GN + Vascular Chapter Flashcards
Use of ACEi or ARB is thought to reduce proteinuria by how much?
40- 50%
Have statins been proven to reduce cardiovascular risk in nephrotic syndrome?
Statins (HMG CoAreductase inhibitors) have not been proven to reduce cardiovascular events in nephrotic
syndrome . However statin use is recommended for hyperlipidemia associated with membranous
glomerulonephropathy (MGN).
What should dietary sodium be restricted to in nephrotic syndrome?
< 2g
When to consider anticoagulation in nephrotic syndrome?
Consider anticoagulation if serum albumin < 2.0 to 2.5 g/dL and one or more of the following: proteinuria > 10
g/d, body mass index > 35 kg/m2
, family history of thromboembolism with documented genetic predisposition;
New York Heart Association class III or IV congestive heart failure, recent abdominal or orthopedic surgery, or
prolonged immobilization
Why might you need a higher heparin dose in nephrotic patients?
During heparin anticoagulation, a higher-than-average dose may be required because part of action of heparin
depends on antithrombin III, which may be lost in urine of nephrotic patients.
What is the most common GN worldwide?
IgA nephropathy
Highest incidence of IgA in which populations?
Asians, (and common in Native Americans)
Lowest in African Americans.
What % of biopsy proven IgA reach ESRD in 10 years?
15- 25%
20- 40% in 20 years.
What is the pathogenesis of IgA nephropathy?
Elevated circulating levels of galactose - deficient at hinge region of IgA1 are produced, presumably due to genetic factors; mistrafficking of B cells from mucosal to systemic compartments may also be
Antibodies directed against the underglycosylated hinge region of Gd- IgA1 are produced likely driven by molecular mimicry. Antibodies may be of IgA or IgG CLASS.
The immune complexes are deposited in the kidney.
Deposited IC activate complement cascade (C3_ and induce mesangial cell proliferation, matrix deposition and activation all leading to irreversible kidney damage.
What are secondary hepatic causes for/ associations with IgA Nephropathy?
Alcoholism Primary biliary cirrhosis Hep B Chronic schistosomiasis. Cirrhotic liver has reduced capacity to metabolise/ clear igA
What cancers are associated with IgA nephropathy?
Lung,
larynx
pancreas
mycosis fungoides
What are the biopsy findings of IgA nephropathy?
Light Microscopy: Mesangial expansion and hypercellularlity, may be segmental and global glomerulosclerosis, endocapillary hypercellularity, crescents
Immunofluorescent microscopy: mesangial deposits of IgA, dominant or codominant with IgG or IgM +/- C3. Staining of anything other than IgA is equal or less intense than IgA.
What is the MEST classification?
“MEST” Oxford Classification for IgAN
Mesangial proliferation (> 50% = M1) Endocapillary proliferation: Most active lesion which suggests best indication for therapy ( >1 occluded glomerular capillary = E1) Segmental Sclerosis (>1 segment of sclerosis = S1) Tubular Atrophy and interstitial fibrosis (T0 = 0 to 25%, T1= 26% - 50%, T2 > 50%) M1, S1, T1 and T2 are associated with worse prognosis and are additive
What are presenting factors indicate worse prognosis for IgA nephropathy?
Proteinuria > 1g/d
HTN or normotensive on antihypertensive therapy
Serum creatinine > 1.5mg/dL
Kidney biopsy with greater degree of tubular atrophy and interstitial fibrosis
Management of moderate or severe IgA disease (i.e. proteinuria>1g/d or 0.5- 1g per day with clinical or histologic features suggesting risk of progression - mesangial hypercellulalrity, endocapillary proliferation, segmental sclerosis
Steroids for 6 months.
Consider cytotoxics - cyclosphos.
If ESRD or advanced disease eGFR <30, biopsy with severe global glomerulosclerosis and tubular atrophy, interstitial fibrosis: immunosuppresive therapy is not recommended.
Or if crescentic igAN: RPGN: > 30- 50% cellular or fibrocellulalr crescents on biopsy: pulse followed by high dose steroids, consider cyclophos
?Ask Ted.
Examples of Large Vessel Vasculitis:
> 50 years of age: Giant Cell Arteritis (Renal involvement rare)
< 50 years of age: Takayasu arteritis (Renal ischaemic due to renal artery stenosis or aortic coarctation.)
Examples + Features of Medium- sized vasculitis:
Necrotising arteritis: Polyarteritis nodosa (microaneurysms may resemble small grapes or "beads on a chain" within the kidneys on angio, age: 40- 60 M:F, 1:1 ) ANCA is negative, bloody stool, mononeuritis multiplex, cardiomyopathy, livedo reticularis...
Involvement of capillaries, aterioles and venous beds exclude PAN.
