Transplantation Reviews xxx (2014) xxx–xxx

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Transplantation Reviews journal homepage: www.elsevier.com/locate/trre

Cardiovascular complications after transplantation: Treatment options in solid organ recipients Keith A. Gillis, Rajan K. Patel, Alan G. Jardine ⁎ Renal Research Group, University of Glasgow, UK

a b s t r a c t Premature cardiovascular disease is the commonest cause of death in solid organ transplant recipients, with coronary artery disease, sudden cardiac death and heart failure being highly prevalent. There are unique factors leading to CV disease in organ transplant recipients that include underlying comorbidities, and metabolic effects of immunosuppression. As a consequence management strategies developed in the general population may have limited benefit. In this review, we will focus on renal transplantation, where most research has been carried out and, despite incomplete understanding of the disease process, the incidence of cardiovascular disease appears to be falling. © 2013 Elsevier Inc. All rights reserved.

1. Introduction

1.1. Kidney transplantation

Solid organ transplantation is the established treatment for end stage organ disease, associated with improved life expectancy and quality of life and, for renal transplantation, substantial cost savings over maintenance dialysis. Improved management of immunosuppression and infection, coupled with improvements in surgical techniques and peri-operative management, have improved transplant survival and significantly reduced short and long term post-transplant morbidity. Partly as a consequence of these developments, we are increasingly aware of the long-term risks to transplant recipients. Cardiovascular disease (CVD) is a leading cause of premature death and hospitalization in solid organ transplant recipients and, due to “death with a functioning graft”, is a leading cause of graft failure. Thus, strategies that reduce the prevalence and impact of CVD would be expected to prolong patients and graft survival. We have greater understanding of the importance of CVD in renal transplant recipients (RTR) and that will be the focus of this review. Pancreatic transplantation is generally performed in patients with diabetes and end stage renal disease (ESRD), either as simultaneous kidney pancreas transplant (SPK) or pancreas after kidney transplant (PAK). These individuals are therefore covered in the section on renal transplantation. Less is known about recipients of lung and liver transplants, whilst obliterative coronary disease – linked to rejection – is a specific problem for heart transplant recipients.

CVD is the commonest cause of death and graft loss in RTR [1,2]. This trend is likely to continue, as we expand the criteria for transplant recipients, to include older patients with co-morbid disease, including CV diseases. The incidence of CVD in RTR is 3–5 times that of age-matched patients in the general population, but is substantially lower than the risk in patients treated by maintenance haemodialysis, where the incidence is 10–20 times that of the general population. Moreover, the increase in risk appears to be greatest in younger patients [1], and the pattern of disease is different from the general population, with a greater incidence of sudden, presumed arrhythmic, cardiac death and heart failure, rather than atherosclerotic coronary artery disease (CAD). In this regard, RTR occupy a position between the general population and patients receiving maintenance dialysis – who have a higher incidence of CV events not due to CAD [3–5]. Patients with ESRD, particularly those receiving maintenance haemodialysis, have a high prevalence of “uraemic cardiomyopathy”, the principal features of which are left ventricular hypertrophy (LVH) and myocardial fibrosis, which predispose to heart failure and arrhythmias. Our understanding of the incidence, prevalence and the natural history of CVD in RTR comes from registry data, observational followup studies and a few large clinical trials. These datasets have strengths and weaknesses: events in clinical trials are independently verified, whilst the numbers of patients in registry and observational analyses are much greater. One caveat is application of caution when pooling end-points. This is commonly used in analyses where end points share common pathophysiology. Thus, in the general population cardiac death, heart failure and myocardial infarction (MI) may all be due to coronary events; however this assumption may not be true in the transplant population.

⁎ Corresponding author at: Institute of Cardiovascular and Medical Research, BHF Cardiovascular Research Centre, University of Glasgow, Glasgow, UK, G12 8TA. Tel.: +44 141 330 2705; fax: +44 141 330 6972. E-mail address: [email protected] (A.G. Jardine). 0955-470X/$ – see front matter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.trre.2013.12.001

Please cite this article as: Gillis KA, et al, Cardiovascular complications after transplantation: Treatment options in solid organ recipients, Transplant Rev (2014), http://dx.doi.org/10.1016/j.trre.2013.12.001

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Fig. 1. Pre and post transplant risk factors for cardiac complications following solid organ transplantation.

