10.2 Glomerular & Tubulointerstitial Diseases
Key Takeaways
- Nephrotic syndrome is defined by heavy proteinuria (>3.5 g/24 h), hypoalbuminemia (<3.0 g/dL), peripheral edema, hyperlipidemia, and lipiduria (oval fat bodies/Maltese crosses).
- Membranous nephropathy is the most common cause of nephrotic syndrome in adults, strongly associated with anti-phospholipase A2 receptor (PLA2R) antibodies, solid tumors, and a high risk of renal vein thrombosis.
- Nephritic syndrome features hematuria with dysmorphic red blood cells and RBC casts, mild-to-moderate proteinuria (<3.5 g/24 h), oliguria, hypertension, and azotemia.
- Acute Interstitial Nephritis (AIN) classically presents 7-14 days after starting a offending drug (NSAIDs, penicillins, cephalosporins, PPIs, sulfonamides) with the triad of fever, rash, and eosinophilia, plus urine eosinophiluria or WBC casts.
- IgA nephropathy (Berger disease) causes recurrent macroscopic hematuria 1-2 days following an upper respiratory infection, whereas Post-Streptococcal Glomerulonephritis (PSGN) manifests 1-3 weeks after streptococcal pharyngitis/impetigo with low complement C3 levels.
Clinical Spectrum of Glomerular Disease
Glomerular diseases are categorized into nephrotic syndromes (podocyte damage resulting in non-inflammatory protein loss) and nephritic syndromes (endothelial and mesangial inflammation resulting in hematuria and renal function decline). On USMLE Step 2 CK, distinguishing between these patterns based on presentation, serologies, and biopsy findings is crucial.
[ Glomerular Disease Suspected ]
|
[ 24-Hour Urine Protein & UA ]
|
+---------------------------+---------------------------+
| |
[ Proteinuria >3.5 g/24h ] [ Proteinuria <3.5 g/24h ]
[ Hypoalbuminemia / Edema ] [ Hematuria / RBC Casts ]
[ Hyperlipidemia / Lipiduria ] [ HTN / Oliguria / Azotemia ]
| |
(Nephrotic Syndrome) (Nephritic Syndrome)
| |
+------+------+ +------+------+
| | | |
[Pediatric] [Adult] [Normal C3] [Low C3]
MCD FSGS / Membranous IgA Neph PSGN / MPGN
Non-Inflammatory Nephrotic Syndromes
Nephrotic syndrome is defined by a characteristic pentad: (1) heavy proteinuria >3.5 g/24 hours (or spot urine protein-to-creatinine ratio >3.5), (2) hypoalbuminemia <3.0 g/dL, (3) generalized peripheral and periorbital edema, (4) hyperlipidemia, and (5) lipiduria featuring oval fat bodies that display a classic "Maltese cross" appearance under polarized light.
| Nephrotic Condition | Epidemiology / Associations | Key Diagnostic & Biopsy Findings | Management |
|---|---|---|---|
| Minimal Change Disease (MCD) | Most common cause in children (80%); triggered by viral illness, immunization, or Hodgkin lymphoma | Normal on light microscopy; effacement of podocyte foot processes on electron microscopy | First-line Corticosteroids (prednisone) with excellent response |
| Focal Segmental Glomerulosclerosis (FSGS) | Most common cause in African American adults; associated with HIV, heroin use, morbid obesity, sickle cell disease | Segmental sclerosis involving subset of glomeruli; effacement of foot processes | Corticosteroids, immunosuppressants, ACEi/ARBs |
| Membranous Nephropathy | Most common cause in Caucasian adults; linked to anti-PLA2R antibodies, HBV/HCV, solid tumors (colon, lung), NSAIDs | Light microscopy: GBM thickening; Electron microscopy: "spike and dome" subepithelial deposits | Immunosuppression (rituximab, cyclophosphamide + steroids) |
| Diabetic Nephropathy | Leading cause of ESRD in the US; hyperfiltration followed by microalbuminuria (30-300 mg/day) | Kimmelstiel-Wilson nodules (nodular glomerulosclerosis), GBM thickening | ACE inhibitors or ARBs, SGLT2 inhibitors |
| Renal Amyloidosis | Associated with Multiple Myeloma (AL) or chronic inflammation/RA (AA) | Congo red stain showing apple-green birefringence under polarized light | Treat underlying dyscrasia or inflammatory disorder |
Major Complications of Nephrotic Syndrome
- Hypercoagulability and Thrombosis: Urinary loss of antithrombin III, protein S, and protein C, combined with hyperfibrinogenemia, predisposes patients to deep vein thrombosis, pulmonary embolism, and renal vein thrombosis (most common in membranous nephropathy, presenting with acute flank pain, gross hematuria, and left-sided varicocele).
- Increased Susceptibility to Infection: Loss of circulating immunoglobulins (IgG) and complement factors increases risk for bacterial peritonitis (spontaneous bacterial peritonitis caused by Streptococcus pneumoniae) and sepsis.
