Is It Possible to Diagnose Primary Anti-phospholipid Syndrome (PAPS) on the Basis of Renal Thrombotic Microangiopathy (PAPS Nephropathy) in the Absence of Other Thrombotic Process?

Abstract

The kidneys are a major target of PAPS. The histologic lesions of PAPS nephropathy are vascular; among them thrombotic microangiopathy (TMA) is the most characteristic. It is still not clear in the literature whether the nephropathy can be the unique manifestation of PAPS in the absence of other thrombotic processes; that is: do the renal microthrombotic lesions allow to make the diagnosis of PAPS in presence of anti-phospholipid antibodies (APA)? With this purpose we present three clinical cases. The first patient had severe hypertension C4 hypocomplementemia, thrombocytopenia, and mitralic valve insufficiency. LAC and anti-cardiolipin antibodies at high titre were positive. The histologic picture was characterized by basement membrane reduplication and arteriolar mucoid degeneration, which are features of early phase of TMA. The second patient had severe hypertension. The detection of anti-cardiolipin antibodies was performed several times and resulted positive three times, four months after the diagnosis as well. The renal histologic features were consistent with late lesions of TMA. The third patient had severe hypertension, rapidly progressive renal failure, tricuspidal valve insufficiency and two positive anti-phospholipid antibodies determinations three weeks apart (in two occasions anti-cardiolipin and in one occasion LAC as well were found). The renal lesions were characteristic for TMA. In conclusion we think that patients with TMA and anti- phospholipid antibodies can be considered affected by PAPS, as the thrombotic process is represented by thrombosis in preglomerular arterioles, which leads to TMA.

• Anti-phospholipid antibody syndrome
• Hypertension
• Nephro-pathy
• Renal failure
• Thrombotic microangiopathy

Introduction

The primary anti-phospholipid syndrome (PAPS) is characterized by recurrent fetal loss, venous, or arterial thrombosis without connective tissue disease.[[1]]

Renal involvement in the course of PAPS has been described in previous years.[[2]], [[3]], [[4]], [[5]], [[6]], [[7]] It has now been recognized that kidney is a main target of PAPS.[[8]] In 1999, Nochy et al.[[9]] has systematically reviewed the histological lesions that can be found in the course of PAPS with renal involvement. Renal lesions are prevalently vascular; among them thrombotic microangiopathy, also reported by other Authors,[[8]], [[10]] recurs with a frequency of 31%.

It remains to be stated whether renal thrombotic microangiopathy as unique thrombotic process detected allows the diagnosis of PAPS when circulating antiphospholipid antibodies (APA) are found.

With this purpose we present three patients with APA positivity, severe hypertension, and renal failure due to thrombotic microangioangiopathy without other thrombotic manifestations, where the diagnosis of PAPS could be made.

Patients

Patient 1

A 43 year-old woman presented to the Emergency Unit because of dyspnea. Severe hypertension (Blood Pressure—BP—210/140 mm Hg) was discovered together with fluid overload.

In the Emergency Unit laboratory examinations showed: hemoglobin: 10.6 g/dL, platelets 95,000/mm³, Serum Creatinine (SCr) 2 mg/dL, Urea 78 mg/dL, γGT 165 U/mL, AST 52 U/mL, ALT 74 U/mL, LDH 675 U/L, partial thromboplastin time 48 s, prothrombin time 94%, proteinuria 0.3 g/L.

Chest X-ray showed interstitial lung edema and increase in cardiac size. Ultrasound examination of the abdomen showed normal liver and spleen; the kidneys had normal size; the cortex was hyperechogenic.

In the Nephrology Unit, SCr was 2.4 mg/dL, proteinuria 0.46 g/24 h, 5 leukocytes/hmf in the urinary sediment, C4 < 10 mg/dL. ANA, C3, anti-DNA antibodies, antiENA, cryoglobulins, Rheuma test, CRP, HCV, VDRL, schistocytes were normal or negative.

Urinary catecholamines and vanillylmandelic acid were in normal range. The dosage of abused drug metabolites was negative.

Anti-cardiolipin antibodies (ACA) (IgG 58 GPL/mL, IgM negative) and lupus anticoagulant (LAC) (aPTT diluted test—in house method—, dilute Russel viper venom time) were found.

Echodoppler of renal arteries showed no signs of stenosis and high intrarenal resistances. Echocardiography showed mitral insufficiency, severe hypertrophy of the left ventricular wall, ejection fraction 46%. Renal scintigraphy with 99 mTcDMSA did not show images suspected for renal infarctions.

Renal biopsy showed ischemic glomerular damage with basement membrane reduplication and arteriolar mucoid degeneration.

The patient was given ticlopidine 250 mg/day, enalapril 20 mg/day, doxazosin 8 mg/day, furosemide 250 mg/day, atenolol 100 mg/day, minoxidil 2.5 mg/day, which she did not assume. Thirty-three months later end-stage renal failure was detected.

