Renal involvement in anti-phospholipid syndrome Ingeborg Bajema
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Transcript of Renal involvement in anti-phospholipid syndrome Ingeborg Bajema
Renal involvement in anti-phospholipid syndrome
Ingeborg Bajema
The anti-phospholipid syndrome (APS)
First described in 1980s by Graham Hughes
-Presence of APA-Thrombosis of large arteries/veins or small vessels-Pregnancy morbidity: recurrent miscarriages
-Closely associated to SLE-Slight majority of patients with APS have no evidence of other AI disease:Primary APS (PAPS)
• Lupus anticoagulant present in plasma on two or more occasions at least 12 weeks apart
• Medium or high of IgG or IgM anticardiolipin antibody in serum or plasma on two or more occasions, at least 12 weeks apart
• Medium or high titre of IgG or IgM anti-β2 glycoprotein I antibody in serum or plasma on two or more occasions, at least 12 weeks apart
Testing for anti-phospholipid antibodies
Renal involvement in APS
• Large series have a broad range of patients with APS and renal involvement: 2.7 to 78% * of cases
• Clinically, renal involvement is probably underestimated:
• Extra-renal symptoms dominate the clinical presentation
• Patients do not undergo renal biopsy because of frequent presence of thrombocytopenia and/or anticoagulant treatment
Renal involvement in catastrophic APS: Asherson’s Syndrome
• Catastrophic APS accounts of circa 1% of cases with APS
• small vessel occlusive disease accounts for the major clinical manifestations (not large vessel occlusion)
• high levels of APA, accompanied by other severe autoimmune disturbances, and a triggering factor in 50%
• Mortality: > 50%
• Death: cerebral, cardial, infections, MOF
Asherson, 2005: Triggers for CAPS
Asherson, 2005: organ involvement in CAPS
• Renal involvement: 73%• No histological / clinical details
• Lungs: 68%
• Brain: 63%
• Skin: 58%
• GI: 24%
• Spleen: 18%
• Adrenal glands: 14%
• Other: pancreas, retina, peripheral nerve involvement
Renal involvement in APS
• Diverse clinical manifestations:
Proteinuria
Nephrotic syndrome
Nephritic syndrome
Acute renal failure
Chronic renal insufficiency
ESRD
Renal involvement in APS: macroscopy / microscopy
Macroscopic:
Renal artery stenosis
Renal infarction
Renal vein thrombosis
Microscopic:
Acute/chronic thrombotic microangiopathy
Vascular nephropathy
Variety of glomerulopathies and glomerulonephritides
Renal artery stenosis: Renal infarction: Renal vein thrombosis: Hypertension Pain Nephrotic Syndrome
Large vessel involvement
Renal involvement in APS: Microscopy
Vascular lesions:
Vascular lesions consistent with APS
Thrombotic microangiopathy
Glomerular lesions:
Glomerular lesions related to vasculopathy in APS
Variety of glomerulopathies/glomerulonephritides:Membranous nephropathy MPGN
Minimal change disease pauci-immune crescentic GN
FSGS
Nochy et al, JASN 1999
Nochy et al, JASN 1999
Retrospective examination of 16 patients with PAPS with 5 year follow-up
10 years after 1st description of APS:
- renal involvement underestimated
- lack of knowledge of renal manifestations, in particular on:
- their frequency
- severity
- symptomatology
- histology
previous knowledge based on case reports: first group study
Nochy et al, JASN 1999
Retrospective examination of 16 patients with PAPS with 5 year follow-up
Exclusion criteria:
- SLE
- biopsies with glomerular Ig deposits (to avoid a silent SLE)
10 males, 6 females, age: 24-60 years
All patients had renal symptoms:
renal insuffciency (87%), proteinuria (75%), hematuria (56%)
Nochy et al, JASN 1999
Retrospective examination of 16 patients with PAPS with 5 year follow-up, renal histological lesions:
Vascular lesions:
Arteriosclerosis and fibrous intimal hyperplasie: 75%
Thrombotic microangiopathy: 31%
Vasculitis: 0%
Glomerular lesions: FSGS in 3 biopsies
Other: focal cortical atrophy, tubular atrophy
Arteriosclerosis (From Nochy, 1999)
Ischemic glomeruli (From Nochy, 1999)
Cystic formation of glomeruli (From Nochy, Fig 3)
Focal cortical atrophy(From Nochy, 1999)
Thrombotic microangiopathy (From Nochy, 1999)
Ultrastructural glomerular changes in APS:Griffiths, 2000
• 8 patients with primary APS
• 4 men and 4 women aged 31–69 years
• Renal presentation ranged from asymptomatic proteinuria to acute renal failure.
• All patients had some proteinuria, 0.2 g/day to 4.8 g/day.
