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This is a clinician-written, evidence-based summary aligned to the 2026 MLA Content Map. It is intended for medical students and junior doctors preparing for the UKMLA. Always cross-reference with NICE guidance, local protocols, and clinical judgement.
The Bottom Line
- Triad: proteinuria >3.5 g/day (uPCR >350 mg/mmol), hypoalbuminaemia (<25 g/L), peripheral oedema
- Also: hyperlipidaemia (liver compensatory lipoprotein production) and lipiduria
- Commonest cause in adults: membranous nephropathy (then FSGS, minimal change disease). In children: minimal change disease (~80%)
- Major complications: VTE (loss of antithrombin III), infection (immunoglobulin loss), hyperlipidaemia, AKI
- Treatment depends on cause: corticosteroids (minimal change), immunosuppression, ACEi/ARB to reduce proteinuria, diuretics for oedema, anticoagulation if high VTE risk
Overview
Nephrotic syndrome results from increased permeability of the glomerular basement membrane, leading to massive urinary protein loss. The primary causes include minimal change disease (commonest in children, steroid-responsive), focal segmental glomerulosclerosis (FSGS), membranous nephropathy (commonest in adults, associated with anti-PLA2R antibodies), and diabetic nephropathy. Secondary causes include diabetes mellitus (commonest secondary cause), SLE (class V lupus nephritis), amyloidosis, drugs (NSAIDs, penicillamine, gold), and infections (hepatitis B, HIV, malaria). The syndrome has specific complications related to the loss of plasma proteins: antithrombin III loss increases thrombotic risk, immunoglobulin loss increases infection risk, and compensatory hepatic lipoprotein synthesis causes hyperlipidaemia.
Epidemiology
Annual incidence of nephrotic syndrome in adults is approximately 3 per 100,000. Membranous nephropathy is the commonest primary cause in Caucasian adults. FSGS is the commonest cause in Black adults. In children, minimal change disease accounts for ~80% of cases and typically responds dramatically to corticosteroids. Secondary causes (particularly diabetic nephropathy) are increasingly common. Approximately 30% of adult minimal change disease and 40% of FSGS progress to end-stage renal disease.
Clinical Features
Symptoms
Peripheral oedema (ankles, legs, periorbital — worse on waking)
Frothy urine (heavy proteinuria)
Weight gain (fluid retention)
Lethargy and malaise
Breathlessness (pleural effusion or pulmonary oedema)
Abdominal distension (ascites)
Symptoms of underlying cause: joint pain and rash (SLE), polyuria/polydipsia (diabetes)
Signs
Pitting peripheral oedema (often severe — sacral in bedridden patients)
Periorbital oedema (particularly in children — often the first sign)
Ascites
Pleural effusions (bilateral transudative)
Leukonychia (hypoalbuminaemia)
Xanthelasma (hyperlipidaemia)
Investigations
First-line
Urinalysis and urine protein:creatinine ratio (uPCR)Nephrotic-range proteinuria: uPCR >350 mg/mmol (equivalent to >3.5 g/day). Dipstick: 3+ or 4+ protein
Serum albumin<25 g/L confirms hypoalbuminaemia (often <20 g/L in severe cases)
BloodsU&Es (renal function), lipid profile (hypercholesterolaemia), FBC, CRP, HbA1c (exclude diabetes), LFTs
Second-line
Immunological screenANA, dsDNA, complement (C3/C4) — screen for SLE. Anti-PLA2R antibodies — specific for membranous nephropathy (~70% sensitivity)
Hepatitis B/C, HIV serologySecondary causes of membranous nephropathy and FSGS
Serum electrophoresis and urine Bence Jones proteinExclude myeloma and amyloidosis in older patients
Renal USSAssess kidney size (small = chronic, normal/large = acute), exclude structural abnormality
Specialist
Renal biopsyEssential in adults to determine histological diagnosis (minimal change, membranous, FSGS, amyloid). In children with typical presentation (<10 years), empirical steroid trial without biopsy is acceptable
Doppler USS/CT venogramIf suspected renal vein thrombosis (particularly in membranous nephropathy — sudden flank pain, haematuria, deteriorating renal function)
1
General measures (all causes)
- ACEi or ARB: reduce proteinuria (renoprotective — first-line for proteinuria reduction)
- Diuretics: furosemide ± spironolactone for oedema. IV furosemide + IV albumin if severe/resistant oedema
- Salt restriction (<2 g/day sodium)
- Statin therapy for hyperlipidaemia
- VTE prophylaxis: consider prophylactic anticoagulation (LMWH or warfarin) if albumin <20 g/L or immobile (especially membranous nephropathy)
- Pneumococcal and influenza vaccination (immunoglobulin loss → infection risk)
2
Cause-specific
- Minimal change disease: prednisolone 1 mg/kg/day (max 80 mg) for 4–8 weeks then taper. >90% respond within 8 weeks. Relapse common (50%) — may need cyclophosphamide or calcineurin inhibitors
- Membranous nephropathy: if anti-PLA2R positive and not spontaneously remitting — rituximab (increasingly first-line), or cyclophosphamide + steroids (Ponticelli regimen), or calcineurin inhibitors
- FSGS: steroids ± calcineurin inhibitors. Often steroid-resistant — may progress to ESRD
- Diabetic nephropathy: optimise glycaemic control, ACEi/ARB, SGLT2 inhibitor (dapagliflozin/empagliflozin)
- Lupus nephritis (class V): steroids + mycophenolate mofetil or cyclophosphamide
Complications
- Venous thromboembolism: DVT, PE, renal vein thrombosis — loss of antithrombin III and other anticoagulant proteins. Membranous nephropathy has highest VTE risk
- Infection: Loss of immunoglobulins → susceptibility to encapsulated organisms (Streptococcus pneumoniae — spontaneous bacterial peritonitis in children with ascites)
- Hyperlipidaemia: Accelerated atherosclerosis — cardiovascular risk
- AKI: From hypovolaemia (intravascular depletion despite oedema), renal vein thrombosis, or interstitial nephritis
- CKD/ESRD: FSGS and membranous nephropathy may progress to end-stage disease
UKMLA Exam Tips
- 1Nephrotic = heavy proteinuria (>3.5 g/day), low albumin, oedema. Nephritic = haematuria, hypertension, oliguria, modest proteinuria
- 2Minimal change disease: normal light microscopy, podocyte foot process effacement on electron microscopy. Steroid responsive
- 3Membranous nephropathy: thickened GBM ("spike and dome" on silver stain), anti-PLA2R antibodies, highest VTE risk of all nephrotic causes
- 4Child with periorbital oedema + frothy urine → nephrotic syndrome → most likely minimal change disease → trial of steroids WITHOUT biopsy
- 5Renal vein thrombosis: sudden flank pain + haematuria in a patient with nephrotic syndrome (especially membranous) — urgent imaging
- 6Diabetic nephropathy is the commonest SECONDARY cause of nephrotic syndrome
practicetest your knowledge on nephrotic syndromeApply what you've learnt with UKMLA-style questions from the iatroX Q-Bank — renal and beyond.
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