Nephrotic Syndrome — Causes, Symptoms, Diagnosis & Treatment Guide — Symptoms, Causes & Treatment | MyMedicPlus

Nephrotic syndrome is a clinical syndrome characterised by the nephrotic triad: massive proteinuria (urinary protein excretion above 3.5 grams per day per 1.73 m2 BSA in adults — urine protein:creatinine ratio above 350 mg/mmol), hypoalbuminaemia (serum albumin below 30 g/L), and peripheral oedema. Dyslipidaemia (elevated total cholesterol, LDL, triglycerides) and lipiduria are additional classic features. It results from glomerular podocyte injury causing loss of the charge and size-selective filtration barrier, allowing large proteins — primarily albumin — to cross into the urine. Major causes in children: minimal change disease (MCD) accounts for 90% of childhood nephrotic syndrome. Major causes in adults: focal segmental glomerulosclerosis (FSGS — most common in Black adults), membranous nephropathy (most common cause of adult primary nephrotic syndrome in white populations — anti-PLA2R antibody in 70-80%), minimal change disease (15-20%), and diabetic nephropathy (most common secondary cause globally). Secondary causes include lupus nephritis, amyloidosis, hepatitis B and C, malignancy (membranous nephropathy with solid tumours), and medications (NSAIDs, gold, penicillamine).

The fundamental defect in nephrotic syndrome is injury to glomerular podocytes — highly specialised epithelial cells forming the filtration barrier with their interdigitating foot processes and slit diaphragms. Podocyte injury causes effacement (flattening) of foot processes, disrupting the filtration barrier and allowing protein leak. In minimal change disease, the injury is mediated by T-cell-derived cytokines (possibly permeability factors — exact mechanism unknown) causing podocyte effacement without light microscopy changes. In FSGS, podocyte loss leads to focal and segmental glomerular scarring; primary FSGS may involve circulating permeability factors (soluble urokinase receptor — suPAR). Membranous nephropathy involves subepithelial immune complex deposition (IgG4 binding anti-PLA2R or anti-THSD7A antigens on podocytes), activating complement. Risk factors vary by aetiology: Black race (FSGS — genetic APOL1 risk variants dramatically increase FSGS risk); middle-age men (membranous nephropathy — anti-PLA2R); autoimmune disease history; solid malignancy in older adults (paraneoplastic membranous nephropathy).

The hallmark symptom is bilateral pitting oedema — typically starting in the dependent areas (ankles and legs), progressing to facial puffiness (periorbital oedema — especially noticeable in the morning), ascites (abdominal swelling), pleural effusions (breathlessness), and in severe cases generalised oedema (anasarca). Frothy urine is a patient-reported symptom caused by protein-rich urine (similar to egg white effect). Fatigue and reduced energy from hypoalbuminaemia and anaemia. Patients may notice decreased urine output. Complications presenting as symptoms: venous thrombosis (deep vein thrombosis, renal vein thrombosis, pulmonary embolism — from loss of antithrombin III and protein C/S in urine), accelerated atherosclerosis (from dyslipidaemia), bacterial infections particularly pneumococcal peritonitis and pneumonia (from loss of immunoglobulins), and slowly progressive chronic kidney disease from ongoing glomerular damage and hyperfiltration.

Urine analysis: urine protein:creatinine ratio (UPCR) or albumin:creatinine ratio (UACR) on spot urine; 24-hour urine protein collection (gold standard — greater than 3.5g/24h diagnostic). Urine dipstick: proteinuria 3+ or 4+. Lipiduria: fatty casts and oval fat bodies on microscopy. Blood tests: serum albumin (below 30 g/L in nephrotic syndrome), total protein, lipid profile (elevated total cholesterol, LDL, VLDL, and triglycerides), serum creatinine and eGFR (assessing renal impairment), FBC (anaemia from transferrin loss), coagulation studies (hypercoagulable state). Secondary cause workup: ANA, anti-dsDNA, complement C3/C4 (lupus nephritis); anti-PLA2R antibody (membranous nephropathy — highly specific); hepatitis B and C serology; cryoglobulins; protein electrophoresis (myeloma); HbA1c; and malignancy screening in older patients. Renal ultrasound: assesses kidney size and structure, excludes obstruction. Renal biopsy: definitive diagnosis for all adults with nephrotic syndrome (except diabetic nephropathy with classic features and long duration, or MCD in children). Light microscopy, immunofluorescence, and electron microscopy characterise the specific glomerular pathology.

