Short- and Long-Term Outcomes of Cardiac Surgery in Kidney Transplant Recipients: A Review
—Kidney Transplant and Cardiac Surgery ()
1. Introduction
Since the first case reported of successful coronary artery bypass graft (CABG) surgery in a patient with kidney transplantation in 1975 [1] , there have been numerous cases and small series supporting the use of cardiac surgery in patients with kidney transplantation [2] - [6] . Cardiovascular diseases remain the leading cause of death in kidney transplant recipients and it is a major barrier to improve the long-term survival of kidney transplant patients. There are multiple risk factors for cardiovascular disease in these patients which include both traditional and transplant-specific risk factors [3] [4] . Traditional risk factors (such as Diabetes Mellitus, hypertension, hyperlipidemia) are prevalent in kidney transplant recipients. Transplant-specific risk factors include immunosuppression therapy, infections, cellular and antibody related rejection and other factors. The outcomes of such patients are constantly improving due to improvement in surgical techniques, perioperative care and organ preservation with improvement in immunosuppression therapy. The aim of this review was to examine and report the short- and long-term outcomes of kidney transplant recipients with functioning renal allograft undergoing cardiac surgery. Predictors of graft failure and long-term survival were also examined and discussed. Understanding these outcomes can lead to the development of preventative strategies and improved outcomes in these patients.
2. Materials and Methods
2.1. Literature Review, Inclusion and Exclusion Criteria
Literature review was conducted in PubMed, Google scholar, Embase databases from inception to 1st June 2022. Literature search was limited to English language only. The following search terms were used [cardiac surgery and renal transplant], [cardiac surgery and abdominal solid organ transplant], [valve surgery and renal transplant], [coronary artery bypass and renal transplant], [renal failure and cardiac surgery], [dialysis and cardiac surgery], [immunosuppression and cardiac surgery]. All titles were screened, and relevant abstracts were extracted. All relevant articles were then reviewed, analyzed and summarized. Individual references from the reference list of each relevant article were also manually searched to expand the search criteria. Case reports and small case series of less than 10 patients were excluded from the study. In the event of duplicate publications from same authors or institution, the largest study was included only. Studies examining the outcomes of cardiac surgery on patients with abdominal solid organ transplantation (ASOT) were included in the study if individual data were available for kidney transplant subset or the kidney transplant subset constituted more than one third of the study population. In addition, articles comparing outcomes of dialysis patients to functioning renal transplants following cardiac surgery were included if the authors provided individual relevant data to kidney transplant groups. Records identified through initial search was 2230. A total of 2199 records were excluded after reviewing of abstracts, elimination of duplicate publication and exclusion of small case series and reports. The number of relevant articles meeting the above criteria included in this analysis was 31 articles [3] - [33] . Outcomes of interest were short-term mortality, predictors of mortality, long-term survival, acute kidney injury post-operatively, renal allograft failure and infections. Outcome variables were tabulated in relevant tables with reference to each published article.
2.2. Definitions of Outcome Variables
Short term mortality was defined as 30-Day mortality following cardiac surgery. Acute kidney injury referred to the use of temporary/permanent dialysis in a patient with no prior history of use preoperatively or worsening of kidney function that was managed conservatively postoperatively. Kidney graft failure referred to the resumption of permanent dialysis or the requirement of re-transplantation following cardiac surgery. Infectious complications referred to surgical site infections (sternum and leg wound) whether deep or superficial, pneumonia or sepsis.
3. Results
3.1. Prevalence of Risk Factors in Kidney Transplant Patients Undergoing Cardiac Surgery
Table 1 is the summary of patients demographics of the included articles. As shown, majority of patients were males (57% - 90%) in their 4th-6th decade of life. Interval from kidney transplantation to cardiac surgery ranged from 3.5 years to 12 years. Cardiac risk factors were prevalent with hypertension occurring in 15% - 100% of patients, diabetes mellitus (DM) occurring in 19% - 93% of patients and hyperlipidemia occurring in 17% - 80% of kidney transplant patients. History of coronary artery disease reported to occur in 11% - 100% of cases. The incidence of endocarditis ranged from zero to 17%. All articles included were retrospective observational studies of single center with exception of five studies which were retrospective analysis of nationwide data system of USA [10] [18] [21] [23] [25] .
