Version May 2024
INTRODUCTION — Cardiovascular disease is the leading cause of morbidity and mortality after kidney transplantation. Death from cardiovascular disease is also the most common cause of graft loss.
This topic reviews the risk factors for cardiovascular disease among kidney transplant recipients. The epidemiology of cardiovascular disease following transplantation, cardiovascular outcomes compared with dialysis patients, and the evaluation of kidney transplant candidates are discussed elsewhere:
●(See "Kidney transplantation in adults: Patient survival after kidney transplantation".)
●(See "Kidney transplantation in adults: Evaluation of the potential kidney transplant recipient".)
OVERVIEW OF CARDIOVASCULAR RISK — Transplant recipients have a lower risk of fatal and nonfatal cardiovascular events compared with waitlisted patients on dialysis [1-4] but a much higher risk compared with the general population [5]. Forty to 60 percent of posttransplant deaths with a reported cause are attributable to cardiovascular disease, with an incidence of ischemic heart disease of approximately 1 per 100 person-years at risk [6-8]. Cardiovascular disease is the most common cause of death with graft function after transplant and accounts for 30 percent of graft loss from death overall, with the greatest rates early after transplant [9]. Notably, the incidence of cardiovascular death after transplantation appears to be declining somewhat despite the aging and increased comorbidity burdens among transplant recipients, which may reflect advances in medical management or competing risks of cancer and infection [10,11].
The high rate of cardiovascular deaths in the transplant population is due in part to the large number of diabetic patients in the end-stage kidney disease (ESKD) population, who are at markedly increased cardiovascular risk compared with nondiabetic transplant recipients. As an example, in one study of 933 predominantly living-donor transplant recipients, cardiovascular disease was the most common cause of death among diabetic recipients; by contrast, most deaths among nondiabetic recipients were due to infection, malignancy, or other causes [12].
However, the cardiovascular risk among transplant recipients who do not have ESKD related to diabetes is still higher than in the general population [9]. The increased cardiovascular risk is due to the following:
●An exacerbation of traditional risk factors present in the general population by immunosuppressive drugs (figure 1)
●Nontraditional risk factors related to immunosuppressive agents or to chronic kidney disease
Coronary heart disease — Traditional risk factors for coronary heart disease after kidney transplantation were investigated in a report of 403 patients who received 464 kidney transplants during a 10-year period [13]. New atherosclerotic complications developed in 16 percent of patients. After accounting for pretransplant vascular disease, multivariate analysis revealed that the following risk factors were independently associated with posttransplant atherosclerotic cardiovascular disease:
●Increasing patient age
●Diabetes mellitus
●Male sex
●Cigarette smoking
●Hypertension
●Elevated serum cholesterol
Similar findings were observed in other studies [14-16].
Nontraditional risk factors that have been associated with increased cardiovascular risk in various studies include reduced kidney function following transplantation, dialysis vintage prior to transplantation, rejection, hyperhomocysteinemia, elevated levels of lipoprotein(a), elevated C-reactive protein and interleukin-6 levels, reduced homoarginine levels, proteinuria, and low levels of physical activity [17-25].
Although not directly linked to cardiovascular disease, the presence of vascular calcifications detected radiographically prior to transplantation (a common finding) is also associated with increased cardiovascular and all-cause mortality posttransplantation [26,27]. (See "Vascular calcification in chronic kidney disease".)
Individual risk factors are discussed below. (See 'Individual risk factors' below.)
Myocardial infarction — Several studies have described the incidence and risk factors for myocardial infarction (MI) among kidney transplant recipients:
●A retrospective study based upon the United States Renal Data System (USRDS) evaluated the clinical correlates of posttransplant MI [1]. Among nearly 36,000 patients, the incidence of MI at 6, 12, and, 36 months was 4.3, 5.2, and 11.1 percent, respectively. The principal risk factors were increased age, recipient of kidneys from older donors and deceased donors, delayed allograft function, and the presence of pretransplant comorbidities, including diabetes, angina, peripheral vascular disease, and MI. The diagnosis of posttransplant diabetes and the development of allograft failure were also significantly associated with the development of an MI.
