A retrospective, longitudinal study estimating the association between interdialytic weight gain and cardiovascular events and death in hemodialysis patients

Table 1 demonstrates baseline characteristics of the 39,256 patients qualifying for study. Overall, mean age was 62.2 years; 43.9 % were female, 46.0 % of patients were white, 31.7 % were black, and 14.7 % were Hispanic. Etiology of ESRD was diabetes in 47.1 %, hypertension in 30.4 %, glomerular disease in 7.2 %, and some other cause in 15.3 % of patients. At baseline, 68.2 % of patients had diabetes, 39.8 % had a history of heart failure, and 25.3 % had a history of myocardial infarction; 1.8 % of patients had received prior transplants and were initiating hemodialysis in the setting of a failed transplant. The distributions of relative and absolute IDWG are shown in Fig. 2. Mean relative IDWG was 3.1 %; the distribution was noticeably right skewed. Mean absolute IDWG was 2.4 kg; the distribution was more symmetrical than relative IDWG distribution, but still somewhat right skewed.

Incidence rates for events of interest during the outcome period are provided in Table 2. Hospitalizations for nonfatal myocardial infarction occurred at a rate of 59.5 events/1000 patient-years, hospitalizations for heart failure/volume overload at a rate of 243 events/1000 patient-years, MACE at a rate of 108 events/1000 patient-years, MACE+ at a rate of 324 events/1000 patient-years, CV mortality at a rate of 55.8 deaths/1000 patient-years, and all-cause mortality at a rate of 142 deaths/1000 patient-years.

Unadjusted associations of absolute and relative IDWG with each outcome of interest are shown in Fig. 3. In general, associations with an outcome were more potent for relative versus absolute IDWG. For most outcomes, associations with relative IDWG were relatively monotonic, whereas the association with absolute IDWG was less consistent and demonstrated threshold effects. For myocardial infarction, a threshold effect was observed with relative IDWG as well; nonetheless, the association was more potent for relative versus absolute IDWG.

Considered dichotomously, compared to patients with low relative and absolute IDWG, respectively, patients with high relative (>3.5 %) and absolute IDWG (>3 kg), respectively, were on average younger and less likely to dialyze via a catheter, but were more likely to have baseline diabetes or heart failure. These and other comparisons are presented in Table 1. Associations were synchronous except that high relative IDWG was associated with lower body weight whereas high absolute IDWG was associated with higher body weight.

Table 3 presents unadjusted and adjusted associations between absolute and relative IDWG and endpoints during the outcome period. On an unadjusted basis, higher relative IDWG was associated with greater risk of each outcome studied. Upon multivariable adjustment, estimates were slightly potentiated but qualitatively similar. Measures of associations ranged from 14 % greater risk (myocardial infarction) to 26 % greater risk (CV mortality).

On an unadjusted basis, higher absolute IDWG was associated with a greater risk of hospitalization for heart failure/volume overload and MACE+, but not other outcomes. Upon multivariable adjustment, estimates were mildly potentiated; significant adjusted associations were observed for all-cause mortality (7 % greater risk), heart failure/volume overload (14 % greater risk), and MACE+ (14 % greater risk). Upon further adjustment for body weight, greater absolute IDWG was associated with all outcomes considered except for heart failure. Measures of association ranged from 11 % (MACE) to 20 % (heart failure/volume overload).

To determine whether risk of poor outcomes might be modified by underlying diabetes or baseline heart failure, we conducted restriction subgroup analyses (Fig. 4). Results demonstrate that associations of high relative IDWG with outcomes were similar in diabetic and nondiabetic patients and in patients with and without baseline heart failure.

Finally, a sensitivity analysis was conducted in which the association between high relative IDWG and CV mortality was analyzed under a competing risks framework. The association was not meaningfully different from that observed in the primary analysis: hazard ratio (95 % CI) for relative IDWG > 3.5 % was 1.26 (1.20–1.33).

CV-related morbidity and mortality are greater in ESRD patients compared to the general population [9]. This is probably related to the vast constellation of underlying conditions that contribute to the deterioration of the circulatory system, such as chronic hypervolemia, high blood pressure, and periodic episodes of intravascular hypovolemia with attendant tissue hypoxia, all superimposed on a background of vascular disease, diabetes, and autonomic nervous system dysfunction. These data suggest that IDWG may contribute independently and substantively to CV burden.

