More than 26 million patients suffer from heart failure worldwide.1 For many of these patients with advanced heart failure, mechanical circulatory support has been shown to decrease both morbidity and mortality.2 When mechanical circulatory support is indicated for patients with heart failure, a vast majority of patients receive left ventricular assist devices (LVADs); however, a subset of them will require biventricular support. This includes patients with severe biventricular failure, failed cardiac allografts, hypertrophic cardiomyopathy, arrhythmogenic right ventricles, postinfarct ventricular septal defects, and large ventricular thrombi.3 The total artificial heart (TAH) (SynCardia, Tucson, AZ), implanted in more than 1,400 patients worldwide, is a Food and Drug Administration–cleared, implantable, long-term, biventricular circulatory support device.
Up to 49% of patients with heart failure have a significant concomitant renal insufficiency, defined as an estimated glomerular filtration rate (eGFR) of less than 60 ml/min/1.73 m2.4 Because renal insufficiency in heart failure patients portend a poor prognosis,5 many of the mechanical circulatory support trials excluded these patients from enrollment.2,6 However, more recent studies showed significant renal recovery among heart failure patients supported by LVADs in the setting of concomitant renal failure.7,8 Although up to 52% of patients requiring TAH support have concomitant renal insufficiency, the renal function outcomes of such patients have not been well studied.9,10 Thus, the aim of this study is to examine and quantify the impact of TAH support on renal function and clinical outcomes among patients with moderate-to-severe preoperative renal dysfunction, including those requiring hemodialysis.
All patients older than 18 years undergoing TAH implantation between January 2008 and December 2013 at Virginia Commonwealth University with significant renal insufficiency defined according to the National Kidney Foundation Dialysis Outcomes Quality Initiative (DOQL) guidelines (National Kidney Foundation, 2002) as an estimated serum creatinine clearance of less than 60 ml/min/1.73 m2 or requiring dialysis were included in the study.11 Prospectively collected preoperative, operative, and postoperative Society of Thoracic Surgeons’ data were analyzed, following standard definitions.12 Additional data on clinical and renal function were acquired retrospectively from electronic medical records. The study protocol was approved by the institutional review board.
Preoperative renal function on the day of TAH implantation was calculated with the estimated creatinine clearance method described by Levey et al.13 and adopted by our laboratory. We used the Modification of Diet in Renal Disease (MDRD) formula to quantify the renal function (i.e., to estimate eGFR), which is expressed in units of ml/min/1.73 m2. Renal recovery data were obtained at 30 days, 3 months, and 6 months after TAH implantation. For those patients who received heart transplantation before 6 months of follow-up, the day of the transplantation was used as the last follow-up day. Because serum creatinine levels do not accurately reflect renal function in patients requiring dialysis, mean eGFR calculations excluded those patients.
Depending on the distribution of data, categorical variables were analyzed by using either the Chi-square test or Fisher’s exact test and are reported as percentages. Continuous variables were analyzed with either the paired Student’s t-test or the Wilcoxon rank sum test and are reported as mean values with standard deviations. p values of less than 0.05 are considered statistically significant. Detailed analysis of the data was performed by using SAS software (Version 9.3; SAS Institute Inc., Cary, NC).
Patient demographics and preoperative clinical characteristics are summarized in Table 1. Of the 46 patients receiving a TAH at our institution during the study period, 20 (43.5%) met the inclusion criteria, having either a preoperative eGFR less than 60 ml/min/1.73 m2 or a preoperative hemodialysis requirement. The mean age of the patients was 51.2 ± 8.8 years, and 85% were men. The average body mass index was 32.7 kg/m2. Significant preoperative comorbidities included diabetes mellitus (30%), prior stroke (10%), history of myocardial infarction (40%), and previous coronary artery bypass grafting (15%). Significant preoperative laboratory data included a serum creatinine of 2.28 ± 1.18 mg/dl, hematocrit of 30.66% ± 6%, platelet count of 203,950 ± 103,210 K/ml, total bilirubin of 1.83 ± 1.25 mg/dl, and serum albumin of 3.31 ± 0.58 g/dl. Atrial and ventricular arrhythmias were present in 30% and 40% of patients, respectively. Mean pulmonary artery pressure was 38.6 ± 9 mm Hg, and moderate-to-severe tricuspid valve regurgitation was noted in 75% of patients. The majorities (90%) of patients were inotrope dependent and were on temporary circulatory support such as an intraaortic balloon pump (70%) or an extracorporeal membrane oxygenator (15%). Operative and postoperative variables are summarized in Table 2. Total artificial heart implantation was either urgent or emergent in 85% and 15% of cases, respectively. Forty-five percent of patients had prior heart surgery. Cardiopulmonary pump and cross-clamp times were 193.5 ± 44 minutes and 174 ± 33 minutes, respectively. At 6 months of follow-up, six patients underwent heart transplantation. Survival at 30, 90, and 180 days after TAH implantation was 95%, 90% and 70%, respectively.
