9 Kidney Disease in Antiphospholipid Syndrome Mary-Carmen Amigo and Romeo García-Torres

Even though the kidney is a major target organ in antiphospholipid syndrome (APS), until recently the renal manifestations associated with antiphospholipid antibodies (aPL) have received scarce attention. This can be explained because APS was first described in patients with systemic lupus erythematosus (SLE) and such research studies were focused on the immune-complex–mediated glomerulonephritis rather than renal vascular lesions that could be secondary. In addition, because of the frequent occurrence of thrombocytopenia and systemic hypertension, renal biopsy in APS patients would often be considered a high-risk procedure to be discouraged if not formally contraindicated [1]. Nevertheless, knowledge about renal vascular involvement in APS has slowly acquired a critical mass and it is now clear that large vessels, both arterial and venous, as well as the intraparenchymatous arteries and microvasculature may all be affected, with the clinical consequences shown in Table 9.1.

Renal Artery Lesions Large- and medium-size vessel occlusion has been associated with APS in the context of SLE as well as in its primary form [2, 3].

Table 9.1. Renal vascular involvement in antiphospholipid syndrome. Vascular lesion

Clinical consequences

Renal artery lesions: (trunk or main branches) Thrombosis/occlusion/stenosis?

Renovascular hypertension (severe) Renal infarcts (silent, painful, hematuria)

Glomerular capillary thrombosis leading to glomerular sclerosis (studied mainly in SLE)

Increased likelihood of renal insufficiency

Renal thrombotic microangiopathy (glomerular capillaries, afferent arterioles, and interlobular arteries) with/without focal or difuse necrosis (cortical necrosis)

Systemic hypertension (usually severe) Renal failure (mild to end stage), Proteinuria (mild to nephrotic range) Cortical atrophy

Renal vein thrombosis (unilateral or bilateral)

Renal failure (if bilateral compromise)

99

100

Hughes Syndrome

Renal artery occlusion/stenosis has been reported in patients with positive assays for aPL. Some of these patients had autoimmune rheumatic conditions, mainly SLE, while others had the primary APS (PAPS). An early observation by Ostuni et al [4] described a 13 year-old girl with SLE and severe systemic hypertension. Bilateral renal artery stenosis/thrombosis resulted in a poorly perfused kidney and cortical irregularities were present in the contralateral kidney. Hernández et al [5] reported on a young woman with sudden, severe hypertension and a renal infarction who, 14 years later, developed SLE. Asherson et al [6] described a young man with PAPS, arterial hypertension, and a right renal artery stenosis with renal infarction which was thought to be caused by thrombotic occlusion. Ames et al [7] reported an instance of bilateral renal artery occlusion in a patient with PAPS and an unclear systemic disease. Of major interest is a paper by Rossi et al [8] reporting 2 cases of renovascular hypertension with renal artery stenosis and suggesting a pathogenetic link between renal artery stenosis, thrombosis, fibromuscular dysplasia, and aPL. Similar considerations were independently made by Mandreoli and coworkers [9, 10]. Particularly interesting is a report by Poux et al [11] on an athletic 35- year-old man with PAPS who suddenly developed arterial hypertension and a left renal infarction. Angiographic studies revealed complete thrombosis of the aorta below the renal arteries plus an extensive colateral circulation arising from the superior mesenteric artery. More recently, several cases of renal artery stenosis, mainly in young patients with PAPS, have been reported. These consistent findings confirm that this syndrome may be a significant cause of renal artery stenosis [12–14]. In the presence of aPL, renal infarctions result from partial or total, transient or permanent occlusion of renal arteries [4, 5, 8, 9, 15, 16]. Such occlusion may be caused by diverse mechanisms such as in situ thrombosis/stenosis of a renal artery or an embolic event originating on a verrucous cardiac valve. In still other cases the cause of a renal infarction was not found [17]. Clinically, severe systemic hypertension, pain in the renal area, hematuria, and renal failure are common forms of presentation of major vessel involvement in PAPS. As commented by Hughes et al [18], arterial hypertension may be labile in early disease. Occasionally, a silent infarct is fortuitously discovered on computed tomography (CT). It cannot be overemphasized that in cases of renal artery stenosis of unknown origin, APS must be excluded. Renal scintigraphy and selective renal angiography are useful procedures to confirm diagnosis and determine the extent of damage. Successful treatment with antihypertensive drugs [8, 15], aspirin [16], anticoagulant therapy [4, 7, 9, 15] as well as transluminal angioplasty [6, 12, 13] has been reported. Nephrectomy, with subsequent normalization of blood pressure and secondary aldosteronism, was performed in 1 patient because the kidney was seriously and irreversibly damaged [14]. However, adverse outcomes may occur [5]. The sooner an arterial lesion causing arterial hypertension is relieved, the likelier a successful outcome.