Inflammatory Nephritic Syndromes & RPGN
Nephritic syndrome manifests with glomerular inflammation, resulting in breakdown of the glomerular basement membrane (GBM). Key features include dysmorphic red blood cells (RBCs), RBC casts, mild-to-moderate proteinuria (<3.5 g/24 h), oliguria, hypertension, and rising serum creatinine.
| Nephritic Condition | Key Clinical Features & Timing | Laboratory & Serologic Findings | Biopsy / Immunofluorescence |
|---|---|---|---|
| Post-Streptococcal Glomerulonephritis (PSGN) | Occurs 1-3 weeks after Group A Strep pharyngitis or impetigo; presents with facial edema, cola-colored urine | Low C3 complement; positive Anti-streptolysin O (ASO) or anti-DNase B titers | Subepithelial "humps" on EM; starry-sky granular IgG/C3 deposition |
| IgA Nephropathy (Berger Disease) | Occurs 1-2 days (synpharyngitic) after upper respiratory or GI infection; recurrent episodic gross hematuria | Normal serum complement (C3/C4); elevated serum IgA levels | Mesangial IgA deposition on immunofluorescence |
| Rapidly Progressive Glomerulonephritis (RPGN) | Rapid renal failure progression over days to weeks; causes pulmonary-renal syndromes | Anti-GBM (+), p-ANCA/mpo-ANCA (+), or c-ANCA/pr3-ANCA (+) | Crescent formation in Bowman's space (fibrin and macrophages) |
| Alport Syndrome | Hereditary X-linked defect in Type IV collagen; presents with hematuria, sensorineural hearing loss, ocular defects | Normal complement levels; family history of early ESRD | Basket-weave appearance of GBM on EM due to thinning and splitting |
Subtypes of Rapidly Progressive Glomerulonephritis (RPGN)
- Type 1 (Anti-GBM Disease / Goodpasture Syndrome): Autoantibodies against alpha-3 chain of Type IV collagen. Linear IgG deposition along GBM. Presents with hemoptysis and glomerulonephritis. Managed with emergent plasmapheresis plus steroids and cyclophosphamide.
- Type 2 (Immune Complex RPGN): Progression of PSGN, Lupus Nephritis, or IgA Nephropathy. Granular pattern on immunofluorescence.
- Type 3 (Pauci-Immune Vasculitis): No antibody deposition on IF. Associated with ANCA positivity:
- Granulomatosis with Polyangiitis (GPA): PR3-ANCA / c-ANCA positive; upper respiratory (sinusitis, nasal bridge collapse), lower respiratory (cavitary pulmonary nodules), and renal involvement.
- Microscopic Polyangiitis (MPA): MPO-ANCA / p-ANCA positive; pulmonary capillaritis and necrotizing glomerulonephritis without granulomas.
Tubulointerstitial Diseases
Tubulointerstitial nephropathies involve non-glomerular inflammatory or ischemic damage primarily targeting the renal tubules and surrounding interstitium.
Acute Interstitial Nephritis (AIN)
Acute Interstitial Nephritis is an immunologically mediated hypersensitivity reaction occurring 7 to 14 days after exposure to an offending pharmacological agent. Common offending drugs include:
- Antibiotics: Penicillins, cephalosporins, sulfonamides (TMP-SMX), ciprofloxacin, vancomycin, rifampin.
- Nonsteroidal Anti-inflammatory Drugs (NSAIDs): Ibuprofen, naproxen, celecoxib.
- Proton Pump Inhibitors (PPIs): Omeprazole, pantoprazole.
Classic Clinical Triad: (1) Fever, (2) Maculopapular skin rash, and (3) Peripheral eosinophilia. Urinalysis reveals white blood cells, WBC casts, and urine eosinophils (Hansel or Wright stain). Treatment requires immediate cessation of the offending drug; systemic corticosteroids are initiated if renal function does not quickly improve.
Renal Papillary Necrosis
Renal papillary necrosis involves ischemic necrosis of the renal papillae, presenting with gross hematuria, flank pain, and tissue sloughing into the urine (causing ureteral obstruction). High-yield causes are remembered by the mnemonic SAID:
- S: Sickle cell disease or trait (microvascular occlusion due to sickling in hypoxic renal medulla).
- A: Analgesic abuse (chronic ingestion of NSAIDs or acetaminophen combination products).
- I: Infection (severe acute pyelonephritis).
- D: Diabetes mellitus (microvascular disease).
A 48-year-old male with no significant past medical history presents to the urgent care clinic with a 2-day history of acute left flank pain and gross hematuria. Physical examination reveals left costovertebral angle tenderness and a newly developed, non-reducing left testicular varicocele. Laboratory evaluation shows serum creatinine of 1.9 mg/dL, serum albumin of 2.1 g/dL, and a 24-hour urine protein collection of 5.6 g. Renal ultrasonography confirms left renal vein thrombosis. Which of the following underlying glomerular pathologies is most strongly associated with this patient's presentation?
A 22-year-old male presents to his primary care physician after noticing dark, tea-colored urine for the past 24 hours. He reports having a mild sore throat and low-grade fever that began yesterday. He recalls a similar episode of dark urine 6 months ago following a flu-like illness. Blood pressure is 134/84 mmHg. Laboratory studies demonstrate a serum creatinine of 1.0 mg/dL, normal serum C3 and C4 complement levels, and urinalysis revealing 3+ blood with dysmorphic red blood cells. A renal biopsy shows mesangial matrix expansion with prominent mesangial IgA immunofluorescence. Which of the following is the most likely diagnosis?
A 52-year-old female was prescribed pantoprazole and trimethoprim-sulfamethoxazole 10 days ago for gastroesophageal reflux and a mild cutaneous infection, respectively. She now presents with malaise, low-grade fever, and a diffuse maculopapular rash over her trunk. Serum creatinine has risen to 2.3 mg/dL from a baseline of 0.8 mg/dL 3 weeks ago. Complete blood count reveals a leukocyte count of 11,500/mm³ with 12% eosinophils. Urinalysis demonstrates 2+ protein, WBC casts, and positive urine eosinophils on Hansel stain. Which of the following is the most likely diagnosis?