3.2. Short-Term 30-Days Mortality and Long-Term Survival Following Cardiac Surgery
Short-term 30-Days mortality ranged across the studies examined from zero to 18.8%. Commonest causes of death (in order of frequency) were cardiogenic, sepsis, gastrointestinal complications, strokes and pulmonary embolism. Long-term follow-up periods varied between the studies and ranged from 2 to 6.5 years. The survival rate for 1 year ranged from 71% to 97%. Survival at 5-years ranged from 31% to 95.7%. Survival beyond 5-years ranged from 12% to 59%. These results are shown in Table 2. Predictors of 30-days mortality included pre-operative, intra-operative and post-operative factors (Table 3). Pre-operative factors were age, diabetes mellitus (DM), chronic obstructive pulmonary disease (COPD), peripheral vascular disease (PVD), left ventricular
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Table 1. Demographics and preoperative variables in the studies reviewed.
CABG: coronary artery bypass graft. NR: not reported. *Median value.
dysfunction, congestive heart failure (CHF), mitral valve disease, lower creatinine clearance, acute renal failure and solid organ transplantation. Intra-operative factors were urgent operation, combined valve surgery, combined cardiac surgery, cardiopulmonary bypass time, blood transfusion and mechanical mitral valve replacement. Post-operative factors were infection, septicemia and new onset dialysis. Predictors of long-term mortality (Table 3) included: Age, female gender, low body mass index (BMI), DM, chronic atrial fibrillation, history of stroke, COPD, higher number of preoperative myocardial infarctions (MI), preoperative unstable angina, congestive heart failure, ejection fraction <30%, renal transplantation before cyclosporin use, urgent surgery, previous CABG, dialysis dependence and solid organ transplant.
3.3. Acute Kidney Injury (AKI) Including the Use of Temporary/Permanent Dialysis and Permanent Kidney Graft Failure Following Cardiac Surgery
Post-operative AKI (with or without dialysis) in kidney transplant patients following cardiac surgery ranged from zero to 74% and the majority were transient (Table 4). Permanent kidney graft failure (defined as return to permanent dialysis or requirement of another kidney re-transplantation) was reported between zero to 45% in different studies. 5-years renal graft survival rates ranged 37% - 80%. One study reported an 8-year kidney graft survival rate at 49% [22] and another study reported a 10-year kidney graft survival at 53% [30] . Interestingly, one study that compared off pump CABG to on pump CABG [19] showed no difference between the two groups in the incidence of AKI or kidney graft failure. Factors predicting kidney graft failure (Table 3) were: preoperative serum creatinine level, DM, hyperlipidemia, preoperative intra-aortic balloon pump use, transient renal failure requiring dialysis post-op, deceased kidney donor, high preoperative trough level of Calcineurin inhibitors.
3.4. Infection Rates and Sites of Infections in Kidney Transplant Patients Undergoing Cardiac Surgery
Postoperative infections in kidney transplant patients undergoing cardiac surgery (Table 5) ranged from 1% to 25.7%. Commonest reported sites (in terms of frequency of occurrence) were pneumonia, septicemia, and surgical site infections
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Table 2. Short-term mortality and long-term survival in kidney transplant patients undergoing cardiac surgery.
ASOT: abdominal solid organ transplants. CABG: Coronary artery bypass graft surgery. GI complication: gastrointestinal complication. IMA: internal mammary artery. PE: pulmonary embolism.
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Table 3. Predictors of mortality (short and long term) and predictors of dialysis in kidney transplant patients undergoing cardiac surgery.
BMI: Body mass index. CABG: coronary artery bypass graft. CHF: congestive heart failure. COPD: chronic obstructive pulmonary disease. CPB: cardiopulmonary bypass. CVA: cerebrovascular accident. IABP: intra-aortic balloon pump.
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Table 4. Post-operative acute kidney injury requiring dialysis and permanent kidney graft failure.
AKI: acute kidney injury. ASOT: abdominal solid organ transplants. CABG: coronary artery bypass graft.
(SSI). Interestingly, 3 studies have reported zero incidence of SSI in their series [29] [31] [33] .
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Table 5. Infections and site of infections in kidney transplant patients undergoing cardiac surgery.
