Approach to glomerular disease
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Approach to glomerular disease

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Questions and Answers

Which of the following is NOT a category of glomerular disease?

  • Glomerulonephritis
  • Cystic fibrosis (correct)
  • Structural abnormalities of the GBM
  • Podocytopathy

    • A syndrome is synonymous with a diagnosis.

    False

    What determines the nature of glomerular injury?

    Functional anatomy

    The term '______' refers to any abnormality of the glomerulus.

    <p>Glomerular Disease</p> Signup and view all the answers

    Match the types of glomerular disease with their definitions:

    <p>Podocytopathy = Disease specifically of the podocyte Glomerulonephritis = Inflammation of the glomerulus Structural abnormalities of the GBM = Changes in the glomerular basement membrane Primary Glomerular Disease = Disorders where glomeruli are the sole tissue involved</p> Signup and view all the answers

    What is primarily characterized by structural abnormalities of the glomerular basement membrane (GBM)?

    <p>Secondary Glomerular Disease</p> Signup and view all the answers

    Asymptomatic hematuria occurs due to inflammatory responses in the glomerulus.

    <p>False</p> Signup and view all the answers

    What condition is associated with significant proteinuria due to intrinsic injury in the podocyte barrier?

    <p>Nephrotic Syndrome</p> Signup and view all the answers

    Damage to the podocyte filtration barrier primarily leads to __________.

    <p>proteinuria</p> Signup and view all the answers

    Match the following presentations with their corresponding conditions:

    <p>Podocytopathy = Proteinuria and nephrotic syndrome Structural abnormality of GBM = Asymptomatic hematuria Endothelial injury = Leukocyturia and nephritic syndrome</p> Signup and view all the answers

    Which of the following is NOT a mechanism of podocyte injury?

    <p>Systemic inflammation</p> Signup and view all the answers

    Excessive protein loss in urine is often due to dysfunction of the podocyte filtration barrier.

    <p>True</p> Signup and view all the answers

    What is a major clinical consequence of nephrotic syndrome?

    <p>Hypoalbuminemia</p> Signup and view all the answers

    Extrarenal factors causing mild proteinuria are primarily related to __________.

    <p>glomerular hypertension</p> Signup and view all the answers

    What is a hallmark of proliferative glomerular diseases?

    <p>Glomerular cellular proliferation</p> Signup and view all the answers

    Immune complexes can damage glomerular cells, leading to apoptosis and proliferation.

    <p>True</p> Signup and view all the answers

    Identify one condition that can cause a direct infection of podocytes.

    <p>HIV</p> Signup and view all the answers

    Which of the following conditions is NOT associated with low complement levels?

    <p>Diabetes Mellitus</p> Signup and view all the answers

    The term __________ refers to non-immunological and non-inflammatory injury to podocytes.

    <p>podocytopathy</p> Signup and view all the answers

    Match the glomerular diseases with their associated features:

    <p>Crescentic GN = Proliferative endocapillary GN Membranoproliferative GN = Mesangioproliferative GN Podocytopathy = Nephrotic syndrome with proteinuria</p> Signup and view all the answers

    Crescentic glomerulonephritis results in a rapid decline in renal function, typically a 50% decline within three months.

    <p>True</p> Signup and view all the answers

    What happens to the epithelial cells in crescentic glomerulonephritis?

    <p>They proliferate in response to injury.</p> Signup and view all the answers

    The presence of ____ in urine is an indicator of nephrotic syndrome.

    <p>proteinuria</p> Signup and view all the answers

    Match the following conditions with their associated features:

    <p>Nephrotic Syndrome = Proteinuria &gt; 3.5g/24 hours Nephritic Syndrome = Always has hematuria Crescentic GN = Rapid loss of renal function MPGN = May present with varying kidney function</p> Signup and view all the answers

    Which of the following is a compensatory response of the renal epithelium to injury?

    <p>Proliferation</p> Signup and view all the answers

    Urinalysis is sufficient alone to diagnose all renal pathological processes.

    <p>False</p> Signup and view all the answers

    Name one of the diseases that can lead to crescentic glomerulonephritis.

    <p>Any severe glomerulonephritis</p> Signup and view all the answers

    In nephritic syndrome, urine output is typically described as _____.

    <p>oligo-anuric</p> Signup and view all the answers

    Which syndrome is caused primarily by podocytopathy?

    <p>Nephrotic Syndrome</p> Signup and view all the answers

    What is the primary purpose of plasmapheresis in treating certain diseases?

    <p>To remove antibodies from the blood</p> Signup and view all the answers

    Focal proliferative glomerulonephritis is associated with a better prognosis compared to diffuse proliferative glomerulonephritis.

    <p>True</p> Signup and view all the answers

    What type of treatment is typically used to reverse engineer the podocyte cytoskeleton?