Glomerular Capillary Thrombosis Hyaline thrombi have been described in patients with active, usually proliferative lupus nephritis. The prevalence and significance of this finding have been carefully

Kidney Disease in Antiphospholipid Syndrome

101

studied by Kant et al [19] and Glueck et al [20]. They found an overall rate of capillary thrombosis of near 50% in cases of proliferative glomerulonephritis, including 78% in patients with detectable lupus anticoagulant (LA) and only 38% in those without. The presence of glomerular thrombi in the initial biopsy was a strong predictor of glomerular sclerosis. Other studies have not shown an association between aPL and prognosis in lupus nephritis [21–23]. However, Moroni et al recently documented the impact of aPL in 111 patients with lupus nephritis followed up for a mean of 173 ± 100 months. A strong association between aPL and the development of chronic renal insufficiency in the long term was found. With multivariate analysis, aPL positivity, high plasma creatinine level at presentation, and chronicity index were independent predictors of chronic renal function deterioration [24]. With these data, one should keep in mind that the detection of aPL in patients with lupus nephritis is useful not only to identify patients at risk for vascular and obstetric manifestations, but also for their potential deleterious impact on renal outcome.

Intra-renal Vascular Lesions Thrombotic Microangiopathy The association of the distinctive lesion known as thrombotic microangiopathy (TMA) with aPL was initially described in patients with SLE [25–27]. In another clinical setting, Kincaid-Smith and coworkers [28] showed acute or healed TMA in 22 biopsies obtained in 12 patients with LA and pregnancy-related renal failure. Subsequently, isolated cases of TMA in patients with PAPS were reported [29, 30]. In 1992, at a time in which some still doubted about the very existence of primary

Figure 9.1. Severe and advanced glomerular thrombotic microangiopathy. Capillary lumina are occluded by severe mesangiolysis and deposition of heterogeneous subendothelial material, leading to a segmental “double contour” aspect (PAS).

102

Hughes Syndrome

Figure 9.2. A small arteriole with a recent, almost occlusive, partially laminated thrombus. Some complete and fragmented white and red cells are seen (hematoxylin/eosin).

PAPS, we had the opportunity to study 5 patients who had renal disease and arterial hypertension among 20 consecutive patients with PAPS [31]. Mild renal failure was present in 3 patients while 2 had end-stage renal failure requiring hemodyalisis. Proteinuria in the mild-to-nephrotic range was also present. Biopsy findings in all 5

Figure 9.3. Chronic cortical lesions. There are obsolescent sclerotic glomeruli and a hypoperfused glomerulus with a wide Bowman´s space and retracted capillaries. On one of its sides there is a small arteriole with a recanalized thrombus and two lumina. On the other side there are two completely occluded arterioles showing thrombosis, recanalization, and refibrosis. A tortuous arteriole with slightly cellular subendothelial fibrosis is also seen (PAS).

