Genetic steroid-resistant nephrotic syndrome (ORPHA:656)
A rare, hereditary nephrotic syndrome characterized by proteinuria, hypoalbuminemia, edema, and hyperlipidemia, with an absence of response to an initial trial of corticosteroids (i.e. steroid-resistant nephrotic syndrome; SRNS) and a generally complicated course.
Epidemiology
The annual incidence is 1/ 200,000- 500,000 children.
Clinical description
Disease onset may occur anywhere between birth and adulthood but predominantly presents in younger populations. The nephrotic syndrome is defined by severe proteinuria (Urinary Protein/Creatinine ration > 200 mg/mmol) with low serum albumin (<30 g/l) and possible edema. Biopsy shows minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS) or, more rarely, diffuse mesangial sclerosis (DMS), and podocyte foot process effacement by electron microscopy. It is multi-drug resistant and usually progresses to end-stage kidney failure; however, patients have a very low risk of recurrence after kidney transplantation.
Etiology
Causative pathogenic variants are identified in approximately 10-15% of young adults presenting with SRNS, 30% of children and at least 66% in congenital and infantile cases. Among these genes, NPHS1 (19q13.12) and NPHS2 (1q25.2) are by far the two main autosomal recessive genes implicated in SRNS while INF2 (14q32.33) and WT1 (11p13) are the leading cause of autosomal dominant SRNS. COQ8B (19q13.2) biallelic variants are commonly found in patients of Asian descent. So far, more than 60 single gene causes of SRNS have been reported, however most novel gene variants are rare and involve few families.
Diagnostic methods
Comprehensive gene panels to include all currently known SRNS genes; alternatively cascade testing starting with screening for pathogenic variants in NPHS2 and WT1, the most commonly mutated genes in children, can be performed at the initial stage and if negative expanded to large next generation sequencing based test.
Differential diagnosis
A number of hereditary renal disorders might present with persistent proteinuria, the hallmark of SRNS. These include defects in ciliary (eg. TTC21B) or tubular (eg. CLCN5, Dent disease) genes or atypical hemolytical syndrome (DGKE). There is also a number of syndromic (i.e. multiorgan) forms associated with defects in WT1, LMX1B, LAMB2, PAX2, etc.
Antenatal diagnosis
The decision regarding preimplantation genetic diagnosis and prenatal genetic testing should be discussed with the family in light of the local financial, social, and legal settings.
Genetic counseling
Recurrence risk counseling should be provided in all cases. Family members who are candidates for living-related kidney donation have to undergo genetic testing as part of evaluation; only heterozygous carriers of a recessive SRNS genetic variant may be considered as a potential donor, while a family member having a variant associated with a dominant inheritance should be dissuaded from kidney donation.
Management and treatment
International Pediatric Nephrology Association 2020 guidelines recommend discontinuing ineffective immunosuppressive therapies, and continuing non -immunosuppressive management, including RAASi and other supportive measures in patients with diagnosis of a hereditary nephrotic syndrome. There is high risk of progression to end-stage kidney disease; however, recurrence of the disease in the grafted kidney after transplantation is exceptional.
Prognosis
Life expectancy is not dramatically affected in SRNS patients, however individual outcome depends on prompt management and access to specific procedures, i.e. dialysis and kidney transplantation.

                            Last update: 
                            January 2021


                            - Expert reviewer(s): 
                            Pr Olivia BOYER | ERKNet* - Pr Beata LIPSKA-ZIETKIEWICZ | ERKNet*


                                * European Reference Network