ASOT: abdominal solid organ transplants. C.Diff: Clostridium Difficile infection. UTI: Urinary tract infection. SSI: surgical site infection.
4. Discussion
4.1. Cardiovascular Disease and Risk Factors in Kidney Transplant Patients
Cardiovascular disease remains the major cause of death after renal transplant and renal transplant recipients continue to have a higher incidence of fatal and non-fatal cardiovascular events than the general population. Traditional cardiac risk factors (such as hypertension, DM, hyperlipidemia) are prevalent in renal transplant patients and are affected by the immunosuppression treatment. Hypertension can be caused or worsened by steroids and Calcineurin inhibitors. Dyslipidemia is prevalent in more than half of renal transplant patients and can be caused by steroids, Calcineurin inhibitors and Sirolimus. The high incidence of post-transplant DM is not surprising due to steroid and Calcineurin inhibitors induced hyperglycemia, and this is compounded by the high prevalence of obesity at the time of renal transplant with estimated 60% being overweight or obese. Many non-traditional risk factors that exacerbate cardiac risk in patients with end stage renal disease also operate after renal transplantation including renal graft loss, proteinuria, anemia, chronic inflammation, hyperhomocysteinemia, hypercoagulation and left ventricular hypertrophy [34] . In a prospective study of 344 consecutive renal transplant patients free of cardiovascular disease, it was found that 7.8% of the cohort developed coronary event. The authors observed that inflammation plays a role in the pathogenesis of atherosclerosis in renal transplant recipients [35] . Similarly, in an autopsy series of 18 renal transplant recipients, cardiovascular pathological findings were evident in 15 out of 18 patients which included severe coronary atherosclerosis with acute MI, left/right ventricular hypertrophy, left/right ventricular dilatation, left/right atrial dilatation and valvular abnormalities [36] . Another paper examined a cohort of 922 patients transplanted between 1993 and 1998. Cardiovascular events (both fatal and non-fatal) occurred in 21% of patients [37] . Multivariate analysis of cardiac events post kidney transplants showed the following factors as predictors: prior cardiovascular event, DM, tobacco history, obesity at transplant, multiple rejections, Dialysis > 1 year. Multivariate analysis of mortality following kidney transplantation showed the following as predictors: Tobacco and deceased donor, age > 45 years, DM pre-transplant, prior cardiovascular event, pulse pressure of 61 mm Hg or greater, dialysis > 1 year and hypercholesterolemia at transplant. The incidence of cardiovascular disease in kidney transplant patients was twice that of the general population. Even young transplant recipients (aged 35 - 45 years) experienced an almost 10-fold increase in cardiovascular disease-related mortality [37] . The commonest cause of late mortality after kidney transplantation was cardiovascular diseases accounting for 40% - 55% of all deaths [14] . As the number of kidney transplantations increases annually, cardiac events are also expected to rise in this population with an increasing number being referred for cardiac surgery. Kidney transplant recipients represents a challenging patient population because of potentially increased risk of postoperative sepsis related to immunosuppression treatment, temporary or permanent allograft failure because of intraoperative non-pulsatile flow of cardiopulmonary bypass and allograft failure. As such, knowledge on the expected post-operative outcome is important to give informed consent to patients and guide clinicians to manage these patients. In addition, the expected long-term survival and kidney graft failure are of paramount importance to predict and reduce its incidence leading to improved survival and outcome. The aim of this review is to summarize the main results of data published over 4 decades with particular emphasis on the outcome data, operative mortality and long-term survival. This review will help clinicians in drawing the proper decision in the management strategies when presented with kidney transplant patients.
4.2. Short-and Long-Term Mortality with Predictors of Mortality in Kidney Transplant Patients
As shown in Table 6, most of the studies [5] [6] [8] - [15] showed 30-Days mortality rates ≤ 10%. Only five studies [15] [23] [26] [27] [33] compared the short-term outcomes of kidney transplant patients undergoing cardiac surgery to non-transplant patients using a variety of matching techniques. Ranjit et al. [15] retrospectively reviewed kidney transplant patients undergoing cardiac surgery over a 10 years’ period in a single center (70 patients with kidney
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Table 6. Summary of outcomes stratified as percentages.
