Cardiovascular disease in the kidney transplant recipient: epidemiology, diagnosis and management strategies

Nephrology Dialysis Transplantation, May 2019

Kidney transplantation (KT) is the optimal therapy for end-stage kidney disease (ESKD), resulting in significant improvement in survival as well as quality of life when compared with maintenance dialysis. The burden of cardiovascular disease (CVD) in ESKD is reduced after KT; however, it still remains the leading cause of premature patient and allograft loss, as well as a source of significant morbidity and healthcare costs. All major phenotypes of CVD including coronary artery disease, heart failure, valvular heart disease, arrhythmias and pulmonary hypertension are represented in the KT recipient population. Pre-existing risk factors for CVD in the KT recipient are amplified by superimposed cardio-metabolic derangements after transplantation such as the metabolic effects of immunosuppressive regimens, obesity, posttransplant diabetes, hypertension, dyslipidemia and allograft dysfunction. This review summarizes the major risk factors for CVD in KT recipients and describes the individual phenotypes of overt CVD in this population. It highlights gaps in the existing literature to emphasize the need for future studies in those areas and optimize cardiovascular outcomes after KT. Finally, it outlines the need for a joint ‘cardio-nephrology’ clinical care model to ensure continuity, multidisciplinary collaboration and implementation of best clinical practices toward reducing CVD after KT.

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Cardiovascular disease in the kidney transplant recipient: epidemiology, diagnosis and management strategies

Abstract Kidney transplantation (KT) is the optimal therapy for end-stage kidney disease (ESKD), resulting in significant improvement in survival as well as quality of life when compared with maintenance dialysis. The burden of cardiovascular disease (CVD) in ESKD is reduced after KT; however, it still remains the leading cause of premature patient and allograft loss, as well as a source of significant morbidity and healthcare costs. All major phenotypes of CVD including coronary artery disease, heart failure, valvular heart disease, arrhythmias and pulmonary hypertension are represented in the KT recipient population. Pre-existing risk factors for CVD in the KT recipient are amplified by superimposed cardio-metabolic derangements after transplantation such as the metabolic effects of immunosuppressive regimens, obesity, posttransplant diabetes, hypertension, dyslipidemia and allograft dysfunction. This review summarizes the major risk factors for CVD in KT recipients and describes the individual phenotypes of overt CVD in this population. It highlights gaps in the existing literature to emphasize the need for future studies in those areas and optimize cardiovascular outcomes after KT. Finally, it outlines the need for a joint ‘cardio-nephrology’ clinical care model to ensure continuity, multidisciplinary collaboration and implementation of best clinical practices toward reducing CVD after KT. cardiovascular disease, chronic kidney disease, kidney transplantation, multidisciplinary management, risk factors INTRODUCTION Kidney transplantation (KT) is the treatment of choice for patients with end-stage kidney disease (ESKD) and is associated with improved outcomes and reduced mortality [1]. Although the survival benefit with KT is largely attributable to reduction in cardiovascular disease (CVD) burden (Figure 1), KT recipients continue to remain at higher risk for CVD-related morbidity and mortality when compared with the general population [3, 4]. Additionally, CVD represents the leading cause of death in KT recipients with a functioning allograft [5, 6]. The post-KT milieu represents the confluence of several traditional and nontraditional cardiovascular (CV) risk factors contributing to the significant CVD risk in this population [7]. KT recipients have a high prevalence of preexisting as well as de novo traditional CVD risk factors, such as hypertension (40–90% of patients) [8, 9], diabetes (24–42%) [10], dyslipidemia (50%) [11] and smoking (25%) [12]. Nontraditional risk factors include the adverse metabolic effects of immunosuppression, chronic anemia, hyperhomocysteinemia, chronic inflammation, proteinuria and chronic allograft nephropathy [13]. These risk factors result in increased risk of the entire spectrum of CVD, such as coronary artery disease (CAD), heart failure (HF), valvopathy, cerebrovascular disease, pulmonary hypertension (PH) and cardiac arrhythmias. FIGURE 1 View largeDownload slide Prevalence of CVD in adult end-stage renal disease (ESRD) patients, by treatment modality (2015). Special analyses, USRDS ESRD Database. Point prevalent hemodialysis, peritoneal dialysis and transplant patients aged ≥22 years, who are continuously enrolled in Medicare Parts A and B and with Medicare as primary prayer from 1 January to 31 December 2015, and ESRD service date is at least 90 days prior to 1 January 2015 [2]. The data reported here have been supplied by the USRDS. The interpretation and reporting of these data are the responsibility of the author(s) and in no way should be seen as an official policy or interpretation of the US government. AMI, acute myocardial infarction; CVA/TIA, cerebrovascular accident/transient ischemic attack; PAD, peripheral arterial disease; VTE/PE, venous thromboembolism and pulmonary embolism; SCA/VA, sudden cardiac arrest and ventricular arrhythmias. FIGURE 1 View largeDownload slide Prevalence of CVD in adult end-stage renal disease (ESRD) patients, by treatment modality (2015). Special analyses, USRDS ESRD Database. Point prevalent hemodialysis, peritoneal dialysis and transplant patients aged ≥22 years, who are continuously enrolled in Medicare Parts A and B and with Medicare as primary prayer from 1 January to 31 December 2015, and ESRD service date is at least 90 days prior to 1 January 2015 [2]. The data reported here have been supplied by the USRDS. The interpretation and reporting of these data are the responsibility of the author(s) and in no way should be seen as an official policy or interpretation of the US government. AMI, acute myocardial infarction; CVA/TIA, cerebrovascular accident/transient ischemic attack; PAD, peripheral arterial disease; VTE/PE, venous thromboembolism and pulmonary embolism; SCA/VA, sudden cardiac arrest and ventricular arrhythmias. The current emphasis on post-KT care is preferentially centered around prevention of rejection and immunosuppression-related complications, with a less clearly defined agenda for prioritizing CVD-related morbidity and mortality as a modifiable outcome. Thus, while a CV evaluation is performed frequently pre-KT, the emphasis on CVD risk factor modification and disease management tends to fall into a ‘snapshot’ assessment pre-KT, rather than on a continuum from the pre-KT to the post-KT sphere. The management of CVD risk factors and disease phenotypes are further limited by the underrepresentation of patients with chronic kidney disease (CKD) and/or KT in major CV outcomes trials, thus resulting is less robust evidence-based practices and delivery of potentially beneficial therapies in this population [14]. In this review, we summarize the risk factors for CVD post-KT and their management. Next, we outline the various CVD phenotypes with pertinent data in the post-KT setting, as well as gaps in the existing literature. Finally, we describe barriers to delivery of optimal CVD care in patients with ESKD, and suggest a multidisciplinary ‘cardio-nephrology’ team approach that may optimize CVD care post-KT. METHODOLOGY Members of the American Society of Transplantation’s Kidney-Pancreas Community of Practice (AST-KPCOP) Cardiovascular Disease Workgroup held a series of teleconferences and web-based communications from July to November 2018 to (i) identify the topics to address in this comprehensive narrative on CVD in KT recipients, (ii) perform literature review and collate a bibliography using MEDLINE (1966–present) and the Cochrane Central Register of Controlled Trials as the primary sources for the literature search limited to human studies and the English language, (iii) identify key conference proceedings and relevant online data sources and (iv) create an outline for the manuscript and identify lead authors for each of the sections. Key relevant search words and medical subject heading (MeSH) descriptors are provided in the Supplementary table, S1. Preliminary drafts were collated into a single draft by two main authors (J.R. and R.O.M.) and distributed to the workgroup for edits prior to finalizing the submission. All authors had continuous access to the working document to provide input, critical review and revisions. CARDIOVASCULAR AND METABOLIC RISK FACTORS AFTER KIDNEY TRANSPLANTATION Hypertension as a risk factor Hypertension following KT is both a result and cause of kidney allograft dysfunction; in addition, it is associated with adverse CV outcomes as well as premature CVD-related mortality [15, 16]. While treatment targets post-KT should probably be similar to those with CKD, there are no trials in post-KT patients comparing different blood pressure (BP) targets [17]. Kasiske et al. performed a retrospective cohort analysis of 1666 KT recipients and identified that each 10 mmHg of systolic blood pressure (SBP) increase was associated with 5% increased risk of allograft failure and death [8]. These data were recently validated in a recent post hoc study of the Folic Acid for Vascular Outcome Reduction in Transplantation (FAVORIT) cohort, which showed that every 20 mmHg increase in SBP over baseline was associated with a 32% increase in CVD and a 13% increase in mortality. Interestingly, a decrease in diastolic blood pressure (DBP) ≤70 mmHg was associated with CVD and mortality as well, while higher levels were not [18]. In addition to preexisting hypertension, transplant-related factors such as CKD stage posttransplant, vascular pathology and treatment with calcineurin inhibitors (CnI) and steroids are involved in the pathogenesis of de novo hypertension post- KT [13]. The use of CnI-based immunosuppressive regimens and steroid maintenance therapy have been associated with a high prevalence of post-KT hypertension [19]. In a meta-analysis of 34 randomized controlled trials (RCTs) comparing a maintenance steroid group with complete avoidance or withdrawal of steroids, Knight and Morris showed a reduced incidence in hypertension with steroid avoidance or withdrawal (SAW) [risk ratio (RR) 0.90; 95% confidence interval (CI) 0.85–0.94] [20]. However, the utilization of SAW for its potential benefits with hypertension and other cardio-metabolic risk factors [including posttransplant diabetes mellitus (DM) and hyperlipidemia] [20] must be weighed against the reported increased risk with acute rejection in pooled data analyses [20, 21]. Finally, despite a demonstrable benefit in long-term renal function with the use of belatacept-based immunosuppression, hypertension was still a significant factor in these KT recipients posttransplantation. In a pooled analysis of belatacept trials, only modest reductions in SBP and DBP were seen in those on belatacept compared with those on CnIs [22, 23]. Early post-KT BP targets tend to be more liberal (<160/90 mmHg) with the intention of maintaining optimal renal allograft perfusion and reducing the risk of renovascular thrombosis [17]. After the first month, BP control targets should mirror nontransplant CKD settings to reduce end organ damage [16]. The American College of Cardiology Foundation/American Heart Association 2017 Guidelines on Blood Pressure Management recommend a treatment target of <130/80 mmHg for post-KT recipients (IIa), as well as a recommendation to use calcium channel blockers as the initial drug of choice (IIa) on the basis of improved glomerular filtration rate (GFR) and allograft survival shown with this drug class [17, 24]. This is likely because of the known effects of intrarenal vasoconstriction and increased systemic vascular resistance with the usage of CnIs [25], which to some extent are reversed by calcium channel blockers [26]. Data supporting the use of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are inconsistent, with a large retrospective study of about 39 000 KT recipients in the Collaborative Study Cohort showing no difference in adverse CV events in the ACEI/ARB group versus other antihypertensive medications [27]. In contrast, another study suggested a cardiovascular benefit for ACEIs/ARBs may be seen, but not until a longer follow time of 10 years [28]. A meta-analysis of eight randomized trials of renin–angiotensin–aldosterone system inhibitors (RAASi) versus placebo/standard of care in KT recipients by Hiremath et al. [29] showed that RAASi did not significantly alter all-cause mortality (RR 0.96; 95% CI 0.62–1.51), transplant failure (RR 0.76; 95% CI 0.49–1.18) or creatinine level doubling (RR 0.84; 95% CI 0.51–1.39) compared with the control group [29]. There was significantly higher risk for hyperkalemia with RAAS blockade (RR 2.44; 95% CI 1.53–3.90). Given the concern for hyperkalemia and the potential to exacerbate pre-renal azotemia with the use of RAASi, the RAASi may be best reserved for the subset of post-KT recipients with hypertension and additional comorbidities that support the need for RAASi therapy (i.e. proteinuria or HF after KT). However, with appropriate potassium and estimated glomerular filtration rate (eGFR) monitoring, the use of RAASi has been demonstrated to be generally safe [30, 31]. The availability of the novel oral antihyperkalemic agents (patiromer and sodium zirconium cyclosilicate) may offer the opportunity to test the potential benefits of RAASi in the post-KT settings in a controlled fashion [32, 33]. It must be mentioned that there are limited data on the risk/benefit profiles of the novel antihyperkalemic agents in the post-KT setting, although small single center experiences have reported the ability to maintain target therapeutic tacrolimus levels with concomitant use of these drugs when administered as per labeling specifications [34]. Dyslipidemia and hyperhomocysteinemia: risk for atherogenic CVD Dyslipidemia is highly prevalent post-KT, and is exacerbated by comorbid conditions such as obesity, posttransplant DM, proteinuria and immunosuppression, especially with the mammalian target of rapamycin (mTOR) inhibitors. In one of the first large randomized control studies of KT and CV outcomes, 2106 recipients were randomized to fluvastatin versus placebo in the Assessment of Lescol in Renal Transplantation (ALERT) study [35]. While low-density lipoprotein (LDL) was decreased by 32%, no difference was seen between groups in the primary composite outcome of adverse cardiac events after mean follow-up of 5.1 years (RR 0.83; 95% confidence interval 0.64–1.06). However, in a 2-year extension study, a long-term benefit was shown in the fluvastatin arm, with 35% relative reduction in the risk of cardiac death or definite nonfatal myocardial infarction (MI) [hazard ratio (HR) 0.65; 95% CI 0.48–0.88] [36]. The most recent Kidney Disease: Improving Global Outcomes (KDIGO) guidelines on dyslipidemia recommend treating all adult KT patients with a statin regardless of LDL concentration [37]. At this time, there are no data reported on the use of the proprotein convertase subtilisin/kexin-9 (PCSK9) inhibitors in KT recipients. Several classes of immunosuppressive agents including glucocorticoids and mTOR inhibitors have been associated with abnormal lipid profiles, including hypertriglyceridemia. Dose adjustments of these agents may improve dyslipidemia to some extent [38, 39]. Interestingly, a recent sub-study of the MECANO randomized trial spoke against increase in cardiovascular outcomes related to use of mTOR inhibitors versus CnI [40]. In this analysis of early transition to mTOR inhibitors from calcineurin inhibitors for graft preservation in 224 Dutch KT recipients, no differences were observed in predicted versus actual cardiovascular outcomes over 7 years following transplantation between the cyclosporine and everolimus groups. The majority of patients in both groups (>70%) received statins and had controlled BP. The findings of this study suggest that prior observational evidence of a possible increased cardiovascular risk profile with mTOR inhibitor use may have been confounded by indication (worsening renal function) or an overall higher risk profile of patients offered mTOR inhibitors. Hyperhomocysteinemia is considered a nontraditional atherogenic risk factor, and is particularly prevalent in CKD [41, 42]. However, therapeutic manipulation of elevated homocysteine levels in advanced CKD and in the KT population has not shown reduction in CV clinical endpoints [43]. The FAVORIT trial randomized 4110 KT recipients with clinically stable and elevated homocysteine levels after 6 months post-KT to either a high-dose folic acid (5 mg), vitamin B6 (50 mg) and vitamin B12 (1000 μg), or low-dose vitamin B6 (1.4 mg) and vitamin B12 (2 μg) without folic acid [44]. After mean follow-up of 4 years, the high-dose multivitamin group did not have reduction in the primary composite arteriosclerotic CVD outcome of MI, stroke, CVD death, resuscitated sudden death, coronary artery or renal artery revascularization, lower extremity arterial disease, carotid endarterectomy or angioplasty, or abdominal aortic aneurysm repair compared with the low-dose multivitamin group (hazard ratio 0.99; 95% CI 0.84–1.17). Finally, a systematic review and meta-analysis also showed no cardiovascular benefits of homocysteine-lowering medication in patients with CKD, including KT [45]. Given the available evidence, homocysteine-lowing therapy as a primary cardiovascular prevention in advanced CKD, ESKD or post-KT is not currently recommended. Tobacco use after KT and cardiovascular risk Cigarette smoking has been associated with increased risk of CVD, malignancies, allograft failure and death in KT recipients. In fact, the negative impact of cigarette smoking on patient survival post-KT is similar to DM [46]. In a study of >1300 KT recipients, a smoking history of 11–25 pack-years was associated with increased relative risk of CV events of 1.56 [12]. The relative risk increased further to 2.14 with >25 pack-years of smoking. Li et al. recently reported the results of a tobacco smoking status survey administered across 2223 US dialysis centers [47]. Of 22 230 patients studied, 13% were active smokers. Mortality probabilities increased with greater exposure to smoking (17, 22, 23 and 27% for never, moderate, former and heavy smokers, respectively; P < 0.001), as did incidence rates for first hospitalization (23, 27, 27 and 30%, respectively; P < 0.001) Thus, KT candidates and recipients should be encouraged to quit smoking via nonpharmacological and pharmacological methods, including physician/provider-based brief advice strategies during office visits [48]. Although there are limited data on the impact of smoking cessation post-KT, it is a reasonable assumption that the KT recipient will also benefit from smoking cessation like the general population. Efforts should be made to screen annually for active cigarette smoking in potential and actual KT recipients, with targeted efforts to reduce the burden of cigarette smoking in this population. Table 1 summarizes the multidisciplinary approach to smoking cessation that is applicable to KT recipients. Table 1 Multidisciplinary approach for smoking cessation strategies after KT Psychosocial counseling Sources of counselors  Physicians/provider brief advice sessions during office visits Telephone quit lines Individual counseling Group counseling Computer program or Internet counseling  Pharmacologic interventions First-line pharmacotherapy Mechanism of action Clinical use Nicotine replacement therapy  Stimulates nicotinic receptors in the ventral tegmental area  First line for pharmacologic intervention Nicotine gum Nicotine inhaler Nicotine lozenge Nicotine nasal spray Nicotine patch  Sustained-release bupropion  Acts via dopamine and norepinephrine reuptake inhibitors   Consider in patients with a prior history of depression Contraindications: alcohol abuse, previous seizures and history of head trauma, stroke, brain injury (bupropion decreases the seizure threshold), history of eating disorders High seizure risk if used concomitantly with cyclosporine.  Varenicline  Partial agonist/antagonist at the α-4 β-2 nicotine receptor  Renally excreted, needs dose adjustment in patients with impaired renal function Second-line pharmacotherapy Nortriptyline Noradrenergic actions substituting for the noradrenergic actions of nicotine receptor antagonist  Consider in patients with a prior history of depression  Clonidine α-2-adrenergic receptor agonist Side effects including dry mouth and sedation is higher in the therapy group in a dose-dependent fashion  Psychosocial counseling Sources of counselors  Physicians/provider brief advice sessions during office visits Telephone quit lines Individual counseling Group counseling Computer program or Internet counseling  Pharmacologic interventions First-line pharmacotherapy Mechanism of action Clinical use Nicotine replacement therapy  Stimulates nicotinic receptors in the ventral tegmental area  First line for pharmacologic intervention Nicotine gum Nicotine inhaler Nicotine lozenge Nicotine nasal spray Nicotine patch  Sustained-release bupropion  Acts via dopamine and norepinephrine reuptake inhibitors   Consider in patients with a prior history of depression Contraindications: alcohol abuse, previous seizures and history of head trauma, stroke, brain injury (bupropion decreases the seizure threshold), history of eating disorders High seizure risk if used concomitantly with cyclosporine.  