Ischaemic heart disease following renal transplantation

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Nephrol Dial Transplant (2000) 15: 269–277

Continuing Nephrological Education (CNE)

Nephrology Dialysis Transplantation

Ischaemic heart disease following renal transplantation Graham Stewart, Alan G. Jardine and J. Douglas Briggs Renal Unit and Department of Medicine & Therapeutics, Western Infirmary, Glasgow, UK

Introduction Premature cardiovascular disease is now the leading cause of death in patients with renal transplants [1,2] and, as a consequence, one of the leading causes of renal allograft failure [3]. Thus, better management of cardiovascular disease (CVD) in renal transplant recipients (RTR), should improve both patient and graft survival. However, the management is difficult and, despite the abundant evidence base for the management of CVD in the non-renal population, the available evidence base in RTR is inadequate. The nature of CVD in RTR is also complex, a combination of accelerated atherosclerosis, leading to coronary artery disease, and myocardial disease (particularly left ventricular hypertrophy—LVH ) leading to chronic heart failure and sudden arrhythmic death. Moreover, CVD develops from the earliest stages of progressive renal disease and transplant recipients may therefore have advanced coronary artery disease or cardiomyopathy, which may not be reversible. Whether the natural history of CVD in renal transplant recipients can be modified, and how, remains to be established.

Case A 62-year-old lady developed end-stage renal failure ( ESRF ) due to obstructive uropathy in 1996. Initially treated by haemodialysis she received a cadaveric renal transplant in 1998. Prior to the transplant she gave no history of symptoms to suggest ischaemic heart disease (IHD). However, she had taken part in a study of exercise training whilst on haemodialysis and had undergone a standard Bruce exercise test. Despite a satisfactory exercise tolerance and no chest pain, she had developed 3 mm of lateral ST depression at peak exercise. She had a normal haemodynamic response to exercise and, since she was asymptomatic, no further investigations were undertaken. In addition she was known to have hypertension (treated with Atenolol and Amlodipine), Correspondence and offprint requests to: Alan G. Jardine, Renal Unit and Department of Medicine & Therapeutics, Western Infirmary, Glasgow G11 6NT, UK. E-mail: A. G. Jardine@clinmed. gla. ac. uk.

and confirmed by ambulatory blood pressure monitoring (ABPM ) which also showed a loss of diurnal variation (Figure 1). This was associated with LVH (LVMI 168 g/m2 by echocardiography, (normal range in females 10 mm/Hg in MAP. This trace shows blunted diurnal variation: day, 143/93 (MAP 110); night, 142/91 (MAP 109).

Discussion

Table 1. Risk factors for IHD in transplant recipients

This case illustrates the presentation of ischaemic heart disease in the early post-transplant period. The patient is not particularly young, a reflection of increasing age of patients on RRT programmes, nor is she free of conventional risk factors for the development of IHD. It also illustrates the complexity of CVD in patients with CRF, the fact that primary and secondary prevention have not been implemented to the extent that they have in the non-renal population, and the difficulties in timing investigation and intervention. The main questions for this patient are (i) how could her ischaemic event have been avoided, and (ii) how can the risk of future events and their consequence be reduced? To appreciate the issues that surround primary and secondary prevention of IHD in renal transplant recipients one must examine the available literature on aetiology and intervention. However, as the report of the recent USRDS taskforce on CVD states [4], despite the evidence for prevention of IHD in the general population, there are almost no published studies in patients on RRT on which to develop an evidencebased strategy.

