Cardiovascular Disease in Renal Transplantation

Introduction

A successful renal transplant is the most effective way of reducing the incidence of cardiovascular disease (CVD) and cardiovascular (CV) mortality in patients with end-stage renal disease (ESRD). Although the risk of CVD in renal transplant recipients (RTR) is approximately three times that of the general population, this is much less than the 10- to 20-fold increase in CV risk in patients receiving maintenance hemodialysis. Premature CVD is also a substantial cause of graft failure, due to “death with a functioning graft.” These observations are well established and illustrated in Fig. 30.1 .

There are specific problems in managing CVD in RTRs compared with the general population. First, RTRs are not a homogeneous group; there is variability in duration and underlying cause of chronic kidney disease (CKD) and dialysis history, which determine the individual burden of accumulated CV risk. Second, the transplant population carries specific risk associated with transplantation surgery and the need for immunosuppressive therapy with agents that have direct and indirect effects on CV risk factors. Third, unlike the general population, in patients with ESRD including RTR, coronary heart disease (CHD) is not the dominant pathophysiologic process. Structural and functional abnormalities in the heart—uremic cardiomyopathy—contribute to an increased risk of heart failure and sudden death; and vascular changes including calcification, together with conventional risk factors, contribute to an increased risk of stroke and peripheral vascular disease. Thus traditional risk factor relationships and therapeutic strategies derived from the general population may not be directly applicable to RTRs. Finally, we are limited in our ability to provide guidelines for the management of CVD in this population because of the lack of epidemiologic and clinical trial data in this patient population.

Background: CVD in CKD

The recognition that CKD is associated with increased CV risk has resulted in the adoption of estimated glomerular filtration rate (eGFR) as a CV risk equivalent. As GFR declines in patients with CKD, the risk of CVD increases progressively, with the highest risk being in ESRD. In early CKD, the pattern of CVD is probably similar to the general population, with an increased risk of lipid-dependent coronary artery disease (CAD). In more advanced CKD, there is a disproportionate increase in deaths due to heart failure and sudden, presumed arrhythmic deaths. The latter pattern is similar to that seen in advanced heart failure, where CHD is uncommon, regardless of the primary etiology of heart failure. In both ESRD and advanced heart failure, total serum cholesterol levels are low, markers of inflammation are elevated, and the conventional relationship between lipids and total CV events (CVE) is lost (or even reversed). Moreover, treatment strategies proven in the general population, specifically statins, have little or no effects in these patient groups, presumably reflecting the low proportion of the overall CV burden which is due to cholesterol-dependent coronary disease.

The determinants of excess CVD in advanced CKD include vascular calcification, elevated phosphate (and fibroblast growth factor-23 [FGF23]), hypertension, inflammation, malnutrition–bone mineral disease, and intravascular volume overload. Vascular stiffness and hypertension, and elevated levels of the phosphaturic hormone FGF23, contribute to the development of uremic cardiomyopathy, the most common form of which is extreme left ventricular hypertrophy (LVH) with fibrosis which, in turn, promotes the development of systolic dysfunction and sudden arrhythmic death. Overall, the pattern of CVD in ESRD, its pathogenesis, and the implications for treatment are markedly different from the general population; although the risk of CHD is increased, the disproportionate increase is in sudden death and death due to heart failure.

Potential RTR recipients carry this burden of accumulated CV risk—conventional and nonconventional—from time spent with CKD and on maintenance hemodialysis to the posttransplant period. After transplantation surgery, there is an abrupt increase in overall (and CV) events and mortality, particularly in the early postoperative period ( Fig. 30.2 ). This falls progressively thereafter, and survivors beyond the first few months have a mortality rate approximately half that of patients receiving maintenance dialysis, and a comparable reduction in nonfatal CV events. After transplantation, several specific CV risk factors are more prevalent. Dyslipidemia and hypertension are both very common, affecting nearly all patients. Lipid levels rise in the weeks after transplantation, reflecting improved well-being, diet, and immunosuppressive agents. Immunosuppressive agents also contribute to hypertension and to the development of diabetes (new-onset diabetes after transplantation [NODAT]). These risk factors, together with the level of posttransplant renal function (the relationship between eGFR and CVD being similar to that seen in primary CKD), preexisting CVD, and the increasing age of RTR, contribute to the overall level of CV risk after transplantation. However, in spite of this, CVD and mortality rates appears to be stable or even falling in RTR, reflecting improved management of transplant recipients and improved graft outcomes.