Kidney Disease in Antiphospholipid Syndrome

103

patients were consistent with TMA . Some biopsies showed diffuse damage while others had only focal parenchymatous lesions. Microangiopathy involved both the vascular tree and the glomerular tufts (Fig. 9.1). Recent and recanalized thrombi were observed (Figs. 9.2 and 9.3), as if acute lesions were superimposed on the chronic, healed damage (Table 9.2). Ultra-estructural studies showed electron lucent subendothelial deposits and ischemic obsolescence of glomeruli in absence of histologic and immunohistochemical findings suggestive of SLE. We concluded that in PAPS, depending on the degree and extension of damage, patients could have isolated hypertension, severe proteinuria, and renal failure including cortical necrosis. In chronic cases, fibrosis and focal atrophy could be found as well as arterial and arteriolar fibromuscular hyperplasia [Figs. 9.4 and 9.5). Subsequent isolated cases or small series have confirmed our findings [32–34]. Recently, it has been emphasized that APS should be considered in the differential diagnosis of systemic hypertension and that APS-related TMA may cause isolated hypertension without significant renal impairment [35]. TMA is the characteristic histologic lesion of the microvasculature in PAPS-related nephropathy. A noninflammatory vasculopathy with or without thrombosis (the “APS vasculopathy”) is a common finding in larger vessels. Of course, TMA is not pathognomonic of PAPS, as there is a wide range of conditions that present the same histological appearance (Table 9.3). Nochy et al [36] have confirmed our initial observations on glomerular and interlobular arteriolar lesions, and, in addition, have emphasized the common presence of focal cortical atrophy (Fig. 9.6). Finally, other types of renal involvement, including membranous glomerulonephritis, IgA nephropathy, pauci-immune crescentic glomerulonephritis, glomerulonephritis with isolated C3 mesangial deposits, focal segmental glomeruTable 9.2. Primary antiphospholipid syndrome–associated nephropathy: main histologic features. Acute lesions

Chronic lesions

Glomerular Mesangial expansion Mesangiolysis Glomerular capillary colapse Basement membrane wrinkling “Double contours” with mesangial interposition Translucent subendothelial deposits Intracapillary thrombi Thrombotic/hemorrhagic infarction

Glomerular Basement membrane thickening Cellular vanishing Glomerular tuft retraction Bowman’s space widening Ischemic obsolescence Segmental or global glomerular sclerosis

Arterioles Recent occlusive thrombi Laminar thrombi Endothelial edema/degeneration Subendothelial mucoid edema Necrosis

Arterioles Mural organized thrombi Recanalizing occlusive thrombi Microaneurisms Plexiform lesions Subendothelial fibrosis Concentric and muscular hyperplasia Myofibroblastic proliferation Diffuse fibrosis

TMA with/without focal necrosis

Ischaemic atrophy

104

Hughes Syndrome

Figure 9.4. Typical histology of an interlobular arteriole which is almost occluded by a slightly cellular mucoid material. The lumen is distorted and the muscular media is partially destroyed and fibrotic. There is interstitial fibrosis with a moderate inflammatory infiltration. A dilated tubule containing hyaline material is seen (Masson).

Figure 9.5. Chronic stage of an intraparenchymatous renal artery. Slight medial hyperplasia, fractures of the internal elastica, severe subendothelial fibrosis, myofibroblastic proliferation, and a drastic reduction of the lumen (Masson).

losclerosis and, vasculitis, associated with aPL or with APS, but without SLE, have been published [37–39]. It is unclear, however, whether in addition to thrombosis, other mechanisms could also contribute to the pathogenesis of APS nephropathy. There is evidence that aCL recognize β2-glycoprotein I (β2-GPI) on the endothelial

Kidney Disease in Antiphospholipid Syndrome

105

Table 9.3. Some conditions that associate with TMA. Thrombotic thrombocytopenic purpura Haemolytic uraemic syndrome Post-partum renal failure Pre-eclampsia/eclampsia Scleroderma Malignant arterial hypertension Oral contraceptives Renal transplantation / allograft rejection Cyclosporine A toxicity Chemotherapy

Figure 9.6. Focal cortical atrophy. There are ischemic glomeruli, an arteriole with “onion skin” hyperplasia of the media, and a “pin point” lumen, generalized tubular atrophy with early dilation in one, and interstitial fibrosis (Masson).

cell membrane, leading to increased expression of adhesion molecules and increased adhesion of monocytes on endothelial cell surface [40]. These events could perhaps explain the inflammation found in some of these uncommon cases.

