Author + information
- Received March 13, 2015
- Revision received July 30, 2015
- Accepted August 4, 2015
- Published online October 20, 2015.
- Nael Hawwa, MD∗,
- Kevin Shrestha, MD†,
- Muhammad Hammadah, MD†,
- Poh Shuan Daniel Yeo, MBBS‡,
- Richard Fatica, MD§ and
- W.H. Wilson Tang, MD∗∗ ()
- ∗Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, Ohio
- †Department of Internal Medicine, Cleveland Clinic, Cleveland, Ohio
- ‡Apex Heart Clinic, Gleneagles Hospital, Singapore
- §Department of Nephrology and Hypertension, Cleveland Clinic, Cleveland, Ohio
- ↵∗Reprint requests and correspondence:
Dr. W.H. Wilson Tang, Department of Cardiovascular Medicine, Cleveland Clinic, 9500 Euclid Avenue, Desk J3-4, Cleveland, Ohio 44195.
Background Cardiac dysfunction influences candidate selection for kidney transplantation. There is a paucity of data regarding predictors of myocardial recovery following kidney transplantation and long-term outcomes.
Objectives The purpose of this study was to identify the extent of reverse remodeling in our kidney transplant population and the predictors of such changes, and to assess outcomes in these patients.
Methods We reviewed 232 patients who underwent kidney transplantation at the Cleveland Clinic from 2003 to 2013 and who had baseline and post-transplant echocardiograms; patients with simultaneous heart transplantation were excluded.
Results Post-transplantation mean left ventricular ejection fraction (LVEF) improved in those with LV dysfunction (increased from 41% to 50%; p < 0.0001; n = 66). There was significant improvement in other parameters, including diastolic function, LV end-diastolic dimension, LV mass, and right ventricular systolic pressure. After adjusting for multiple clinical variables, increased hemoglobin following transplantation was associated with an improved LVEF (odds ratio: 1.50; 95% confidence interval [CI]: 1.07 to 2.14; p = 0.016) and reduced mortality (hazard ratio [HR]: 0.65; 95% CI: 0.49 to 0.87; p = 0.004). An improved LVEF ≥10% predicted survival independently of a pre-transplantation LVEF (HR: 0.46; 95% CI: 0.21 to 0.93; p = 0.031).
Conclusions Kidney transplantation is associated with improved cardiac structure and function. A rise in post-transplantation hemoglobin was a significant factor associated with such changes, in addition to conferring a survival advantage.
In patients with end-stage renal disease (ESRD), progressive cardiorenal compromise often results in the development of adverse cardiovascular outcomes, which is one of the leading causes of mortality in this population (1). Although ESRD was previously thought to be the result of accelerated atherosclerosis and subsequent coronary artery disease, it is now believed that other pathophysiologic processes play a contributing role. Although patients with ESRD have a high prevalence of “conventional” cardiovascular risk factors, including hypertension, diabetes, and hyperlipidemia, these do not account for all the cardiovascular risks (2). Other contributing factors include hemodynamic overload from volume and pressure, anemia, arteriovenous shunts, and arterial remodeling, as well as biochemical mediators and uremic toxins, such as alterations in calcium, phosphate, parathyroid hormone, urea, homocysteine, and endothelin (3).
Despite significant progress in the care of patients with heart failure (HF), patients with ESRD and concomitant cardiac dysfunction are generally considered less suitable candidates for kidney transplantation due to the increased risk of operative morbidity and mortality. Nevertheless, an emerging concept has challenged this notion that cardiac dysfunction is a forbidding comorbidity. Reports have shown that kidney transplantation may actually improve cardiac function, as measured by serial radionuclide ventriculography (4), a factor that should be taken into consideration when evaluating these patients. Herein, our objective is to describe the longitudinal experience of cardiac remodeling in our kidney transplantation population, their respective mortality risk following transplantation, and their propensity for reverse remodeling, as well as elements that influence these changes.