Patient 2

A 41 year-old man was found to be hypertensive (BP 210/150 mmg). During hospitalization in another town, laboratory examinations revealed: SCr 5.4 mg/dL, serum K 3.4 mEq/L, platelets 116,000/mm³, and proteinuria 3 g/24 h.

Kidneys were of normal size at echography; echocardiography showed severe hypertrophy of left ventricular wall; funduscopic examination revealed Keith-Wegener stage IV hypertensive retinopathy; renal arteriography did not show signs of stenosis. Plasma renin was high (PRA I 23 ng/mL/h, PRA II 30 ng/24 h; urinary aldosterone 47 pg/mL).

The patient was sent to our Nephrology Unit, where laboratory examinations showed: SCr 3.7 mg/dL, rare red blood cells in the urinary sediment, proteinuria 1.7 g/24 h, platelets 119,000/mm³, Hb 11 g/dL, prothrombin time 96%, partial thromboplastin time 39′′; normal liver enzymes, thyroid hormones, urinary catecholamines.

Rheuma test, CRP, ANCA, schistocytes, ANA, anti-DNA antibodies, C3, C4, cryoglobulins, LDH were negative or normal.

ACA were detected (IgG 33 GPL/mL, IgM negative); LAC (aPTT diluted test—in house method—, dilute Russel viper venom time) was negative.

Renal biopsy showed ischemic glomerular lesions with global glomerular sclerosis (25%), or diffuse collapse of the glomerular basement membranes. The interlobular arteries were thickened by an intense myofibroblastic cellular proliferation with “onionskin” pattern and preglomerular arteries occluded by organizing thrombi.

Ticlopidine 250 mg/day, losartan 50 mg/day, metoprolol 200 mg/day, doxazosin 4 mg/day, amlodipine 10 mg/day, minoxidil 2.5 mg/day were given. Renal function initially improved (SCr 2.4 mg/dL), then worsened again (SCr 5.3 mg/dL after three years).

During the follow-up, ACA persisted positive at low titre (IgG 21, IgM 22 GPL/mL) and LAC became positive three months later.

Patient 3

A 40 year-old man complained of headache and leg edema. Two months before he presented hematuria and emoftoe. Severe hypertension (BP 210/150 mm Hg) and renal failure (SCr 3.2 mg/dL) were found and he was hospitalized in Nephrology. At admission in our unit SCr had increased (8.7 mg/dL); proteinuria was 1.7 g/day. Other laboratory examinations were: total proteins 4.9 g/dL, LDH 1059 U/L, AST 24 U/L, ALT 31 U/L, gamma GT 102 U/Lm, Hb 9.1 g/dL, platelets 152,000/mm³, prothrombin time 98%, partial thromboplastin time 44′′.

Cryoglobulins, HCV, ANA, anti-DNA antibodies, C3, C4, ANCA, anti-glomerular basement membrane antibodies were negative or normal.

Anti-cardiolipin antibodies (IgM 15 GPL/mL) and LAC (aPTT diluted test—in house method—, dilute Russel viper venom time) were positive. ACAIgG were negative.

Funduscopic examination revealed Keith-Wegener stage IV hypertensive retinopathy. Ultrasound examination showed kidneys of small size (9.6 cm right, 10 cm left), hyperechogenic cortex. Echocardiography: ejection fraction 58%, left ventricular wall hypertrophy, slight tricuspidal insufficiency. Angio MRI showed normal renal and splenic arteries and aorta.

Renal biopsy evidenced global glomerular sclerosis (40%), collapse or reduplication of glomerular basement membranes, fibrous intimal hyperplasia with myofibroblastic proliferation or organizing thrombi of interlobular and preglomerular arterioles. Mucoid degeneration is occasionally present in small arteries.

The patient was given prednisone (0.5 mg/kg/day), warfarin, ramipril 10 mg/day, amlodipine 10 mg/day, furosemide 250 mg/day, and doxazosin 4 mg/day.

Six months later SCr was 2.2 mg/dL. Renal function worsened but then remained stable (SCr 4 mg/dL) in a follow-up of one year and a half. During the follow-up ACAIgM was confirmed positive at low titre (19 GPL/mL) three weeks later.

Discussion

Renal involvement in the course of PAPS is still relatively unrecognized and underestimated, even though renal failure may represent an important feature of the syndrome.[[1]], [[2]], [[3]], [[9]], [[10]] Only recently the kidney has emerged as a main target of PAPS.[[8]] Renal histological lesions show a vascular damage characterized by thrombotic microangiopathy (TMA) and configure the PAPS-associated nephropathy.[[9]]

However, it is not clear in the literature whether this nephropathy may allow, in the absence of other thrombotic lesions, to set a diagnosis of PAPS.