In RTR the incidence of CVD is high. The Patient Outcomes in Renal Transplantation (PORT) study followed 23, 575 adult RTR over a median of 4.5 years and demonstrated cumulative incidence of CV events (pooled from proven myocardial infarction, coronary intervention and cardiac death) as 3.1, 5.2 and 7.6% at one, three and five years after transplantation respectively [5]. In the placebo arm of the Assessment of LEsecol in Renal Transplantation (ALERT) [3] study, which investigated the effect of fluvastatin on CV outcome in RTR with stable graft function, the rate of CV events (pooled from CV death or non-fatal MI) was 21.5 per 1000 patient-years. In the ALERT study there was a similar rate of fatal and non-fatal CV events, in contrast to populations at comparable, overall CV risk (e.g. WOSCOPS and 4S trial), where non-fatal events predominate. The ALERT study also showed that individual cardiac events may have different determinants. For example, myocardial infarction was dependent upon lipids and conventional risk factors for CAD, whereas the risk factors for cardiac death included renal dysfunction, blood pressure and LVH [6]. Thus, in RTR the risk of CVD is increased, the prevalence of “conventional” CV risk factors is high but the relative proportions of CV events may differ compared to the general population. Individual risk factors may be more strongly associated with one or more CV outcomes and in order to explore the CVD-risk factor relationship, and to understand the management of CVD in RTR, it is necessary to examine individual risk factors (Fig. 1). 2. Risk factors for cardiovascular disease in renal transplant recipients 2.1. Hypertension Hypertension is a conventional CV risk factor, which affects the majority of RTR. Its development is associated with pre-transplant hypertension, poorer allograft function and the effects of immunosuppression, specifically calcineurin inhibitors (CNIs), especially cyclosporine, and corticosteroids [7,8]. The mechanism of CNI induced hypertension is believed to be tubular sodium retention and CNIinduced nephrotoxicity, whereas corticosteroids increase blood pressure by increasing salt and water retention and activation of the sympathetic nervous system [9]. As a result, antihypertensive therapy

is very commonly required in RTR. In registry analyses and clinical trials, there is a strong association between blood pressure (even within “normal” range) and graft failure, mortality and adverse CV outcome in RTR [3,10–12]. In these studies, higher systolic and pulse pressure (indicating increased vascular stiffness) were risk factors for cardiac death and stroke [8,13,14] to a greater extent than CAD. Hypertension is also a major cause of LVH, both prior to and after transplantation [12], LVH being independently associated with CV death. Blood pressure may be reduced in RTR by alterations to immunosuppressive therapy such as minimization, withdrawal or avoidance of corticosteroids; minimisation of CNI; conversion from cyclosporine to tacrolimus or the use of CNI-free immunosuppressive strategies. For example, replacing CNIs with the co-stimulation blocker belatacept, or mammalian targets of rapamune inhibitors (mTORi; sirolimus or everolimus) is associated with blood pressure levels around 10/5 mmHg lower than CNI containing regimens [15– 17]. In practice, few clinicians would modify immunosuppression to control blood pressure, preferring to add antihypertensive agents. Patients typically require two or more agents [8,18]. Recommended drugs therapies and targets for blood pressure control in RTR have generally been taken from trials in other populations, particularly patients with kidney disease however there have been a number of short-term efficacy studies in transplant recipients that have shown that blockers of the renin-angiotensin system and calcium channel blockers have similar blood pressure lowering effects and safety to patients with essential hypertension [19]. It is not clear which antihypertensive agent or blood pressure target is appropriate for RTR due to the lack of specific, large scale CV outcome studies of antihypertensive therapies in this population. Dihydropyridine calcium channel antagonists are effective at reducing blood pressure, may reduce the vasoactive nephrotoxic effects of CNI, and regress LVH in RTR [20]. Although there was an initial reluctance to prescribe drugs affecting the renin-angiotensin system due to concerns about ‘functional’ transplant artery stenosis [18], the PORT study [5] has shown a progressive increase in the use of these agents during the last decade. In a retrospective study by the Austrian transplant registry, use of ACE inhibitors or angiotensin receptor blockers was associated with improved patient and graft survival [21],

Please cite this article as: Gillis KA, et al, Cardiovascular complications after transplantation: Treatment options in solid organ recipients, Transplant Rev (2014), http://dx.doi.org/10.1016/j.trre.2013.12.001

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although a similar study by Opelz et al. in a subset of the Collaborative Transplant Study dataset, failed to confirm this [22]. These studies are indicative of the absence of clinical trials of antihypertensive therapy in RTR, and the need to rely on retrospective analyses. One of the few interventional trials - the Study on Evaluation of Candesartan Cilexetil after Renal Transplantation (SECRET) - investigating the effect of candesartan on blood pressure control and CV outcome in RTR, was abandoned due to low event rates [23]. However, it did confirm the safety and anti-hypertensive effects of candesartan, and also superior reduction in urinary protein loss with this agent. More recently, a small randomised controlled trial of RTR with stable graft function (albeit with only 70 patients followed for a decade) demonstrated a statistically significant reduction in CV outcome [24]. Although further studies would be extremely useful, it seems unlikely in the current environment that a large scale outcome trial of antihypertensive therapy will be performed and it is likely that we will remain reliant on registry data. Evidence is also lacking for blood pressure targets. The observational studies of Opelz that demonstrated improved graft, patient and CVD-free survival in the Collaborative Transplant Study showed a progressive benefit with systolic blood pressures as low as 120 mmHg [25], well within the “normal” range. These data have been used to support the notion that “lower is better” and, in conjunction with data from trials in CKD, the Kidney Disease Improving Global Outcomes (KDIGO) guidelines suggest a target of 130/80 mmHg [19], and the use of blockers of the renin angiotensin system in patients with significant proteinuria (above 1 g/day in adults) or diabetes. In practice, however, these targets may be difficult to achieve and the majority of patients require multiple agents [5]. As noted above, LVH is one consequence of hypertension both in CKD and following transplantation, which increases the risk of sudden death and death due to heart failure. Renal transplantation is not associated with regression of LVH [26] although echocardiographic studies may show an apparent reduction. Some studies have suggested that improved blood pressure control associated with CNI avoidance may also be associated with reduction of LV mass. In one report, switching patients to sirolimus was associated with reduction in LV mass in 12 of 13 patients compared to 10 out of 26 in the usual treatment arm [27], but this has yet to be confirmed in larger studies. Overall, although trials of CNI avoidance, and corticosteroid withdrawal or minimisation [28–31] have shown lower blood pressures, the trend over the last decade has been to progressively increase the use of all classes of antihypertensive agent [5] rather than tailoring immunosuppression. There are other therapeutic options: RTR who have pre-transplant bilateral native nephrectomy have lower blood pressure, but post-transplant native nephrectomy or embolisation is less effective. In the general population percutaneous renal sympathectomy has recently [32,33] been shown to lower BP in patients with resistant essential hypertension. Two trials of this procedure are currently in progress in RTR, and there is currently no evidence to support its use.

