9.2 Glomerular Disorders & Nephrotic Syndrome
Key Takeaways
- Lupus nephritis, minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, membranoproliferative glomerulonephritis, IgA nephropathy and anti-glomerular basement membrane disease are enumerated glomerular topics.
- Nephrotic syndrome is defined by proteinuria exceeding 3.5 grams per day with hypoalbuminemia, edema and hyperlipidemia.
- Membranous nephropathy carries the highest thrombotic risk of the nephrotic syndromes, and renal vein thrombosis presents with flank pain and gross hematuria.
- Primary membranous nephropathy is associated with anti-phospholipase A2 receptor antibodies, whose presence can obviate biopsy in selected patients.
- Focal segmental glomerulosclerosis has primary and secondary forms whose treatment differs, since secondary disease is managed by addressing the underlying driver rather than with immunosuppression.
Last updated: August 2026
1. Glomerular Diseases: Nephrotic vs. Nephritic Spectrum
Glomerular diseases are categorized into primary nephrotic syndromes (characterized by podocyte injury and massive proteinuria) and nephritic syndromes (characterized by inflammatory endocapillary proliferation and glomerular basement membrane rupture).
Comparison of Nephrotic vs. Nephritic Syndromes
| Feature | Nephrotic Syndrome | Nephritic Syndrome |
|---|---|---|
| Defining Proteinuria | >3.5 g / 24 hours (or Spot Urine Protein-to-Creatinine Ratio UPCR >3.5 g/g; Urine Albumin-to-Creatinine Ratio UACR >3000 mg/g) | Sub-nephrotic (<3.5 g / 24 hours, typically 0.5–2.0 g/day) |
| Serum Albumin | Severe hypoalbuminemia (<3.0 g/dL) | Normal or mildly decreased |
| Edema | Marked, generalized, anasarca (periorbital, peripheral, ascites, pleural effusions) | Mild-to-moderate dependent edema (facial/periorbital and pretibial) |
| Urinary Sediment | Bland, oval fat bodies, fatty casts, "Maltese cross" birefringence under polarized light | Active sediment: Dysmorphic RBCs (acanthocytes), RBC casts, WBCs |
| Hematuria / Urine Color | Microscopic or absent (clear / yellow urine) | Macroscopic or microscopic (coca-cola / tea-colored / smoky urine) |
| Blood Pressure | Usually normal (except in secondary forms like diabetic nephropathy) | Hypertension (due to fluid retention and impaired natriuresis) |
| Renal Function | Initially preserved GFR (unless severe intravascular depletion or ATN) | Rapidly declining GFR / Acute Kidney Injury (Oliguria) |
2. Nephrotic Syndromes: Subtypes & Clinical Pearls
Complications of Nephrotic Syndrome
- Hypercoagulability & Thromboembolism: Urinary loss of endogenous anticoagulant proteins (Antithrombin III, protein C, protein S) combined with hepatic overproduction of prothrombotic factors (fibrinogen, factor V, factor VIII) and thrombocytosis. Highest risk in Membranous Nephropathy with serum albumin <2.0–2.5 g/dL. Manifests as Renal Vein Thrombosis (sudden flank pain, gross hematuria, worsening proteinuria, acute GFR decline; left renal vein > right due to anatomical drainage into the IVC), deep vein thrombosis, and pulmonary embolism. Prophylactic anticoagulation (e.g., Warfarin or DOAC) is indicated for high-risk patients with albumin <2.0–2.5 g/dL.
- Infection Susceptibility: Urinary loss of immunoglobulins (IgG) and complement factors (properdin factor B) leads to impaired opsonization of encapsulated organisms (Streptococcus pneumoniae, Haemophilus influenzae). Patients require pneumococcal and influenza immunizations.
- Severe Hyperlipidemia & Accelerated Atherosclerosis: Hypoalbuminemia stimulates generalized hepatic protein synthesis, resulting in elevated total cholesterol, LDL, and VLDL, and reduced lipid catabolism (decreased lipoprotein lipase activity).
Primary & Secondary Nephrotic Subtypes
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Minimal Change Disease (MCD):
- Epidemiology: Accounts for ~85–90% of pediatric nephrotic cases and ~10–15% of adult nephrotic syndrome.
- Histopathology: Light microscopy (LM) appears completely normal; Immunofluorescence (IF) is negative; Electron microscopy (EM) demonstrates diffuse effacement of visceral epithelial cell (podocyte) foot processes.
- Secondary Causes: Hodgkin lymphoma and other hematologic malignancies, NSAID use.
- Treatment: High-dose oral corticosteroids (Prednisone 1 mg/kg/day up to 80 mg/day for 8–16 weeks in adults). Adults have a slower initial response than children (up to 12–16 weeks required for full remission) and high relapse rates (~50%; treated with repeated steroids, cyclophosphamide, calcineurin inhibitors, or rituximab).