●In a similar study of 53,297 patients, a markedly increased risk of acute MI was observed early after transplantation, less than three months postsurgery [28]. Compared with waitlist patients, the risk also varied by recipients of a deceased-donor kidney (relative risk [RR] 3.57, 95% CI 3.21-3.96) and living-donor kidney (RR 2.81, 95% CI 2.31-3.42).
●In a retrospective analysis of the placebo arm of the Assessment of LEscol in Renal Transplantation (ALERT) study, independent risk factors for nonfatal MI by multivariate analysis were preexisting coronary heart disease (hazard ratio [HR] 3.69), total cholesterol level (HR 1.55 per 50 mg/dL), and prior acute rejection (HR 2.36) [15]. Age, diabetes, ST-T changes, and elevated serum creatinine levels were independent risk factors for cardiac death.
Heart failure — Cardiovascular disease includes both ischemic coronary heart disease and cardiomyopathy. Patients with ESKD, including transplant recipients, are at higher risk for both, compared with the general population. Cardiac endpoints are often pooled in epidemiologic studies, with the presumption that all reflect ischemic atherosclerotic disease [5]. Some studies have examined the risk of specific cardiac endpoints among transplant recipients.
Data on pretransplant heart failure (HF) prevalence and prognosis are limited, but the prevalence of HF with reduced ejection fraction in patients referred or wait-listed for transplantation may be as high as 25 percent [4,29-32].
Studies have shown that cardiomyopathy, either with or without clinical HF, is common among kidney transplant recipients. As examples:
●A retrospective analysis of data derived from the USRDS showed that the cumulative incidence of new-onset HF was 10.2 and 18.3 percent at 12 and 36 months, respectively [4].
●In a retrospective study of 638 consecutive kidney transplant recipients who were free of cardiac disease at one year, new-onset HF occurred as frequently as new-onset ischemic heart disease (1.26 versus 1.22 events per 100 patient-years, respectively) [18].
●The USRDS reports that HF is second only to infection as a cause of hospitalization after kidney transplantation [33].
Independent risk factors for new-onset HF after transplantation include age, diabetes, anemia, and hypertension [4,18]. Studies of USRDS data have identified obesity, donor factors that may predict suboptimal graft function, and graft loss as risk factors for HF [4,34].
Obesity and smoking are associated with increased risk of HF [4,29].
Body mass index (BMI) was independently associated with HF in several USRDS registry studies [4,35,36]. In one study, BMI ≥30 kg/m2 predicted up to 59 percent RR increase, compared with BMI <30 kg/m2 [35]. In another study of USRDS data, BMI > 28.3 kg/m2 independently predicted a 57 percent relative increase in the risk of hospitalized HF, compared with lower BMI [34].
A portion of obesity-related cardiovascular risk may be mediated by impacts on metabolic health including diabetes [37]. A meta-analysis of six studies including 4111 patients demonstrated an increased risk of posttransplant diabetes mellitus associated with BMI >30 compared with <30 kg/m2 (pooled RR 2.24, 95% CI 1.46-3.45).
HF is associated with increased mortality after transplantation [4,30]. In a single-center study, left ventricular systolic dysfunction, defined as left ventricular ejection fraction ≤45 percent by gated single photon emission computed tomography at the time of transplantation, was associated with 4.8 times the risk of cardiac death, 2 times the risk of all-cause mortality, and 1.8 times the risk of cardiac complications, compared with normal cardiac function [30]. A study of USRDS data identified clinical diagnosis of new-onset HF after transplant as a potent predictor of subsequent death (adjusted HR [AHR] 2.6) [4].
Pulmonary hypertension — Right HF and pulmonary hypertension at the time of transplantation have been associated with both delayed graft function and mortality [38,39]. In a study of 215 potential kidney transplant candidates, estimated right ventricular systolic pressure ≥50 mmHg was associated with an increased risk of posttransplant death (HR 3.75) [39]. Dialysis vintage was the strongest correlate of an elevated right ventricular systolic pressure. Among 739 transplant candidates assessed at a single center in New Zealand from 2000 to 2009, pulmonary hypertension and/or right ventricular dysfunction were independently associated with nearly twice the risk of all-cause mortality (AHR 1.91, 95% CI 1.28-2.83) over an average of 4.2 years after the echocardiographic evaluation in multivariate regression including age, diabetes, transplant listing status, severely impaired left ventricular ejection fraction, and presence of regional wall motion abnormalities [40].
