GN + Vascular Chapter Flashcards
(129 cards)
1
Q
Use of ACEi or ARB is thought to reduce proteinuria by how much?
A
40- 50%
2
Q
Have statins been proven to reduce cardiovascular risk in nephrotic syndrome?
A
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).
3
Q
What should dietary sodium be restricted to in nephrotic syndrome?
A
< 2g
4
Q
When to consider anticoagulation in nephrotic syndrome?
A
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
5
Q
Why might you need a higher heparin dose in nephrotic patients?
A
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.
6
Q
What is the most common GN worldwide?
A
IgA nephropathy
7
Q
Highest incidence of IgA in which populations?
A
Asians, (and common in Native Americans)
Lowest in African Americans.
8
Q
What % of biopsy proven IgA reach ESRD in 10 years?
A
15- 25%
20- 40% in 20 years.
9
Q
What is the pathogenesis of IgA nephropathy?
A
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.
10
Q
What are secondary hepatic causes for/ associations with IgA Nephropathy?
A
Alcoholism Primary biliary cirrhosis Hep B Chronic schistosomiasis. Cirrhotic liver has reduced capacity to metabolise/ clear igA
11
Q
What cancers are associated with IgA nephropathy?
A
Lung,
larynx
pancreas
mycosis fungoides
12
Q
What are the biopsy findings of IgA nephropathy?
A
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.
13
Q
What is the MEST classification?
A
“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
14
Q
What are presenting factors indicate worse prognosis for IgA nephropathy?
A
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
15
Q
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
A
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.
16
Q
Examples of Large Vessel Vasculitis:
A
> 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.)
17
Q
Examples + Features of Medium- sized vasculitis:
A
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)
18
Q
Examples of Small Vessel Vasculitis:
A
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.
19
Q
anti - PR3
A
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.
20
Q
What % of anti GBM positive patients have concurrent ANCA?
A
30% of patients with antiglomerular basement membrane (anti-GBM) positive sera and 25% of patients with
idiopathic immune-complex crescentic GN have concurrent ANCA.
21
Q
What % of those who have ANCA + sera also have anti GBM + sera?
A
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.
22
Q
Causes of drug induced ANCA production?
A
• Drug-induced ANCAproduction (propylthiouracil, methimazole, hydralazine, pencillamine) is associated with
pauciimmune crescentic GN and small-vessel vasculitis
23
Q
5 year renal and patient survival with ANCA vasculitis
A
65% - Renal survival
75% - Patient survival
24
Q
What % of ANCA vasculitis is thought to have:
gastric involvement?
cardiac involvement?
peripheral neuropathy
A
(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.
25
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.
26
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.
27
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.
28
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.
29
HLA types predisposing to Anti GBM:
HLA- DR2: HLA- DRB1*1501
HLA-DR4: DRB1*1501 or DR4
DR1 + DR7 confer strong + dominant protection
30
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.
31
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.
32
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
33
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.
34
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
35
True/ False - Renal outcome in LN protends worse prognosis in males rather than females.
True
36
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)
37
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
38
What is the maximum lifetime dose of cyclophosphamide suggested to minimise haematologic malignancies?
36g
39
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
40
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
41
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
42
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
43
How do you manage anticoagulation in women with known anti phosphoipid syndrome receiving chronic anticoagulation?
convert warfarin to unfractionated or LMWH during pregnancy
44
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)
45
Should you continue hydroxychloroquine during pregnancy?
Hydroxychloroquine maintenance therapy should be continued during pregnancy. Discontinuation of
hydroxychloroquine may lead to lupus flares including LN.
46
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.
47
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
48
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.
49
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
50
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
51
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
52
```
What are the-
Neurologic:
Dermatologic:
Cardiac:
GI:
Renal:
Features of Fabry Disease
```
Neurologic: neuropathic pain in extremities, stroke in early age
• Dermatologic: telangiectasias, angiokeratomas in groin, hip, periumbilical areas, corneal opacities, thickened lips,
bullous nose, hypohidrosis or hyperhidrosis and associated heat/exercise or cold intolerance, respectively
• Cardiac: arrhythmias, left ventricular hypertrophy
• Gastrointestinal: abdominal pain, diarrhea
• Renal: proteinuria (both tubular and glomerular proteinuria possible), progressive CKD, Fanconi syndrome due to
proximal tubular injury, polydipsia and polyuria due to distal tubular injury and associated defective urinary
concentrating ability, multiple renal sinus, and parapelvic cysts on imaging studies.
53
What are the biopsy findings of fabry disease?
LM:
• Vacuolization/foamy appearance of podocytes and rarely distal tubular epithelial cells due to glycolipid
accumulation (Fig. 7.19)
• Nonspecific findings: FSGS or global glomerulosclerosis, tubulointerstitial fibrosis
• EM: “myeloid” or “zebra” bodies which are concentric lamellated inclusions often with a striped (zebra)
appearance formed by Gb3 deposits within enlarged secondary lysosomes.
• NOTE: lamellar inclusions may be seen prominently in podocytes associated with chloroquine or plaquenil
administration. Less often they occur in gentamicin toxicity, or silicosis, predominantly in proximal, not distal,
tubules.
54
Does enzyme replacement in Fabry's reduce deposition of Gb3 in the podocytes?
Enzyme-replacement therapy effectively reduces deposition of Gb3 in most tissues except for podocytes and
vascular smooth muscle. Nonetheless replacement therapy may slow kidney function decline in early disease.
55
Biopsy findings in HIVAN?
LM: collapsing FSGS, tubular microcystic dilatation with proteinaceous casts, and variable acute tubular injury,
tubular atrophy, lymphocytic infiltrates, interstitial fibrosis (Fig. 7.18)
• EM: presence of tubuloreticular inclusions in endothelial cell cytoplasm in untreated patients
56
Renal side effect of tenofovir /lamivudine/ abacavir, didanosine
Fanconi Syndrome
57
HIV Medication associated with crystal induced nephropathy/ urolithiasis
Protease inhibitors =
Indinavir, atazanavirm nelfinavir, amprenavir, saquinavir, lopinavir/ ritonavir.
