Nephrotic Syndrome

Nephrotic syndrome is a clinical tetrad of massive proteinuria, hypoalbuminaemia, oedema and hyperlipidaemia arising from increased glomerular permeability to plasma proteins. It is one of the most heavily tested topics in Nephrology for NEET PG — expect questions on age-based aetiology, steroid responsiveness, electron microscopy patterns and complications.

Definition & diagnostic criteria

Nephrotic syndrome is defined by all of the following:

• Massive proteinuria: >3.5 g/1.73 m²/day (adults) or >40 mg/m²/hour (children); spot urine protein:creatinine ratio (UPCR) >3–3.5 mg/mg.
• Hypoalbuminaemia: serum albumin <3.0 g/dL (often <2.5 g/dL).
• Oedema: typically periorbital, dependent, may progress to anasarca.
• Hyperlipidaemia & lipiduria: raised cholesterol/LDL, fatty casts, oval fat bodies ("Maltese cross" under polarised light).

High-yield: The single defining feature is proteinuria >3.5 g/day. Hypoalbuminaemia, oedema and hyperlipidaemia are all downstream consequences. If proteinuria is sub-nephrotic but with haematuria, hypertension and falling GFR, think nephritic, not nephrotic.

Nephrotic vs Nephritic — the classic comparison

Feature	Nephrotic syndrome	Nephritic syndrome
Proteinuria	Heavy (>3.5 g/day)	Mild–moderate (<3.5 g/day)
Haematuria	Absent/minimal	Marked, dysmorphic RBCs, RBC casts
Oedema	Generalised, periorbital	Periorbital, less severe
Blood pressure	Usually normal	Hypertension common
Urine sediment	"Bland", fatty/oval fat bodies	"Active", RBC casts
Hypoalbuminaemia	Marked	Mild
Underlying lesion	Podocyte injury (effacement)	Inflammatory/proliferative GN

High-yield: RBC casts = nephritic; oval fat bodies / Maltese cross = nephrotic. This single distinction resolves many MCQs.

Aetiology — primary vs secondary

Primary (idiopathic) glomerular diseases

• Minimal change disease (MCD) — commonest in children.
• Focal segmental glomerulosclerosis (FSGS) — commonest primary cause in adults (esp. African ancestry); commonest overall cause in many recent Indian series.
• Membranous nephropathy (MN) — classic cause in older Caucasian adults.
• Membranoproliferative GN (MPGN) — can present nephrotic or mixed nephrotic-nephritic.

Secondary causes (very high yield)

• Diabetes mellitus — the single commonest cause of nephrotic-range proteinuria overall (Kimmelstiel–Wilson nodules).
• Amyloidosis (AL/AA) — Congo red apple-green birefringence.
• SLE — lupus nephritis, especially Class V (membranous).
• Infections — hepatitis B (membranous), hepatitis C (MPGN/cryoglobulinaemia), HIV (collapsing FSGS), malaria, syphilis.
• Drugs — NSAIDs (MCD/membranous), gold, penicillamine, captopril.
• Malignancy — solid tumours (membranous), Hodgkin lymphoma (MCD).

High-yield: Age-based aetiology is the most repeated MCQ. Child → Minimal change disease. Young adult → FSGS. Older adult → Membranous. Diabetic → Diabetic nephropathy.

Age / setting	Most likely cause	Light microscopy	EM hallmark
Child (2–8 yr)	Minimal change disease	Normal glomeruli	Diffuse foot-process effacement
Adolescent/young adult	FSGS	Focal, segmental sclerosis	Effacement + segmental sclerosis
Older adult (Caucasian)	Membranous nephropathy	Thick GBM, "spike & dome" on silver	Subepithelial deposits
Diabetic	Diabetic nephropathy	Kimmelstiel–Wilson nodules	GBM thickening, mesangial expansion
Hep C / cryoglobulin	MPGN	"Tram-track" GBM	Subendothelial deposits

Pathophysiology

The central lesion is podocyte injury with loss of the glomerular charge and size barrier, allowing albumin to leak into urine.

Mechanism flow:

Podocyte injury / foot-process effacement → loss of slit-diaphragm integrity → massive albuminuria → hypoalbuminaemia → fall in plasma oncotic pressure + primary renal Na⁺ retention → oedema → hepatic compensatory protein synthesis → hyperlipidaemia (↑ LDL/VLDL, ↓ lipoprotein lipase activity).

Two theories explain oedema:

1. Underfill — low oncotic pressure → fluid into interstitium → ↓ intravascular volume → RAAS activation (classic in MCD).
2. Overfill — primary distal tubular Na⁺ retention (activation of epithelial Na⁺ channel by filtered proteases) → expanded volume (commoner in many adults).