Epidemiology of Posttransplant CVD

Registry and cohort studies, and a small number of clinical trials, have examined the natural history and determinants of CVD in RTR. In looking at these data it is important to consider background improvements in immunosuppressive therapy, the increasing age of transplant recipients, and the use of kidneys from extended criteria donors (where the expectations for graft function are less good). Each of these factors is likely to influence the pattern of CVD in RTR in the future. It is also important to remember that endpoints recorded in registries may be inaccurate, and investigators in clinical trials often pool CV endpoints that are believed to share common pathophysiologic mechanisms, which may not be true in atypical populations, including RTR. A final issue that is often ignored is that of “competing risk,” where an individual risk factor may contribute to more than one adverse outcome. In transplant recipients, for example, smoking may increase the risk of infection, malignancy, and CVD, thus diminishing the apparent effect on any single outcome.

The early studies of Kasiske and colleagues, who followed up more than 1000 RTRs in a single US center, demonstrated a high incidence of CVEs and CV mortality, and a high prevalence of preexisting CVD in RTR. They confirmed that conventional CV risk factors, including age, sex, smoking status, and the presence of diabetes mellitus (either preexisting or developing after transplantation), were associated with the development of CVEs (which they termed “coronary heart disease”). For each year of life, the risk of a CVE was increased by 3% to 5%; males and patients with diabetes had a twofold increase in risk of a CVE. However, the strongest risk factors were preexisting CHD, peripheral vascular disease, or cerebral vascular disease, reflecting the importance of the burden of CV disease that individual patients carry at the time of transplantation. Most of the risk factors they identified, such as preexisting disease, age, and sex, are irremediable, and it has proved more difficult to identify any relationship between modifiable risk factors and CVEs.

Kasiske’s initial analysis revealed no association between posttransplant levels of triglyceride, total or low-density lipoprotein (LDL) cholesterol, and CVE in RTR. However, a subsequent larger analysis did show an association of risk with hyperlipidemia, albeit only with very high levels of total cholesterol and increased risk of long-term CVE. Unlike the general population there is not a clear, progressive relationship between lipid levels and CVEs. This observation, in keeping with the pattern seen in patients with ESRD receiving maintenance dialysis, provides support for the notion that CVD in RTR differs from the traditional atherosclerotic model. Similar observations have been reported in single-center studies from Europe. Long-term follow-up of clinical trials provides additional data, with the benefit that endpoints are externally validated and more accurate than registry data. The ALERT (Assessment of LEscol in Renal Transplantation) and, more recently, the FAVORIT (Folic Acid for Vascular Outcome Reduction in Transplantation) studies have been used to provide data on CVEs collected during follow-up of potential interventions in large populations of RTR. In the ALERT study 2100 stable RTRs were randomized to receive placebo or fluvastatin (40–80 mg/day) and followed for up to 8 years. Compared with studies of statin therapy in nontransplant populations at comparable high risk of CVEs, there are clear differences. Nontransplant patients with dyslipidemia and a history of CAD are likely to have further coronary events, and the risk of cardiac death is approximately one-third that of a nonfatal event. In contrast, patients with ESRD receiving maintenance dialysis are much more likely to suffer cardiac death than a nonfatal coronary event. RTRs occupy a position intermediate between these populations, with the increase in CVEs associated with an equal risk of cardiac death and nonfatal coronary events. It is likely that this alteration in proportions reflects an increase in the risk of death due to primary arrhythmia or heart failure, a pattern similar to that seen in patients with congestive heart failure. Of note, around 10% of otherwise stable RTRs experienced a cardiac event during the first 5 years of follow-up—an event rate (2% per annum) comparable to the annual mortality rate of stable RTR and the annual graft failure rate after the first year.

In the FAVORIT study 4110 stable RTRs were randomized to high-dose folic acid, the primary endpoint being a vascular composite of myocardial infarction, CV death, resuscitated CVD, revascularization procedures (coronary and noncoronary), and stroke. Given these analyses and the potentially disparate nature of the pooled endpoints, it is perhaps not surprising that there was no benefit of the intervention, that LDL cholesterol had no relationship with the composite outcome, and that the main determinants were age, preexisting CVD, diabetes, systolic blood pressure, and low eGFR. Table 30.1 shows the relationship between risk factors and CVEs in this population.