Indinavir crystals have been described as "plate like rectangles + fan- shaped or starburst forms"
58
Major drug interaction for HIV patient receiving kidney transplant
Protease inhibitors ( eg darunavir, ritonavir) can markedly increase CNI levels.
Less than 5% of usual dose CNI is typically required.
59
Most common GN associated with hepatitis B
Membranous GN with or without concurrent anti PLA2R antibodies is most common
Other common lesions:
MPGN - Type 1
IgA - associated with chronic liver disease
PAN - IC deposits formed by HBsAG and anti HBs antibody IgM along vessel walls.
60
Virus that causes haemorrhagic nephritis
Hantavirus.
61
Renal manifestations of parvovirus?
Collapsing FSGS
MPGN
diffuse proliferative GN
62
Biopsy of kidney graft that has appearance of "intracytoplasmic inclusions with owl like appearance"
CMV infection.
63
Extra hepatic manifestations of hepatitis C
Cryoglobulinaemia, immune complex and lymphoproliferative disoder associated with arthralgias, fatigue, palpable purpura, digital ischaemic, renal disease, peripheral neuropathy, CNS vasculitis, hypocomplementaemia
64
Renal manifestations of hepatitis C
MPGN with or without cryoglobulinaemia:
Lab findings: Positive rheumatoid factor, hypocomplementaemia
Chronic active HCV may be associtaed with B cell lymphoproliferative diseases, with the most common monoclonal gammopathy being IgM, kappa light chain
EM: Cryoglobulins resemble "fingerprint" pattern of fibrils of 30nm.
Other HCV associated renal lesions:
Membranous - 2/3 of patients have a poistive anti PLA2R and fibrillary/ immunotactoid GN, PAN.
For patients with hepatitis C-related renal disease and cryoglobulinemia: Interferon-based regimens have been
shown to reverse proteinuria and nephrotic syndrome, but not necessarily ameliorate azotemia
65
Prevalence of hep c in dialysis population in the States
8- 9%
66
Haemoglobin dropping by 2 in renal patient with Hepatitis C on ribavirin
look out for haemolysis.
67
Most common GN associated with sickle cell disease
FSGS
- Others:
MPGN - commonly occurs with IC deposits, may be associated with blood borne viral infections from transfusion
"Sickle Cell glomerulopathy" defined as glomerular hypertrophy with or without mesangial hypercellularity.
TMA (assoc. with hx of retinitis)
68
Genetic features of sickle cell nephropathy
Genetic variants of M7H9 and APOL1 are associated with proteinuria, CKD and loss of kidney function in sickle cell disease
Higher fetal haemoglobin is protective against sickel cell nephropathy
Coinheritance with alpha thalassemia appears to be protective against proteinuria and sickle cell nephropathy in Sickle Cell Disease patients.
69
Target Hb with EPO in Sickle Cell Disease
Do not exceed 10.5
70
Most notable renal manifestation of sickle cell trait
Renal medullary carcinoma-
• Medullary carcinoma: occurs exclusively in sickle cell trait and typically presents as an aggressive metastatic
disease at the time of diagnosis in young patients (20 to 30 years old).
• Prognosis is poor (median survival is 3 months following diagnosis).
• Hematuria/flank pain/abdominal mass must be taken very seriously in sickle cell trait!
71
Renal manifestations of Sickle Cell Disease
Cortical manifestations
Medullary manifestations
Tubular manifestations
Cortical manifestations are thought to arise from haemolysis associated endothelial dysfunction:
Early alterations: hyperfiltration, glomerular hypertrophy + hypermetabolism
- Supranormal proximal tubular function: Increased reabsorption of sodium, phosphate.
Late alterations:
Proteinuria,
GN - FSGS most common.
Medullary manifestations are thought to arise from viscosity associated vasoocclusion.
- Micro- macroscopic haematuira.
10% bilatera - left kidney affected 4 times greater than the right due to increased venous pressure in left renal vein.
There is increased sickling of RBC in vasa recta due to low oxygen tension, low pH, high osmolality in the renal medulla. Sickling leads to increased blood viscosity, microthrombus formation, and ischaemic necrosis.
Tubular manifestations:
Impaired concentrating ability (urine osmo < 450) May present with polyuria, hypovolaemia, nocturnal enuersis in young patient., May be reversible with transfusion but may become uncorrectable by age 15.
Incomplete RTA - voltage dependent hyperkalaemic distal RTA: patients fail to secrete both H+ and K+ (thus urine pH> 5.5)
or selective aldosterone deficiency distal RTA: Patients have hyperkalaemia induced suboptimal ammoniagenesis, but can secrete H+, thus urine pH can be <5.5 These patients respond to fludrocortisone.
72
How do you manage haematuria in a patient with sickle cell disease?
Management of hematuria:
• Conservative: bed rest, volume repletion, rule out papillary necrosis
• For persistent hematuria, consider vasopressin or ε aminocaproic acid (synthetic inhibitor of the
plasmin-plasminogen system) 2 to 3 g daily over several days, not to exceed 12 g daily due to risk of
thrombosis.
• For medical therapy failure or life-threatening bleeding, arterial embolization or surgical intervention
must be considered.
• Papillary necrosis (typically asymptomatic) ± acute obstructive uropathy. NOTE: current data suggest that
hematuria and papillary necrosis do not portend greater risk for renal failure. Papillary necrosis with
sloughing can give the appearance of “egg in a cup” or “golf ball and a club” on contrast computed
tomogram urography.
73
What is the most common primary diagnosis for patients who start dialysis?
Diabetic Kidney Disease
74
What is the cumulative prevalence of proteinuria 25 years after a diagnosis of diabetes?
50- 60%
75
What is the cumulative prevalence of progression to ESRD 5 years after onset of proteinuria?
