Steroid Resistant Nephrotic Syndrome-Genetic Consideration

Abstract

Nephrotic syndrome is defined as the association of massive proteinuria, hypoalbuminaemia, edema, and hyperlipidemia. It is separated to steroid-sensitive or steroid-resistant (SRNS) forms in respect to the response to intensive steroid therapy. SRNS usually progresses to end-stage renal failure. According to the North American Pediatric Renal Trials and Collaborative Studies SRNS constitutes the second most frequent cause of ESRD in the first two decades of life. Unfortunately, there is no curative treatment for majority of patients. Majority of the SRNS patients have the histologic picture of focal segmental glomerulosclerosis. Interestingly, the risk of recurrence in the kidney graft in patients with hereditary SRNS is lower than in those who do not have genetic background. The etiology and pathogenesis of SRSN has remained enigma for decades. The discovery of 39 dominant or recessive SRNS genes enabled better understanding of the function of the glomerular podocytes and slit membrane. Hildebrandt's group has shown that 85% of the SRNS cases with onset by 3 months of age and 66% with onset by 1 year of age can be explained by recessive mutations in one of four genes only (NPHS1, NPHS2, LAMB2, or WT1). The same group used modern diagnostic techniques such as the next generation sequencing and tested a large international cohort of SRNS patients (n = 1783 families). The diagnostic panel included 21 genes with a recessive mode of inheritance and 6 genes with a dominant mode of inheritance. Single-gene cause was detected in 29.5% (526 of 1783) of the families with SRNS that manifested before 25 years of age. The identification of causative single-gene mutations may have important therapeutic consequences in some cases. This is very important for patients who carry mutations in a gene of coenzyme Q10 biosynthesis (COQ2, COQ6, ADCK4, or PDSS2). In these patients the treatment with coenzyme Q10 may be indicated. Also, patients with recessive mutations in PLCE1 may respond fully to the treatment with steroids or cyclosporine A. The patients with CUBN may benefit the treatment with vitamin B12. The detection of causative mutations may also be very important for familial genetic counseling and for prenatal diagnosis.

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

“…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].…”

“…Idiopathic nephrotic syndrome (INS) is one of the most common renal diseases in the pediatric population, which is characterized by massive proteinuria, hypoalbuminemia, edema, and hyperlipidemia [1]. About 10-20% of affected children have steroid-resistant nephrotic syndrome (SRNS) and do not respond well to steroid therapy [2,3].…”

Molecular genetic analysis of Steroid Resistant Nephrotic Syndrome: Detection of a novel mutation

“…( 0.058, 0.671,_) ( Table.3) . NPHS2 mutations have been reported as the most common cause of childhood onset in autosomal recessive SRNS (Sadowski et al 2015;Guaragna et al 2015;Tasic et al 2015). The most frequent renal histological feature Associated with SRNS is focal segmental glomerulosclerosis (FSGS) (Joshi et al 2013;Liu and Wang 2017).…”

“…Patients in whom proteinuria does not stop after about one month are classified as resistant which describe as steroid resistant nephrotic syndrome(SRNS) (Mekahli et al 2009). SRNS is considered as a poor prognostic disease, in which 30-40% of it progresses to end stage renal disease(ESRD), requiring dialysis and transplantation (Tasic et al 2015). The most frequent renal histological feature associated with SRNS is focal segmental glomerulosclerosis (FSGS).…”

The importance of genetic study in steroid-resistant nephrotic syndrome

“…Steroid-resistant nephrotic syndrome (SRNS) is a challenging clinical task since it has heterogeneous etiology and extremely variable clinical outcomes (1). The prevalence of SRNS is 15% in children and 40% in adults (2). Renal histology in most of SRNS cases displays the presence of focal segmental glomerulosclerosis (FSGS), proliferative glomerulonephritis, and minimal change disease (MCD) (2,3).…”