Cortical Renal Ischemia Occlusion of small isolated parenchymatous renal vessels gives rise to small foci of cortical necrosis. These are generally asymptomatic; however, if they are multiple or generalized they may lead to patchy or diffuse cortical necrosis as described in the catastrophic APS [41]. These cases feature oligo/anuria, severe hypertension, and frequently have a fatal outcome. Some patients eventually recover, leaving a variable degree of renal impairment expressing cortical ischemia. Isolated cases and series of patients with cortical renal ischemia and aPL have been published [17, 35, 42, 43]. One of the first reported cases [42] was a 27-year-old man with coronary occlusion, arterial hypertension, thrombophlebitis, atrial thrombus, and positive aPL. An abdominal CT

106

Hughes Syndrome

scan revealed cortex hypodensity in both kidneys. Renal biopsy showed diffuse interstitial fibrosis, mononuclear infiltration, sclerotic and ischemic glomeruli, and negative immunofluorescence studies. These findings suggested cortical sclerosis and atrophy as sequelae from old cortical necrosis. In this patient, aside from arterial hypertension, there were no additional clinical evidences of renal damage. Cacoub’s series of 5 cases [17] included patients with sudden presentation of malignant hypertension. While large renal vessels were patent on angiography, renal biopsy revealed glomerular ischemia, interstitial fibrosis, tubular atrophy, and vascular sclerosis with thrombosis. There was no vasculitis and immunofluorescence studies were negative. Four of these patients did well and 1 died, probably as a result of a catastrophic syndrome. Pérez et al [43] reported on a man with PAPS and multi-organ arterial and venous thrombosis, seemingly a catastrophic syndrome. This patient had a 2-cm renal cortical infarction and multiple petechiae in the renal cortex. At autopsy, an organizing interlobular vein thrombus plus microthrombi in the microvasculature of the medulla were found. This case illustrates medium- and small-vessel thrombosis affecting the intra- and extra-renal vasculature. From the above observations, it may be concluded that cortical renal ischemia (Fig. 9.6) is a well-defined clinico-pathologic entity in patients with APS. The lesion may recover ad integrum or it may leave a variable impairment of renal function. An additional presentation of renal cortical ischemia was described by Leaker et al [44]. This is an insidious, slowly progressive nephropathy that causes renal failure in the long term. Clinically, patients have arterial hypertension, mild proteinuria, and a slowly progressive renal failure. In a recent multicenter study, Nochy et al [36] reported 16 patients with PAPS followed for at least 5 years, all of whom had renal biopsy. In all patients there were small vessel vaso-occlussive lesions and focal cortical atrophy was present in 10.

Renal Vein Thrombosis The main renal vein, as well as minor veins, may thrombose in APS. Asherson [45] first described the association between aPL and renal vein thrombosis in 2 cases of SLE with proliferative nephritis and nephrotic syndrome. An interesting study by Glueck et al [20] demonstrated renal vein thrombosis in 3 of 18 SLE patients with LA, compared with none in the 59 LA-negative patients without. Liano et al [46] described a man with SLE, LA, and end-stage renal disease who received a renal transplant. Nineteen months after transplantation, thrombosis of the graft’s renal vein occurred and autopsy showed membranous glomerulonephritis. Isolated cases of renal vein thrombosis have been reported in patients with PAPS [47], including 1 case with bilateral renal vein thrombosis in the postpartum period [48].

End-stage Renal Disease (ESRD) A poorly studied issue is the occasional presence of aPL in patients with ESRD [49]. The information at hand about this interesting finding is incomplete and little more

Kidney Disease in Antiphospholipid Syndrome

107

can be said about it. Similar considerations apply to the high titers of aCL and positive LA found in patients undergoing hemodialysis, a setting in which vascular access thrombosis is very common [50]. Recently, in a study of 97 hemodialysis patients, Brunet et al [51] found a prevalence of 31% of aPL (LA in 16.5% and aCL in 15.5%). The presence of aPL was independent of age, time on dialysis, gender, type of dialytic membrane used, drugs used, or presence of hepatitis B or C. There was a higher prevalence of aPL when the cause of the ESRD could not be determined. Analyzing the association between vascular access thrombosis and aPL, they found a striking correlation with the presence of LA (62% vs. 26%; P = 0.01) but not with aCL.