60%
76
Differential diagnosis of nodular glomerulosclerosis
- DM
- dysproteinaemias (amyloidosis + monoclonal immunoglobulin deposition disease + immunotactoid gN)
- fibronectin glomerulopathy
- Collagen 3 glomerulopathy
- chronic hypoxic/ ischaemic conditions
- chronic MPGN
- idiopathic
77
What are the benefits of strict glycaemic control for DKD?
DCCT (type 1) - Mean a1c OF 7% had 35-45% lower risk for development of microalbuminuira.
Type 2 DM - Kumamoto study - 60% reduction in microalbuminuria with Hba1c of 7 versus 9.4
UKPDS - relative risk reduction for devepment of microalbuminuria
Impact on cardiovascular disease less certain -
ACCORD - Action to control cardiovascular risk in diabetes - higher mortality with very tight control - 6.5%
Veterans affairs diabetes trial A1C 6.9% versus 8.4% no difference in reduction in cardiovascular deaths or events.
78
Prevalence of Alport Syndrome
1/ 50,000 live births.
79
Clinical Manifestations of Alport Syndrome
- Asymptomatic persistent microscopic or gross haematuria
- Boys aged 10 without haematuria are unlikely to have alport syndrome.
ESRD:
- X linked or autosomal recessive disease: ESRD usually occurs by age 35 But may be later in life.
- Autosomal dominant: ESRD occurs later in life, generally by age 45 to 60.
Extra renal manifestations:
1. Sensorineural hearing loss:
Thought to be due to impaired adhesion of the auditory sensory cell containing organ of Corti to the inner ear basilar membrane which lacks the normal Alpha 3-4-5 (IV) collagen network.
Rate of hearing loss is similar to the rate of kidney disease progression.
2. Ocular abnormalities:
Anterior lenticonus due to abnormal (alpha3, alpha4 and alpha 5(IV)) and associated with thinning of the lens capsule.
Other ocular findings: spherophakia, anterior polar and posterior cortical cataracts, corneal changes with recurrent corneal erosions.
Retinal findings: drusen, perioveal dot + fleck retinopathy + neovascularisation.
3. Leiomyomas:
Associated with x linked alports but rare:
Affected patients carry deletions that involve COL4A5 extending into the adjacent COL4A6 gene.
Arterial aneurysms have been reported in young males and may involve thoracic, abdominal aorta + even intracranial artery.
80
Traditional Classifiication of MPGN
Was based on EM findings:
MPGN 1: Subendothelial deposits.
- Idiopathic
- Secondary causes: subacute/ chronic infections, Hep C> B, cryoglobulinaemia. lymphomproliferative malignancies, carcinomas. C3 or C3 deficiency, autosimmmune disease, C3 gn.
MPGNIII: MPGN Type 1 features with additional subepithelial and/ or intramembranous deposits.
(So subendothelial deposits = 1, subepithelial deposits and/ or intramembranous = 3; 1 and 3 may be either immune complex mediated or complement mediated GN)
MPGN II: Dense Deposit Disease - Dense Deposits in the GBM
- Idiopathic
- Secondary causes: complement dysregulation due to deficiency or mutations of complement regulatory proteins, autoantibody formation against regulatroy proteins, C3 nephritic factor autoantibodies, familial and acquired partial lipodystrophy
(But NB NB the current classification of MPGN is based on its underlying pathogenesis as immune complex mediated,
81
Features of Immune Complex MPGN
- Involves classical pathway
- IF typically shows both Immunoglobulin + Complement deposits.
Typically low C3 + C4
Causes:
- Infections:
chronic viral infections (Hep C>> B +/- cryoglobulins) bacterial infections (endocarditis shunt/ indwelling catheter nephritis,
abscess,
common organisms: Staphylococcus, mycobacterium,, tuberculosis, streptococci, priopioacterium acnes, mycoplasma pneumonia, brucella, coxiellla burnetti, nocardia, meningococcus, fungal infections + parasitic infections.
Autoimmune disease: SLE, Sjogren syndrome, RA, mixed connective tissue disease.
Paraproteinemias: Monoclonal gammopathies +/- cryoglobulins.
82
Features of Complement Mediated MPGN
- Involves complement dysregulation in the alternative pathway
Typically low C3 (may be normal) and C4 is normal.
(Stains for Complement, not for immune complexes)
Dysregulation of complement activation may occur via different mechanisms:
- Antibody formation against:
1. C3 convertase (Antibodies against this (abs are called C3NF) bind to C3 convertase and stabilise it thereby prolonging its half life and allowing continuing activation of the alternative pathway.
2. Complement regulators (Factors H, I or B)
- Mutations of complement regulators: factor H, factor I, membrane cofactor protein MCP/CD46, complement factor H related protein, CFHR
- Dysregulation of the alternative pathway may be subdivided into DDD and C3GN based on EM findings. Both disease entities are thought to be part of a continuum of the same condition.
DDD - Osmiophilic, sausage shaped, wavy dense deposits that replace GBM and also occur in the mesangium ( old classification MPGNII) MPGNII is associated with partial lipodystrophy + ocular drusen
CSGN - Is characterised by mesangial, subendothelial and sometimes subepithelial + intramembranous deposits ( old classification I or III)
83
Differential diagnosis for MPGN without complement or immuno- complexes on IF
ICE - Think of endothelial dysfunction.
TMA
Pathologic characteristics: absence of immunoglobulins or complements on IF; absence of electron-dense
deposits in mesangium or capillary walls on EM
```
Associated conditions:
TTP or HUS
aHUS
Anti phospholipid syndrome
Drug induced TMA
Malignant hypertension
Radiation nephritis
Bone marrow transplant associated nephropathy
Connective tissue disorders.
```
84
Management of MPGN:
- Use ACEi or ARB
- If you are calling it idopathic need to investigate for a secondary cause.
- KDIQO suggests that patients with presumed idiopathic MPGN accompanied by nephrotic syndrome and decline
in kidney function may be treated with either PO CYC or MMF and alternating or daily steroids, with initial
therapy limited to 6 months
Secondary MPGN -
Treat the underlying cause.
MPGN due to complement dysregulation due to factor H abnormality or C3 nephritic factor autoantibody formation:
- Steroids + cytotoxic agents.