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Focal Segmental Glomerulosclerosis (FSGS):
- Epidemiology: Most common primary cause of nephrotic syndrome in African American adults. Strongly linked to APOL1 risk alleles (G1/G2 variants) which provide evolutionary protection against Trypanosoma brucei rhodesiense sleeping sickness but predispose podocytes to lysosomal injury.
- Primary FSGS: Mediated by a circulating podocyte permeability factor (e.g., suPAR). Presents with acute, explosive nephrotic syndrome, severe hypoalbuminemia, and diffuse foot process effacement (>80%) on EM. Treatment: High-dose oral prednisone (1 mg/kg/day for >=16 weeks) +/- Calcineurin Inhibitors (Cyclosporine, Tacrolimus).
- Secondary FSGS (Adaptive / Maladaptive Hyperfiltration): Due to structural nephron loss or hemodynamic overload:
- Causes: Advanced obesity, sickle cell nephropathy, severe solitary kidney hyperfiltration, chronic reflux nephropathy, HIV-associated nephropathy (HIVAN, classic collapsing glomerulopathy variant), IV heroin nephropathy, anabolic steroid abuse.
- Features: Slow, insidious onset of proteinuria, normal or near-normal serum albumin, absence of severe anasarca, and patchy/focal foot process effacement on EM.
- Treatment: Treat underlying etiology, strict blood pressure control, maximum tolerated ACE inhibitor / ARB, and SGLT2 inhibitor. Immunosuppression is contraindicated in secondary FSGS.
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Membranous Nephropathy (MN):
- Epidemiology: Most frequent cause of primary nephrotic syndrome in non-diabetic white adults >40 years of age.
- Primary Membranous (~75–80%): Autoantibodies against the M-type Phospholipase A2 Receptor (anti-PLA2R) expressed on podocytes (detected by ELISA or indirect immunofluorescence); ~5% against THSD7A (Thrombospondin type-1 domain-containing 7A).
- Secondary Membranous (~20–25%): Must be ruled out before establishing primary diagnosis:
- Infections: Chronic Hepatitis B, Hepatitis C, Syphilis.
- Malignancy: Solid organ carcinomas (colon, lung, prostate, breast, stomach; age-appropriate cancer screening is mandatory).
- Autoimmune: Systemic Lupus Erythematosus (Class V Lupus Nephritis; "full-house" IF), Hashimoto thyroiditis.
- Drugs: NSAIDs, penicillamine, gold salts.
- Renal Biopsy: LM reveals diffuse thickening of the glomerular basement membrane; Silver stain shows characteristic "spike and dome" appearance (subepithelial basement membrane projections surrounding immune deposits); IF shows granular capillary wall staining for IgG and C3; EM reveals subepithelial electron-dense deposits.
- Treatment Strategy:
- Low Risk (normal eGFR, non-nephrotic proteinuria <3.5 g/d, anti-PLA2R low/negative): Conservative supportive therapy with ACEi/ARB, SGLT2i, statin, and blood pressure control for 6 months.
- Moderate-to-High Risk (persistent proteinuria >4 g/d, declining eGFR, or high anti-PLA2R titers): Immunosuppressive therapy with Rituximab (375 mg/m2 weekly x 4 or 1000 mg on days 1 and 15; now preferred first-line via MENTOR trial) or Cyclical Corticosteroid + Cyclophosphamide regimen (Modified Ponticelli Regimen) for 6 months.
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Diabetic Nephropathy:
- Characterized by mesangial expansion, nodular glomerulosclerosis (Kimmelstiel-Wilson nodules), arteriolar hyalinosis, and GBM thickening. Progresses from microalbuminuria (30–300 mg/g) to overt macroalbuminuria (>300 mg/g) and GFR decline.
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Renal Amyloidosis:
- Deposition of insoluble beta-pleated fibrillar protein sheets. Congo red stain shows pathognomonic apple-green birefringence under polarized light. Electron microscopy confirms randomly oriented non-branching 7.5–10 nm fibrils. Subdivided into AL Amyloidosis (clonal plasma cell light chains; treated with Daratumumab + CyBorD) and AA Amyloidosis (serum amyloid A in chronic inflammation: RA, Crohn's, osteomyelitis, familial Mediterranean fever; treated by controlling underlying disease).
Test Your Knowledge
A 52-year-old woman presents with 3 weeks of progressive bilateral lower extremity swelling, facial puffiness, and a 6-kg weight gain. Laboratory studies reveal serum albumin of 2.1 g/dL, total cholesterol 360 mg/dL, serum creatinine 1.0 mg/dL, and a 24-hour urine protein collection demonstrating 7.2 grams of protein. Urinalysis shows oval fat bodies with a "Maltese cross" pattern under polarized light and no red blood cells. Serum serologies are positive for anti-PLA2R antibodies at high titer. She suddenly develops acute right flank pain and gross hematuria. Which complication has most likely occurred?
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