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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

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Renal involvement in anti-phospholipid syndrome Ingeborg Bajema

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  1. Renal involvement in anti-phospholipid syndromeIngeborg Bajema

  2. 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)

  3. Testing for anti-phospholipid antibodies • 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

  4. 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

  5. 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

  6. Asherson, 2005: Triggers for CAPS

  7. 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

  8. Renal involvement in APS • Diverse clinical manifestations: Proteinuria Nephrotic syndrome Nephritic syndrome Acute renal failure Chronic renal insufficiency ESRD

  9. 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

  10. Large vessel involvement Renal artery stenosis: Renal infarction: Renal vein thrombosis: Hypertension Pain Nephrotic Syndrome

  11. 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

  12. Nochy et al, JASN 1999

  13. 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

  14. 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%)

  15. 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

  16. Arteriosclerosis (From Nochy, 1999)

  17. Ischemic glomeruli (From Nochy, 1999)

  18. Cystic formation of glomeruli (From Nochy, Fig 3)

  19. Focal cortical atrophy(From Nochy, 1999)

  20. Thrombotic microangiopathy (From Nochy, 1999)

  21. 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

  22. 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

  23. Multiple complex basement membrane contours. Griffiths M et al. QJM 2000;93:457-467

  24. 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

  25. EM: wrinkling of BM, interposition with new subendothelial basement membrane Griffiths M et al. QJM 2000;93:457-467

  26. 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.

  27. 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

  28. 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

  29. 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)

  30. 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)

  31. Classification of lupus nephritis and APA

  32. 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

  33. Pseudo-thrombi and real thrombi in lupus nephritis Pseudothrombi are vast subendothelial deposits: PAS positive Real thrombi are PAS-negative; positive in PTAH-staining

  34. 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

  35. APS-nephropathy in combination with lupus nephritis • 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

  36. 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

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