• 1 patient had microscopic haematuria
• 1 patient went into acute renal failure during clinical work-up
• All patients underwent renal biopsy, and all had vascular lesions characteristic of APS
In some glomeruli, simple ischaemic collapse and basement membrane wrinkling occur, presumably due to occlusion of a more proximal vessel.
Griffiths M et al. QJM 2000;93:457-467
Multiple complex basement membrane contours.
Griffiths M et al. QJM 2000;93:457-467
At higher power the basement membranes have double contours, the outer basement membrane being longer and slightly wrinkled (arrow).
Griffiths M et al. QJM 2000;93:457-467
EM: wrinkling of BM, interposition with new subendothelial basement membrane
Griffiths M et al. QJM 2000;93:457-467
Ultrastructural glomerular changes in APS:Griffiths, 2000
• Reduplication of the GBM, sharing features with other causes of glomerular endothelial injury: HUS and transplant GP.
• Most likely represents recanalization of previously occluded and collapsed glomerular capillaries. Presence of multiple GBM layers explained by recurrent episodes of thrombosis.
• No evidence immune complex deposits in primary APS.
• Glomerular pathology does not correlate with level of proteinuria; severity of the vascular lesions correlates with renal function.
Renal involvement in APS: Histopathology
Vascular lesions:
Vascular lesions consistent with APS
Thrombotic microangiopathy
Glomerular lesions:
Glomerular lesions related to vasculopathy in APS
Variety of glomerulopathies/glomerulonephritides:Membranous nephropathy MPGN
Minimal change disease pauci-immune crescentic GN
FSGS
The expanding spectrum: renal disease associated with APS
• Fakhouri et al, 2003:
• Previous reports focused mainly on vascular lesions in APS, i.e.: microthrombi and vessel nephropathy
• In this study, 9 cases with glomerulonephritis and APS are reported
• Period: 1980 – 2002
• 29 biopsies of patients with primary APS• 20 cases with APS nephropathy
• 9 cases with glomerulonephritis and APS
The expanding spectrum: renal disease associated with APS,Fakhouri et al, 2003
9 cases with glomerulonephritis and APS:
• 3: membranous nephropathy
• 3: minimal change diseases/FSGS
• 2: mesangial C3 nephropathy
• 1: pauci-immune crescentic glomerulonephritis
6 cases had vascular lesions characteristic of APS:
TMA, intimal fibrocellular hyperplasia, focal cortical atrophy
• All cases had proteinuria, nephrotic syndrome in 4
• No anti-DNA antibodies (no lupus nephritis)
The expanding spectrum: renal disease associated with APS
Are these glomerulopathies occurring concomitantly with APS or are they linked to this syndrome?
Transfer of peripheral blood lymphocytes of patient with APS into SCID mouse
Production of APA
membranous nephropathy
Levy et al: Membranous nephropathy in primary antiphospholipid syndrome: description of a case and induction of renal injury in SCID mice (1996)
Classification of lupus nephritis and APA
SLE, anti-phospholipid antibodies, TMA
TMA in lupus nephritis became a hallmark for the presence of antiphospholipid antibodies
TMA can occur in any class of lupus nephritis
TMA in lupus nephritis should not be confused with intracapillary coagula of immunoglobulines
TMA in lupus nephritis is associated with ESRD
The incidence of TMA in patients with SLE and APA is much lower than in PAPS
Pseudo-thrombi and real thrombi in lupus nephritis
Pseudothrombi are vast subendothelial deposits: PAS positive
Real thrombi are PAS-negative; positive in PTAH-staining
APS-nephropathy in combination with lupus nephritis
• Daugas, 2002; based on 114 renal biopsies with lupus nephritis:
• APSN is found in SLE and is independent of the class of LN• 32% of biopsies showed histological signs of APSN
• Patients with APSN were significantly more hypertensive
• Patients with APSN had higher serum creatinine levels
• Prognosis is worse in cases of APSN superadded to lupus nephritis classification for lupus nephritis
• …………………….
• Both microthrombi and vascular lesions should be histological alarm signals for APA
• Silvarino, 2011; based on 79 renal biopsies:
• APSN was found in 9 biopsies (11%)
• Group 1: LN without APSN
• Group 2: LN with APA but without APSN
• Group 3: LN with APA and with APSN
• No significant differences in remission or renal damage
• However, 2 patients from Group 3 required renal transplantation; 1 patient from Group 2 died of CAPS
APS-nephropathy in combination with lupus nephritis
Lessons learned
• The pathologist should be conspicuous of microthrombi and vascular lesions in the renal biopsy, and suggest the possibility of anti-phospholipid antibodies, in particular in patients with established lupus nephritis, but also in other glomerulonephritides
• The clinician should be aware of the difficulties in determining the presence of anti-phospholipid antibodies, of the difficulties in managing patients with APA, and the possibility of their adverse effects on clinical outcome