2.2. Dyslipidaemia Dyslipidaemia is a common complication of solid organ transplantation, affecting at least 60% of all RTR [34] and patients with renal diseases have different patterns of dyslipidaemia depending on their stage of CKD. Haemodialysis patients have low or normal total cholesterol, but elevated triglyceride and triglyceride-rich particles. Following transplantation all of the major lipid sub-fractions increase (including HDL) and peak within 3–6 months [35], before falling, following the intensity of immunosuppression. Total cholesterol is typically increased by 30%, in addition to similar increases in LDL and HDL cholesterol, triglycerides, and high levels of atherogenic proteins such as apolipoprotein B and lipoprotein A [36].

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Table 1 Effect of maintenance immunosuppression of cardiovascular risk factors.

Lipids HTN Diabetes eGFR Acute rejection

Corticosteroids

Ciclosporin

Tacrolimus

mTORi

Belatacept

↑↑ * ↑↑ ↑↑ ↔ *↓

↑↑

↑

↑↑↑

↑↑

↑↑ ↑ ↓ ↓↓

↑ ↑↑ ↓ ↓↓

·· ·· ↔ ↓

·· ·· ↔ ↓

Direction of arrows shows effect, with number of arrows demonstrating semi quantitative effect. HTN = Hypertension eGFR = Estimated glomerular filtration rate mTORi = Inhibitors of mammalian target of rapamune.

The pathophysiology of dyslipidaemia is complex, reflecting the differential effects of individual immunosuppressant agents, renal impairment and proteinuria. Specific pre- transplant risk factors which have been identified include male gender, obesity and ethnicity [37]. Glucocorticoids cause hyperglycaemia, hyperinsulinaemia, and in turn a reduction in lipoprotein lipase activity with concomitant increase in triglyceride levels and secretion of VLDL [38]. CNIs alter lipid metabolism by reducing LDL receptor expression, reducing lipoprotein lipase activity, and altering bile acid metabolism. Tacrolimus is associated with lesser effects than cyclosporineswitching from cyclosporine to tacrolimus has been associated with a 25% reduction in LDL cholesterol [39]. Inhibitors of mTOR, such as sirolimus and everolimus, cause marked hyperlipidaemia [40], although less than initially reported when these agents were first introduced and higher doses were commonplace. The mechanism underlying the dyslipidaemia of mTORi is incompletely understood but typically there are increases in all lipid subfractions including HDL. The long term impact of mTORi is uncertain however, because of the potential benefits on atherosclerotic plaques which may ameliorate the deleterious effects of dyslipidaemia. Not only are sirolimus and everolimus coated coronary stents effective, but in animal models sirolimus causes regression of atherosclerosis. The use of belatacept, coupled with CNI minimisation or avoidance, is associated with lower lipid levels post-transplantation [16,29,31]. The impact of immunosuppressive agents is summarised in Table 1. As with hypertension, few clinicians change immunosuppression to manage dyslipidaemia, nor is there any evidence to support this strategy. However, in contrast to the management of hypertension, there are clinical trial data to support the use of lipid lowering therapy, specifically statins, endorsed by recent national (The Renal Association, UK) and international (KDIGO) guidelines [19,41]. Statins inhibit HMG-CoA reductase, the rate limiting step in cholesterol biosynthesis, and reduce total and LDL-cholesterol primarily, with lesser effects on TG and HDL cholesterol. Observational data initially provided evidence of the efficacy of statins to reduce cardiovascular events in RTR [42]. Subsequently, large, randomised, placebocontrolled trials have provided support for the use of statin therapy in RTR. In the ALERT study, 2100 stable cyclosporine treated RTR were randomised to fluvastatin 40 – 80 mg daily, or placebo, and followed for up to eight years [4]. Therapy with fluvastatin reduced LDLcholesterol by a mean of 1.0 mmol/L and was associated with a 35% reduction (HR 0.65; 95% CI 0.48–0.88) in the composite end point of cardiac death or non fatal myocardial infarction. Further analysis of the cohort demonstrated that early introduction of statin therapy was associated with increased survival benefit (Fig. 2) [43]. Although fluvastatin therapy did not demonstrate statistical benefit for the primary composite cardiac end-point (which included coronary interventions) on initial analyses, significant reduction was shown during extended follow-up of the main study [44]. Additional support for the use of statins in CKD has come from the Study of Heart and Renal Protection (SHARP) study of patients with chronic kidney disease [45]. In this study 9000 subjects with CKD were recruited including one third maintenance dialysis patients. During the course

