Glomerular Disease Overview

Glomerular Disease Definition

• Glomerular disease involves any abnormality of the glomerulus

Categories of Glomerular Disease

• Podocytopathy: Disease specifically affecting the podocyte
• Glomerulonephritis: Inflammation of the glomerulus
• Structural abnormalities of the GBM: May coexist with other types

Key Concepts in Glomerular Disease

• Syndrome (Clinical presentation) ≠ Diagnosis
• Clinical presentation is determined by the nature of the glomerular insult (≈ histology)
• Glomerular insult depends on the underlying disease pathophysiology
• Treatment and prognosis are influenced by underlying disease, glomerular insult, and clinical presentation

Structure and Function of the Glomerulus

• Filtration: The glomerulus filters blood
• Protein "sieving": The glomerulus acts as a barrier for proteins, depending on their size, charge, and shape

Clinical Presentation and Histology

• The size and permeability of glomerular structures influence how immune complexes deposit and cause injury

• Small filtration pores: Relatively impermeable to immune complexes and antigens, favoring non-inflammatory injury

• Large fenestrae: Permeable to immune complexes, exposing antigens to circulating leukocytes, favoring inflammatory injury

Primary Glomerular Disease

• Affects the glomeruli as the sole or predominant tissue involved
• Can be idiopathic or with described pathophysiology

Secondary Glomerular Disease

• Glomerular injury is a feature of a systemic disease affecting multiple organs or systems

Structural Abnormality of the GBM

• The glomerular basement membrane (GBM) is a size barrier preventing red blood cell entry into Bowman’s space
• Abnormalities lead to dysmorphic haematuria without inflammation or nephritic syndrome
• Haematuria is usually asymptomatic, except in cases of Alport syndrome which can lead to chronic kidney disease (CKD)

Glomerulonephritis

• For inflammation to occur, complexes must be deposited in sites exposed to circulating leukocytes in the capillary lumen:

  • Endothelium
  • Subendothelially (between endothelium and GBM)
  • On the GBM
  • In the mesangium

• The size of immune complexes typically prevents deposition subepithelially (between GBM and podocyte)

Podocyte Injury (Podocytopathy)

• Mechanisms of Injury:
  • Immune (antibodies)
  • Infection (HIV, parvovirus B19, vaccines)
  • Drugs (interferon)
  • Ischemia (hypertension, diabetes, ACE inhibitors, heroin)
  • Inherited defects (NEPH1, APOL1/MYH9 mutations)

Functional Anatomy and Presentation

• Podocytopathy: Causes proteinuria and nephrotic syndrome
• Structural abnormality of the GBM: Results in asymptomatic haematuria
• Endothelial injury (Glomerulonephritis): Leads to leukocyturia, haematuria, and nephritic syndrome

Podocytopathies

• Not necessarily immunological or inflammatory
• Can arise from genetic defects or acquired podocyte injury from non-immune causes (drugs, toxins, infections)

Proteinuria

• Extra-glomerular proteinuria: Mild (< 1 g/24hr) proteinuria due to extra-renal factors causing podocyte barrier dysfunction, such as:
  • Pregnancy
  • Sepsis
  • Anaemia
  • Cardiac failure (cardio-renal syndrome type 1)
• Glomerular proteinuria: Significant proteinuria due to intrinsic injury to the podocyte barrier, resulting in nephrotic syndrome

Consequences of Proteinuria: Nephrotic Syndrome

• Proteinuria leads to loss of proteins with various functions, leading to:
  • Reduced immunity
  • Altered coagulation
  • Malnutrition
  • Edema
  • Tubular dysfunction

Glomerulonephritis: Proliferative Glomerular Diseases

• Proliferative glomerulonephritis (GN) is characterized by glomerular cellular proliferation due to deposition of complexes in the mesangium and subendothelium, as well as complement activation
• Hypocomplementemia is frequently associated with proliferative GN but not exclusive to it.

Glomerulonephritis: Low Complement Levels

• Glomerular diseases associated with low complement levels include:
  • Post-infectious GN
  • Systemic lupus erythematosus (SLE)
  • Membranoproliferative GN (MPGN)
  • Cryoglobulinemia associated GN
  • Atheroembolic disease

Glomerular Cell Responses to Injury: Crescentic Glomerulonephritis (RPGN)

• RPGN is characterized by rapid decline in kidney function (50% within 3 months) and glomerular crescent formation
• Crescents are formed by proliferation of Bowman's epithelium due to translocation of immune complexes and antibodies.
• Can occur as a complication of any severe GN

Glomerulonephritis: Classification

• Pauci-immune: ANCA vasculitis
• Immune: Includes antiGBM disease, immune complex disease (e.g. SLE, IgA nephropathy), post-infectious GN, etc.

