Nephrotic Syndrome

Definition

Nephrotic syndrome is defined by three cardinal features (Harrison's, p. 8392):

Feature	Threshold
Proteinuria	> 3.5 g/day
Hypoalbuminemia	< 3.5 g/dL
Edema	Periorbital, peripheral, ascites

Additional findings include hyperlipidemia (high LDL, low HDL), lipiduria, oval fat bodies, fatty casts, and Maltese cross-shaped cholesterol crystals under polarized light.

Pathophysiology

The primary defect is increased glomerular permeability to plasma proteins, particularly albumin. This leads to:

Proteinuria → loss of oncotic pressure → hypoalbuminemia
Reduced plasma oncotic pressure → fluid shifts to interstitium → edema
Compensatory hepatic lipoprotein synthesis + reduced lipoprotein lipase activity → hyperlipidemia
Loss of anticoagulant proteins (antithrombin III, proteins C and S) → hypercoagulable state
Loss of immunoglobulins → increased infection susceptibility

Causes

Primary (Glomerular)

Disease	Population	Key Features
Minimal Change Disease (MCD)	Children (#1), young adults	Abrupt onset, steroid-responsive, normal LM
Focal Segmental Glomerulosclerosis (FSGS)	Adults, African Americans	Focal/segmental scarring, higher resistance to therapy
Membranous Nephropathy	Adults (#1 cause in adults)	Spike-and-dome on EM, anti-PLA2R antibody
Membranoproliferative GN (MPGN)	Any age	Low complement, tram-track pattern
IgA Nephropathy	Young adults	Mesangial IgA deposits

Secondary Causes

Diabetes mellitus (most common secondary cause worldwide — diabetic nephropathy)
Systemic lupus erythematosus (lupus nephritis class V)
Amyloidosis (AA or AL)
Infections: Hepatitis B/C, HIV, malaria, syphilis
Drugs: NSAIDs, gold, penicillamine, heroin
Malignancy: Hodgkin lymphoma (MCD), solid tumors (membranous)
Preeclampsia

Clinical Features

Edema: Periorbital (especially morning), dependent edema, anasarca in severe cases
Frothy urine (heavy proteinuria)
Ascites and pleural effusions
Xanthelasma (chronic hyperlipidemia)
Increased thrombosis risk: Deep vein thrombosis, renal vein thrombosis, pulmonary embolism
Increased infection risk: Spontaneous bacterial peritonitis, cellulitis, pneumonia (encapsulated organisms)

Diagnosis

Initial Workup

Urinalysis: Proteinuria, lipiduria, oval fat bodies, fatty casts
Urine protein-to-creatinine ratio (spot) or 24-hour urine protein (> 3.5 g/day)
Serum albumin (< 3.5 g/dL)
Lipid panel: Elevated total cholesterol, LDL; low HDL
BMP/CMP: Assess renal function
CBC, coagulation studies

Secondary Cause Workup

ANA, anti-dsDNA, complement (C3/C4) — for lupus
Anti-PLA2R antibody — for membranous nephropathy
Serum/urine protein electrophoresis — for amyloidosis/myeloma
Hepatitis B/C serology, HIV
Blood glucose, HbA1c — for diabetes
Age-appropriate cancer screening

Kidney Biopsy

Indicated in adults with nephrotic syndrome (except presumed diabetic nephropathy). Generally deferred in children with initial presentation (empirically treated as MCD).

FSGS Evaluation (Management of Glomerular Diseases, p. 163)

When FSGS is found on biopsy, management depends on whether nephrotic syndrome is present:

With nephrotic syndrome (proteinuria > 3.5 g/day + albumin < 30 g/L ± edema, especially with diffuse foot process effacement): Treat as primary FSGS with immunosuppression; consider genetic testing if non-responsive.
Without nephrotic syndrome: Evaluate for secondary/genetic causes, provide supportive therapy, and monitor. Escalate to immunosuppression only if nephrotic syndrome develops.

Management

General Measures (Harrison's, p. 8592)

Problem	Treatment
Edema	Loop diuretics (furosemide); avoid intravascular volume depletion
Hypercholesterolemia	Statins (all patients — increased CV risk)
Proteinuria	ACE inhibitors or ARBs (reduce proteinuria, slow progression)
Hypercoagulability	Anticoagulation if thromboembolism develops (some guidelines favor prophylactic anticoagulation if albumin < 2.5 g/dL)
Hypertension	ACE inhibitors/ARBs preferred
Infection risk	Pneumococcal vaccination; prompt antibiotic treatment

Disease-Specific Treatment

Cause	First-Line Treatment
MCD	Prednisone (high remission rate > 90%)
Primary FSGS	High-dose corticosteroids; calcineurin inhibitors (cyclosporine, tacrolimus) if steroid-resistant
Membranous Nephropathy	Spontaneous remission possible; rituximab (anti-CD20) now preferred; cyclophosphamide + steroids (Ponticelli protocol)
Lupus nephritis (class V)	Hydroxychloroquine; mycophenolate mofetil ± steroids
Diabetic nephropathy	Glycemic control, RAAS blockade, SGLT2 inhibitors (empagliflozin, dapagliflozin)

Complications

Complication	Mechanism
Thromboembolism	Loss of antithrombin III, proteins C/S; renal vein thrombosis is classic
Infections	Loss of IgG and opsonins; encapsulated organisms (Streptococcus pneumoniae)
AKI	Volume depletion, over-diuresis, renal vein thrombosis
CKD progression	Ongoing proteinuria is nephrotoxic
Hypothyroidism	Loss of thyroid-binding globulin (affects function tests)
Malnutrition	Protein loss, protein-energy wasting
Cardiovascular disease	Chronic hyperlipidemia accelerates atherosclerosis

Prognosis

Prognosis depends heavily on the underlying cause:

MCD: Excellent — most children and many adults achieve full remission with steroids; frequent relapsers exist
Primary FSGS: Variable — up to 50% progress to ESRD within 10 years without treatment
Membranous nephropathy: "Rule of thirds" — 1/3 spontaneous remission, 1/3 stable, 1/3 progressive
Diabetic nephropathy: Progressive without aggressive management; SGLT2 inhibitors have improved outcomes
Amyloidosis: Poor prognosis; depends on treatment of underlying disease

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