Varenicline  Partial agonist/antagonist at the α-4 β-2 nicotine receptor  Renally excreted, needs dose adjustment in patients with impaired renal function Second-line pharmacotherapy Nortriptyline Noradrenergic actions substituting for the noradrenergic actions of nicotine receptor antagonist  Consider in patients with a prior history of depression  Clonidine α-2-adrenergic receptor agonist Side effects including dry mouth and sedation is higher in the therapy group in a dose-dependent fashion  View Large Table 1 Multidisciplinary approach for smoking cessation strategies after KT Psychosocial counseling Sources of counselors  Physicians/provider brief advice sessions during office visits Telephone quit lines Individual counseling Group counseling Computer program or Internet counseling  Pharmacologic interventions First-line pharmacotherapy Mechanism of action Clinical use Nicotine replacement therapy  Stimulates nicotinic receptors in the ventral tegmental area  First line for pharmacologic intervention Nicotine gum Nicotine inhaler Nicotine lozenge Nicotine nasal spray Nicotine patch  Sustained-release bupropion  Acts via dopamine and norepinephrine reuptake inhibitors   Consider in patients with a prior history of depression Contraindications: alcohol abuse, previous seizures and history of head trauma, stroke, brain injury (bupropion decreases the seizure threshold), history of eating disorders High seizure risk if used concomitantly with cyclosporine.  Varenicline  Partial agonist/antagonist at the α-4 β-2 nicotine receptor  Renally excreted, needs dose adjustment in patients with impaired renal function Second-line pharmacotherapy Nortriptyline Noradrenergic actions substituting for the noradrenergic actions of nicotine receptor antagonist  Consider in patients with a prior history of depression  Clonidine α-2-adrenergic receptor agonist Side effects including dry mouth and sedation is higher in the therapy group in a dose-dependent fashion  Psychosocial counseling Sources of counselors  Physicians/provider brief advice sessions during office visits Telephone quit lines Individual counseling Group counseling Computer program or Internet counseling  Pharmacologic interventions First-line pharmacotherapy Mechanism of action Clinical use Nicotine replacement therapy  Stimulates nicotinic receptors in the ventral tegmental area  First line for pharmacologic intervention Nicotine gum Nicotine inhaler Nicotine lozenge Nicotine nasal spray Nicotine patch  Sustained-release bupropion  Acts via dopamine and norepinephrine reuptake inhibitors   Consider in patients with a prior history of depression Contraindications: alcohol abuse, previous seizures and history of head trauma, stroke, brain injury (bupropion decreases the seizure threshold), history of eating disorders High seizure risk if used concomitantly with cyclosporine.  Varenicline  Partial agonist/antagonist at the α-4 β-2 nicotine receptor  Renally excreted, needs dose adjustment in patients with impaired renal function Second-line pharmacotherapy Nortriptyline Noradrenergic actions substituting for the noradrenergic actions of nicotine receptor antagonist  Consider in patients with a prior history of depression  Clonidine α-2-adrenergic receptor agonist Side effects including dry mouth and sedation is higher in the therapy group in a dose-dependent fashion  View Large Posttransplantation DM as a CVD risk factor The development of posttransplantation diabetes mellitus (PTDM) and worsening of preexisting DM represent a major cardiovascular risk factor post-KT [49]. In a study of 1410 consecutive KT recipients observed for a median of 6.7 years (range 0.3–13.8 years), those with PTDM had higher all-cause and CV mortality [1.54 (1.09–2.17) and 1.80 (1.10–2.96)], while patients with impaired glucose tolerance (IGT) had higher all-cause, but not CV mortality [1.39 (1.01–1.91) and 1.04 (0.62–1.74)] compared with those with a normal glucose tolerance test [50]. CnIs are known to affect pancreatic beta cell function and the increased risk of PTDM with tacrolimus compared with cyclosporine was demonstrated in the DIRECT (Diabetes Incidence after Renal Transplantation: Neoral C(2) Monitoring Versus Tacrolimus) trial, which was a 6-month, open-label, randomized, multicenter study of 682 KT recipients randomized to cyclosporine (CsA) versus tacrolimus-based maintenance regimens [51]. The primary safety endpoint of PTDM or impaired fasting glucose (IFG) occurred in 26% of CsA-treated patients compared with 34% in tacrolimus group (P = 0.046). A recent randomized control study by Wissing et al. showed the benefit of switching tacrolimus to CsA in KT recipients who developed PTDM, with 34% of subjects in the CsA conversion group versus 10% in the tacrolimus continuation group resolving their PTDM (P = 0.01) [52]. However, it must be remembered that nephrotoxicity profiles associated with tacrolimus and CsA, albeit somewhat different, are still important and may have long-term consequences on the graft survival [53]. mTOR inhibitors, by reducing pancreatic beta cell proliferation and decreasing insulin sensitivity, may also increase the risk of PTDM [54]. The use of maintenance corticosteroids is another major risk factor for PTDM and patients on steroid-free regimens for a long term carry a 30% reduced risk overall of developing PTDM [55]. However, steroid withdrawal may not be beneficial based on data from a RCT of patients on chronic steroids versus early withdrawal, where 36% of subjects were diagnosed with PTDM at 5 years in both groups [56]. In a meta-analysis of RCTs comparing a steroid maintenance group versus complete avoidance or withdrawal in KT, Knight and Morris found a relative risk reduction for PTDM of 36% (RR 0.64; 95% CI 0.50–0.83); however, this benefit came with an increased risk of acute rejection when compared with the group on maintenance steroids (RR 1.56; 95% CI 1.31–1.87) [20]. The increased risk of rejection and a null signal for patient and allograft loss with steroid avoidance or withdrawal after KT was also confirmed in a Cochrane analysis by Haller et al. [21]. A systematic review and meta-analysis of six RCTs comparing KT outcomes between belatacept and CnI showed lower rates of PTDM at 12 months (odds ratio 0.43; 95% CI 0.24–0.78, P = 0.006, I2 = 18%) with the use of belatacept, in addition to better median eGFR at 12 and 24 months [23]. The risk/benefit analysis of using belatacept to reduce CVD risk post-KT must be weighed against potential risk for posttransplant lymphoproliferative disorder, especially in Epstein-Barr virus-negative recipients. Given the elevated CVD risk with PTDM, initiating screening for PTDM with glycated hemoglobin levels after 3 months post-KT is desirable, to provide early and goal directed management for reduction of cardio-metabolic risk after KT. Obesity Obesity at the time of KT is associated with both increased mortality as well as death-censored graft loss [57]. It exacerbates several other CVD risk factors, including hypertension, PTDM, dyslipidemia, metabolic syndrome and inflammation while still independently predicting increased adverse CV events [57, 58]. Additional weight gain post-KT is common, with an average weight gain of 5–10% in the first year, with age >45 years, female gender, African American ethnicity and preexisting obesity associated with highest risk [59]. The relationship between obesity and metabolic syndrome/PTDM after KT is complex and represents the confluence of preexisting metabolic risk with the superimposed effects of immunosuppressive regimens that may complicate glycemic control [60, 61]. For KT candidates, lifestyle changes should be strongly encouraged, with a role for bariatric surgery in selected patients to make otherwise good transplant candidates acceptable for the KT wait list. Though data for bariatric surgery are limited in patients with CKD, one study suggested that despite higher length of stay and reoperation rates, 30-day mortality was the same in CKD subjects when compared with those without CKD [62]. Emerging data suggest that bariatric surgery may be an effective and safe option for achieving a body mass index goal of <35 kg/m2 prior to transplantation [62]. Bariatric surgery following KT has also been associated with favorable clinical outcomes, notably improvements in glycemic and BP control [64]. A review by Camilleri et al. identified potential complications in the KT recipient, following bariatric surgery [64]. The greatest risk noted is the risk of hyperoxaluria and resultant nephrolithiasis or oxalate nephropathy [65]. The risk of hyperoxaluria and related problems appears to be most common after Roux-En-Y gastric bypass surgery. The risk following restrictive bariatric surgery (gastric banding or sleeve gastrectomy) appears to be much lower; however, longer term studies are needed to ensure that this conclusion is correct [64]. Thus, close monitoring of renal function would be required following bariatric surgery in a KT recipient, especially if bypass surgery is performed. Finally, immunosuppression dosing following bariatric surgery is less predictable [64]. Many immunosuppressants (tacrolimus, mycophenolate and sirolimus) may need increased dosing following bariatric surgery and close monitoring of levels of these medications should be undertaken if bariatric surgery is performed in a KT recipient. Figure 2 provides a summary of the management of traditional cardiovascular risk factors after KT. FIGURE 2 View largeDownload slide Approach to the management of traditional cardiovascular risk factors in kidney transplant recipients [13, 17, 37]. HbA1C, glycosylated hemoglobin; ASA, aspirin; BMI, body mass index. FIGURE 2 View largeDownload slide Approach to the management of traditional cardiovascular risk factors in kidney transplant recipients [13, 17, 37]. HbA1C, glycosylated hemoglobin; ASA, aspirin; BMI, body mass index. ATHEROSCLEROTIC CARDIOVASCULAR DISEASE IN THE KIDNEY TRANSPLANT RECIPIENT Recent reports indicate that noncardiovascular causes of mortality, specifically infection and malignancy combined, exceed CV mortality risk in KT patients with or without diabetes. This was explored in the FAVORIT study cohort by Weinrauch et al. [66]. In their analysis, the authors found that the long-term survival of KT recipients was significantly impacted by infectious and malignant complications as well as CV complications. However, the differences were small, and CVD, specifically atherosclerotic CVD, remained a major contributor to death with a functioning allograft. Thus, despite competing causes of mortality and adverse outcomes, CAD is an important cause of morbidity and mortality among KT recipients [67]. CAD is one of the targets of preoperative medical clearance among patients undergoing evaluation for KT [68]. CAD pre-KT increases the risk of the primary composite outcome of cardiovascular mortality, acute coronary syndrome (ACS) and need for revascularization after KT [69]. Noninvasive testing is the preferred initial screening modality for CAD, including dobutamine stress echocardiography and myocardial perfusion imaging; however, the predictive value of a positive noninvasive test for immediate posttransplant cardiovascular outcomes is unclear [70, 71]. Coronary angiography is a better predictor of posttransplant CVD-associated mortality, but the use of angiography is limited due to concerns about adverse events, especially renal injury in those not yet on dialysis [72]. However, it remains to be determined if preoperative risk stratification and ultimately revascularization, when indicated, will improve cardiovascular outcomes following KT. Two RCTs (Coronary Artery Revascularization Prophylaxis—CARP and the Dutch Echocardiographic Cardiac Risk Evaluation Applying Stress Echo-V—DECREASE-V) demonstrated that there was no postoperative mortality or adverse CV event reduction with a prophylactic revascularization approach among patients with angiographically confirmed CAD or stress-induced ischemia about