How do I clinically and biochemically differentiate glomerular, renal vascular, and tubular kidney diseases?

Clinical and Biochemical Differentiation of Glomerular, Vascular, and Tubular Kidney Disease

Glomerular disease typically presents with proteinuria (often >1-3 g/day), hematuria with dysmorphic RBCs and RBC casts, edema, and hypertension, while tubular disease manifests with electrolyte abnormalities, non-nephrotic proteinuria (<1-2 g/day), and specific tubular dysfunction patterns, and vascular disease shows hypertension, minimal proteinuria, and evidence of ischemic injury. 1

Glomerular Disease: Clinical and Biochemical Features

Clinical Presentation

• Acute glomerulonephritis syndrome: Abrupt onset of hematuria, edema, hypertension, and renal dysfunction due to sodium and water retention 2, 3
• Proteinuria: Typically nephrotic range (>3.5 g/day) or significant sub-nephrotic proteinuria measured by 24-hour urine or protein-to-creatinine ratio 1
• Hematuria: Microscopic or gross hematuria with dysmorphic red blood cells and RBC casts on urinalysis 1, 2
• Edema: Periorbital or peripheral edema from sodium retention and hypoalbuminemia 2, 3

Biochemical Markers

• Serum creatinine elevation: Variable degree of renal dysfunction 1
• Complement levels: Low C3 and/or C4 in immune-complex mediated diseases 1
• Serologic testing:
  • ANCA (anti-MPO and anti-PR3) for vasculitis 1
  • Anti-GBM antibodies for Goodpasture syndrome 1
  • ANA and anti-dsDNA for lupus nephritis 1
  • Hepatitis serologies and cryoglobulins for infection-related GN 1
• Protein electrophoresis: To detect monoclonal proteins in monoclonal immunoglobulin-related GN 1

Urinalysis Patterns

• Active sediment: RBC casts, dysmorphic RBCs, and white blood cells 1, 2
• Proteinuria pattern: Predominantly albumin (glomerular proteinuria) 1

Tubular Disease: Clinical and Biochemical Features

Clinical Presentation

• Electrolyte abnormalities: Hypokalemia, metabolic acidosis, or alkalosis depending on tubular segment affected 1
• Polyuria or nocturia: From concentrating defects 1
• Minimal to no edema: Unlike glomerular disease 1
• Normal blood pressure: Or less severe hypertension compared to glomerular disease 1

Biochemical Markers

• Low-grade proteinuria: Typically <1-2 g/day, often tubular proteins (β2-microglobulin, retinol-binding protein) rather than albumin 1, 4
• Fractional excretion abnormalities: Elevated fractional excretion of sodium, potassium, or phosphate 1
• Urinary acidification defects: Inability to acidify urine appropriately (pH >5.5 in distal RTA) 1
• Glycosuria with normal serum glucose: Indicates proximal tubular dysfunction 1
• Tubular secretory solute clearance: Altered clearance of secretory solutes like isovalerylglycine and kynurenic acid 4

Urinalysis Patterns

• Bland sediment: Minimal hematuria, few or no casts 1
• Specific findings: White blood cell casts in acute interstitial nephritis, crystals in crystal nephropathy 1
• Casts and crystals: Document presence and type 1

Histologic Clues

• Acute tubular injury: Tubular epithelial cell necrosis, loss of brush border 1
• Interstitial inflammation: Type and location of inflammatory infiltrate 1
• Tubular basement membrane abnormalities: Thickening or thinning 1

Vascular Disease: Clinical and Biochemical Features

Clinical Presentation

• Hypertension: Often severe and difficult to control 1
• Minimal proteinuria: Usually <1 g/day 1, 4
• Gradual renal function decline: Progressive increase in creatinine over time 1
• Ischemic symptoms: May have evidence of systemic vascular disease 1

Biochemical Markers

• Serum creatinine: Progressive elevation reflecting ischemic nephropathy 1
• Lower tubular secretory clearances: Vascular disease shows reduced clearance of secretory solutes compared to glomerular disease 4
• Minimal serologic abnormalities: Unless vasculitis is present (then ANCA positive) 1

Histologic Features

• Arteriosclerosis and arteriolosclerosis: Graded as absent, mild, moderate, or severe 1
• Arteritis: Vessel wall inflammation in vasculitis 1
• Thrombosis or emboli: Acute vascular occlusion 1
• Ischemic glomeruli: Globally sclerosed glomeruli with wrinkled basement membranes 1
• Atubular glomeruli: Disconnection of glomeruli from tubules in chronic ischemic disease 5

Algorithmic Approach to Differentiation

Step 1: Urinalysis Assessment

• Active sediment with RBC casts + significant proteinuria (>1-3 g/day) → Suspect glomerular disease 1, 2
• Bland sediment + low proteinuria (<1-2 g/day) + electrolyte abnormalities → Suspect tubular disease 1
• Minimal proteinuria + bland sediment + severe hypertension → Suspect vascular disease 1, 4

Step 2: Quantify Proteinuria

• >3.5 g/day (nephrotic range) → Glomerular disease highly likely 1
• 1-3 g/day → Consider glomerular or mixed disease 1
• <1 g/day with tubular pattern → Tubular or vascular disease 1, 4

Step 3: Serologic Testing

• Order complement levels (C3, C4) → Low in immune-complex GN 1
• ANCA testing → Positive in ANCA-associated vasculitis 1
• ANA/anti-dsDNA → Positive in lupus nephritis 1
• Anti-GBM antibodies → Positive in Goodpasture syndrome 1

Step 4: Assess Renal Function Pattern

• Acute decline with active sediment → Acute GN or acute tubular necrosis 2, 3, 6
• Gradual decline with hypertension → Vascular disease or chronic glomerular disease 1
• Electrolyte-predominant presentation → Tubular disease 1

Critical Pitfalls to Avoid

• Do not assume normal-appearing glomeruli on biopsy exclude glomerular disease: Atubular glomeruli may appear structurally intact but are functionally disconnected, explaining preserved glomerular appearance despite severe renal dysfunction 5

• Do not rely solely on serum creatinine for AKI diagnosis in acute histologic disease: Only 65-79% of patients with acute histologic findings (like ATN) meet AKI criteria by creatinine; many have slower rises classified as AKD/non-AKI 6

• Do not overlook mixed patterns: Diabetic kidney disease and glomerular disorders show higher tubular secretory clearances than vascular disease, indicating preserved tubular function despite glomerular injury 4

• Do not confuse mesangial hypercellularity (>3 cells/mesangial area) with pathologic mesangial proliferation: The former is a quantitative threshold while the latter requires pattern recognition 7, 8

• Do not miss secondary diagnoses: Coexisting lesions like diabetic nephropathy can occur alongside primary glomerular disease and contribute to overall renal dysfunction 1

• Document percentage of globally sclerotic glomeruli and degree of interstitial fibrosis/tubular atrophy (IFTA): These chronic changes predict outcomes regardless of primary disease type and should be graded as mild (10-25%), moderate (26-50%), or severe (>50%) 1, 8