Malignancy Associated Nephrotic Syndrome

Malignancy associated nephrotic syndrome is nephrotic syndrome caused by a cancer. The cause is either a paraneoplastic glomerular lesion or the effects of cancer treatment.

It can precede the cancer diagnosis by up to a year. Remission after tumour treatment supports the link.

Lesions by tumour type.

• Membranous nephropathy is the commonest lesion with solid tumours (lung, colon, stomach, prostate, breast, kidney, oesophagus and melanoma). It is found in about 10% of adults with membranous nephropathy, and over 20% of those over 65 years.
• Minimal change disease occurs with Hodgkin lymphoma, other lymphomas, thymoma and some solid tumours.
• Focal segmental glomerulosclerosis, membranoproliferative disease (chronic lymphocytic leukaemia, lymphoma), amyloid and light chain disease (myeloma) occur with haematological cancers.

Treatment induced lesions.

• Minimal change disease and thrombotic microangiopathy, from immune checkpoint inhibitors and anti-VEGF agents.
• Collapsing focal segmental glomerulosclerosis, from interferon and bisphosphonates (pamidronate).
• Membranous lesions, from some targeted agents.

Pathophysiology.

• Tumour antigens may form immune complexes that deposit in the subepithelial space (membranous nephropathy).
• Tumour derived cytokines and T-cell factors injure podocytes (minimal change disease).
• Monoclonal proteins deposit or alter glomerular structure (amyloid, light chain disease).

In membranous nephropathy associated with cancer, the target antigens are often not the phospholipase A2 receptor. Others include thrombospondin type 1 domain containing 7A and NELL1. IgG1 and IgG2 predominate over IgG4 on biopsy.

• Nephrotic syndrome: oedema, frothy urine, hypoalbuminaemia, hyperlipidaemia, usually in an adult over 50 with no other cause.
• Constitutional: weight loss, fever, night sweats, anorexia, fatigue; symptoms of a primary tumour (cough, haemoptysis, change in bowel habit, rectal bleeding, breast or prostate symptoms, dysphagia, haematuria).
• Venous thromboembolism: markedly raised risk from the combination of cancer and nephrotic syndrome.
• Hodgkin lymphoma: lymphadenopathy and B symptoms, with minimal change disease and relapse tracking the lymphoma.
• Features of paraproteinaemia: bone pain, anaemia, hypercalcaemia, neuropathy, macroglossia (amyloid).

Red flags

• Membranous nephropathy in a patient over 60, in a smoker, or with negative anti-phospholipase A2 receptor antibody.
• Rapid decline in kidney function or nephrotic syndrome in the first year after a cancer diagnosis.
• Venous or arterial thrombosis, or unexplained weight loss.
• Hypertension, proteinuria and thrombotic microangiopathy during anti-VEGF or checkpoint inhibitor therapy.
• Hypercalcaemia, lytic lesions or a monoclonal band.

• Urine protein:creatinine ratio, albumin, lipids, creatinine, eGFR, urine microscopy, full blood count and film, calcium, lactate dehydrogenase, liver tests, C-reactive protein.
• Anti-phospholipase A2 receptor antibody (negative or low titre favours secondary disease), serum protein electrophoresis with immunofixation and free light chains, hepatitis B and C, HIV, antinuclear antibodies, C3 and C4.
• Kidney biopsy with immunostaining for the phospholipase A2 receptor, thrombospondin type 1 domain containing 7A and NELL1 where available.
  • IgG1 and IgG2 dominance and absence of staining for the phospholipase A2 receptor favour cancer.
  • Inflammatory cells in glomeruli (more than 8 each glomerulus) suggest malignancy.
• Age appropriate cancer screening in all adults with membranous nephropathy: history and examination, chest radiograph or CT of chest, abdomen and pelvis (especially in smokers and over 60), faecal immunochemical test or colonoscopy, mammography, PSA and prostate assessment, cervical screening, skin check, and further targeted tests for symptoms.
• Repeat screening if proteinuria persists without a clear cause over 6 to 12 months.
• Haematology: bone marrow biopsy and lymph node biopsy when lymphoproliferative disease is suspected.

Differential diagnosis

• Primary membranous nephropathy, infection associated membranous nephropathy (hepatitis B, syphilis), drug induced membranous nephropathy (NSAIDs, penicillamine), lupus nephritis, minimal change disease from NSAIDs or atopy, amyloid, diabetic nephropathy.

