Secondary Nephrotic Syndrome

Secondary nephrotic syndrome is nephrotic syndrome (proteinuria above 3.5 g daily, albumin under 30 g/L, oedema) caused by a systemic disease, infection, drug, malignancy or inherited condition. It is not due to a primary glomerular disease. It accounts for about 20 to 30% of adult nephrotic syndrome and a smaller share in children.

Identifying the cause matters. Treatment of the cause often controls the proteinuria. Immunosuppression given for a primary disease can harm patients with an infection.

The commonest causes are:

• diabetes, lupus and amyloidosis
• infections (hepatitis B, hepatitis C, HIV, syphilis, malaria, schistosomiasis, leprosy and tuberculosis)
• drugs (NSAIDs, lithium, interferon, pamidronate, penicillamine, gold, mTOR inhibitors, anti-VEGF agents)
• malignancy (lymphoma, leukaemia, solid tumours)
• obesity, sickle cell disease, reflux nephropathy and genetic disease

Geography changes the pattern. In sub-Saharan Africa, hepatitis B, HIV (with APOL1 risk alleles), quartan malaria, schistosomiasis and sickle cell disease contribute heavily.

Pathophysiology. Mechanisms include immune complex deposition (lupus, infections), deposition of abnormal proteins (amyloid, light chains), podocyte injury by drugs or viruses (collapsing focal segmental glomerulosclerosis), adaptive hyperfiltration (obesity, reduced nephron mass, sickle cell disease), and diabetic injury.

• Nephrotic features: oedema, ascites, pleural effusions, frothy urine, hyperlipidaemia, thrombosis.
• Clues to the underlying cause:
  • rash, arthritis, serositis and cytopenias (lupus)
  • retinopathy and neuropathy (diabetes)
  • macroglossia, bruising and neuropathy (AL amyloid)
  • weight loss and fever (infection or malignancy)
  • jaundice and risk factors for blood borne viruses
  • travel and residence in endemic areas
  • drug history including over-the-counter NSAIDs and herbal remedies
• Active urine sediment (red cells, red cell casts) and low complement suggest immune complex disease. A bland sediment suggests podocytopathy.
• Kidney size is large in diabetes, amyloid and HIV associated nephropathy. It is small in reflux nephropathy and long standing disease.

Red flags

• Rapid decline in kidney function or crescents.
• Nephrotic syndrome in an adult over 50 (cancer, paraprotein, amyloid).
• Positive HIV, hepatitis B or C result, or syphilis serology.
• Fever with weight loss, night sweats or lymphadenopathy.
• Pregnancy with nephrotic syndrome.

• Urine protein:creatinine ratio, albumin, lipids, creatinine, eGFR, urine microscopy, full blood count, glucose and HbA1c, liver tests, thyroid function.
• Systemic screen: antinuclear antibodies, anti-dsDNA, C3, C4, ANCA, hepatitis B surface antigen and core antibody, hepatitis C antibody, HIV, syphilis serology, serum protein electrophoresis with free light chains, cryoglobulins, anti-phospholipase A2 receptor antibody.
• Where endemic: malaria film and antigen test, and urine and stool for schistosomiasis. Check sickle status.
• Cancer screening by age and symptoms (chest imaging, colonoscopy, mammography, PSA, CT).
• Kidney biopsy in most adults to establish the pattern and direct treatment:
  • membranous (infection, lupus, drugs, malignancy)
  • membranoproliferative (hepatitis C, hepatitis B, cryoglobulins, quartan malaria)
  • collapsing focal segmental glomerulosclerosis (HIV, interferon, bisphosphonates)
  • minimal change (NSAIDs, lymphoma)
  • amyloid (Congo red)
  • nodular glomerulosclerosis (diabetes)
• Genetic testing when familial disease or onset in early childhood.

Differential diagnosis

• Primary nephrotic syndrome (minimal change, focal segmental glomerulosclerosis, membranous nephropathy), non-renal oedema (cardiac, hepatic, protein losing enteropathy), eclampsia and pre-eclampsia.