MPGN: Injury, Histology, and Presentation

• Factors modifying MPGN injury:

  • Race (African / Caucasian)
  • Genetic mutations (MYH9/APOL1)
  • HIV infection

• Podocyte apoptosis and abnormalities in cytoskeletal structure can contribute to both nephrotic and nephritic presentations of MPGN.

History and Examination

• Symptoms:
  • Edema, especially periorbital in the morning
  • Foamy or bubbly urine
  • Dark urine
  • Decreased urine output
  • Fatigue and weakness
  • Leg edema
  • Anasarca
  • Ascites
  • Pleural effusions

Urinalysis

• Essential part of renal system examination to confirm pathology and indicate etiology
• Dipstix: Serves as a screening test, semi-quantifiable; requires formal quantification with urine protein:creatinine ratio and microscopy
• Important considerations for urinalysis:
  • Proper sample collection
  • Use fresh, midstream, fresh-catch samples
  • Analyze samples timeously
  • Ensure dipsticks are within expiry date and stored correctly

Clinical Syndromes

• Nephrotic Syndrome:
  • Caused by podocytopathy
  • Peripheral edema
  • Proteinuria > 3.5 g/24 hours
  • Dyslipidaemia
  • Usually normal urine output
  • Variable hypertension
  • Variable renal function
  • Variable haematuria
  • Inactive/bland urinary sediment
• Nephritic Syndrome:
  • Caused by glomerulonephritis
  • Peripheral edema
  • Variable proteinuria
  • No dyslipidaemia
  • Oligo-anuric
  • Always hypertensive
  • Always renal dysfunction
  • Always hematuria
  • “Active” urinary sediment

Asymptomatic Proteinuria

• Nephrotic range proteinuria without symptoms

Injury Determines Treatment in Glomerulonephritis

• Remove the source of antigen:
  • Antibiotics for post-streptococcal GN
  • Antivirals for HBV/HCV
• Remove the antibody:
  • Plasmapheresis (plasma exchange)
  • High-dose steroids
  • Cyclophosphamide
  • Mycophenolate mofetil (MMF), azathioprine (AZA), rituximab

Prognosis in Glomerulonephritis

• Depends on the underlying disease and severity of glomerular injury
• Good prognosis for post-streptococcal GN, poor prognosis for ANCA vasculitis.

Injury Determines Treatment in Nephrotic Syndrome

• Symptomatic treatment:
  • ACE inhibitors to reverse podocyte cytoskeletal changes and reduce proteinuria
  • Statins
• Specific treatment:
  • Treat the underlying cause if secondary
  • For primary disorders:
    • Minimal change nephropathy (MCN), focal segmental glomerulosclerosis (FSGS): Prednisone (possible immune cause); Calcineurin inhibitors (CNI) (act on the cytoskeleton)
    • MPGN: Eculizumab (complement inhibitor)
    • Membranous nephropathy (MN): Cyclophosphamide and prednisone (to reduce antibody production).

Histology Determines Clinical Presentation

• Nephrotic syndrome: Based on the degree of podocyte injury
• Renal function: Influenced by histological injury

Primary and Secondary Glomerular Disorders

• Primary disorders:
  • MC, MN, FSGS, MPGN, Focal/Diffuse Proliferative GN
• Secondary disorders:
  • Autoimmune diseases
  • Infections
  • Drugs/toxins
  • Genetic abnormalities of the podocyte structure, GBM structure, complement regulation, or immune regulation

Conclusions

• Vulnerability of the glomerulus:

  • High blood flow
  • Nature of the ultrafilter (good at retaining proteins)
  • Extensive glomerular surface area
  • High glomerular pressure

• Factors determining glomerular injury:

  • Underlying disease process
  • Patient-related factors

• Variability in glomerular injury and clinical presentation:

  • A single disease process can have multiple histological forms of injury
  • Similar histological patterns can occur with different disease processes

• Clinical Syndromes:

  • Asymptomatic proteinuria
  • Nephrotic Syndrome
  • Mixed nephrotic-nephritic
  • Nephritic Syndrome
  • Asymptomatic hematuria

• Further steps:

  • Confirm diagnoses with formal urinalysis
  • Consult a nephrologist
  • Obtain a definitive diagnosis
  • Implement specific therapy

Explore the essential aspects of glomerular diseases, including definitions, categories, and key concepts. Understand how various forms such as podocytopathy and glomerulonephritis affect kidney function and filtration. This quiz will test your knowledge on the structure, function, and clinical implications of glomerular health.