Objectives: Left ventricular hypertrophy is one of the most typical cardiac abnormalities detected in patients with end-stage renal disease. In patients with congestive heart failure, the most crucial factor determining patient survival is left ventricular ejection fraction. Herein, we present our experience with living donor kidney transplant recipients with a left ventricular ejection fraction of <50%.
Materials and Methods: Patients who underwent living donor kidney transplant in our center between November 2008 and November 2021 and had pretransplant left ventricular ejection fraction <50% were included. All patients had dialysis the day before surgery. All patients underwent 2-dimensional echocardiograms after dialysis and were categorized according to New York Heart Association classification, pretransplant and on posttransplant day 5. Demog-raphic parameters and additional data, including pretransplant and posttransplant day 5 New York Heart Association classification, left ventricular ejection fraction at 6 months, and graft survival at 6 months, as well as patient survival data, were analyzed.
Results: Our study included 31 patients (mean age of 46.6 ± 18.3; range, 11-77 years). We found significant differences in New York Heart Association classifi-cations before and after transplant, indicating that kidney transplant had a positive effect on pretransplant congestive heart failure in patients with low left ventricular ejection fraction (P = .001). The mean pretransplant left ventricular ejection fraction was 32 ± 9.9% (range, 1%-45%), whereas the mean 6-month posttransplant left ventricular ejection fraction was 52 ± 8.7% (range, 28%-63%) (P < .001). Both graft loss and all-cause mortality rates were 12.9%.
Conclusions: Low left ventricular ejection fraction is not a contraindication for kidney transplant. We suggest that myocardial scintigraphy should be performed in patients with end-stage renal disease and low left ventricular ejection fraction, and kidney transplant should be considered in those without ischemic findings.

Key words : Congestive heart failure, End-stage renal disease, Uremic cardiyomyopathy

Introduction

Cardiovascular disease is the most common cause of mortality in patients with end-stage renal disease (ESRD).¹ Cardiovascular disease-related mortality rate has been shown to be 30% higher in patients with ESRD than in the general population.² Left ventricular hypertrophy is one of the most common cardiac abnormalities detected in ESRD patients.³ This finding is probably because these patients are usually hypervolemic. Of note, hypervolemia is associated with a 4- to 5-fold increase in the rate of mortality in these patients.²

Congestive heart failure (CHF) is defined as the inability of the heart to pump enough blood to the peripheral tissues despite normal or elevated filling pressures.³ The most critical factor determining patient survival has been reported to be left ventricular ejection fraction (LVEF).⁴ Echocardiography, particularly 2-dimensional echocardiography, is the most common noninvasive method for measuring the LVEF.⁵

Previous work showed that ~45% of patients on dialysis have CHF.⁶ Researchers also found that the median survival varied between 38 and 66 months in patients with ESRD and an LVEF of <50%.⁷ These studies also reported that an LVEF of <50% was associated with functional and structural damage and thus is a risk factor for high cardiac morbidity after kidney transplant (KT).⁸

Kidney transplant is the gold standard treatment for patients with ESRD.⁹ However, despite the relationship between ESRD and CHF, the literature on KT recipients with low LVEF is scarce.^7,8,10,11 Therefore, we aimed to present our experience with living donor KT in patients with an LVEF of <50%.

Materials and Methods

Pediatric or adult patients who underwent living donor KT in Antalya Medical Park Hospital Solid Organ Transplantation Center between November 2008 and November 2021 and had a LVEF pretransplant of <50% constituted the target population of our study. All patients previously consented to use their medical data for research purposes. Patients who underwent deceased donor KT, patients who underwent simultaneous heart-kidney transplant or liver-kidney transplant, and those who did not have posttransplant 6-month follow-up data were not included in our study.

All donors underwent laparoscopic donor nephrectomy, and all recipients underwent KT with an open retroperitoneal approach. The same surgical team performed both the donor and recipient surgeries. All recipients were referred to the intensive care unit after completion of surgery. Recipients were given standard maintenance immunosuppression with methylprednisolone/prednisone, mycophe-nolate mofetil (MMF), and tacrolimus (Prograf, Astellas). Antithymocyte globulin (ATG) was used for induction immunosuppression. Of note, mycophenolate sodium (Myfortic) was given to patients who had gastrointestinal side effects from MMF. The target trough tacrolimus level was 8 to 10 mg/dL during the first post-KT year and 6 to 8 mg/dL during the second year. Prednisone dose was gradually tapered in all patients.

