Drug Induced Nephrotic Syndrome

Drug induced nephrotic syndrome is nephrotic range proteinuria (above 3.5 g daily, albumin under 30 g/L, oedema) caused by a medicine or toxin. It is one of the few forms of nephrotic syndrome that often remits once the cause is removed. Drug exposure accounts for an estimated 2 to 5% of adult nephrotic syndrome.

The commonest culprits and the lesions they cause:

• NSAIDs and selective cyclo oxygenase 2 inhibitors: minimal change disease, often with interstitial nephritis.
• Gold, penicillamine and tiopronin: membranous nephropathy.
• Lithium: minimal change disease and focal segmental glomerulosclerosis.
• Interferon alfa, beta and gamma: collapsing focal segmental glomerulosclerosis and minimal change disease.
• Bisphosphonates, especially pamidronate: collapsing focal segmental glomerulosclerosis.
• mTOR inhibitors such as sirolimus and everolimus: focal segmental glomerulosclerosis.
• Immune checkpoint inhibitors: minimal change disease, focal segmental glomerulosclerosis.
• Anti-VEGF agents and tyrosine kinase inhibitors: thrombotic microangiopathy.
• Captopril at high dose: membranous nephropathy.
• Heroin and anabolic steroids: focal segmental glomerulosclerosis.
• Antimicrobials including rifampicin, ampicillin and sulphasalazine or mesalazine: minimal change disease.

Herbal and skin lightening products containing mercury cause membranous nephropathy and minimal change disease. They are an important cause in many low resource settings.

Pathophysiology. Mechanisms include:

• Direct podocyte toxicity (pamidronate, interferon, heroin).
• T-cell or cytokine dysregulation (NSAIDs, lithium, checkpoint inhibitors).
• Hapten induced immune complex formation on the glomerular basement membrane (gold, penicillamine, mercury).
• Loss of podocyte survival signalling (anti-VEGF agents, mTOR inhibitors).

• Oedema, frothy urine, weight gain, and hypoalbuminaemia developing days to weeks after starting an NSAID, weeks to months after starting interferon, bisphosphonates or checkpoint inhibitors, and 3 to 12 months after starting gold or penicillamine.
• NSAID associated minimal change disease: abrupt onset, bland sediment, often acute kidney injury (30 to 50%) from hypovolaemia and interstitial nephritis.
• Collapsing focal segmental glomerulosclerosis: rapidly progressive loss of function with heavy proteinuria.
• Membranous drug lesions: insidious proteinuria, bland sediment.
• Thrombotic microangiopathy: hypertension, proteinuria, falling platelets and haemolysis (anti-VEGF agents).
• Extrarenal clues: rash, fever, eosinophilia (hypersensitivity), skin changes or neurological symptoms (mercury), injection marks (heroin).

Red flags

• Acute kidney injury with nephrotic syndrome in an NSAID user.
• Hypertension, schistocytes and rising creatinine on anti-VEGF therapy.
• Skin lightening cream, traditional medicine or occupational exposure to mercury.
• Albumin under 20 g/L, with high thrombotic risk.

• Drug and exposure history covering the 12 months before onset, including over-the-counter NSAIDs, herbal and traditional remedies, skin creams and recreational drugs. Compare the timing of first dose against onset of proteinuria.
• Urine protein:creatinine ratio, albumin, lipids, creatinine, eGFR, urine microscopy, full blood count and film, complement, hepatitis B and C, HIV, antinuclear antibodies, serum protein electrophoresis.
• Anti-phospholipase A2 receptor antibody (negative favours secondary disease).
• Urine mercury (spot or 24-hour; above 10 microg/g creatinine is raised, above 50 microg/g toxic) when a skin cream or traditional remedy is suspected.
• Kidney biopsy for most adults:
  • Minimal change disease or collapsing focal segmental glomerulosclerosis: effaced foot processes, no deposits.
  • Membranous nephropathy: spikes, IgG and C3, often with unusual IgG subclass and negative phospholipase A2 receptor staining.
  • Acute interstitial nephritis: infiltrate with eosinophils.
  • Thrombotic microangiopathy.
• Test for the underlying drug indication to avoid missing the true cause (lupus, cancer, infection).