AKI: Acute Kidney Injury.
transplants were matched to 895 controls). The authors showed that kidney transplant patients were on average 9 years younger with higher incidence of DM, PVD, chronic renal failure and unstable angina when compared to controls. Prior kidney transplant was not a predictor of 30 days’ mortality in that study and multivariate analysis of 30-Days mortality were: preoperative CHF, urgent surgery, prolong cardiopulmonary bypass, PVD and lower creatinine clearance. Vargo et al. [23] retrospectively analyzed 3535 ASOT patients (kidney transplants were 2712 patients) from a nationwide inpatient sample over 4 years’ period and these were propensity matched in 1:3 to non-transplant patients undergoing cardiac surgery. The authors found no significant difference in in-hospital mortality between transplant and non-transplants patients (7% vs. 4%, respectively). However, total hospital costs were significantly higher for transplant patients. Farag et al. [26] retrospectively reviewed single center database of 70 patients with ASOT (49 patients were kidney transplants) over 13 years’ period and matched them in 1:1 with non-transplant patients undergoing cardiac surgery based on age, gender and cardiac risk factors. The authors found that 30-Days mortality was significantly higher in the kidney transplant group compared to controls (12.2% vs. 5.7%) with higher long-term mortality over median follow-up time of 32 months (36% vs. 11.4%). Transplant survival compared to controls at 1-year, 5-years and 10-years were significantly lower than controls (74% vs. 93% at 1 year, 66% vs. 88% at 5-years, 56% vs. 81% at 10 years). Multivariate predictors of mortality were organ transplant (Hazard ratio 3.7), intra-op transfusion (Hazard ratio 1.0) and post-op increase in bilirubin concentration (Hazard ratio 1.3). Kohmoto et al. [27] retrospectively reviewed 115 patients with ASOT undergoing cardiac surgery over 16 years’ period in a single center and performed propensity match (1:3) to 345 patients with no prior transplant. The study showed no difference in the rate of 30-Days mortality between the two groups (4% for transplants vs. 2% for controls). Fazmin et al. [33] retrospectively reviewed 38 patients with kidney transplant patients matched as 1:2 to 76 patients with no prior transplant over 8 years’ period in a single center. Matching was based on age, gender, left ventricular function, body mass index, preoperative creatinine level, logistic EURO SCORE, operation urgency and operation category. The study showed higher in-hospital mortality in transplant patients compared to controls (15.8% vs. 1.3% respectively) with significantly lower 5-years survival in kidney transplant patients compared to controls (63% vs. 91%, respectively). Most of the studies reviewed [5] [7] [8] [11] [14] showed 5-years survival in kidney transplant patients undergoing cardiac surgery to be ≥ 50% (Table 6).
4.3. Acute Kidney Injury and Renal Allograft Failure in Kidney Transplant Patients
As shown in table 6, more than half of the studies reviewed [4] - [8] showed the incidence of acute kidney injury (AKI) with or without dialysis to be ≤ 10% with ≤10% rate of permanent kidney graft failure [11] - [17] . Only 6 previous studies were a matched case control design [3] [15] [23] [26] [27] [33] . Ranjit et al. [15] reported significant difference in the need of postoperative dialysis in kidney transplant patients compared to controls (11.7% vs. 1% respectively) and significantly higher incidence of AKI in transplant patients vs. controls (33% vs. 6%, respectively). However, this was all temporary and none of their transplant patients had permanent kidney graft failure. Vargo et al. [23] showed significantly increased risk of AKI in transplant patients vs. controls (38% vs. 27%, Odds ratio 1.6). However, kidney graft failure was only 2%. Farag et al. [26] showed significantly higher need for dialysis in transplant patients compared to controls (17% vs. 6%, respectively) with 12% kidney graft failure. Kohmoto et al. [27] showed no difference in the rate of AKI between transplant and non-transplant patients undergoing cardiac surgery. However, over 15-years follow-up, 37% of kidney transplant patients have lost their kidney graft function. Fazmin et al. [33] , showed higher incidence of AKI in transplant patients compared to controls (74% vs. 38%, respectively) with higher requirement of dialysis in transplant patients (45% vs. 5%, respectively). However, the authors did not report the rate of permanent kidney graft failure. Hundemer et al. [3] investigated incidence and risk factors for AKI retrospectively over 3 years’ period in patients with kidney transplants undergoing cardiac surgery and matched them 1:1 with control group. Matching was based on age, preoperative glomerular filtration rate and type of cardiac surgery. The study was conducted in 2 centers and showed that renal transplant patients had significantly higher AKI rate compared to control (46% vs. 28%, Odds ratio 2.7). In addition, the study showed that the presence of diseased donors and high preoperative level of Calcineurin inhibitors had additive effect on incidence of AKI (88% for patients with these two risk factors vs. 25% for patients with neither).