First line: treat the cancer

• Surgical resection, chemotherapy, radiotherapy or targeted therapy under oncology.
• Proteinuria usually remits within weeks to months of effective tumour control. It relapses with recurrence, which can mark tumour recurrence.
• Hodgkin lymphoma and minimal change disease: treat the lymphoma. For steroid responsive minimal change disease, add prednisolone 1 mg/kg daily (maximum 80 mg), tapered over 3 to 6 months once in remission.
• Chronic lymphocytic leukaemia associated membranoproliferative disease: treat the haematological disease with haematology (ibrutinib 420 mg daily or rituximab based regimens).
• Myeloma, amyloid and light chain disease: clone directed therapy.
  • Bortezomib 1.3 mg/m² subcutaneously on days 1, 8, 15 and 22.
  • Cyclophosphamide 300 mg/m² (maximum 500 mg) weekly.
  • Dexamethasone 20 to 40 mg weekly.
  • Daratumumab 1800 mg subcutaneously (weekly for 8 weeks, every 2 weeks for 16 weeks, then monthly).

Immunosuppression for membranous nephropathy

• Avoid immunosuppression where possible until the cancer is controlled. It may promote tumour progression and infection, and it is rarely effective alone.
• If severe nephrotic syndrome persists after cancer treatment and the tumour is controlled, rituximab 1 g intravenously on days 1 and 15 can be used with oncology agreement.

Treatment induced lesions

• Immune checkpoint inhibitors (nivolumab, pembrolizumab, ipilimumab): stop the drug in 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 refractory.
• Anti-VEGF agents (bevacizumab) and tyrosine kinase inhibitors: stop or reduce dose. Treat hypertension (amlodipine 5 to 10 mg daily, ramipril 2.5 mg to 10 mg daily). Proteinuria above 3 g daily or thrombotic microangiopathy warrants permanent discontinuation.
• Pamidronate collapsing focal segmental glomerulosclerosis: stop pamidronate. For hypercalcaemia or bone metastases, switch to zoledronic acid at a renally adjusted dose or denosumab 120 mg every 4 weeks (with calcium and vitamin D, and calcium monitoring).
• Interferon: stop. Give prednisolone 1 mg/kg daily if proteinuria persists beyond 4 weeks.

Supportive care

• Sodium under 2 g daily.
• Furosemide 40 to 80 mg once or twice daily.
• Blood pressure below 130/80 mmHg with ramipril 2.5 mg increasing to 10 mg daily. Check creatinine and potassium at 1 to 2 weeks, and stop if potassium exceeds 6.0 mmol/L.
• Atorvastatin 20 mg daily.
• Anticoagulation: high thrombotic risk. Give prophylactic enoxaparin 40 mg subcutaneously daily (20 mg if eGFR is under 30) when albumin is under 25 g/L in membranous nephropathy, or under 20 g/L in other lesions, if bleeding risk is acceptable.
• Established thrombosis: enoxaparin 1 mg/kg twice daily (or 1.5 mg/kg daily; reduce to 1 mg/kg daily when eGFR is under 30), or apixaban 10 mg twice daily for 7 days then 5 mg twice daily (caution with albumin under 20 g/L and low eGFR; avoid when eGFR is under 15). Continue for at least 6 months and until the cancer and nephrotic syndrome remit.
• Monitor anti-Xa levels with enoxaparin in kidney impairment.
• Infection prophylaxis during chemotherapy; vaccination; nutrition support.
• Dose adjust chemotherapy and avoid nephrotoxins (cisplatin, ifosfamide, methotrexate at high dose) to preserve kidney function. Check eGFR before each cycle.

Kidney failure. Dialysis at eGFR 5 to 10 with symptoms when prognosis and goals of care warrant. Discuss conservative kidney management for advanced cancer. Kidney transplantation requires a cancer free interval, usually 2 to 5 years depending on the tumour.

Monitoring. Urine protein:creatinine ratio, albumin and creatinine every 4 to 8 weeks during cancer treatment, then every 3 months. Rising proteinuria in remission prompts re-staging for recurrent cancer.

Referral and escalation. Nephrology with oncology or haematology from the first suspicion. Urgent for thrombosis, acute kidney injury, hypercalcaemia or sepsis.

Special groups

• Older adults: highest incidence; shared decisions around biopsy and treatment intensity.
• Children: Wilms tumour, neuroblastoma and lymphoma may cause nephrotic syndrome; investigate atypical features.
• Pregnancy: rare; manage with oncology and obstetrics; avoid cytotoxic agents in the first trimester.
• Sub-Saharan Africa: Burkitt lymphoma, HIV associated lymphoma and Kaposi sarcoma can occur with kidney disease; test for HIV and hepatitis B and C.