- Consider plasmapheresis in severe cases
MPGN due to congenital mutations leading to complement dysregulation
Consider therapy that inhibits membrane attack complex formation (eculizumab)
anti C5 monoclonal antibody that inhibits C5 activation.
May be effective in some patients with DDD
85
Recurrence rates of MPGN after transplant?
```
MPGN 1 ( 15- 50%)
DDD ( 80- 100%)
```
86
Features of Minimal Change on Kidney Biopsy
LM: Normal glomeruli.
- Tubules may have acute injury and luminal proteinaceous material due to heavy proteinuria.
- Other GN may present with minor changes on LM include: IgM nephropathy, C1q nephropathy + minimal mesangial LN.
IF: No immunoglobulin nor complement depesoition
EM: Podocyte foot process effacemen (75%)
87
Clinical Conditions Associated with Minimal Changes Disease
THINK MAID.
Malignancies: Lymphomas, Hodgkins, non- hodgkins leukaemia, rarely solid organ tumours.
Allergy, atopy, insect/ bee stings.
Immunisations.
Drugs: NSAIDs and selective COX2 inhibitors, pamidrone, aldendronate (both bisphosphonates are also associated with FSGS) lithium, d- penicillamine, tiopronin, interferon gamma, sulfasalazine, 5 ASA derivatives and antimicrobials (rifampin)
88
Management of Minimal Change Disease
Pred 1mg/kg/day for > 4- 6 weeks as dictated by remission or alternative day dose of 2mg/kg.
Once remission - slowly taper to off for up to 6 months.
If intolerant of steroids (severe osteoporosis, psychiatric issue, poorly controlled diabetes) consider po cyclophos or calcineurin inhibitor.
For patients with infrequent relapses --> Steroids.
For patients with frequent relapses ( >2 in 6 months or>4 within 12 months) or steroid dependent (2 relapses on steroid taper or within 1 month of ending therapy) -
1. Oral cyclophos for 8 weeks ( Lower rate of relapse + shorter duration of therapy than CNI in trials)
2. Calcineurin inhibitor - cyclosporine or tac for 1 to 2 years in those who wish to preserve fertility
3. MMF for those who are intolerant of corticosteroids, cyclophos or CNI.
FROM UPTODATE: For frequently relapsing or glucocorticoid dependent patients who have failed trials of cyclophos + cyclosporin, a trial of rituximab is recommended - largest trial to do this did so 1 dose and another 6 months later.
Benefit of statin has not been proven in MCD
If frequent relapses rebiopsy to evaluate for FSGS
89
Prednisolone within four months leads to remission in what % of adults patients minimal change disease and what % will have a relapse
90% will respond
50% will have a relapse
(Taken from uptodate)
90
Most common cause of GN related ESRD in the United States in Black and White patients
FSGS
91
Most common cause of nephrotic syndrome in African American adults
FSGS
92
Aetiologies of FSGS
Primary FSGS.
All other aetiologies:
- Familial/ genetic mutations.
- Viral
- Drugs
- Adaptive Structural Responses
- Malignancy
- Association with underlying GN diseases
Expanded:
- Familial/ genetic mutations: mutations - including nephrin (NPHS1), podocin (NPHS2), alpha- actinin 4, TRPC6, WT1, informin2, SCARB2(LIMP2), formin (INF2), CD2- associated protein, mitochondrial cytopathies
- Viral: HIVtype 1, parvovirus B19, simian virus 40, CMV, EBV
- Drugs: heroin, interferon alpha, beta, gamma, lithium, pamidronate, alendronate, sirolimus, anabolic steroids, CN1
- Adaptive Structural Responses:
Reduced renal mass: low birth weight, oligomeganephronia, premature birth, unilateral kidney agenesis, reflux uropathy, chronic allography nephropathy.
Initially normal renal mass: HTN, DM, atheroembli, obesity, increased lean body mass, anabolic steroids, cyanotic heart disease, sickle cell anaemia.
- Malignancy (lymphoma)
- Association with underlying GN diseases: IgA nephropathy, pauci immune focal necrotising + crescentic GN, hereditary nephritis (alport syndrome) membranous GN, TNA
93
What chromosome is APOL1 on?
APOL1: located on chromosome 22, in linkage disequilibrium with MYH9, codes for apolipoprotein L-1
• Missense mutations of APOL1 are thought to predispose patients of African descents (rather than MYH9 in earlier
reports) to an excess risk of FSGS, HIVAN and chronic hypertensive nephrosclerosis. Greatest risk: mutation of
2 alleles.
• The same APOL1 mutations are protective against Trypanosoma brucei, a parasite spread by tsetse flies in Africa.
94
Histopathologic classification of FSGS:
In general: Histopathologic findings: segmental increase of mesangial matrix with obliteration of capillaries, sclerosis, hyalinosis, foam cells, podocyte hypertrophy with or without hyperplasia, and adhesions between glomerular tuft and Bowman capsule.
Histopathology of FSGS variants:
- NOS - Not otherwise Specified
- Perihilar FSGS
- Cellular FSGS
- Tip lesion FSGS
- Collapsing FSGS
Histopathology of FSGS variants:
- NOS - Not otherwise Specified -
Generic form not meeting any variant. Most common subtype + can occur with primary, secondary, including genetic form.
- Perihilar FSGS
Lesions at the glomerular vascular pole thought to reflect increased filtration pressures at the afferent arterioles with compensatory demand - glomerular hypertrophy. Associated with adaptive FSGS
Clinical Features: typically subnephrotic proteinuria + normal albumin levels.
- Cellular FSGS
Least common variant. "Endocapillary hypercellularity" = including foam cells. Severe foot process effacement.
Usually primary. But can be secondary.
Clinically: Nephrotic syndrome.
```
- Tip lesion FSGS
Segmental lesion involving tubular pole - Least tubular atrophy + interstitial fibrosis + severe foot process effacement is typical
Usually primary
More common in white race.
Highest response to steroids.
```
- Collapsing FSGS
Implosive glomerular tuft collapse.
