Steroid-resistant nephrotic syndrome in a 4-year-old boy
A 4-year-old boy presents with 3 weeks of periorbital and leg oedema. Urine dipstick is 4+ protein, no blood. Serum albumin 17 g/L, total cholesterol 9.8 mmol/L, creatinine 28 micromol/L, complement C3 normal. He is started on prednisolone 60 mg/m2/day. After 4 weeks of daily treatment his urine remains 3+ protein and he has gained 2 kg; parents report poor adherence on some days. He then receives 4 weeks of alternate-day prednisolone 40 mg/m2, with persistent proteinuria. Blood pressure is on the 95th centile, and he has developed cushingoid features and mild hypertension. There is no family history of kidney disease. He has had no macroscopic haematuria and no known trigger.
1. Is this steroid-resistant nephrotic syndrome? What else must you consider before escalating treatment?
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Yes. Steroid-resistant nephrotic syndrome is defined as failure to achieve remission after 4 weeks of daily prednisolone at 60 mg/m2/day. This boy has persistent 3+ proteinuria after 4 weeks of daily treatment and a further 4 weeks of alternate-day prednisolone, so he meets the definition. Before escalating, I would confirm adherence. The parents report missed doses, and poor adherence is a common cause of apparent resistance. I would check a prednisolone level or supervised administration, review the dosing and administration, and ensure he has not been underdosed.
I would also exclude other causes of persistent proteinuria: infection (urinary or respiratory), thrombosis, and, less commonly, a secondary nephrotic syndrome. His complement is normal, which argues against post-infectious glomerulonephritis, and he has no haematuria or hypertension at onset. The new mild hypertension and cushingoid features are likely steroid effects. I would recheck urine protein over several days and confirm with a first-morning urine protein:creatinine ratio. If adherence is assured and proteinuria persists, he has steroid-resistant disease and needs a renal biopsy.
2. What investigations and treatment would you arrange next?
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Arrange a renal biopsy to distinguish minimal change disease from focal segmental glomerulosclerosis and other lesions; the biopsy guides prognosis and treatment. Send genetic testing for NPHS1, NPHS2, WT1, LAMB2 and other podocyte genes, especially given the early age and the possibility of a genetic form, which would make immunosuppression less likely to work. Check complement, hepatitis B and C, HIV, varicella immunity, and baseline renal function, blood pressure and bone density.
For treatment, start an ACE inhibitor or angiotensin receptor blocker for antiproteinuric effect, with monitoring of blood pressure and renal function. The first-line second agent is usually a calcineurin inhibitor: cyclosporine or tacrolimus, with therapeutic drug monitoring. If a genetic mutation is found, calcineurin inhibitors may not be effective, and the focus shifts to conservative care. Cyclophosphamide is an alternative but has gonadal toxicity. Continue supportive care: low-salt diet, fluid balance, vitamin D and calcium, and pneumococcal vaccination. Treat relapses and monitor for complications of nephrotic syndrome, including infection and thrombosis.
3. How would you monitor him and counsel the family?
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Monitor urine protein:creatinine ratio, serum albumin, renal function, blood pressure, growth, and for signs of infection. Check calcineurin inhibitor trough levels, magnesium, potassium and renal function regularly; watch for nephrotoxicity and hypertension. Monitor bone health with vitamin D and calcium intake and consider DEXA if prolonged steroids. Arrange ophthalmology review if steroids continue, and growth monitoring because steroids suppress growth.
Counsel the family that steroid-resistant disease has a higher risk of progression to chronic kidney disease than steroid-sensitive disease, and that the biopsy result will refine the prognosis. Explain that genetic testing may reveal a cause and inform recurrence risk in future children and in a transplanted kidney. Discuss the importance of adherence, the side effects of immunosuppression, and the need to report fever or infection promptly. Involve a paediatric nephrologist and dietitian, and provide written information about when to seek urgent care.