Improvement of heart failure after renal transplantation

The complex maze of cardio-renal interaction

“Learn to see, learn to hear, learn to feel and know by practice alone you can become expert. Medicine is learned at the bedside and not in the classroom.”Sir William Osler (1)

Offering an insightful proposition, Osler correctly surmised the importance of observation in the practice of medicine. Despite rapid medical advances in the last century, observation and reasoning remain integral guiding principles for the practice of medicine. In this issue of the Journal, Wali et al. (2) report an observational study of 103 patients with symptomatic systolic heart failure (HF) accompanying end-stage kidney disease that underwent renal transplantation. Contrary to prevailing assumptions of a nihilistic attitude toward such patients, these investigators noted that HF symptoms and ventricular function improved in the vast majority of individuals, an effect notably achieved with a low perioperative morbidity and mortality. Thus, this study dispels two widely prevalent myths. First, most clinicians decry such patients as too high-risk to undergo kidney transplantation and second, that the HF is unlikely to improve and will necessarily be responsible for determining the clinical fate after renal transplantation.

Nearly two centuries ago, Richard Bright (3) associated kidney and cardiovascular disease when he wrote “the obvious structural changes in the heart [in patients with shrunken kidneys] have consisted chiefly of hypertrophy with or without valve disease; and, what is most striking, out of 52 cases of hypertrophy, no valvular disease whatsoever could be detected in 34.” More recently, clinical and epidemiological studies demonstrated that cardiac disease is a frequent complication of advanced chronic kidney disease and the major cause of death in patients on renal replacement therapy (1,4–7). Greaves and Sharpe (8) have shown that when compared to age-matched controls, dialysis-dependent patients exhibit a 3.5-fold higher mortality. Atherosclerosis and HF are highly prevalent among patients on renal replacement therapy, and the latter is an important predictor of mortality (6–8). Stack et al. (9) have shown that the diagnosis of HF is recorded in 36% of patients undergoing dialysis therapy. In this analysis, the prevalence of HF was the greatest among diabetics, and, in addition, patients with HF had a higher prevalence of coronary artery disease, cerebrovascular disease, and peripheral vascular disease. Another study by Harnett et al. (7) demonstrated that independent risk factors for the development of HF in patients with end-stage renal disease (ESRD) at the time of initiation on dialysis were systolic dysfunction, diabetes mellitus, older age, and ischemic heart disease. Clinical symptoms of HF recurred in 56% of the patients during dialysis, and this recurrence was linked with the presence of ischemia and systolic dysfunction, anemia, hypoalbuminemia, and hypertension during dialysis. More importantly, the median survival of patients with HF at baseline was 36 months compared to 62 months in patients without HF. Recently, an analysis of the U.S. Renal Data System Dialysis Morbidity and Mortality Study (DMMS) Wave 2 demonstrated that HF is a major risk factor for hospitalization and is associated with an 83% mortality at three years after a hospitalization for HF, similar to that following myocardial infarction (80%) (10,11).

Renal transplantation has become standard of care for patients with end-stage kidney disease because of the improvement in surgical techniques and the introduction of new and more powerful immunosuppressive agents (12). Wolfe et al. (13) compared the outcomes of patients awaiting transplantation on dialysis with patients who received kidney transplantation and demonstrated that after three to four years of follow-up, kidney transplantation reduced the risk of death overall by 68%. Moreover, kidney transplantation has been shown to be more cost-effective than dialysis in the long term (14). Cardiovascular disease is the leading cause of death in patients after kidney transplantation; however, its rate is lower than patients on dialysis. The cumulative incidence of coronary heart disease, cerebrovascular disease, and peripheral vascular disease 15 years after renal transplantation has been estimated at 23%, 15%, and 15%, respectively (12).