Hyperplastic glomerular epithelial cells may fill the urinary space. Severe foot process effacement
Associations: Primary or secondary.
Clinical features: Most aggressive variant of primary FSGS, black racial predominance and severe nephrotic syndrome, worse prognosis, poor response to steroids.
(• NOTE: The deep inner juxtamedullary glomeruli are preferentially affected in early primary FSGS. Renal biopsies containing <15 glomeruli or only cortical glomeruli cannot exclude FSGS.)
95
Management of FSGS
Raas inhibition
Dietary sodium restriction
Primary FSGS with subnephrotic proteinuria:
- If no response or worsening of disease with aove - add steroids for up to 16 weeks.
- If no improvement or intolerance to steroids ( uncontrolled diabetes, psychiatric conditions, severe osteoporosis) consider CNI
Once remission is achieved - taper steroids slowly.
Steroid resistant FSGS - CNI + pred.
- cyclosporine thought to expert an anti proteinuric effect independent of its immunosuppresive action.
target levels 125 - 175
Or tac - target 5- 10.
If remission - then continue CNI for 12 months followed by a slow taper.
If no remission by 6 months discontinue therapy
For steroid resistant FSGS + cyclosporine intolerance, combination of MMF + high dose dex is suggested.
Steroid dependent FSGS - ( 2 relapses during or within 2 weeks of completing steroid therapy) - treatment is similar to relapsing MCD in adults
Primary FSGS with nephrotic range proteinuria - steroids daily, or alternate day x 16 weeks trial
If no improvement or intolerance to steroids, consider CNI
Adaptive FSGS - no immunosuppresive therapy - encourage weight loss if obese
Secondary FSGS - treat underlying cuase.
96
How frequent is recurrence of FSGS when transplanted?
Recurrence occurs in 20- 50% of primary FSGS
Increased risk of recurrence
- Children younger than 15 years old
- Rapid course of ESRD (<3 years in native kidneys)
- Heavy proteinuria prior to transplant
- Loss of previous graft to recurrence.
97
Biopsy findings of membranous nephropathy
LM: Variably thick wall.
No hypercellularity nor inflammatory changes.
On silver stain: Projections of the GBM between deposits
giving a characteristic "spike like" pattern.
Resorption of subepithelial and intramembranous immune deposits leads to
GBM thickening with lucencies or double contours.
Glomerular leucocytes infiltration may occur in association with malignancy.
Polymorphonuclear leukocytes infiltrates with renal vein thrombosis.
Concurrent FSGS maybe present in 30% of cases. Worse prognosis. Poor
response to therapy.
IF: IgG and complement component deposits. Staining for IgG4 dominates in
idiopathic membranous, whereas IgG1,2, and/ or 3 dominate in secondary.
C3 is present in around 50% of patients. C1 & C4 are usually absent.
Strong capillary staining for C1q, C3, IgG, IgM, and IgA aka "full house" is associated with membranous lupus.
EM: Diffuse subepithelial granular electron dense deposits that parallel IgG staining. Foot process effacement. In idiopathic MN, deposits are not seen in the mesangial or subendothelial sites, whereas in secondary MGN there may be mesangial hypercellularity +/- endothelial sites.
98
What is the pathogenesis of membranous GN?
- Antibody- antigen formation at podocytes leads to complement activation, formation of C5b-9.
Antibody- antigen complexes are capped and shed to form subepithelial deposits. C5b- 9 complexes are incorporated into multivesicular bodies + transported by podocyte into urinary space. Increased levels of C5b- 9 activate podocytes which injure the underlying GBM.
99
What antigens are responsible for development of idiopathic MPGN?
- Antigens assoc. with idiopathic MGN
Phospholipase A2 receptor 1 antigen -- antibodies. IgG4 subtype (80% of iMGN)
Anti- PLA2R1 correlates with disease activity, & predicts outcome: lower titre is assoc with better rate of spontaneous remission + time to remission in those requiring therapy.
Thrombospondin type- 1 domain containing 7A antigen (THSD7A) ( 10% of iMGN. )
100
What antigens are responsible for development of secondary MPGN?
- Autoimmune (dysregulated autoantibody formation against self antigen): SLE, diabetes, RA, mixed CTD, dermatomysositis, ank spond, crohns, GVHD, temporal arteritis, sjogrens, bullous pemphigoid, autoimmune thyroid disease
- Infectious antigens (think of chronic active infection) Hep B > Hep C, syphilis, TB, HIV, enterococcal endocarditis, leprosy, filariasis, malaria, schistosomiasis, hydatid disease
- Drugs/ Toxins: captopril, gold, penicillamine, NSAIDs, COX2 inhibitors, hydrocarbons, mercury, formaldehyde, lithium, clopidogrel.
- Malignancies - (tumour antigen) Solid organs(Lung, GI, breast, kidney etc)
- Neutral endopeptidase - NEP antigen expressed on podocytes - mothers without NEP may make abs against fetal NEP and transfer the abs to the fetus. These infants are born with nephrotic syndrome.
101
Rule of thirds with idiopathic membranous
One third achieve spontaneous remission
One third remain the same.
One third progress to failure.
102
Risks for worse renal outcome in membranous
```
Male
Older
HTN
Severe hypalbuminaemia
reduced GFR
severe proteinuria > 8g
Increased urinary IgG
Beta 2 microglobulin or C5b-9 excretion,
biopsy with marked tubulointerstitial disease,
glomerular focal sclerosis
extensive GBM damage
```
103
How do you risk stratify idiopathic membranous GN
- Low risk (<5% chance of progression)
Normal kidney function + proteinuria <4g/d
Conservative management if disease deteriorates, initiate immunosuppressive therapy.
- Medium risk:
Normal kidney function + persistent proteinuria >4 and <8g/d
Conservative management for 6 months: if no improvement or deterioration of disease, iniate immunosuppresive therapy.
- High risk:
Abnormal kidney function and/ or persistent proteinuria >8g/d
Conservative mangement <6 months, if no improvement, initiate immunosuppressive therapy.