High-yield: Hyperlipidaemia results from increased hepatic lipoprotein synthesis (driven by low oncotic pressure) plus reduced catabolism. Loss of antithrombin III in urine + increased hepatic clotting factors → hypercoagulable state.

Clinical features

• Oedema: periorbital on waking, dependent (legs) later in the day, scrotal/labial, ascites, pleural effusions, anasarca.
• Frothy urine (proteinuria).
• Hyperlipidaemia signs: xanthelasma, xanthomata in chronic cases.
• Muffled lines / Muehrcke's lines on nails (hypoalbuminaemia).
• Features of complications: leg swelling/pain (DVT, renal vein thrombosis with loin pain + haematuria), infections.

Investigations

Urine

• Dipstick: 3+/4+ albumin (dipstick detects albumin, not light chains — important in myeloma).
• 24-hour urine protein (gold standard quantification) or spot UPCR.
• Microscopy: oval fat bodies, fatty casts, Maltese cross with polarised light.

Blood

• Serum albumin, lipid profile, renal function (urea/creatinine), electrolytes.
• Cause-directed serology: ANA/anti-dsDNA (SLE), C3/C4 (low in MPGN, lupus, post-strep), HBsAg, anti-HCV, HIV, serum/urine electrophoresis (myeloma/amyloid).
• Anti-PLA2R antibody — positive in ~70–80% of primary membranous nephropathy; a NEET PG favourite.

Renal biopsy

• Indicated in: all adults with new nephrotic syndrome (to define histology), children who are steroid-resistant, atypical features (haematuria, hypertension, low complement, raised creatinine), or relapsing disease.
• Not routinely done in a typical 2–8 year old child — empirical steroids are given first, assuming minimal change disease.

High-yield: A child aged 2–8 with nephrotic syndrome, normal complement and no haematuria/hypertension is treated with steroids without biopsy, presuming minimal change disease.

Investigation of choice (quick recall)

• Quantify protein → 24-hr urine protein / UPCR.
• Confirm histology in adult → renal biopsy.
• Primary membranous → anti-PLA2R antibody.
• Amyloid → Congo red stain (apple-green birefringence).
• MCD on EM → diffuse podocyte foot-process effacement with normal light microscopy and negative immunofluorescence.

Histology pearls (electron microscopy / IF)

Disease	Light microscopy	Immunofluorescence	Electron microscopy
Minimal change	Normal	Negative	Diffuse foot-process effacement (lipoid nephrosis)
FSGS	Focal segmental sclerosis	Often negative / IgM, C3 in sclerotic areas	Effacement + segmental sclerosis
Membranous	Diffuse GBM thickening, "spikes" on silver stain	Granular IgG + C3 along GBM	Subepithelial deposits ("dome")
MPGN type I	Lobular, tram-track double contour	C3 ± Ig	Subendothelial deposits
Dense deposit disease (MPGN II)	Tram-track	C3 only	Intramembranous dense deposits
Diabetic nephropathy	Kimmelstiel–Wilson nodules	Linear (non-specific)	GBM thickening

High-yield: "Lipoid nephrosis" = minimal change disease — normal light microscopy, negative IF, foot-process effacement on EM. Classic single-best-answer trap.

Management

General / supportive (applies to all)

• Proteinuria reduction: ACE inhibitor or ARB — reduce intraglomerular pressure and proteinuria (cornerstone in non-MCD disease).
• Oedema: dietary salt restriction + loop diuretics (furosemide); add thiazide/metolazone if resistant; cautious albumin in severe hypoalbuminaemic states.
• Dyslipidaemia: statin.
• Dietary protein: moderate (not high) protein intake.
• Thromboprophylaxis: anticoagulation considered when serum albumin <2.0–2.5 g/dL (especially membranous nephropathy).

Disease-specific

• Minimal change disease: Corticosteroids (prednisolone) are the drug of choice — >90% of children respond. Relapsers/steroid-dependent: levamisole, cyclophosphamide, calcineurin inhibitors (ciclosporin/tacrolimus), or rituximab.
• FSGS: prolonged steroids; calcineurin inhibitors if resistant; poorer prognosis, may progress to ESRD.
• Membranous nephropathy: many remit spontaneously; high-risk patients get immunosuppression — rituximab or cyclophosphamide + steroids (Ponticelli regimen), or calcineurin inhibitor.
• Lupus nephritis (Class V): ACEi/ARB ± immunosuppression based on class.
• Secondary causes: treat underlying disease (glycaemic control, antiviral therapy for HBV/HCV, chemotherapy for amyloid).

