Ischaemic heart disease following renal transplantation

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. 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), 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 <100 g/m2)) but good systolic function. Fasting lipids measured at the time of the echocardiogram showed an elevated fasting total cholesterol of 6.21 mmol/l. Twenty-four hour ambulatory blood pressure profile demonstrating a loss of diurnal variation. Monitoring began at 09:00 h and finished at the same time the next day. Readings were taken every 30 min during the day (07:00–23:00 h) and every 60 min during the night. The dotted lines represent the normal range for systolic and diastolic blood pressure (140/90–day, 120/80–night). □, ambulatory systolic blood pressure readings; +, ambulatory diastolic blood pressure readings; ×, calculated mean arterial pressure (MAP). Normal expected diurnal variation is >10 mm/Hg in MAP. This trace shows blunted diurnal variation: day, 143/93 (MAP 110); night, 142/91 (MAP 109). Additional relevant history included type 2 diabetes mellitus, diagnosed in 1992 and treated with oral hypoglycaemics, treated autoimmune hypothyroidism and coeliac disease. She was a lifelong non-smoker and her father had died of a myocardial infarction aged 60 years. Following transplantation she was maintained on cyclosporin, azathioprine and prednisolone, the prednisolone dose being reduced to 5 mg per day within 6 months, and insulin was introduced to maintain glycaemic control. Her post-operative recovery was complicated by an episode of unstable angina. This settled with intravenous nitrates, heparin and re-introduction of atenolol. Although an electrocardiogram (ECG) showed transient anterolateral T wave inversion, there was no elevation of serum creatinine kinase (CK). To investigate the episode of post-operative angina she underwent an exercise tolerance test 3 months following transplantation, which was again positive, with ST depression in the antero-lateral leads. Coronary angiography was performed which showed a 70% circumflex artery stenosis, and two stenoses of 90% in the proximal and mid section of the left anterior descending (LAD) artery. Bypass grafting was recommended but she declined because of her concern about the possible risk of the operation to the function of her renal transplant. Instead, she underwent angioplasty of the distal LAD lesion, with stenting of the circumflex and proximal LAD lesions. The initial outcome appeared satisfactory and thereafter she received aspirin (75 mg/day) and statin therapy. In July 1999 she presented again with worsening exertional chest pain and coronary angiography was repeated. This showed a new 40% stenosis of the circumflex artery, a 90% restenosis of the distal LAD lesion and an 80% stenosis of the LAD stent. The renal allograft function is good, her last serum creatinine being 101 μmol/l. 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 evidence-based strategy. 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. Risk factors for IHD in transplant recipients Risk factors for IHD in transplant recipients 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. 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]. 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. 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 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]. 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 long-term transplant recipients. The implications for long-term 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 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. 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 levels of and can identify patients with an adverse [5]. Although these studies not identify a for increased risk or they at least suggest that therapy is likely to be the same time a of studies have shown that of cholesterol using survival of patients with and ischaemic heart disease Moreover, they have confirmed the benefits of both primary and secondary prevention using and, analyses have benefits in high-risk are and effective in RTR The only to this is that by the which is by and have much higher in most transplant Thus, they are more and have a higher incidence of a consequence, and should be at lower are no outcome studies for renal transplant recipients although at least one is The effect of on the coronary event in and renal transplant recipients has 3 years of and will report in with a different pattern of is common to transplantation, from the earliest stages of progressive renal disease Like hypertension, CV risk management in transplant recipients should include the that this should as early as possible in the of the disease. has evidence confirmed the relationship between cigarette and CVD in patients with CRF and to more loss of renal function studies have now shown that rejection or graft failure to are associated with premature CVD and death Although this may a between survival on dialysis and transplantation, it may also be a consequence of common in and Regardless, it is a risk for and one which must be in the management of transplant recipients. other and established risk factors are known to be in renal transplant recipients. These include elevated levels of associated with such as and is to the and is associated with In transplant recipients the prevalence of elevated levels is in with CVD and RTR have higher levels than the general population such as the acute and are associated with the development of disease and the progression of to unstable angina levels of both factors are more in haemodialysis patients than the general population, particularly in and are associated with cardiovascular mortality Whether they have a role in transplant recipients remains Although primary prevention is a in the present case it is useful to the The patient had hypertension, using conventional therapy. Despite she had evidence of on and Although the relative importance of blood and blood determinants of LV mass in patients with renal disease, remains the of LVH that control is The of LV mass specifically regression of as a for blood pressure control has not been studied, but may a useful in this population. targets for blood pressure control are almost for renal transplant recipients at any stage in the natural history of their and it is likely that lower targets or at of ABPM or LV mass may be more The benefits of statin therapy in primary prevention of CV events have been established in the and studies. However, whether these are to patients with progressive renal disease is not of diabetic patients in several of the large outcome studies benefits to the thus it is likely that that the patient described would have from statin therapy. It is likely that the and of in patients with progressive renal disease will to increased and will the of studies as the and study in the The of a statin in the reported case have the progression and of ischaemic heart disease. The of aspirin has been shown to reduce the incidence of events in the in with the levels the higher levels of in haemodialysis and diabetic the of aspirin have the of this IHD by studies suggest replacement therapy has a in the management of CV risk in Although by prospective data in a secondary prevention that the for further the of it is likely that cardiovascular in the through effect on in transplant recipients premature is common in patients on and in addition to potential to the development of may in cardiovascular in these The patient described was a and no other risk factors were However, the potential benefits of agents such as should