A prospective multinational study—the PORT (Patient Outcomes in Renal Transplantation) study —followed 23,575 adult RTRs for a median of 4.5 years. CVD disease was defined as a composite of proven myocardial infarction, coronary intervention, and cardiac death. The overall cumulative incidence was 3.1%, 5.2%, and 7.6% at 1, 3, and 5 years after transplantation, respectively. In the first year the distribution of events was nonfatal myocardial infarction (49%), coronary intervention (38%), and cardiac death (13%); beyond 1 year the corresponding values were 39%, 38%, and 23%. Conventional modifiable CV risk factors were very poor predictors of cardiac events, and varied with time after transplantation. Early events were predicted by age, male sex, history of cancer or diabetes, obesity, preexisting CV disease (CHD, peripheral vascular disease, or cerebrovascular disease), deceased donor transplant, and time on dialysis before transplantation. Conventional risk factors such as smoking, hypercholesterolemia, and hypertension were not significant, although they did correlate with a past history of CVD. Later events were dependent on poor graft function (low eGFR; and factors that adversely influence graft function such as acute rejection, delayed graft function, and posttransplant lymphoproliferative disease), the development of NODAT, and race.

Some of the differences in the analyses just discussed may be explained by pooling endpoints. The ALERT study also allows us to examine the relationship between risk factors and individual CVE (e.g., acute myocardial infarction [aMI] or cardiac death; Fig. 30.3 ), and to examine relationships masked by pooling of CVE with different determinants. In a multivariate analysis, the leading potentially remediable determinants of aMI (in addition to age, gender, and preexisting diabetes) were lipid levels. As in the general population, all major serum lipid subfractions were associated with aMI: total and LDL cholesterol, and triglyceride with an increased risk; HDL cholesterol with reduced risk. In contrast, no lipid subfraction was significantly associated with cardiac death, the main determinants of which were low eGFR and LVH, particularly when associated with subendocardial ischemia (LVH with “strain”) and pulse pressure. These observations strongly support the established literature on “uremic cardiomyopathy” and suggest that severe LVH, driven by renal dysfunction, hypertension, and the presence of LVH at the time of transplantation, may lead to increased risk of death due to heart failure or arrhythmia—with or without coexistent coronary disease.

The key message from these observations is that RTRs do suffer from CAD (fatal and nonfatal MI), the determinants of which are similar to the general population. However, cardiac death is perhaps a greater problem, the determinants of which are LVH, vascular stiffness, and hypertension. Studies by other investigators, including Abbott and Rigatto support these findings and underscore the observation that noncoronary events such as heart failure are common. In addition, they demonstrated that specific transplant risk factors including graft dysfunction (specifically graft failure) were associated with an approximately threefold increase in CVEs, including heart failure. Anemia proved to be a risk factor for the development of heart failure, although with improved anemia management a relationship with hemoglobin is now difficult to confirm.

Novel and Transplant-Specific Risk Factors

In the general population, the limited predictive ability of conventional CV risk factors has led to the search for novel risk factors and potential therapeutic targets. The presence of inflammation has become a central mechanism, with the recognition that inflammatory cells are involved in atherosclerosis and that circulating markers of inflammation, such as C-reactive protein, can identify patients at increased risk of atherosclerotic vascular disease who may benefit from established treatments. In RTRs there are similar initiatives. Markers of inflammation and circulating inhibitors of endothelial function have been studied in transplantation and are associated with an increased risk of CVD. Patients with simple features of inflammation, such as low albumin, are at higher risk. There are also transplant-specific risk factors, including those factors that contribute to poor graft function. These include the occurrence and severity of acute rejection episodes, delayed graft function, chronic rejection, cytomegalovirus infection, and other factors.

Specific Risk Factors and Management

In this section we will cover individual CV risk factors, their role, and their management. As noted previously, it is important to realize that transplantation is one phase in the course of progressive renal disease. Patients bring with them to transplantation accumulated risk, much of which is irremediable. For example, vascular stiffness and calcification, which develop in advanced CKD, contribute to hypertension after transplantation. Moreover, nearly all of the immunosuppressive drugs that have revolutionized the management of transplant recipients have effects on CV risk factors—some good, such as higher GFR; others potentially bad, such as hypertension and dyslipidemia. The pattern of effects of immunosuppressive agents is shown in Table 30.2 , and discussed in more detail later.

Hypertension and Uremic Cardiomyopathy

Hypertension is an almost invariable accompaniment of renal transplantation—a consequence of preexisting hypertension at the time of transplantation and the effects of immunosuppressive agents. Both increased vascular resistance and increased intravascular volume contribute to the development of hypertension. With declining GFR as CKD progresses, salt and water excretion are impaired, and volume-dependent mechanisms assume greater importance; after transplantation the contribution of volume-dependent mechanisms will similarly depend on the level of graft function, Details on the role of vasoconstrictor mechanisms and the relevance for treatment are described later.