On biopsy: acute nodular inflammatory lesion and aneurysm in arties. Segmental transmural fibrinoid necrosis, LM changes are indistinguishable from ANCA assoc GN.
Kawasaki disease (if they mention mucocutaneous lymph node syndrome (fevers, swollen strawberry tongue, desquamation of tips of digits) its kawasaki disease, Young children peaks at age 1, more common in asians)
Examples of Small Vessel Vasculitis:
Immune Complex Deposits in Vessel Walls:
- Cryoglobulins
- IgA dominant deposits (HSP)
- SLE
- Others: Postinfectious, hypocomplementemic urticarial (anti C1q) vasculitis.
Circulating ANCA with a paucity of vascular or glomerular immunoglobulin staining:
- Granumoas and no asthma = granulomatosis polyangiitis
- Eosinophilia, asthma + granuloma: eosinophilic granulomatosis with polyangiitis
No asthma or granulomas = Microscopic polyangiitis.
anti - PR3
C-ANCA is anti pR3 (Antibodies against PR3 are found in a cytoplasmic pattern)
Cytoplasmic ( c-ANCA) or perinuclear (p-ANCA) pattern. reflects an artifact that occurs with alcoholfixation of neurtophils. All antigens above including MPO are cytoplasmic in vivo.
What % of anti GBM positive patients have concurrent ANCA?
30% of patients with antiglomerular basement membrane (anti-GBM) positive sera and 25% of patients with
idiopathic immune-complex crescentic GN have concurrent ANCA.
What % of those who have ANCA + sera also have anti GBM + sera?
5% of patients with ANCA-positive sera also have anti-GBM positive sera
Patients with concurrent anti-GBM and ANCAantibodies:
• Thought to be either fortuitous coexistence of both anti-GBM and ANCAor anti-GBM develops following
glomerular basement membrane (GBM) injury from ANCA-associated GN.
• Disease course is similar to anti-GBM GN in early disease, but relapse pattern is similar to ANCAdisease.
Lone anti-GBM GN typically does not relapse.
Causes of drug induced ANCA production?
• Drug-induced ANCAproduction (propylthiouracil, methimazole, hydralazine, pencillamine) is associated with
pauciimmune crescentic GN and small-vessel vasculitis
5 year renal and patient survival with ANCA vasculitis
65% - Renal survival
75% - Patient survival
What % of ANCA vasculitis is thought to have:
gastric involvement?
cardiac involvement?
peripheral neuropathy
(Microscopic Polyangiitis, GPA, Eosinophilic granulomatosis with polyangiitis)
Gastric involvement 50%
Cardiac involvement 20- 50% ( 50% in EGPA - Eosinophiliic infiltration)
Neuropathy: 30% (MPA), 50% GPA, 70% EGPA
But:• Patients with eosinophilic granulomatous polyangiitis (Churg–Strauss) typically present with less-severe kidney
involvement.
Regimen of plasmapharesis for vasculitis with pulmonary haemorrhage
Or with anti GBM antibodies?
Vasculitis: seven treatments over 14 days if diffuse pulmonary hemorrhage, daily until bleeding stops, then
every other day, up to total of 7 to 10 treatments.
■ Vasculitis in association with anti-GBM antibodies: daily for 14 days or until anti-GBM antibodies are
undetectable
■ Must monitor daily prothrombin time and fibrinogen and replace with fresh frozen plasma (FFP) and
cryoprecipitates respectively as needed to correct any coagulopathy associated with removal of coagulant
factors with apheresis.
When can you transplant in a patient with ANCA vasculitis?
Delaying transplant until complete remission for 6 - 12 months is recommended.
Delaying transplant in patients in complete remission with positive ANCA is not recommended.
Pathogenesis of Anti GBM
Autoimmunity with antibody formation against the non- collagenous (NC1) domain of type IV collagen chain, alpha3(IV)NC1 aka the Good pasture antigen or
antibodies to other GBM constituentsm alpha 3- alpha 5 (IV) chains.
These type IV collagen chains are also present in alveolus, cochlea, parts of the eye, choroid plexus of brain, some endocrine organs.
Biopsy findings of Anti GBM disease:
LM: Glomerular crescents without mesangial hypercellularlity. Crescents are in the same stage ( all active, all subacute or all chronic) due to “one shot” anti GBM antibody production ( in contrast to presence of crescents in diferent stages with ANCA GN)
IF: Glomerular capillary wall IgG in a liner a pattern.
HLA types predisposing to Anti GBM:
HLA- DR2: HLA- DRB11501
HLA-DR4: DRB11501 or DR4
DR1 + DR7 confer strong + dominant protection
Precipitating factors for Anti GBM disease
- Underlying exposure to hydrocarbons, cigarette smoking, pulmonary infection, and fluid overload leads to an initial alveolar injury
- Prior kidney injury/ inflammation may predispose the kidney to the development of anti GBM disease.