Renal Transplantation Very few studies have addressed the impact of aPL on renal transplantation. Reports of aPL-related morbidity among SLE transplant patients are limited by the relatively small number of subjects available for study at any given center. In the UCSF study, 15.4% of allograft failures were attributed to aPL-associated events [52]. Radhakrishna et al [53] in a retrospective study of SLE, compared 8 patients with aCL to 5 patients without, transplanted during the same period. Thrombotic episodes occurred in 3 patients in the aCL-positive group but none in the aCL-negative group. Neither of the 2 groups differ in the number of rejection episodes, rate of graft loss, or renal function at follow up. The authors concluded that patients with SLE and aCL can be successfully transplanted. Findings have been quite different in PAPS. Mondragón-Ramírez et al [54] reported 2 cases of PAPS with renal TMA who underwent renal transplantation and in whom, despite intensive anticoagulant therapy, the disease relapsed in the graft. Massive thrombosis in the graft in 1 case [Figs. 9.7 and 9.8) and TMA in the other suggested recurrence of the disease. We postulated that the surgical procedure plus endothelial damage, a common feature of allograft rejection, may act synergistically in amplifying the hypercoagulable state. Both patients also had thrombosis in the vascular access used for hemodialysis as has been reported by others [49, 50]. In an interesting report by Knight et al [55], a woman with aCL lost a renal allograft in the immediate postoperative period due to renal artery thrombosis. Six months later she underwent successful re-transplantation under full anticoagulation despite the presence of postoperative bleeding. Vaidya et al [56] confirmed that patients with APS are at high risk for post-transplant renal thrombosis. Within a group of 78 patients who received renal transplant, 6 had APS. Each of these 6 patients thrombosed their renal allografts within a week of the transplant. In contrast, the remaining 72 patients were all doing well 1 year post-transplant. More recently, isolated cases as well as retrospective and prospective studies have addressed the impact of aPL on renal transplantation. In 1999, a retrospective study in 96 patients with ESRD quantified the negative impact of aPL on renal transplantation [57]. In another multicenter study, 502 ESRD patients awaiting renal transplantation were screened for APS. The potential risks associated with APS were assessed, and strategies for therapeutic intervention were reviewed. The conclusion of this study was that patients with APS are at high risk of

108

Hughes Syndrome

Figure 9.7. Fragment of the transplanted kidney in a female patient with PAPS. The whole vascular tree (from the intraparenchymatous vessels to the main intrarenal artery and vein) shows recent thrombotic occlusion (hematoxilin/eosin).

Figure 9.8. This micrograph belongs to the same kidney shown in Figure 7. There is generalized thrombosis of the microvasculature including glomerular capillaries, afferent arterioles, and interlobular arteries. Generalized necrosis without inflammatory cell infiltration is also observed (Masson).

post-transplant renal thrombosis and that anticoagulant therapy could prevent this complication [58]. Interestingly, the same group of investigators reported their experience with 9 APS renal-transplant patients. Seven patients were treated with coumadin, whereas 2 were treated with heparin. Of the 2 patients treated with

Kidney Disease in Antiphospholipid Syndrome

109

heparin, 1 had early allograft loss, whereas the other patient is doing well at 5 years post-transplant. Of the 7 patients treated with coumadin, 2 are doing well, 2 had early allograft loss, and the remaining 3 patients returned to dialysis after they were taken off the coumadin because of bleeding complications. The conclusions of this study are that anticoagulation therapy is beneficial to some but not all APS renaltransplant patients and, in addition, bleeding complications are a serious side effect in this setting [59]. With these data, one should question which patients with APS should be transplanted and which therapeutic intervention(s) could be used to avoid a catastrophic outcome.

Concluding Comments In agreement with Nochy et al [36], we believe the TMA to be the characteristic nephropathy of PAPS. The lesion may have an abrupt or an insidious onset and may vary in severity and exent. All vascular structures of the kidney may be affected including glomeruli, arterioles, and parenchymatous arteries. Acute lesions as they heal give way to reparative fibrosis and focal atrophy. They are worsened by recurrent acute damage. In other cases, the lesion is insidious and slowly progressive, causing similar focal reparative fibrosis and tissue atrophy, arterial hypertension, and in some instances ESRD. In patients with PAPS, renal involvement is probably underestimated. Hopefully, current knowledge of renal disease in APS will soon permeate all branches of internal medicine making possible an appropriate diagnosis.