Male sex Increasing age Family history of premature cardiovascular disease Previous acute transplant rejection Elevated BMI Diabetes mellitus Smoking Dyslipidaemia Left ventricular hypertrophy Pro-thrombotic state Hyperhomocysteinaemia Elevated circulating inflammatory markers

Risk factors and their management In the general population a number of risk factors for CVD are well established, based on large-scale epidemiological studies. These include cigarette smoking, hyperlipidaemia, hypertension, family history and a number of other more minor influences ( Table 1). Relating these risk factors to the development of CVD, and specifically coronary artery disease, in renal transplant recipients has proved difficult for a variety of reasons. First, it is likely that CVD evolves at different

rates during the different stages of the life of a patient with progressive renal disease; the relative importance of risk factors such as hyperlipidaemia and hypertension are also different depending on the disease stage ( Figure 2). Thus, for example, sampling a group of transplant recipients will reveal a higher level of cholesterol than the same patients would have had whilst on dialysis. Secondly, some potential risk factors, such as hypertension are so common following renal transplantation (at least using the definitions applied to the general population of 140/90) as to have no discriminatory potential. Finally, the numbers of transplant patients available for epidemiological studies are small, and there are no large-scale prospective studies that have followed patients through from the earliest phases of progressive renal disease until their terminal event. The most informative data on risk factors for cardiovascular disease in renal transplantation has come from the studies of Kasiske et al. Follow-up studies of several large cohorts of patients following renal transplantation have identified age, male sex, increased total cholesterol, reduced HDL, and acute rejection episodes as determinants of premature CVD [5].

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Fig. 2. The development of cardiovascular disease in renal failure. Risk amplification is relative to the general population. References for risk amplification are in brackets. Interventions with an evidence base in the renal population are shown in bold type while potentially beneficial interventions are in normal type.

Age and sex The strongest associations with outcome and CVD following transplantation include age and male sex. Neither are remediable risk factors and are only useful to identify high-risk individuals.

Diabetes mellitus The patient described had diabetes mellitus, although this was not the cause of CRF. Although the mortality

of patients with diabetic nephropathy and ESRF is much higher than for other causes of ESRF, the consequence of coincidental or post-transplant diabetes is much less clear. Post-transplant diabetes mellitus (PTDM ) is a complication of immunosuppression, specifically steroids and, to a lesser extent, calcineurin inhibitors. Detrimental effects on patient and graft survival have been reported within 3 years and a recent study demonstrated a stronger association between CVD and PTDM than with pre-transplant diabetes [6 ]. However, whether modification of immunosuppression reduces the incidence and impact of PTDM

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remains to be seen. Kasiske et al. did not discriminate between co-incident diabetes and diabetes as a cause of ESRF in his analyses and it is likely that patients with co-incident diabetes will have an increased risk but less than patients with diabetic nephropathy. Improved blood pressure and glycaemic control are known to have established benefits in patients with diabetes and, in the absence of specific information for transplant recipients, it would seem reasonable to employ similar targets for diabetes of any type following transplantation [7].

Hypertension and LVH The relationship between hypertension and cardiovascular risk in the general population is well established. Similarly, it is well recognized that LVH is a complication of hypertension that is associated with increased risk. However, the relationship between ‘hypertension’ and outcome is less clear post-transplantation, probably because the conventional definition of hypertension includes over 70% of transplant recipients thus limiting the discriminatory potential of this diagnosis. Recent studies, however, have shown that increased blood pressure levels within the normal range have an adverse effect on allograft survival [8,9]. Such studies suggest that lower targets for blood pressure control may prolong graft, and either directly or as a consequence, patient survival [9]. Whether lower targets can be met, whether some agents are more effective than others, and whether improved outcomes can be achieved remain to be established. LVH is very common at the time of transplantation and in longterm transplant recipients. The implications for longterm survivors have not been studied, although it is known that LVH at the time of transplantation and in patients starting renal replacement therapy is associated with an adverse outcome [10]. To what extent LVH is reversible is also uncertain, as potentially irreversible fibrotic changes may be present in patients commencing dialysis [11], although regression of LVH has been reported [12]. Twenty-four hour ABPM has a stronger association with CVD than clinic blood pressure readings [13] and ABPM measurements, particularly systolic blood pressure (SBP), are more closely related to LV mass measurements than clinic readings [14]. A loss of diurnal variability has also been shown to be common in patients with renal transplants [15], and night-time ambulatory SBP was demonstrated to be the strongest marker of LVH in patients with CRF [14]. However, there are conflicting data on the role of ABPM in transplant recipients; and no outcome studies are available. Regardless, it is likely that reduced targets for blood pressure control, with the aim of restoring the diurnal pattern in ABPM or achieving a normal LV mass will lessen CV risk. The role of hypertension in progression of renal disease, the benefits of intervention and the superiority of ACE inhibitors and the importance of lower blood

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pressure targets (circa 125–130/75–80) are well recognized. One cannot be sure whether the same will be true for hypertension following renal transplantation, but this question is of major importance to the transplant recipient. Treatment that delays the onset of graft failure and the requirement to re-start dialysis should, intuitively, prolong life and may also reduce the prevalence of associated risk factors such as LVH.

