Nephritic Syndrome Flashcards
What are the three major symptoms of nephritis?
Renal failure
Hypertension
Hematuria: acute, chronic, or rapidly progressive
- deformed urine RBC, RBC casts
What makes the glomerulus susceptible to injury?
20-25% of cardiac output passes through
High glomerular capillary pressure
Fenestrated endothelium
Concentration (sieving effect)
What are the ways that you can get immunologic injury to glomerulus?
Glomerular deposition of Ag-Ab complexes
Binding of circulating Ab to fixed glomerular Ag
In situ immune complex formation
What are the consequences of glomerular immune complex deposition in acute glomerulonephritis?
Leukocytes come into capillary lumen
Releases proteases, elastase, ROS whcih digests GBM producing gas & rupturing it
These holes allow RBC to leak
It also damages the endothelium, causing activation of clotting system, fibrin can form
Also releas of interleukins & cytokines that activate platelets and mesangial cells leading to mesangial proliferation
What patterns of proliferation do you see in the glomerulus secondary to this inflammation?
Endocapillary
Extracapillary = Crescentic
(outside the confines of the glomerular capillaries)
Usually much more severe disease = rapidly progressing
Which patterns of glomerular disease can you get?
Focal v. diffuse: how many glomeruli
Global v. segmental: how much of the tuft
post-strep glomerulonephritis: patholophysiology
It’s an acute nephritic syndrome: decreased GFR: elevated BUN/creat, oliguria, edema, hypertension, urinary red cells & red cell casts
Latent period 10-14 days after strep infection, then glomerulonephritis, which is self-resolving
Diffuse & global endocapillary proliferation
Humps: electron dense deposits of ab-ag complexes, supepithelial: between epithelial cell & GBM, some in the mesangium too = in contact with circulating blood
Grossly: chronic: granular, leather grain appearance, kidney is contracted due to sclerosis of nephrons; atrophied, thin cortex
The antiobody is thought to be pyrogenic exotoxin B & the humps become more electron lucent and resolve within 6 weeks in most patients (rarely it can progress to end stage renal failure)
High complement, especially C3
IgG
Clinical presentation of post-strep glomerulonephritis?
More common in kids
10-14 days after infection
Nephritic picture common
Low serum complement and C3
Positive serological tests for recent strep infection
Prognosis is excellent in children, good in adults
Which glomerulonephritis do you get low serum complement levels? normal levels?
Low levels: acute post infection GN (including post strep)
Lupus nephritis
Idiopathic MPGN
Cyroglobulinemic GN
Normal levels: everything else
This is a good tests to do on a desert island, because there are only 4 with low serum complement!!
IgA Nephropathy
Most common glomerular disease seen worldwide
Diffuse mesangial proliferation, mesangial IgA aggregates in mesangium, RBC in urinary space
What’s the pathogenesis of IgA nephropathy?
4 options:
Defective hepatic clearance
Increased IgA production: most commonly; it’s associated with elevated serum IgA, onset may follow upper respiratory tract infection or gastroenteritis
Defect of antigen exclusion at the mucosal surface: URI or gastroenteritis, celiac dz/inflammatory bowel dz
Defective galactosylation of IgA hinge region of polymeric IgA1: hinge region can be immunogenic if it’s galactose deficient, & an autoimmune response drives the dz, may be resistant to clearance against mesangial cells which promotes their deposition
What is the systemic equivalent of IgA Nephropathy?
Henoch-Scholein Purpura
IgA-dominant immune deposits affecting small vessels –> vasculitis in capillaries, venules, arterioles
Typically involves skin, gut, glomeruli & is associated with arthralgias or arthritis
What is the clinical presentation of IgA Nephropathy?
Hematuria following upper resp tract infection or gastroenteritis or physical exercise – no lag time!!
Normal serum complements
Gross hematuria
Treatment of IgA nephropathy?
ACEI & ARB’s - slow the progression bc reduce intraglomeular pressure
Steroids: 6 month course - has long term effect on preventing ESRD even 10 years later
fish oil, mycophenolate
Systemic Lupus Nephritis: clinical features & pathological process
Systemic autoimmune disease
Reduced complement (it’s one of the 4 with reduced complement)
Nephritic features- decreased GFR (elevated creat), high blood pressure, RBC/casts in urine
Diffuse and global endocapillary proliferation with leukocyte infiltration
Full house immunofluorescence staining: IgG, IgM, IgA, C3, C1q
Wile loop deposits = subendothelial Ag-Ab deposits that lead to thickening of glomerular capillary wall
Hematoxyphil bodies = exposed nuclei (from leukocytes that have undergone cell death) complexed with ANA (antinuclear antibody): deposit in mesangium and subendothelial regions
Stages of lupus nephritis
Class I: minimal mesangial
II: mesangial proliferative
III: focal proliferative
IV: diffuse proliferative
V: membranous
VI: chronic sclerosing
How do you treat lupus nephritis? by class
I: treat extrarenal lupus
II: treat extrarenal lupus
III: steroids, cytotoxics
IV: steroids, cytotoxics
V: steroid, cytotoxics
VI prepare for renal replacement
What are the side effects of prednisone?
