Chronic Fluid Overload and Mortality in ESRD

Discussion

Chronic exposure to FO as quantified by repeated measurements of body fluids by bioimpedance spectroscopy substantially increased the risk of death across discrete BP categories in a large cohort of patients on incident hemodialysis. The magnitude of death risk attributable to chronic FO was comparable with that of coronary artery disease or congestive heart failure per se or an increase in age of ≥12 years.

Only three studies have tested the relationship between directly measured FO and the risk of death in the ESRD population.^4–6 In these studies—all on the basis of prevalent patients and collectively including just 667 patients—FO was measured only at baseline. We tested the relationship between exposure to FO and mortality by two approaches. By the first approach, we estimated the risk of death associated with baseline FO in incident patients, which is a survival bias–free approach. By the second approach, we investigated the relationship between cumulative exposure to FO over 1 year and death beyond the first year, an approach surmising that, like for traditional risk factors,^7–10 the effects of FO are cumulative in nature. In both analyses, the link between FO and mortality was robust and resisted adjustment for a large series of potential confounders, including heart failure and major comorbidities. The risk of death portended by cumulative FO was higher than the risk estimated solely on the basis of the baseline FO measurement, suggesting that, in patients on incident hemodialysis, persistent FO is a much stronger risk predictor than FO as measured at only one time point. The initial (baseline) FO measurement in patients with incident ESRD may be an imprecise marker of the chronic fluid status in this population, because detection of a high FO value may prompt the prescription of an intensification of ultrafiltration to correct overhydration, an intervention that eventually dissociates the baseline FO assessment from the actual chronic exposure to FO. The risk of FO was almost equally strong in hypertensive and hypotensive patients, and such risk also remained substantial in normotensive patients as defined by predialysis BP, which is the BP metric most commonly applied to guide the ultrafiltration regimen and antihypertensive therapy in the dialysis population. This was true across the 26 countries and the types of extracorporeal treatment (hemodialysis and hemofiltration), suggesting that our findings are generalizable to a vast population of patients. The risk of death dictated by systolic BP categories per se was modest and of the same order of that registered in the Dialysis Outcomes and Practice Patterns Study,¹¹ ranging from 6% in patients with low BP to 26% in those with high BP. Predialysis systolic BP is a measurement performed at peak FO, and therefore, it is a proxy of left ventricular function rather than a metric of long-term BP burden.¹² In patients in the Chronic Renal Insufficiency Cohort who progressed to ESRD, the relationship of predialysis BP with mortality was U shaped. However, standardized BP measurements outside the hemodialysis environment were linearly related with mortality in the same patients.¹³ Therefore, more reliable metrics of the actual BP burden, such as 24-hour ambulatory blood pressure monitoring,¹⁴ standardized BP,¹³ or home BP,¹⁴ may show stronger links between BP and mortality than predialysis BP. Notwithstanding this limitation, this BP metric remains the method whereupon most renal physicians base their decisions about BP treatment, including decisions about the ultrafiltration regimen. Recently, a comprehensive survey including 172 centers serving 62% of the hemodialysis population in Great Britain³ showed that 78% of the centers have no concurring policy for managing fluid balance. Most centers relied on clinical assessment, including predialysis BP, and only 27% of the centers applied bioimpedance to measure body fluids. Given the strong association between chronic FO and mortality, which far exceeds that of low and high predialysis BP, our study suggests that treatment policies guided by fluid status monitoring might be preferable to policies guided solely by predialysis BP measurement. Pilot studies on the basis of surrogates, such as left ventricular mass index and/or pulse wave velocity,^15,16 support the contention that systematic body fluids measurements may produce favorable effects.

Our study has limitations. The first limitation is the purely observational nature of our observations. Although we adjusted for a large series of potential confounders, residual confounding by imprecisely measured concomitant risk factors and/or other risk factors that we did not measure might have altered the precision of the estimate of the mortality risk of FO. Also, the study of the cumulative exposure to FO over 1 year is open to survival bias. However, although restricted to the ESRD population with survival of at least 1 year, which is about 80%–85% of the hemodialysis population in European countries¹ and the United States,² these data clearly indicate that sustained FO is an independent risk factor of the same magnitude as heart failure per se or an increase in age of ≥12 years. The incident nature of our cohort and the very large sample size including diverse populations across 26 countries are important strengths.

In conclusion, chronic exposure to FO (as quantified by >200,000 measurements of body fluids by bioimpedance spectroscopy in about 35,000 patients on incident hemodialysis) is a strong risk factor for death across discrete BP categories. These findings support a strong call for a randomized trial on the basis of clinical end points comparing a clinical policy on the basis of FO measurements by BCM with the standard clinical policy guided by BP, symptoms, and clinical signs, which is the standard currently adopted by the majority of centers worldwide.