For the most part, dialysis patients are completely reliant on the dialysis procedure for fluid removal. There is sound biologic basis as to why greater IDWG may be harmful. Acutely, greater volumes of retained fluid increase cardiac filling pressures and predispose patients to left ventricular strain, pulmonary edema, and excessive blood pressure. In addition, because dialysis treatment time is essentially fixed for most US patients, greater IDWG implies a greater rate of fluid removal during dialysis (i.e., ultrafiltration), which is associated with hemodynamic instability and death [4, 10‐14]. Chronic or repeated episodes of fluid retention contribute to maladaptive changes in cardiac structure, such as left ventricular hypertrophy and fibrosis, which may distort electrical conduction pathways and promote ventricular tachyarrhythmia and sudden cardiac death. Moreover, data demonstrate that asymptomatic pulmonary congestion and overhydration on bioimpedance are potently associated with increased risk of death in otherwise stable hemodialysis patients [15, 16]. Hur et al. found significant improvements of left ventricular hypertrophy, blood pressure, and pulse wave velocity targeting normohydration amid the interdialytic period instead of the end of the dialysis session with the help of bioimpedance, implying that restricting fluid exposure reduces CV complications [17]. There are several plausible mechanisms behind the findings, including stunning, strain of IDWG itself, or dry weight that is greater than optimal, as these patients are difficult to bring down to normohydration. Further, it is possible that IDWG necessitates rapid ultrafiltration since the duration of dialysis is fixed from a practical standpoint. However, the distinction between these 2 circumstances is not possible with the current study design, but shows only that minimizing IDWG is potentially important. Earlier studies have demonstrated that ESRD patients experiencing large IDWG have an increased risk of death compared to those with lesser weight gain between dialysis sessions [4, 13].

The results presented here are consistent and extend prior findings by demonstrating potent associations between IDWG and CV morbid events and CV mortality [3, 18]. In building upon these prior data, the present findings are noteworthy because they provide a physiologic and clinical link between fluid accumulation and mortality, demonstrate profound clinical and economic implications, and imply that mitigating IDWG could improve health and survival among ESRD patients. Unlike past studies that considered only composite endpoints, our robust sample size enabled us to assess associations with individual outcomes of interest. Moreover, it afforded greater statistical power to detect associations between smaller increments in IDWG and outcomes than have been previously reported.

There are 2 ways of expressing IDWG for clinical and research purposes: absolute IDWG and relative IDWG, the latter expressed as a percentage of body weight. There is no clear consensus in the literature as to which of these metrics is more clinically relevant. Our data indicate that relative IDWG is more potently, consistently, and monotonically associated with the outcomes studied than is absolute IDWG, and therefore may be the more relevant parameter. If so, this would suggest that small patients may be particularly vulnerable to the effects of high IDWG by virtue of having less ability to “store” excess fluid between dialysis sessions. However, inference in this regard should be undertaken cautiously. High relative IDWG was associated with smaller body size whereas high absolute IDWG was associated with larger body size. Considering the known association between body size and clinical outcomes [19], this distinction could explain the discrepancies observed. Of note in this regard is that the associations between absolute IDWG and outcomes were potentiated upon adjustment for body weight. Analogous adjustment for relative IDWG could not be undertaken because—when body weight is held analytically constant as in the case of statistical adjustment—absolute and relative IDWG converge to the same construct. Further research is needed to elaborate the contributions of relative and absolute IDWG, including dilutional studies demonstrating distribution of accumulated fluid within relevant body compartments. Until such is known, the most conservative interpretation of these findings would be to consider the weight-adjusted outcomes for absolute IDWG: that greater IDWG is associated with heart failure exacerbation, MACE, MACE+, CV mortality, and all-cause mortality but not with myocardial infarction.

Study limitations include the retrospective design of this analysis, which can lead to confounding. Specific to this study, we lacked data on residual urine output. This could potentially have confounded findings if, and to the degree that, residual urine output impacts outcomes independently of effects mediated through IDWG. There may have been residual confounding due to comorbid conditions not considered, or the severity of those that were. It is noteworthy that in the study by Lee et al., high relative IDWG was associated with an increased risk of MACE, even after adjustment for urine production and nutritional status [18]. Another confounding factor to acknowledge is that patients may have been nonadherent to dialysis, leading to larger IDWG between sessions, thereby inflating the measurement of IDWG. Again, this could confound findings to the degree that poor dialysis attendance impacted outcomes independent of intermediary effects on IDWG. The duration of follow-up in this study was relatively short (potential follow-up time ranged from 1–3 years based on the date of accrual). However, normative data demonstrate that median survival time for hemodialysis patients in the United States is only 3 years, and thus our time horizon is relevant [20].

Finally, of note this study considered IDWG. This is a separate, though related concept to chronic fluid accumulation (eg, as measured by bioimpedance, online hematocrit monitoring, or soluble biomarkers) [21, 22]. Additional studies are needed to better understand how cyclical fluid changes represented by IDWG and chronic volume expansion interact with respect to clinical outcomes.