1/31 Glomerular Disease - Mann Flashcards
algorithm for renal dysfx
general features of glomerular disease
- heavy proteinuria
- RBC/RBC casts
- oval fat bodies
most immune mediated
- some T cell, but most have big roles for B cell/antibodies/immune-complex formation/complement
antibodies and glom disease
antibodies can be formed in response to
- endogenous antigens (tumor, nuclear, or endog antigens within kidney, as well as Ig)
- exogenous antigens (drugs, invading orgs)
abs hit target either in periphery or within kidney
type of renal injury is dependenty on CLASS OF AB formed and the LOCATION OF IMMUNE COMPLEX within the glom
notable: glomeruli
4 places for immune complex deposition
easiest deposition?
worst prognosis deposition?
WHY?
- portion of capillary that is adj to mesangium DOES NOT have basement membrane
- endotelial cell that lines capillaries is fenestrated
- podocytes have foot processes
immune complexes can be deposited within kidney in 4 locations
- mesangium
- subendothelial space (below endothelial cell, but on the blood side of bm)
- penetration into basement membrane
- subepithelial space
- easiest? mesangium! → only have to beat a single fenestrated cap to make it in!
- worst? subendothelial → can activate complement, trigger massive infl response (nephritic response) bc right next to blood
urinalysis in…
nephrotic vs nephritic
nephrotic
- heavy proteinuria
- oval fat bodies
- few fat droplets
- few cellular elements
nephritic
- red cells → if dysmorphic, want to consider glom disease
- red cell casts/granular casts
- variable proteinuria
- WBCs
algorithmic approach to glomerular disease
- nephritic
- focal nephritic (nl complement)
- diffuse nephritic (low complement)
- rapidly progressing GN/crescentic (some low, some nl complement)
- nephrotic (ALL normal complement levels)
- minimal change
- fsbs
- membranous
- diabetic nephropathy
- amyloid
- pre-eclampsia
- TMA (thrombotic microangiopathies)
nephrotic syndrome
- heavy proteinuria
- hypoalbuminemia
- edema
- hyperlipidemia
- normal complement levels
minimal change disease
nephrotic syndrome
- most common glom disease in kids
- normal complement, low IgG, high IgM
- normal light, immunofluorescent microscopy
- fused foot processes on EM → podocyte disorder!
- usually idiopathic )sometimes assoc w lymphoma, leukemia, renal cell carinoma, NSAIDs)
pic: fused food processes
FSGS
basics
incidence
microscopy shows
which glom involved first?
etiology
types of lesions
focal and segmental glomerulosclerosis
nephrotic disease
podocyte disease: injury to podocyte → rearrangement of actin cytoskeleton (irreversible and progressive in FSGS - unlike in MCD)
- incr incidence: most common primary glom disorder leading to ESRD in US
- incidence HIGHER and rate of renal survival WORSE in AfAms
- microscopy shows:
- focal/segmental glomerulosclerosis
- fused foot processes
- coarse granular deposits of IgM and C3 (immunofluorescence)
- juxtamedullary glom are involved first
- often idiopathic, but can be secondary to HIV, obesity, reflux, heroin use, malignancies, podocyte mutations (nephron and podocin most frequent), hemodynamic adaptations due to reduction in number of fxing nephrons
- most likely to see blood in urine:
lesion variants
- “tip” lesion
- involves tubular pole
- least tubular atrophy and interstitial fibrosis
- best prognosis
- “collapse” lesion
- collapse of glom tuft
- severe tubular injury
- AfAm predom
- worst prognosis
unusual features of HIVAN (assoc. nephropathy)
- prominent “collapse” or retraction of glom capillary tufts
- tendency for glom sclerosis to be DIFFUSE w LITTLE/NO INCR IN MESANGIAL MATRIX
- minimal glom hyalinosis
- prominent hypertrophy and degen of visceral epithelium in glom
- striking TI disease: large casts distend all nephron segments
- lots of “tubuloreticular structures” and other inclusions
more common in men, mostly AfAm
membranous nephropathy
most common cause ofidiopathic nephrotic syndrome in adults
- except for AfAms → FSGS
- diffuse thickening of glom basement membrane w little incr in cellularity
- progressive engulfment of subepithelial deposits
- “spikes”
- endog or exog antigens
- 75% of idiopathic have ab binding to PLA2R (M type phospholipase A2 receptor), which is a podocyte antigen
- 100% specific for idiopathic MN!
tend to be somewhat hypercoagulable due to leak of ATIII into urine
- most hypercoag location? renal vein!
