Rapidly Progressive Glomerulonephritis (RPGN) Flashcards
rapidly progressive glomerulonephritis (RPGN) - defined
*clinical syndrome: acute glomerulonephritis associated with a rapid onset of severe acute kidney injury
*pathologic feature: crescents on light microscopy
*usually caused by processes that cause nephritic syndrome (the “extreme” of nephritic syndrome)
rapidly progressive glomerulonephritis (RPGN) - clinical features
*oliguria
*rapid renal failure
*variable proteinuria
*hematuria
*hypertension, often severe
essentially, severe nephritic syndrome with rapid loss of GFR
oliguria - defined
low urine output < 400 ml/day
rapidly progressive glomerulonephritis (RPGN) - urine findings
*RBCs and RBC casts
*dysmorphic RBCs
rapidly progressive glomerulonephritis (RPGN) - the CRESCENT
*crescents consist of fibrin & plasma proteins with glomerular parietal cells, monocytes, macrophages
*crescents are induced in the glomerular capillary wall, resulting in:
-movement of plasma products, including fibrinogen, into Bowman’s space with subsequent fibrin formation
-influx of macrophages and T cells
-release of proinflammatory cytokines (IL-1, TNF-alpha)
*crescent organization: cellular → fibrocellular → fibrous
3 main glomerular insults that cause RPGN
- anti-GBM disease (antibodies directly targeting the GBM)
- immune complex diseases (nephritic type immune complex disease, typically with subendothelial immune complexes that can cause severe injury)
-
Pauci immune glomerulonephritis (anti-neutrophil cytoplasmic antibodies [ANCA] activate circulating immune cells which result in cell-mediated damage)
-includes GPA, EGPA, and microscopic polyangiitis (MPA)
anti-glomerular basement membrane disease (anti-GBM) - light microscopy findings
*breaks of the GBM due to fibrinoid necrosis
*CRESCENTS
anti-glomerular basement membrane disease (anti-GBM) - immunofluorescence findings
*strong linear GBM staining for IgG
*this is DIAGNOSTIC
anti-glomerular basement membrane disease (anti-GBM) - electron microscopy findings
no deposits
anti-glomerular basement membrane disease (anti-GBM) - etiology
*development of (usually IgG) autoantibodies against the non-collagenous C-terminal domain of alpha 3 subunit of type IV collagen
*development of disease is sometimes preceded by a flu-like illness (virus) or hydrocarbon or solvent exposure
*also associated with cigarette smoking
*exposure of an antigen/domain of type IV collagen that is not normally seen by the immune system
*anti-GBM disease can occur in Alport Syndrome patients who have received kidney transplant
anti-glomerular basement membrane disease (anti-GBM) - epidemiology
*renal and pulmonary: men aged 20-40
*renal limited: women aged > 60
anti-glomerular basement membrane disease (anti-GBM) - clinical presentation
*isolated renal disease or with cross-reaction with alveolar basement membranes, causing pulmonary hemorrhage (Goodpasture’s Syndrome)
*flu-like illness may precede the onset
*acutely ill with oliguria, fluid overload, nephritic syndrome, and pulmonary hemorrhage if Goodpasture’s
*positive anti-GBM antibodies; can also have positive ANCA
anti-glomerular basement membrane disease (anti-GBM) - treatment
*plasma exchange to remove the antibody
*immunosuppression to decrease antibody production (corticosteroids, cyclophosphamide)
anti-glomerular basement membrane disease (anti-GBM) - prognosis
*kidney and patient survival correlate with the degree of kidney injury at presentation
*patients who survive the first year with intact kidney function do well, relapses are uncommon
immune complex-mediated RPGN
*any nephritic immune complex-mediated glomerulonephritis can cause crescents/RPGN
*most likely to see crescentic RPGN from nephritic processes with subendothelial deposits:
-proliferative lupus nephritis
-post-infectious glomerulonephritis
-IgA nephropathy
-MPGN
lupus nephritis (class III and IV) - etiology
*immune complex deposition causing proliferative glomerulonephritis
*genetic predisposition
*inadequate clearance of nuclei from cells undergoing apoptosis
*excess nuclear antigens + B and T cell abnormalities result in auto-antibody formation (ANA and anti-dsDNA)
*activation of toll-like receptors and dendritic cells and high interferon alpha levels
*location of antibody-antigen complexes deposit determines the injury response