Hypertension in RTRs is known to be associated with poorer patient and graft outcomes. There is no trial evidence for specific blood pressure targets in the RTR population, but data from the European Registry support the need to manage hypertension and inform treatment targets. In a series of RTRs with a functioning graft 1 year after transplantation, Opelz and colleagues demonstrated that blood pressure—recorded at outpatient clinics—is a major determinant of long-term patient and graft survival, albeit not independently from graft function. Current guidelines recommend a blood pressure target <130/80 mmHg, irrespective of the level of proteinuria, but in fact, the data suggest that graft outcomes start to deteriorate when systolic blood pressure is above 120 mmHg. Similarly, there appears to be an important relationship between blood pressure across the range from “normal” to hypertensive and the development of posttransplant CV disease ( Fig. 30.4 ). Epidemiologic studies, which include the placebo arms of interventional trials in transplant recipients, have confirmed that hypertension is associated with CVEs, specifically stroke, cardiac death, and heart failure, rather than nonfatal coronary events. Hypertension was the strongest determinant of cardiac death in the ALERT study, the most significant blood pressure parameters being systolic blood pressure and pulse pressure, both markers associated with vascular stiffness, rather than diastolic blood pressure.

Most clinics use “office-based” blood pressure measurements, using a standard sphygmomanometer. Blood pressure should preferably be assessed using repeated measurements, with the patient seated after a period of rest, or measuring ambulatory or home blood pressures as a more informative measure. In patients with essential hypertension these methods are recommended for patients with resistant hypertension, or where “white coat” syndrome is suspected. In transplant recipients ambulatory recordings are associated with prognosis, and loss of diurnal profile, or loss of the “nocturnal dip,” confers additional prognostic information. These methods should be used in patients with poor blood pressure control and may provide additional information in clinical trials.

Hypertension exhibits unfavorable effects indirectly through development of end-organ damage in RTRs—specifically proteinuria and LVH. Hypertension is the major contributor to LVH in patients with ESRD, including RTRs, and LVH is strongly associated with poor outcome in RTRs. The pathophysiology of LVH in CKD (uremic cardiomyopathy) is marked by the presence of subendocardial ischemia and myocardial fibrosis. Fibrosis is believed to promote aberrant conduction and is associated with markers of arrhythmogenicity, such as prolonged QT interval and abnormal T-wave alternans, which provide the likely link to fatal arrhythmias and sudden cardiac death. Arrhythmias may be spontaneous or complicate otherwise minor ischemic episodes. These observations identify hypertension, LVH, and electrocardiographic abnormalities as markers of adverse outcome in RTR, and as potential targets for intervention. The less common manifestation of uremic dilated cardiomyopathy (with systolic dysfunction) may be a sequel of LVH or may be associated with (often silent) CHD. Uremic cardiomyopathy develops, primarily, during the time patients spend with advanced CKD, and on maintenance dialysis programs, and is therefore common in new transplant recipients. Although there are studies that suggest that the manifestations of uremic cardiomyopathy may improve after transplantation, with apparent regression of LVH and improved systolic function, these studies may not reflect the true situation. Echocardiographic analyses are highly dependent on chamber diameters (e.g., in the estimation of left ventricular [LV] mass) which are, in turn, dependent on hydration status. Although patients with advanced CKD and treated by dialysis have a tendency to volume overload, this improves after successful transplantation, correcting artifactual overestimation of LV mass and systolic dysfunction. Hence, studies that use volume-independent technology (specifically cardiac magnetic resonance imaging) have not shown similar improvement. Long-term risks associated with the various manifestations of uremic cardiomyopathy in patients receiving maintenance dialysis are carried forward in patients who undergo transplantation. After transplantation, there are limited data on uremic cardiomyopathy, restricted to LVH, suggesting that effective blood pressure control and the avoidance of calcineurin inhibitors (CNIs) may reduce LVH. A series of small short-term studies suggests that the use of dihydropyridine calcium antagonists ; mammalian target of rapamycin (mTOR) inhibitors, sirolimus or everolimus, in place of CNI; or CNI withdrawal is associated with improvement in blood pressure and regression—or lack of progression—of LVH in RTRs.

There is evidence of increased or inappropriate activation of vasoconstrictor mechanisms in RTRs, including the sympathetic nervous system, the renin–angiotensin system, and endothelin both in humans and experimental animals. These, coupled with evidence of impaired endothelium-dependent (nitric oxide-mediated) vascular relaxation, shift the balance toward vasoconstriction. The mechanisms underlying these phenomena are less well understood. Corticosteroids are associated with hypertension in other clinical conditions and have two principal actions—to promote retention of salt and water due to actions of corticosteroids on the kidney and to enhance sympathetic activity, leading to increased vascular tone. CNIs cause hypertension through direct renal sodium retention and increased vasoconstrictor tone as well as indirectly via renal impairment, as a consequence of the nephrotoxic effects of CNI.

