Long-Term Outcome of Steroid-Resistant Nephrotic Syndrome in Children

Abstract

We investigated the value of genetic, histopathologic, and early treatment response information in prognosing long-term renal outcome in children with primary steroid-resistant nephrotic syndrome. From the PodoNet Registry, we obtained longitudinal clinical information for 1354 patients (disease onset at >3 months and <20 years of age): 612 had documented responsiveness to intensified immunosuppression (IIS), 1155 had kidney biopsy results, and 212 had an established genetic diagnosis. We assessed risk factors for ESRD using multivariate Cox regression models. Complete and partial remission of proteinuria within 12 months of disease onset occurred in 24.5% and 16.5% of children, respectively, with the highest remission rates achieved with calcineurin inhibitor-based protocols. Ten-year ESRD-free survival rates were 43%, 94%, and 72% in children with IIS resistance, complete remission, and partial remission, respectively; 27% in children with a genetic diagnosis; and 79% and 52% in children with histopathologic findings of minimal change glomerulopathy and FSGS, respectively. Five-year ESRD-free survival rate was 21% for diffuse mesangial sclerosis. IIS responsiveness, presence of a genetic diagnosis, and FSGS or diffuse mesangial sclerosis on initial biopsy as well as age, serum albumin concentration, and CKD stage at onset affected ESRD risk. Our findings suggest that responsiveness to initial IIS and detection of a hereditary podocytopathy are prognostic indicators of favorable and poor long-term outcome, respectively, in children with steroid-resistant nephrotic syndrome. Children with multidrug-resistant sporadic disease show better renal survival than those with genetic disease. Furthermore, histopathologic findings may retain prognostic relevance when a genetic diagnosis is established.

The status quo and challenges of genetic diagnosis in children with steroid-resistant nephrotic syndrome

“…Detection of a hereditary podocytopathy is a prognostic indicator of favorable and poor long-term outcomes [4]. Genetic SRNS is associated with a high rate of ESRD in 66% of patients.…”

“…Patients with non-genetic disease developed ESRD less frequently than patients with genetic disease (27 versus 74%). Trautmann et al showed that 10-and 15-year ESRD-free survival rates in patients with a genetic diagnosis (27 and 17%) were much lower than those in patients without a genetic diagnosis (53 and 48%) [4]. Further breakdown by genetic diagnosis showed largely uniform renal survival times of the major genetic entities, with estimated 10-year ESRD-free survival rates of 28% for NPHS2-associated nephropathy, 23% for WT1-associated disease, and 29% for the less common podocytopathies [4].…”

“…For example, variants in the NPHS2 gene should avoid steroid and immunosuppressive agents, and renal transplantation is the suitable choice for these patients; patients with ADCK4 or CUBN variants may be amenable to supplementation with coenzyme Q10 or vitamin B12 [10]; patients with recessive variants in PLCE1 may respond fully to the treatment with steroids or cyclosporine A (CsA) [1]; and patients with a WT1 mutation may respond to CsA and methylprednisolone pulses [4]. However, Buscher et al showed that 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 [34].…”

“…About 10-20% of affected children have steroid-resistant nephrotic syndrome (SRNS) and do not respond well to steroid therapy [2,3]. Treatment of SRNS is very challenging due to its poor response to therapy and poor prognosis [4,5]. Among the patients with SRNS, 20-40% will gradually progress to end-stage renal disease (ESRD) [6].…”

“…About 11-50% of patients with FSGS are at risk of recurrence after kidney transplantation and eventually progress to terminal renal failure [8,9], but the risk for recurrence is lower in FSGS patients with monogenic (single gene) forms of SRNS than those with nonhereditary forms [10]. One of the new factors that may predict response to therapy and renal outcomes is genetic variants of nephrotic syndrome [4]. Patients with genetic mutations are less likely to respond to immunosuppressant therapy and more likely to develop ESRD [11].…”