Nephrotic Syndrome - Comprehensive Overview

Definition

• Proteinuria >3.5 g/24 hours (nephrotic range)
• Hypoalbuminemia (serum albumin <3.5 g/dL; practically <2.5 g/dL in most criteria)
• Edema (pitting peripheral edema, often anasarca)
• Hyperlipidemia (total cholesterol usually >180 mg/dL)

• National Kidney Foundation Primer on Kidney Diseases, 8e, p. 190
• Frameworks for Internal Medicine, p. 464

Pathophysiology

Glomerular Filtration Barrier Disruption

1. Fenestrated endothelial cells - with their glycocalyx providing a charge barrier
2. Glomerular basement membrane (GBM) - a collagen IV scaffold rich in heparan sulfate proteoglycans (anionic, repels albumin)
3. Podocytes - specialized epithelial cells with interdigitating foot processes bridged by the slit diaphragm, composed mainly of nephrin and podocin

• Robbins & Kumar Basic Pathology, p. 452-453

Edema Mechanism: "Underfill" vs. "Overfill"

• Underfill: Loss of albumin reduces plasma oncotic pressure → fluid shifts to interstitium → intravascular volume contraction → RAAS activation → sodium/water retention
• Overfill (more common): Primary distal tubular sodium retention occurs independently of the RAAS, driving volume expansion

• Brenner and Rector's The Kidney, p. 2277

Classification of Causes

Primary (Idiopathic) Causes - Incidence in Adults

• Goldman-Cecil Medicine, Table 107-2

Secondary Causes

• Goldman-Cecil Medicine, Table 107-3

Major Disease Entities

1. Minimal Change Disease (MCD)

• Accounts for >70-90% of nephrotic syndrome in children but only ~5-10% in adults
• Pathogenesis is unknown; associations with NSAID use, Hodgkin lymphoma, and thymoma suggest a T-cell-mediated mechanism
• Light microscopy: Normal (hence the name - "minimal changes")
• Electron microscopy: Diffuse foot process effacement
• Immunofluorescence: Negative
• In children with pure nephrotic syndrome (no hematuria, normal GFR), MCD is presumed and biopsy is not routinely required; adults require biopsy
• Treatment: Corticosteroids are the cornerstone; anti-CD20 monoclonal antibodies (rituximab) for steroid-resistant/dependent cases
• Underfill edema pattern; RAAS activated

2. Focal Segmental Glomerulosclerosis (FSGS)

• Focal (only some glomeruli affected) and segmental (only part of the affected glomerulus scarred) on light microscopy, but EM shows foot process effacement even in "unaffected" glomeruli
• ~25% of adult nephrotic syndrome; most common cause among African-Americans (linked to APOL1 risk variants)
• Presents with nephrotic-range proteinuria, often with hypertension, reduced GFR, and microscopic hematuria
• Classification:
  • Primary FSGS: Circulating podocyte permeability factor; >80% foot process effacement on EM; abrupt onset
  • Secondary FSGS: Viral (HIV, parvovirus B19, COVID-19), drugs (heroin, pamidronate, interferon, anabolic steroids), adaptive (obesity, reduced nephron mass); <80% foot process effacement
  • Genetic FSGS: Mutations in NPHS1 (nephrin), NPHS2 (podocin), PLCE1, ACTN4, INF2, APOL1
• Collapsing FSGS (a variant): Strongly associated with HIV; presents with abrupt, severe nephrotic syndrome and rapidly progressive renal failure
• Treatment: Corticosteroids for primary FSGS; addressing the underlying cause for secondary

3. Membranous Nephropathy (MN)

• Most common cause of nephrotic syndrome in White adults (25-30%)
• More frequently associated with thromboembolism than other causes, especially renal vein thrombosis (particularly with severe proteinuria >10 g/24hr and albumin <2 g/dL)
• Pathogenesis: Subepithelial immune complex deposition with in situ antibody-antigen reactions
• Key antigens:
  • PLA2R (M-type phospholipase A2 receptor) - primary MN
  • THSD7A - primary MN and malignancy-associated
  • NELL-1 - primary MN and malignancy-associated
  • EXT1/2 - autoimmunity (SLE)
  • Semaphorin 3b - younger/pediatric patients
• Secondary causes: SLE, hepatitis B, penicillamine, solid tumors (colon cancer, lung)
• Light microscopy: Thickening of GBM with "spike and dome" pattern (silver stain)
• EM: Subepithelial dense deposits with podocyte effacement
• IF: Granular IgG + C3 deposits along GBM
• Treatment: Observation for partial remission, then immunosuppression (cyclophosphamide + steroids, or rituximab) for high-risk patients

