Renal artery stenosis in hypertensive patients with antiphospholipid (Hughes) syndrome: outcome following anticoagulation

Rheumatology 25;44:372 377 Advance Access publication 3 November 24 Concise Report Renal artery stenosis in hypertensive patients with antiphospholipid (Hughes) syndrome: outcome following anticoagulation S. R. Sangle, D. P. D Cruz, I. C. Abbs, M. A. Khamashta and G. R. V. Hughes doi:1.193/rheumatolgy/keh49 Objective. We have demonstrated a point prevalence of 26% renal artery stenosis in patients with antiphospholipid syndrome (APS) and uncontrolled hypertension. We describe the effect of anticoagulation on blood pressure control and renal function. Methods. We studied 23 patients retrospectively with renal artery stenosis (RAS). Fourteen received oral anticoagulation for more than 1 yr (target International Normalized Ratio () of 3. 4.5). Five patients had primary APS. Patients were divided into two groups based on their (<3. and 3.). Nine patients had repeat magnetic resonance angiography (MRA) or an angiogram of the renal arteries after 2 yr. Results. Only 8/14 patients managed to maintain their 3. (median 3.1, range 2.8 3.7) while six had a <3. (median 1.9, range 1.2 2.4). Patients with a median <3. had poorly controlled blood pressure and there was significant deterioration in mean serum creatinine values (Wilcoxon s test, P<.3). Nine patients underwent follow-up renal artery imaging. Three of nine patients with an <3. (median 1.9) had re-stenosis and a fourth developed bilateral renal artery stenosis. Five patients with 3. (median 3.1) did not show re-stenosis of the renal arteries; their renal function was stable and blood pressure was well controlled. One other patient with secondary APS (mixed connective tissue disorder) with >3. showed recanalization of the stenosed renal artery. Conclusion. Anticoagulation with maintained 3. helped to control the blood pressure and prevent the progression of renal disease. KEY WORDS: Antiphospholipid syndrome, Antiphospholipid antibodies, Anticoagulation, Renal artery stenosis. Since the advent of magnetic resonance imaging, the number of patients with documented renovascular disease has increased. The majority of these patients (9%) has atherosclerotic renal arterial disease, the rest having fibromuscular dysplasia [1, 2]. We have recently found renovascular disease to be more prevalent in hypertensive patients with antiphospholipid syndrome (APS) [3]. APS is characterized by arterial and venous thrombosis and pregnancy-related morbidity [4]. Hypertension is a recognized feature seen in relatively young patients with APS. We describe 23 patients with renal artery stenosis and hypertension in patients with APS and the effect of anticoagulation on renal function and blood pressure control in 14 of these patients. Patients and methods We investigated 91 APS patients with poorly controlled hypertension with magnetic resonance angiography (MRA) and/or arteriography. Twenty-three patients (26%) had renal artery stenosis in this cohort [3]. Twenty-one fulfilled the Sapporo criteria for APS and two had only positive antiphospholipid antibodies [5]. Five patients had primary APS, 14 had secondary APS [12 systemic lupus erythematosus (SLE), one mixed connective tissue disorder (MCTD) with predominant scleroderma and one Wegener s granulomatosis], and two patients with SLE had persistently positive antiphospholipid antibodies. All SLE patients fulfilled the ACR classification criteria [6]. Mean age of the patients was 46 (range 22 61) yr and all were Caucasian. Five patients received aspirin alone, as anticoagulation was contraindicated or not justified, or the patients refused to take warfarin. Five patients had primary APS. All the patients had their antihypertensive drugs and immunosuppressive therapy (in secondary APS) documented. Fourteen patients had received warfarin for at least 1 yr with a target International Normalized Ratio () of 3. 4.5 and form the basis for this report (Table 1). We studied the outcome of anticoagulation in these patients retrospectively. All patients received antihypertensive drugs so as to achieve a target blood pressure of 12/8 mmhg. Twelve of these had previous thrombotic episodes. During the 1 yr period, blood pressure was recorded by the general practitioner, at their clinic visits, and during the patients home monitoring (whenever possible). All patients had their monitored at the anticoagulation clinic and data were collected from anticoagulation books. Drug compliance was ascertained by direct questioning of the patients on clinic visits and correlation with the data and communication with their general practitioner. A follow-up MRA was performed in nine of the 14 patients, who were receiving warfarin, after 2 yr, and five had required angioplasty after the initial St Thomas Hospital, Lupus Research Unit, London, UK. Submitted 14 January 24; revised version accepted 19 October 24. Correspondence to: S. R. Sangle. E-mail: shirish.sangle@gstt.sthames.nhs.uk 372 Rheumatology Vol. 44 No. 3 ß British Society for Rheumatology 24; all rights reserved