Please cite this article as: Gillis KA, et al, Cardiovascular complications after transplantation: Treatment options in solid organ recipients, Transplant Rev (2014), http://dx.doi.org/10.1016/j.trre.2013.12.001

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Fig. 2. Kaplan–Meier curve of time of cardiac death and non-fatal acute myocardial infarction in the ALERT study. Adapted from reference [3].

of the study a large number of patients received transplants; all patients shared the same CV risk reduction (relative risk of major atherosclerotic event 0.83, 95% CI 0.74–0.94, p = 0.0021) associated with therapy with a combination of simvastatin and ezetimibe. The ALERT trial and smaller trials have confirmed the benefits of statin therapy in RTR. They also demonstrated favourable side effect profiles. However, not all statins are the same: lovostatin and simvastatin are metabolised by the microsomal enzyme CyP 3A4 which is inhibited by cyclosporine and to a lesser extent tacrolimus, resulting in much higher statin levels and risk of side effects. Fluvastatin, rosuvastatin and atorvastatin have alternate metabolic pathways. As a result it is sensible to start statin therapy – particularly simvastatin – at low doses. The PORT study has shown progressive increase in the use of statins over recent years, with current overall usage of around 60% in RTR. There is little evidence to support the use of other agents. Ezetimibe inhibits small intestinal lipid absorption and lacks independent evidence of CV protection in any population. There are concerns that it may alter bioavailability and absorption of fat-soluble drugs, which is of concern in transplant recipients [46–49]. Cholestyramine is contraindicated due to interference with absorption of CNIs, fibrates can cause adverse effects such as myopathy when used concomitantly with statins and CNIs, and niacin can cause hepatotoxity. These agents lack evidence that supports their use in RTR and, given their adverse effects, should be used with caution. The existing KDIGO guidelines suggest early measurement of lipid profile abnormalities within 2–3 months of transplantation [19], and at least annually thereafter. Lipid targets are based on studies in the general population (triglycerides b 5.65 mmol/L (500 mg/dL), LDL cholesterol b 2.59 mmol/L (100 mg/dL) and non HDL cholesterol b 3.35 mmol/L (130 mg/dL)) due to the scarcity of data in transplant recipients. However, the current guidelines, which are in draft, have suggested a single measurement and initiation of treatment in all patients – a “fire and forget” strategy. 2.3. Diabetes and impaired glucose tolerance Diabetes mellitus is the most common cause of ESRD and increasingly common following transplantation, reflecting pre-existing disease and the development of post-transplant diabetes (new onset diabetes after transplantation; NODAT). NODAT is similar to type 2 Diabetes Mellitus (T2DM) and its peak incidence is in the first few months after transplantation – due to high doses of corticosteroids and tacrolimus. Thereafter, the incidence drops back to the rate associated with the development of T2DM in the general population [50] and in some cases NODAT may be reversible by reduction in

immunosuppression. Although previously considered a “nuisance” in the management of RTR, NODAT is now known to be associated with poorer long-term survival and increased CV risk. Importantly, the risk of NODAT to patient and transplant survival is greater than the impact of acute rejection within the first year [51]; an observation that has focused more attention on this condition. Risk factors for development of NODAT have been identified, some of which are common to development of diabetes in the general population, whilst others are specific to recipient characteristics. Age [52], obesity [51], and ethnicity [53] are well recognised risk factors, whilst the role of gender is controversial [51,54]. Patients who have previously had stress induced diabetes (e.g. pregnancy, surgery) are at increased risk, as are patients who have a high blood sugar immediately following transplantation where it is common practice to give high dose intravenous corticosteroids. Family history is a strong predictor of NODAT [55]. The pathophysiology of NODAT reflects a combination of insulin resistance and reduced insulin secretion. Insulin sensitivity of patients with NODAT is reduced by 60% compared to unaffected patients [56], and insulin secretion reduced to 50% and 25% in patients treated with cyclosporine and tacrolimus respectively [56]. Sirolimus is also associated with NODAT, reflecting the role of FKBP-12 in insulin secretion and as a target protein for sirolimus and tacrolimus [57]. Several studies demonstrate NODAT to be commoner in tacrolimus treated patients; Kasiske et al. reported a 70% higher incidence [37] compared to patients treated with other agents. A recent meta analysis [58] comparing patients switched to tacrolimus with those on other CNIs demonstrated a 12% reduction in acute rejection episodes, but an additional 5% of patients developed ‘insulin dependent NODAT’. Insulin resistance is also associated with corticosteroids in a dose dependent manner, with a 5% increase in risk of developing NODAT for every 0.01 mg/kg increase in prednisolone dose [59]. The contribution of immunosuppressive agents to the development of NODAT is shown in Table 1. The natural history of NODAT is highly variable. When it develops early after transplantation it may be severe and require insulin to control glucose levels. In patients with older grafts, NODAT tends to have a more insidious onset, with a continuum from impaired glucose tolerance to diabetes mellitus, and a management strategy similar to T2DM in the general population is usually employed. Guidelines published in 2006 [60] regarding the management of NODAT and impaired glucose tolerance (IGT) advise that diagnosis is based on the 2006 World Health Organisation definition of conventional diabetes and IGT [61], which rely on fasting plasma glucose levels and oral glucose tolerance testing (OGTT). In practice, the OGTT is seldom performed, and fasting glucose alone may have a false negative rate of up to 30% [62]. As a result studies investigating the prevalence of NODAT may underestimate the extent of impaired glucose tolerance in the transplant population. A meta-analysis by Montori et al. [63] found the incidence of NODAT to range widely between 2% and 50%, with many studies not employing routine oral glucose tolerance testing. Bee et al. [64] reported a cumulative incidence of 15.%, 22.8% and 24.5% at 1, 3 and 5 years respectively in 388 RTR although these were predominately South East Asian in origin, whilst Kasiske et al. [53] showed a cumulative incidence of 9.1%, 16% and 24% at 3, 12 and 36 months in a mostly Caucasian cohort. Both studies relied upon fasting and non fasting serum glucose levels for diagnosis and again may have underestimated the true burden of disease. Diet and lifestyle represent important interventions for glucose intolerance, although evidence is derived from studies in the general population. The risk of diabetes development can be reduced by 58% in high risk individuals by weight loss achieved with a structured diet and exercise plan [65]. Increased fibre consumption to 15 g per 100 kcal, as well as higher intake of fruit, vegetables and whole grains, together with a reduction in saturated fats, can reduce the risk of IGT. Pharmacological management of NODAT should proceed in the same