to undergo elective vascular surgery [73, 74]. The American College of Cardiology Foundation/American Heart Association 2012 Guidelines on the risk stratification of CVD prior to KT does not recommend routine revascularization in asymptomatic patients as part of the workup process for KT listing [75]. In a recent propensity score-matched analysis of 17,304 patients in the United States Renal Data System (USRDS) database transplanted between 2006 and 2013, stress testing in the 18 months prior to KT was not associated with a reduction in death, total MI or fatal MI within 30 days of KT after adjustment for differences in demographics and comorbidities [71]. That the stress tests were intended for screening as opposed to investigation of ischemic symptoms is supported by the low rate of coronary angiography (13.3%) and revascularization (2.1%) in the propensity-matched cohort. Nevertheless, once evidence of ischemic heart disease (typically by noninvasive cardiac stress testing) is found in the potential KT candidate, careful serial cardiovascular assessment must continue during wait-list time [76]. Naylor et al. have reported on overall stability in trends in early hospital readmission after KT between 2002 and 2014 despite increasing recipient age and comorbidities [77]. Despite these data, long-term CAD-related adverse events remain an important concern in KT recipients. Hypolite et al. explored the relationship of KT with ACS hospitalizations using information on ESKD patients on the wait list and within 3 years after transplantation [78]. Among diabetic patients, pretransplantation medical optimization and ultimately renal replacement therapy with a KT led to significant reductions in the incidence of hospitalization for ACS. Subsequent analyses have suggested the importance of preoperative CAD on long-term posttransplantation outcomes. Specifically, the presence of abnormal noninvasive stress testing and/or abnormal coronary angiography have been identified as predictors of long-term adverse outcomes, including cardiovascular outcomes, post-KT [79, 80]. In addition, the correction of angiographically significant CAD, with either percutaneous coronary intervention or coronary artery bypass grafting, is associated with improved long-term survival following KT than medical management [81]. A major limitation of the analyses is the observational nature of the studies and the inherent associated biases and confounders. Large prospective randomized studies will be needed to determine the efficacy of preoperative coronary revascularization on posttransplant cardiovascular outcomes. Specific treatments for CAD in KT recipients have only been analyzed in a small number of studies. The ALERT trial did not demonstrate a significant difference in the primary combined CV endpoint (RR 0.83; 95% CI 0.64–1.06; P = 0.139) [35], but there was a significant reduction in the separate outcomes of cardiac death and nonfatal MI with fluvastatin therapy [0.65 (0.48–0.88); P = 0.005]. The cholesterol treatment trialists collaboration evaluated the ALERT trial as part of a large meta-analysis of trials examining cholesterol lowering among patients with CKD or on dialysis [82]. In this meta-analysis, the outcome of interest was major vascular event (major coronary event—nonfatal MI or death from coronary heart disease), coronary revascularization or stroke, and mortality, subdivided into vascular and nonvascular causes. The individual HR for this outcome identified for the ALERT trial was 0.76 (95% CI 0.64–0.92). In general, there seems to be little harm and likely cardiovascular benefit to initiating or continuing statin therapy in patients with a functioning KT. Aspirin use has not been studied in a formal RCT in patients with a functioning renal transplant. Dad et al. performed a secondary analysis of aspirin use in the FAVORIT trial [83]. This was a post hoc analysis that found no benefit to baseline use of aspirin on multiple CVD-related outcomes or mortality, after propensity score matching. Currently, no clear recommendation can be made regarding aspirin use for primary prevention of CAD in KT recipients. VALVULAR HEART DISEASE IN THE KIDNEY TRANSPLANT RECIPIENT Echocardiographic evidence of valvular heart disease (VHD) in patients with CKD is common and appears to be more prevalent as eGFR decreases [84]. This observation is important as ESKD patients with severe VHD are often excluded from KT [85]. Characteristics of CKD patients that contribute to VHD include accelerated calcification, myocardial hypertrophy and increasing cavity size due to increased volume. There is a graded relationship between progressive decline in eGFR and the prevalence of calcification, hospitalizations, adverse CV events and death. It is not known if KT reverses valvular calcification. Kocyigit et al. examined the prevalence of aortic and mitral valve calcification in KT recipients [86]. Of 89 KT recipients examined, only 14 patients had no evidence of valvular calcification. Correlation analysis found no association of valvular calcification with either pre-KT dialysis vintage or post-KT duration. Further studies will be needed to identify the effects of KT on stabilization of preexisting valvular calcification and related morbidities. It is not known if the progression of VHD is slower post-KT compared with pre-transplant status. However, progression of VHD over time is likely in patients with long-term kidney allografts and many will eventually need valve replacement. In a study by Abbott and colleagues, hospitalizations for VHD (aortic, mitral, tricuspid, pulmonic or combined) were lower among patients after KT as compared with before KT (0.68/1000 person-years and 0.84/1000 person-years, respectively) [85]. A study of valve surgeries between 1991 and 2004 by Sharma et al. showed that aortic valve replacement (66%) was most frequent, followed by mitral (25%), and only 9% underwent combined aortic/mitral valve repair [87]. Mitral valve replacement was associated with a higher risk of death as compared with aortic valve replacement. Additionally, the use of tissue valves versus non-tissue valves was associated with a lower mortality rate. Aortic valve replacement has seen dramatic advances in recent years, particularly with the introduction of Transcatheter Aortic Valve Replacement/Implantation (TAVR/TAVI, hereafter will be referred as TAVR). Outcomes among patients with KT undergoing TAVR versus open surgical replacement have only been examined in retrospective analyses, with variable outcomes reported. Fox et al. reported minimal complications following TAVR in a small sample of 26 KT recipients comparing TAVR with surgical repair (one stroke at 12 months following TAVR) [88]. On the other hand, Al-Rashid et al. reported a series of cases from a single center in Germany in which KT recipients experienced a 2-year mortality following TAVR of 53%, as compared with 31% in patients with open surgical repair [89]. Larger studies will be needed to identify more reliable estimates of outcomes following TAVR in KT recipients. HEART FAILURE IN THE KIDNEY TRANSPLANT RECIPIENT HF is a major cause of morbidity and mortality in patients with ESKD, with a reported prevalence among dialysis patients of 12–36 times that of the general population [2, 90, 91]. The strong correlation between reduced ejection fraction (EF) and mortality was demonstrated by de Mattos et al. in a population selected for KT wait listing, such that every point increase in left ventricular EF (LVEF) was associated with a 2.5% decrease in adjusted mortality risk [92]. HF post-KT remains a major contributor to CVD-related hospitalizations after KT since 2005, with HF accounting for 16% of all hospitalizations [93]. Recent data suggest that while absolute rates of major adverse cardiovascular events (MACE) were stable over the period of 2004–13, 78% of all MACE (6.5% of the study population) were driven by HF [94]. Although preexisting cardiomyopathy impacts KT outcomes, a functioning KT can also influence the magnitude and clinical course of preexisting cardiomyopathy. KT is associated with improvement in EF over time in most individuals. Wali et al. described a cohort of 103 patients with LVEF <40% (mean EF 31.6 ± 6.7%) with a median of two HF hospitalizations before KT evaluation with no inducible ischemia [95]. In this cohort, mean pre KT EF increased from 32% to 52% at 1 year of transplantation (P = 0.002). By 1-year post-KT, 72/103 (70%) patients had an EF of >50% and 16 patients improved their EF to 40–50%. Similar experiences have been reported in other single institution studies [96–98]. Another single center experience reported that KT patients with baseline mean EF of 35% had similar outcomes to those with normal EF in terms of graft and patient survival, largely due to improvement in EF post-KT [99]. These data suggest that restoration of eGFR and reversal of the uremic milieu may play a role in restoration or improvement of myocardial mechanics and function in patients with preexisting cardiomyopathy. This is further strengthened by observations showing improvement in global longitudinal strain (GLS) serially in children with CKD and maintenance dialysis, after KT [100]. However, in an analysis of left ventricular and right ventricular (RV) strain in subjects on maintenance dialysis with follow-up values post-KT (mean follow-up post-KT was 338 days) by Xu et al., biventricular strain abnormalities persisted post-KT even with preserved EF, thus suggesting that subclinical abnormalities in myocardial mechanics may persist even when other conventional measures of myocardial function such as EF are within normal range [101]. This also suggests that the duration required for recovery of strain abnormalities may extend to longer periods of time post-KT, warranting long-term follow-up and the use of goal-directed therapies for HF to optimize these findings, even beyond preservation/restoration of EF post-KT. There are limited controlled data on the optimal pharmacotherapy of HF specific to KT recipients. Management of HF in the context of KT involves integrating available evidence-based therapies for HF in CKD (based on the degree of allograft function) as well as transplant-specific factors such as immunosuppressive agents. In terms of the potential differential effects of CnI versus mTOR inhibitors on cardiovascular effects, the open-label, Efficacy, Safety and Evolution of Cardiovascular parameters in Renal Transplant Recipients (ELEVATE) trial randomized KT recipients at 10–14 weeks after transplant to convert from CnI to everolimus or remain on standard CnI therapy [102]. The mean change in left ventricular mass index from randomization was similar with everolimus versus CnI, and mean pulse wave velocity remained stable with both everolimus and CnI. At Month 24, left ventricular hypertrophy was present in 42% versus 38% of everolimus and CnI patients, respectively. Major adverse cardiac events occurred in 1.1% and 4.2% of everolimus-treated and CnI-treated patients at 12 months (P = 0.018) and 2.3% and 4.5% at 24 months (P = 0.145), respectively. Thus, switching from a CnI to an mTOR-based regimen did not reduce prespecified cardiovascular metrics in this analysis, and the optimal immunosuppressive regimen in terms of hypertension and HF risk