In our routine clinical practice, patients with low LVEF receive dialysis the day before surgery, and ultrafiltration is performed during these dialysis sessions as needed. All patients undergo 2-dimensional echocardiography, performed by our transplant cardiologist after completion of dialysis. All patients were categorized based on the New York Heart Association (NYHA) classification, pretransplant and on day 5 posttransplant. In accordance with the NYHA classification, patients with no limitations of physical activity were categorized as class I. In contrast, those unable to perform any physical activity without discomfort were categorized as class IV.¹²

After discharge from the center, all recipients were followed at our outpatient clinic as per our institutional follow-up protocol. According to this protocol, all recipients presented to the clinic twice per week during the first month of follow-up, once per week during the second month, once every 2 weeks during the third month, and once per month afterward, unless advised otherwise by the transplant team. During the post-KT 6-month follow-up visits, the patients were referred to the same cardiologist for echocardiography.

We reviewed and recorded demographic information, etiology of ESRD, pre-KT dialysis status (ie, preemptive/hemodialysis/peritoneal dialysis), pretransplant NYHA classification (ie, class I, II, III, IV), posttransplant day 5 NYHA classification, pret-ransplant and posttransplant 6-month LVEF results, other echocardiography findings, comorbidities, presence or absence of delayed graft function, and 6-month graft survival, and patient survival.

The donors of all patients were their relatives. The donors of 12 patients were their partners, 9 were their mothers, 7 were their fathers, and 3 were siblings. Two-dimensional echocardiographs were performed by various cardiologists during the study period. Interobserver variability may have been a limitation.

Statistical analyses
We used Statistical Package for Social Sciences (version 12.0; SPSS Inc) software for statistical analyses. We compared continuous parameters with t tests. We used chi-square tests to analyze the effects of change in differences in categorical data. The McNemar-Bowker test was used to determine differences in dichotomous-dependent variables between 2 related groups. Friedman variance analysis was used for nonnormally distributed data. Given the small sample size, no multivariate analysis was performed. P < .05 was considered significant.

Results

Our retrospective review revealed that 5565 KT surgeries were performed during the study period. Application of inclusion and exclusion criteria resulted in 31 patients included in our study. Among our KT recipient group, 19 were male patients (61.3%) and 12 were female patients (38.7%). The mean age was 46.6 ± 18.3 years (range, 11-77 years). There were only 2 pediatric patients in the cohort, who were aged 11 and 12 years. The median duration of follow-up was 385 days (range, 7-1580 days).

The primary reasons for ESRD are listed in Table 1. Most of the cases were idiopathic. Among those with known reasons for ESRD, hypertension and diabetes mellitus combination was the most common cause.

Twelve patients (38.7%) underwent KT preem-ptively. Among the 19 patients who were on dialysis at the time of KT, 15 were on hemodialysis, 1 was on peritoneal dialysis, and 3 were on both hemodialysis and peritoneal dialysis. Mean dialysis duration was 32.1 ± 42.4 months (range, 1-144 months). All patients were induced by ATG, and none of the patients required a switch from MMF to mycophenolate sodium or from tacrolimus to cyclosporine.

The distribution of study patients based on NYHA classification pretransplant and post-transplant is shown in Table 2. As shown in Table 2, 6 of 11 patients with NYHA class IV CHF were switched to NYHA class I and 4 were switched to class II after KT. Only 1 of the 11 patients did not shift to another class. However, 6 of the 12 patients who were classified with NYHA class III CHF switched to NYHA class I, and the remaining 6 patients shifted to NYHA class II. Among the 8 patients who had NYHA class II CHF, 3 patients switched to NYHA class 1, whereas 5 did not shift to another NYHA class after KT. Comparisons of the pre-KT and post-KT distributions based on NYHA by the performance of the McNemar-Bowker test revealed significant differences, indicating that KT had a positive impact on pretransplant CHF in patients with low LVEF (P = .001).

In our patient group, the mean LVEF pret-ransplant was 32 ± 9.9% (range, 1%-45%), and the mean LVEF at 6 months posttransplant was 52 ± 8.7% (range, 28%-63%) (P < .001). The pretransplant LVEF was 1% for both pediatric patients. These 2 patients were waitlisted for heart transplant.

Analysis of surgical histories of the patients revealed that 10 patients had a positive past surgical history. The findings revealed by this analysis are shown in Table 3.