Dyslipidaemia Hyperlipidaemia is very common in renal transplant recipients, being a consequence of the combination of immunosuppressive therapy with calcineurin inhibitors and steroids, and of newer agents such as rapamycin and the pre-existing uraemic state. Like hypertension, the relationship between hyperlipidaemia and CVD is well established in the general population but is less clear in RTR. Recent studies from Kasiske have shown that reduced HDL cholesterol following transplantation is associated with reduced survival and that subdivision of transplant recipients by median levels of lipid and lipid sub-fraction can identify patients with an adverse prognosis [5]. Although these studies do not identify a threshold for increased risk or intervention, they at least suggest that lipid-lowering therapy is likely to be beneficial. At the same time a plethora of studies have shown that reduction of cholesterol using statins improves survival of patients with hypercholesterolaemia and ischaemic heart disease [16,17]. Moreover, they have confirmed the benefits of both primary and secondary prevention using statins and, post-hoc analyses have suggested benefits in high-risk groups including diabetics [16–20]. Statins are safe and effective in RTR [21]. The only caveat to this statement is that those drugs metabolized by the enzyme CYP 3A4, which is inhibited by cyclosporin and tacrolimus, have much higher plasma concentrations in most transplant patients. Thus, they are more potent and have a higher incidence of side effects, notably rhabdomyolysis. As a consequence, Simvastatin, Lovastatin, Cerivastatin and Atorvastatin should be initiated at lower dosages. There are no outcome studies for renal transplant recipients although at least one is on-going. The effect of Fluvastatin on the coronary event rate in 2100 northern European and Canadian renal transplant recipients (the ALERT study) has completed 3 years of followup and will report in 2002 [22]. Hyperlipidaemia, albeit with a different pattern of lipoprotein abnormalities, is common prior to transplantation, from the earliest stages of progressive renal disease [23,24]. Like hypertension, CV risk management in transplant recipients should include the appreciation that this process should begin as early as possible in the course of the disease.

Cigarette smoking Only recently has evidence confirmed the relationship between cigarette smoking and CVD in patients with

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CRF [5], and linked smoking to more rapid loss of renal function [25].

Rejection, graft and patient survival Several studies have now shown that rejection episodes, or graft failure (itself linked to rejection), are associated with premature CVD and death [5,26 ]. Although this may reflect a difference between survival on dialysis and transplantation, it may also be a consequence of common inflammatory mechanisms involved in atherosclerosis and rejection. Regardless, it is a unique risk factor for RTR, and one which must be addressed in the overall management of transplant recipients.

Other potential risk factors Several other emerging and established risk factors are known to be abnormal in renal transplant recipients. These include elevated levels of markers associated with endothelial dysfunction such as fibrinogen, von Willibrand factor, PAI-1, and homocysteine. Homocysteine is toxic to the endothelium [27] and is associated with atherosclerosis [28]. In transplant recipients the prevalence of elevated homocysteine levels is greater in those with CVD [29]; and RTR have higher levels than the general population [29]. Inflammatory markers, such as the acute phase proteins CRP and fibrinogen, are associated with the development of vascular disease [30,31] and the progression of stable to unstable angina [32]. Elevated levels of both factors are more prevalent in haemodialysis patients than the general population, particularly in diabetics, and are independently associated with cardiovascular mortality [33–35]. Whether they have a role in transplant recipients remains uncertain.

Primary prevention in the present case Although primary prevention is a missed opportunity in the present case it is useful to consider the possibilities.

