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