Minimal change disease (MCD): oral prednisolone 1 mg/kg/day (maximum 80 mg) — remission achieved in 80-90% of adults within 8-16 weeks; taper slowly over 6-8 months. Relapsing or steroid-dependent MCD: cyclophosphamide, tacrolimus, or rituximab for steroid-sparing. Children: MCD responds to prednisolone in >90%; most nephrologists treat presumptively without biopsy. Primary FSGS: high-dose prednisolone (similar dose to MCD) for extended period; renal replacement therapy (dialysis/transplant) for ESRD from steroid-resistant FSGS — FSGS may recur post-transplant. Membranous nephropathy: Ponticelli regimen (alternating monthly cyclophosphamide and methylprednisolone for 6 months) — traditional therapy. Rituximab (anti-CD20) has become the preferred treatment for primary membranous nephropathy — achieves remission in 60-70% and is now recommended by KDIGO guidelines. Monitor anti-PLA2R antibody levels to guide treatment response. Supportive treatment for all nephrotic syndrome: ACE inhibitor or ARB for antiproteinuric effect and renoprotection; loop diuretics (furosemide) for oedema management; statin for dyslipidaemia; anticoagulation (LMWH or DOAC) if albumin below 20 g/L or high thrombotic risk; salt restriction; low-protein diet is NOT recommended (worsens malnutrition).

Nephrotic syndrome generates severe complications related to the massive protein loss, oedema, and metabolic derangements that define the condition. Thromboembolic disease is the most dangerous acute complication — occurring in 25-40% of adults with nephrotic syndrome, particularly minimal change disease and membranous nephropathy: loss of anticoagulant proteins (antithrombin III, protein C, protein S) in urine combined with elevated procoagulant factors creates profound hypercoagulability. Renal vein thrombosis — occurring in up to 50% of membranous nephropathy — may cause acute worsening of renal function and pulmonary embolism; pulmonary embolism occurs in 12% of nephrotic adults. Hypoalbuminaemia below 20 g/L causes severe generalised oedema including pleural effusions, ascites, and pericardial effusion — impairing respiratory function and cardiac output. Severe infection — particularly spontaneous bacterial peritonitis from E. coli or pneumococcal peritonitis — occurs from loss of immunoglobulins in urine and complement dysfunction; children with nephrotic syndrome have 20-60 fold increased risk of pneumococcal infection. Hyperlipidaemia (LDL above 5 mmol/L) and lipiduria accelerate cardiovascular disease with prolonged nephrotic syndrome. Malnutrition from protein loss impairs growth in children and wound healing. Progressive chronic kidney disease develops in focal segmental glomerulosclerosis (FSGS), diabetic nephropathy, and membranous nephropathy unresponsive to treatment.

Thrombotic complications are a major source of morbidity and mortality in nephrotic syndrome — particularly when serum albumin is below 20-25 g/L (increased fibrinogen, reduced antithrombin III, protein C and S loss in urine). Prophylactic anticoagulation is recommended for albumin below 20 g/L, particularly in membranous nephropathy. Pneumococcal and influenza vaccination for all patients — susceptibility to encapsulated bacteria from immunoglobulin loss and impaired opsonisation. ACE inhibitors/ARBs reduce proteinuria and slow CKD progression in all causes of nephrotic syndrome. Sodium restriction below 2g/day and diuretics control oedema. Monitor for CKD progression with regular eGFR and UPCR measurements. Avoid nephrotoxic medications (NSAIDs, aminoglycosides, contrast without adequate hydration). Patients with persistent significant proteinuria or progressive CKD should be co-managed with a specialist renal dietitian for protein and sodium guidance.

See a doctor promptly for: new-onset rapidly worsening ankle swelling combined with frothy urine; facial puffiness on waking; sudden unexplained weight gain of 3-5 kg in a few days; or worsening breathlessness with leg swelling. Emergency presentation is required for: sudden severe leg swelling with pain (possible DVT); chest pain and breathlessness (possible pulmonary embolism — a major complication of nephrotic syndrome); or fever with severe abdominal pain (possible spontaneous bacterial peritonitis). All patients with unexplained significant proteinuria (protein:creatinine ratio above 100-150 mg/mmol) on urine testing should be urgently referred to nephrology for diagnosis, biopsy if appropriate, and specific treatment of the underlying glomerular disease.