We retrospectively reviewed our single-center experience of adult patients with ESRD who underwent living donor and cadaveric kidney transplantation at the Cleveland Clinic between January 2003 and December 2013 and who had pre- and post-transplant transthoracic echocardiograms. All patients were in chronic stable condition and were carefully reviewed by an interdisciplinary committee that deemed them eligible for transplantation after weighing the risks and benefits. All transplantation recipients received a protocol-driven standardized post-transplantation medical regimen, including tacrolimus, mycophenolate mofetil, and prednisone. We excluded those who did not have post-transplantation follow-up documented in their electronic medical record or those with simultaneous heart–kidney transplantation. The Cleveland Clinic Institutional Review Board approved the study.
Demographic, clinical, echocardiographic, and laboratory data were obtained directly from the electronic medical record. Estimated glomerular filtration rate (eGFR) was calculated using the Modification of Diet in Renal Disease equation (5). Reference values for echocardiographic parameters were defined on the basis of the recent American Society of Echocardiography (ASE) guidelines (6) as follows: mild systolic dysfunction, left ventricular ejection fraction (LVEF) ≤51% for men and ≤53% for women, but >40%; moderate dysfunction, LVEF ≤40% for both sexes; abnormal LV mass indexed to body surface area (BSA) >115 g/m2 in men and >95 g/m2 in women; and severely abnormal LV mass/BSA >148 g/m2 in men and >121 g/m2 in women. Hypertension was defined by a cutoff of ≥130/80 mm Hg (7), and alternatively as ≥140/90 mm Hg on the basis of the more recent Eighth Joint National Committee (JNC-8) guidelines (8). Anemia was defined as hemoglobin <13 g/dl in men and <12 g/dl in women on the basis of KDIGO (Kidney Disease–Improving Global Outcomes) guidelines for patients with chronic kidney disease (CKD) (9). These parameters were obtained from the most recent pre-transplantation and 12-month post-transplantation office visits. One exception was echocardiographic data, the timing of which could not be controlled for in this retrospective study. Echocardiograms were obtained during the pre-transplantation evaluation, with the most recent one taken into account, and obtained at the time closest to 12 to 24 months post-transplantation (see Results section).
Assessment of cardiac structure and function
All echocardiograms were performed at our institution. For each echocardiographic examination, interventricular septal diameter, posterior wall diameter, and left ventricular end-diastolic dimension (LVDd) were measured according to ASE recommendations (6). LVEF was calculated by the biplane Simpson method. LV mass, calculated using the ASE equation, was defined as: 0.8 × (1.04 × [interventricular septal diameter + posterior wall diameter + LVDd]3 – [LVDd3]) + 0.6, and was indexed to BSA. LV diastolic function was graded as either normal or as stages I to IV on the basis of mitral inflow profiles and tissue Doppler imaging. Right ventricular systolic pressure (RVSP) was estimated from the tricuspid regurgitation velocity using the modified Bernoulli equation.
Continuous variables were reported as mean ± SD if normally distributed or as median and interquartile range (IQR) if non-normally distributed. Normality was assessed by the Shapiro-Wilk W test. Differences in clinical variables were assessed using the Student t test or analysis of variance. Linear regression analysis was used to analyze the association between clinical variables and reverse remodeling. Odds ratio (OR) for predicting clinical outcomes was calculated using logistic regression analysis and evaluated according to the likelihood ratio test. Kaplan-Meier survival analysis was used to compare unadjusted survival, and the log-rank test assessed the differences between groups. The Cox proportional hazards model was used to test for independent predictors of mortality. All reported p values are from 2-sided tests, and a p value <0.05 was considered statistically significant. Statistical analyses were performed using JMP (version 11.2.0; SAS Institute, Cary, North Carolina).
Of the 1,697 adult patients who underwent kidney transplantation, we identified 232 patients who fulfilled the inclusion and exclusion criteria (Figure 1). Per the baseline demographic data (Table 1), the predominant etiology of ESRD was diabetes (31%) and hypertension (23%). The majority of patients were dialysis-dependent (mostly intermittent hemodialysis), and the median duration of dialysis was 778 days (IQR: 239 to 1,741 days). Pre-emptive transplantation occurred in 17% of patients. Simultaneous kidney–pancreas or kidney–liver transplantation accounted for 11% of the cohort. The pre-transplantation echocardiogram was performed at a median duration of 257 days (IQR: 125 to 460 days) versus the post-transplantation echocardiogram, which occurred at a median of 422 days (IQR: 241 to 735 days). The baseline echocardiogram revealed a reduced LVEF in 28% of patients (taking all 1,375 patients who underwent pre-transplantation echocardiography into account, 18% had LV dysfunction). An abnormal LV mass/BSA was identified in 65% of patients.