104
Management of Membranous Nephropathy
ACEI or ARB
Consider prophylactic anticoagulation - warfarin.
Statin if LDL > 100
BP control - consider less than 125/ 75 if more than 1g of proteinuria
Evaluate for secondary causes: (particularly if > 60)
CTTAP, Kidney US, urine cytology, mammogram, scopes, prostate US + biopsy, colposcopy
Immunosuppressive therapy should be considered in patients with nephrotic syndrome and at least one of the following-
Urine protein excretion persistently >4g/day + remains >50% of baseline value for an observation period of 6 months.
Presence of severe, disabling, or life threatening symptoms related to nephrotic syndrome
Serum creatinine increases by >30% within 6 - 12 months from time of diagnosis but baseline eGFR still >30
Do not use immunosuppresive therapy if eGFR <30mL/min/1.73m2 and reduction of kidney size on ultrasound or concomitant severe or potentially life threatening infections.
Immunosuppressive therapy -
Ponticelli Protocol:
Months 1, 3,5 - methylpred for 3 days and then oral pred
2,4,6 - oral chlorambucil or po cyclophos (cyclophos preferred) for 30 days.
For idiopathic Membranous resistant to initial steroids + alkylating agent - switch to CNI therapy.
MMF( give with steroids) another option but not as effective as cyclosporin in terms of remission + relapse.
UPTODATE:
If high risk - Treat.
High or very high risk of progression with stable renal function = treatment with rituximab rather than cytotoxic therapies. CNI is reasonable alternative in patients who are anti PLA2R -
If considered high or very high risk of progression because of abnormal or declining kidney functiona t presentation or rapidly declining kidney function due to MN - they suggest combination treatment with steroids + cytotoxic agent i.e. cyclosphosphamide rather than ritux. In patients who wish to avoid cytotoxic therapy - treatment with ritux is a reasonable alternative.
In moderate risk patients - proteinuria rising, or stable throughout a 6 month period reasonable to introduce immunosuppresion would opt for ritux over cyclophos or a CNI.
105
Features of TMA
Platelets <150,000 or 25% decline from baseline
Microangiopathic haemolytic anaemia ( hence the presence of schistocytes)
End organ dysfunction (brain, kidneys, GI)
106
Features and Associations of DIC
Classic presentation - reduced platelet survival.
Elevated PT, increased fibrinogen degradation products, increased d-dimer
Low grade or chronic DIC: PT/ PTT + fibrinogen may be normal but MAHA will be present and FDP and ddimer will be increased.
Associations of DIC: Sepsis, liver failure, malignancy, tissue death, pre-eclamspia, + septic abortion.
107
What is the function of ADAMTS13
ADAMTS13 is a protease
that normally cleaves ultra-large vWF multimers on endothelial cell surface into smaller fragments to make
them “less sticky” to circulating platelets. The absence of normally functioning ADAMTS13 leads to the
presence of ultra-large wWF multimers, increased platelet trapping, and subsequent intravascular formation of
microthrombi.
108
What % of TTP have kidney failure
20% - 60%
109
Whats the classic pentad associated with thrombotic thrombocytopaenic purpura?
```
Fever
MAHA
Kidney failure
Neurological signs
Thrombocytopaenia.
```
110
Conditions associated with primary and secondary TTP-HUS
TTP & HUS may have overlap of symptoms at presentation. 30% of TTP & aHUS may present with diarrhoea.
- If unclear - immediate initiation of plasma exchange
Conditions associated with primary:
- Idiopathic/ acquired (decreased functional ADAMTS13 or presence of inhibitory anti ADAMTS13 antibody)
- Hereditary/ congenital
Secondary:
- Autoimmune disease
- Drugs (clopidogrel, oral contraceptives, quinine, valaciclovir, chemotherapy, ticlopidine (antiplatelet drug, ciclosporin, TAC, sirolimus, mitomycin C)
- Infections (HIV, strep. pneumonia)
- Pregnancy/ postpartum
- Pancreatitis
- Malignancy
- Systemic sclerosis
- Malignant hypertension
- Stem cell transplant
- Sporadic
111
Indications for therapeutic plasma exchange for TMA
- TTP
- 50% of atypical HUS will respond. All of these patients will respond to eculizumab, very expensive. Need pretreatment with meningococcal vaccination and prophylactic antibiotic coverage is mandatory.
- Diarrhoeal HUS with neurologic or renal involvement.
- TTP- HUS at presentation unless known association with mitomycin C, stem cell transplant, malignancy, systemic sclerosis or dHUS without severe neurologic or renal involvement
112
When does TTP occur in pregnancy?
May occur early in pregnancy - but typically occurs in late second + third trimesters with median gestational age of 23 weeks.
113
Features of pregnancy associated atypical HUS:
Typically occurs postpartum - 80% but may occur early in pregnancy
Complement dysregulation associated with 75%
Pregnancy-associated aHUS is associated with higher incidence of fetal losses (4.6% vs. 2% to 3%) and
preeclampsia (7.4% vs. 4% to 5%) compared to the general population.
• Two-third of affected patients develop ESRD within a month of diagnosis.
114
What is meant by renal anti phosphopholipid syndrome?
Renal APS may present with renal artery or venous thrombosis or "antiphospholipid nephropathy".
Antiphospholipid nephropathy is a vasoocclusive kidney injury due to a TMA and is a subset of renal aps.
Antiphospholipid nephropathy is reported in 10% of those with lupus nephritis and in 20- 30% of those with SLE
Up to one third of patients with APS nephropathy do not have systemic APS.
Clinical manifestations: renal vascular fibrointimal hyperplasia, renal artery or vein thrombosis with or without associated
hypertension, cortical ischemia/necrosis, hematuria, kidney injury, tubulointerstitial fibrosis, glomerulosclerosis,
and any glomerular lesions noted below.