Several short-term studies have demonstrated that the most commonly used antihypertensive drugs, such as angiotensin receptor blockers, angiotensin-converting enzyme (ACE) inhibitors, and calcium channel blockers, have effects on blood pressure comparable to those seen in other populations. Dihydropyridine calcium channel antagonists, such as nifedipine and amlodipine, may attenuate the nephrotoxic effects of CNI and have been favored in the early phases after transplantation. Blockers of the renin–angiotensin system have been favored in patients with proteinuria and LVH, although the uptake has been slow because of concerns about the possible adverse effects in patients with undiagnosed, functional stenosis of the single transplant renal artery. Caution should also be taken with regard to hyperkalemia in the context of ACE inhibition and CNI. More radical approaches to the treatment of hypertension, such as embolization or laparoscopic removal of the native kidneys, have been employed and may be effective. Whereas patients with bilateral native nephrectomy before transplantation (including pediatric patients) may have good blood pressure control, the benefits are less clear in patients with established hypertension after transplantation.

Patient and graft survival is associated with prescription of ACEI/ARB in retrospective analyses ( Fig. 30.5 ). There are few prospective trials of antihypertensive treatment in RTRs. In recent years, two trials have assessed the prescription of ACE inhibitors on “hard” CV endpoints, with inconclusive results. Paoletti et al. report that treatment with lisinopril (5 mg once daily then titrated to response) is associated with a reduction in major CVEs and a composite endpoint of death, major CVE, renal graft loss, or creatinine doubling, compared with placebo. Knoll et al. report no effect of ramipril 5 mg once daily (OD) versus placebo on doubling of creatinine, graft loss, or all-cause mortality. Most RTRs with hypertension require treatment with more than one antihypertensive agent. In the absence of specific evidence of CV risk reduction with any particular class of drug, the choice of antihypertensive agent, as in other populations, should consider the need to treat other comorbidities, for example, beta-blockers for patients with symptomatic angina, and blockers of the renin–angiotensin system for patients with proteinuria.

Phosphate and the FGF23-Klotho Axis

FGF23, a phosphaturic hormone, works in conjunction with vitamin D and parathyroid hormone (PTH) to maintain correct serum levels of phosphorus. Phosphate handling and metabolism is impaired early in the course of CKD, and FGF23 has been established as a more sensitive biomarker for disordered phosphate metabolism in CKD than serum phosphate or PTH. FGF23 becomes elevated early in the disease course, whereas phosphate and PTH may become abnormal at GFR <30 (CKD stage 4), FGF23 levels are elevated even in CKD stage 2, with around one-third of patients with GFR 60 to 69 with elevated FGF23 levels.

FGF23 appears to be responsible for persistent hypophosphatemia seen in the early posttransplant period, but FGF23 levels usually will fall around 3 months after transplantation, then can reach a state of normal or near-normal from 1 year after transplant. Higher levels of FGF23 are again seen as transplant function declines. In a cross-sectional, observational study of 279 stable, prevalent RTRs, fewer than 50% of those with CKD stage 1 or 2 had normal FGF23 and PTH, and this reduced to 26.3% in those with more advanced transplant CKD. FGF23 is associated with LVH, inducing hypertrophy of isolated cardiac myocytes, and in in vivo mouse models, and this effect can be ameliorated by administration of FGF23 antagonists, independent of blood pressure. FGF23 is associated with cardiovascular and all-cause mortality, and allograft loss after transplantation, after adjustment for known cardiovascular risk factors and markers of mineral handling. It is likely that LVH induced by elevation of FGF23 explains some of the excess CV morbidity and mortality in RTRs.

Independent of FGF23, phosphate is a risk factor for vascular disease in patients with CKD and renal transplantation. By contrast to FGF23, this is likely mediated through direct effects on blood vessels, and by promoting vascular calcification (discussed later). In 1501 patients from the Chronic Renal Insufficiency Cohort (CRIC), coronary and thoracic aorta calcification were measured by computed tomography scan. Serum phosphate, but not FGF23, was found to be associated with presence and severity of arterial calcification, through a direct effect on inducing calcification of vascular smooth muscle cells. Furthermore, in vitro studies support a direct effect of high phosphate on endothelial function (via interference with the nitric oxide pathway), and high dietary phosphate load effects on vascular function, with impairment of vessel relaxation, independent of serum phosphate. Thus although FGF23 and phosphate are intrinsically linked in maintaining phosphate homeostasis, they appear to contribute to cardiovascular risk in RTRs independently and via distinct mechanisms.