reduction is still a subject for future studies. This was additionally reviewed recently by Paoletti wherein the benefit of mTOR inhibitors on left ventricular mass appears to be BP independent and may also extend to reductions in arterial stiffness. Again, further studies will be needed to confirm such benefits [103]. There is conflicting evidence on the efficacy of RAASi and HF outcomes in KT recipients. The Study on Evaluation of Candesartan Cilexetil after Kidney Transplantation (SECRET) trial, which randomized 700 KT recipients to candesartan versus placebo, was terminated prematurely after mean follow-up of 20 months, due to a much lower than expected rate of the primary outcome of all-cause mortality, cardiovascular morbidity or graft failure [104]. In contrast, Paoletti et al. reported on 70 KT recipients on standard immunosuppression with CnI (CsA or tacrolimus), mycophenolate mofetil and steroids randomized to lisinopril versus usual care [28]. Event-free survival for a composite endpoint of death, major cardiovascular events, renal graft loss or creatinine doubling was better with ACEI but no significant differences in renal outcomes allograft loss. In a meta-analysis of eight trials examining clinical outcomes with RAASi in KT recipients by Hiremath et al. (only one trial specifically used HF as a primary outcome), no difference in all-cause mortality was observed with ACEI/ARB therapy versus placebo (RR for all-cause death 0.96; 95% CI 0.62–1.51; P = 0.9). There was significantly higher risk for hyperkalemia with RAAS blockade noted (RR 2.44; 95% CI 1.53–3.90) [29]. Currently, there are limited data on the impact of other goal-directed medical therapies including beta blockers, vasodilators and mineralocorticoid receptor antagonists on HF outcomes after KT, highlighting the need for future studies to define best strategies for the use of these agents in HF after KT. The deleterious impact of preexisting and de novo HF on KT outcomes has been described in in large database analyses as well as single center investigations. Among 27 011 KT recipients whose outcomes were tracked in the USRDS database by Lentine et al. (1995–2011), the cumulative incidence of de novo HF was 10.2% at 12 months and 18.3% at 36 months [105]. De novo HF predicted death (HR 2.6; 95% CI 2.4–2.9) and death-censored graft failure (HR 2.7; 95% CI 2.4–3.0) in this report. Another analysis of the incidence de novo HF after KT over the period of 1998–2010 within the USRDS by Lenihan et al showed that the risk for developing de novo post-KT HF had declined significantly between 1998 and 2010, with no apparent change in subsequent mortality [106]. A recent study of 111 subjects showed that reduced GLS peritransplant is associated with increased risk of CVD events or death post-KT [107]. Patients who experienced an event were older, more frequently had a history of CAD and had higher left ventricular filling/longitudinal diastolic annular velocity (E/e′) than those who did not. GLS was significantly associated with event-free survival even after adjusting for age, sex, race–ethnicity, hypertension, diabetes, history of CAD or HF, and E/e′. Larger studies are needed in the future to define the incremental predictive value of GLS over clinical and other echocardiographic parameters for adverse CVD events following KT. PULMONARY HYPERTENSION IN THE KIDNEY TRANSPLANT RECIPIENT PH is a major comorbidity in patients with CKD and ESKD and has emerged as a major prognostic factor pre- and post-KT. PH is defined by a mean pulmonary artery (PA) pressure of 25 mmHg or more at rest, as measured by right heart catheterization (RHC) [108]. While RHC is the ‘gold standard’ for the diagnosis of PH, transthoracic echocardiography is the most commonly used technique to assess pulmonary pressures in practice, given the expensive and invasive nature of RHC [109]. In the absence of significant RV outflow obstruction, estimation of the RV systolic pressure (RVSP) from peak tricuspid regurgitation velocity allows the interchangeable use of RVSP and PA systolic pressure (PASP) in studies and clinical practice. The severity of PH based on PASP is classified as: normal, <35 mmHg, mild, 35–45 mmHg, moderate, 45–60 mmHg and severe, >60 mmHg. The current World Health Organization classification of PH comprises of five groups, of which several underlying conditions that predispose to Groups 1–4 of PH are highly prevalent in CKD and ESKD [109]. The PEPPER study (PH in patients with CKD on dialysis and without dialysis) identified pre-capillary PH (pulmonary arterial hypertension in the absence of elevated PCWP) in 13% of patients (4/31) with RHC data before and after dialysis initiation [110]. Group 2 PH represents the most common type of PH in patients with CKD, given that left ventricular HF is estimated to affect 30–50% of patients with CKD [111]. Hypoxic lung disease that underlies the pathophysiology of Group 3 PH often coexists with CKD. These include unusually the high burden of obstructive sleep apnea (OSA), obesity and Chronic obstructive pulmonary disease (COPD) reported in CKD population [112, 113]. The 3- to 8-fold higher risk of pulmonary embolism reported in patients with CKD when compared with those without CKD, may contribute to chronic thromboembolic pulmonary hypertension (Group 4 PH) in these patients [114]. Finally, Group 5 PH encompasses unexplained PH in patients with CKD and ESKD, of which PH secondary to the hemodynamic effects of arteriovenous fistulae is an important etiology. Figure 3 briefly summarizes the approach to PH in the KT recipient. Detailed recommendations for the workup of PH in the potential/actual KT recipient are provided in the 2012 American Heart Association/American College of Cardiology Foundation Guidelines for the evaluation of PH among KT candidates as well as in a comprehensive summary by Lentine et al. [109, 115]. FIGURE 3 View largeDownload slide Clinical approach to the kidney allograft recipient with suspected pulmonary hypertension. FIGURE 3 View largeDownload slide Clinical approach to the kidney allograft recipient with suspected pulmonary hypertension. Issa et al. demonstrated that a pretransplant RVSP of >50 mmHg was independently associated with worse renal allograft outcomes, in a cohort of 215 KT recipients [116]. The HR for posttransplant death was 3.75 (P = 0.016) with RVSP values of >50 mmHg, with dialysis vintage being the strongest correlate with RVSP severity. In a cohort of 638 transplant recipients, patients with PH prior to transplant had a lower graft survival rate at 5 years versus patients without PH (54.6% versus 76.0%, P < 0.05) and were nearly twice as likely to experience overall graft failure [adjusted hazard ratio (AHR) 1.3; 95% CI 1.11–1.51] during the study period [117]. In a single-center cohort of 35 patients who underwent simultaneous heart kidney transplantation during 1996–2015, delayed graft function of the renal allograft occurred in 37% of patients, for which preoperative PH was identified as an independent risk factor [118]. These data demonstrate the importance of managing PH preoperatively in both kidney and heart–kidney allograft recipients. ARRHYTHMIAS IN THE KIDNEY TRANSPLANT RECIPIENT Patients with CKD have an increased risk for cardiac arrhythmias and sudden death given the unphysiological electrolyte balance associated with diminished renal function as well as the structural and functional changes that accompanied the uremic milieu [119, 120]. Atrial fibrillation (AF) represents the most common sustained arrhythmia in CKD [119]. In a study of over 60 000 Medicare patients, it was found that approximately 6.4% of patients were diagnosed with AF prior to KT [121]. A USRDS database analysis in 2006 demonstrated the 12- and 36-month incidence of new onset AF after KT to be 3.6% and 7.3%, respectively [122]. AF requiring hospitalization was shown to be associated with a 34% increase in all-cause mortality driven largely by CVD deaths in KT recipients in a historical cohort study of 39 628 subjects in the USRDS database. Similarly, Lentine et al. demonstrated that AF is also associated with an increased risk of death (AHR 3.2; 95% CI 2.9–3.6) and death-censored graft loss (AHR 1.9; 95% CI 1.6–2.3) [122]. In this analysis, risk factors for posttransplantation AF included older recipient age, male gender, white race, CKD from hypertension and CAD. Extended pretransplantation dialysis duration, PTDM and graft failure were also identified as potentially modifiable correlates of AF. Patients with AF are typically on anticoagulation for stroke prevention and therefore many will require continued anticoagulation in the peritransplant period. Small series have demonstrated acceptable bleeding risk in patients who are on warfarin therapy at the time of transplant [123, 124]. There currently is a paucity of data on the use of the new direct oral anticoagulants (DOACs) and their safety in the peritransplant period. Careful consideration of the different DOACs and their dosing adjustments in renal impairment is critical to maintaining the safety profile of these drugs in transplant patients. In this context, the reader is directed to the summary from the recently concluded KDIGO consensus conference on CKD and arrhythmias for more details on DOAC dosing in CKD [119]. Apixaban and rivaroxaban have minimal drug interactions with tacrolimus, while dabigatran has potential for more significant interactions with CnIs, with CsA having more potential drug–drug interactions than those seen with tacrolimus [125]. CnI levels should be carefully monitored when using these newer medications. In addition, fluctuating renal function after transplant may alter the half-life of these drugs. Ventricular arrhythmias are of increased concern after KT as they are associated with sudden death and poor outcomes in subjects with CKD [126]. The risk of sudden death in KT patients is reportedly as high as 15% [127, 128], and it is presumed that many of these deaths are related to ventricular arrhythmias. A single-center experience with electrophysiological monitoring in the early post-KT period demonstrated that ventricular arrhythmias occurred in as many as 30% of patients after transplantation [129]. Male gender, dialysis vintage and high preexisting coronary calcification scores were predictors of post-KT ventricular arrhythmias in this study. Higher quality data are needed to quantify the burden of post-KT ventricular arrhythmias to reduce the risk of sudden death in this population. CONCLUSIONS AND FUTURE DIRECTIONS CVD remains an understudied and undertreated source of morbidity and mortality in KT recipients. While the magnitude of disease burden is reduced when compared with patients on maintenance dialysis, it still remains a significant contributor to worse patient and allograft outcomes post-KT. Patients with CKD are generally excluded from major cardiovascular outcome trials, and this phenomenon of aversion to including patients with CKD in cardiovascular trials and providing appropriate goal-directed medical and interventional therapies (renalism) extends into KT [130, 131]. KT recipients continue to be undertreated with regards to cardiovascular risk factor management despite the well-known burden of CVD [132]. In addition, cardiovascular care is fragmented across