Hypertension The patient had long-standing hypertension, apparently adequately controlled using conventional antihypertensive therapy. Despite this, she had evidence of LVH, on ECG, echocardiography and MRI. Although the relative importance of blood pressure, and blood pressure-independent determinants of LV mass in patients with renal disease, remains unresolved, the presence of LVH suggests that BP control is suboptimal. The use of LV mass (and specifically regression of LVH ) as a target for blood pressure control has not been studied, but may provide a useful target in this population. Conventional targets for blood

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pressure control are almost certainly inappropriate for renal transplant recipients [8] at any stage in the natural history of their condition and it is likely that lower targets or treatment aimed at normalization of ABPM or LV mass may be more effective.

Hyperlipidaemia The benefits of statin therapy in primary prevention of CV events have recently been established in the TEXCAPS/AFCAPS [18] and WOSCOPS [19] studies. However, whether these results are applicable to patients with progressive renal disease is not known. Subgroup analysis of diabetic patients in several of the large outcome studies suggests comparable benefits to the non-diabetic patient; thus it is likely that that the patient described would have benefited from statin therapy. It is likely that the efficacy and safety of statins in patients with progressive renal disease will lead to increased usage and will precede the results of ongoing studies (such as the Heart and Renal Protection (HARP) study in the UK ). The use of a statin in the reported case might have delayed the progression and severity of ischaemic heart disease.

Aspirin The use of aspirin has been shown to significantly reduce the incidence of cardiac events in previously healthy men, the maximum benefit noted in men with the highest CRP levels [30]. Given the higher levels of CRP noted in haemodialysis and diabetic patients, the regular use of aspirin might have altered the course of this patient’s IHD by its anti-inflammatory action.

HRT Observational studies suggest hormone replacement therapy (HRT ) has a place in the management of CV risk in postmenopausal women [36 ]. Although recently challenged by prospective data in a secondary prevention setting [37], that highlights the need for further controlled trials. Given the weight of observational evidence, it is likely that HRT offers cardiovascular protection in the long term, predominantly through its effect on lipid metabolism. Though unproven in transplant recipients premature menopause is common in patients on dialysis, and HRT, in addition to its potential to offset the development of osteoporosis, may prove important in cardiovascular protection in these patients.

Other factors The patient described was a non-smoker, and no other risk factors were determined. However, the potential benefits of innocuous agents such as folic acid (by

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reducing homocystine) should not be ignored. In addition, the possible benefits of optimum glycaemic control in diabetics is likely to be important. It is easy, in retrospect, to identify failings in primary prevention. However, many of these interventions have only become established in the last few years, physicians are disinclined to add to the already considerable number of drugs that patients consume and some treatment targets (in particular BP control ) may be unachievable and intolerable in patients with advanced renal disease.

Pre-transplant screening An opportune time to investigate patients for CVD is when they are accepted onto the transplant waiting list. The lengthy waiting lists for cadaveric transplantation, however, mean that serial assessments may be necessary and, even when patients have normal investigations or undergo revascularization, they may develop significant disease by the time of transplantation. Moreover, such investigation provides an opportunity to reduce operative risk and improve CV health for all potential transplant recipients, including those who are never transplanted. Angiographic studies have demonstrated a high prevalence of clinically silent ischaemic heart disease in patients awaiting transplantation [38], particularly in diabetes mellitus [39]. Dahan et al. showed that 13 of 60 haemodialysis patients, none of whom had overt IHD and 8 of whom were diabetic, had angiographic disease. The subsequent cardiac event rate and mortality over 2 years in those with disease was 61%, compared with 9% in those who had normal coronary arteries [40]. Non-invasive tests are more difficult to assess in patients on dialysis. Standard treadmill exercise tests may give false negative results, due to the inability of patients to achieve maximal heart rates. The resting ECG is often abnormal, and a high proportion of transplant recipients and potential recipients, have LVH and repolarization abnormalities [41] that make interpretation of exercise-induced changes difficult. Dobutamine stress echocardiography [42] and thallium dipyridamole stress testing [40] overcome the problems with exercise capacity and reliance on ECG recordings. These tests are recommended by centres that use routine pre-transplant assessment. Patients who have evidence of reversible ischaemia should then undergo coronary angiography. The patient described above had CVD investigations as part of a cross-sectional research study of cardiovascular risk factors. The ETT was positive but with adequate exercise tolerance. In the absence of symptoms further investigations were not pursued. The subsequent events show the failings of this approach. Symptoms are less likely in patients whose exercise tolerance is compromised on RRT, and patients may therefore commonly have ‘silent disease’. Stress thallium or echocardiographic investigations may have