References 1. Piette JC, Cacoub P, Wechsler B. Renal manifestations of the antiphospholipid syndrome. Semin Arthritis Rheum 1994;23:357–366. 2. Harris EN, Gharavi AE, Boey C, Mackworth-Young CG, Loizou Z, Hughes GR. Anticardiolipin antibodies: detection by radioimmunoassay and association with thrombosis in systemic lupus erythematosus. Lancet 1983;ii:1211–1214. 3. Alarcón-Segovia D, Cardiel MH, Reyes E. Antiphospholipid arterial vasculopathy. J Rheumatol 1989;16:762–767. 4. Ostuni PA, Lazzarin P, Pengo V, Ruffarti A, Schiavon F, Gambari P. Renal artey thrombosis and hypertension in a 13 year-old girl with antiphospholipid syndrome. Ann Rheum Dis 1990;49:184–187. 5. Hernández D, Domínguez ML, Díaz F, et al. Renal infarction in a severely hypertensive patient with lupus erythematosus and antiphospholipid antibodies. Nephron 1996;72:298–301. 6. Asherson RA, Noble GE, Hughes GRV. Hypertension, renal artery stenosis and “primary “antiphospholipid syndrome. J Rheumatol 1991;18:1413–1415. 7. Ames PRJ, Cianciaruso B, Vellizzi V, et al. Bilateral renal artery occlusion in a patient with primary antiphospholipid antibody syndrome: thrombosis, vasculitis or both? J Rheumatol 1992;19:1802–1806. 8. Rossi E, Sani C, Zini M, Casoli MC, Restori G. Anticardiolipin antibodies and renovascular hypertension. Ann Rheum Dis 1992;51:1180–1181. 9. Mandreoli M, Zuccala A, Zucchelli P. Fibromuscular dysplasia of the renal arteries associated with antiphospholipid auotantibodies: two case reports. Am J Kidney Dis 1992;20:500–503. 10. Mandreoli M, Zucchelli P. Renal vascular disease in patients with primary antiphospholipid antibodies. Nephrol Dial Transplant 1993;8:1277–1280. 11. Poux JM, Boudet R, Lacroix P, et al. Renal infarction and thrombosis of the infrarenal aorta in a 35 year-old man with primary antiphospholipid syndrome. Am J Kidney Dis 1996;27:721–725.