Renal artery stenosis in hypertensive patients 373 imaging. One patient with MCTD and APS was investigated after 18 months for sudden deterioration in renal function and hypertensive crisis. Serial serum creatinine and, whenever possible, EDTA glomerular filtration rate (GFR) estimation was used to measure the renal parameters. TABLE 1. APS patients with renal artery stenosis on warfarin Patients (n ¼ 14) Patients with <3. (n ¼ 6) (median 1.9) A B 25 2 15 1 5 18 16 14 12 1 8 6 4 2 Patients with 3. (n ¼ 8) (median 3.1) Primary APS 3 2 Secondary APS 3 6 Male 1 Female 5 8 Origin All Caucasian All Caucasian Lupus nephritis 3 5 (2 with TMA*) (3 with TMA*) TMA* 2 3 Mycophenolate mofetil 2 3 Azathioprine 1 2 ACE inhibitors None 3 *TMA, thrombotic microangiopathy. St Thomas Research Ethics Committee approval was given for this study. Informed consent of the patients was not sought. Results Eight of the 14 patients managed to maintain their 3. (median 3.1, range 2.8 3.7), six consistently failed to maintain the target 3. 4.5 and their was <3. (median 1.9, range 1.2 2.4). All patients with an inadequate (<3.) had poorly controlled BP (Fig. 1A) and there was significant deterioration in median serum creatinine values (Wilcoxon test, P <.4) (Table 2). Of the nine patients who had repeat MRA, three with <3. (median 1.9) developed re-stenosis (after angioplasty) of the renal arteries and a fourth developed bilateral renal artery stenosis (Figs 2A, B and 3). Five patients with 3. (median 3.1) did not show re-stenosis of the renal arteries; their renal function was stable and blood pressure was well controlled (Fig. 1B) One patient with a median of 3.4 did not need angioplasty and on warfarin alone her blood pressure control was excellent and she needed fewer hypotensive drugs. Her serum creatinine returned to normal (135!12 mol/1.5! 1.1 mg/dl). One other patient (MCTD and APS) was readmitted for sudden deterioration in renal function [serum creatinine 1 2 3 4 5 6 Patients 1 2 3 4 5 6 7 8 Patients 4 3 2 1 Systolic Diastolic FIG. 1. (A) Graph showing median blood pressures over a period of 1 yr in patients with <3. (median 1.9). (B) Graph showing median blood pressure over a period of 1 yr in patients with >3. (median 3.1). 4 3 2 1 Systolic Diastolic

374 S. R. Sangle et al. TABLE 2. The effect of anticoagulation on hypertension and renal parameters Number of anticoagulated patients (n ¼ 14) Target 3. 4.5 (n ¼ 14) Change in median serum creatinine (mol/mg/dl) Median systolic Median diastolic 6 <3. (median 1.9, range 1.2 2.4) 192! 243 (P <.3)* (2.17! 2.79 mg/dl) 167 14 8 3. (median 3.1, range 2.8 3.7) 127! 117 (1.38! 1.33 mg/dl) 145 85 *P was calculated using Wilcoxon s test. A Pre-angioplasty Post-angioplasty B 1999 DSA angiogram 1999 (post-angioplasty) DSA angiogram 23 Target 3. 4.5 FIG. 2. (A) Digital substruction angiogram (DSA) showing right renal artery stenosis in a patient with APS and hypertension. (B) Follow-up. Restenosis of right renal artery (after angioplasty) in a patient with APS and hypertension (median 1.8).

Renal artery stenosis in hypertensive patients 375 MRA 2 MRA 23 Recommended 3. 4.5 FIG. 3. Left renal artery stenosis progressing to bilateral stenosis in a patient with APS and hypertension (median 2.1). DSA angiogram 22 DSA angiogram 24 Target 3. 4.5 FIG. 4. Recanalization of right renal artery stenosis in a patient APS with hypertension on anticoagulation (median 3.3). 35 mol/l (4. mg%)]. Her median was maintained above 3. for 18 months. Her renal biopsy was consistent with scleroderma renal crisis but there was no evidence of thrombotic renal microangiopathy. Renal arteriography showed recanalization of her right renal artery (Fig. 4) Discussion Renal artery stenosis impairs renal perfusion, leading to renal ischaemia, which in turn activates the renin angiotensin axis. The production of angiotensin II leads to sodium retention, vasoconstriction and increased sympathetic activity. It also has detrimental effects on nitric oxide protection and endothelial function [8 1]. Renovascular hypertension is the result of this process. Until recently renal arterial hypertension was classified into atherosclerotic renal artery stenosis (RAS) and fibromuscular dysplasia. Atherosclerotic RAS is mainly seen in elderly patients with diabetes mellitus, coronary artery disease and peripheral vascular disease. Within 5 yr more than 5% of these patients develop complete occlusion of the renal artery and mortality is high [11 15]. Fibromuscular dysplasia accounts for fewer than 1% of patients with RAS and is predominantly seen in young

