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R9 Glomerular Disease I

  1. General Pathophysiology of Glomerulonephritis
    • Protein Leakage
    • -proteinuria
    • -hypoalbuminemia
    • -edema

    • Red Cell Leakage
    • -hematuria
    • -red cell casts

    • Increased Renin
    • -hypertension

    • Impaired Filtration
    • -renal failure
  2. Quantitation of Proteinuria
    • > 3.5 g/24hrs:
    • -Nephrotic range
    • -implies glomerular origin

    • 1.5-3.5 g/24hrs:
    • -probable glomerular origin

    • <1.5 gm/24hrs:
    • -glomerular or tubular origin

    • <0.15g/24hrs:
    • -normal
  3. General Pathology of Glomerulonephritis
    • 1. Ultrastructural alterations
    • -causes protein leakage
    • -"nephrotic"

    • 2. Inflammation, Cell Proliferation etc
    • -causes red cell leakage, increased renin, impaired filtration
    • -"nephritic)
  4. Pathophysiology of Nephrotic Syndrome
    • Infection
    • -loss of immunoglobulins

    • Hypoalbuminemia
    • -edema
    • -hyperlipidemia (increased liver synthesis of vLDL)

    • Arterial and Venous Thrombosis
    • -loss of endogenous anticoagulants --> hypercoagulable state
  5. Clinical Syndromes of Glomerulonephritis
    • Proteinuria
    • -may be an isolated finding or first sign of disease

    • Nephrotic Syndrome
    • -proteinuria
    • -hypoalbuminemia
    • -edema

    • Hematuria
    • -microscopic or gross
    • -can be +/- red cell casts
    • -may also be benign recurrent hemturia syndrome

    • Hypertension
    • -frequent in acute or progressive GN

    • Acute Nephritic Syndrome
    • -abrupt onset
    • -microhematuria
    • -reduced urine volume
    • -reduced GFR
    • -hypertension
    • -edema

    • Rapidly Progressive Glomerulonephritis
    • -severe
    • -usually irreversible
    • -nephritic illness
    • -rapid: normal to end stage within weeks

    • Chronic Glomerulonephritis
    • -end stage renal failure from any type of GN
  6. Classification of Glomerular Diseases
    • Immunological Derangements etc:
    • 1. Primary GN
    • 2. Secondary GN

    • Genetic Defects
    • -Familial GNs

    • Metabolic Disorders
    • -Diabetes
    • -Amyloid
    • -Etc
  7. Primary GN Classification
    • 1. Non-proliferative Forms
    • -Minimal Change Nephropathy
    • -Focal Glomerulosclerosis
    • -Membranous GN

    • 2. Proliferative Forms
    • -Membranoproliferative GN
    • -Mesangial IgA GN
    • -Acute (postinfectious) GN
    • -Cresentic (rapidly progressive GN) (3 types)
  8. Minimal Change Nephropathy
    • "Nil Disease"
    • -most common cause of nephrotic syndrome in children

    • Etiology:
    • -usually idiopathic
    • -rarely associated with NSAIDs or Hodgkin lymphoma

    • Pathogenesis:
    • -damage to integrity of glomerular filter
    • -caused by a circulating factor (possible T cell cytokine)
    • -damages podocytes

    • Pathology:
    • -LM: normal or minor changes
    • -EM: podocyte foot process fusion
    • -IF: negative

    • Clinical Features:
    • -nephrotic syndrome
    • -remitting and relapsing
    • -typically one-few attacks then resolves
    • -a few persist into adulthood
    • -onset in adulthood has worse prognosis
    • -normal serologies

    • Treatment:
    • -good response to corticosteroids
    • -cyclophosphamide for relapsers
  9. Focal Segmental Glomerulosclerosis (FSGS)
    • Etiology: (idiopathic/primary, renal ablation nephropathy, secondary to previous insult, HIV, IV drug use, hereditary)
    • 1. Classic immune type
    • -possible nephrotoxic circulating factor
    • -can recur in transplants

    • 2. Cellular/Collapsing type
    • -idiopathic
    • -parvo B19
    • -HIV

    • 3. Genetic Defect
    • -podocyte protein
    • -defect of slit diaphragm structure

    • 4. Secondary
    • -reduced renal mass
    • -obesity
    • -hyperfiltration injury

