Hereditary steroid-resistant nephrotic syndrome

Hereditary steroid-resistant nephrotic syndrome (SRNS), also known as familial steroid-resistant nephrotic syndrome, is a group of genetically determined kidney disorders characterized by massive proteinuria (protein loss in the urine), hypoalbuminemia (low blood albumin levels), edema (swelling), and hyperlipidemia (elevated blood fats) that do not respond to standard corticosteroid therapy. The condition primarily affects the glomeruli — the tiny filtering units within the kidneys — leading to damage of the podocytes, which are specialized cells critical for maintaining the kidney's filtration barrier. Histologically, the most common finding is focal segmental glomerulosclerosis (FSGS), though minimal change disease and diffuse mesangial sclerosis may also be observed. Hereditary SRNS can be caused by mutations in numerous genes, including NPHS1 (nephrin), NPHS2 (podocin), WT1, LAMB2, PLCE1, TRPC6, ACTN4, INF2, CD2AP, and many others. These genes encode proteins essential for podocyte structure and function or for the integrity of the glomerular basement membrane. The genetic heterogeneity is substantial, with both autosomal recessive forms (more commonly presenting in childhood) and autosomal dominant forms (often presenting later in life). Some forms are syndromic, involving extrarenal manifestations such as neurological abnormalities, eye defects, or skeletal anomalies, while others are isolated to the kidneys. Because the disease is resistant to corticosteroids by definition, treatment options are limited. Calcineurin inhibitors (such as cyclosporine or tacrolimus) may achieve partial remission in some genetic subtypes, but many patients progress to end-stage kidney disease (ESKD) requiring dialysis or kidney transplantation. Importantly, patients with certain genetic forms (particularly NPHS2 mutations) have a lower risk of disease recurrence after transplantation compared to non-genetic FSGS. Supportive care includes ACE inhibitors or angiotensin receptor blockers to reduce proteinuria, management of edema with diuretics, and treatment of hyperlipidemia. Genetic testing is strongly recommended to guide prognosis, treatment decisions, and genetic counseling for affected families.

Data sourced from FDA regulatory filings and ClinicalTrials.gov. Updated periodically.

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