the continuum of CKD, dialysis and transplantation, with shifting clinical care teams, variable screening protocols and lack of consensus on optimal management of CVD pre- and post-KT [133] (Figure 4). To this end, encouraging participation of KT recipients in cardiovascular trials will facilitate a better understanding of the nuances of CVD management in this unique population based on high-quality data. Public reporting of long-term allograft and patient outcomes will help potential KT recipients and referring nephrologists compare outcomes of patient with CVD, and thus set higher and competitive standards for optimizing long-term patient survival. Finally, encouraging ‘cardio-nephrology’ multidisciplinary clinical care models pre- and post-KT may help reduce care fragmentation and prioritize CVD screening and treatment [134]. These measures will help reduce the impact of CVD in KT recipients and optimize long-term patient and allograft outcomes in a cost-effective manner. FIGURE 4 View largeDownload slide Care fragmentation in patients with cardiovascular disease before and after kidney transplantation. FIGURE 4 View largeDownload slide Care fragmentation in patients with cardiovascular disease before and after kidney transplantation. ACKNOWLEDGEMENTS This manuscript is a work product of the American Society of Transplantation's (AST) Kidney/Pancreas Work Group on Cardiovascular Disease. The Writing Group wishes to acknowledge the Education Committee of the American Society of Transplantation, staff members of the American Society of Transplantation and the Kidney/Pancreas Community of Practice and the peer reviewers for Nephrology Dialysis Transplantation for their valuable input and feedback with this project. The Writing Group also acknowledges Professor Carlos Zayas, MD, Director of Transplant Nephrology at Augusta University, Georgia for his input during the preparation of this manuscript. CONFLICT OF INTEREST STATEMENT None declared. The authors declare that this manuscript has not been published previously in whole or in part. (See related article by Van Laecke and Abramowicz. Cardiovascular disease in kidney transplant recipients: leave no stone unturned. Nephrol Dial Transplant 2019; 34: 727--730) REFERENCES 1 Wolfe RA , Ashby VB , Milford EL. Comparison of mortality in all patients on dialysis, patients on dialysis awaiting transplantation, and recipients of a first cadaveric transplant . N Engl J Med   1999 ; 341 : 1725 – 1730 Google Scholar Crossref Search ADS PubMed   2 United States Renal Data System 2017 USRDS Annual Data Report: Epidemiology of kidney disease in the United States  . Bethesda, MD : National Institute of Health, National Institute of Diabetes and Digestive and Kidney Diseases , 2017 3 Anavekar NS , McMurray JJ , Velazquez EJ. Relation between renal dysfunction and cardiovascular outcomes after myocardial infarction . N Engl J Med   2004 ; 351 : 1285 – 1295 Google Scholar Crossref Search ADS PubMed   4 Arend SM , Mallat MJ , Westendorp RJ et al.  Patient survival after renal transplantation; more than 25 years follow-up . Nephrol Dial Transplant   1997 ; 12 : 1672 – 1679 Google Scholar Crossref Search ADS PubMed   5 Ojo AO , Hanson JA , Wolfe RA et al.  Long-term survival in renal transplant recipients with graft function . Kidney Int   2000 ; 57 : 307 – 313 Google Scholar Crossref Search ADS PubMed   6 US Renal Data System. USRDS 2008 Annual Data Report: Atlas of End-Stage Renal Disease in the United States. Bethesda, MD: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, 2008 7 Liefeldt L , Budde K. Risk factors for cardiovascular disease in renal transplant recipients and strategies to minimize risk . Transplant Int   2010 ; 23 : 1191 – 1204 Google Scholar Crossref Search ADS   8 Kasiske BL , Anjum S , Shah R et al.  Hypertension after kidney transplantation . Am J Kidney Dis   2004 ; 43 : 1071 – 1081 Google Scholar Crossref Search ADS PubMed   9 Premasathian NC , Muehrer R , Brazy PC et al.  Blood pressure control in kidney transplantation: therapeutic implications . J Hum Hypertens   2004 ; 18 : 871 – 877 Google Scholar Crossref Search ADS PubMed   10 Kasiske BL , Snyder JJ , Gilbertson D et al.  Diabetes mellitus after kidney transplantation in the United States . Am J Transplant   2003 ; 3 : 178 – 185 Google Scholar Crossref Search ADS PubMed   11 Badiou S, Cristol JP, Mourad G. Dyslipidemia following kidney transplantation: diagnosis and treatment . Curr Diab Rep   2009 ; 9 : 305 – 311 12 Kasiske BL , Klinger D. Cigarette smoking in renal transplant recipients . J Am Soc Nephrol   2000 ; 11 : 753 – 759 Google Scholar PubMed   13 Kidney Disease: Improving global outcomes (KDIGO) Transplant Work Group. KDIGO clinical practice guideline for the care of kidney transplant recipients . Am J Transplant   2009 ; S1 – S155 14 O’Shaughnessy MM , Liu S , Montez-Rath ME et al.  Cause of kidney disease and cardiovascular events in a national cohort of US patients with end-stage renal disease on dialysis: a retrospective analysis . Eur Heart J   2018 ; doi: 10.1093/eurheartj/ehy422 15 Mangray M , Vella JP. Hypertension after kidney transplant . Am J Kidney Dis   2011 ; 57 : 331 – 341 Google Scholar Crossref Search ADS PubMed   16 Opelz G , Dohler B. Improved long-term outcomes after renal transplantation associated with blood pressure control . Am J Transplant   2005 ; 5 : 2725 – 2731 Google Scholar Crossref Search ADS PubMed   17 Whelton PK , Carey RM , Aronow WS et al.  2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prev-ention, Detection, Evaluation, and Management of High Blood Pressure in Adults: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines . J Am Coll Cardiol   2018 ; 71 : e127 – e248 Google Scholar Crossref Search ADS PubMed   18 Carpenter MA , John A , Weir MR et al.  BP, cardiovascular disease, and death in the Folic Acid for Vascular Outcome Reduction in Transplantation trial . J Am Soc Nephrol   2014 ; 25 : 1554 – 1562 Google Scholar Crossref Search ADS PubMed   19 Taler SJ , Textor SC , Canzanello VJ et al.  Cyclosporin-induced hypertension: incidence, pathogenesis and management . Drug Saf   1999 ; 20 : 437 – 449 Google Scholar Crossref Search ADS PubMed   20 Knight SR , Morris PJ. Steroid avoidance or withdrawal after renal transplantation increases the risk of acute rejection but decreases cardiovascular risk. A meta-analysis . Transplantation   2010 ; 89 : 1 – 14 Google Scholar Crossref Search ADS PubMed   21 Haller MC , Royuela A , Nagler EV et al.  Steroid avoidance or withdrawal for kidney transplant recipients . Cochrane Database Syst Rev   2016 ( 8 ); doi: 10.1002/14651858.CD005632.pub3 22 Rostaing L , Vincenti F , Grinyo J et al.  Long-term belatacept exposure maintains efficacy and safety at 5 years: results from the long-term extension of the BENEFIT study . Am J Transplant   2013 ; 13 : 2875 – 2883 Google Scholar Crossref Search ADS PubMed   23 Talawila N , Pengel LH. Does belatacept improve outcomes for kidney transplant recipients? A systematic review . Transpl Int   2015 ; 28 : 1251 – 1264 Google Scholar Crossref Search ADS PubMed   24 Cross NB , Webster AC , Masson P et al.  Antihypertensives for kidney transplant recipients: systematic review and meta-analysis of randomized controlled trials . Transplantation   2009 ; 88 : 7 – 18 Google Scholar Crossref Search ADS PubMed   25 Hoorn EJ , Walsh SB , McCormick JA et al.  Pathogenesis of calcineurin inhibitor-induced hypertension . J Nephrol   2012 ; 25 : 269 – 275 Google Scholar Crossref Search ADS PubMed   26 Shin GT , Cheigh JS , Riggio RR et al.  Long-term beneficial effects of a nifedipine-supplemented immunosuppressive regimen in kidney transplantation . Transplant Proc   1996 ; 28 : 1309 – 1310 Google Scholar PubMed   27 Opelz G , Dohler B. Cardiovascular death in kidney recipients treated with renin-angiotensin system blockers . Transplantation   2014 ; 97 : 310 – 315 Google Scholar Crossref Search ADS PubMed   28 Paoletti E , Bellino D , Marsano L et al.  Effects of ACE inhibitors on long-term outcome of renal transplant recipients: a randomized controlled trial . Transplantation   2013 ; 95 : 889 – 895 Google Scholar Crossref Search ADS PubMed   29 Hiremath S , Fergusson DA , Fergusson N et al.  Renin-angiotensin system blockade and long-term clinical outcomes in kidney transplant recipients: a meta-analysis of randomized controlled trials . Am J Kidney Dis   2017 ; 69 : 78 – 86 Google Scholar Crossref Search ADS PubMed   30 Jennings DL , Taber DJ. Use of renin-angiotensin-aldosterone system inhibitors within the first eight to twelve weeks after renal transplantation . Ann Pharmacother   2008 ; 42 : 116 – 120 Google Scholar Crossref Search ADS PubMed   31 Aziz F , Clark D , Garg N et al.  Hypertension guidelines: How do they apply to kidney transplant recipients . Transplant Rev   2018 ; 32 : 225 – 233 Google Scholar Crossref Search ADS   32 Weir MR , Bakris GL , Bushinsky DA et al.  Patiromer in patients with kidney disease and hyperkalemia receiving RAAS inhibitors . N Engl J Med   2015 ; 372 : 211 – 221 Google Scholar Crossref Search ADS PubMed   33 Packham DK , Rasmussen HS , Lavin PT et al.  Sodium zirconium cyclosilicate in hyperkalemia . N Engl J Med   2015 ; 372 : 222 – 231 Google Scholar Crossref Search ADS PubMed   34 Rattanavich R , Malone AF , Alhamad T. Safety and efficacy of patiromer use with tacrolimus in kidney transplant recipients . Transpl Int   2019 ; 32 : 110 – 111 Google Scholar Crossref Search ADS PubMed   35 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 – 2031 Google Scholar Crossref Search ADS PubMed   36 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 – 2936 Google Scholar Crossref Search ADS PubMed   37 Wanner C , Tonelli M. KDIGO Clinical Practice Guideline for Lipid Management in CKD: summary of recommendation statements and clinical approach to the patient . Kidney Int   2014 ; 85 : 1303 – 1309 Google Scholar Crossref Search ADS PubMed   38 Pascual M , Curtis J , Delmonico FL et al.  A prospective, randomized clinical trial of cyclosporine reduction in stable patients greater than 12 months after renal transplantation . Transplantation   2003 ; 75 : 1501 – 1505 Google Scholar Crossref Search ADS PubMed   39 Schena FP , Pascoe MD , Alberu J et al.  Conversion from calcineurin inhibitors to sirolimus maintenance therapy in renal allograft recipients: 24-month efficacy and safety results from the CONVERT trial . Transplantation   2009 ; 87 : 233 – 242 Google Scholar Crossref Search ADS PubMed   40 van Dijk M , van Roon AM , Said MY et al.  Long-term cardiovascular outcome of renal transplant recipients after early conversion to everolimus compared to calcineurin inhibition: results from the randomized controlled MECANO trial . Transpl Int   2018 ; 31 : 1380 – 1390 Google Scholar Crossref Search ADS PubMed   41 van Guldener C. Why is homocysteine elevated in renal failure and what can be expected from homocysteine-lowering? Nephrol Dial Transplant   2006 ; 21 : 1161 – 1166 Google Scholar Crossref Search ADS PubMed   42 Jungers P , Chauveau P , Bandin O et al.  Hyperhomocysteinemia is associated with atherosclerotic occlusive arterial accidents in predialysis chronic renal failure patients . Miner Electrolyte Metab   1997 ; 23 : 170 – 173 Google Scholar PubMed   43 Jamison RL , Hartigan P , Kaufman JS et al.  