Cardiorenal Resynchronization Therapy: Strengthening the Heart and Kidneys

CKD and heart failure are closely linked conditions that often coexist. Prior studies have shown that nearly one third of patients with heart failure have concomitant stage III or greater CKD (1–4). In addition, the majority of individuals with advanced kidney disease who initiate RRT will develop clinical heart failure or left ventricular dysfunction (5). The combination of these two conditions results in nearly three times the mortality risk compared with patients without significant kidney disease (2,6). As a result, medical interventions to prevent and treat cardiorenal complications have the potential to reduce morbidity and mortality in this population. Unfortunately, pharmacologic management of heart failure in patients with CKD may be limited by medication intolerance, electrolyte derangements, and other metabolic toxicities (1,7). Cardiac resynchronization therapy (CRT) is intended for patients with heart failure with systolic dysunction and ventricular dyssynchrony, which is the lack of simultaneous contraction in the right and left ventricles. CRT involves biventricular pacing to allow for coordinated contraction or more synchrony between both ventricles (Figure 1). This intervention has the potential to improve myocardial function and may have particular appeal in select individuals with CKD and heart failure.

Figure 1.

Conceptual model linking cardiac resynchronization to an improvement in eGFR and clinical outcomes. CV, cardiovascular; LV, left ventricular; RAAS, renin-angiotensin-aldosterone system.

Although initial, randomized controlled trials (RCTs) that evaluated the benefits of CRT in patients with heart failure, left ventricular dysfunction, and a wide QRS complex on the standard 12-lead electrocardiogram were published nearly 15 years ago (8–10), there are limited data on patients with CKD. In particular, individuals with advanced kidney disease were consistently excluded from all major RCTs. Subgroup analyses from some of these trials and observational studies have shown that patients with heart failure with mild to moderate CKD derive benefit from CRT; however, the magnitude of improvement in left ventricular remodeling is lower compared with patients with heart failure and preserved kidney function (11,12). In the Resynchronization Reverses Remodeling in Systolic Left Ventricular Dysfunction (REVERSE) study, kidney disease had a strong independent effect on inhibiting improvements in left ventricular ejection fraction, left ventricular end systolic volume (LVESV), and left ventricular end diastolic volume with resynchronization therapy (11). In particular, the magnitude of the remodeling benefit with resynchronization was greater in participants without CKD versus participants with CKD. Additional analysis from the REVERSE Study compared left ventricular remodeling among participants with CKD with and without CRT. Those individuals with CKD who were treated with CRT had a nearly 10% greater reduction in both LVESV and left ventricular end diastolic volume compared with those who were not receiving CRT. Similar findings were observed from registry data from the Leiden University Medical Center in The Netherlands (13). CRT reduced the LVESV in 43% of patients with an eGFR<60 ml/min per 1.73 m². This response rate is lower than the approximately 60% of patients with an eGFR>60 ml/min per 1.73 m² that had reverse remodeling. In both of these studies as well as other subgroup analyses from large RCTs (12), the overall level of kidney disease was mild to moderate, and limited data exist on the effects of CRT in more severe CKD populations.

The observational study by Höke et al. (14) expands the evaluation of CRT to patients with heart failure and severe kidney disease. Höke et al. (14) compared changes in left ventricular measurements, eGFR, and clinical outcomes between 73 patients that received CRT with defibrillator function and 18 patients with an implantable cardioverter defibrillator (ICD) only. Several important differences between these two groups prevent a thorough understanding of the effects of CRT in this population. The control population was comprised of only 18 patients and had less dyssynchrony as evidenced by a narrower QRS complex and a shorter conduction time from the interventricular septum to the lateral wall as measured by tissue Doppler imaging using echocardiography. In addition, the control population in this analysis had smaller end systolic and end diastolic dimensions and a better New York Heart Association functional class at baseline. As a result, the population selected for CRT implantation in this study would have been expected to benefit more from biventricular or simultaneous left ventricular-right ventricular pacing than the group of patients that did not have as much dyssynchrony and heart failure at baseline. This point is consistent with CRT guidelines that provide the strongest level of support for biventricular pacing in patients with left bundle branch block and a wide QRS complex (15).