Pulmonary hypertension in transplant candidates and recipients is generally a secondary, rather than idiopathic, process driven by left HF, high cardiac output from an arteriovenous fistula, hypoxic lung diseases, and metabolic derangements associated with kidney disease. Categorizing pulmonary hypertension according to underlying pathophysiologies, hemodynamic characteristics, and treatment responses as defined by the World Health Organization (WHO) can be challenging in this population but should be pursued to direct appropriate management [41,42]. (See "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults".)
RISK STRATIFICATION — Cardiovascular risk stratification after kidney transplantation may be based upon traditional and nontraditional risk factors (see 'Individual risk factors' below), clinical parameters (eg, blood pressure), structural or functional parameters (eg, left ventricular hypertrophy), and biomarkers (eg, cardiac troponins) [43].
Framingham risk score — The Framingham risk score is a composite index designed to predict coronary heart disease in the general population based upon traditional risk factors of age, sex, cholesterol levels, hypertension, and diabetes status. (See "Cardiovascular disease risk assessment for primary prevention: Risk calculators".)
Although the Framingham risk score performs well in the general population, it generally underestimates the risk of cardiovascular events among kidney transplant patients [17,44]. The individual Framingham risk factors are significantly associated with cardiovascular risk among kidney transplant recipients, but some effect sizes are increased among such patients.
This prediction error is greatest among patients at highest risk and is driven in part by an underestimate of diabetes-related risk [17,44]. As examples:
●In a retrospective study of 1124 kidney transplant recipients with stable graft function at one year, the observed increase in risk conferred by diabetes was greater in transplant recipients compared with the Framingham Heart Study population (RRs of 2.8 versus 1.5, respectively, among men, and 5.4 versus 1.8, respectively, among women) [44]. The risks conferred by age and smoking were also underestimated by the Framingham risk score, though to a lesser extent [44].
●In a historical cohort study of transplant recipients with functional allografts at one year, the Framingham risk score predicted only 59 percent of observed coronary events [17]. This was entirely due to an underestimate among high-risk patients (defined as greater than 20 percent risk of event at 10 years according to the Framingham heart score). The risk score performed well among low-risk patients (less than 20 percent risk at 10 years).
●In a prospective cohort study of 540 transplant recipients, the Framingham risk score underestimated cardiac events but not stroke, with ratios of observed-to-predicted cardiac events of 1.64 and 0.96, respectively [45]. As noted in the previous study, the risk score performed least well among the highest risk patients; subgroup analysis showed higher observed-to-predicted cardiac event ratios among patients with pretransplant diabetes, prior cardiac disease, or both (2.12, 2.00, and 2.74, respectively).
Others composite risk scores have been developed for the transplant population, but only a few have been externally validated [46,47].
Cardiac troponins — Measurement of cardiac troponins may allow more accurate cardiovascular risk stratification than is provided by currently available methods. Persistent elevations in cardiac troponins may result from volume overload, uncontrolled hypertension, or left ventricular hypertrophy, all which confer a higher risk of cardiovascular events [48].
As an example, in a single-center retrospective cohort study, elevated troponin T concentrations prior to transplantation (measured at the initial pretransplant evaluation and then annually for patients on the waiting list) were independently associated with posttransplantation cardiac events and death [49]. Over a mean follow-up of 28 months, troponin T concentrations of 0.01 to 0.03, 0.04 to 0.1, and greater than 0.10 ng/mL were associated with increased relative risks (RRs) of major adverse cardiac events after transplantation (hazard ratios [HRs] 2.52, 4.48, and 6.12, respectively).
In a prospective observational study of 331 kidney or kidney-pancreas recipients, each 0.01 mcg/L increase in troponin I measured at the time of transplantation was associated on multivariate analysis with a 17 percent increase in the risk of major adverse cardiac events within three months after transplantation (adjusted odds ratio [OR] 1.17) [50].