Differential diagnosis

• Primary minimal change disease, primary focal segmental glomerulosclerosis, primary membranous nephropathy, secondary causes (lupus, infection, malignancy, amyloid, diabetes), reduced nephron mass focal segmental glomerulosclerosis, pre-eclampsia.

First line: remove the causative agent

• Stop the drug at once and avoid re-challenge, including the whole class where a class effect applies (all NSAIDs and cyclo oxygenase 2 inhibitors).
• Document the reaction in the record.
• NSAID associated minimal change disease: remission usually follows within 2 to 12 weeks of stopping. If proteinuria is still nephrotic after 2 to 4 weeks, or kidney function is falling, start prednisolone 1 mg/kg daily (maximum 60 mg) until remission (usually 4 to 8 weeks), then taper over 8 to 12 weeks.
• Gold and penicillamine membranous nephropathy: remission takes 6 to 18 months after stopping. Treat supportively. Reserve immunosuppression for persistent nephrotic syndrome with falling function (rituximab 1 g on days 1 and 15).
• Interferon: stop. Give prednisolone 1 mg/kg daily (maximum 60 mg) when proteinuria persists beyond 4 weeks or function falls. Switch to an alternative antiviral where possible (for example direct acting antivirals for hepatitis C).
• Pamidronate: stop and switch to zoledronic acid 4 mg intravenously (reduce the dose for eGFR under 60 mL/min/1.73 m² and give over at least 30 minutes) or denosumab 120 mg subcutaneously every 4 weeks with calcium and vitamin D. Collapsing disease often leaves residual loss of function.
• mTOR inhibitors: reduce the dose or switch to a calcineurin inhibitor or belatacept with the transplant team.
• Immune checkpoint inhibitor: stop the drug for grade 3 injury. Give prednisolone 1 mg/kg daily (maximum 60 mg) tapered over 4 to 6 weeks. Add mycophenolate mofetil 1 g twice daily if there is no response in 1 to 2 weeks.
• Anti-VEGF agents and tyrosine kinase inhibitors: stop or reduce the dose. Treat hypertension (amlodipine 5 to 10 mg daily, ramipril 2.5 to 10 mg daily). Discontinue permanently for thrombotic microangiopathy or proteinuria above 3 g daily.
• Mercury: stop exposure. Chelation with succimer 10 mg/kg orally every 8 hours for 5 days then every 12 hours for 14 days (adult dose by body surface area), in a toxicology unit. Steroids help in minimal change disease only.
• Lithium: review with psychiatry for a safer alternative. Give steroids for minimal change disease if proteinuria is nephrotic.

Supportive care

• Sodium under 2 g daily; furosemide 40 to 80 mg once or twice daily.
• Blood pressure below 130/80 mmHg: ramipril 2.5 mg daily increased to 10 mg daily (creatinine and potassium at 1 to 2 weeks; accept a rise up to 30%; stop if potassium exceeds 6.0 mmol/L).
• Dapagliflozin 10 mg daily (eGFR at least 25) or empagliflozin 10 mg daily (eGFR at least 20) for persistent proteinuria after the drug is removed.
• Atorvastatin 20 mg daily for persistent hyperlipidaemia.
• Prophylactic enoxaparin 40 mg daily (20 mg when eGFR is under 30) when albumin is under 20 g/L with another risk factor.
• Co-trimoxazole 480 mg daily and a proton pump inhibitor during high dose prednisolone.

Kidney replacement therapy. Dialysis for acute kidney injury meeting the usual criteria (potassium above 6.5 mmol/L refractory to treatment, pH under 7.15, fluid overload, uraemic complications). Most NSAID injuries recover.

Monitoring. Urine protein:creatinine ratio, albumin and creatinine weekly during acute kidney injury, then every 2 to 4 weeks until remission, then every 3 months for a year. Relapse suggests ongoing exposure.

Referral and escalation. Nephrology for all adults with nephrotic syndrome; toxicology for mercury or lead; oncology for checkpoint inhibitor or anti-VEGF toxicity; urgent for acute kidney injury or thrombosis.

Special groups

• Older adults: NSAIDs are the commonest cause; avoid all NSAIDs and cyclo oxygenase 2 inhibitors permanently.
• Pregnancy: stop the drug; avoid penicillamine, gold and angiotensin blockers; aspirin 75 to 150 mg daily from 12 weeks.
• Low resource settings: ask about traditional medicines, skin lightening creams and over-the-counter analgesics.