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identified the extent of reversible ischaemia more clearly and pointed to the presence of significant disease. However, coronary angiography is mandatory if non-invasive tests are positive.

Revascularization One of the most important developments in the last decade has been the development of non-surgical approaches to coronary revascularization. However, the place for coronary angioplasty and stenting, and of coronary artery bypass grafting in patients with progressive renal disease remains uncertain. In the general population, CABG, angioplasty or stenting all improve symptoms of patients with coronary artery disease. In patients with triple vessel or left main stem disease, CABG improves mortality but thereafter the outcome benefits of intervention are less clear. Angioplasty is complicated by a high restenosis rate that may be offset by the primary placement of stents. The use of concomitant treatment with statins, anticoagulant or anti-platelet therapy may also reduce restenosis. In patients with renal disease there is limited evidence on the use of CABG. Retrospective data shows that peri-operative mortality is higher, (8% vs 1–3%) [43] and morbidity is greater, ( longer ventilation time, and increased infective and haemorrhagic complications) [44], than in the general population. Long term survival is also worse, (50% 5-year survival ) [45], although it may not be worse than that of the general dialysis population. CABG improves symptoms to a similar extent as in the general population (80–90% improved ) [46 ]. The benefit of CABG in asymptomatic coronary disease in ESRF is more speculative, in the absence of prospective data. The mortality of such disease is high (approximately 80% in 2 years in diabetics awaiting transplantation) [47] and the prevalence of asymptomatic disease, even in non-diabetics, is also high. However, prospective studies are required to determine the optimal timing of CABG and of other intervention, and of the survival benefits. The data available (all retrospective) on PTCA in RTR suggest a limited role. The peri-operative complications of PTCA are greater than in the general population [48], and the restenosis rates are much higher than those in the general population [49]. In comparison with ESRF patients who had CABG, higher rates of subsequent cardiac events and mortality rates have been reported [50]. There is no data on coronary artery stenting in ESRF, however the benefit over PTCA alone is proven in the general population in terms of both symptomatic benefit, technical success and restenosis rates [51]. Stenting should thus improve the poor outcome after PTCA in RTR. There is no evidence on the relative benefits of revascularization versus medical therapy in RTR and the indications are therefore those from the general population that revascularization should be considered for symptomatic benefit and where there is survival

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data. The only prospective comparative data for medical against surgical intervention is a study of 26 diabetics with asymptomatic or atypical disease who received medical therapy or CABG. There was a significantly greater event rate in those in the medical arm of the trial. However the study was terminated early, the numbers were small and medical therapy was only aspirin and a calcium antagonist [52]. While effective pre-transplant screening will identify patients at excess risk for transplant surgery, the usual finding is of advanced disease that responds poorly to intervention. Restenosis is a common problem in the general population following angioplasty and, to a lesser extent, the placement of intracoronary stents. The poor outcome following angioplasty and stenting in the present case illustrates the potential problems with non-surgical coronary revascularization.

