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Dr. Nyan Saeed Omer

  • Title: Histopathologist
  • Qualifications: MBChB, FKBMS (pathology)
  • Focus: Glomerular disease

Glomerulus

  • Definition: A tuft of capillaries located within Bowman's capsule at the end of a renal tubule in the vertebrate kidney.
  • Function: Filters waste products from the blood, initiating urine formation.
  • Significance: It is the basic filtration unit of the kidney.

Schematic Diagram of a Normal Glomerulus

  • Components:
    • Capillary loops
    • Red cells
    • Proximal tubule
    • Basement membrane
    • Foot processes
    • Urinary space
    • Mesangium
    • Parietal epithelium and Visceral epithelium (podocytes)
    • Fenestrae in the endothelium
    • Mesangial cells and Mesangial matrix

Glomerular Diseases

Definition and Classification

  • General Term: Glomerulonephritis (GN), also known as Bright's disease, refers to diseases primarily involving renal glomeruli.
  • Classification: Two broad groups:
    1. Primary Glomerulonephritis: Glomeruli are the predominant site of involvement.
    2. Secondary Glomerular Diseases: Result from systemic and hereditary diseases that secondarily affect glomeruli.

Histological Classification

  • The classification is based on histology:
    • Diffuse: Involvement of all glomeruli.
    • Global: Entire glomerulus is involved.
    • Focal: Portion of glomeruli is affected.
    • Segmental: Part of each glomerulus is involved.
    • Mesangial: Affecting the mesangial region.

Pathogenesis of Glomerular Diseases

Mechanisms

  1. Circulating Immune Complex Deposition:

    • Process: Antigen + Antibody leads to deposition in glomeruli, binding with complement, resulting in inflammation and glomerular injury.
      • Antigens: Can be exogenous or endogenous.

  2. Antibodies Against Antigen on Glomerular Capillary Membrane:

    • Examples:
      • Anti-GBM Antibody Disease: e.g. Goodpasture syndrome where antigen is fixed in the Glomerular Basement Membrane (GBM).
      • Antibodies Against Non-GBM Antigen.

Nephrotic Syndrome

Clinical Complex

  • Characteristics:
    • Heavy proteinuria (≥ 3.5 g/day)
    • Hypoalbuminemia
    • Edema
    • Hyperlipidemia and Hyperlipiduria due to compensatory mechanisms
  • Mechanism:
    • Injury to the Capillary Wall: Increased permeability allows plasma proteins to escape, resulting in clinically significant proteinuria.
    • Plasma Protein Levels: < 3 g/dL; increases in lipoprotein synthesis occur in the liver.

Causes of Nephrotic Syndrome

I. Primary Glomerulonephritis
  1. Minimal Change Disease: Most common in children.
  2. Membranous Glomerulonephritis: Most common in adults.
  3. Lupus Nephritis.
  4. Membranoproliferative Glomerulonephritis.
  5. Focal Segmental Glomerulosclerosis.
  6. Diffuse Proliferative GN.
  7. IgA Nephropathy.
II. Systemic Diseases
  1. Diabetes Mellitus
  2. Amyloidosis
  3. Systemic Lupus Erythematosus (SLE)
III. Systemic Infections
  1. Viral Infections: HBV, HCV, HIV
  2. Bacterial Infections: Bacterial endocarditis, syphilis, leprosy.
  3. Protozoan and Parasitic Infections: P. falciparum malaria, filariasis.
IV. Hypersensitivity Reactions
  1. Drugs: Heavy metals (gold and mercury), penicillamine, trimethadione, tolbutamide, heroin.
  2. Others: Bee stings, snake bites, poison ivy.
V. Malignancy
  1. Myeloma
  2. Carcinomas
  3. Hodgkin's Disease
VI. Pregnancy
  • Toxaemia of Pregnancy
VII. Circulatory Disturbances
  1. Renal Vein Thrombosis
  2. Constrictive Pericarditis
VIII. Hereditary Diseases
  1. Alport's Disease
  2. Fabry's Disease
  3. Nail-Patella Syndrome

Detailed Overview of Selected Nephrotic Syndromes

Minimal Change Disease (Lipoid Nephrosis)

  • Description: Most frequent cause of nephrotic syndrome in children, with a peak incidence at ages 2-6. Often follows a respiratory infection or prophylactic immunization.

  • Clinical Features:

    • Highly selective proteinuria (primarily albumin).
    • Dramatic responsiveness to corticosteroid therapy.

  • Morphology:

    • Light Microscopy: Normal glomeruli.
    • Immunofluorescence: No immunoglobulin or complement deposits.
    • Electron Microscopy: Normal GBM; foot process effacement is observed.