Among the 31 patients in our cohort, 4 patients (12.9%) lost their renal grafts. Two of these patients died 17 and 18 months after losing the graft. Two patients died with a functioning renal graft. One of the patients died on posttransplant day 7 from acute myocardial infarction, and the other died 7 months after posttransplant from cardiopulmonary arrest. This patient, a 62-year-old man, had coronary artery disease and had developed delayed graft function. The other patient who died with a functioning graft, a 63-year-old man, had diabetes mellitus and hypertension. Both patients had LVEF rates of 40% and 45% before KT and after KT, respectively. Both had serum creatinine levels of 1.8 mg/dL at time of death.

Retrospective analysis of the patients who lost their grafts revealed that one of these patients was a 57-year-old man with diabetes mellitus and hypertension. This patient was readmitted to our center 3 months after KT with sepsis and severe graft dysfunction. Intravenous hydration and antibiot-herapy were initiated. In addition, he was put on hemodialysis; however, despite all efforts, his graft never functioned afterward. His LVEF rates before and 6 months after KT were 40% and 30%, respectively. Currently, he is on hemodialysis 3 times per week.

Another patient who lost the renal graft was a 24-year-old woman whose primary reason for ESRD was preeclampsia. This patient developed venous thrombosis and had to undergo graft nephrectomy the day after KT. Her LVEF before transplant was 28%. She was put on a hemodialysis program after her nephrectomy. Another patient with preeclampsia as the primary reason for ESRD also lost her graft. She was a 21-year-old woman with a pretransplant LVEF of 30%. She lost her graft 7 months after KT due to acute antibody-mediated rejection resulting from medication noncompliance. Her LVEF at 6 months after KT was 55%, while she had a functioning graft. Hemodialysis was started, and she was placed on a waitlist for a deceased donor KT. However, she died from pulmonary thromboembolism after diagnosis with atrial fibrillation 17 months after KT.

The fourth patient whose renal graft failed was a 63-year-old man who had uncontrolled diabetes mellitus as the primary reason for ESRD. This patient underwent left lower leg amputation 5 years before KT. His LVEF pre-KT was 40%. He had normal graft function until 7 months after KT, and his 6-month LVEF post-KT was 50%. He was sensitized due to a history of blood transfusions, thus, he received ATG induction for immunosuppression. He was readmitted to our center for 3 acute rejection episodes, and his graft failed after the third episode during month 11 after KT.

The characteristics of the patients are shown in Table 4.

Discussion

Cardiovascular disease is a significant cause of morbidity in patients with ESRD, accounting for almost 50% of deaths.¹³ Congestive heart failure, which is present in 45% of ESRD patients, can independently predict early mortality among ESRD patients as it does among nonuremic patients.¹⁴ Myocardial dysfunction is common in this patient population since only 25% of these patients have normal echocardiograph findings.⁸ Risk factors for CHF in uremic patients include volume overload, hypertension, anemia, malnutrition, and the uremic milieu.

An LVEF of <50% has been shown to be a risk factor for high cardiac morbidity in the perioperative period after transplant surgery.¹⁵ Although some authors denoted that systolic dysfunction in the KT recipient was associated with delay in graft function and worse graft survival with poorer renal function, others have suggested that KT resulted in an increase in LVEF and improved the functional status of the patients with CHF.^3,4,10,15,16

Melchor and colleagues prospectively followed 29 CKD patients with an LVEF of <50% on dialysis who underwent KT.⁸ The mean LVEF before transplant was 37.8%. One month and 12 months after KT, mean LVEF improved to 52% and 58.2%, respectively (both P = .01). In addition, the study showed that 69% of the patients had normal echocardiograph findings at the end of 1-year follow-up, with left ventricular hypertrophy detected in only 14% of the patients.

In a prospective study, Wali and colleagues reported on 103 patients with an LVEF of <40% before KT.¹⁰ They analyzed the left ventricular function at 6 months and 12 months after KT by radionuclide ventriculography. In line with our study, these researchers categorized their patients based on NYHA classification before and after KT. According to their report, 95% of their patients were in NYHA class III (41%) and class IV (54%) before KT. The LVEF was in the range of 20% to 30% in 49% of the patients, and 10% of the patients had an LVEF of <20%. The investigators reported that mean pre-KT LVEF increased from 31.6 ± 6.7% to 52.2 ± 12% (P < .05) 12 months after KT. There was no perioperative mortality, and 70% of the patients with previously low LVEF achieved normal (≥50%) LVEF rates. Assessments post-KT revealed that 51% of the patients were in NYHA class I, 31% in class II, 11% in class III, and 7% in class IV. Wali and colleagues concluded that KT led to significant improvement in CHF symptoms. Our findings are consistent with this study.¹⁰

