In this multicenter, randomized trial of frequent, as compared with conventional, in-center hemodialysis, we observed statistically significant and clinically meaningful benefits with respect to both coprimary composite end points — death or 12-month change in left ventricular mass and death or 12-month change in self-reported physical health.
Our results extend those that have been shown in several observational studies and clinical trials comparing conventional and more frequent hemodialysis. DePalma et al.25
reported the initial findings regarding an increased frequency of hemodialysis more than 40 years ago; in 1988, Buoncristiani et al.26
found that control of hypertension and multiple metabolic factors were improved when patients underwent hemodialysis five to six times per week. Ting et al.27
showed that among 42 patients who responded poorly to conventional hemodialysis, frequent in-center hemodialysis was associated with fewer days in the hospital, improved health-related quality of life, and improved control of hypertension and anemia. Ayus et al.28
compared 23 patients undergoing frequent in-center hemodialysis with 51 matched controls and found that patients undergoing frequent hemodialysis had a reduction in left ventricular hypertrophy and lower concentrations of phosphate and C-reactive protein. Other studies have examined the effects of frequent home-based hemodialysis, often performed overnight (so-called nocturnal hemodialysis).29,30
Although these studies were pioneering, they were limited by small sample sizes, inadequate or no controls, selection bias, dropout bias, and an emphasis on within-group, rather than between-group, inference tests. We elected not to allow participants to perform frequent hemodialysis at home, so that the benefits and risks of home-based therapies and the effects of session frequency could be disentangled.
In the conventional-hemodialysis group, the prescribed dialysis dose was at or above the levels recommended in clinical practice guidelines. In both groups, other aspects of hemodialysis and related care were standardized and monitored. Given the excellent adherence to both treatment regimens, the difference between the groups with respect to solute clearance was maintained. The vast majority of participants in the frequent-hemodialysis group completed at least five sessions per week; participants in the conventional-hemodialysis group rarely had extra hemodialysis sessions.
The trial met its prespecified criteria for showing overall benefit. The results of the FHN Daily Trial can be compared with those of the HEMO Study,12
in which 1846 patients were randomly assigned to conventional or more intensive thrice-weekly in-center hemodialysis. In the HEMO Study, there was no overall effect on mortality, the rate of hospitalization, or health-related quality of life among patients randomly assigned to a target per-session equilibrated Kt/Vurea
of 1.45 or 1.05, although subgroup analyses suggested a possible benefit among women and a trend toward harm among men with the more intensive treatment.31
It is possible that the benefit we observed in the FHN trial among patients in the frequent-hemodialysis group was due to an even greater between-group difference with respect to urea clearance, a marker of low-molecular-weight solutes. Alternatively, the benefit of frequent hemodialysis may result from improved control of other metabolic by-products, such as phosphate or other retained uremic solutes, more physiologic removal of solutes (yielding lower and less variable time-averaged solute concentrations), or improved control of extracellular volume excess (reducing the time-averaged fluid load). Consistently high weight gain between dialysis sessions may induce hypertension, left ventricular hypertrophy, and other adverse effects32-34
; the lower weight gain between dialysis sessions in the frequent-hemodialysis group may be responsible for some of the benefit that we observed with respect to left ventricular mass. Although frequent hemodialysis is far from perfect, it may more closely approximate the capacity of a native or transplanted kidney to regulate extracellular volume and solute composition.
However, the benefits of hemodialysis performed six times per week were gained at the cost of more frequent interventions related to vascular access. Although we cannot exclude the possibility that these interventions were prompted by more frequent contact with the patient or by providers' fears, the fact that needle cannulation of a fistula or graft or manipulation of a catheter occurred approximately twice as frequently in the frequent-hemodialysis group as in the conventional-dialysis group could have contributed directly to the complications we observed.
The study has several strengths, including its relatively large sample size, the use of cardiac MRI for the assessment of left ventricular mass, the diversity of the study population, high adherence rates, and the wide array of outcomes linked to death and complications among patients with end-stage renal disease.35,36
The study also has several important limitations. Owing to feasibility and other logistic concerns, the sample size was insufficient to determine the effects of frequent in-center hemodialysis on death, cause-specific death, hospitalization, or other events. Although we determined a priori that favorable effects on both coprimary composite outcomes would be required in order to consider the trial to have had positive results, the rate of death in both groups was low, and the bulk of the treatment effect was seen in intermediate outcomes. Studies involving patients with37
and patients without38
end-stage renal disease have suggested that treatments targeted to reducing left ventricular mass are associated with lower rates of death and cardiovascular events. In observational analyses, differences in left ventricular mass33
and self-reported physical health39
of lesser magnitude than those shown in our study have been associated with significantly improved outcomes in this population. We excluded patients who had ample residual kidney function and patients who were not expected to survive for more than 6 months; we cannot generalize the study's results to these large and important segments of the population undergoing hemodialysis. To limit the risk of the “false discovery” of multiple effects, we designated a single outcome for each domain as a key secondary outcome (except in the case of hypertension, for which we specified two main secondary outcomes). These designations were somewhat arbitrary.
In summary, as compared with conventional hemodialysis, frequent hemodialysis was associated with favorable changes in the composite coprimary outcomes of death or 12-month change in left ventricular mass and death or 12-month change in the RAND-36 physical-health composite score. Frequent hemodialysis improved the control of hypertension and hyperphosphatemia but had no significant effects on cognitive performance, self-reported depression, serum albumin concentration, or use of erythropoiesis-stimulating agents. Patients who underwent frequent hemodialysis were significantly more likely to undergo interventions related to vascular access. Before major changes in practice can be recommended, the net effects of frequent hemodialysis will need to be balanced against the added burden for the patient and societal cost.