Glomerular Diseases¶
Chapter 326 | Part 9: Disorders of the Kidney and Urinary Tract
KEY CLINICAL POINTS¶
- Glomerular diseases encompass a spectrum of conditions affecting the glomerulus, including glomerulonephritis, nephrotic syndrome, and systemic vasculitides.
- Key diagnostic features include hematuria, proteinuria, and immune deposits on renal biopsy.
- Classification systems like the Oxford Classification for lupus nephritis and MEST-C score guide prognosis and treatment.
- Management involves controlling blood pressure, immunosuppression, and addressing underlying causes like infections or autoimmune disorders.
- Renal biopsy is critical for diagnosing glomerular diseases and determining therapeutic strategies.
1. DEFINITION & OVERVIEW¶
Glomerular diseases involve injury to the glomerular filtration barrier, leading to hematuria, proteinuria, and progressive kidney dysfunction. The glomerulus consists of capillary tufts surrounded by Bowman's capsule, with podocytes, endothelial cells, and mesangial cells forming the structural and functional unit. Pathogenesis involves immune complexes, complement activation, or direct injury to glomerular structures.
TABLE 326-1 Urine Assays for Albuminuria/Proteinuria¶
| 24-h ALBUMINa (mg/24 h) | ALBUMINa/CREATININE RATIO (mg/g) | DIPSTICK PROTEINURIA | 24-h URINE PROTEINb (mg/24 h) |
|---|---|---|---|
| 8–10 | <30 | – | <150 |
| 30–300 | 30–300 | –/Trace/1+ | –/>150 |
| >300 | >300 | Trace–3+ | >150 |
1.1 Pathophysiology¶
Glomerular injury results from immune complex deposition, complement activation, or direct cellular damage. Immune complexes trigger inflammation, while complement activation leads to endothelial injury and mesangial proliferation. Podocyte dysfunction and basement membrane abnormalities contribute to proteinuria and glomerulosclerosis.
1.2 Clinical Spectrum¶
Conditions range from acute nephritic syndromes (e.g., post-streptococcal glomerulonephritis) to chronic glomerulosclerosis (e.g., diabetic nephropathy). Syndromes include nephrotic syndrome, acute kidney injury, and systemic vasculitis.
2. EPIDEMIOLOGY¶
Glomerular diseases affect 1–2% of the population. Diabetic nephropathy is the leading cause of end-stage kidney disease (ESKD) globally. Post-streptococcal glomerulonephritis is more common in developing countries, while lupus nephritis and IgA nephropathy are prevalent in industrialized nations.
2.1 Risk Factors¶
Hypertension, diabetes, autoimmune diseases (e.g., lupus), infections (e.g., HIV, hepatitis B/C), and genetic disorders (e.g., Alport syndrome) increase risk. Ethnicity and geographic regions influence disease prevalence.
2.2 Demographics¶
Males are more commonly affected in many glomerular diseases. Age varies by condition: e.g., minimal change disease peaks in childhood, while diabetic nephropathy is more common in older adults.
3. ETIOLOGY & PATHOPHYSIOLOGY¶
Diverse mechanisms drive glomerular injury: immune complex-mediated (e.g., lupus, post-streptococcal), complement-mediated (e.g., HUS), or direct toxic injury (e.g., drug-induced nephrotoxicity). Genetic factors (e.g., APOL1 variants) contribute to disease susceptibility.
TABLE 326-2 Patterns of Clinical Glomerulonephritis¶
| GLOMERULAR SYNDROMES | PROTEINURIA | HEMATURIA | VASCULAR INJURY |
|---|---|---|---|
| Poststreptococcal glomerulonephritis | +/++ | ++/+++ | – |
| Lupus nephritis | +/++ | ++/+++ | + |
| Anti-GBM disease | ++ | ++/+++ | – |
| IgA nephropathy | +/++ | +++ | – |
| Membranoproliferative glomerulonephritis | ++ | ++/+++ | – |
3.1 Immune-Mediated Pathways¶
Immune complexes deposit in glomeruli, activating complement and recruiting inflammatory cells. C3 and C5b-9 complexes mediate endothelial damage, while T-cell responses drive glomerular inflammation.
3.2 Genetic Factors¶
APOL1 variants increase risk of FSGS in African Americans. Mutations in COL4A5, COL4A3, and COL4A4 cause Alport syndrome and other hereditary glomerulopathies.
4. CLINICAL FEATURES¶
Presentations vary by syndrome: acute nephritic syndrome (hematuria, proteinuria, hypertension), nephrotic syndrome (heavy proteinuria, hypoalbuminemia), or systemic vasculitis (purpura, renal failure).