4. Membranoproliferative Glomerulonephritis (MPGN)

• ~5% of nephrotic syndrome; can present as nephrotic, nephritic, or mixed syndrome
• Two main mechanisms:
  • Immune complex-mediated (hepatitis B/C, autoimmune diseases)
  • Complement-mediated (C3 glomerulopathy, dense deposit disease)
• Light microscopy: "Tram track" appearance (GBM duplication/splitting) due to mesangial interposition

Clinical Features

Symptoms

• Peripheral edema (often progressing to anasarca)
• Periorbital edema (classically prominent on awakening)
• Fatigue, dyspnea
• Foamy urine (surfactant effect of protein in urine)
• Weight gain

Physical Signs

• Hypertension
• Generalized dependent pitting edema
• Ascites, pleural effusions
• Muehrcke's lines (paired white transverse lines on nails, from hypoalbuminemia)
• Eruptive xanthomata, xanthelasma (from hyperlipidemia)

Complications

1. Hypercoagulability / Thromboembolism

• Antithrombin III (major)
• Protein C and Protein S
• Plasminogen

2. Infection

• Loss of IgG in urine leads to hypogammaglobulinemia
• Reduced complement activity (loss of Factor B/D)
• Impaired T-cell function
• Increased susceptibility to encapsulated organisms (Streptococcus pneumoniae, Haemophilus influenzae) - spontaneous bacterial peritonitis in ascites is a classic complication

3. Hyperlipidemia

• Low oncotic pressure upregulates hepatic apolipoprotein synthesis
• Elevated total cholesterol, LDL, VLDL, lipoprotein(a); low or normal HDL
• Increased risk of atherosclerotic cardiovascular disease
• Lipiduria ("fatty casts," oval fat bodies, Maltese cross pattern under polarized light)

4. Nutritional Deficiencies

• Iron deficiency anemia - loss of transferrin
• Vitamin D deficiency - loss of vitamin D-binding protein (leading to hypocalcemia, secondary hyperparathyroidism)
• Hypothyroidism - loss of thyroid-binding globulin
• Zinc deficiency - loss of zinc-binding proteins

5. Acute Kidney Injury

• Due to reduced effective circulating volume (underfill)
• Thrombosis
• Tubular toxicity from heavy proteinuria

Diagnosis

Laboratory Workup

• Fasting glucose + HbA1c (diabetes)
• ANA, anti-dsDNA, complement levels (SLE)
• Hepatitis B surface antigen, Hepatitis C antibody
• HIV serology
• SPEP/immunofixation (myeloma, amyloid)
• Anti-PLA2R antibody (primary membranous)
• ANCA, anti-GBM (if nephritic features also present)
• Low complement (C3, C4) suggests immune complex-mediated disease

Kidney Biopsy

• Required in adults with nephrotic syndrome unless diabetes is a clear underlying cause
• Guides specific diagnosis, prognosis, and therapy
• Not routinely needed in children (<12 years) presenting with pure nephrotic syndrome (presumed MCD; treat empirically with steroids)
• Processing: light microscopy (H&E, PAS, Masson trichrome, silver stain), immunofluorescence, and electron microscopy are all needed for complete evaluation

Management

General (Non-Disease-Specific) Measures

• Furosemide is highly protein-bound; in hypoalbuminemia, delivery to the tubular lumen is impaired
• Albumin infusion to "pre-mix" with furosemide has NOT been confirmed to reliably enhance diuresis and is not generally recommended
• Adding ACE inhibitor/ARB to reduce proteinuria is a more rational approach to diuretic resistance

Disease-Specific Treatment

Nephrotic vs. Nephritic Syndrome: Key Distinction

Recent Evidence

• Frameworks for Internal Medicine, pp. 463-466
• National Kidney Foundation Primer on Kidney Diseases, 8e, pp. 190-196
• Goldman-Cecil Medicine, Tables 107-2 and 107-3
• Brenner and Rector's The Kidney, p. 2277
• Robbins & Kumar Basic Pathology, pp. 452-458