    <p>ACE Inhibitors</p> Signup and view all the answers

    In nephrotic syndrome, the primary drug used for immune-related causes is ______.

    <p>prednisone</p> Signup and view all the answers

    Match the following histological patterns with their associated diseases:

    <p>FSGS = HIVAN MPGN = HIVICK MN = SLE MCN = Primary Nephrotic Syndrome</p> Signup and view all the answers

    Which of the following conditions does NOT typically require removing the source of antigen?

    <p>Minimal change nephropathy</p> Signup and view all the answers

    Statins are recommended for symptomatic treatment in nephrotic syndrome.

    <p>True</p> Signup and view all the answers

    Name one genetic abnormality that could lead to podocyte injury.

    <p>Podocyte structure abnormalities</p> Signup and view all the answers

    One possible treatment for turning off complement activation in MPGN is ______.

    <p>eculizumab</p> Signup and view all the answers

    Which condition is characterized by nephritic syndrome and is often associated with immune system compromise?

    <p>HIV-related nephropathy (HIVAN)</p> Signup and view all the answers

    Study Notes

    Glomerular Disease Definition

    • Glomerular disease refers to any abnormality of the glomerulus.
    • There are three main categories of glomerular disease: podocytopathy, glomerulonephritis, and structural abnormalities of the glomerular basement membrane (GBM).
    • Combinations of these categories can co-exist.

    Key Concepts

    • “Syndrome” does not equal “Diagnosis”.
    • “Syndrome” is the clinical presentation of the disease.
    • The clinical presentation depends on the nature of the glomerular insult.
    • The nature of the glomerular insult depends on the underlying disease pathophysiology.
    • Treatment and prognosis depend on disease, insult nature, and clinical presentation.

    Structure and Function of the Glomerulus

    • The glomerulus functions in filtration and protein "sieving".

    Glomerular Injury and Structure

    • The nature of glomerular injury is determined by functional anatomy.
    • Small filtration pores are relatively impermeable to immune complexes, antigens, and immunoglobulins. It favours non-inflammatory injury.
    • Large fenestrae are permeable to immune complexes and antigens. It favours inflammatory injury.

    Types of Glomerular Disease

    • Primary glomerular disease is where the glomeruli are the sole or predominant tissue involved. It can be idiopathic or have a known pathophysiology.
    • Secondary glomerular disease is where glomerular injury is a feature of a systemic disease.

    Structural Abnormality of the GBM

    • The GBM is a barrier that prevents erythrocytes from entering Bowman’s space.
    • Abnormalities of the GBM result in glomerular (dysmorphic) haematuria.
    • No inflammatory response occurs as these are structural lesions.
    • This results in asymptomatic haematuria.

    Glomerulonephritis

    • Glomerulonephritis requires immune complexes to be deposited at sites where they are exposed to circulating leukocytes.
    • These sites include the endothelium, between the endothelium and the GBM ("subendothelially"), the GBM, and the mesangium.
    • Immune complexes usually (but not always) are too large to deposit between the GBM and the podocyte ("subepithelially").

    Podocyte Injury (Podocytopathy)

    • Podocytopathy is injury specific to the podocyte.
    • Mechanisms of injury can include:
      • Immune (antibodies): IgG2/IgG4 conformation favours translocation through endothelial and GBM barriers.
      • Infection of the podocyte: HIV, parvovirus B19, vaccines.
      • Drugs: interferon.
      • Ischemia: hypertension, diabetes, ACE inhibitors, heroin.
      • Inherited defects in structure: NEPH1, APOL1/MYH9 gene mutations.

    Functional Anatomy Determines Presentation

    • Podocytopathy is presented as proteinuria and nephrotic syndrome.
    • Structural abnormality of the GBM presents as asymptomatic haematuria.
    • Endothelial injury (glomerulonephritis) presents with leukocyturia, haematuria, and nephrotic syndrome.

    Clinical Presentation Depends Upon Histology

    • Podocytopathy is related to damage to the podocyte (visceral epithelium).
    • Endothelial injury is related to damage to the endothelium within the capillary lumen.
    • These lesions are localized around the GBM and mesangium.
    • These lesions are all localized within Bowman's space.

    The Podocytopathies

    • Podocytopathy can be non-immunological or non-inflammatory.
    • It can be due to either genetic defects in structure or function, or acquired podocyte injury from non-immune causes, such as drugs, toxins, and infections.

    Clinical Presentation of Podocytopathy

    • The podocyte filtration barrier prevents loss of large molecules (proteins) into urine.
    • It does not prevent filtration of smaller molecules such as electrolytes.
    • Damage to or dysfunction of the barrier will therefore cause proteinuria.
    • The severity of proteinuria varies depending on the severity of podocyte injury.