It remains uncertain how biomarker assessment should be used to direct therapies or subsequent diagnostic testing before or after kidney transplantation. Measurement of cardiac troponin concentrations in transplant recipients may be considered as an additional prognostic marker.
RISK REDUCTION — The reduction of cardiovascular risk requires the accurate assessment of risk in transplant candidates and the appropriate pharmacologic and nonpharmacologic interventions. (See 'Individual risk factors' below.)
A reduction in cardiovascular risk may be achieved through appropriate medical therapies.
●(See "Overview of primary prevention of cardiovascular disease".)
●(See "Aspirin for the secondary prevention of atherosclerotic cardiovascular disease".)
There is considerable practice variation in the use of potentially cardioprotective medications in kidney transplant recipients, even among patients considered to be at high risk based upon preexisting diabetes or cardiovascular disease. Studies suggest that primary and secondary cardiovascular preventive measures are underutilized among transplant recipients [51-53]. As examples:
●The Long-Term Deterioration of Kidney Allograft Function (DeKAF) study, a multicenter, prospective, observational study of transplant recipients, revealed that fewer than 30 percent of participating transplant recipients with preexisting cardiovascular disease or diabetes received angiotensin-converting enzyme (ACE) inhibitor/angiotensin-II receptor blocker (ARB) therapy at six months posttransplant; fewer than 60 percent received aspirin; and one-half received a statin [51].
●Predicting Outcomes in Renal Transplantation (PORT), a multicenter, collaborative database investigation of nonimmunosuppressive medication use, found no difference in the use of most cardiovascular medications between diabetic and nondiabetic patients. Although the use of multiple cardiovascular medications was higher in patients with a previous cardiovascular event compared with patients with no previous cardiovascular disease, fewer than 75 percent of patients with previous cardiovascular disease were using a statin or antiplatelet agent [52].
●Use of integrated Organ Procurement and Transplantation Network (OPTN) registry and pharmacy billing claims data to characterize cardiovascular medication prescriptions early after myocardial infarction (MI) showed that, within the first 60 days after acute MI (AMI), prescriptions for beta blockers, antiplatelet agents, ACE inhibitors/ARBs, and statins were submitted in only 83, 48, 65, and 72 percent, respectively, which was roughly comparable with nontransplant patients matched by demographic and measured clinical characteristics [53].
●Linked OPTN and pharmacy data from 2005 to 2010 demonstrated that approximately 18 to 25 percent of kidney transplant recipients were treated with an ACE inhibitor/ARB, and 25 to 45 percent received a statin at one year posttransplant, depending upon kidney function and immunosuppressive regimen [54,55]. These data also suggest variation with immunosuppression regimen. Compared with those taking triple immunosuppression, recipients taking tacrolimus-based dual- and monotherapies had lower use of statins and ACE inhibitors/ARBs.
While there may be legitimate reasons for not prescribing potentially cardioprotective medications in transplanted patients (eg, allograft dysfunction, hyperkalemia, and anemia may limit use of ACE inhibitors/ARBs), these studies suggest potential room for improvement in the treatment of cardiovascular risks among high-risk transplant recipients.
INDIVIDUAL RISK FACTORS
Traditional risk factors
Pretransplant cardiovascular disease — Pretransplant cardiovascular disease continues to be the most important predictor of posttransplant cardiovascular events [13,56,57].
Dyslipidemia — Despite advances in short-term allograft survival due to improvements in immunosuppressive regimens, dyslipidemia remains a significant problem in the transplant population. Glucocorticoids, cyclosporine, sirolimus, and, to a lesser extent, tacrolimus increase serum triglyceride and cholesterol concentrations. This is discussed in detail separately. (See "Lipid abnormalities after kidney transplantation".)
Blood pressure — Hypertension is a well-known risk factor for cardiovascular disease and stroke in both the general population and transplant recipients due in part to its association with left ventricular hypertrophy. (See "Cardiovascular risks of hypertension".)