4.4. Postoperative Infections in Kidney Transplant Patients
Post operative infection is a major complication with significant impact on kidney transplant patients undergoing cardiac surgery as these patients are on chronic immunosuppression therapy and steroids. These medications predispose such patients to both general systemic and opportunistic infections. As shown in Table 6, more than half of the studies reviewed [8] [9] [12] [14] [15] showed infection rates ≤ 10% in renal transplant patients undergoing cardiac surgery. Only 5 studies were matched case control design [15] [23] [26] [27] [33] . Ranjit et al. [15] showed no difference in the rate of postoperative infections in transplant patients compared to controls (2.9% vs. 2%, respectively) and no difference in the rates of sepsis (2.9% vs. 1.7%, respectively) or pneumonia (1.4% vs. 6.7%, respectively). However, patients with kidney transplants were less likely to have left internal mammary artery (LIMA) used for revascularization compared to controls (62% vs. 88%, respectively) and 73 of 74 patients that had kidney transplant underwent CABG either alone or in combination with valve surgery in the same study. The use of LIMA is a risk factor in postoperative infections post cardiac surgery. Vargo et al. [23] , showed no difference between transplant patients and controls in the rate of wound infections (1.4% vs. 1.3%, respectively) or pneumonia (7.5% vs. 6%, respectively). Farag et al. [26] , showed that sepsis was significantly higher in renal transplant patients compared to controls in patients undergoing cardiac surgery (10% vs. 1.4%). Rates of post-operative infections were also significantly higher in transplant patients compared to controls (25.7% vs. 12.9%, respectively). However, the rate of wound infections was not significantly different between the two groups (5.7% for transplants vs. 4.3% for controls). Kohmoto et al. [27] showed no difference in the rate of surgical site infections in kidney transplant patients compared to controls (1% for kidney transplants vs. 2% for controls) and no difference in postoperative pneumonia rate (5% each group). Fazmin et al. [33] , showed that renal transplant patients had significantly higher incidence of non-wound and non-respiratory infections compared to non-transplant patients (21% vs. 4%, respectively). Wound infections were not different in the two groups in that study.
4.5. Future Directions
Key features in the perioperative management of renal transplant patients include appropriate management of immunosuppression, careful maintenance of renal perfusion before and during cardiopulmonary bypass, and monitoring of renal function postoperatively. Ideally, patients at higher risk for mortality and renal allograft failure could be identified preoperatively and managed selectively to minimize their risk. Multidisciplinary approach (cardiac surgeons, intensivists, anesthetists, transplant clinicians and infectious disease specialists) is of foremost importance when managing these patients.
5. Limitations of the Study
Although this is a comprehensive review of the outcome of renal transplant recipients undergoing cardiac surgery, the review has several limitations. Firstly, the references used were solely observational studies and were mostly single center studies. Secondly, there was no prospective study and no randomized trial performed in these study population that was reported and as such, these studies will have inherent selection bias associated with them. Thirdly, although the general principles of management for the kidney transplant patients following cardiac surgery were applied in the various studied used, the management strategies differed between centers with lack of standardization between them. This might have biased the results of observed outcomes and partially explain the differences in outcomes seen between the studies examined.
6. Conclusion
Cardiac surgery can be safely performed in patients with prior functioning kidney transplants with good short-term morbidity and mortality. Long-term results are encouraging both in terms of survival and functionality of kidney graft. Understanding these observations may lead to improved outcomes in the future and improve detection and management strategies aiming at reducing the adverse outcomes.
Data Availability
All data were extracted from previously published articles reviewed from the three databases used in method section.