4.1 Acute Nephritic Syndrome¶
Features include hematuria, red blood cell casts, hypertension, and proteinuria. Classic presentation is post-streptococcal glomerulonephritis with IgA or IgG immune deposits.
4,2 Nephrotic Syndrome¶
Marked proteinuria (>3.5 g/24 h), hypoalbuminemia, edema, and hyperlipidemia. May present with nephrotic-range proteinuria without overt hematuria.
5. DIFFERENTIAL DIAGNOSIS¶
Distinguish glomerular diseases from tubular disorders, interstitial nephritis, or systemic conditions. Key differentiators include immune deposits, proteinuria patterns, and renal biopsy findings.
5.1 Immune-Driven vs. Non-Immune¶
Immune-mediated diseases (e.g., lupus, IgA nephropathy) show immune deposits. Non-immune causes (e.g., diabetic nephropathy) present with glomerular basement membrane thickening.
5.2 Systemic Associations¶
Link to systemic vasculitis (e.g., GPA, MPA), autoimmune diseases (e.g., lupus), or infections (e.g., HIV, hepatitis B/C).
6. INVESTIGATIONS & DIAGNOSIS¶
Urinalysis, serum creatinine, and urine albumin/creatinine ratio (UACR) are initial tests. Renal biopsy with immunofluorescence and electron microscopy confirm diagnosis and guide classification.
TABLE 326-3 Classification for Lupus Nephritis¶
| CLASS | DESCRIPTION |
|---|---|
| Class I | Minimal mesangial: Normal histology with mesangial deposits |
| Class II | Mesangial: Mesangial hypercellularity with expansion of mesangial matrix |
| Class III | Focal: Focal endocapillary ± extracapillary hypercellularity |
| Class IV | Diffuse: Diffuse endocapillary ± extracapillary hypercellularity |
| Class V | Membranous: Thickened basement membranes with subepithelial immune deposits |
6.1 Urinary Biomarkers¶
UACR >30 mg/g indicates microalbuminuria. 24-h urine protein >300 mg indicates proteinuria. Presence of red blood cell casts suggests glomerular injury.
6.2 Renal Biopsy¶
Light microscopy identifies glomerular patterns (e.g., mesangial proliferation, crescents). Immunofluorescence detects IgG, IgA, IgM, or complement deposits. Electron microscopy reveals subepithelial or subendothelial deposits.
7. MANAGEMENT & TREATMENT¶
Treatment depends on disease type: ACE inhibitors/ARBs for proteinuria, immunosuppression for lupus or vasculitis, and dialysis for ESKD. Lifestyle modifications and control of comorbidities are critical.
7.1 Immunosuppression¶
Cyclophosphamide, rituximab, or mycophenolate mofetil for lupus nephritis. Corticosteroids for acute glomerulonephritis or RPGN.
7.2 Renal Replacement Therapy¶
Dialysis for ESKD. Kidney transplantation may be considered after remission, with improved outcomes in selected cases.
8. PROGNOSIS & COMPLICATIONS¶
Prognosis varies by syndrome: minimal change disease has excellent response to steroids, while FSGS or RPGN may progress to ESKD. Complications include hypertension, cardiovascular disease, and infections.
8.1 Disease-Specific Outcomes¶
Lupus nephritis: 20–30% progress to ESKD. Diabetic nephropathy: 30–40% develop ESKD within 10 years. RPGN: 50% progress to ESKD without treatment.
8.2 Long-Term Risks¶
Chronic kidney disease progression, cardiovascular mortality, and proteinuria-related complications (e.g., thrombosis, infections).
9. SPECIAL CONSIDERATIONS¶
Pregnancy, pediatric, and geriatric considerations: gestational hypertension, pediatric nephrotic syndrome, and age-related glomerulosclerosis. Ethnic disparities in disease expression (e.g., APOL1 variants in African Americans).
9.1 Pregnancy¶
Preeclampsia, HELLP syndrome, and glomerular injury in pregnancy. Monitoring for proteinuria and renal function is critical.
9.2 Ethnic Variations¶
APOL1 variants increase risk of FSGS in African Americans. Genetic testing may guide management in hereditary glomerulopathies.
10. KEY POINTS & CLINICAL PEARLS¶
- Glomerular diseases require renal biopsy for definitive diagnosis and classification. 2. Immunosuppression is central to managing lupus nephritis and vasculitis. 3. ACE inhibitors/ARBs reduce proteinuria and slow progression. 4. Early detection of microalbuminuria is critical in diabetes. 5. Genetic testing aids in diagnosing hereditary glomerulopathies.