376 S. R. Sangle et al. women presenting with hypertension. Angioplasty in these patients may lead to correction of hypertension [16]. Recently, a third aetiological group has been identified. The RAS seen in APS is different from that observed in atherosclerosis and fibromuscular dysplasia. These APS patients are relatively young hypertensives (mean age 46 yr) and mainly Caucasian. Two types of stenotic lesions are seen in this group. The more common pattern is distal to the ostium of the renal artery and, unlike atherosclerosis or fibromuscular dysplasia, these are smooth, well delineated and often non-critical stenoses. The less common pattern is similar to atherosclerotic lesions, situated proximally and occasionally involving the aorta. The exact mechanism of renal artery stenosis in APS patients remains unclear. APS is predominantly a thrombotic condition, though there is now enough evidence to suggest that antiphospholipid antibodies also play a role in the accelerated atherosclerosis seen in some patients. This perhaps explains the two different types of lesions in our patients with APS [17 19]. We describe 14 of 23 (63%) patients with APS and renal artery stenosis in our cohort who received anticoagulants with a target 3. 4.5 for more than 1 yr [7]. There is an increased risk of bleeding on anticoagulation with target 3. 4.5, which is estimated at not more than.25% per annum. Thereafter, the risk of bleeding increases proportionally with >4. and increasing age. In APS the risk of serious bleeding was no higher than that in other thrombotic conditions [7, 2 22]. We have previously briefly described the effect of anticoagulation in five of these patients [3]. The data presented here extend these observations with a longer follow-up in more patients. In patients in this series who maintained their 3. (median 3.1) blood pressure was controlled (median 145/85 mmhg, although we aimed to achieve a blood pressure of 12/8 mmhg) and renal parameters remained stable or improved. In this cohort, one patient with bilateral renal artery stenosis and hypertension showed improvement in her renal parameters. Her serum creatinine returned to normal, her blood pressure control remained excellent and she needed fewer drugs to control her blood pressure. One other patient with MCTD and APS with right renal artery stenosis was re-admitted for sudden worsening of renal function and hypertensive crisis. Although her median was in the acceptable range of 3., the first impression was either complete occlusion of renal artery or thrombotic micro-angiopathy. There was no evidence of thrombotic micro-angiopathy on renal biopsy but histopathology was consistent with scleroderma renal crisis. Interestingly her renal arteriogram revealed complete recanalization of the stenosed renal artery (Fig. 4). Previously, Remondino et al. have described recanalization of bilateral renal artery stenoses and normalization of blood pressure in a young female with hypertension and APS. She needed no hypotensive drugs after 2 yr [23]. In other group with <3. (median 1.9), blood pressure was uncontrolled (median 167/14 mmhg) and renal function deteriorated. Repeat MRA/arteriography in this group showed re-stenoses of renal arteries (after angioplasty) in three patients and a fourth patient had bilateral renal artery stenosis (Figs 2A, B and 3). It is certainly possible that patients with both low and uncontrolled blood pressure were non-compliant and were not taking either their anticoagulants or their antihypertensive drugs. However, we believe, this is unlikely as all these patients were regularly followed by their general practitioner, anticoagulation clinics and our clinic, their drugs were documented in the notes and books and in general they were well motivated. Furthermore, in our experience, patients who are non-compliant with warfarin are likely to have normal s, rather than a median of 1.9, as we found. Apart from two patients with 1.2 (for minor surgical procedures) transiently, all other patients had of at least >1.5. The rationale behind the low in some patients is that in patients with APS it is difficult to achieve a stable. In Ruiz-Irastorza s series of 66 patients with APS treated with oral anticoagulation, the target of 3. 4. was achieved in only 37% of patients, suggesting that the patients may have been resistant to warfarin [24]. This perhaps explains the re-stenosis of renal arteries, poor blood pressure control and renal outcome in the low-intensity group. Even in the apparently controlled patients, only 55% (5/9) achieved target blood pressure of 12/8 mmhg, suggesting that it may be difficult to achieve this target even in patients who are fully compliant. Of course, other possibilities, such as irreversible renal damage due to thrombotic micro-angiopathy and/or lupus nephritis, may be contributing to a certain extent. We cannot, however, completely exclude the possibility that poor compliance (in the low- group) is the explanation for the poor outcome. There is also an another possibility: that the deterioration in renal function and uncontrolled blood pressure in the group with low (<3.) was secondary to uncontrolled lupus nephritis. However, all patients with secondary APS continued to receive immunosuppressive therapy along with warfarin (Table 1). They did not have any other overt signs of active lupus and, most importantly, re-stenosis of the renal arteries argues against the active lupus nephritis being the only reason for worsening renal function and blood pressure control. Our preliminary data suggest that patients whose was maintained 3. did well, their blood pressure was better (our target blood pressure was 12/8 mmhg), renal function remained stable or improved and were able to reverse the renal artery stenosis (Fig. 4 and Table 2). In patients with <3., blood pressure control was poor and renal function deteriorated (Fig. 1A, B) and had re-stenosis (4/9) of their renal arteries (Figs 2A, B and 3). This argues persuasively that anticoagulation may have a role in preventing the progression of these renal artery lesions [25]. 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