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)

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

APS Kidney involvement SLE

APS Kidney involved SLE Renal involvement in APS: as low as 2.7 % of cases to as high as 78% in catastrophic APS. Underestimation in non-catastrophic situations

Which should warn us for the following situation APS Kidney involved Another disease SLE Which should warn us for the following situation

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 Despite aggressive treatment with plasmaferesis

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 Going through the case reports and group studies, diverse clinical manifestations are noticed in patients with renal involvement and APA. The clinicopathological situation is a bit like diabetes: a biopsy will not always be taken – and most likely, biopsy findings may be biased towards those patients in whom another glomerular disease is expected than either APS or lupus nephritis.

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

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

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. In some glomeruli, simple ischaemic collapse and basement membrane wrinkling occur, presumably due to occlusion of a more proximal vessel. Patient 1. Hexamine silver×400. Griffiths M et al. QJM 2000;93:457-467

Multiple complex basement membrane contours. In this glomerulus there are multiple complex basement membrane contours. Patient 2. Hexamine silver×400. 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). At higher power the basement membranes have double contours, the outer basement membrane being longer and slightly wrinkled (arrow). Hexamine silver×1000. Griffiths M et al. QJM 2000;93:457-467

EM: wrinkling of BM, interposition with new subendothelial basement membrane Electron micrograph. A capillary loop shows pronounced wrinkling of the basement membrane. Where interposition occurs there is an apparently ‘new’ subendothelial basement membrane through which the interposed cell contacts the endothelial cell (arrow).×5200. 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)

Which should warn us for the following situation APS Kidney involved Another disease SLE Which should warn us for the following situation

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

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

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