Weight gain
Stretch marks
What are the side effects of cyclophosphamides?
Hypertension, ischemic heart dz, hyperlipidemia, valvular heart dz, avascular necrosis, osteoporosis, premature menopause, infections, herpes zoster infection
What are alternative treatments to lupus nephritis instead of prednisone & IV cyclophsophamide?
MMF: mycophenolate
Cyclophosphamide (shorter course) followed by MMF
What is rapidly progressive glomerulonephritis?
Rapidly progressive renal failure: days to weeks!
Crescentic GN
Pathogenesis can be due to: anti-GBM dz, immune complex GN, pauci-immune GN
How is rapidly progressing glomerulonephritis rapid?
Progresses to renal failure in days to weeks rathern than months to years
Wegener’s granulomatosis: what organs it affects and pathogenesis in the kidney
Also known as granulomatosis with polyangiitis
Sinusitis, cavitary lesion on chest xray, and nephritis
Rapidly progressing/crescent-shaped glomerulonephritis: proliferation of parietal epithelial cells = extracapillary inflammation
GBM rupture and fibrin extravasion
No immune type deposits: only fibrin is seen on immunofluorescence staining, in areas of necrosis & inflammation
No electron dense, immune deposits
You can also see:
- necrotizing arteritis in interlobular artery of lung;
- capillaritis and alveolitis (neutrophils marginated in the capillaries rupture and can go to alveolar spaces, leading to pulm hemorrhage)
- granulomatous inflammation in the lungs, cartilage, and bone too!
Wegener’s granulomatosis: which antigen?
ANCA: antineutrophil cytoplasmic antibody- 2 varieties
C-ANCA: cytoplasmic (in both alcohol and formalin fix)
P-ANCA: perinuclear (in alcohol fix)
It’s not just a serologic marker- it’s pathogenic!
ANKA Ab is normally sequestered in the neutrophil, until a priming event: i.e. upper resp tract infection –> neutrophil priming mobilizes ANKA to surface of the cell –> can compelx with ANKA Ag –> tell neutrophil to undergo activation & neutrophil degranulation –> NEUTROPHIL ACTIVATION is the mediator of the dz, not deposits of antigen-antibody complexes
What are the forms of pulmonary-renal syndromes?
Pauci-immune: usually ANCA mediated, no immune deposits so paucity of immune staining
Wegener’s granulomatosis
Microscopic polyangiitis
- *Immune Complex Deposits** = granular immunofluorescence pattern, leaves deposits in the lung and in the kidney
- systemic lupus
- cryoglobulinemic vasculitis
- *Anti-glomerular basement membrane antibody deposits** (linear immunofluoresence pattern)
- also known as Goodpasture’s Syndrome
Anti-GBM nephritis
Difficult to distinguish from ANKA mediated disease because both can cause severe crescentic nephritis
Crescents contain fibrin from large ruptures in GBM
In fluoresence, you see linear staining (not paucity of immune staining like in ANKA dz)
You see the same type of linear staining in the lungs!!
Risk of life-threatening pulmonary hemorrhage!
The kidney on autoposy has areas of RBC cast formation due to the massive GBM rupture
What is the antigen in anti-GBM nephritis?
Collagen 4, which is why the immuno staining is linear- because it’s binding to a local antigen of the GBM one-to-one
You get release of chemokines, attract neutrophils, which release their enzymes-proteases, ROS- on the GBM, which produces gaps, leads to activation of the clotting system, and fibrin comes out into the urinary spaces & stimulates the parietal epithelial cells to proliferate and gives rise to the crescent
Non-collagenous portion of alpha-3 collagen IV chain present in GBM and alveolar BM
The insult i.e. upper resp tract infection –> exposure of this part of the collagen 3 that’s not normally exposed –> antibody can form against it
How do we rapidly progressive glomerulonephritis?
Depends on etiology and stage of dz
Anti-GBM dz: steroids, cytotoxics (to prevent production of cytokines), plasmapheresis (to remove the antibodies)
Immune-complex GN: treat underlying dz i.e. lupus
ANCA-associated/pauci-immune GN: cytotoxics (PO, IV) or plasmapheresis (to remove the ANCA) or rituximab
ANCA (antibodies) is to rapidly progressive glomerulo-nephritis
just like
Anti-DNA is to systemic lupus erythematosus
High titer of these antibodies means that the are likely to have bad disease
High titer to anti-DNA means that they are likely to have glomerulonephritis in lupus