Please cite this article as: Gillis KA, et al, Cardiovascular complications after transplantation: Treatment options in solid organ recipients, Transplant Rev (2014), http://dx.doi.org/10.1016/j.trre.2013.12.001

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manner as that of T2DM in the general population [66], with the caveat that most clinicians and guidelines recommend the use of metformin with caution because of the high prevalence of renal dysfunction in RTR. There have been few studies of specific agents in RTR and the guidelines suggest the use of agents used in the nontransplant population, [66–68] including sulphonylureas and thiazolidendiones (where available [69]). Dipeptidyl peptidase-4 (DPP-4) inhibitors are also recommended for second line therapy, alone or in combination. A recent study by Werzowa et al., found that both pioglitazone and vildagliptin improved glucose tolerance in patients with stable RTR with newly diagnosed impaired glucose tolerance [70], establishing the safety and efficacy of these agents for RTR. Combination therapy may be indicated if glucose control is inadequate, and insulin is only recommended if glycaemic targets are not met, when NODAT develops early in the post transplant period, or when glucose levels are very high [60]. Individualised target based therapies are to be recommended, with each patient having a stated target glucose and HBA1c. Both the ACCORD [71] and ADVANCE [72] trials have raised concerns regarding intensive hypoglycaemic therapy in non-transplant diabetic individuals, and an HBA1c target of 6.5–7.5% would be recommended in RTR, with adjustment based on the risk and potential sequelae of hypoglycaemia. Recently a trial of early use of insulin suggests that pre-emptive insulin reduces the longer-term consequences and prevalence of NODAT [73], by “resting” the pancreas. Whether this strategy should be endorsed by guidelines requires further study. 2.4. Renal impairment and proteinuria Analysis of two large cardiovascular risk trials in kidney transplantation (FAVORIT [74] and ALERT [3]) has shown that renal impairment is a major determinant of graft loss and patient outcomes, with a progressive linear relationship between estimated glomerular filtration rate (eGFR) and CV risk. In the ALERT study, poor renal function increased the risk of stroke and cardiac death, rather than MI. Graft failure, in particular, is associated with sudden cardiac death, cardiac dysfunction and all cause mortality. Maintenance of good renal function is thus an important component of CV risk management in RTR, and newer agents that allow CNI avoidance or minimisation, specifically, sirolimus, everolimus and belatacept, have been associated with improved graft function [15,31,75,76] despite a higher incidence of acute rejection compared to established CNI-based regimens. In fact, in studies with these alternative agents, the established link between acute rejection episodes and poorer graft function is not as closely linked, as with CNI. In the ZEUS study [77], tacrolimus was discontinued at 4.5 months post-transplant, and patients were maintained on everolimus without CNI. These patients had a higher 12 month eGFR in comparison with patients who remained on CNIs. Similar observations have been seen in another study investigating earlier (7 weeks after transplantation) substitution of CNI with mTORi [77,78]. However, later switches are ineffective, particularly if they are in response to poor graft function, or in the presence of proteinuria [79]. The high incidence of side effects with mTORi that necessitate cessation of therapy has been a limiting factor in their widespread use. The co-stimulation blocker belatacept [16] when used to allow CNI avoidance, has also been associated with better graft function in both standard donor transplantation and extended criteria donors (BENEFIT-ext) but the increased risk of lymphoma in the early clinical trials, cost, and the absence of long-term outcome data have limited the use of belatacept to date. In addition to reduced GFR, the presence of proteinuria confers additional risk to the graft and to the patient. Proteinuria has been shown to predict death censored graft loss and to a lesser extent, all cause mortality in RTR, such that patients with an albumin to creatinine ratio of greater than 100 mg/μmol in combination