lupus nephritis - epidemiology
*of patients with SLE, 75% have an abnormal urinalysis
*1/3 have lupus nephritis
lupus nephritis - clinical presentation
*variable: asymptomatic proteinuria/hematuria to edema to RPGN
*lupus nephritis can change classes over time
lupus nephritis - treatments
*class I/II: monitor, ACEi/ARB
*class III/IV: steroids, immunosuppression
*maintenance therapy: MMF, azathioprine
*class V: immunosuppression
mixed cryoglobulinemic vasculitis - light microscopy findings
*MPGN-like appearance
*lobular accentuation of glomeruli
*leukocyte infiltration
*tram track double contours
*capillary lumina with hyaline thrombi “cryo plugs”
mixed cryoglobulinemic vasculitis - immunofluorescence findings
*IgM, IgG, C3, and C1q deposits (IgM prominent)
mixed cryoglobulinemic vasculitis - electron microscopy findings
*subendothelial deposits with an organized structure (crystalline)
mixed cryoglobulinemic vasculitis - etiology
*cryoglobulins are immunoglobulins that precipitate at temperatures lower than 37 C (lower than body temp)
*mixed cryos consist of polyclonal IgG and IgM that targets the IgG
*can cause immune complex formation and MPGN
*often result from chronic viral infections such as HEPATITIS C or from SLE
mixed cryoglobulinemic vasculitis - clinical presentation
*can cause multisystem disease (arthralgias, neuropathy, erythematous macules to papules)
*renal presentation can range from isolated hematuria and/or proteinuria to nephrotic or nephritis syndrome to RPGN
mixed cryoglobulinemic vasculitis - treatment
*treat underlying disorder (hep C, etc)
*in RPGN: plasma exchange, corticosteroids, immunosuppression
Pauci immune glomerulonephritis - light microscopy findings
*breaks of the GBM due to fibrinoid necrosis
*crescents
Pauci immune glomerulonephritis - immunofluorescence findings
*NEGATIVE (pauci-immune means no immune complexes)
note - this means that GPA & EGPA are negative on IF
Pauci immune glomerulonephritis - electron microscopy findings
*no deposits
Pauci immune glomerulonephritis - etiology
*necrotizing vasculitis within glomerular capillaries
*anti-neutrophil cytoplasmic antibodies (ANCA) thought to play a role:
1. c-ANCA (anti-PR3) in GPA
2. p-ANCA (anti-MPO) in MPA and EGPA
*activating of neutrophils/monocytes via binding of ANCA to target antigens on the surface of neutrophils/monocytes
Pauci immune glomerulonephritis - clinical presentations
*variable: systemic sx of weight loss, decreased appetite, polymyalgia, hematuria, proteinuria; often presents as RPGN
1. GPA: upper respiratory involvement (RHINOSINUSITIS, hemoptysis) (recall: GPA is associated with c-ANCA / anti-PR3)
2. EGPA: ASTHMA (recall: EGPA is associated with p-ANCA / anti-MPO)
Pauci immune glomerulonephritis - treatment
*GPA: plasma exchange, immunosuppression
*MPA: immunosuppression
polyarteritis nodosa (PAN) - overview
*systemic necrotizing vasculitis of small to MEDIUM SIZED ARTERIES
*transmural inflammation with fibrinoid necrosis of arterial wall → patchy aneurysmal dilation
*causes kidney dysfunction through narrowing of inflamed arteries and ischemia
*many have HEPATITIS B
*low complements (serum C3, C4)
*HTN, azotemia, microaneurysm rupture with renal infarction
*signs of systemic inflammation: abdominal pain, fever, myalgias, rash, peripheral neuropathy
cyclophosphamide - MOA
*ALKYLATING AGENT that prevents cell division by cross-linking DNA strands → decreased DNA synthesis
*cell cycle phase nonspecific agent
*potent immunosuppresive drug
*prodrug; must be metabolized by the liver
cyclophosphamide - pharmacodynamics
*well absorbed orally
*metabolized by the liver, excreted by the kidney
cyclophosphamide - ADEs
*alopecia
*gonadal suppression / infertility
*HEMORRHAGIC CYSTITIS (give MESNA)
*leukopenia
rituximab - MOA
*monoclonal antibody directed against CD20 antigen on B-lymphocytes
*regulates cell cycle initiation
*binds to antigen on the cell surface, activating complement-dependent B cell cytotoxicity
*goal = inhibit antibody production
rituximab - pharmacodynamics
*detectable in serum 3-6 months after completion of treatment
*B-cell recovery begins about 6 mo following completion of tx
rituximab - ADEs
*allergic reactions
*CYTOPENIAS
*neuropathy, weakness, muscle spasms, arthralgia
*REACTIVATION OF HEP B; PML; TUBERCULOSIS
*reactivation of other viruses (shingles)