Renal Function Data
Renal function data from the study cohort are summarized in Table 3. As mentioned earlier, eGFR calculations excluded patients requiring dialysis. Mean eGFR for the group at the time of surgery was 48 ± 7 ml/min/1.73 m2. A follow-up eGFR value was calculated from 12, 10, and 7 patients at 30, 90, and 180 days, respectively. The reasons for the different numbers of patients at each follow-up interval include a need for dialysis, heart transplantation, or death (Figure 1). The calculated mean eGFR (ml/min/1.73 m2) values at 30, 90, and 180 days were 66 ± 31.3, 65 ± 21.7, and 56 ± 13.2, respectively. Notably, mean eGFR at each follow-up interval was higher than the cohort’s mean preoperative eGFR. The absolute changes in eGFR (ml/min/1.73 m2) values at 30, 90, and 180 days, when compared with preoperative values, were 21.9 ± 35.2, 16.46 ± 18.3, and 9.70 ± 9.03, respectively, with a statistically significant difference at 90 days of follow-up (p = 0.05).
Six of the 20 (30%) patients required preoperative dialysis (Table 4). Of these, four recovered renal function (three by day 30 and one by day 180), one remained on dialysis, and one died before 30 days of follow-up. Six of the 20 (30%) patients’ renal insufficiency progressed after TAH implantation, resulting in a new dialysis requirement (Table 5). Of these, one recovered renal function within 30 days; two were off of dialysis by 90 days. The remaining three patients died during the study period while on dialysis (Figure 2). Mortality in patients on new-onset dialysis was (three of six) 50%. Overall, 75% (15 of 20) of our patients’ renal insufficiency improved after TAH implantation, including 66% (four of six) of patients who were on dialysis at the time of surgery.
The presence of significant end-organ damage is a contraindication to heart transplantation. In the case of renal insufficiency, the end-organ damage may represent a process that is reversible with adequate support of cardiac output. However, there are currently no definitive tests to predict the reversibility of renal insufficiency in advanced heart failure. Therefore, it would be of great benefit to both patients and clinicians if the reversibility of renal impairment with TAH could be quantified. Our study focused on those patients who had significant renal insufficiency and received TAH support. We observed that with TAH support, renal insufficiency, as defined by eGFR, improved at 30, 90, and 180 days of follow-up when compared with preoperative values. In particular, a majority of patients who were either on dialysis at the time of TAH implantation or developed a need for dialysis after surgery also recovered renal function with TAH support.
Because a majority of renal function tests are based on serum creatinine that fluctuates considerably based on patient’s gender, race, nutrition, and health status, there is no single test that can uniformly and accurately measure the renal function. Among the available renal function assessment tools, the MDRD formula was deemed more accurate13 and was adopted by our hospital laboratory. We used the MDRD formula to quantify renal function (eGFR) among those patients not requiring dialysis.
Mechanisms leading to renal insufficiency in patients with advanced heart failure are complex. The plasma volume is mediated by the renin–aldosterone system and other molecular regulators such as arginine–vasopressin, atrial natriuretic peptide, and B-type natriuretic peptide (BNP), which are deranged significantly in patients with advanced heart failure. Restoration of adequate circulation in heart failure patients with LVAD support has been shown to normalize the previously mentioned biomarkers along with clinical improvement.14 Possible mechanisms for this include restoration of circulation, adequate renal perfusion, and decompression of the heart chambers with LVAD support. However, these mechanisms have not yet been examined in patients supported with the TAH. Total artificial heart implantation is unique from LVAD support in that it involves removing both ventricles. As the ventricles are a main source of BNP, their removal results in an abrupt drop in BNP.15,16 B-type natriuretic peptide is a key hormone secreted by myocytes primarily in response to stretch. In addition to systemic vasodilation and increases in renal perfusion, BNP promotes natriuresis and suppresses the renin–angiotensin system. In small case series, it has been shown that immediately after removing the ventricles for TAH implantation, despite restoring adequate circulatory support, renal function of patients deteriorates, mirroring the abrupt drop in circulatory BNP levels.15,16 Interestingly, supplementation of a synthetic BNP analog (nesiritide) restores urine output and improves renal function. On the basis of these observations, it is recommended that physiologic levels of BNP should be supplemented intravenously starting in the operating room and weaned gradually over 2 to 3 weeks. During this time, alternate source of endogenous BNP secretion will restore the internal milieu.15,17
It is well established that mechanical circulatory support is superior to optimal medical management of patients with advanced heart failure.2 Although a majority of patients with heart failure awaiting heart transplantation receive LVAD support, a distinct group of patients require biventricular support. At our institution, TAH support is offered to patients with severe biventricular failure, those who failed LVAD support alone, or in cases of heart failure in the setting of massive acute myocardial infarction involving both ventricles. In addition, TAH is an option for patients with ventricular septal defects, failed cardiac allografts, arrhythmogenic ventricular failure, a large thrombus burden in the ventricles, and in select patients with hypertrophic cardiomyopathy where the left ventricle cavity size is too small to accommodate LVAD support. These indications are well recognized and were the reasons for TAH support in multiple studies.3,18,19
The prevalence of preoperative renal failure is not well defined in patients supported with TAH because patients requiring dialysis or a serum creatinine level of greater than 5 mg/dl were excluded from the large TAH multicenter trial.6 In this same study, 31% of patients developed dialysis requiring renal failure after TAH implantation and in 15% of them renal failure delayed listing patients for heart transplantation. Other studies noted a significant preoperative renal failure in 38–60% of patients requiring TAH support, similar to our study finding of 43.5%.9,10 Our patient demographics and preoperative morbidities are also similar to the reported data on patients undergoing TAH implantation.3,9,10 The majority of them were classified as Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) level I, with 90% dependent on inotropic support and more than 70% requiring temporary circulatory support. Given the overall acuity of illness at the time of TAH implantation, it is not surprising that those with pre-existing significant renal failure are likely to develop further renal insufficiency and others with preserved renal function may develop new-onset renal failure. Postoperative renal failure requiring dialysis with TAH implantation in patients with no significant preoperative renal failure was noted in 15–38% of patients,10,18,20 whereas we observed this in 30% of our patients. To allow adequate time for stabilization of overall circulation with TAH support and, in particular, for renal function recovery, we elected to monitor renal recovery beginning at 30 days after TAH implantation.