Effect of homocysteine lowering on mortality and vascular disease in advanced chronic kidney disease and end-stage renal disease: a randomized controlled trial . JAMA   2007 ; 298 : 1163 – 1170 Google Scholar Crossref Search ADS PubMed   44 Bostom AG , Carpenter MA , Kusek JW et al.  Homocysteine-lowering and cardiovascular disease outcomes in kidney transplant recipients: primary results from the folic acid for vascular outcome reduction in transplantation trial . Circulation   2011 ; 123 : 1763 – 1770 Google Scholar Crossref Search ADS PubMed   45 Jardine MJ , Kang A , Zoungas S et al.  The effect of folic acid based homocysteine lowering on cardiovascular events in people with kidney disease: systematic review and meta-analysis . BMJ   2012 ; 344 : e3533 Google Scholar Crossref Search ADS PubMed   46 Cosio FG , Falkenhain ME , Pesavento TE et al.  Patient survival after renal transplantation: II. The impact of smoking . Clin Transplant   1999 ; 13 : 336 – 341 Google Scholar Crossref Search ADS PubMed   47 Li NC , Thadhani RI , Reviriego-Mendoza M et al.  Association of smoking status with mortality and hospitalization in hemodialysis patients . Am J Kidney Dis   2018 ; 72 : 673 – 681 Google Scholar Crossref Search ADS PubMed   48 El-Shahawy O , Shires DA , Elston Lafata J. Assessment of the efficiency of tobacco cessation counseling in primary care . Eval Health Prof   2016 ; 39 : 326 – 335 Google Scholar Crossref Search ADS PubMed   49 First MR , Gerber DA , Hariharan S et al.  Posttransplant diabetes mellitus in kidney allograft recipients: incidence, risk factors, and management . Transplantation   2002 ; 73 : 379 – 386 Google Scholar Crossref Search ADS PubMed   50 Valderhaug TG , Hjelmesæth J , Hartmann A et al.  The association of early post-transplant glucose levels with long-term mortality . Diabetologia   2011 ; 54 : 1341 – 1349 Google Scholar Crossref Search ADS PubMed   51 Vincenti F , Friman S , Scheuermann E et al.  Results of an international, randomized trial comparing glucose metabolism disorders and outcome with cyclosporine versus tacrolimus . Am J Transplant   2007 ; 7 : 1506 – 1514 Google Scholar Crossref Search ADS PubMed   52 Wissing KM , Abramowicz D , Weekers L et al.  Prospective randomized study of conversion from tacrolimus to cyclosporine A to improve glucose metabolism in patients with posttransplant diabetes mellitus after renal transplantation . Am J Transplant   2018 ; 18 : 1726 – 1734 Google Scholar Crossref Search ADS PubMed   53 Nankivell BJ , P'ng CH , O'Connell PJ et al. Calcineurin inhibitor nephrotoxicity through the lens of longitudinal histology: comparison of cyclosporine and tacrolimus eras . Transplantation   2016 ; 100 : 1723 – 1731 Google Scholar Crossref Search ADS PubMed   54 Shivaswamy V , Boerner B , Larsen J. Post-transplant diabetes mellitus: causes, treatment, and impact on outcomes . Endocr Rev   2016 ; 37 : 37 – 61 Google Scholar Crossref Search ADS PubMed   55 Luan FL , Steffick DE , Ojo AO. New-onset diabetes mellitus in kidney transplant recipients discharged on steroid-free immunosuppression . Transplantation   2011 ; 91 : 334 – 341 Google Scholar Crossref Search ADS PubMed   56 Pirsch JD , Henning AK , First MR et al.  New-onset diabetes after transplantation: results from a double-blind early corticosteroid withdrawal trial . Am J Transplant   2015 ; 15 : 1982 – 1990 Google Scholar Crossref Search ADS PubMed   57 Meier-Kriesche HU , Arndorfer JA , Kaplan B. The impact of body mass index on renal transplant outcomes: a significant independent risk factor for graft failure and patient death . Transplantation   2002 ; 73 : 70 – 74 Google Scholar Crossref Search ADS PubMed   58 Lentine KL , Rocca-Rey LA , Bacchi G et al.  Obesity and cardiac risk after kidney transplantation: experience at one center and comprehensive literature review . Transplantation   2008 ; 86 : 303 – 312 Google Scholar Crossref Search ADS PubMed   59 Chan W , Bosch JA , Jones D et al.  Obesity in kidney transplantation . J Ren Nutr   2014 ; 24 : 1 – 12 Google Scholar Crossref Search ADS PubMed   60 Obayashi PA. Posttransplant diabetes mellitus: cause, impact, and treatment options . Nutr Clin Pract   2004 ; 19 : 165 – 171 Google Scholar Crossref Search ADS PubMed   61 Jenssen T , Hartmann A. Post-transplant diabetes mellitus in patients with solid organ transplants . Nat Rev Endocrinol   2019 ; 15 : 172 – 188 Google Scholar Crossref Search ADS PubMed   62 Turgeon NA , Perez S , Mondestin M et al.  The impact of renal function on outcomes of bariatric surgery . J Am Soc Nephrol   2012 ; 23 : 885 – 894 Google Scholar Crossref Search ADS PubMed   63 Freeman CM , Woodle ES , Shi J et al.  Addressing morbid obesity as a barrier to renal transplantation with laparoscopic sleeve gastrectomy . Am J Transplant   2015 ; 15 : 1360 – 1368 Google Scholar Crossref Search ADS PubMed   64 Camilleri B , Bridson JM , Sharma A et al. From chronic kidney disease to kidney transplantation: the impact of obesity and its treatment modalities . Transplant Rev   2016 ; 30 : 203 – 211 Google Scholar Crossref Search ADS   65 Troxell ML , Houghton DC , Hawkey M et al.  Enteric oxalate nephropathy in the renal allograft: an underrecognized complication of bariatric surgery . Am J Transplant   2013 ; 13 : 501 – 509 Google Scholar Crossref Search ADS PubMed   66 Weinrauch LA , D'Elia JA , Weir MR et al.  Infection and malignancy outweigh cardiovascular mortality in kidney transplant recipients: post hoc analysis of the FAVORIT Trial . Am J Med   2018 ; 131 : 165 – 172 Google Scholar Crossref Search ADS PubMed   67 Paizis IA , Mantzouratou PD , Tzanis GS et al.  Coronary artery disease in renal transplant recipients: an angiographic study . Hellenic J Cardiol   2018 ; doi: 10.1016/j.hjc.2018.07.002 68 Pilmore H. Cardiac assessment for renal transplantation . Am J Transplant   2006 ; 6 : 659 – 665 Google Scholar Crossref Search ADS PubMed   69 Felix R , Saparia T , Hirose R et al.  Cardiac events after kidney transplantation according to pretransplantation coronary artery disease and coronary revascularization status . Transplant Proc   2016 ; 48 : 65 – 73 Google Scholar Crossref Search ADS PubMed   70 Wang LW , Fahim MA , Hayen A et al.  Cardiac testing for coronary artery disease in potential kidney transplant recipients: a systematic review of test accuracy studies . Am J Kidney Dis   2011 ; 57 : 476 – 487 Google Scholar Crossref Search ADS PubMed   71 Dunn T , Saeed MJ , Shpigel A et al.  The association of preoperative cardiac stress testing with 30-day death and myocardial infarction among patients undergoing kidney transplantation . PloS One   2019 ; 14 : e0211161 Google Scholar Crossref Search ADS PubMed   72 Enkiri SA , Taylor AM , Keeley EC et al.  Coronary angiography is a better predictor of mortality than noninvasive testing in patients evaluated for renal transplantation . Cathet Cardiovasc Intervent   2010 ; 76 : 795 – 801 Google Scholar Crossref Search ADS   73 McFalls EO , Ward HB , Moritz TE et al.  Coronary-artery revascularization before elective major vascular surgery . N Engl J Med   2004 ; 351 : 2795 – 2804 Google Scholar Crossref Search ADS PubMed   74 Poldermans D , Schouten O , Vidakovic R et al.  A clinical randomized trial to evaluate the safety of a noninvasive approach in high-risk patients undergoing major vascular surgery: the DECREASE-V Pilot Study . J Am Coll Cardiol   2007 ; 49 : 1763 – 1769 Google Scholar Crossref Search ADS PubMed   75 Lentine KL , Costa SP , Weir MR et al.  Cardiac disease evaluation and management among kidney and liver transplantation candidates: a scientific statement from the American Heart Association and the American College of Cardiology Foundation . J Am Coll Cardiol   2012 ; 60 : 434 – 480 Google Scholar Crossref Search ADS PubMed   76 Glicklich D , Vohra P. Cardiovascular risk assessment before and after kidney transplantation . Cardiol Rev   2014 ; 22 : 153 – 162 Google Scholar Crossref Search ADS PubMed   77 Naylor KL , Knoll GA , Allen B et al.  Trends in early hospital readmission after kidney transplantation, 2002 to 2014: a population-based multicenter cohort study . Transplantation   2018 ; 102 : e171 – e179 Google Scholar Crossref Search ADS PubMed   78 Hypolite IO , Bucci J , Hshieh P et al.  Acute coronary syndromes after renal transplantation in patients with end-stage renal disease resulting from diabetes . Am J Transplant   2002 ; 2 : 274 – 281 Google Scholar Crossref Search ADS PubMed   79 Delville M , Sabbah L , Girard D et al.  Prevalence and predictors of early cardiovascular events after kidney transplantation: evaluation of pre-transplant cardiovascular work-up . PloS One   2015 ; 10 : e0131237 Google Scholar Crossref Search ADS PubMed   80 Atkinson P , Chiu DY , Sharma R et al.  Predictive value of myocardial and coronary imaging in the long-term outcome of potential renal transplant recipients . Int J Cardiol   2011 ; 146 : 191 – 196 Google Scholar Crossref Search ADS PubMed   81 Kahn MR , Fallahi A , Kim MC et al.  Coronary artery disease in a large renal transplant population: implications for management . Am J Transplant   2011 ; 11 : 2665 – 2674 Google Scholar Crossref Search ADS PubMed   82 Herrington WG , Emberson J , Mihaylova B et al.  Impact of renal function on the effects of LDL cholesterol lowering with statin-based regimens: a meta-analysis of individual participant data from 28 randomised trials . Lancet Diabetes Endocrinol   2016 ; 4 : 829 – 839 Google Scholar Crossref Search ADS PubMed   83 Dad T , Tighiouart H , Joseph A et al.  Aspirin use and incident cardiovascular disease, kidney failure, and death in stable kidney transplant recipients: a post hoc analysis of the Folic Acid for Vascular Outcome Reduction in Transplantation (FAVORIT) Trial . Am J Kidney Dis   2016 ; 68 : 277 – 286 Google Scholar Crossref Search ADS PubMed   84 Samad Z , Sivak JA , Phelan M et al.  Prevalence and outcomes of left-sided valvular heart disease associated with chronic kidney disease . J Am Heart Assoc   2017 ; 6 : pii: e006044 Google Scholar Crossref Search ADS PubMed   85 Abbott KC , Hshieh P , Cruess D et al.  Hospitalized valvular heart disease in patients on renal transplant waiting list: incidence, clinical correlates and outcomes . Clin Nephrol   2003 ; 59 : 79 – 87 Google Scholar Crossref Search ADS PubMed   86 Kocyigit I , Unal A , Elcik D et al.  Association between cardiac valvular calcification and serum fetuin-A levels in renal transplant recipients . Transplant Proc   2015 ; 47 : 1398 – 1401 Google Scholar Crossref Search ADS PubMed   87 Sharma A , Gilbertson DT , Herzog CA. Survival of kidney transplantation patients in the United States after cardiac valve replacement . Circulation   2010 ; 121 : 2733 – 2739 Google Scholar Crossref Search ADS PubMed   88 Fox H , Buttner S , Hemmann K et al.  Transcatheter aortic valve implantation improves outcome compared to open-heart surgery in kidney transplant recipients requiring aortic valve replacement . J Cardiol   2013 ; 61 : 423 – 427 Google Scholar Crossref Search ADS PubMed   89 Al-Rashid F , Bienholz A , Hildebrandt HA et al.  Transfemoral transcatheter aortic valve implantation in patients with end-stage renal disease and kidney transplant recipients . Sci Rep   2017 ; 7 : 14397 Google Scholar Crossref Search ADS PubMed   90 Harnett JD , Foley RN , Kent GM et al.  