110

Hughes Syndrome

12. Godfrey T, Khamashta MA, Hughes GRV, Abbs I. Antiphospholipid syndrome and renal artery stenosis. Q J Med 2000;93:127–129. 13. Aizawa K, Nakamura T, Sumino H, et al. Renovascular hypertension observed in a patient with antiphospholipid-antibody syndrome. Jpn Circ J 2000;64:541–543. 14. Riccialdelli L, Arnaldi G, Giacchetti G, Pantanetti P, Mantero F. Hypertensin due to renal artery occlusion in a patient with antiphospholipid syndrome Am J Hypertens 2001;14:62–65. 15. Sonpal GM, Sharma A, Miller A.Primary antiphospholipid antibody syndrome, renal infarction and hypertension. J Rheumatol 1993;20:1221–1223. 16. Peribasekar S, Chawla K, Rosner F, Depestre M. Complete recovery from renal infarcts in a patient with mixed connective tissue disease. Am J Kidney Dis 1995;26:649–653. 17. Cacoub P, Wechsler B, Piette JC, et al. Malignant hypertension in antiphospholipid syndrome without overt lupus nephritis. Clin Exp Rheumatol 1993;11:479–485. 18. Hughes GRV, Harris EN, Gharavi AE. The anticardiolipin syndrome. J Rheumatol 1987;13:486–489. 19. Kant KS, PollaK VE, Weiss MA, Glueck HI, Miller MA, Hess EV. Glomerular thrombosis in systemic lupus erythematosus: Prevalence and significance. Medicine (Baltimore) 1981;60:71–86. 20. Glueck HI, Kant KS, Weiss MA, Pollak VE, Miller MA, Coots M. Thrombosis in systemic lupus erythematosus. Relation to the presence of circulating anticoagulants. Arch Intern Med 1985;145:1389–1395. 21. Leaker B, Cairley KF, Dowling J, Kincaid-Smith P. Lupus nephritis: clinical and pathological correlation. Q J Med 1987;238:163–179. 22. Cervera R, Khamashta MA, Font J, et al. Systemic lupus erythematosus: clinical and immunologic patterns of disease expression in a cohort of 1,000 patients. Medicine (Baltimore) 1993;72:113–124. 23. Miranda JM, García-Torres R, Jara LJ, Medina F, Cervera H, Fraga A. Renal biopsy in systemic lupus erythematosus: significance of glomerular thrombosis. Analysis of 108 cases. Lupus 1994;3:25–29. 24. Moroni G, Ventura D, Riva P, et al. Antiphospholipid antibodies are associated with an increased risk for chronic renal insufficiency in patients with lupus nephritis. Am J Kidney Dis 2004;43:28–36. 25. Bhathena DB, Sobel BJ, Migdal SD. Non-inflammatory renal microangiopathy of systemic lupus erythematosus. (“lupus vaculitis”). Am J Nephrol 1981;1:144–159. 26. Baldwin DS, Gluck MC, Lowenstein J, Gallo GR. Lupus nephritis: clinical course as related to morphological forms and their transitions. Am J Med 1997;62:12–30. 27. Kleinknecht D, Bobrie G, Meyer O, Noel LH, Callard P, Ramdane M. Recurrent thrombosis and renal vascular disease in patients with a lupus anticoagulant. Nephrol Dial Transplant 1989;4:854–858. 28. Kincaid-Smith P, Fairley KF, Kloss M. Lupus anticoagulant associated with renal thrombotic microangiopathy and pregnancy-related renal failure. Q J Med 1988;69:795–815. 29. Becquemont L, Thervet E, Rondeau E, Lacave R, Mougenot B, Sraer JD. Systemic and renal fibrinolytic activity in a patient with anticardiolipin syndrome and renal thrombotic microangiopathy. Am J Nephrol 1990;10:254–258. 30. D’Agati V, Kunis C, Williams G, Appel GB. Anti-cardiolipin antibody and renal disease: a report of three cases. J Am Soc Nephrol 1990;1:777–784. 31. Amigo MC, García-Torres R, Robles M, Bochiccio T, Reyes PA. Renal involvement in Primary Antiphospholipid Syndrome. J Rheumatol 1992;19:1181–1185. 32. Hughson MD, Nadasdy T, McCarty GA, Sholer C, Min K-W, Silva F. Renal thrombotic microangiopathy in patients with systemic lupus erythematosus and the antiphospholipid syndrome. Am J Kidney Dis 1992;20:150–158. 33. Lacueva J, Enríquez R, Cabezuelo JB, Arenas MD, Teruel A, González C. Acute renal failure as first clinical manifestation of the primary antiphospholipid syndrome. Nephron 1993;64:479–480. 34. Domrongkitchaiporn S, Cameron EC, Jetha N, Kassen BO, Sutton RAL. Renal microangiopathy in the primary antiphospholipid syndrome: a case report with literature review. Nephron 1994;68:128–132. 35. Karim MY, Alba P, Tungekar MF, et al. Hypertension as the presenting feature of the antiphospholipid syndrome. Lupus 2002;11:253–256. 36. Nochy D, Daugas E, Droz D, et al. The intrarenal vascular lesions associated with Primary Antiphospholipid Syndrome. J Am Soc Nephrol 1999;10:507–518. 37. Wilkowski M, Arroyo R, McCabe K. Glomerulonephritis in a patient with anticardiolipin antibody. Am J Kidney Dis 1990;15:184–186. 38. Almeshari K, Alfurayh O, Akhtar M. Primary antiphospholipid syndrome and self-limited renal vasculitis during pregnancy: case report and review of the literature. Am J Kidney Dis 1994;24:505–508. 39. Fakhouri F, Noel LH, Zuber J, et al. The expanding spectrum of renal diseases associated with antiphospholipid syndrome. Am J Kidney Dis 2003;41:1205–1211.