The association of high systolic blood pressures with cardiovascular disease among transplant recipients has been shown in post hoc analyses of two randomized trials [58,59]. In an analysis of data from the Folic Acid for Vascular Outcomes Reduction in Transplantation (FAVORIT) trial, each 20 mmHg increase in systolic pressure was associated with an increased risk of cardiovascular disease (hazard ratio [HR] 1.32, 95% CI 1.19-1.46) and mortality (HR 1.13, 95% CI 1.01-1.27) [58]. At diastolic blood pressures of <70 mmHg, each 10 mmHg decrease in diastolic blood pressure was associated with increased risk of cardiovascular disease (HR 1.31, 95% CI 1.06-1.62) and mortality (HR 1.31, 95% CI 1.03-1.66). However, virtually all participants had kidney function impairment, which may limit the generalizability of observations [60].
Reinforcing the outcome implications of low blood pressure, an analysis of integrated national transplant registry, pharmacy fill, and medical claims data found that pretransplant midodrine use, an indicator of symptomatic hypotension, also predicted posttransplant complications [61]. Midodrine use in the year before transplant was associated with increased adjusted risks of delayed graft function, hypotension, acute myocardial infarction (AMI), cardiac arrest, graft failure, and death over the first year posttransplant.
The immunosuppressive agents that can cause new-onset hypertension or exacerbate preexisting hypertension include calcineurin inhibitors and, to a lesser extent, because of rapid dose reduction, corticosteroids.
Details concerning these issues and the management of hypertension in kidney transplant recipients are discussed separately. (See "Hypertension after kidney transplantation".)
Diabetes mellitus — Both pretransplant and posttransplant diabetes mellitus are associated with the risk of posttransplant cardiovascular complications such as MI and heart failure (HF) [1,4]. Antirejection medications that contribute to posttransplant diabetes mellitus include glucocorticoids, calcineurin inhibitors, and mammalian (mechanistic) target of rapamycin (mTOR) inhibitors, although risk may be modified by other factors such as age and body mass index (BMI) [62]. (See "Kidney transplantation in adults: Posttransplantation diabetes mellitus".)
Chronic kidney disease — As observed among nontransplanted patients, kidney function impairment in kidney transplant patients is a significant risk factor for adverse cardiovascular outcomes [23,35,63] (see "Chronic kidney disease and coronary heart disease"):
●Among nearly 60,000 patients in one registry study, there was a graded increase in the risk of cardiac death with serum creatinine levels above 1.5 mg/dL (133 micromol/L) at one year posttransplant, up to more than twice the relative risk (RR) among those with serum creatinine levels 2.6 to 4.0 mg/dL compared with <1.5 mg/dL (adjusted HR [AHR] 2.6) [23].
●In a second registry study of almost 30,000 kidney transplant recipients, a decreased estimated glomerular filtration rate (eGFR) of <45 mL/min/1.73 m2 at one year posttransplant correlated with increased risk of acute coronary syndrome (AHR 2.2) and HF (AHR 2.95) [35].
●Among over 1000 placebo-treated patients in the Assessment of LEscol in Renal Transplantation (ALERT) trial, an increased serum creatinine concentration, particularly higher than 2.3 mg/dL (200 micromol/L), was strongly associated with an increased risk of adverse cardiac events and cardiac death [63,64].
●In a post hoc analysis of data for 3511 prevalent kidney transplant recipients in the FAVORIT trial, cardiovascular event rates over four years were higher among those with both lower eGFRs and higher urinary albumin-to-creatinine ratios at randomization [65].
Obesity and the metabolic syndrome — The epidemic of obesity in the United States has not spared kidney transplant candidates. Obesity trends in transplant recipients tend to mimic the general population (see "Obesity in adults: Prevalence, screening, and evaluation"). While less than 20 percent of candidates were classified as having any level of obesity (BMI >30 kg/m2) in the 1990s, in 2011, 23 percent of United States recipients were classified with class I obesity (BMI 30 to 34.9 kg/m2), 9.4 percent with class II obesity (BMI 35 to 39.9 kg/m2), and 2.1 percent with class III obesity (BMI >40 kg/m2) [66].