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with graft dysfunction are more than twice as likely to encounter graft failure [80,81]. 2.5. Lifestyle The British Transplantation Society recommend smoking cessation prior to kidney or liver transplantation [82]. Smoking increases the risks of a wide range of pathologies and the specific risk of cardiovascular disease is likely to be underreported due to the competing risks of malignancy and graft loss. Studies have shown that smoking is associated with increased CV risk in RTR [3,10,74,83] and a Cochrane review has shown the efficacy of smoking cessation therapy in the general population. Although this has not been investigated specifically in the transplant population, behavioural and pharmacologic intervention should be similarly effective. Exercise and weight loss are also part of the guidelines for post transplant management. One small interventional study showed benefit of exercise in a kidney transplant cohort [84]; however other studies have failed to demonstrate significant differences in CV events, lipid profile or BMI [85]. 2.6. Novel, non-conventional risk factors: oxidative stress, and endothelial dysfunction Data from observational and interventional studies suggest that conventional CV risk factors and CVD are less closely linked in RTR compared to the general population, and this has lead to a search for alternative, novel risk factors. The vascular endothelium is an important regulator of vascular tone, platelet adhesion, inflammatory cell chemotactants and smooth muscle cell proliferation. Endothelial dysfunction (ED) has a significant role in development of coronary artery disease in the general population and patients with renal impairment [86,87]. Oxidative stress refers to a state of increased oxidant burden in comparison with antioxidant capacity, resulting in endothelial dysfunction through a number of pathways including depletion of key vascular mediators such as nitric oxide (NO), radical mediated DNA damage, and activation of deleterious redox sensitive cell signalling cascades. RTR have impaired endothelial function in vivo and in vitro compared to the general population, although endothelial function is better than in dialysis patients. Passauer et al. found flow mediated dilatation improved in 8 recipients after kidney transplantation [88] when compared to measurements taken during their time on the waiting list. Furthermore, small resistance vessels removed from transplant recipients show impaired vasodilator response compared to patients with normal renal function, suggesting a degree of ongoing dysfunction after transplantation [89]. Circulating inhibitors of NO synthase such as asymmetric dimethyl arginine (ADMA) are elevated in RTR and associated with adverse CV outcomes [90]. It is difficult to tease out the independent effects of ED and oxidative stress because of links with other risk factors. However, the beneficial effects of statins may be mediated by ameliorating mitochondrial production of reactive oxygen species [86], and reducing caveolin present in lipid rich domains on the cell membrane responsible for binding and inactivating NO synthase [91]. Administration of antioxidants such as B vitamins and folic acid have been investigated in RTR but no benefit on CV risk has been observed result from the FAVORIT trial [92] found that high-dose folic acid, B6, and B12 multivitamin did not reduce a composite CVD outcome, all-cause mortality, or kidney failure in RTR. Hyperphosphataemia [93] and hyperuricaemia [94] are nonconventional CV risk factors in the general population however further research is required to determine whether these are independently associated with CV disease in RTR or intervention is effective in improving CV outcome. Anaemia is prevalent in the transplant population especially when there is function is impaired [95]; however administration of erythropoietin stimulating agents to

Please cite this article as: Gillis KA, et al, Cardiovascular complications after transplantation: Treatment options in solid organ recipients, Transplant Rev (2014), http://dx.doi.org/10.1016/j.trre.2013.12.001

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significantly elevate haemoglobin levels in RTR has been associated with increased mortality [96] and their use remains controversial. 2.7. Treatment of coronary artery disease Management of coronary artery disease in transplant recipients should be no different from that of the general population. Studies have suggested that RTR are less likely to undergo intervention for acute coronary syndromes (such as primary angioplasty or thrombolysis) compared to the general population but intervention rates are higher than in ESRD patients receiving maintenance dialysis. Although RTR are less likely to receive cardioprotective agents after myocardial infarction compared to patient with normal renal function [18], there has also been a progressive increase recently [97]. Pre-transplant screening for CAD has become routine practice for potential RTR in some guidelines and centres. The aim is to identify and treat significant CAD prior to transplantation [3] by coronary intervention. However, this approach is controversial in asymptomatic patients [98]. Patients on maintenance dialysis often have poor exercise capacity, limiting symptom development, the coronary intervention rate is low and there is no evidence of a survival benefit [98]. A trial of screening has been proposed [99], and without this it is unlikely that the benefits (or otherwise) of screening will be resolved. Pre-transplant exercise capacity, however, is a very strong determinant of post-transplant survival [98]. 2.8. Liver and pancreas transplantation and cardiovascular disease This review has focused on renal transplantation. However, liver transplant recipients (LTR) are also at elevated risk of premature CV disease, and like RTR, CV events are a common cause of death [100]. CV risk factors have been identified including age, male gender, alcohol related disease, idiopathic primary disease, pre transplant hypertension and post transplant renal impairment [101,102]. Coronary artery disease is common in patients with cirrhosis, and is often undiagnosed. In one study up to 25% of patients referred for liver transplant demonstrated obstructive CAD on angiography [103]. Cirrhosis is associated with low systemic vascular resistance, high cardiac output, and left ventricular hypertrophy, resulting in a state of “cirrhotic cardiomyopathy” [104]. There is also impaired response to stress due to autonomic dysfunction [105], particularly during the peri-operative period which is associated with marked changes in haemodynamic status even in patients without conventional cardiac risk factors or CAD. As with RTR, LTR are at risk of metabolic disturbances secondary to maintenance transplant immunosuppression. Dyslipidaemia is common in LTR, and the incidence decreases significantly with time following transplantation [106,107]. Statin therapy has been found to be safe and efficacious in ameliorating lipid abnormalities [106,108] however no large randomised control trial has been carried out in LTR to determine if this confers improved cardiovascular outcome. NODAT is detected commonly in LTR, although the reported incidence varies widely. One centre reported an incidence of 41.2% at 6 months and 35.9% at 12 months [109]. Older age, obesity, pretransplant impaired glucose tolerance, haemochromatosis, alcohol related disease and autoimmune hepatitis are all reported risk factors [110] for NODAT. Hepatitis C virus infection is also an independent risk factor, most likely due to viral promotion of hepatic insulin resistance [111]. As previously discussed, CNIs and glucocorticoids can cause impaired glucose tolerance and reduced insulin secretion. Severe hyperglycaemia associated with high dose glucocorticoid use in the early post-operative period or treatment of acute rejection, can be managed with insulin therapy, which can subsequently be reduced or withdrawn as steroid reduction ensues. Otherwise a step wise, target based approach to management utilising oral hypoglycaemic agents is to be encouraged [60]. Some therapies such as pioglitazone