Poor prognostic indicatiors for anti GBM disease
Higher presenting serum creatinine and higher percentage of crescents protend worse prognosis
Need for dialysis, particularly if in association with 100% crescents.
Do patients with Anti GBM disease go on maintenance immunosuppresion?
Maintenance immunosuppressive therapy for anti-GBM glomerulonephritis is not recommended. This disease is
not characterized by frequently relapsing course. Antibodies tend to disappear spontaneously after 12 to 18
months. Recurrence, if occurs, presents at a mean time of 4.3 years, range 1 to 10 years. Recurrence may
manifest as kidney involvement or pulmonary hemorrhage. Treatment is similar to initial regimen outlined
earlier.
• Exception to immunosuppressive therapy initiation: patients who are dialysis-dependent at presentation and have
100% crescents in an adequate biopsy sample, and do not have pulmonary hemorrhage
• Routine daily coagulation laboratory tests should be performed with additional FFP replacement as needed to
correct any plasmapheresis-induced coagulopathy due to removal of coagulant factors.
• Corticosteroids should be started prior to tissue diagnosis if high suspicion due to rapidly progressive disease.
Following diagnosis confirmation, add CYC and plasmaphere
When can you transplant a patient with anti GBM disease?
• Defer transplantation until anti-GBM antibodies are undetectable for at least 6 months.
• Recurrent of disease is very unusual when transplant is performed six months or longer after antibody
disappearance.
• New-onset anti-GBM disease following kidney transplantation should raise the possibility of Alport syndrome in
the native kidneys.
What % of patients with SLE will develop clinically significant LN in the course of their disease?
60%
The majority of patients who develop LN are younger than 55,
Severe nephritis is more common in children than in elderly patients
True/ False - Renal outcome in LN protends worse prognosis in males rather than females.
True
What are the six classes of lupus nephritis?
Class I- Minimal Mesangial: normal glomeruli by LM; mesangial deposits by IF.
Class II - Mesangial proliferative: Mesangial hypercellularity + matrix expansion on LM; mesangial deposits by both IF + EM
Class III: Focal LN (<50% of glomeruli are involved)
IIIA: Active lesions (leukocytes, karyhorrexis, cellular or fibrocellular crescents, large subendothelial depoists forming “wire loops” or “hyaline thrombi”
IIII(A/C) Active + Chronic Lesions
IIII C: Chronic lesions (segmental or global glomerulosclerosis, fibrotic crescents)
Class IV: Diffuse LN (>50% glomeruli)
Class V Membranous LN (> 50% subepithelial deposits with or without mesangial hypercellularity)
Class VI: Advanced sclerosing LN ( >90% globally sclerosed glomeruli without residual activity)
How do you treat Lupus Nephritis?
Class II LN >3g/d protein - steroids, calcineurin inhibitors.
Class III and IV - Induction: Steroids plus either cyclophos or MMF. Steroids taper over 6 - 12 months as per clinical response. Initial IV methylpred may be considered at induction for aggressive disease.
Class III and IV LN - Maintenance
Either azathioprine or MMF and low dose steroids is recommended. With the exception of the ALMS trial where MMF is a better maintenance agent compared to AZAin
composite treatment failure endpoint (death, ESRD, kidney failure, sustained doubling of SCr, or requirement
for rescue therapy), AZAand MMF generally have comparable maintenance efficacy.
• Maintenance therapy with AZAor MMF has been suggested to be superior to CYC based on risk of death
and development of CKD.
• Use of CNIs is suggested for patients who cannot tolerate MMF or AZA
What is the maximum lifetime dose of cyclophosphamide suggested to minimise haematologic malignancies?
36g
What is the evidence for MMF versus cyclophoshamide in the management of lupus nephritis?
- MMF shown to have similar efficacy compared to po Cyclophos in chinese population ( but severe LN was excluded)
Aspreva Lupus Management Study - ALMS - RCT involving patients with class III, IV, V LN MMF had equivalent response rate for induction compared with IV cyclophos at 6 months with similar incidence of serious infections and deaths. Post hoc analysis suggested cyclophos had INFERIOR outcomes compared to MMF if black, hispanic or mixed- race
FOR INDUCTION THERAPY:
If disease worsens as evidenced by increasing SCr or proteinuria during the first 3 months of therapy with
either CYC or MMF, switch therapy (e.g., from CYC to MMF or vice versa) or use alternative therapy (see
options below). Consider rebiopsy
• Response rates appear equivalent, but current data suggest a trend for more relapses, prolonged proteinuria >
1 g/d, and persistent SCr > 2 mg/dL in MMF compared to CYC induction therapy.