Karthikeyan and colleagues retrospectively reviewed KT patients to assess the effects of low (<50%) LVEF on KT outcomes.⁷ Similar to our study, they measured the LVEF by noninvasive echocardiography. They compared patients with low LVEF (36.4 ± 8.4%) with patients with normal LVEF (57.5 ± 3.5) with regard to graft loss (6.5% vs 8%) and all-cause mortality (12.1% vs 10.6%) and concluded that KT led to favorable outcomes in patients with low LVEF. In our study, both graft loss and all-cause mortality rates were 12.9%. However, we did not perform a comparative analysis between patients with low LVEF and normal LVEF.

Kute and colleagues compared the KT outcomes between patients who had an LVEF of <45% (n = 63) with those who had a normal (ie, >50%) LVEF (n = 537).¹¹ This retrospective analysis revealed that 98% of the patients demonstrated normalization of LVEF 3 months after KT. In addition, there was no difference between the 2 groups concerning graft survival and patient survival rates and the rates of adverse cardiac events. These authors concluded that KT outcomes were not adversely affected by the pre-KT LVEF.

Yilmaz and colleagues evaluated the effects of KT on cardiac function¹⁷ by comparing pre-KT and post-KT echocardiograph findings. They reported that patients with a pre-KT LVEF rate of <50% had a significant increase during the post-KT follow-up period (40.1 ± 6.2% vs 48.4 ± 9.4%; P = .012). They concluded that KT might improve the myocardial function in patients with low LVEF, and KT should be performed in these patients as early as possible.

Yamada and colleagues reported a case of a successful KT in a patient who had a pre-KT LVEF of 14%.¹⁸ They noted that they gave special attention to the cardiac, operative, and anesthetic risks and referred the patient to the intensive care unit. Our approach was aligned with Yamada and colleagues; we performed KT in 2 pediatric patients whose LVEF rates were 1%.¹⁸ These patients were on waitlists for heart transplant. Because deceased organ donations are relatively rare in our country, refusing these patients a transplant was not an option. We believe that we saved their time with this approach. Both of these patients survived with functioning renal grafts, and their post-KT LVEF rates were 52% and 57%.

Our cohort included patients who had a history of cardiac surgeries and interventions. For example, we had 3 patients who underwent coronary artery bypass graft and 2 who underwent mitral valve clip (MitraClip) insertion procedure because of third-degree and fourth-degree mitral valve incompetence. The latter procedure is an alternative to mitral valve replacement.¹⁹ Of note, there was only a 1-week interval between MitraClip insertion and KT.

Fluid overload can lead to CHF in patients with ESRD. Dialysis cannot be effective in these patients because of low LVEF. In patients with diminished cardiac pumping function due to uremic toxins, fluid overload, and other factors, dialysis cannot be very effective, and a vicious cycle starts because of cardiorenal or renocardiac failure. This cycle can lead to mortality. We believe that the most effective treatment modality for patients with uremic cardiomyopathy without cardiac ischemia is KT. However, these patients are high-risk and challenging patients for KT.

In ESRD patients with low LVEF, the major concerns of the transplant surgeons and nephro-logists are intolerance of these patients to general anesthesia during KT and impaired post-KT graft perfusion. Significant hypotension during hemo-dialysis due to intravascular volume depletion is the most common complication in these patients. It is known that the cardiac pumping function is crucial for an effective hemodialysis. We suggest that, if a patient’s cardiac reserve is sufficient to tolerate hemodialysis, this patient can also tolerate general anesthesia lasting as long as a hemodialysis session. The previously published data and our findings showed that these patients had a relatively higher risk for general anesthesia, but they could tolerate it despite low LVEF.^8-10,20

Our study has some limitations. First, it was a retrospective review. Second, data such as duration of stay in the intensive care unit and hospital and glomerular filtration rates were not included. Third, pre-KT myocardial scintigraphy results were also not included and a comparative analysis between patients with low LVEF and those with normal LVEF was not conducted. It is known that myocardial scintigraphy is an effective and noninvasive method for assessing the coronary reserve and ischemia.^21,22

Despite these weaknesses, we conclude that low LVEF should not refrain nephrologists or surgeons from planning KT. We suggest that myocardial scintigraphy should be performed in patients with ESRD and low LVEF, and KT should be considered in those who do not have ischemic findings.

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