Several studies have demonstrated regression of left ventricular hypertrophy and improvement of left ventricular function after successful kidney transplantation (15–17). Ferreira et al. (15) prospectively studied 24 patients with ESRD in whom 24-h ambulatory blood pressure monitoring and echocardiography were performed before and at 3, 6, and 12 months after renal transplantation. The authors demonstrated that at one year, patients with successful kidney transplantation had a significant decrease in blood pressure, prevalence of left ventricular hypertrophy and left ventricular dilatation, and an improvement in left ventricular function. Moreover, another study (16) demonstrated that regression of left ventricular hypertrophy continues beyond the first year after renal transplantation, persisting into the third and fourth years after transplantation. Failure to regress was associated with older age, hypertension, high pulse pressure in normal-sized hearts, and low pulse pressure in dilated hearts. De Lima et al. (17) performed carotid ultrasound and echocardiograms to evaluate the impact of renal transplantation on the morphological and functional characteristics of the carotid arteries and heart in a group of end-stage renal failure patients without overt cardiovascular disease. Twenty-two patients were evaluated 2 to 3 weeks after renal transplantation, and again 12 and 40 months after transplant. The authors demonstrated that successful renal transplantation improves, but does not cause, complete regression of the cardiovascular alterations of end-stage kidney disease. Only intima-media thickness was normalized by transplantation, whereas left ventricular mass index and carotid and ventricular distensibility improved but remained abnormal. Interestingly, they also conclude that, in this group of patients, the duration of dialysis, weight gain, high blood pressure, and high hematocrit adversely affect the rate of change of post-transplant cardiovascular hypertrophy (17).

The hypothesis of an improvement in HF after kidney transplantation has been explored in small case series (15,18,19) and in a study utilizing data from the U.S. Renal Data System (20). The latter included 11,369 patients with ESRD due to diabetes that were placed on a renal and kidney pancreas transplant list from July 1994 to June 1997. In comparison to patients maintained on dialysis, those who underwent renal transplantation had a lower incidence of HF hospitalizations. Although clinically important, this study did not include a systematic evaluation of left ventricular function. On the contrary, the strengths of the investigation by Wali et al. (2) lies in the large patient numbers, comprehensive nature of preoperative evaluation, and systematic collection of data on left ventricular function by multiple gated acquisition (MUGA) scans. During follow-up after kidney transplant, MUGA scans were repeated at six months, one year, and at the last evaluation of the follow-up period. Additionally, these investigators determined that a longer duration of dialysis in patients with HF was detrimental for improvement in ventricular function after renal transplantation. Unfortunately, the current study only reports on left ventricular ejection fraction and does not detail other cardiac structural or volumetric parameters to definitively determine whether these favorable changes were truly accompanied by remodeling of the ventricle. This is important because shifts in ejection fraction can occur simply in response to hemodynamic alterations in preload. Nevertheless, the clinical implications of the study lend credence to the notion that renal transplantation can be performed safely in patients with advanced stages of HF due to left ventricular dysfunction.

The mechanisms by which renal transplantation normalizes ventricular function remain a matter of speculation and were not evaluated in the Wali et al. (2) study. It is increasingly recognized that the heart and kidney rely closely upon each other for physiological health. Some have dubbed aberrations in this close knit circuit to represent the “cardio-renal syndrome” (21). Even subclinical alterations in renal function possess prognostic implications in patients with ventricular dysfunction (22,23). Conversely, the uremic environment characterized by metabolic aberrations has been shown to be deleterious to cardiac structure and function (24). Thus, studies have linked the development of secondary parathyroidism and anemia as important correlates of functional cardiac decline in patients with end-stage kidney disease (25,26). Similarly, the inflammatory milieu that accompanies uremia is also thought to be a pathophysiological candidate linked to cardiac dysfunction (27). Indeed, case reports exist wherein parathyroidectomy is associated with recovery from ventricular failure in patients on renal replacement therapy (28). Furthermore, the therapeutic use of erythropoietin in HF with accompanying renal insufficiency has been demonstrated to improve ventricular function (29). Thus, it is tempting to speculate that the improvement of renal function after kidney transplantation and consequent resurrection of metabolic abnormalities might be responsible for the resolution of HF, even beyond the hemodynamic effects of blood pressure and volume control. It is interesting that Wali et al. (2) noted trends in improvement of parathyroid hormone levels in those who benefited compared to increases in this hormone in the cohort that showed no improvement in ventricular function. Much work is needed to better understand the reasons underlying the observed benefits on HF after renal transplantation. The importance of insightful observations such as the one reported herein is depicted in the sayings of William Osler. He wrote: “There is no more difficult art to acquire than the art of observation, and for some men it is quite as difficult to record an observation in brief and plain language” (1).

• American College of Cardiology Foundation