• CYC RCTs included patients with more severe LN compared to MMF trial. CYC may thus be preferred over
MMF in patients with severe LN
What is a complete response in lupus nephritis?
Definitions of response:
• Complete response: return of SCr to baseline, plus a decline in urine protein to creatinine ratio (uPCR) <500 mg/g
• Partial response: stabilization (±25%) or improvement of SCr plus ≥ 50% decrease in uPCR where final uPCR is <3,000 mg/g
How does azathioprine compare to cyclophos in management of lupus nephritis?
AZA+ corticosteroids had similar induction response rate compared with that for IV CYC + corticosteroids at 2 years. AZAhad fewer adverse effects, but had higher late relapse rate, risk of doubling of SCr, and more chronic changes on late follow-up biopsies
What is the risk of preeclampsia in a patient with active SLE compared to that of the general population?
30% compared to 5%
Also active SLE is associated with increased risk of fetal death + preterm birth.
Increased maternal adverse outcomes including increased risk of gestational HTN, preeclampsia, and maternal
death. There is evidence to suggest that LN classes III and IV may be associated with greater risk for
hypertension/preeclampsia compared to other LN classes
How do you manage anticoagulation in women with known anti phosphoipid syndrome receiving chronic anticoagulation?
convert warfarin to unfractionated or LMWH during pregnancy
How do you distinguish preeclampsia from lupus flare in pregnancy?
Preeclampsia- AKI only occurs after 20 weeks of gestate with absence of findings seen in lupus flare (presence of low compelemnts, red blood cells casts and leukopenia)
Should you continue hydroxychloroquine during pregnancy?
Hydroxychloroquine maintenance therapy should be continued during pregnancy. Discontinuation of
hydroxychloroquine may lead to lupus flares including LN.
How do you manage pregnancy in lupus nephritis?
Delay pregnancy until complete remission
Use of cyclophos, MMF, ace inhibitor and arb not recommended. Methotrexate is teratogenic and should be discontinued 3 months prior to conception.
Continue hydroxychloroquine.
LN patients who become pregnant while being treated with MMF should be switched to azathioprine.
Patients who relapse during pregnancy should be treated with corticosteroids and if necessary azathioprine.
Patients receiving corticosteroids or azathioprine during pregnancy should not be tapered until at least 3 months postpartum
Administration of low dose aspirin during pregnancy is suggested to reduce risk of fetal loss.
What is considered to be the pathogenesis of post infectious GN?
Likely C3-mediated. Previously thought to be Ab-mediated against bacterial antigens: glyceraldehyde-3-phosphate
dehydrogenase (GAPDH), streptococcal pyrogenic exotoxin B (SPEB) and its more immunogenic precursor
zymogen
What are laboratory findings associated with post infectious GN?
+ Strep culture in up to 70% during epidemics.
ASOT are increased in greater than 2/3 of cases with post streptococcoal GN
anti DNAse B titres are increased in 73% of impetigo cases.
C3 is decreased in > 90%
C4 normal
IgG and IgM are elevated in 80%
Cryoglobulins and Rf are increased in up to 1/3 of cases.
What are the biopsy findings of post infectious GN?
LM: Leukocytes, often neutrophils, in and occluding glomerular capillaries (large “bloodless” glomeruli).
Crescents may be present (Fig. 7.4)
• IF: Irregular granular capillary and mesangial strong staining for C3 usually with small amounts of IgG and/or IgM. Has been described as “starry sky,” “garland” and “mesangial” patterns likely related to timing of biopsy
• EM: Large single subepithelial “hump” or “gumdrop” shaped deposits often at the mesangial waist or notch area where the capillary meets the mesangium
What are the biopsy features of MPGN?
LM: Mesangial hypercellularity, endocapillary proliferation and capillary wall remodelling ( with formation of double contours) all leading to a lobular accentuation of glomerular tufts ( chunky segments/ pieces)
EM: Subendothelial deposits with mesangial migration and interposition with duplication the basement membrane forming capillary double contours, variable mesangial deposits, subepithelial and intramembranous deposits in type III MPGN
IF: Define the underlying pathogenesis of MPGN
What is Fabry Disease?
• X-linked inborn error with deficiency or defect of lysosomal hydrolase α-galactosidase A(α-Gal A), an enzyme
that normally catalyzes the hydrolytic cleavage of the terminal galactose from globotriaosylceramide (Gb3). The
enzymatic deficiency/defect leads to lysosomal accumulation of Gb3 in various cells including vascular
endothelium and smooth muscle cells, cardiac muscle cells and conduction fibers, kidneys, and nerve root
ganglia
Second most prevalent lysosomal storage disease
