1. Renal involvement in anti-phospholipid syndrome Ingeborg 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. APS
Kidney involvement
SLE

5. 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

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

7. 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

8. 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

9. Asherson, 2005: Triggers for CAPS

10. 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

11. 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.

12. 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

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

14. 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

15. Nochy et al, JASN 1999

16. 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

17. 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: years All patients had renal symptoms: renal insuffciency (87%), proteinuria (75%), hematuria (56%)

18. 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

19. Arteriosclerosis (From Nochy, 1999)

20. Ischemic glomeruli (From Nochy, 1999)

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

22. Focal cortical atrophy(From Nochy, 1999)

23. Thrombotic microangiopathy (From Nochy, 1999)

24. 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

25. 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:

26. 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:

27. 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:

28. 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:

29. 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.

30. 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

31. 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

32. 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)

33. 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)

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

35. Classification of lupus nephritis and APA

36. 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

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

38. 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

39. 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

40. 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