Weight gain after transplant is common and may be related to improved appetite with reversal of uremia and relatively high glucocorticoid doses in the peritransplant period but is also associated with physical inactivity [67]. Obesity among transplant recipients is frequently associated with the metabolic syndrome. The metabolic syndrome was identified among 63 percent of 606 kidney transplant recipients assessed at a median of six years posttransplant at one center [68].
Obesity increases the risk of cardiovascular disease in the general population (see "Obesity: Association with cardiovascular disease"). Among kidney transplant recipients, the presence of obesity, particularly in association with the metabolic syndrome, also appears to be associated with an increased number of adverse cardiovascular events. In one study of 337 kidney transplant recipients, one-third had metabolic syndrome by the first transplant anniversary, whereas only 20 percent had metabolic syndrome before transplant [69]. Over eight years of follow-up, 42 percent of the sample developed atherosclerotic disease events, and the risk of these events was significantly increased among patients with metabolic syndrome by one year after transplant (HR 3.4, 95% CI 1.6-7.3).
High BMI has also been associated with an increased risk of cardiac death after kidney transplantation. In a study of nearly 52,000 patients in the United States Renal Data System (USRDS) registry, the adjusted risk of cardiac death increased at both low BMI (AHR 1.3 for BMI of <20 kg/m2) and high BMI (AHR 1.2 for BMI 30 to 32 kg/m2; AHR 1.4 for BMI >36 kg/m2), compared with the reference group with BMI 22 to 24 kg/m2 [70].
Obesity also increases the risk of HF and atrial fibrillation. As an example, in a single-center study, the five-year incidence of cardiac diagnoses increased from 9 to 30 percent as the BMI quartiles increased from the lowest to highest [29]. This was largely due to increases in the incidence of HF and atrial fibrillation.
BMI was independently associated with increased risk of HF and atrial fibrillation in several USRDS registry studies [4,35,36]. As an example, BMI ≥30 kg/m2 predicted up to 59 percent RR increase compared with BMI < 30 kg/m2 [35]. In other studies of USRDS data, BMI > 28 kg/m2 independently predicted a 57 and 79 percent relative increase in the risk of hospitalized HF and atrial fibrillation, respectively, compared with lower BMI [34,36].
Lifestyle changes based in diet and exercise, with supervision by a kidney dietician as needed, are first-line strategies to achieve and maintain normal body weight among obese transplant recipients [71]. Cases of bariatric surgery among transplant recipients with obesity have been reported [72], but surgical therapies warrant prospective evaluation to quantify risks and benefits in this population.
Smoking — In the general and transplant populations, smoking increases the risk of cardiovascular disease [73,74]. Among transplant recipients, smoking has been independently associated with the risk of death with graft function [74], all-cause mortality [75], and events such as HF [4], ischemic stroke [3], and new-onset cardiovascular disease after transplant [75]. With smoking cessation, the increased risk dissipates over time [73]. We recommend complete smoking cessation, with the adoption of measures to encourage smoking cessation.
Unfortunately, no clinical trial data address the safety and utility of pharmacologic interventions to promote smoking cessation in the transplant population:
●Nicotine replacement options probably carry little risk and may promote successful cessation.
●The use of varenicline may be problematic in kidney allograft recipients with poor kidney function as this drug is renally excreted. Dosing of this agent in those with decreased kidney function is discussed separately. (See "Overview of smoking cessation management in adults".)
Albuminuria — As in the general population, albuminuria appears to be a risk factor for cardiovascular disease in kidney transplant recipients. A post hoc analysis of data from the FAVORIT trial found that, compared with urinary albumin-to-creatinine ratio <10 mg/g at randomization, urinary albumin-to-creatinine ratios of 30 to 299 and ≥300 mg/g were independently associated with an increased risk of major adverse cardiac events (HRs 1.25, 95% CI 0.96-1.61, and 1.55, 95% CI 1.13-2.11, respectively), graft failure (HRs 3.40, 95% CI 2.19-5.30, and 9.96, 95% CI 6.35-15.62, respectively), and all-cause death (HRs 1.65, 95% CI 1.23-2.21, and 2.07, 95% CI 1.46-2.94, respectively) over four years [65]. Similarly, among 1069 kidney transplant recipients in Canada, over a median follow-up of six years, the adjusted rate of all-cause mortality and cardiovascular events was 2.7-fold higher for recipients with an eGFR of 15 to 29 mL/min/1.73 m2 and heavy albuminuria (>300 mg/g) compared with recipients with an eGFR ≥60 mL/min/1.73 m2 and normal albuminuria (rate ratio 2.7, 95% CI 1.3-5.7) [76]. Recipients with heavy albuminuria had a threefold increased risk of all-cause mortality and HF compared with recipients with eGFR ≥60 mL/min/1.73 m2 and normal albuminuria.