Membranous Glomerulopathy (MG)

  • Description: Most common cause of nephrotic syndrome in adults.

  • Pathogenesis:

    • Immune complex-mediated disease. Non-selective proteinuria (excretion of albumin and globulin).
    • Poor response to corticosteroid therapy.

  • Morphology:

    • Light Microscopy: Diffuse thickening of glomerular basement membrane.
    • Electron Microscopy: Appearance of subepithelial deposits causing a spike-like morphology.
    • Immunofluorescence: Granular immunofluorescent deposits of IgG along the GBM.

Focal Segmental Glomerulosclerosis (FSGS)

  • Description: Characterized by sclerosis affecting some glomeruli (focal) and only a portion of affected glomeruli (segmental).

  • Clinically: Presents as nephrotic syndrome.

  • Causes: Genetic, drug use (e.g., anabolic steroids), infections (e.g., HIV), chronic pyelonephritis, diabetes, hypertension, or idiopathic.

  • Morphology:

    • Observed segmental sclerosis on PAS staining, with hyaline and lipid accumulation in the affected areas.

Lupus Nephropathy

  • Classification: Classified by WHO into six renal patterns, assessing severity and prognosis.

    1. Type I: No renal involvement.
    2. Type II: Mesangial proliferative.
    3. Type III: Focal proliferative.
    4. Type IV: Diffuse proliferative (characterized by wire-loop lesions).
    5. Type V: Membranous form (global/segmental subepithelial immune deposits).
    6. Type VI: Advanced sclerotic form.

  • Prognosis: Correlates with severity of renal lesions.

Diabetic Nephropathy

  • Clinical Features: Includes three syndromes:

    1. Non-nephrotic proteinuria (preceded by microalbuminuria).
    2. Nephrotic syndrome.
    3. Chronic renal failure.

  • Morphological Changes: GBM thickening, mesangial matrix increase, diffuse or nodular glomerulosclerosis (Kimmelstiel-Wilson disease).

  • Pathogenesis: Involves metabolic defects and hemodynamic effects, leading to glomerular hypertrophy and sclerosis.

Renal Amyloidosis

  • Description: A cause of nephrotic syndrome with subendothelial and mesangial amyloid deposits.

  • Staining Characteristics:

    • Congo Red Stain: Produces red color under light microscopy and apple green birefringence under polarized light.

  • Types:

    1. Primary (AL) Amyloidosis: Related to plasma cell dyscrasias (multiple myeloma).
    2. Secondary (AA) Amyloidosis: Associated with neoplasia or chronic inflammation, related to serum amyloid A protein produced in the liver.

IgA Nephropathy (Berger’s Disease)

  • General Information: Most common type of GN globally, frequently seen in ages 20-40.
  • Pathogenesis: Abnormal immune regulation leads to increased IgA synthesis; complexes trapped in the mesangium.
  • Morphology: Shows mesangial proliferation and IgA deposits predominantly in the mesangium on immunofluorescence microscopy.

Hereditary Nephritis (Alport Syndrome)

  • General Information: X-linked form is most common, males express syndrome while females are carriers.
  • Clinical Features: Progressive nephritis, renal failure, nerve deafness, and eye disorders; carriers may have only hematuria.
  • Pathogenesis: Defective GBM synthesis due to mutations in the α5 chain of type IV collagen.
Rapidly Progressive (Crescentic) GN

  • Clinical Features: Rapid loss of renal function, severe oliguria.

  • Crescents: Formed by proliferation of epithelial cells, fibrin deposition, and leukocyte infiltration.

  • Classification:

    1. Type I: Anti-GBM antibodies (Goodpasture syndrome).
    2. Type II: Immune complex-mediated.
    3. Type III: Pauci-immune, lacking immune deposition (ANCA-associated).

  • Morphology: Collapsed glomerular tufts, crescent-shaped cellular masses, characteristic changes in GBM (wrinkling, focal disruptions).

Post-Streptococcal Glomerulonephritis

  • Description: Occurs 1-4 weeks post streptococcal infection, mostly in children.
  • Etiology and Pathogenesis: Associated with nephritogenic strains of group A β-hemolytic streptococci; antibody production leads to immune complex deposition.
  • Morphology: Glomerular hypercellularity, electron-dense subepithelial humps visible.

Conclusion

  • The understanding of glomerular diseases is crucial for diagnosing and managing kidney-related pathologies. Recognizing the different forms of GN, their classifications, clinical implications, and pathology is vital for effective treatment and patient care. The multifactorial nature of these diseases necessitates an integrated approach to study and address various etiological factors. Understanding the pathophysiology, clinical manifestations, and diagnostic criteria is essential for nephrologists and healthcare professionals involved in the management of these conditions.