High-yield: Drug of choice for minimal change disease = oral prednisolone. Steroid-responsiveness itself supports the diagnosis of MCD in children.

Steroid-response terminology (paediatric — frequently asked)

Term	Definition
Remission	Urine protein nil/trace (UPCR <0.2) for 3 consecutive days
Relapse	Reappearance of 3+/4+ proteinuria for 3 consecutive days
Frequent relapser	≥2 relapses in 6 months or ≥4 in 12 months
Steroid-dependent	2 consecutive relapses during steroid taper or within 14 days of stopping
Steroid-resistant	No remission despite 4–6 weeks of daily prednisolone (2 mg/kg/day) — biopsy indicated

Complications (high yield)

1. Thromboembolism / hypercoagulability — loss of antithrombin III in urine; renal vein thrombosis is classically associated with membranous nephropathy (presents with loin pain, haematuria, ↓ renal function, varicocele on left). Also DVT, PE.
2. Infection — loss of immunoglobulins and complement factor B in urine → susceptibility to encapsulated organisms; spontaneous bacterial peritonitis (Streptococcus pneumoniae) in children — vaccinate against pneumococcus.
3. Hyperlipidaemia / accelerated atherosclerosis.
4. Acute kidney injury — from hypovolaemia, sepsis, drugs, or renal vein thrombosis.
5. Protein malnutrition / muscle wasting.
6. Vitamin D deficiency (loss of vitamin D–binding protein), iron-resistant microcytic anaemia (loss of transferrin), and hypothyroid tendency (loss of thyroxine-binding globulin).

High-yield: Renal vein thrombosis ↔ membranous nephropathy is the classic linked pair. SBP with pneumococcus ↔ nephrotic child is another.

Mnemonic for nephrotic complications — "TIME": Thromboembolism, Infection, Malnutrition/Metabolic (lipids, vit D), Edema/AKI.

Key differentials

• Nephritic syndrome / acute GN — haematuria, RBC casts, hypertension, sub-nephrotic protein.
• Cardiac / hepatic / nutritional oedema — distinguished by absence of heavy proteinuria.
• Protein-losing enteropathy — hypoalbuminaemia + oedema but no proteinuria (raised faecal alpha-1 antitrypsin).
• Diabetic nephropathy — gradual proteinuria with retinopathy, long-standing diabetes; usually no biopsy needed.
• Amyloidosis — older patient, organomegaly, Congo red positive.

Recently asked / exam angle

• Commonest cause of nephrotic syndrome in children → minimal change disease; in adults (primary) → FSGS (membranous in older Caucasians); overall/secondary → diabetic nephropathy.
• EM finding in MCD → diffuse effacement of podocyte foot processes ("lipoid nephrosis").
• Antibody in primary membranous nephropathy → anti-PLA2R.
• Light-microscopy nodules in diabetic nephropathy → Kimmelstiel–Wilson nodules.
• Glomerulonephritis associated with renal vein thrombosis → membranous nephropathy.
• Drug of choice in childhood MCD → prednisolone; steroid-resistant → biopsy.
• "Spike and dome" / subepithelial deposits → membranous.
• "Tram-track"/double-contour GBM with low C3 → MPGN.
• Cause of hypercoagulability → urinary loss of antithrombin III.
• Apple-green birefringence with Congo red → amyloidosis.
• Stain for membranous spikes → silver methenamine.
• Hodgkin lymphoma associated nephrotic lesion → minimal change disease; solid tumours → membranous.

Rapid revision

1. Diagnostic core = proteinuria >3.5 g/day + hypoalbuminaemia + oedema + hyperlipidaemia.
2. Child → MCD; young adult → FSGS; older adult → membranous; diabetic → diabetic nephropathy.
3. MCD = normal LM, negative IF, foot-process effacement on EM = lipoid nephrosis.
4. Membranous = subepithelial deposits, "spike & dome", anti-PLA2R, linked to renal vein thrombosis.
5. MPGN = tram-track GBM, low C3, hep C/cryoglobulinaemia.
6. Diabetic nephropathy = Kimmelstiel–Wilson nodules; commonest overall cause of nephrotic-range proteinuria.
7. Amyloid = Congo red apple-green birefringence.
8. Hypercoagulability from urinary loss of antithrombin III; oedema from podocyte injury ± Na⁺ retention.
9. Child 2–8 yr, no atypical features → steroids first, no biopsy; adults → biopsy.
10. Drug of choice for MCD = oral prednisolone; steroid-resistant → biopsy + calcineurin inhibitor/rituximab.
11. Infection risk from loss of Ig/complement → pneumococcal SBP; vaccinate.
12. Urine shows oval fat bodies / Maltese cross; nephritic shows RBC casts — never confuse the two.