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General Pathophysiology of Glomerulonephritis
- Protein Leakage
- -proteinuria
- -hypoalbuminemia
- -edema
- Red Cell Leakage
- -hematuria
- -red cell casts
- Increased Renin
- -hypertension
- Impaired Filtration
- -renal failure
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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
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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)
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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
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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
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Classification of Glomerular Diseases
- Immunological Derangements etc:
- 1. Primary GN
- 2. Secondary GN
- Genetic Defects
- -Familial GNs
- Metabolic Disorders
- -Diabetes
- -Amyloid
- -Etc
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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)
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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
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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
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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"
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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)
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Locations of Immune Complex Deposition
- 2. Intramembranous
- -MPGN (type II)
- 3. Subendothelial
- -MPGN (type I)
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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
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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)
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Types of Proliferative Changes
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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)
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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
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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
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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
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ANCA
- -ANCA involved in MP and WG principally directed against lysosomal enzymes
- -myeloperoxidase
- -proteinase-3
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