    Extra-glomerular Proteinuria

    • No intrinsic injury to the podocyte barrier.
    • Extra-renal factors cause barrier dysfunction, hence mild (< 1g/24hr) proteinuria.
    • Mainly caused by glomerular hypertension.
    • Examples: pregnancy, sepsis, anemia, cardiac failure (cardio-renal syndrome type 1).

    Glomerular Proteinuria

    • Intrinsic (intra-glomerular) injury to the podocyte barrier results in significant proteinuria.
    • These result in nephrotic syndrome.
    • Podocytes respond to injury in a predictable manner, the mechanism of injury therefore determines histological response and clinical presentation.
    • All podocytopathies share electron microscopy features of podocyte injury.

    Clinical Consequences of Proteinuria

    • Loss of proteins carrying hormones, metals, vitamins, and immunoglobulin results in the following:
      • Altered immunoglobulin turnover.
      • Reduced cellular immunity.
      • Altered coagulation factors.
      • Hypoalbuminaemia.
      • Malnutrition.
      • Increased infection susceptibility.
      • Tubular dysfunction.
      • Increased tubular reabsorption.
      • Thrombosis/embolism.
      • Oedema.

    Clinical Presentation Depends on Histology: Podocytopathy

    • Podocytopathy can present histologically as:
      • Proliferative endocapillary glomerulonephritis.
      • Crescentic glomerulonephritis.
      • Membranoproliferative glomerulonephritis.
      • Mesangioproliferative glomerulonephritis.

    Overview of Immune System Activation

    • An antigen can trigger an immune response, leading to antibody production.
    • This immune response can cause cytotoxicity (cell injury), complement activation, and inflammatory cell recruitment.

    Immune Response to Glomerular Disease

    • An immune response can occur against:
      • Glomerulus-specific antigens.
      • Systemic antigens also expressed in the glomerulus.
      • Antigens deposited in the glomerulus.
    • Antibody-antigen (immune) complexes form in the glomerulus (in-situ formation).
    • Preformed antigen-antibody complexes can be deposited in the glomerulus.
    • This process can damage glomerular cells through apoptosis or proliferation.
      • This is known as “proliferative GN”.
    • Infiltrating leukocytes breach the urinary space.
    • Red cells pass through damaged barriers, leading to dysmorphic haematuria.
    • Endothelial, epithelial, and mesangial cell proliferation reduces filtration.
    • This results in:
      • Renal dysfunction.
      • Fluid retention.
      • Oedema.
      • Hypertension.

    Proliferative Glomerular Diseases

    • Glomerular cellular proliferation is largely related to immune complex deposition in the mesangial sub-endothelium.
    • Complement activation plays a role, and hypocomplementemia is more common with these diseases.
    • However, not all proliferative glomerulonephritis is hypocomplementemic.

    Glomerular Diseases Associated with Low Complement Levels

    • These diseases are usually associated with hypocomplementemia:
      • Post-infectious glomerulonephritis.
      • Systemic lupus erythematosus (SLE).
      • Membranoproliferative glomerulonephritis (MPGN).
      • Cryoglobulinemia-associated glomerulonephritis.
      • Atheroembolic disease.

    Glomerular Cell Responses to Injury: Crescentic Glomerulonephritis

    • Crescentic glomerulonephritis is defined as rapidly declining renal function (usually a 50% decline within 3 months) with glomerular crescent formation in at least 50% of glomeruli.
    • This occurs when the filtration barrier ruptures allowing translocation of immune complexes/antibodies into Bowman’s space which injures the Bowman (parietal) epithelium.
    • The injured epithelium proliferates in response, forming a crescent.
    • It can occur as a complication of any severe glomerulonephritis.

    Disease and Glomerular Injury

    • The type of disease determines the site and mechanism of glomerular injury:
      • Mesangium and GBM.
      • Endothelium and subendothelium.
    • Disease examples:
      • IgA nephropathy.
      • Anti-GBM disease ("Goodpasture’s").
      • Post-infectious glomerulonephritis.
      • Systemic Lupus Erythematosus (SLE).
      • Amyloidosis.
      • Thrombotic microangiopathy (TMA).
      • Hepatitis B and C virus.

    Classification of Glomerulonephritis

    • Two main categories of glomerulonephritis:
      • Pauci-immune: including ANCA-associated vasculitis and anti-GBM disease ("Goodpasture’s").
      • Immune: all others (including IgA nephropathy, SLE, post-infectious glomerulonephritis).

    Injury, Histology, and Presentation: Membranoproliferative Glomerulonephritis (MPGN)

    • MPGN presents with a characteristic histological pattern related to the specific type of injury.

