Nephrotic syndrome

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Researching nephrotic syndrome across etiology, clinical presentation, diagnosis, management, and associated imaging/histology.

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nephrotic syndrome etiology pathophysiology clinical features diagnosis

Harrison's Principles of Internal Medicine, Twenty First Edition

Page 8392

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nephrotic syndrome management treatment complications

Harrison's Principles of Internal Medicine, Twenty First Edition

Page 8592

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nephrotic syndrome histology glomerulonephritis

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Here is a comprehensive overview of nephrotic syndrome:

Nephrotic Syndrome

Definition

Nephrotic syndrome (NS) is defined by the triad of:

Proteinuria >3.5 g/day (or >3.5 g/1.73 m²/day)
Hypoalbuminemia (<3.5 g/dL)
Edema

Frequently accompanied by hyperlipidemia (high LDL, low HDL) and lipiduria (Harrison's, p. 8392).

Etiology

Primary (Idiopathic) Glomerulopathies

Disease	Key Feature	Common Age
Minimal Change Disease (MCD)	No light microscopy changes; effacement of foot processes on EM	Children (most common)
Focal Segmental Glomerulosclerosis (FSGS)	Segmental scarring of glomeruli	Adults; African Americans
Membranous Nephropathy	Subepithelial immune deposits; "spike and dome" on EM	Adults (most common primary NS in adults)
Membranoproliferative GN (MPGN)	Mesangial proliferation + GBM thickening	Adolescents/young adults

Secondary Causes

Diabetes mellitus — diabetic nephropathy (most common secondary cause worldwide)
Systemic lupus erythematosus (SLE) — lupus nephritis (especially class V)
Amyloidosis — AL or AA type
Infections — HBV, HCV, HIV, malaria, syphilis
Drugs — NSAIDs, gold, penicillamine, heroin
Malignancy — solid tumors (membranous), lymphoma (MCD)
Preeclampsia

Pathophysiology

Glomerular injury → loss of the glomerular filtration barrier (charge and/or size selectivity)
Massive proteinuria (especially albumin) → hypoalbuminemia
Reduced oncotic pressure → fluid shifts into interstitium → edema
Compensatory hepatic lipoprotein synthesis → hyperlipidemia
Loss of lipoproteins in urine → lipiduria
Loss of regulatory proteins → hypercoagulable state (loss of antithrombin III, proteins C and S), increased infection risk (loss of IgG, complement factors), thyroid/endocrine abnormalities

Clinical Features

Feature	Description
Edema	Periorbital (especially morning), pedal, ascites, pleural effusion
Frothy urine	Due to heavy proteinuria
Pallor	From edema/anemia
Signs of complications	DVT/PE, infections, cushingoid features (if on steroids)

Urinalysis findings:

Heavy proteinuria (3–4+ on dipstick)
Oval fat bodies — large tubular epithelial cells engulfed with lipid
Maltese crosses under polarized light (cholesterol monohydrate crystals)
Fatty casts

Diagnosis

Initial Workup

Urine dipstick + microscopy — proteinuria, oval fat bodies, fatty casts
Spot urine protein:creatinine ratio — >3.5 mg/mg indicates nephrotic-range proteinuria
24-hour urine protein — gold standard (>3.5 g/day)
Serum albumin, lipid panel, BMP/CMP
Secondary cause workup: ANA, anti-dsDNA, complement (C3/C4), hepatitis B/C serology, HIV, HbA1c, serum protein electrophoresis, cryoglobulins

Kidney Biopsy

Indicated in adults with NS of unclear etiology. Not routinely done in children (MCD presumed and treated empirically with steroids).

Histological patterns:

Light microscopy (LM) — MCD appears normal; FSGS shows segmental sclerosis; membranous shows GBM thickening
Immunofluorescence (IF) — granular IgG + C3 deposits in membranous; "full house" in lupus
Electron microscopy (EM) — foot process effacement (all causes), subepithelial deposits (membranous), mesangial deposits (IgA/lupus)

Management

Disease-Specific Therapy

(Harrison's, p. 8592)

Cause	Treatment
MCD	Prednisone (first-line); cyclophosphamide or calcineurin inhibitors for frequent relapse
FSGS	High-dose steroids; tacrolimus/cyclosporine for steroid-resistant
Membranous	Conservative first; rituximab (now preferred); cyclophosphamide + steroids (Ponticelli)
Diabetic nephropathy	ACE inhibitor/ARB; SGLT-2 inhibitors; glycemic control
Lupus nephritis	Mycophenolate mofetil + steroids; belimumab/voclosporin for resistant disease

Supportive Therapy (All Patients)

Edema — sodium restriction (<2 g/day); loop diuretics (furosemide); avoid aggressive diuresis (risk of intravascular depletion)
Hyperlipidemia — statins (HMG-CoA reductase inhibitors); all patients with hypercholesterolemia secondary to NS should be treated due to elevated cardiovascular risk (Harrison's, p. 8592)
Proteinuria reduction — ACE inhibitors or ARBs (reduce intraglomerular pressure and proteinuria, independently of BP)
Anticoagulation — for venous thromboembolism prophylaxis/treatment; serum albumin <2.5 g/dL is a major risk factor, especially in membranous nephropathy
Infection prevention — pneumococcal vaccine; immunoglobulin replacement in refractory cases

Complications

Complication	Mechanism
Thromboembolic events (DVT, PE, renal vein thrombosis)	Loss of antithrombin III, protein C/S; platelet hyperactivation
Infections (peritonitis, cellulitis, sepsis)	Loss of IgG and complement (opsonins); edema as culture medium
Acute kidney injury	Hypovolemia from aggressive diuresis; bilateral renal vein thrombosis
Dyslipidemia / accelerated atherosclerosis	Increased hepatic VLDL synthesis; decreased lipoprotein lipase activity
Endocrine abnormalities	Loss of thyroid-binding globulin → low total T4 (free T4 normal)
Vitamin D deficiency	Loss of vitamin D-binding protein
Protein malnutrition	Ongoing urinary protein losses

Nephrotic vs. Nephritic Syndrome

Feature	Nephrotic	Nephritic
Proteinuria	>3.5 g/day	<3.5 g/day (mild-moderate)
Hematuria	Absent or minimal	Prominent (RBC casts)
Hypertension	Mild or absent	Common
Edema	Marked	Mild-moderate
Serum complement	Normal (except MPGN, lupus)	Often low
Renal function	Usually preserved initially	Often reduced

Prognosis

Depends heavily on the underlying cause:

MCD: Excellent — >90% respond to steroids; tendency to relapse in children
Membranous: ~30% spontaneous remission; ~30% progress to ESRD; rituximab improves outcomes
FSGS: Poor without treatment; high rate of progression to ESRD, especially steroid-resistant forms
Diabetic nephropathy: Progressive without aggressive management; SGLT-2 inhibitors (empagliflozin, dapagliflozin) have changed the prognosis significantly

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