and sulphonylureas are hepatically metabolised, and to be avoided unless graft function is satisfactory. The role of pancreas transplant alone (PTA) in patients with diabetes and preserved renal function is controversial, but the procedure is considered in patients with severe metabolic complications of diabetes or significant physical or psychological complications of insulin therapy. The benefits in terms of glycaemic control, avoidance of hypoglycaemia and other complications of insulin therapy have to be balanced with the adverse effects of immunosuppression including the risk of nephrotoxicity and progressive renal impairment associated with CNI therapy. Interestingly, PTA is associated with improvement in markers of CVD. In a prospective observational study, PTA recipients were shown to have reduced carotid intima media thickness at one year, in comparison with patients on the PTA waiting list [112]. A 5 year retrospective analysis of 71 PTA recipients found improved HbA1C and serum glucose, lipid profile, and blood pressure in transplant recipients, as well as greater left ventricular ejection fraction [113]. In these patients, although proteinuria was significantly reduced renal function worsened, and one patient developed end stage renal disease. Five year graft survival was 73.2%. 2.9. Lung transplantation and cardiovascular disease The longevity of lung transplant recipients is mostly limited by graft failure, with much poorer graft survival rates compared to recipients of other solid organ transplants. The incidence of cardiac complications is therefore reduced by the competing risk of death due to graft loss [114]. Cardiovascular causes of death account for only 11.4% of deaths within 30 days of transplantation, and 4.6% of deaths after 5 years, with chronic rejection and infection being the commonest causes of mortality [115]. Nevertheless, lung transplant recipients are exposed to complications of glucocorticoid and CNI based maintenance immunosuppression and are at increased risk of cardiovascular disease. By 3 years post transplant 90% of patients develop one CV risk factor: hypertension in 65% of recipients, hypercholesterolaemia in 33% and NODAT in 6% [116]. Renal impairment is a common consequence of lung transplantation, often due to CNI nephrotoxicity, and some studies have indicated that 3–10% of patients will progress to end stage renal disease. Development of renal impairment in solid organ transplant recipients has been associated with a 4–5 fold greater risk of death and, similar to the general population, and there is an incremental risk of cardiovascular disease relative to the severity of renal impairment [117]. 2.10. Heart transplantation Heart transplant recipients (HTR) are at risk of a number of cardiac complications relating to graft rejection and conventional CV risk factors are also common. Eight years following transplantation, 40% of patients will have hypertension, 40% diabetes and 10% of end stage renal disease [118]. Chronic allograft vasculopathy (CAV) and unexplained graft failure account for almost a third of mortality [118] and a discussion of the diagnosis, monitoring and management of this condition is out with the remit of this review. Addressing CV risk factors is recommended in HTR although there is a paucity of data to support this approach. Anti-hypertensive therapy has benefits in HTR similar to the general population and similar therapeutic targets have been established in these patients. Calcium channel blockers are commonly used but polypharmacy is often necessary and inhibitors of the renin angiotensin system may be preferable in patients with diabetes or renal impairment [119]. Statin therapy has been shown to be safe and effective and may reduce the risk of CAV, in addition to the benefit on lipid profiles and plaque stability. Guidelines recommend the commencement of statin therapy within 1 to 2 weeks of transplant regardless of cholesterol levels [119]. Management of NODAT should proceed in the manner

Please cite this article as: Gillis KA, et al, Cardiovascular complications after transplantation: Treatment options in solid organ recipients, Transplant Rev (2014), http://dx.doi.org/10.1016/j.trre.2013.12.001