First line: treat the cause

• Diabetes: intensify glycaemic control, and add an SGLT2 inhibitor and finerenone.
• Lupus: glucocorticoids with mycophenolate mofetil or cyclophosphamide, with hydroxychloroquine 200 to 400 mg daily (maximum 5 mg/kg actual weight daily).
• Hepatitis B: entecavir 0.5 mg daily (renal adjustment: 0.25 mg daily when eGFR is 30 to 49; 0.15 mg daily when 10 to 29; 0.05 mg daily when under 10 or on haemodialysis) or tenofovir alafenamide 25 mg daily.
• Hepatitis C: glecaprevir and pibrentasvir 300 mg and 120 mg daily for 8 weeks.
• HIV: antiretroviral therapy irrespective of CD4 count (dolutegravir 50 mg with tenofovir alafenamide 25 mg and emtricitabine 200 mg daily when eGFR is at least 30).
• Syphilis: benzathine benzylpenicillin 2.4 million units intramuscularly weekly for 3 weeks (late disease) or a single dose (early disease).
• Quartan malaria: artemether and lumefantrine 20 mg and 120 mg (4 tablets at 0, 8, 24, 36, 48 and 60 hours for adults over 35 kg); steroids are ineffective and relapse is common without vector control.
• Schistosomiasis: praziquantel 40 mg/kg orally as a single dose (60 mg/kg in 2 to 3 divided doses for Schistosoma japonicum).
• Tuberculosis: multi-drug regimen with renal dose adjustment; rifampicin interacts with prednisolone, tacrolimus and antiretrovirals.
• Drug induced: stop the agent (NSAIDs, lithium, penicillamine, gold, bisphosphonates, anti-VEGF agents, interferon); steroid cover for minimal change from NSAIDs (prednisolone 1 mg/kg daily, maximum 60 mg) if proteinuria persists beyond 2 to 4 weeks.
• Malignancy: treat the tumour; remission often follows resection or chemotherapy.
• Amyloid: clone directed therapy for AL (bortezomib, cyclophosphamide, dexamethasone with daratumumab); anti-inflammatory therapy for AA.
• Sickle cell disease: ACE inhibitor and hydroxycarbamide 15 mg/kg daily (maximum 35 mg/kg).
• Obesity: weight loss; ACE inhibitor; SGLT2 inhibitor.

Symptomatic and renoprotective measures (all patients)

• Sodium under 2 g daily; furosemide 40 to 80 mg once or twice daily (add metolazone 2.5 to 5 mg or spironolactone 25 to 50 mg for resistance); 20% albumin 100 mL with furosemide 40 mg only for refractory oedema with albumin under 20 g/L.
• Ramipril 2.5 mg daily increased to 10 mg daily; blood pressure below 130/80 mmHg; 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 adults; finerenone 10 mg daily (20 mg if eGFR is at least 60) when potassium is under 5.0 mmol/L (diabetic kidney disease).
• Atorvastatin 20 mg daily (up to 80 mg).
• Anticoagulation: prophylactic enoxaparin 40 mg daily (20 mg when eGFR is under 30) when albumin is under 20 g/L with another risk factor and bleeding risk is low; treat thrombosis with full dose anticoagulation for at least 6 months.
• Vaccination (pneumococcal, influenza, hepatitis B), and avoidance of NSAIDs and contrast.

Immunosuppression. Reserved for immune mediated disease (lupus, vasculitis, primary lesion with secondary features) and given only after infection is excluded or controlled; give co-trimoxazole 480 mg daily with prednisolone 20 mg or more for 4 weeks, proton pump inhibitor, and hepatitis B screening before rituximab.

Kidney replacement therapy. Dialysis at eGFR 5 to 10 with symptoms or complications; transplantation once the cause is controlled.

Monitoring. Urine protein:creatinine ratio, albumin and creatinine at 2 to 4 weeks, then every 3 months; markers of the underlying disease (complement, viral load, light chains, HbA1c).

Referral and escalation. Nephrology for every case; haematology, rheumatology, hepatology, infectious diseases or oncology according to the cause; urgent for acute kidney injury, thrombosis or infection.

Special groups

• Children: hepatitis B associated membranous disease, infantile genetic disease and Alport syndrome.
• Pregnancy: lupus nephritis and diabetic disease increase the risk; stop ACE inhibitors and mycophenolate; aspirin 75 to 150 mg from 12 weeks.
• Older adults: always search for malignancy and amyloid.
• Sub-Saharan Africa: test for HIV, hepatitis B and C, malaria and schistosomiasis in every nephrotic patient before immunosuppression.