Steroid-Resistant Nephrotic Syndrome

Steroid resistant nephrotic syndrome is nephrotic syndrome that fails to remit after 4 to 6 weeks of daily prednisolone 60 mg/m2. Biopsy usually shows focal segmental glomerulosclerosis, minimal change disease or diffuse mesangial proliferation.

It makes up about 10 to 20% of childhood nephrotic syndrome. A genetic cause is found in about 30% overall and in a higher proportion of children with onset under 1 year, familial disease, or syndromic features. Genes include NPHS1, NPHS2, WT1, LAMB2, COL4A3, COL4A4, COL4A5 and TRPC6.

Prognosis depends on the response to treatment. Children who respond to calcineurin inhibitors have a good prognosis, while those with genetic or persistent disease often progress to end stage kidney disease within 10 years.

Pathophysiology.

Podocyte genes encode slit diaphragm, cytoskeletal and basement membrane proteins. Loss of function causes podocyte injury and focal segmental glomerulosclerosis that does not respond to immunosuppression.

In non-genetic disease, circulating permeability factors or immune dysregulation damage the filtration barrier, and recurrence after transplantation can occur.

• Persistent oedema, proteinuria and hypoalbuminaemia despite steroids.
• Hypertension, haematuria and reduced kidney function.
• Syndromic features in some genetic forms: genital anomalies, Wilms tumour (WT1), eye anomalies (LAMB2), deafness (COL4 genes).

Red flags.

• Onset under 1 year, family history, consanguinity, or extrarenal features.
• Rapid decline in kidney function.
• Severe oedema with hypovolaemia, thrombosis or infection.

• Confirm steroid resistance after adequate daily prednisolone, and exclude infection, non-adherence and a wrong diagnosis.
• Kidney biopsy with light microscopy, immunofluorescence and electron microscopy before starting calcineurin inhibitors.
• Genetic testing (panel or exome) in all children with steroid resistance, particularly infantile onset, familial or syndromic disease.
• Urea, creatinine, estimated glomerular filtration rate, C3, C4, antinuclear antibody, hepatitis B and C, HIV and urinalysis.

Differential diagnosis. Lupus nephritis, membranous nephropathy, IgA nephropathy, post-infectious glomerulonephritis, C3 glomerulopathy, Alport syndrome, congenital nephrotic syndrome and secondary causes (infection, drugs).

• Calcineurin inhibitor in non-genetic disease: tacrolimus 0.1 to 0.2 mg/kg/day in 2 doses (trough 5 to 8 ng/mL) or ciclosporin 3 to 5 mg/kg/day in 2 doses (trough 80 to 120 ng/mL), with low dose alternate day prednisolone, continued for at least 12 months if there is a response.
• Reduce proteinuria and protect kidneys with an angiotensin converting enzyme inhibitor (enalapril 0.1 mg/kg/day, increased up to 0.5 mg/kg/day, maximum 40 mg) or angiotensin receptor blocker, monitoring potassium and creatinine.
• Rituximab 375 mg/m2 IV, or mycophenolate mofetil 1200 mg/m2/day, for resistant disease under specialist direction.
• Genetic forms usually do not respond to immunosuppression, which should be stopped to avoid toxicity.
• Supportive care: salt restriction, diuretics for oedema, treatment of hyperlipidaemia, hypertension, infection and thrombosis, vaccinations, and nutritional support.
• End stage kidney disease: dialysis and transplantation. Recurrence after transplantation (about 30% in non-genetic disease) is treated with plasma exchange and rituximab.

Monitoring. Proteinuria, kidney function, blood pressure, drug trough levels, growth and calcineurin inhibitor toxicity, with repeat biopsy if function worsens.

Referral and escalation. All children should be under a paediatric nephrology service, with genetic counselling for the family.