Management of acute coronary syndromes The first symptomatic presentation of IHD in the case above was unstable angina in the early post-operative period. Our local policy is to stop anti-hypertensive therapy at the time of transplantation and reintroduce treatment as required thereafter, initially with a calcium antagonist (for the potential benefits on cyclosporin nephrotoxicity). In this case, the patient received atenolol prior to transplantation and, although atenolol would be expected to remain in the circulation for several days in patients with ESRF and in the early post-transplant period, withdrawal may have contributed to the development of unstable angina. The stress of surgery and of fluid challenge following transplantation may also have contributed to the development of symptoms. The patient was treated with intravenous nitrates, aspirin and low dose heparin and atenolol was reintroduced with resolution of symptoms. Although heparin and aspirin must be used with caution in patients who have undergone surgery, there is no evidence to suggest that modification of conventional therapy is required in transplant recipients [53]. It is also likely that third generation platelet inhibitors, glycoprotein IIa/IIIb receptor antagonists can be used safely in these patients. Although prolonging the bleeding time, they have been shown to reduce risk of myocardial infarction and death by up to 25% over aspirin and heparin alone. They should therefore should be considered in transplant patients with unstable angina or non-Q-wave myocardial infarction refractory to conventional treatment [54]. The same is true for the management of patients with suspected acute myocardial infarction. Although pre-existing ECG abnormalities may make the diagnosis of myocardial infarction difficult, as does the increase in CK levels following surgery, the proven benefits of thrombolytic therapy in patients with myocardial infarction mandate the use of these agents in transplant recipients. Thus, transplant patients (beyond the immediate post-transplant period ) with suspected myocardial infarction should receive conven-

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tional thrombolytic therapy with intravenous streptokinase, tPA or related agents [55].

Secondary prevention In the general population measures introduced in the last decade have revolutionized the prognosis of patients with myocardial infarction, chronic heart failure or MI complicated by LV dysfunction. A series of landmark studies have shown the survival benefits of ACE inhibition following MI in patients with echocardiographic or clinical evidence of LV dysfunction, and in patients with chronic heart failure [56,57]. Angiotensin II receptor antagonists have also been shown to improve survival of patients with chronic heart failure [58]. b-blockade improves outcome following myocardial infarction, as does aspirin therapy. Most importantly, the use of statins reduces recurrent cardiovascular events by about one third [16 ]. For none of these treatments is there specific evidence in renal transplant recipients, nor is it likely that the necessary trials will ever be performed. However, it seems likely that renal transplant recipients will benefit from these treatment strategies. Most physicians would use ACE inhibitors in patients with LV dysfunction following an MI. Although LV dysfunction is associated with an adverse outcome following transplantation there is no consensus on recommendations for the use of ACE inhibitors in patients with asymptomatic LV dysfunction. ACE inhibitors should be used with caution in RTR in case there is unexpected stenosis of the transplant renal artery. A transient increase in serum creatinine is often seen following introduction of ACE inhibitors in transplant recipients with heart failure and if possible one should perform a Doppler ultrasound of the renal artery to exclude transplant artery stenosis prior to starting therapy. The use of statins is also unproven in this group but, unlike the use of statins for primary prevention, most physicians seem to accept the use of statins following a CV event. In the ALERT study (above) open label statin therapy is given to patients who have had an MI [22]. The patient described here was treated with Atenolol to control angina, aspirin and a statin but did not require an ACE inhibitor, as she had neither symptomatic nor echocardiographic LV dysfunction. However, despite this therapy symptoms rapidly recurred following angioplasty.

Conclusions Although there is increasing appreciation of the importance of CVD in renal transplant recipients there is little evidence derived from studies in these patients for the benefits of primary or secondary intervention. Questions also remain about whether the pathophysiology of IHD in transplant recipients is the same as in the general population. The size of the renal transplant population makes it unlikely that many CV outcome

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studies will be performed and, although specific outcome studies are desirable, treatment strategies, certainly in the meantime, must be developed from available data in the general population. The case described illustrates a number of key problems. First, patients often have advanced disease when a cadaveric transplant becomes available, regardless of previous symptoms or screening investigations that may have been performed some years previously at the time of acceptance for transplantation. Secondly, nonsurgical revascularization procedures do not appear to have as good an outcome as in the non-renal population. Finally, with increasing appreciation of the importance of cardiovascular disease following transplantation the time to tackle this problem is not following transplantation but in the very earliest phases of progressive renal disease. An appreciation that CV risk is increased in most patients by the time they present with progressive renal disease and the early use of statins, and antihypertensive therapy (with reduced BP targets and revised goals to include the reversal of LVH ) will do as much to improve patient and graft survival as forseeable developments in immunosuppression.

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