    • Pathology:
    • -deeper glomeruli affected first
    • -LM: focal segmental glomerular sclerosis (accumulation of hyaline material in mesangial regions)
    • -EM: foot process effacement
    • -IF: negative, non-specific trapping of IgM/C3

    • Clinical Features:
    • -mainly teenagers, young adults
    • -persistent proteinuria
    • -30-50% have nephrotic syndrome
    • -most common cause of nephrotic syndrome in African Americans and Hispanics
    • -often HTN
    • -sometimes persistent hematuria
    • -progressive renal failure (70% at ESRD in 10y)

    • Treatment:
    • -20-40% may be helped by steroids
    • -cyclophosphamide
    • -ACEIs/ARBs
  10. Membranous Glomerulonephritis
    • Etiology:
    • -idiopathic (vast majority)
    • -rarely secondary to: HepB, SLE, solid tumors, drugs

    • Pathogenesis:
    • -autoantibody to podocyte antigen (PLA2R)
    • -glomerular injury due to subepithelial accumulation of immune complexes
    • -complexes cause local C' activation (C5b-9 insertion into podocyte membrane)

    • Pathology:
    • LM: diffuse GBM thickening
    • EM: dense subepithelial "humps" with intervening spikes of BM-like material
    • IF: granular IgG and C3 along GBM

    • Clinical Features:
    • -nephrotic syndrome (60-80%)
    • -persistent proteinuria (20-40%)
    • -30% progress to renal failure, others remain stable or improve

    • Treatment:
    • -steroids help in progressive or severely nephrotic cases
  11. Type of Membranous Change (MGN vs MPGN)
    • 1. Membranous GN
    • -GBM thickened on the outside
    • -spike like projections grow out between the subepithelial immune deposits

    • 2. Membranoproliferative GN
    • -GBM is reduplicated on the inside
    • -mesangial cell pseudopodia lie between the original and the new GBM
    • = "tram tracks"
  12. Membranoproliferative Glomerulonephritis
    • Etiology:
    • -idiopathic
    • -some Type I secondary to hep C
    • -Type I: subendothelial deposits
    • -Type II: intramembranous deposits (C3 nephritic factor)

    • Pathogenesis:
    • -due to immune complex deposition
    • -Type II: intense activation of alternative C' pathway (C3) --> due to C3 nephritic factor
    • -C3NeF stabilizes C3 convertase (overactivation of C', inflammation, low levels of circulating C3)

    • Pathology:
    • LM: mesangial proliferation plus thickening of GBM (double contour --> "tram tracks")
    • EM:
    • -Type I: subendothelial/mesangial deposits
    • -Type II: dense intramembranous deposits
    • IF: granular C3 (IgG in only 50%)

    • Clinical Features:
    • -onset: 5-30 years in idiopathic cases
    • -nephrotic syndrome + hematuria
    • -(can be nephrotic/nephritic or both!)
    • -progresses to renal failure in 6-7y (75%)
    • -HTN in most

    • Treatment:
    • -no benefit from steroids/cytotoxic drugs
    • -100% recurrence in transplants in Type II patients (but slow, transplant still worthwhile)
  13. Locations of Immune Complex Deposition


    • 1. Subepithelial
    • -MGN

    • 2. Intramembranous
    • -MPGN (type II)

    • 3. Subendothelial
    • -MPGN (type I)
  14. IgA Nephropathy
    • "Mesangial IgA GN"
    • "Berger's Disease"

    • Etiology:
    • -defective β-galactosyl transferase activity --> increased galactose-deficient IgA in circulation
    • -50-90% sporadic

    • Pathogenesis:
    • -GD IgA is defective in the hinge region, more anionic and polymerizes --> autoantibody response
    • -Immune complexes precipitate in mesangium
    • -Deposits activate inflammatory systems
    • -Exacerbated during mucosal infections

    • Pathology:
    • LM: focal, segmental mesangial proliferation
    • EM: deposits in mesangium
    • IF: IgA and C3 in granular pattern in mesangium

    • Clinical Features:
    • -most common form of GN in the world
    • -in adults male>female
    • -usually Benign Recurrent Hematuria Syndrome (gross hematuria triggered by fever, URI etc)
    • -usually with persistent microscopic hematuria and proteinuria
    • -10% progress to renal failure
    • -most cases NOT nephrotic
    • -normal blood C3
    • -blood IgA levels not reliable

