Nephrotic Syndrome — Proteinuria, Oedema, Rituximab & Treatment Guide — Symptoms, Causes & Treatment | MyMedicPlus

Nephrotic syndrome is a clinical syndrome defined by the triad of: heavy proteinuria (protein loss over 3.5 g per 24 hours in adults, or protein:creatinine ratio over 350 mg/mmol, or 3+ or 4+ on urine dipstick); hypoalbuminaemia (serum albumin below 25 g/L); and oedema (from oncotic pressure loss). It is frequently accompanied by hyperlipidaemia (compensatory hepatic apolipoprotein synthesis) and hyperlipiduria (lipid casts in urine). The pathophysiology involves glomerular basement membrane (GBM) damage causing loss of the normal charge and size selectivity barrier — allowing large protein molecules (primarily albumin) to leak into the filtrate. Nephrotic syndrome occurs in 3 per 100,000 adults per year. Primary (idiopathic) causes include minimal change disease (MCD — most common in children, particularly boys aged 1-8; 20% in adults), focal segmental glomerulosclerosis (FSGS), membranous nephropathy (MN — most common primary cause in adults aged 40-60), and mesangiocapillary glomerulonephritis (MCGN). Secondary causes include diabetic nephropathy (the most common cause globally), lupus nephritis, amyloidosis, multiple myeloma, solid tumours (paraneoplastic MN), and medications (NSAIDs, gold, penicillamine, captopril, mercury).

Primary nephrotic syndrome — by glomerular pathology: Minimal change disease (MCD): characterised by normal light microscopy but diffuse foot process effacement on electron microscopy; typically presents acutely with rapid onset of severe oedema; strongly associated with atopy and NSAIDs; 80% of paediatric nephrotic syndrome; responds dramatically to corticosteroids. Focal segmental glomerulosclerosis (FSGS): segmental sclerosis in some (focal) glomeruli; primary (podocyte injury — suPAR, anti-NEPHRIN antibodies) or secondary (adaptive FSGS from hypertension, obesity, reduced nephron mass, heroin, HIV); less responsive to corticosteroids than MCD. Membranous nephropathy (MN): subepithelial immune deposits containing IgG4; 70% are primary (anti-PLA2R antibody — M-type phospholipase A2 receptor antibody — highly specific for primary MN); secondary causes: solid tumours (lung, colorectal, breast — 25% of MN over age 60 is paraneoplastic), hepatitis B, hepatitis C, lupus, drugs (NSAIDs, gold). Secondary causes: diabetic nephropathy (most common cause globally — characterised by Kimmelstiel-Wilson nodular glomerulosclerosis on biopsy; proteinuria is initially microalbuminuria, progressing to macroalbuminuria); amyloidosis (AL — light chain from plasma cell dyscrasia; AA — from chronic inflammatory disease like RA or familial Mediterranean fever); lupus nephritis (Class V membranous lupus nephritis causes nephrotic syndrome); multiple myeloma (cast nephropathy or amyloid).

Oedema is the cardinal presenting feature: periorbital oedema (particularly noticeable in the morning on waking — the most common first sign in children); bilateral pitting lower limb oedema extending to the thighs; scrotal or labial oedema; ascites (transudate from low oncotic pressure); pleural effusions (dyspnoea, reduced breath sounds at lung bases). Frothy or foamy urine: from heavy proteinuria causing surface tension reduction — a characteristic symptom prompting medical review. Hypoalbuminaemia features: generalised oedema; low plasma oncotic pressure causing transudative effusions; malnutrition from protein wasting (muscle wasting may be masked by oedema). Hyperlipidaemia: xanthomata, arcus senilis — due to elevated LDL and VLDL from compensatory hepatic lipoprotein synthesis (Kayser-Fleischer rings in Wilson disease provide context — but lipid xanthelasma can form in severe nephrotic hyperlipidaemia). Thromboembolism: renal vein thrombosis presents with loin pain, haematuria, deteriorating renal function, and asymmetrical leg oedema; DVT and PE. Increased infection susceptibility: loss of immunoglobulins and complement components in urine (particularly IgG and factor B — increasing pneumococcal and gram-negative infection risk). Hypertension and declining renal function in FSGS and advanced disease.

Urinalysis: dipstick proteinuria (3+ or 4+); frothy urine; lipid droplets (oval fat bodies) on microscopy. 24-hour urine protein (gold standard): over 3.5 g per 24 hours. Spot urine protein:creatinine ratio (PCR): over 350 mg/mmol (equivalent to over 3.5 g/g) — simpler and correlates closely with 24-hour collection. Serum biochemistry: albumin (below 25 g/L); total cholesterol (elevated — often over 8 mmol/L); triglycerides; renal function (creatinine, eGFR); electrolytes. Immunological screen to identify cause: ANA, anti-dsDNA, complement (C3, C4), ANCA (lupus nephritis); anti-PLA2R antibody (highly specific for primary membranous nephropathy — positive in 70%, allows non-biopsy diagnosis in typical cases); anti-GBM antibody; hepatitis B sAg, hepatitis C Ab, HIV Ab; serum immunoglobulins and protein electrophoresis (myeloma); cryoglobulins. Renal biopsy: indicated in most adults with nephrotic syndrome (except typical MCD in children who respond to steroids without biopsy) — confirms pathological diagnosis guiding immunosuppressive treatment. Imaging: renal ultrasound (size, echogenicity, obstruction); CT chest/abdomen if paraneoplastic MN suspected. Thromboembolism work-up: Doppler USS legs and renal veins; CT pulmonary angiogram if PE suspected.