As expected, hypertension was a prevalent comorbidity, accounting for 82% of our cohort, and 71% of patients had anemia.
Reverse remodeling following kidney transplantation
The changes in echocardiographic, clinical, and laboratory variables in the post-transplantation period are listed in Table 2. During the study, none of these patients underwent coronary revascularization or cardiac resynchronization therapy to explain the improvements seen, and only 1 patient had an aortic valve replacement. LVEF improved by 9 ± 13% in those with any degree of systolic dysfunction (p < 0.0001; n = 66), and by 15 ± 13% in those with moderate systolic dysfunction (p < 0.0001; n = 28). Regression in LV mass was noted following transplantation. LV mass/BSA improved by 20 g/m2 (p < 0.0001; n = 151) in those with baseline abnormalities. Statistically significant improvements in LVDd, wall diameter, diastolic function, and RVSP were similarly observed (Table 2). Those with a baseline systolic blood pressure (SBP) ≥130 mm Hg or diastolic blood pressure (DBP) ≥80 mm Hg demonstrated an 18 ± 26 mm Hg and 10 ± 17 mm Hg improvement, respectively (p < 0.0001). These results remained consistent when a cutoff of ≥140/90 mm Hg was used.
Anemia and changes in hemoglobin were closely associated with changes in cardiac structure and function. In patients with pre-transplantation anemia, post-transplantation hemoglobin improved by 1.1 g/dl (p < 0.0001). Table 3 lists the correlation between clinical variables and reverse remodeling. Changes in hemoglobin showed correlation with changes in LVEF (in all 232 patients: coefficient: 1.22; 95% confidence interval [CI]: 0.61 to 1.83; p < 0.001; in those with baseline LV dysfunction: coefficient: 2.17; 95% CI: 0.94 to 3.40; p < 0.001) (Central Illustration). In addition, multiple factors were correlated with LV mass regression, including post-transplantation improvements in hemoglobin, SBP, DBP, and lower baseline body mass index (BMI). Change in hemoglobin was the only independent factor associated with improved LVEF of ≥10% using logistic regression analysis. This held true when corrected for multiple demographic parameters, including age at transplantation, sex, race, and BMI (OR: 1.68; 95% CI: 1.20 to 2.39; p = 0.002), as well as clinical factors, including dialysis duration, eGFR at 12 months, and changes in SBP and DBP (OR: 1.50; 95% CI: 1.07 to 2.14; p = 0.016).
Unadjusted mortality was higher in patients with an abnormal baseline LVEF, as assessed in all 1,375 patients who underwent pre-transplantation echocardiography (log-rank p < 0.001) (Figure 2A). Nevertheless, despite pre-transplantation systolic dysfunction, those who had improved LVEF of ≥10% had similar mortality outcomes with those with normal pre-transplantation LV function (log-rank p = 0.120) (Figure 2B). Changes in hemoglobin predicted improved survival when adjusted for demographic and clinically relevant variables, independent of pre-transplantation LVEF or post-transplantation improvement in LVEF (hazard ratio: 0.65; 95% CI: 0.49 to 0.87; p = 0.004) (Table 4).
We observed an overall favorable impact of kidney transplantation on cardiac structure and function, with a corresponding improvement in long-term survival seen with reverse remodeling in kidney transplantation recipients with baseline cardiac dysfunction. Specifically, LV systolic dysfunction was not uncommonly observed in patients undergoing kidney transplantation; it was seen in 1 of 6 patients in this contemporary series of patients who underwent echocardiographic evaluation. Although the presence of baseline LV systolic dysfunction was associated with poorer overall long-term outcomes following kidney transplantation, improvement of LVEF ≥10% following kidney transplantation in patients with underlying LV systolic dysfunction was associated with better long-term outcomes. Another key finding was that improvement and preservation of hemoglobin was identified as a major contributor to both reverse remodeling and prognosis. Taken together, our present findings imply that metabolic factors associated with ESRD likely contribute to cardiac dysfunction, and that structural and functional parameters of cardiac dysfunction may reverse with metabolic improvement following kidney transplantation.
