CsA-induced complete remission (normalbuminemia and no proteinuria) maintained a normal renal function. Genetic SRNS, on the contrary, is associated with a high rate of ESRD in 66% of patients. Only 3% of patients with genetic SRNS experienced a complete remission and 16% of patients with genetic SRNS experienced a partial remission after CsA therapy.

Conclusions: The efficacy of CsA is high in nonhereditary SRNS, with an excellent prognosis of renal function in the large majority of patients. CsA should be given for a minimum period of 6 months in these patients with nongenetic SRNS. In genetic SRNS, response to CsA was low and restricted to exceptional patients.

Keywords: FSGS; NPHS1; NPHS2; WT1; cyclosporine A; humans; kidney failure, chronic; mutation; steroid resistant nephrotic syndrome.

Figure 1.

Age at onset of congenital nephrotic syndrome/steroid–resistant nephrotic syndrome in age groups. Patients with genetic disease are depicted in black; patients with nongenetic disease are depicted in light gray. Percentages refer to the fraction of patients with genetic disease.

Figure 2.

Distribution of podocyte gene mutations in patients with genetic congenital nephrotic syndrome (CNS) and steroid–resistant nephrotic syndrome (SRNS). (A) Gene mutations in the total study cohort of patients with genetic disease (n=131). 85% of mutations were identified in NPHS1, NPHS2, and WT1. All other gene mutations were rare events affecting a small number of patients. (B) Distribution of podocyte gene mutations in patients with genetic CNS (left panel; n=60) and genetic SRNS (right panel; n=71).

Figure 3.

Response to cyclosporin A (CsA) treatment and renal outcome in patients with either nongenetic or genetic disease. (A) Response to CsA treatment. Patients (numbers) with complete remission (CR) are depicted in light gray, patients with partial remission (PR) are depicted in gray, and patients with no remission (NR) are depicted in black. The group of patients with genetic congenital nephrotic syndrome (CNS) /steroid–resistant nephrotic syndrome (SRNS) is further divided into patients with CNS and patients with SRNS (on the right). The two patients with nongenetic CNS were not exposed to CsA and are, therefore, not depicted in this graph. Percentages refer to CR and PR. **P<0.001. (B) Renal function in patients with either nongenetic or genetic disease depending on their response to CsA treatment. Patients (numbers) with a normal renal function at the end of the observation time are shown in light gray, patients with chronic CKD are shown in gray, and patients with ESRD are shown in black. *P=0.002; **P<0.001.

Figure 4.

Time to response to cyclosporin A (CsA) in nongenetic patients with complete remission. 50% of patients responded within 2.5 months of treatment (median; dashed line), and 82% of patients responded within 6 months of treatment (dotted line).