    Factors Modifying Glomerular Injury Mechanism

    • Black African origin is associated with MYH9/APOL1 mutation.
    • Caucasoid origin is associated with abnormalities of T/B cell regulation.
    • HIV infection can contribute to podocyte apoptosis and inflammation.
    • Abnormalities of cytoskeletal structure can lead to proliferative inflammatory responses or podocyte apoptosis.
    • These factors can lead to either nephrotic syndrome or nephritic syndrome.

    History and Examination

    • Common symptoms:
      • Swelling of extremities, especially periorbital in the morning.
      • Foamy or bubbly urine ("frothy" urine).
      • Dark urine.
      • Decreased urine output.
      • Fatigue and weakness.
      • Ankle and leg edema in the morning ("morning edema"), potentially progressing to anasarca, ascites, and pleural effusions.

    Urinalysis

    • Urinalysis is essential for confirming renal pathology and indicating the etiology of glomerular disease.
    • Dipstick testing is a screening test only and should be followed up by formal quantification with urine protein:creatinine ratio, and microscopy.
    • Ensure adequate sample is collected.
    • Ensure adequate dipstix and correct storage.

    Clinical Syndromes: Nephrotic Syndrome and Nephritic Syndrome

    • Nephrotic Syndrome

      • Caused by podocytopathy.
      • Presents with:
        • Peripheral oedema.
        • Proteinuria > 3.5g / 24 hours.
        • Dyslipidaemia.
        • Usually normal urine output.
        • Variably hypertensive.
        • Variable renal function.
        • Variable haematuria.
        • Inactive / bland urinary sediment.

    • Nephritic Syndrome

      • Caused by glomerulonephritis.
      • Presents with:
        • Peripheral oedema.
        • Variable proteinuria.
        • No dyslipidaemia.
        • Oligo-anuric.
        • Always hypertensive.
        • Always renal dysfunction.
        • Always haematuria.
        • “Active” urinary sediment.

    Clinical Presentation: Asymptomatic Proteinuria

    • Asymptomatic nephrotic range proteinuria.
    • Asymptomatic subnephrotic range proteinuria.
    • Asymptomatic haematuria.

    Injury Determines Treatment in Glomerulonephritis

    • Primary treatment goals:
      • Remove the source of the antigen.
        • Antibiotics in post-streptococcal glomerulonephritis.
        • Antivirals in hepatitis B/C virus infections.
      • Remove the antibody.
        • Plasmapheresis (plasma exchange).
        • High-dose steroids (solumedrol).
        • Cyclophosphamide.
        • Mycophenolate mofetil (MMF), azathioprine (AZA), rituximab.
    • Prognosis depends on the disease and severity of the glomerular injury.

    Injury Determines Treatment in Nephrotic Syndrome

    • Symptomatic treatment:
      • ACE inhibitors.
      • Statins.
    • Specific treatment:
      • Treat the underlying cause if secondary.
      • For primary disorders:
        • Minimal change disease (MCN), focal segmental glomerulosclerosis (FSGS): prednisone (potential immune cause), calcineurin inhibitors (CNIs).
        • Membranoproliferative glomerulonephritis (MPGN): eculizimab (complement inhibition).
        • Membranous nephropathy (MN): cyclophosphamide and prednisone (antibody reduction).

    Histology Determines Clinical Presentation

    • Nephrotic Syndrome
      • Clinical presentation depends on the histological damage.
      • It can be further clarified by assessing renal function.

    Primary and Secondary Glomerular Disease

    • Primary disorders:
      • Genetic abnormalities of podocyte structure, GBM structure, complement regulation, and immune regulation.
    • Secondary disorders:
      • Autoimmune diseases.
      • Infections.
      • Drugs/toxins.
    • Both can lead to podocytopathy, endothelial, and mesangial injury.
    • The classification of glomerular diseases is complex and requires careful evaluation by a nephrologist.
    • The specific histological pattern of injury determines the clinical presentation.

    Conclusions: Glomerular Vulnerability

    • The glomerulus is vulnerable to injury due to:
      • High blood flow.
      • Nature of the ultrafilter.
      • Extensive glomerular surface area.
      • High glomerular pressure.

    Conclusions: Glomerular Injury

    • The underlying disease process and patient-related factors determine how the glomerulus is injured.
    • A single disease can produce multiple histological forms of injury.
    • A similar histological pattern can be produced by different disease processes.
    • The histological pattern determines the clinical presentation.

    Conclusions: Glomerular Disease Presentation

    • Glomerular disease can present as:
      • Asymptomatic proteinuria.
      • Nephrotic syndrome.
      • Mixed nephrotic-nephritic syndrome.
      • Nephritic syndrome.
      • Asymptomatic hematuria..

    Conclusions: Glomerular Disease Diagnosis and Treatment

    • Confirm the clinical syndrome with a formal urinalysis.
    • Refer the patient to a nephrologist for basic investigations and definitive diagnosis.
    • Initiate specific therapy based on the diagnosis.

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