Successful treatment of steroid-resistant nephrotic syndrome associated with WT1 mutations

Abstract

The Wilms' tumor suppressor gene 1 (WT1) encodes a transcription factor involved in kidney and gonadal development. WT1 is also a key regulator of podocyte functions and mutations have been found in a small percentage of children with isolated or syndromal steroid-resistant nephrotic syndrome. It is commonly assumed that the nephrotic syndrome (NS) in patients with WT1 mutations is unresponsive to therapy and characterized by rapid progression to end-stage renal disease. We report long-term observations in 3 children with focal-segmental glomerulosclerosis associated with WT1 mutations and NS (2 cases) or nephrotic range proteinuria (1 case). All patients showed a favorable response to an intensified therapy consisting of cyclosporin A (CyA) in combination with induction therapy with intravenous and oral prednisone. Treatment with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers was added to the regimen at various times. As shown both by the short-term response and during long-term follow-up, this treatment resulted in clinical remission of the NS and/or significant reduction of proteinuria, while normal renal function could be maintained over many years. Thus, glomerular diseases in selected patients with mutations in genes regulating renal development and podocyte function may respond to combination therapy with CyA and corticosteroids.

Immunosuppression and Renal Outcome in Congenital and Pediatric Steroid-Resistant Nephrotic Syndrome

“…Recently, it was demonstrated that the antiproteinuric properties of CsA may also result from a direct stabilization of the actin cytoskeleton (19). The hypothesis of these authors suggests that CsA might be a promising therapeutic agent for SRNS patients of all entities, immunological as well as hereditary, and it is supported by a few case reports describing a (partial) response to CsA treatment in patients with WT1, NPHS2, and PLCE1 mutations (7,(15)(16)(17)(18). In the study by Ruf et al reporting NPHS2 mutational analysis in 190 SRNS patients, 29 patients with mutations in NPHS2 were included who have received CsA or cyclophosphamide.…”

“…However, the benefit of intensified immunosuppressive therapy in these patients has not yet been demonstrated by a systematic analysis. The clinical experience is limited to single-center observations demonstrating a partial response to CsA in selected patients (7,(15)(16)(17)(18).…”

Podocyte directed therapy of nephrotic syndrome—can we bring the inside out?

“…Additional evidence derives from studies in children with genetic podocytopathies. Here cyclosporine A was demonstrated to have an anti-proteinuric effect in cases with mutations in the WT-1, podocin and phospholipase C epsilon genes [45][46][47].…”

Wilms' tumor suppressor gene mutations in girls with sporadic isolated steroid-resistant nephrotic syndrome

“…Previous studies have reported that the IVS9+5G>A mutation in WT1 can cause Denys-Drash and Frasier syndromes and also lead to isolated SRNS Aucella et al, 2006;Löwik et al, 2008;Chernin et al, 2010;Li et al, 2010;Gellermann et al, 2010;Megremis et al, 2011). A total of 11 girls had isolated SRNS caused by the IVS9+5G>A WT1 mutation (Table 2).…”