Week 3: Nephritic Syndrome Flashcards
Describe nephritic syndrome.
- acute onset
- hematuria: dysmorphic RBC and RBC casts
- acute renal failure
- proteinuria
- HTN
- complements may be low or normal
- LOW complement: post-infectious GN, lupus, membranoproliferative GN
- NORMAL complement: igA, anti-GBM (goodpastures)
Describe glomerulonephritis.
-inflammatory disorder involving primarily the glomerulus and affecting other renal structures
-due to deposition of circulating immune complexes or formation of in situ immune complexes in glomeruli–>glomerular damage by activating complement and enlisting inflammatory cells
ETIOLOGY-general
-mesangium: monocytic cells phagocytose deposits–>mesangial cell proliferation, increased production of matrix
-subendothelium: deposits can extend to sub endothelium from mesangium because in continuity. Can attract inflammatory cells from blood
-subepithelial: antigens from epithelial cells (podocytes) trapped by anionic charge of lamina rare externa, circulating antibody complexes with it.
OR
-deposition of antibody to antigen of BM (good pastures)
Define post-infectious Glomerulonephritis.
- diffuse proliferative GN occurring 1-2 weeks after infection
- children 3-14
- commonly due to Strep, but also other infections
Clinical presentation of post-infectious GN.
- abrupt onset
- hematuria: “tea colored” urine
- edema
- oliguria
- nephritic UA: red cells, red cell casts, leukocyte casts, protienuria
- serum complement is low (C3)
- elevated ASO
- great prognosis in children with full recovery of renal fxn, adults have worse prognosis, some get progressive disease
Pathological features of post-infectious GN.
- global mesangial and endocapillary proliferation with infiltrating PMNs
- EM: subepithelial humps along GBM, large dome electron dense deposits that protrude from outer surface of BM into urinary space
- less conspicuous mesangial and sub endothelial deposits
- the sub endothelial deposits are attractive to PMNs and drives inflammation
- immunofluorescence: IgG and C3 in granular (starry sky or lumpy bumpy) pattern
- later: C3 becomes dominant
pathogenesis of post infection GN
- bacterial antigens (mainly Strept pyrogenic exotoxin B SPEB) planted at sub epithelial and sub endothelial aspects of GBM, they activate complement directly
- SPEB reaches sub-epithlial aspect due to cationic charge
- circulating immune-complexes may be responsible for mesangial and sub endothelial deposits and activation of complement that drives influx of inflammatory cells
Clinical features of lupus nephritis.
- glomerulonephritis due to circulating (and planted) immune complexes occurring in the course of SLE
- typically present with acute renal failure, hematuria, and proteinuria
- +ANA and + DsDNA
- low complements
- symptoms of SLE
- requires steroids and cytotoxic agents
- 1/3 progress to ESRD
Pathology of lupus nephritis.
- ranges based on class
- EM findings: electron dense deposits corresponding to immune complex deposits, may extend from mesangial regions to sub endothelial areas in more severe cases.
- Tubulo-reticular structures: TRS-proliferation of smooth ER in endothelial cells and lymphocytes, secondary to high interferon state
- fingerprints: organized electron-dense deposits or immune complex depotis, secondary to cryoprecipitable immune deposits
- immunofluorescence: granular immune deposits, full house of Igs (IgG, IgA, IgM), classical pathway of complement activation-early complement components present, including C3
Pathogenesis of lupus nephritis.
- large circulating immune-complexes easily penetrate the fenestrated endothelium but blocked in sub endothelium by lamina dense of BM
- shunt into mesangial matrix, which is in continuity with sub endothelial space
- mesangial hypercellularity due to influx of macrophages and proliferation of mesangial cells to phagocytose immune deposits
- phagocytic ability overwhelmed–>back up into sub endothelium
- subendothelial deposits attract neutrophils and macrophages–>GN
Clinical features of IgA Nephropathy (Berger’s Disease)
- Definition: nephropathy characterized by mesangial/subendothelial localization of IgA, with less intense IgG and C3
- most common cause of recurrent hematuria world wide
- young men and adolescents
- may occur 1-3 days after viral like GI or URI illness
- mild proteinuria, rarely nephrotic syndrome
- IgA levels elevated in 50% patients
- chronic and variable progressive disease
Pathology of IgA Nephropathy
- circulating immune complexes of large size are deposited in the kidneys, mimicking spectrum of changes seen in lupus nephritis
- mesangial hypercellularity, focal GN, or diffuse GN all possible
- predominance of IgA and C3, with or without IgG or IgM
- immune deposits of IgA in dermal vessels-another site to biopsy
- variant: Henoch-Schonlein Purpura
Pathogenesis of IgA Nephropathy
- glomerular deposition of immune complexes containing IgA, IgG, C3–>mesangial hypercellularity–>subendotheilial regions when mesangial overwhelmed–>GN
- similar to lupus nephritis
- links with certain genetic markers on 6q 22-23 and 6p
- pts have heightened mucosal sensitivity to infectious pathogens or certain food antigens such as gluten and ovalbumin
- IgA itself may be abnormal -may trigger autoimmune reaction. Abnormal IgA1 may be more sticky and clump into aggregates
Clinical features of membranoproliferative GN TYPE 1.