The criteria for PAPS diagnosis have been settled in the workshop held in 1999.[[11]] The criteria include one or more thrombotic events or recurrent abortions in the presence of the positivity for anti-phospholipid antibodies on two or more occasions at least six weeks apart. The thrombotic events can be arterial, venous, or occurring in small vessels in any tissue or organ.[[11]]

The renal lesions occurring in the kidney in course of PAPS have been described by Nochy et al.[[9]] She studied 16 patients with previously diagnosed PAPS and she found: cortical atrophy in 62% of cases, arteriosclerosis (75%), fibrous intimal hyperplasia (75%), arterial and arteriolar fibrous and fibrocellular occlusions (68%), TMA with fibrin thrombi (31%). These lesions are characteristic but not specific for PAPS, as they can be found in other vascular nephropathies. In particular TMA, which defines hemolytic-uremic syndrome and thrombotic thrombocytopenic purpura, can be present in other diseases, such as malignant hypertension, scleroderma, eclampsia, and Systemic Lupus Erythematosus.

The problems that we would like to underline are: (1) do these patients have lesions due to PAPS or to malignant hypertension and why, in the latter case, they present a positivity for anti-phospholipid antibodies? (2) can diagnosis of PAPS be made in patients with anti-phospholipid antibodies and renal damage leading to early or late lesions of TMA, or other thrombotic processes are necessary for fulfilling the diagnostic criteria?[[11]]

As regards the first problem, the vascular lesions via stimulation of the renin-angiotensin-aldosterone system can cause hypertension, but it is also plausible that the lesions can be secondary to hypertension as during the course of nephroangiosclerosis. In this regard, Nochy et al.[[9]] states that “the severity of the vascular lesions in five patients who were normotensive or mildly hypertensive would seem to favor the first hypothesis.” Moreover the thickened arterial intima in PAPS tends to be cellular, in contrast to the lesions of nephroangiosclerosis, and there tends to be less arterial medial fibrosis.[[9]] These considerations would suggest that it seems more reasonable that hypertension is secondary to a renal damage caused by the syndrome.

Moreover, in favor of the hypothesis of damage due to PAPS, in our patients a secondary cause of hypertension was not evident and the persistent positivity for these antibodies strengthen their possible pathogenetic role.

In the alternative hypothesis that the renal lesions are secondary to hypertension, future studies should investigate the mechanisms leading to the formation of APA, in the hypothesis, for instance, that they represent an epiphenomenon of the endothelial damage.

As regards the second problem, we would like to do some considerations.

Our first patient had several clinical aspects suggestive for PAPS: she had C4 hypocomplementemia, thrombocytopenia, and mitralic valve insufficiency. LAC and ACA were positive, and ACA was at high titre. The importance of high titer of ACA, >40 GPL, for their clinical significance has been stressed by Andreassi et al.[[12]] in an “in vitro” study. The histologic picture was characterized by basement membrane reduplication and arteriolar mucoid degeneration, which are features of early phase of TMA.

The second patient had a two-month history of known severe hypertension; he had been submitted to renal angiography, which did not show a renal artery stenosis. The detection of anti-cardiolipin antibodies was performed several times and resulted positive three times, four months after the diagnosis as well. Moreover he also presented intermittent thrombocytopenia. The renal histologic features were consistent with late lesions of TMA.

The third patient had rapidly progressive renal failure, tricuspidal valve insufficiency and two positive anti-phospholipid antibodies determinations three weeks apart (in two occasions anti-cardiolipin and in one occasion LAC as well were found). The renal lesions were characteristic for TMA.

Hence, all these patients presented features compatible with PAPS, in particular TMA, and multiple determinations of anti-phospholipid antibodies in a clinical context of renal failure and severe hypertension, with no evident causes of secondary hypertension.

In conclusion, like other Authors,[[6]] we propose that patients with TMA and anti-phospholipid antibodies may be considered affected by PAPS, because the consensus conference criteria of 1999[[11]] are fulfilled in that the thrombotic process is represented by thrombosis in preglomerular arterioles, which leads to TMA.

The literature reports no definite indications about treatment of kidney disease in course of PAPS.[[2]], [[3]], [[4]], [[5]] The treatment that we gave to our patients was meant to control the renin-angiotensin system activation. In one case we also gave anticoagulant drugs and this patient showed a stabilization of his renal damage in a follow-up of one year and a half. Future studies are needed to understand if TMA can represent the indication for giving an anticoagulant treatment as in other thrombotic processes and which is the best therapeutical approach for patients with PAPS nephropathy.

In conclusion, our patients had features of TMA with severe hypertension, renal failure, and positive anti-phospholipid antibodies determination. We propose that renal microthrombotic lesions may be the thrombotic expression that allows diagnosing PAPS.