It is interesting to note that despite the CRT group having a greater degree of clinical heart failure at baseline (New York Heart Association class III versus 1.5), greater left ventricular dimensions, and increased dyssynchrony, Höke et al. (14) showed that the CRT group had improved clinical outcomes reflected by the combination of appropriate ICD therapies, heart failure hospitalization, and all-cause mortality. The combined end point was observed in nearly all patients with ICDs (17 of 18) after a median follow-up period of <3 years. The rate of events is much higher than would be expected in a primary prevention ICD population and raises the question of whether these patients had another indication for ICD implantation. If the ICD group was comprised of individuals who had a prior cardiac arrest or episode of ventricular fibrillation (secondary prevention), they would be expected to have a higher risk of appropriate ICD therapies and meet the clinical end point. These data emphasize the importance of having a well matched control group and eventually, prospective RCTs that evaluate the efficacy and safety of CRT in patients with heart failure and mild, moderate, or severe kidney disease.

In the context of the prior studies that have assessed CRT in mild to moderate CKD, the study by Höke et al. (14) adds insight to our understanding of the potential for left ventricular remodeling in patients with heart failure and severe kidney disease. Approximately 30% of the CRT population (n=22 patients) in this analysis were classified as CRT responders, which was defined as a ≥15% reduction in the LVESV after 6 months of follow-up. As indicated earlier, a similar observational design from another study at the Leiden University Medical Center reported a slightly higher response rate in patients with mild to moderate CKD (13). These findings suggest that patients with more severe CKD may still derive benefit from CRT; however, the remodeling effects seem to attenuate with progressive declines in eGFR. Importantly, the reduction in left ventricular dimensions does not necessarily correlate with an improvement in clinical outcomes. Larger prospective studies will be necessary to assess corresponding reductions in heart failure symptoms, hospitalization, and mortality.

CRT may contribute to improvement in kidney function, and the analysis by Höke et al. (14) certainly provides important insight in this regard. Initial reports on CRT resulting in an increase in the eGFR were derived from subgroup analyses of the Multicenter InSync Randomized Clinical Evaluation Study, which was one of the initial RCTs to evaluate the efficacy of CRT in patients with heart failure, left ventricular systolic dysfunction, and a wide QRS complex. Among participants with an eGFR between 30 and 60 ml/min per 1.73 m², CRT improved eGFR after 6 months compared with the control group (2.7±1.2 versus −2.4±1.2 ml/min per 1.73 m²; P=0.003) (16). Höke et al. (14) have extended these initial observations to a group of individuals with more advanced CKD and showed even greater changes in eGFR. At 6 months, the CRT group had an improvement in eGFR from 25±4 to 30±9 ml/min per 1.73 m² (P<0.001) compared with no change in the eGFR in the ICD group. Additional analyses showed that the change in eGFR was only significant in those individuals who also had a positive remodeling effect on the left ventricle (reduction in LVESV by ≥15%): from 25±3 to 34±9 ml/min per 1.73 m² (P<0.001). In addition, among the participants with severe CKD and CRT, there was minimal progression to stage V CKD. These findings are in contrast to the natural progression of kidney disease over time in most patients with an eGFR=15–29 ml/min per 1.73 m² as evidenced by the nearly 25% of patients in the ICD control group that progressed to stage V CKD. The approximately 10 ml/min per 1.73 m² improvement in eGFR observed in CRT responders from the study by Höke et al. (14) may delay kidney disease progression and the need for more advanced RRTs. In addition, the improvement in eGFR raises physiologic questions regarding the mechanisms through which CRT improves kidney function. Using CRT in select patients with heart failure and advanced CKD may not only result in improved eGFR but also a reduction in cardiovascular events.

In summary, the study by Höke et al. (14) is thought provoking and focuses on a high-risk population that is understudied from the standpoint of clinical trials and cardiac devices. As the implantable cardiac device technology continues to advance, future studies should focus on evaluating rigorously whether CRT benefits individuals with CKD. In addition, more studies should also focus on evaluating other clinical and biologic markers that identify patients with CKD most likely to derive a benefit from implantable cardiac devices.

Disclosures

None.