-diffuse form of GN where almost all or all glomeruli have mesangial cell proliferation with mesangial cell processes extending peripherally into capillaries. Thickened and reduplicated BM
-idiopathic form affects children and young adults
-secondary forms associated with chronic immune complex diseases: Hep C
-Presentation:
Nephrotic syndrome in 50% cases, hematuria common, 20% present with nephritic and nephrotic syndrome
-disease usually preceded by URI
-50% have decreased C3 levels and C4
Clinical features of MPGN Type 2-dense deposit disease
- capillary thickening and mesangial cell proliferation associated with dense deposits within lamina dense of BM
- rare in comparison to type I
- older children and young adults with proteinuria or nephrotic syndrome, hematuria, HTN
- persistent or constant hypocomplemntemia
- alternative pathway activation
Pathology of Type 1 MPGN.
- thickened capillary walls with hyper cellular glomeruli
- proliferated mesangial cells
- peripheral extension of mesangial cell cytoplasm with interposition of cytoplasm internal to BM
- new BM made internal to original BM
- double counter or tram track appearance in silver stain
- immunofluorescence: C3 and IgG (+/- IgM and IgA) in granular pattern
- hyperlobar appearance
Pathogenesis of MPGN Type 1
- antigenic stimulus–>formation of immune complexes
- stimulus is unknown, autoimmune disease and chronic infection are known to cause secondary forms of MPGN type 1
- many patients have onset of disease or flares after infection
Pathology of MPGN type 2
- capillary wall thickening and mesangial cell proliferation associated with presence of ribbon like dense deposits within lamina dense of GBN by EM
- pathognomonic: elongated sausage like electron dense deposits within lamina dens of GBM and BM of bowman’s capsule and tubules
- immunofluorescence: intense isolated linear staining for C3 in GBMs
Pathogenesis of MPGN Type II
- composition of glomerular deposits: C3,5,6,7,8,9
- dysregulation of alternative complement pathway–>persistent activation and glomerular deposition of C3
- mutations in factor H and I-regulators of alternative pathway that promote decay of active C3 convertase
- C3NeF is autoantibody that stabilizes C3 convertase and protects it from factor H and I. detectable in DDD
- associated with acquired partial lipodystrophy
- MGUS in patients >49
Clinical features of Goodpasture’s disease.
- 60-80% men
- crescentic GN and pulmonary hemorrhage (it is anti-GBM if no pulmonary involvement)
- young men or older men and women 50-60 yrs
- crescentic GN: majority of glomeruli contain accumulation of cells within Bowman’s space, fibrin in bowman’s space, rapid progression to renal failure
Which are crescentic GN associated diseases?
- post infectious GN
- lupus
- IgA
- goodpasture’s disease or anti-GBM disease
Pathology of Goodpasture’s disease
- crescentic glomerulonephritis seen in most patients
- crescents: macrophages derived from blood and proliferated visceral epithelial cells within Bowman’s space
- rupture of GBMs seen in silver and PAS stains
- Crescent preceded by physical breaks in GBM
- extravasated RBCs and fibrin in Bowman’s space
- linear deposition of IgG along GBM
- fibrinogen in Bowman’s space
- no electron dense deposits-small number of IgG
- lung shows pulmonary hemorrhage and focal linear IgG in alveolar septa
Pathogenesis of Goodpasture’s Disease.
- autoimmune disease-antibody to BM collagen a-3-chain of type 4 collagen–binds to glomerular and alveolar septal BM, fixes complement and causes inflammatory reaction
- genetic predisposition (HLA DR and DQ antigens) in 85% patients
- triggers: hydrocarbons, cigarette smoking, respiratory viral infections.
Nephrotic and nephritic syndromes based on deposit location
- Subepithelial
- membranous nephropathy (spike and dome)
- post-infectious GN (humps) - Subendothelial
- Lupus nephritis
- MPGN Type 1 - BM
- MPGN Type 2: worm like deposits - Mesangial area
- lupus–>goes to subendo
- IgA nephropathy