Kidney Disease in Antiphospholipid Syndrome

111

40. Branch DW, Rodgers GM. Induction of endothelial cell tissue factor activity by sera from patiens with antiphospholipid syndrome: a possible mechanism for thrombosis. Am J Obstet Gynecol 1993;168:206–210. 41. Asherson RA. The catastrophic antiphospholipid syndrome. J Rheumatol 1992;19:508–512. 42. Ramdane M, Gryman R, Bacques P, Callard P, Kleinknecht D. Ischémie rénale corticale, thrombose auriculaire droite et occlusion coronaire au cours d’un syndrome des anticorps antiphospholipides. Néphrologie 1989;10:189–193. 43. Pérez RE, McClendon JR, Lie JT. Primary antiphospholipid syndrome with multiorgan arterial and venous thromboses. J Rheumatol 1992;19:1289–1292. 44. Leaker B, Mc Gregor AO, Griffiths M, Snaiyh A, Neild GH, Isenber D. Insidious loss of renal function in patients with anticardiolipin antibodies and absence of overt nephritis. Br J Haematol 1991;30:422–425. 45. Asherson RA, Lanham JG, Hull RG, Boey ML, Gharavi AE, Hughes GR. Renal vein thrombosis in systemic lupus associated with the lupus anticoagulant. Clin Exp Rheumatol 1984;2:47–51. 46. Liano F, Mampaso F, García Martín F. Allograft membranous glomerulonephritis and renal vein thrombosis in a patient with a lupus anticoagulant factor. Nephrol Dial Transplant 1998;3:684–689. 47. Morgan RJ, Feneley CL. Renal vein thrombosis caused by primary antiphospholipid syndrome. Br J Urol 1994;74:807–808. 48. Asherson RA, Buchanan N, Baguley E, Hughes GRV. Postpartum bilateral renal vein thrombosis in the primary antiphospholipid syndrome. J Rheumatol 1993;20:874–876. 49. García-Martín F, De Arriba G, Carrascosa T, et al. Anticardiolipin antibodies and lupus anticoagulant in end stage renal disease. Nephrol Dial Transplant 1991;6:543–547. 50. Nied Prieto L, Suki NW. Frequent hemodyalisis graft thrombosis: association with antiphospholipid antibodies. Am J Kidney Dis 1994;23:587–590. 51. Brunet P, Aillaud MF, SanMarco M, et al. Antiphospholipids in hemodialysis patients: relationship between lupus anticoagulant and thrombosis. Kidney Int 1995;48:794–800. 52. Stone J, Amend W, Criswell L. Outcome of renal transplantation in SLE: 97 cyclosporine –era patients and matched controls. Arthritis Rheum 1997;27:17–26. 53. Radhakrishna J, Williams GS, Appel GB, Cohen DJ. Renal transplantation in anticardiolipin antibody-positive lupus erythematosus patients. Am J Kidney Dis 1994;23:286–289. 54. Mondragón-Ramírez G, Bochicchio T, García-Torres R, et al. Recurrent renal thrombotic angiopathy after kidney transplantation in two patients with primary antiphospholipid syndrome (PAPS). Clin Transplantation 1994;8:93–96. 55. Knight RJ, Schanzer H, Rand JH, Burrows L. Renal allograft thrombosis associated with the antiphospholipid antibody syndrome. Transplantation 1995;60:614–615. 56. Vaidya S, Wang CC, Gugliuzza C, Fish JC. Relative risk of post-transplant renal thrombosis in patients with antiphospholipid antibodies. Clin Transplant 1998;12:439–444. 57. Stone J, Amend W, Criswell L. Antiphospholipid antibody syndrome in renal transplantation: ocurrence of clinical events in 96 consecutive patients with systemic lupus erythematosus. Am J Kidney Dis 1999;34:1040–1047. 58. Vaidya S, Sellers R, Kimball P. Frequency, potential risk and therapeutic intervention in end-stage renal disease patients with antiphospholipid antibody syndrome: a multicenter study. Transplantation 2000;69:1348–1352. 59. Vaidya S, Gugliuzza K, Daller J. Efficacy of anticoagulation therapy in end-satge renal disease patients with antiphospholipid antibody syndrome. Transplantation 2004;77:1046–1049.