antigens that can cause MN
endogenous
- DNA (SLE)
- tumor
exogenous
- hepB
- syphillis
- malaria
- captopril
- Hg
- Au
- penicillamine
idiopathic
pathophys of membranous nephropathy
4 elements
four elements required
- ab deposition in subepithelial location
- complement activation
- C5b-9 (MAC) formation
- disabled regulatory proteins (cell defense shot)
diabetic nephropathy
leading cause of ESRD: 25-40% of DM1, DM2
hyperglycemia leading to:
- incr growth factors (TGFbeta)
- activation of protein kinase C
- activation of cytokines
- formation of ROS
- incr formation of glycation pdts
- incr activity of aldose reductase pathway
- decr glycosaminoglycan content of bm
don’t need to know all details
but know: →→→ expansion of eosinophilic bm like material in mesangium → expands mesangium and occludes adj capillaries → glom hyalinization and diffuse glomerulosclerosis
- vasc hyalinization and interstitial nephritis common
pic:
- left: diffuse GS
- right: nodular GS
amyloidosis
groups of disorders: soluble proteins aggregate and deposit extracellularly in tissues as insoluble fibrils → cause progressive organ dysfx
initial event in amyloid fibril formation? misfolding
-
primary amyloidosis: AL = light chain or fragment produced by clonal plasma cells
- many pts will have mulitple myeloma
- secondary amyloidosis: serum amyloid A (SAA - scute phase reactant prod by liver in resp to inf/infl)
characterized by amorphous nodular, hyalin material in mesangium and capillary loops, subendo and mesangial fibrils
congo red? see green birefringence
pre-eclampsia
pathogen not well understood but def involves invasion by trophoblasts of the spinal arteries supplying the placenta
- deficiency of PP13 protein which usually downregs maternal immune response against arteries
- placental ischemia → abnormal PG metabolism, intravasc activation of coag, vasoconst
characteristic swelling of endothelial cells (glomerular endotheliosis) and subendo deposition of hyalin/fibrin-like material
clinically, see gradual increase in bp during latter half of preg → HTN resolves within 6wk of delivery
IgA nephropathy
(Berger’s disease)
mesangial prolif GN
- characterized by segmental areas of incr mesangial matrix and hypercellularity
- mesangial deposits of IgA1 and C3, sometimes IgG and IgM
- subendothelial and mesangial dense deposits
episodic gross hematuria and nonnephrotic range proteinuria
- hematuria often assoc with viral resp ir GI illness
NORMAL SERUM COMPLEMENT LEVELS help distinguish from nephrotic
if have arthritis, vasculitis, and nonthrombocytopenic purpura → Henoch Schonlein purpura
postStreptococcal GN
- follows inf with groupAbeta hemolytic strep
- abrupt onset of gross hematuria, renal insuff
- increased mesangial matrix and mesangial cell prolif, neutrophil infiltration, closure of cap loops
- IgG and C3 in mesangium and along cap walls
- subepithelial “humps”
- after a month or two, lesions begin to resolve and usually completely resolve over 9mo-yrs
- kids >> adults
- usually follows pharyngitis by 10d, impetigo by 3wk
membranoproliferative glomerulonephritis
basic incidence/association
two types
- relatively uncommon
- usually seen in young adults, presenting in one of following ways
- hematuria/proteinuria on u/a
- acute nephritic syndrome with hematuria, HTN, edema (like postStrep)
- recurrent gross hematuria (like IgA)
- insidious onset of edema and nephrotic syndrome
- mostly idiopathic, sometimes in assoc with hepC
two types
- immune complex mediated
- IC deposition secondary to chronic inf, autoimmune disease, or paraproteinemias due to monoclonal gammopathies
- IC → activation of classical pathway of complement and depo of complement factors in mesangium/along cap walls
- complement mediated
- complement factors induce potent infl response → phagocyte chemotaxis and opsonization and lysis of cells
- activation of complement thru classical/lectin/alt pathways →→→ converge to form C3 convertase, which cleaves C3 → C3a, C3b
- C3b (in presence of factorB and factorD) assoc with C3 convertase →
- amplify C3conv
- stimulate formation of C5conv → MAC → lysis
- complement factors induce potent infl response → phagocyte chemotaxis and opsonization and lysis of cells
tram track appearance
RPGN
or
crescentic GM
rapidly progressive glomerulonephritis
- group of disorders assoc with rapid decline in renal fx as well as prominent crescent formation
- evolve from cellular crescents → fibrocellular crescents → fibrous crescents
proliferative GN with crescents in 30-70% of glom
three subcategories
RPGN
3 subcategories
- ANCA: antineutrophilic cytoplasmic autoantibodies
- anti-GBM autoantibodies
- by themselves? just anti-GBM disease
- also depo in lungs and hemoptysis? Goodpasture’s
- immune-complex
P-ANCA vs C-ANCA
P: perinuclear
C: cytoplasmic
SLE
systemic lupud erthematosus
autoimmune disorder of unknown etiology
- immunoregulatory defects and polyclonal B cell activation
- net effect: poorly regulated autoantibody and IC formation → tissue destruction in a variety of organ systems
disorder may present in many diff ways, glom injury may take many forms