General measures for all causes: ACE inhibitors or ARBs (ramipril, losartan) reduce proteinuria by 30-50% through reducing intraglomerular pressure — cornerstone of non-immunosuppressive management; BP target below 125/75 mmHg. Diuretics (furosemide, spironolactone) for oedema — use cautiously in hypoalbuminaemia to avoid intravascular depletion. Statins for hyperlipidaemia (elevated cardiovascular risk). Anticoagulation: low-molecular-weight heparin (LMWH) or warfarin for serum albumin below 20-25 g/L (risk of renal vein thrombosis and PE — the risk-benefit threshold is debated). SGLT2 inhibitors (dapagliflozin, empagliflozin): approved for diabetic nephropathy and CKD — significantly reduce proteinuria and slow eGFR decline. Minimal change disease: prednisolone 1 mg/kg/day (maximum 60-80 mg) — achieves complete remission in 80-90% of children within 4-8 weeks and 80% of adults within 16 weeks; taper over 6 months. Frequently relapsing/steroid-dependent MCD: cyclophosphamide (induction), cyclosporin/tacrolimus (maintenance), or rituximab (anti-CD20 — highly effective for steroid-dependent MCD, sustained remission in 60-70%). Membranous nephropathy (primary): anti-PLA2R positive — rituximab 375 mg/m2 weekly for 4 doses is now first-line immunosuppressive therapy (the MENTOR trial showed superiority over cyclosporin for sustained remission at 24 months); second-line: cyclophosphamide plus alternating corticosteroids (Ponticelli regimen). Secondary MN: treat the underlying cause. FSGS (primary): prednisolone high-dose for 16+ weeks; for resistant cases: tacrolimus, mycophenolate mofetil, rituximab; novel therapies: sparsentan (dual endothelin/angiotensin receptor antagonist — FDA approved for FSGS).

Thromboembolism: the most dangerous acute complication — renal vein thrombosis occurs in 25-40% of membranous nephropathy patients (from hypercoagulability due to urinary loss of antithrombin III, protein C, protein S, and factor XII, combined with elevated fibrinogen and platelet activation); deep vein thrombosis and pulmonary embolism also occur and can be fatal. Risk is highest when serum albumin is below 20 g/L. Infection: urinary loss of IgG, IgA, and complement factor B impairs opsonisation and antibody-mediated immunity — severe infections (peritonitis from Streptococcus pneumoniae, gram-negative sepsis) are life-threatening complications, particularly in children; pneumococcal vaccination is recommended. Acute kidney injury: from severe hypovolaemia (particularly in children — plasma volume depletion despite oedema), NSAIDs (reduce GFR), contrast nephropathy, and renal vein thrombosis. Chronic kidney disease: progressive glomerular scarring — particularly in FSGS and membranous nephropathy with persistent heavy proteinuria. Cardiovascular disease: lipid-driven atherosclerosis from prolonged nephrotic hyperlipidaemia.

Diabetic nephropathy prevention — the most important form of secondary nephrotic syndrome prevention: achieve HbA1c target below 48 mmol/mol (below 7%); blood pressure control below 130/80 mmHg; ACE inhibitor or ARB for microalbuminuria (even in normotensive diabetics — renally protective); SGLT2 inhibitors (dapagliflozin or empagliflozin) in type 2 diabetes with CKD reduce the risk of progressive kidney disease by 40-50%. For established nephrotic syndrome: strict salt restriction (below 2 g sodium/day) reduces oedema and blood pressure — the most important dietary modification; avoid nephrotoxic medications (NSAIDs — significantly reduce GFR in hypovolaemic nephrotic patients; avoid contrast agents without adequate hydration and prophylaxis); avoid prolonged immobility (thromboembolism risk). Regular nephrological follow-up every 3-6 months monitors disease activity (PCR, albumin, eGFR), treatment response, and complications. Influenza and pneumococcal vaccination for all patients with nephrotic syndrome, regardless of immunosuppressive therapy.

See a GP promptly for: significant leg or facial (periorbital) swelling without an obvious cause; frothy or foamy urine persisting for over 1 week; urine dipstick showing 2+ or more proteinuria; or unexplained fatigue with leg swelling. Attend A&E immediately for: loin pain with leg swelling and haematuria (possible renal vein thrombosis); acute breathlessness with pleuritic chest pain (possible pulmonary embolism — a potentially fatal complication of nephrotic syndrome); or severe generalised oedema causing respiratory compromise. Any patient with confirmed proteinuria over 1 g/day requires nephrologist referral for investigation including renal biopsy in most adults. Patients already under nephrological care should seek urgent review for: worsening oedema or breathlessness despite diuretics; rising creatinine; new symptoms of thromboembolism; or fever with peritonism (possible spontaneous bacterial peritonitis in patients with ascites).