Other risk factors
Anemia — Anemia defined by World Health Organization (WHO) criteria affects up to 30 to 40 percent of kidney transplant recipients [77,78]. Posttransplant anemia has been correlated with the risk of subsequent cardiovascular complications such as HF [4] and atrial fibrillation [79], as well as with increased risk of posttransplant graft loss and patient death [80,81].
Recommendations regarding the management of posttransplant anemia are discussed separately. (See "Anemia and the kidney transplant recipient".)
Hyperhomocysteinemia — Homocysteine is a nonessential amino acid that is an intermediate in the synthesis of cysteine and a precursor of the essential amino acid, methionine. Since homocysteine is normally cleared by the kidneys, serum concentrations are increased in chronic kidney disease [82]. Hyperhomocysteinemia is also caused by an absolute or relative deficiency of vitamins B6, B12, and folate, all of which are involved in methionine metabolism and by defects in the methylene tetrahydrofolate reductase enzyme. (See "Overview of homocysteine".)
The presence of elevated homocysteine levels in peripheral venous blood has been identified as an independent risk factor for ischemic heart disease and stroke in the general population, as well as being a predictor of mortality in patients with coronary heart disease in some studies [83]. (See "Overview of homocysteine", section on 'Disease associations'.)
This association has also been found among kidney transplant recipients [17,84,85]:
●In one prospective study of 207 stable patients, fasting mean total homocysteine levels were significantly higher among patients who experienced a cardiovascular event at follow-up of 21 months (32 versus 18 micromol/L for those without such an event) [84].
●Among 733 kidney transplant recipients during a six-year period, elevated homocysteine levels were associated with 2.44 times the mortality risk of patients with normal levels (HR 2.44, 95% CI 1.45-4.12) [85].
Effective reduction in serum homocysteine levels in kidney transplant recipients may be obtained with the administration of folic acid and vitamins B6 and B12 [86]. However, although hyperhomocysteinemia is an independent risk factor for cerebrovascular, peripheral vascular, and coronary heart disease, lowering homocysteine levels has not been shown to decrease cardiovascular risk in kidney transplant recipients. As an example, the multicenter randomized trial FAVORIT showed no reduction in all-cause mortality, end-stage kidney disease (ESKD), or in a composite outcome including cardiovascular death, MI, resuscitated sudden death, stroke, revascularization, amputation, or aortic aneurysm repair among 4110 kidney transplant recipients treated with vitamin B6 and vitamin B12 and with either high- or low-dose folic acid, despite the fact that homocysteine was effectively lowered with high-dose folic acid [87]. Based upon this study, a 2015 Cochrane review concluded that there is no evidence to support the use of homocysteine-lowering therapy for cardiovascular disease prevention in kidney transplant recipients [88].
Homoarginine deficiency — Homoarginine is a lysine-derived amino acid that is primarily synthesized in the kidney and increases intracellular concentrations of L-arginine, which is the main substrate for nitric oxide (NO) synthase [89]. Homoarginine may decrease endothelial injury and cardiovascular risk, and homoarginine deficiency may increase cardiovascular risk. In a post hoc analysis of the ALERT trial, among kidney transplant recipients who were randomly assigned to the placebo arm (n = 829), at an average of 6.7 years of follow-up, compared with those in the highest homoarginine quartile (>2.34 micromol), patients in the lowest quartile (<1.40 micromol/L) had 2.6 times increased risk of cerebrovascular events (AHR 2.56, 95% CI 1.13-5.82) and 2.3 times increased risk of graft loss or doubling of serum creatinine (AHR 2.34, 95% CI 1.36-4.02) [25].