Patients with ESRD and underlying LV systolic dysfunction showed remarkable and consistent improvements in LVEF following kidney transplantation, with a mean increase of 15% in those with a baseline LVEF ≤40%. Ventricular dilation, as assessed by LVDd, improved, and LV hypertrophy, as assessed by LV mass, substantially regressed post-transplantation. Moreover, positive changes were seen in diastolic function and RVSP in the post-transplantation period.
A few previous studies demonstrated positive changes in LV systolic function following kidney transplantation, albeit in very small cohorts (10–13). Our findings are consistent with findings from Wali et al. (4) more than a decade ago, who identified 103 patients with LV systolic dysfunction by radionuclide ventriculography gated-blood pool scan; these patients had significant improvement in their LVEF in the post-transplantation period. Similarly, other studies showed improvements in LV mass post-transplantation (14), as well as a correlation between LV mass regression and SBP (15). Because this was the largest and most contemporary study to address this question to date, we demonstrated a similar correlation; in addition, we identified correlations between LV mass regression and DBP and lower baseline BMI.
An understanding of cardiorenal interactions is paramount in appreciating the pathophysiological processes that explain such reverse remodeling (16). Hemodynamic abnormalities in ESRD result in increased afterload, a phenomenon that had been considered the primary driver for cardiac dysfunction. A multitude of factors contribute to this phenomenon, including interdialytic volume overload, elevated blood pressure, and decreased vessel compliance (17). Nevertheless, it is the nonhemodynamic derangements that occur in ESRD, including anemia (18), secondary hyperparathyroidism (19), overactivity of the renin-angiotensin-aldosterone system (20,21), as well as the presence of uremic toxins (22), that likely contribute to a hostile inflammatory milieu for the myocardium. Ultimately, cardiac dysfunction ensues, further activating neurohormonal pathways, and culminating in the vicious cycle of cardiorenal syndrome. Although there may be a point at which the uremic milieu induces irreversible cardiac damage, our study theoretically demonstrates the continued overall benefit to the heart following kidney transplantation, despite being preceded by dialysis for a median duration of >2 years.
There is a paucity of data on factors associated with reverse remodeling following kidney transplantation. In our study, hemoglobin was a significant predictor of improved LVEF and LV mass in the post-transplantation period (Central Illustration). This improvement in anemia translated into superior outcomes. Despite correcting for important clinical variables (including baseline LVEF, post-transplantation improvement in LVEF, and post-transplantation eGFR), improved hemoglobin remained an independent factor associated with reduced mortality. Although it is not possible to determine causality in this observational study, the impact of anemia on cardiac structure and clinical outcomes has been extensively analyzed. Multiple studies have demonstrated anemia to be a predictor of mortality in the HF population (23–25). In addition, an inverse correlation was noted between changes in hemoglobin and LV mass on cardiac magnetic resonance (26).
The interconnected relationship between CKD, HF, and anemia has been referred to as the “cardiorenal anemia syndrome” (27). The predominant etiology of anemia in this setting is a combination of reduced erythropoietin production and function related to CKD and the inflammatory state of HF, medication-related inhibition of the pro-erythropoetic effects of angiotensin, and disturbances in iron metabolism (28). Iron deficiency in patients with HF is a highly prevalent, but often overlooked condition. Although its presence may be suspected in the setting of anemia, it should be noted that in 1 study, 32% of nonanemic HF patients were iron deficient (29). Randomized placebo-controlled trials have assessed intravenous iron in the setting of HF. The recent CONFIRM-HF (Ferric Carboxymaltose Evaluation on Performance in Patients With Iron Deficiency in Combination With Chronic Heart Failure) trial identified improvements in functional capacity, symptoms, quality of life, and reduced risk of HF hospitalization (30). Importantly, these benefits were irrespective of hemoglobin, highlighting the potential adverse nature of iron deficiency independently of anemia. Other trials have similarly demonstrated improved symptoms, health status measures, N-terminal pro–B-type natriuretic peptide, peak maximum oxygen consumption, and improvements in cardiac and renal function (31–33).