Histopathology of APS nephropathy
• Arterial/arteriolar fibrin thrombi ± fibrin extending into the vascular intima and endothelial cell swelling with
narrowed lumens
• Fragmented red blood cells in vessel lumens, or walls, or in areas of glomerular mesangiolysis
• Concentric thickening (onion skinning) ± mucoid subendothelial widening of arterial/arteriolar walls
• Glomerular capillary ischemic wrinkling, sometimes with double contours
• IF: Fibrin in glomerular capillaries and/or vessel walls and lumens
• EM: subendothelial electron lucent widening between glomerular capillary basement membrane and swollen
endothelium
• Glomerular lesions commonly associated with APS:
• Primary APS: membranous, MCD, FSGS
• Secondary APS: typically LN of any World Health Organization class
115
Is low ADAMTS13 in SLE always TMA?
Unclear utility of ADAMTS13 in SLE: reduced ADAMTS13 levels and/or presence of ADAMTS13 antibodies may
be detected in SLE patients without overt TMA. However, SLE patients with TTP do have severely depressed
ADAMTS13 levels or high titers of anti-ADAMTS13 inhibitory antibodies.
116
Features of light chain cast nephropathy
Most common renal presentation ( 40- 60%) of myeloma in association with raised serum creatinine.
LM: Light chain casts which are angulated, fractured or coarsely granular staining
orange on Masson trichrome and PAS negative in distal tubules. Casts are often surrounded or engulfed by multinucleated giant cells. IF: casts stain strongly for the abnormal light chain, with minimal staining forother immune reactants
May also be associated with fanconi syndrome: proximal tubular injury de to reabsorption and accumulation of crystallised nondegradeable toxic domain fragments. Patients may present with various proximal tubular transport defects including proximal renal tubular acidosis, phosphate wasting, uricosuria (hence hypouricemia), euglycemic glucosuria, and aminoaciduria.
Histopathology: LM: Crystalline inclusions (stain as light blue on H&E) with tubular damage may
be seen in proximal tubular cells. EM: proximal tubular cells are filled with electron-dense light-chain crystals with needle, rod, rhomboid, or rectangular shapes
May get a proteinuria - mismatch.
” Proteinuria from cast nephropathy arises from the large amount of
filtered free light chains (FLC) “Bence Jones protein,” which, unlike albumin, are not well detected by the
routine urinalysis dipstick. That is, while a urine dipstick may indicate “trace” or “1+” proteinuria, the actual
quantification of proteinuria from a 24-hour urine collection or uPCR would be equivalent to “≥3+”
proteinuria. Proteinuria mismatch may also be unmasked by the addition of sulfosalicylic acid (SSA) to the urine sample because SSAprecipitates all proteins including all albumin as well as light chains.
117
Features of primary amyloidosis
Two third of cases are from lambda light chains.
Light chains are partially metabolised by macrophages and then secreted. The metabolised fragments then precipitate into granular deposits and beta pleated fibrils as "amyloid" which is congo red +.
118
Features of monoclonal immunoglobulin deposition disease
Monoconal Immunoglobulin Deposition Disease (MIDD) involves the deposition of monoclonal light chain
(80%), and less commonly heavy chain (10%), or both (10%) in the mesangium and tubular and GBMs.
• Monoclonal κ-light chain is most common with MIDD (two-third of cases)
• Same pathogenesis as amyloidosis, but light chain fragments in this case do not form β-pleated fibrils and are
Congo red negative.
• As GBM is affected and significant albuminuria can occur, MIDD does not present with proteinuria mismatch.
119
Are complements normal in PGNMID and immunotactoid GN?
May be low in a third of cases.
120
Amyloidosis features on biopsy:
• LM: Amyloid stains as silver and PAS negative material in mesangial regions and/or capillary walls. It is Congo
red positive and displays apple green birefringence when viewed with polarized light (Fig. 7.11).
• IF: Smudgy amorphous staining for the appropriate light and/or heavy chain. If it is a non-AL amyloid (AA
amyloid, transthyretin, Lect2, fibrinogen Aα), there is no light chain or immunoglobulin staining.
• EM: 10 nm haphazardly arranged fibrils.
121
Monoclonal Immunoglobulin deposition disease
LM: Glomeruli may appear nodular identical to diabetic glomerulosclerosis, mesangial proliferative, crescentic or normal
• IF: Diffuse strong linear staining of all renal basement membrane and extracellular material for the abnormal light and/or heavy chain.
• EM: Coarse granular electron dense material along/within glomerular and tubular basement membranes.
122
Features of Amyloidosis
Clinical Manifestations: Depends on type of amyloid: Typical: waxy skin, easy bruising, enlarged muscles, liver, tongue, heart failure, abnormal cardiac conduction, proteinuria, peripheral, autonomic neuropathy, coagulopathy
Clinical Associations: Primary (AL) predominantly due to monoclonal immunoglobulin light chain fragments and secondary (AA) due to chronic inflammatory diseases (Think of broken down car with a chronic disease - call AA) due to chronic inflammatory disease, periodic fever syndromes (eg familial mediterranean fevers)
Monoclonality - Yes AL
Light microscopy: Nodular or diffuse pink, deposits of amorphouse material in mesangial matrix and basement membranes of capillary loops, arteriolar walls, nodular lesions resemble diabetic kimmelstiel- wilson nodules.
EM: 10nm fibrils.
Congo red stain: Positive; may be negative in very early disease, heavy chain amyloidosis
Management:
Treat underlying disease
Kidney transplant in dialysis related amyloidosis
Liver transplant in certain hereditary amyloidosis
Do a fat pad biopsy over a liver or kidney biopsy lowest risk from bleeding afterwards.
123
Features of Fibrillary GN
Clinical Manifestations: Mean age: 50 years of age
Haematuria, proteinuria, nephrotic syndrome, HTN, elevated serum cr
Clinical assoc: Idiopathic, may be assoc. with malignancy, low association with monoclonal gammopathy (15%) autoimmune disease, hepatitis C
Monoclonality: Oligotypic - IgG1 + IgG4- much more common than monotypic deposits.
Light microscopy: Focal mesangial or diffuse proliferative or membranoproliferative or membranous GN
IF: Mesangial or glomerular capillary wall deposis for IgG, C3, both kappa and lambda light chains ; C1q depositions possible.
