Nephrotic syndrome and membranous nephropathy in the elderly

Definition. Nephrotic syndrome is proteinuria >3.5 g/24 h with hypoalbuminaemia (<3 g/dL), oedema and hyperlipidaemia. It accounts for about 50% of all renal biopsy indications in older adults.

Commonest causes in old age. Membranous nephropathy, minimal change disease, diabetic nephropathy and amyloidosis. Among older patients biopsied for glomerulonephritis, 59% had primary and 20% secondary glomerulonephritis.

Age-related shift in histology. Membranous nephropathy, membranoproliferative GN, minimal change disease, crescentic GN and post-streptococcal GN are all more frequent in older than younger patients. Only FSGS and IgA / non-IgA mesangioproliferative nephritis are less frequent.

Membranous nephropathy is often secondary in the elderly. In about 20% it is related to an underlying malignancy — mainly lung or colon adenocarcinoma — or to drug ingestion. A malignancy screen is mandatory before labelling it primary.

Minimal change disease behaves atypically. Senile structural renal changes make histology difficult; presentation is usually atypical with hypertension, microhaematuria and/or renal failure, and it may be drug-related (NSAIDs) or associated with lymphoma.

Crescentic GN must not be missed. Its incidence peaks between 60–79 years and it presents as rapidly progressive acute renal failure. Renal vasculitis (granulomatosis with polyangiitis, microscopic polyangiitis) is probably the commonest primary cause of renal failure in older adults.

Other secondary glomerulopathies frequent in the elderly: diabetic nephropathy, nephroangiosclerosis from essential hypertension, glomerular vasculitis, and diseases with abnormal plasma-cell proteins — light chain, fibrillary and immunotactoid nephropathy.

Investigations. Urine protein-creatinine ratio, serum albumin, lipid profile, creatinine (mg/dL), anti-PLA2R antibody, blood glucose, serum protein electrophoresis and free light chains, ANA/ANCA, hepatitis B and C serology, and an age-appropriate malignancy screen.

Supportive management. Salt restriction, loop diuretics, RAS blockade for antiproteinuric effect, statin, and anticoagulation when albumin is very low — membranous nephropathy carries the highest thromboembolic risk of the primary glomerular diseases. Watch closely for AKI and hyperkalaemia.

Immunosuppression. Steroids and cyclophosphamide can be used in older as in younger adults, but with special attention to their side effects — infection, bone marrow suppression, hyperglycaemia, osteoporosis and delirium.

KDIGO Glomerular Diseases guideline — biopsy-free diagnosis and rituximab first-line. In nephrotic syndrome with a positive anti-PLA2R antibody and preserved kidney function, kidney biopsy is not required to diagnose membranous nephropathy. Rituximab is first-line for moderate- and high-risk disease (1 g × 2 doses two weeks apart, or 375 mg/m² weekly), while cyclophosphamide + steroid remains preferred in the very-high-risk category.

Antibody-guided therapy and the elderly caveat. Serial anti-PLA2R titres at 3–6 months predict remission; immunosuppression can be stopped once the antibody is undetectable at 6 months. Recent 2025 series support low-dose / personalised rituximab in frail older patients. Important caveat: in the elderly, membranous nephropathy may co-exist with renal amyloidosis or diabetic nephropathy, so anti-PLA2R positivity alone should not stop you from biopsying an atypical case.