    • Treatment:
    • -no specific tx
    • -ACE/ARBs in progressive cases
  15. Acute Postinfectious Glomerulonephritis
    • "Acute Proliferative GN"
    • "Post Streptococcal GN"

    • Etiology:
    • -usually follows streptococcal pharyngitis or skin infection
    • -associated with nephritogenic strains (M protein virulence factor)
    • -occasionally after non-strep infections

    • Pathogenesis:
    • -probably "planted antigen" mechanism

    • Pathology:
    • -LM: proliferation of endothelial and mesangial cells/Neutrophil infiltrate
    • -EM: Subepithelial "humps"
    • -IF: granular C3 and IgG
    • **Only other GN with subepithelial deposits is MGN

    • Clinical Features:
    • -children > adults
    • -incidence declining
    • -acute nephritic syndrome
    • -most recover in a few eeks
    • -low serum C3, normal C4
    • *occaisionally severe cases don't recover renal function

    • Treatment:
    • -antibiotics (appropriate but may not change course once established)
  16. Types of Proliferative Changes
  17. Rapidly Progressive Glomerulonephritis
    "Crescentic GN"

    • Etiology:
    • -3 immunologic subtypes
    • -Type 1: anti-GBM (linear IgG)
    • -Type 2: immune complex type (granular IgG)
    • -Type 3: pauci-immune (ANCA-associated)

    • Pathogenesis:
    • -severe injury of glomerular tuft --> bleeding and fibrin deposits in Bowman's Space (cresents)

    • Pathology:
    • -LM: Macrophage/epithelial cell crescents
    • -EM: various
    • -IF: Type 1 (linear IgG), Type 2 (granular IgG), Type 3 (pauci-immune)

    • Clinical Features:
    • -rapid loss of renal function (weeks)
    • -often prodromal systemic symptoms
    • -progressive development of oliguria or anuria
    • -"active" urinary sediment (hematuria, red cell casts)
    • -Modest proteinuria (NOT nephrotic)
    • -often have HTN
    • -rare recovery of renal function (depends on type and degree of progression)
  18. Type 1 Rapidly Progressive Glomerulonephritis
    Linear IgG along GBM

    • Idiopathic Crescentic GN (anti-GBM type)
    • -anti-IgG against NC domain on type IV collagen in GBM
    • -causes glomerular inflammation, hemorrhage and progressive loss of renal function

    • Goodpasture's Syndrome
    • -antibody also cross-reacts with alveolar BM
    • -causes GN plus alveolar inflammation, hemorrhage and progressive loss of pulmonary function

    • Treatment:
    • -steroids
    • -plasmapheresis
    • -cyclophosphamide
    • *ineffective if Cr > 6mg/dL
  19. Type 2 Rapidly Progressive Glomerulonephritis
    Immune Complex type

    • Etiology:
    • -crescents secondary to systemic diseases
    • -SLE
    • -other rheumatologic diseases
    • -severe bacterial infections
    • -other

    • Treatment:
    • -high-dose steroids
    • -IV cyclophosphamide
    • -can be helpful even if oliguric or Cr > 6mg/dL
  20. Type 3 Rapidly Progressive Glomerulonephritis
    • Pauci-immune type (ANCA-associated)
    • -absence of immune complex deposits in the kidney
    • -most exhibit small vessel vasculitis

    • Etiology:
    • -ANCA are pathogenic
    • -crescentic/focal necrotizing GN with systemic vasculitis
    • -Wegener's Granulomatosis (C-ANCA): renal pulmonary and sinus disease
    • -Microscopic Polyangiitis (P-ANCA): granulomas, no sinus involvement

    • Treatment:
    • -cyclophosphamide, steroids, plasmapheresis
    • -maintenance phase with mycophenolate
    • -can be helpful even if oliguric or Cr > 6mg/dL
  21. ANCA
    • -ANCA involved in MP and WG principally directed against lysosomal enzymes
    • -myeloperoxidase
    • -proteinase-3
Author
jknell
ID
205588
Card Set
R9 Glomerular Disease I
Description
Renal II
Updated

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