EM: Randomly arranged fibrils 16- 24nms - much more randomly arranged than immunotactoid
Congo stain negative.
Management: Annual screening for associated diseases. SFLCR, Hep C, use acei or arb. Use of immunosuppressive therapy. dialysis support.
124
Features of Immunotactoid GN
Clinical Manifestations: Older population compared to fibrillary GN, one third of patients have hypocomplementaemia
Idiopathic: Frequent association with Chronic lymphocytic leukaemia, and B cell lymphoma. 60- 70% with monoglonal gammopathy, cryoglobulinaemia, lupus and Hep C.
Monoclonality: Predominantly monoclonal
Light microscopy: same as fibrillary GN. (Focal mesangial or diffuse proliferative or membranoproliferative or membranous GN )
IF: Monoclonal immunoglobulin deposition with a restricted light chain, either kappa or lambda.
EM: 30- 50 nm size
Remember size: A (10) - F (16- 24) - I (30-50nm)
Management: Annual screening for associated diseases. SFLCR, Hep C, use acei or arb. Use of immunosuppressive therapy. dialysis support.
125
Pathogenesis of Alport Syndrome
There are 6 genetically distinct collagen type IV chains (α1, α2, α3, α4, α5, α6) that form three
triple helical protomers [α1, α1, α2], [α3, α4, α5], and [α5, α5, α6], where
• [α1, α1, α2] protomer is present in all basement membranes.
• [α3, α4, α5] protomer is present in kidney, lung, testis, cochlea, and eye.
• [α5, α5, α6] protomer is present in skin, smooth muscle, esophagus, and kidney.
• COL4A1 and COL4A2 at 13q34, encodes α1, α2 respectively.
• COL4A3 and COL4A4 at 2q35-37, encodes α3, α4 respectively.
• COL4A5 and COL4A6 on chromosome X, encodes α5, α6 respectively.
Mutations affecting any of the α3, α4, or α5(IV) chains impair the deposition of the entire triple helical complex into the GBM collagen network, leading to alterations in the GBM composition that predispose the kidney to glomerulosclerosis
• In most patients with α5(IV) mutations, the α3, α4, and α5(IV) chains are all absent from the GBM despite continuing transcription of the α3(IV) and α4(IV) genes. The GBM is characterized by the absence of the α3, α4, and α5(IV) chains and persistence of the fetal distribution of α1 and α2(IV) chains.
• In patients with autosomal recessive Alport syndrome, primary mutations in the α3(IV) chain prevent the expression of the α3, α4, and α5(IV) chains in GBM.
• Large deletion or nonsense mutations lead to more severe disease than those with missense mutations.
126
What is the inheritance of Alport syndrome and thin basement membrane disease?
- X linked (80%)
Mutations involving the COL4A5 gene which codes the alpha 4 ( IV) chain.
Female heterozygous carriers: almost all have haematuria, but with variable outcome. Only a minority develop ESRD presumably due to lyonisation - a process whereby only one X chromosome is active per cell. Lyonisation leads to a generally less severe phenotype than that compared with effective males.
- Autosomal recessive (15%)
Mutations involving COL4A3 or COL4A4 genes which code for alpha 3 (IV) chain - which contains the goodpasture antigen- and alpha4 (IV) chain,respectively. Females are as severely effected as males. Clinical manifestations in both sexes are identical to those of classic X- linked alports in males.
- Autosomal dominant (5%)
Heterozygous mutations in either the COL4A3 or the COL4A4 genes. Similar clinical and pathologic features as those of X linked disease, but with slower kidney function decline. While some heterozygous mutations in the COL4A3, or COL4A4 genes cause autosomal dominant alport syndrome and progressive kidney failure, others only develop thin basement membrane ephropathy - a typically more benign conditions where patients present with microscopic haematuria without progression to ESRD.
127
Performing skin biopsy in alports - staining for alpha 5 (IV ) chain.
If absent or segmental suggests X linked alports - but the staining is normal but all features are in keeping with alports - Why?
Autosomal recessive alport syndrome involving either alpha 3 of alpha4(5) chains.
or a mutation of alpha5 (IV) that affects the function but not structure of the chain
- Could be disease other than alport
* In males with X-linked disease, antibodies are directed primarily against the α5(IV) chain, but antibodies against the α3(IV) chain are also found in some patients.
* In patients with autosomal recessive Alport syndrome who develop posttransplant anti-GBM disease, the predominant target of anti-GBM antibodies is the α3(IV) chain.
* Retransplantation in patients who have developed posttransplant anti-GBM is questionable due to high risk of recurrence.
128
Can Alports syndrome reoccur in transplanted graft?
No.
The donor kidney has a normal GBM.
But anti GBM disease occurs in 3-4% of affected males who receive transplants. X linked females do not develop post transplant anti GBM disease because they generally do carry a normal copy of the affected gene and do express the normal counterpart.
129
Biopsy Findings of Alport Syndrome:
Light Microscopy: Interstitial foamy macrophages.
EM: Classic Alport: GBM with irregular thinning and thickening, layered or lamellated “basket-weave” appearance in the thickened area due to GBM injury and remodeling, and subepithelial scalloping. There are no electron dense deposits.
IF: Pattern of staining depends on chain being stained for and type of mutation.
• Staining for the α3(IV) or α5(IV) chain will be positive within the normal GBM since the protomers [α3, α4, α5] are distributed within the GBM.
• In an X-linked Alport male (mutation of the α5(IV) chain), staining for α3,4 and 5 (IV) chains is typically negative due to the lack of [α3, α4, α5] protomer formation.
• In an X-linked Alport female (mutation of the α5(IV) chain), IF staining for α3,4 and 5(IV) is segmental due to lyonization.
• In an autosomal recessive Alport, no α3(IV)- α5(IV) labeling may be detected in the GBM, but α5(IV) from the [α5, α5, α6] protomer will be positive in Bowman’s capsule and basement membrane of collecting ducts.