Compared with the highest homoarginine quartile, the lowest and second homoarginine quartiles were associated with increased risks of noncardiovascular mortality, while the lowest quartile was associated with 2.5 times the risk of all-cause mortality (AHR 2.50, 95% CI 1.38-4.55). Otherwise, risks did not differ significantly for the second and third compared with the highest quartile, and there were no significant associations of homoarginine levels with major adverse cardiovascular events or nonfatal MI. Another study of 704 kidney transplant recipients found an inverse association of higher urinary homoarginine with lower all-cause mortality and graft failure over an average of three years [90]. Further research is needed to determine whether homoarginine supplementation modifies cardiovascular risk in this population.
Hyperphosphatemia — Hyperphosphatemia has been associated with a higher risk of cardiovascular disease in kidney transplant patients. In a post hoc analysis of data for 3138 kidney transplant recipients participating in the FAVORIT trial, a 1 mg/dL higher serum phosphorus level was associated with a significant increase in the risk of major adverse cardiac events (HR 1.14, 95% CI 1.00-1.31), transplant failure (HR 1.72, 95% CI 1.46-2.01), and mortality (HR 1.34, 95% CI 1.15-1.54) over four years, after adjustment for trial treatment allocation, traditional cardiovascular risk factors, type of kidney transplant, transplant vintage, and use of calcineurin inhibitors, glucocorticoids, and lipid-lowering drugs [91]. Associations were attenuated after adjustment including eGFR and albuminuria: cardiovascular events (HR 1.06, 95% CI 0.92-1.22), transplant failure (HR 1.36, 95% CI 1.15-1.62), and total mortality (HR 1.21, 95% CI 1.04-1.40).
Dialysis vintage — Increasing dialysis vintage prior to transplantation is associated with a graded increase in the risk of cardiovascular death after transplant [23]. A likely explanation for this is that accelerated atherogenesis is observed as part of the uremic syndrome. Proatherogenic factors that contribute to the progression of vascular disease prior to transplantation may include anemia, abnormalities of mineral metabolism, dyslipidemia [92], and hyperhomocysteinemia [83].
These factors become increasingly important with the onset of chronic allograft dysfunction that leads to progressive uremia. (See "Kidney transplantation in adults: Risk factors for graft failure".)
SUMMARY AND RECOMMENDATIONS
●Overview – Cardiovascular disease is the leading cause of morbidity and mortality after kidney transplantation. Death from cardiovascular disease is also the most common cause of graft loss. Transplant recipients have a lower risk of fatal and nonfatal cardiovascular events compared with waitlisted patients on dialysis but a much higher risk compared with the general population. The high rate of cardiovascular deaths in the transplant population is due in part to the large number of patients with diabetes in the end-stage kidney disease (ESKD) population, who are at markedly increased cardiovascular risk compared with transplant recipients without diabetes. (See 'Overview of cardiovascular risk' above.)
●Risk stratification – The Framingham risk score underestimates the risk of cardiovascular events among kidney transplant patients. Although the individual Framingham risk factors are significantly associated with cardiovascular risk among kidney transplant recipients, the effect sizes are increased among such patients, especially among patients at highest risk. (See 'Framingham risk score' above.)
●Risk reduction – The reduction of cardiovascular risk requires the accurate assessment of risk in transplant candidates and the appropriate pharmacologic and nonpharmacologic interventions. (See 'Risk reduction' above.)
●Traditional risk factors – Traditional risk factors present in the general population also exist in kidney transplant recipients. These factors include pretransplant cardiovascular disease, dyslipidemia, hypertension, diabetes mellitus, chronic kidney disease, obesity and the metabolic syndrome, smoking, and albuminuria. Some of these factors may be exacerbated by immunosuppressive medications. (See 'Traditional risk factors' above.)
●Other risk factors – Other nontraditional risk factors present in kidney transplant recipients include posttransplant anemia, hyperhomocysteinemia, homoarginine deficiency, hyperphosphatemia, and dialysis vintage. (See 'Other risk factors' above.)
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