not be In the possible benefits of glycaemic control in is likely to be It is in to identify in primary However, of these interventions have only established in the last are to to the number of that patients and some targets may be and in patients with advanced renal disease. time to investigate patients for CVD is they are the transplant The for cadaveric transplantation, however, mean that may be and, patients have normal investigations or they may develop disease by the time of Moreover, such investigation an to reduce risk and improve CV for potential transplant recipients, are studies have demonstrated a prevalence of ischaemic heart disease in patients transplantation particularly in diabetes mellitus et al. showed that of 60 haemodialysis of had IHD and of were had disease. The event and mortality over 2 years in with disease was with in had normal coronary are more difficult to in patients on dialysis. exercise may due to the of patients to heart The is and a of transplant recipients and potential recipients, have LVH and that of changes and the with exercise and on These are recommended by that pre-transplant have evidence of reversible should coronary The patient described had CVD investigations as part of a study of cardiovascular risk The was but with exercise In the absence of symptoms further investigations were not The events the of this are less likely in patients exercise tolerance is on and patients may therefore have or investigations may have identified the extent of reversible more and to the of disease. However, coronary angiography is are One of the most in the last has been the development of to coronary However, the for coronary angioplasty and and of coronary artery grafting in patients with progressive renal disease remains In the general population, angioplasty or stenting improve symptoms of patients with coronary artery disease. In patients with or left main disease, mortality but thereafter the outcome benefits of intervention are less clear. is complicated by a restenosis that may be by the primary of The of with or therapy may also reduce In patients with renal disease there is evidence on the of data shows that mortality is and is and increased and than in the general population. survival is also although it may not be than that of the general dialysis population. symptoms to a similar extent as in the general population The of in coronary disease in ESRF is more in the absence of prospective The mortality of such disease is 80% in 2 years in and the prevalence of disease, in is also However, prospective studies are to the timing of and of other and of the survival The data available on in RTR suggest a The of are than in the general population and the restenosis rates are much higher than in the general population In with ESRF patients had higher rates of events and mortality rates have been reported is no data on coronary artery stenting in ESRF, the over is in the general population in of both and restenosis rates should thus improve the outcome in RTR. is no evidence on the relative benefits of therapy in RTR and the are therefore from the general population that should be for and there is survival The only prospective data for intervention is a study of with or disease received therapy or was a event in in the of the the study was the numbers were and therapy was only aspirin and a effective pre-transplant will identify patients at risk for transplant the is of advanced disease that to intervention. is a common in the general population following angioplasty and, to a lesser extent, the of The outcome following angioplasty and stenting in the present case illustrates the potential with coronary The presentation of IHD in the case was unstable angina in the early post-operative period. is to therapy at the time of transplantation and as with a the potential benefits on In this the patient received to transplantation and, although would be expected to remain in the for several in patients with ESRF and in the early post-transplant may have to the development of unstable angina. The of and of following transplantation may also have to the development of The patient was treated with intravenous nitrates, aspirin and dose heparin and was with of Although heparin and aspirin must be with in patients have undergone there is no evidence to suggest that modification of conventional therapy is in transplant recipients It is also likely that can be in these Although the they have been shown to reduce risk of myocardial infarction and death by to over aspirin and heparin should therefore should be in transplant patients with unstable angina or myocardial infarction to conventional The same is true for the management of patients with acute myocardial Although pre-existing may the of myocardial infarction as the in levels following the benefits of therapy in patients with myocardial infarction the of these agents in transplant recipients. Thus, transplant patients the post-transplant with myocardial infarction should conventional therapy with intravenous or related agents In the general population introduced in the last have the of patients with myocardial chronic heart failure or complicated by LV A of studies have shown the survival benefits of ACE following in patients with or evidence of LV and in patients with chronic heart failure have also been shown to improve survival of patients with chronic heart failure outcome following myocardial as aspirin therapy. the of reduces cardiovascular events by about one of these is there specific evidence in renal transplant recipients, nor is it likely that the will be However, it likely that renal transplant recipients will from these would ACE inhibitors in patients with LV following an Although LV is associated with an adverse outcome following transplantation there is no on for the of ACE inhibitors in patients with LV ACE inhibitors should be with in RTR in case there is stenosis of the transplant renal artery. A transient in serum creatinine is following of ACE inhibitors in transplant recipients with heart failure and possible one should a of the renal artery to transplant artery stenosis to starting therapy. The of is also in this group the of for primary most seem to the of following a CV event. In the study statin therapy is to patients have had an The patient described was treated with Atenolol to control aspirin and a statin but did not an ACE as she had nor LV However, despite this therapy symptoms following Although there is increasing of the importance of CVD in renal transplant recipients there is evidence from studies in these patients for the benefits of primary or secondary intervention. also remain about whether the of IHD in transplant recipients is the same as in the general population. The of the renal transplant population it that CV outcome studies will be performed and, although specific outcome studies are in the must be developed from available data in the general population. The case described illustrates a number of First, patients have advanced disease a cadaveric transplant of symptoms or investigations that may have been performed some years at the time of for Secondly, not to have as good an outcome as in the non-renal population. Finally, with increasing of the importance of cardiovascular disease following transplantation the time to this is not following transplantation but in the very earliest phases of progressive renal disease. that CV risk is increased in most patients by the time they present with progressive renal disease and the early of and therapy reduced targets and to include the of will as much to improve patient and graft survival as in