Patients with baseline systolic dysfunction had expected worse outcomes on the basis of unadjusted analyses in our study. However, we highlighted a salient point; specifically, those who underwent reverse remodeling fared no worse than those with normal pre-transplantation LVEF. Therefore, impaired cardiac function should not necessarily preclude a patient from undergoing kidney transplantation, especially in the absence of other criteria that indicate the presence of underlying advanced HF (e.g., severe functional impairment or hemodynamic compromise). Continued efforts should be made to identify those factors that might predict reverse remodeling.
One of the limitations of the study is its observational nature, which inherently may have resulted in some bias. This study cohort only included those selected for kidney transplantation and those who survived during the treatment period to allow both pre- and post-transplantation echocardiography; this might have influenced the prognostic conclusions that can be drawn. However, we did use the date of post-transplantation echocardiography for censoring to reduce possible confounding. Moreover, we could not control for the timing of echocardiograms. Because of the high prevalence of cardiac structural abnormalities in ESRD and variations in intravascular volume in dialysis, echocardiography may have some limitations in this population (34). Cardiac magnetic resonance is considered the “gold standard” for assessing cardiac dimensions and mass, because it is independent of geometric assumptions (35). However, considering its availability and practicality, echocardiography remains an important clinical and research tool when assessing these parameters. The study did not assess for symptoms and functional status, or metabolic parameters, including iron studies, parathyroid hormone, phosphorous, and calcium.
In kidney transplantation patients, post-transplantation improvement in anemia was an important factor associated with the observed significant reverse remodeling and an independent factor associated with reduced mortality. Importantly, we demonstrated favorable survival in patients with pre-transplantation LV dysfunction who underwent reverse remodeling. Additional studies should analyze the prognostic implications that these changes pose, and the findings from this study, as well as others, should be taken into consideration when determining criteria for kidney transplantation candidacy.
COMPETENCY IN MEDICAL KNOWLEDGE: In patients with mild to moderate ventricular dysfunction, cardiac structure and function can improve following kidney transplantation concurrent with an improvement in anemia.
TRANSLATIONAL OUTLOOK: Further studies are needed to explore the role of iron metabolism in the myocardial reverse remodeling that follows kidney transplantation.
This research was supported by a grant from the National Institutes of Health (R01HL103931). The authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- body surface area
- body mass index
- chronic kidney disease
- diastolic blood pressure
- estimated glomerular filtration rate
- end-stage renal disease
- heart failure
- left ventricular
- left ventricular end-diastolic dimension
- left ventricular ejection fraction
- right ventricular systolic pressure
- systolic blood pressure
- Received March 13, 2015.
- Revision received July 30, 2015.
- Accepted August 4, 2015.
- 2015 American College of Cardiology Foundation
- Wali R.K.,
- Wang G.S.,
- Gottlieb S.S.,
- et al.
- Bock J.S.,
- Gottlieb S.S.
- Vlahakos D.V.,
- Hahalis G.,
- Vassilakos P.,
- Marathias K.P.,
- Geroulanos S.
- Al-Ahmad A.,
- Rand W.M.,
- Manjunath G.,
- et al.
- Mozaffarian D.,
- Nye R.,
- Levy W.C.
- Tang W.H.,
- Tong W.,
- Jain A.,
- Francis G.S.,
- Harris C.M.,
- Young J.B.
- Anand I.,
- McMurray J.J.,
- Whitmore J.,
- et al.
- Silverberg D.S.,
- Wexler D.,
- Iaina A.,
- Schwartz D.
- Toblli J.E.,
- Lombrana A.,
- Duarte P.,
- Di Gennaro F.
- Okonko D.O.,
- Grzeslo A.,
- Witkowski T.,
- et al.
- Glassock R.J.,
- Pecoits-Filho R.,
- Barberato S.H.