13.3 Glomerular & Tubulointerstitial Diseases

Glomerular & Tubulointerstitial Diseases

PANCE High-Yield Focus: Differentiating nephritic from nephrotic syndrome is one of the most common glomerular disease tasks on the PANCE. Focus on the hallmark laboratory findings: nephritic syndrome presents with hematuria, red blood cell (RBC) casts, and mild proteinuria, whereas nephrotic syndrome is characterized by heavy proteinuria (> 3.5 g/day), hypoalbuminemia, and hyperlipidemia. Additionally, you must recognize drug-induced acute interstitial nephritis (AIN) by its classic presentation of fever, rash, eosinophilia, and sterile pyuria with WBC casts.

Glomerular Diseases: Nephritic vs. Nephrotic Syndrome

Glomerular disorders are divided into nephritic and nephrotic syndromes based on the underlying pathophysiological mechanism of injury.

1. Nephritic Syndrome (Glomerulonephritis)

Nephritic syndrome is driven by immune-mediated inflammation of the glomerulus. This inflammatory process leads to cellular infiltration, which occludes capillaries and ruptures the glomerular basement membrane.

• Clinical Presentation:
  • Hematuria: Characterized by "smoky" or "cola-colored" urine.
  • Microscopy: Dysmorphic red blood cells and red blood cell (RBC) casts (pathognomonic for glomerulonephritis).
  • Oliguria: Reduced GFR leads to decreased urine output.
  • Hypertension and Edema: Fluid and salt retention due to reduced GFR. Edema is typically mild-to-moderate, presenting in periorbital and peripheral regions.
  • Proteinuria: Mild-to-moderate, always < 3.5 g/24 hours.
• Key Etiologies:
  • Post-Streptococcal Glomerulonephritis (PSGN): Occurs 1-3 weeks after a Group A Beta-Hemolytic Streptococcus pharyngitis or skin infection (impetigo). Diagnostics show elevated antistreptolysin O (ASO) titers and low C3 complement levels. Biopsy shows subepithelial humps (lumpy-bumpy appearance) on electron microscopy. Treatment is supportive.
  • IgA Nephropathy (Berger Disease): The most common primary glomerulonephritis worldwide. Characterized by gross hematuria that occurs 1-2 days after an upper respiratory infection (URI) or gastrointestinal infection (synpharyngitic hematuria). Complement levels are normal. Biopsy shows IgA deposition in the mesangium. Treated with ACEis to control blood pressure and reduce proteinuria; corticosteroids are used for severe cases.
  • Membranoproliferative Glomerulonephritis (MPGN): Strongly associated with Hepatitis C infection. Light microscopy shows a characteristic "tram-track" or double-contour appearance of the glomerular basement membrane.
  • Rapidly Progressive Glomerulonephritis (RPGN): Characterized by rapid loss of renal function (days to weeks). Biopsy shows crescent formation in the glomeruli. RPGN is caused by conditions such as Goodpasture's disease (anti-GBM antibodies targeting collagen in kidneys and lungs, presenting with hemoptysis and hematuria) or granulomatosis with polyangiitis (ANCA-associated vasculitis).

2. Nephrotic Syndrome

Nephrotic syndrome is caused by non-inflammatory damage to the podocytes and glomerular basement membrane, resulting in an increase in permeability to plasma proteins.

• Diagnostic Criteria (Must Memorize):
  1. Massive Proteinuria: > 3.5 g/24 hours (or random urine protein-to-creatinine ratio > 3.5).
  2. Hypoalbuminemia: Serum albumin < 3.0 g/dL.
  3. Generalized Edema: Loss of oncotic pressure leads to fluid shifting into the interstitium, causing pitting edema, ascites, and anasarca.
  4. Hyperlipidemia and Lipiduria: The liver increases lipoprotein synthesis in response to low oncotic pressure. Urine microscopy reveals fatty casts and oval fat bodies showing a "Maltese cross" pattern under polarized light.
• Complications:
  • Hypercoagulability: Loss of anticoagulant proteins, particularly Antithrombin III, in the urine. This predisposes patients to deep vein thrombosis, pulmonary embolism, and renal vein thrombosis (suspect if sudden flank pain and hematuria develop).
  • Infection: Loss of immunoglobulins (IgG) increases susceptibility to encapsulated bacterial infections.
• Key Etiologies:
  • Minimal Change Disease: The most common cause in children. Light microscopy is normal; electron microscopy shows effacement of podocyte foot processes. Excellent response to corticosteroids (prednisone).
  • Focal Segmental Glomerulosclerosis (FSGS): The most common cause in African American adults. Associated with HIV infection, heroin use, and obesity. High rate of progression to ESRD.
  • Membranous Nephropathy: The most common cause in Caucasian adults. Primary cases are associated with antibodies to the phospholipase A2 receptor (PLA2R). Secondary causes include NSAIDs, gold therapy, systemic lupus erythematosus (SLE), and solid tumors. Biopsy shows a "spike and dome" pattern on electron microscopy.

Tubulointerstitial Diseases

Acute Interstitial Nephritis (AIN)

AIN is an immunologically mediated hypersensitivity reaction localized to the renal tubules and interstitium, resulting in acute kidney injury.

• Pathophysiology: A T-cell mediated hypersensitivity reaction, most commonly triggered by exposure to drugs (70-80% of cases).
• Common Offending Medications:
  • Antibiotics: Penicillins, cephalosporins, sulfonamides (e.g., TMP-SMX), and rifampin.
  • NSAIDs: Indomethacin, ibuprofen, naproxen (often presents without fever/rash and with concurrent nephrotic-range proteinuria).
  • Proton Pump Inhibitors (PPIs): Omeprazole, pantoprazole.
  • Diuretics: Loop and thiazide diuretics.
• Clinical Presentation: The classic clinical presentation includes a history of starting a new medication followed by the triad of:
  1. Fever
  2. Maculopapular Rash
  3. Arthralgias
  • Note: The full triad is present in only a minority of patients. Peripheral eosinophilia is common.
• Diagnostics:
  • Urinalysis: Characterized by sterile pyuria (WBCs present without bacteriuria), white blood cell (WBC) casts, and mild proteinuria.
  • Urine Eosinophils: Eosinophiluria (detected by Wright or Hansel stain) is a classic finding.
  • Renal Biopsy: The gold standard, showing interstitial edema and inflammatory infiltrate rich in eosinophils and lymphocytes.
• Management: Discontinue the offending drug immediately. If renal function does not improve within several days of drug cessation, initiate a short course of oral corticosteroids (e.g., prednisone).

Classic PANCE Traps & Clinical Pearls

• The URI Timing Trap:
  • IgA Nephropathy: Gross hematuria occurs 1-2 days after a URI.
  • PSGN: Gross hematuria occurs 1-3 weeks after a URI or skin infection.
  • Tip: Remember "IgA" is "Immediate" (1-2 days), while PSGN has a delayed lag phase.
• Sterile Pyuria: If you see a patient with white blood cells in the urine but a negative urine culture, think of Acute Interstitial Nephritis (with WBC casts) or renal tuberculosis (acid-fast bacilli).