Congestive heart failure in dialysis patients: prevalence, incidence, prognosis and risk factors . Kidney Int   1995 ; 47 : 884 – 890 Google Scholar Crossref Search ADS PubMed   91 Stack AG , Bloembergen WE. A cross-sectional study of the prevalence and clinical correlates of congestive heart failure among incident US dialysis patients . Am J Kidney Dis   2001 ; 38 : 992 – 1000 Google Scholar Crossref Search ADS PubMed   92 de Mattos AM , Siedlecki A , Gaston RS et al.  Systolic dysfunction portends increased mortality among those waiting for renal transplant . J Am Soc Nephrol   2008 ; 19 : 1191 – 1196 Google Scholar Crossref Search ADS PubMed   93 Mathur AK , Chang YH , Steidley DE et al.  Patterns of care and outcomes in cardiovascular disease after kidney transplantation in the United States . Transplant Direct   2017 ; 3 : e126 Google Scholar Crossref Search ADS PubMed   94 Goyal A , Chatterjee K , Mathew RO et al.  In-hospital mortality and major adverse cardiovascular events after kidney transplantation in the United States . Cardiorenal Med   2019 ; 9 : 51 – 60 Google Scholar Crossref Search ADS PubMed   95 Wali RK , Wang GS , Gottlieb SS et al.  Effect of kidney transplantation on left ventricular systolic dysfunction and congestive heart failure in patients with end-stage renal disease . J Am Coll Cardiol   2005 ; 45 : 1051 – 1060 Google Scholar Crossref Search ADS PubMed   96 Burt RK , Gupta-Burt S , Suki WN et al.  Reversal of left ventricular dysfunction after renal transplantation . Ann Intern Med   1989 ; 111 : 635 – 640 Google Scholar Crossref Search ADS PubMed   97 Parfrey PS , Foley RN , Harnett JD et al.  Outcome and risk factors for left ventricular disorders in chronic uraemia . Nephrol Dial Transplant   1996 ; 11 : 1277 – 1285 Google Scholar Crossref Search ADS PubMed   98 Melchor JL , Espinoza R , Gracida C. Kidney transplantation in patients with ventricular ejection fraction less than 50 percent: features and posttransplant outcome . Transplant Proc   2002 ; 34 : 2539 – 2540 Google Scholar Crossref Search ADS PubMed   99 Kute VB , Vanikar AV , Patel HV et al.  Significant benefits after renal transplantation in patients with chronic heart failure and chronic kidney disease . Ren Fail   2014 ; 36 : 854 – 858 Google Scholar Crossref Search ADS PubMed   100 Rumman RK , Ramroop R , Chanchlani R et al.  Longitudinal assessment of myocardial function in childhood chronic kidney disease, during dialysis, and following kidney transplantation . Pediatr Nephrol   2017 ; 32 : 1401 – 1410 Google Scholar Crossref Search ADS PubMed   101 Xu B , Harb S , Hawwa N et al.  Impact of end-stage renal disease on left and right ventricular mechanics: does kidney transplantation reverse the abnormalities? JACC Cardiovasc Imaging   2017 ; 10 : 1081 – 1083 Google Scholar Crossref Search ADS PubMed   102 Holdaas H , de Fijter JW , Cruzado JM et al.  Cardiovascular parameters to 2 years after kidney transplantation following early switch to everolimus without calcineurin inhibitor therapy: an analysis of the randomized ELEVATE study . Transplantation   2017 ; 101 : 2612 – 2620 Google Scholar Crossref Search ADS PubMed   103 Paoletti E. mTOR inhibition and cardiovascular diseases: cardiac hypertrophy . Transplantation   2018 ; 102 : s41 – s43 Google Scholar Crossref Search ADS PubMed   104 Philipp T , Martinez F , Geiger H et al.  Candesartan improves blood pressure control and reduces proteinuria in renal transplant recipients: results from SECRET . Nephrol Dial Transplant   2010 ; 25 : 967 – 976 Google Scholar Crossref Search ADS PubMed   105 Lentine KL , Schnitzler MA , Abbott KC et al.  De novo congestive heart failure after kidney transplantation: a common condition with poor prognostic implications . Am J Kidney Dis   2005 ; 46 : 720 – 733 Google Scholar Crossref Search ADS PubMed   106 Lenihan CR , Liu S , Deswal A et al.  De novo heart failure after kidney transplantation: trends in incidence and outcomes . Am J Kidney Dis   2018 ; 72 : 223 – 233 Google Scholar Crossref Search ADS PubMed   107 Fujikura K , Peltzer B , Tiwari N et al.  Reduced global longitudinal strain is associated with increased risk of cardiovascular events or death after kidney transplant . Int J Cardiol   2018 ; 272 : 323 – 328 Google Scholar Crossref Search ADS PubMed   108 McLaughlin VV , Archer SL , Badesch DB et al.  ACCF/AHA 2009 expert consensus document on pulmonary hypertension: a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association: developed in collaboration with the American College of Chest Physicians, American Thoracic Society, Inc., and the Pulmonary Hypertension Association . Circulation   2009 ; 119 : 2250 – 2294 Google Scholar Crossref Search ADS PubMed   109 Lentine KL , Villines TC , Axelrod D et al.  Evaluation and management of pulmonary hypertension in kidney transplant candidates and recipients: concepts and controversies . Transplantation   2017 ; 101 : 166 – 181 Google Scholar Crossref Search ADS PubMed   110 Pabst S , Hammerstingl C , Hundt F et al.  Pulmonary hypertension in patients with chronic kidney disease on dialysis and without dialysis: results of the PEPPER-study . PloS One   2012 ; 7 : e35310 Google Scholar Crossref Search ADS PubMed   111 Sise ME , Courtwright AM , Channick RN. Pulmonary hypertension in patients with chronic and end-stage kidney disease . Kidney Int   2013 ; 84 : 682 – 692 Google Scholar Crossref Search ADS PubMed   112 Terzano C , Conti V , Di Stefano F et al.  Comorbidity, hospitalization, and mortality in COPD: results from a longitudinal study . Lung   2010 ; 188 : 321 – 329 Google Scholar Crossref Search ADS PubMed   113 Lentine KL , Delos Santos R , Axelrod D et al.  Obesity and kidney transplant candidates: how big is too big for transplantation? Am J Nephrol   2012 ; 36 : 575 – 586 Google Scholar Crossref Search ADS PubMed   114 Kumar G , Sakhuja A , Taneja A et al.  Pulmonary embolism in patients with CKD and ESRD . Clin J Am Soc Nephrol   2012 ; 7 : 1584 – 1590 Google Scholar Crossref Search ADS PubMed   115 Lentine KL , Costa SP , Weir MR et al.  Cardiac disease evaluation and management among kidney and liver transplantation candidates: a scientific statement from the American Heart Association and the American College of Cardiology Foundation: endorsed by the American Society of Transplant Surgeons, American Society of Transplantation, and National Kidney Foundation . Circulation   2012 ; 126 : 617 – 663 Google Scholar Crossref Search ADS PubMed   116 Issa N , Krowka MJ , Griffin MD et al.  Pulmonary hypertension is associated with reduced patient survival after kidney transplantation . Transplantation   2008 ; 86 : 1384 – 1388 Google Scholar Crossref Search ADS PubMed   117 Lai Y-L Wasse H, Kim W et al. Association of pulmonary hypertension at kidney transplant evaluation and subsequent outcome following kidney transplantation . Am J Transplant   2015 ; Abstract 118 Grupper A , Grupper A , Daly RC et al.  Renal allograft outcome after simultaneous heart and kidney transplantation . Am J Cardiol   2017 ; 120 : 494 – 499 Google Scholar Crossref Search ADS PubMed   119 Wanner C , Herzog CA , Turakhia MP. Chronic kidney disease and arrhythmias: highlights from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference . Kidney Int   2018 ; 94 : 231 – 234 Google Scholar Crossref Search ADS PubMed   120 Girgis I. Arrhythmias and risk assessment in patients with renal failure . Card Electrophysiol Rev   2002 ; 6 : 155 – 159 Google Scholar Crossref Search ADS PubMed   121 Lenihan CR , Montez-Rath ME , Scandling JD et al.  Outcomes after kidney transplantation of patients previously diagnosed with atrial fibrillation . Am J Transplant   2013 ; 13 : 1566 – 1575 Google Scholar Crossref Search ADS PubMed   122 Lentine KL , Schnitzler MA , Abbott KC et al.  Incidence, predictors, and associated outcomes of atrial fibrillation after kidney transplantation . Clin J Am Soc Nephrol   2006 ; 1 : 288 – 296 Google Scholar Crossref Search ADS PubMed   123 Jonsson A , Kayler LK. Kidney transplantation without interruption of warfarin . Clin Transplant   2015 ; 29 : 665 – 666 Google Scholar Crossref Search ADS PubMed   124 Connaughton DM , Phelan PJ , Scheult J et al.  The impact of peritransplant warfarin use on renal transplant outcome . J Nephrol   2010 ; 23 : 587 – 592 Google Scholar PubMed   125 Salerno DM , Tsapepas D , Papachristos A et al.  Direct oral anticoagulant considerations in solid organ transplantation: A review . Clin Transplant   2017 ; 31 : doi: 10.1111/ctr.12873 126 Di Lullo L , Rivera R , Barbera V et al.  Sudden cardiac death and chronic kidney disease: From pathophysiology to treatment strategies . Int J Cardiol   2016 ; 217 : 16 – 27 Google Scholar Crossref Search ADS PubMed   127 Kasiske BL , Guijarro C , Massy ZA et al.  Cardiovascular disease after renal transplantation . J Am Soc Nephrol   1996 ; 7 : 158 – 165 Google Scholar PubMed   128 West M , Sutherland DE , Matas AJ. Kidney transplant recipients who die with functioning grafts: serum creatinine level and cause of death . Transplantation   1996 ; 62 : 1029 – 1030 Google Scholar PubMed   129 Marcassi AP , Yasbek DC , Pestana JO et al.  Ventricular arrhythmia in incident kidney transplant recipients: prevalence and associated factors . Transplant Int   2011 ; 24 : 67 – 72 Google Scholar Crossref Search ADS   130 Chertow GM , Normand SL , McNeil BJ. ‘Renalism’: inappropriately low rates of coronary angiography in elderly individuals with renal insufficiency . J Am Soc Nephrol   2004 ; 15 : 2462 – 2468 Google Scholar Crossref Search ADS PubMed   131 Rossignol P , Agarwal R , Canaud B et al.  Cardiovascular outcome trials in patients with chronic kidney disease: challenges associated with selection of patients and endpoints . Eur Heart J   2017 ; doi: 10.1093/eurheartj/ehx209 132 Carpenter MA , Weir MR , Adey DB et al.  Inadequacy of cardiovascular risk factor management in chronic kidney transplantation - evidence from the FAVORIT study . Clin Transplant   2012 ; 26 : E438 – E446 Google Scholar Crossref Search ADS PubMed   133 Chaudhry RI , Mathew RO , Sidhu MS et al.  Detection of atherosclerotic cardiovascular disease in patients with advanced chronic kidney disease in the cardiology and nephrology communities . Cardiorenal Med   2018 ; 8 : 285 – 295 Google Scholar Crossref Search ADS PubMed   134 Kazory A , McCullough PA , Rangaswami J et al.  Cardionephrology: proposal for a futuristic educational approach to a contemporary need . Cardiorenal Med   2018 ; 8 : 296 – 301 Google Scholar Crossref Search ADS PubMed   Author notes Janani Rangaswami and Roy O. Mathew authors contributed equally to this manuscript. © The Author(s) 2019. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)


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Rangaswami, Janani, Mathew, Roy O, Parasuraman, Raviprasenna, Tantisattamo, Ekamol, Lubetzky, Michelle, Rao, Swati, Yaqub, Muhammad S, Birdwell, Kelly A, Bennett, William, Dalal, Pranav, Kapoor, Rajan, Lerma, Edgar V, Lerman, Mark, McCormick, Nicole, Bangalore, Sripal, McCullough, Peter A, Dadhania, Darshana M. Cardiovascular disease in the kidney transplant recipient: epidemiology, diagnosis and management strategies, Nephrology Dialysis Transplantation, 2019, 760-773, DOI: 10.1093/ndt/gfz053