Baseline eGFR in our study cohort was 48 ± 7 ml/min/1.73 m2. The calculated eGFR (ml/min/1.73 m2) value at 30, 90, and 180 days after TAH implantation was 66 ± 31, 65 ± 21, and 56 ± 13 respectively. The absolute increase in eGFR (ml/min/1.73 m2) value compared with the baseline eGFR at 30, 90, and 180 days was 22 ± 35, 16 ± 21, and 9.7 ± 9, respectively. Although the greatest improvement in eGFR was noted at 30 days after TAH implantation followed by a plateau and a slight decline in eGFR at 180 days, statistical significance was observed only at 90 days (Figure 1). This pattern of eGFR improvement with mechanical circulatory support is well documented with LVAD support.7 It has been postulated that with improvement in circulation and overall well-being, patients regain muscle mass, which in turn increases serum creatinine, and hence a relative decline in eGFR is observed at 6 months of follow-up.
There is a steady attrition of patients for eGFR calculation in our study at each interval because of ongoing dialysis support, new-onset dialysis, heart transplantation, or death as described in Figure 1. Overall mortality at 6 months of follow-up was 30%, similar to the reported mortality of 21–52% with TAH implantation.9,10,20 Although renal failure was the most common morbidity and component of multisystem organ failure after TAH implantation in the reported literature,9,18,20 in our study cohort mortality among patients with preoperative dialysis dependency was 16% (one of the six patients); however, three of the six patients (50%) who developed a need for new-onset dialysis died of multisystem organ failure.
Data on recovery of renal function in those requiring new-onset dialysis after TAH implantation are sparse. In a study reported by Copeland et al.20 where 19% of patients developed a new-onset dialysis requirement after TAH implantation, renal recovery was noted in 41% and 59% died. Thus, failure of renal recovery in patients with new-onset dialysis after TAH implantation is a marker of poor prognosis.
Prognosis of patients requiring TAH implantation with preoperative dialysis need was encouraging in our study (Figure 2). Of the six patients (30%), four recovered renal function (66.6%), one remained on dialysis, and one died at 6 months of follow-up. Thus, it is very encouraging to note that despite an existing significant renal insufficiency at the time of TAH implantation, a vast majority of patients (15 of 20, 75%) do improve renal function, including 66% (four of six) of patients who were on dialysis at the time of surgery and remained eligible for heart transplantation.
Limitations inherent to any retrospective analysis are applicable to our study. A relatively small sample size and having only a single institution’s results limit us from making generalizations of our clinical outcomes. Similarly, a small sample size precluded us from performing detailed multivariable analysis to identify predictors of renal recovery or worsening renal function. However, our TAH patient sample includes all TAH patients with renal insufficiency at our institution. We achieved 100% follow-up on clinical outcomes and renal function at 6 months, adding strength to our stated results. Because there is no single, accurate renal function assessment tool available for critically ill, hospitalized patients, we selected the eGFR measurement by MDRD formula. However, this prevented us from calculating eGFR on patients who required dialysis, thus effectively decreasing the overall sample size. In addition, by excluding eGFR calculations on patients requiring dialysis, mean eGFR for the study cohort is spuriously elevated, as the true eGFR of these patients is undoubtedly lower than their dialysis-independent peers. With this in mind, it is worth noting that mean eGFR remained above preoperative values even as fewer patients required hemodialysis during the study period.
In our study of 20 advanced heart failure patients with moderate or severe renal insufficiency, TAH support improved renal function in 75% of patients, including those who were on dialysis at the time of surgery. Worsening renal function requiring dialysis after TAH implantation is associated with a poor prognosis.
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