steroid‑resistant nephrotic syndrome (SRNS)

- Introduction

Most nephrotic children have steroid-sensitive nephrotic syndrome (SSNS), with only 20% of them having steroid resistant nephrotic syndrome (SRNS), depending on the geographic area [1]. MCD is the most common histopathology in SSNS, while children with SRNS have MCD, mesangial proliferative glomerulonephritis, or focal and segmental glomerulosclerosis (FSGS) [2]. In children, SRNS is defined as those who do not show remission after 6 weeks and standard dose of oral steroids ± 3 IV MPD doses [3]. Most nephrotic children (85–92%) show idiopathic type that affects only the kidney without extrarenal involvement and without identifiable cause. MCD pathology constitutes (75–85%) and FSGS (7–10%), while other histological types are rare [KDIGO 2021] [4]. The secondary type where the immune complex renal injury is mediated by a primary cause is less common and is related to drugs, infections, and autoimmune diseases such as lupus, IgAV, ANCA vasculitis, Wegner granulomatosis, AGBM, sarcoidosis, malignancies, and sickle cell disease.

Congenital and hereditary podocytopathies constitute two thirds of SRNS presenting in the first year of life and result from mutation in podocytes regulating genes [KDIGO 2021] [4]. Identification of a podocyte gene defect is fundamental to determine treatment response to steroids and calcineurin inhibitors. It is far superior to histopathology classification in predicting response to immune suppression, clinical course and progress to ESRD, and risk of post-transplant recurrence, thereby subsequent management of SRNS. To date, over sixty

genes have been identified as causing monogenic forms of SRNS recessive or dominant with an onset before 25 years [5–8]. Family counseling, screening of at-risk family members, and prenatal diagnosis are major steps following genetic diagnosis.

Renal biopsy and antibody serology is also crucial. Light microscopy identifies histopathology as MCD, FSGS, DMS or MP, MN and grade tubular atrophy, interstitial fibrosis, and glomerulosclerosis as prognostic markers of chronicity [9]. Occasionally, SRNS is secondary to infectious disease, drugs, and autoimmune disease such as SLE, IgA vasculitis, and malignancy. Therefore, infection screen for viruses and bacteria as well as serology tests for antibodies (ASOT, ANA, ADNA, ANCA, PLA2R ab) are important. Renal biopsy with immunofluorescence reports immune complex/complement deposits with pauci or linear or granular pattern. This helps in the diagnosis of SLE, IgAV, ANCAV, C3 C4/DDD, and immune complement mediated with membranoproliferative changes [KDIGO 2021] [4]. Electron microscopy reports the ultrastructure of glomerular basement membrane

(GBM) and podocytes that are helpful in many hereditary and syndromic types. Light microscopy without IF and EM is not enough as it would report only histopathology without referring to pathogenesis if immune complex mediated or genetic in origin [10].

SRNS without genetic mutation is expected to respond to immunosuppressive drugs with complete remission in up to 60% of cases and with partial remission in up to 19%. Those with no genetic mutation have a substantial advantage in terms of kidney survival over 10 years, with ESRD occurring in 71% of those with a genetic disease versus 29% in those without [11, 12]. Genetic types need transplantation with less rate of disease recurrence. Early treatment of infections (bacterial, viral, parasitic) [13–15], and proper treatment of auto immune disease according to its therapy plan is mandatory to prevent progress of renal injury [16, 17]. Current EPG/SRNS is an adaptation GL using both de novo IPNA 2020 and KDIGO 2021 guidelines customized to our community with high rate of infections,

consanguinity, autoimmune diseases such as SLE, and with shortage of genetic testing as routine screening for all SRNS. Renal biopsy and lab immunology are more available and thereby were suggested for EPG based on immune suppressive drug therapy plans. However, exclusion of genetic and secondary types is mandatory, as this significantly determine therapy plan.