K.A. Gillis et al. / Transplantation Reviews xxx (2014) xxx–xxx

described for RTR [66,119] following national guidance pertaining to the use of oral hypoglycaemic agents. Various CNI avoidance or minimisation regimes have been suggested utilising mTOR inhibitors in order to avoid the nephrotoxicity and the CV associated with renal impairment. Late replacement of CNI with sirolimus or everolimus has been found to reduce renal impairment but can be associated with increased acute rejection rates [120,121]. Furthermore, use of mTORi in HTR is supported by the finding their use is associated with reduced rates of CAV [122,123]. 3. Conclusions Premature CV disease has become a focus for research and management in solid organ recipients due to its high prevalence and impact on patient and graft survival. There is evidence to support antihypertensive therapy, lipid lowering with statins and the prevention of post-transplant diabetes for prevention of CVD in solid organ transplant recipients. Furthermore, good graft function is significantly associated with reduction in CV risk and, despite the metabolic consequences of immunosuppressive therapy, their net effect is to reduce CV risk. Thus, in addition to the adoption of CV risk management strategies from other populations, strategies to improve graft survival will hopefully reduce CV risk in organ transplant recipients. KAG and RKP have no conflicts of interest. AGJ- Editorial Board for Transplantation. Consulting fees were funded by Sanofi Aventis, Novartis, Merke Sharpe Dome, and Astellas. References [1] Foley RN, Parfrey PS, Sarnak MJ. Clinical epidemiology of cardiovascular disease in chronic renal disease. Am J Kidney Dis 1998;32:S112-9. [2] Baigent C, Burbury K, Wheeler D. Premature cardiovascular disease in chronic renal failure. Lancet 2000;356:147-52. [3] Holdaas H, Fellstrom B, Jardine AG, et al. Effect of fluvastatin on cardiac outcomes in renal transplant recipients: a multicentre, randomised, placebo-controlled trial. Lancet 2003;361:2024-31. [4] Holdaas H, Fellstrom B, Cole E, et al. Long-term cardiac outcomes in renal transplant recipients receiving fluvastatin: the ALERT extension study. Am J Transplant 2005;5: 2929-36. [5] Israni AK, Snyder JJ, Skeans MA, et al. Predicting coronary heart disease after kidney transplantation: Patient Outcomes in Renal Transplantation (PORT) Study. Am J Transplant 2010;10:338-53. [6] Holdaas H, Fellstrom B, Cole E, et al. Long-term cardiac outcomes in renal transplant recipients receiving fluvastatin: the ALERT extension study.[Erratum appears in Am J Transplant. 2006 Aug;6(8):1986]. American Journal of Transplantation 2005;5(12):2929-36. [7] Ponticelli C, Cucchiari D, Graziani G. Hypertension in kidney transplant recipients. Transpl Int 2011;24:523-33. [8] Hillebrand U, Suwelack BM, Loley K, et al. Blood pressure, antihypertensive treatment, and graft survival in kidney transplant patients. Transpl Int 2009;22: 1073-80. [9] Walker BR. Glucocorticoids and cardiovascular disease. Eur J Endocrinol 2007;157:545-59. [10] Kasiske BL, Chakkera HA, Roel J. Explained and unexplained ischemic heart disease risk after renal transplantation. J Am Soc Nephrol 2000;11:1735-43. [11] Abbott KC, Hypolite IO, Hshieh P, et al. Hospitalized congestive heart failure after renal transplantation in the United States. Ann Epidemiol 2002;12:115-22. [12] Rigatto C, Parfrey P, Foley R, et al. Congestive heart failure in renal transplant recipients: risk factors, outcomes, and relationship with ischemic heart disease. J Am Soc Nephrol 2002;13:1084-90. [13] Jardine AG, Fellstrom B, Logan JO, et al. Cardiovascular risk and renal transplantation: post hoc analyses of the Assessment of Lescol in Renal Transplantation (ALERT) Study. Am J Kidney Dis 2005;46:529-36. [14] Soveri I, Holdaas H, Jardine A, et al. Renal transplant dysfunction – importance quantified in comparison with traditional risk factors for cardiovascular disease and mortality. Nephrol Dial Transplant 2006;21:2282-9. [15] Oberbauer R, Segoloni G, Campistol JM, et al. Early cyclosporine withdrawal from a sirolimus-based regimen results in better renal allograft survival and renal function at 48 months after transplantation. Transpl Int 2005;18:22-8. [16] Vanrenterghem Y, Bresnahan B, Campistol J, et al. Belatacept-based regimens are associated with improved cardiovascular and metabolic risk factors compared with cyclosporine in kidney transplant recipients (BENEFIT and BENEFIT-EXT studies). Transplantation 2011;91:976-83. [17] Larsen CP, Grinyo J, Medina-Pestana J, et al. Belatacept-based regimens versus a cyclosporine A-based regimen in kidney transplant recipients: 2-year results from the BENEFIT and BENEFIT-EXT studies. Transplantation 2010;90:1528-35.

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Please cite this article as: Gillis KA, et al, Cardiovascular complications after transplantation: Treatment options in solid organ recipients, Transplant Rev (2014), http://dx.doi.org/10.1016/j.trre.2013.12.001