Nephrotic syndrome

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nephrotic syndrome etiology pathophysiology clinical features diagnosis

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nephrotic syndrome management treatment complications

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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:

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

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

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

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

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:

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

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)

(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

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

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

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

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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