Intensive Hemodialysis
Authors: T. Alp Ikizler
Journal: Journal of the American Society of Nephrology (2012)

Despite the recent advances in science and technology, as well as the vast clinical experience with renal replacement therapies, patients with ESRD on maintenance dialysis suffer from unacceptably high mortality rates.1 The epidemic of obesity and diabetes mellitus combined with the lack of robust therapies proven to delay progression of CKD render manipulation of the dialytic management strategies an obvious target for improving clinical outcomes in this highly complex patient population. A number of landmark randomized clinical trials have been published comparing the effects of different dialytic prescriptions. The National Cooperative Dialysis Study and the Hemodialysis study paved the way for the current dialysis practice recommendations and performance measures and also suggested that minor alterations in dialysis techniques are unlikely to make a significant impact on survival.2,3 More recently, the Frequent Hemodialysis Network (FHN) trials of daily and nocturnal dialysis were conducted to test the hypothesis that more radical modifications in hemodialysis treatment time and/or frequency would improve patient outcomes.4,5 The FHN trials were designed to examine the effects of treatment on a composite of mortality, change in left ventricular mass change, and change in self-reported physical functioning. There was also a range of secondary outcomes that were evaluated in these studies. The results of these important studies are highly publicized and discussed in various forums. An important aspect of both of these studies is that neither was powered to examine the effects of the treatment interventions on either mortality or hospitalization risks. Given the current economic climate and the priorities of the funding agencies, additional randomized clinical trials examining the effects of increasing hemodialysis frequency and/or treatment time with adequate power to assess hard outcomes are not on the horizon, which makes epidemiologic research even more important for assessing the clinical implications of increasing hemodialysis frequency and/or treatment time. In this issue of JASN, the results of two important observational studies are reported examining the effects of frequency and length of hemodialysis on mortality and other important clinical outcomes. Using the International Quotidian Dialysis registry, Nesrallah et al.6 conducted a retrospective cohort study to examine whether intensive hemodialysis is associated with better survival than conventional hemodialysis. They matched 420 patients who received intensive home hemodialysis in France, the United States, and Canada between January 2000 and August 2010 with 1388 patients in the Dialysis Outcomes and Practice Patterns Study who received in-center conventional hemodialysis during the same time period by country, ESRD duration, and a propensity score based on the probability of receiving intensive hemodialysis. Their results show that intensive home hemodialysis is associated with markedly improved patient survival (hazard ratio, 0.55) compared with conventional in-center hemodialysis. The strength and direction of the observed association between intensive hemodialysis and improved survival were consistent across all prespecified subgroups and in sensitivity analyses. In a companion article, Lacson et al.7 examine survival and clinical changes associated with conversion from conventional hemodialysis to in-center nocturnal hemodialysis in 959 consecutive patients in 77 Fresenius Medical Care (FMC) facilities during 2006 and 2007. The investigators compared mortality risk in a 1:3 propensity score–matched cohort of 746 nocturnal and 2062 control patients on conventional hemodialysis. Their results show that nocturnal hemodialysis associated with a 25% reduction in the risk for death after adjustment for age, body mass index, and dialysis vintage. Furthermore, there were favorable changes in intermediate clinical outcomes in patients on nocturnal therapy. These include improvements in serum albumin, phosphorus and hemoglobin, lower predialysis systolic BP, slower ultrafiltration rate, and lower white blood cell count during the 2-year follow-up. The studies by Nesrallah et al. and Lacson et al. have obvious strengths in comparison to previously published reports on the same subjects. Both studies are the largest of their kind, demonstrating generally similar results to previous smaller studies. Both studies have applied rigorous statistical methods to analyze the data. Multiple sensitivity and subgroup analyses are performed, showing high internal consistency. Nesrallah et al. used a prospectively designed data source providing the most reliable information available for examination of quotidian dialysis. Lacson et al. examined the FMC database for their analysis, which has been carefully constructed and has been subject to peer review in multiple publications. There are certain limitations of these studies, which are appropriately acknowledged by the authors. In particular, two issues are worth mentioning. First, and foremost, these are observational studies subject to bias and therefore cannot prove causality. Similarly, despite significant efforts to adjust for differences between comparison groups, a degree of residual confounding remains highly likely. For example, the higher transplantation rate observed in the nocturnal group in the study of Lacson et al. is an example of unaccounted partiality toward assigning select patients to nocturnal dialysis. The inherent bias to allocate a healthier and more suitable patient to more frequent or nocturnal hemodialysis can only be overcome by randomization. Notwithstanding the aforementioned strengths and limitations, the results of these two studies have important clinical implications. Undoubtedly, these particular studies represent the largest and best-constructed cohorts to examine the effects of frequent or longer dialysis on survival. Given the low likelihood of an adequately powered randomized clinical trial to examine the effects of these interventions on similar outcomes in the near future, these reports will be the reference standard for clinical decision-making regarding modality choice in ESRD patients. Given their strengths, these studies may also help shape the policy regarding the payment decision (allocation) for ESRD, at least in the United States. Current ESRD payment structure does not favor frequent treatments, and there are no financial incentives for prolonging treatment time.8 The accumulation of more reliable evidence favoring frequent and/or prolonged hemodialysis may lead to incorporation of certain financial incentives within the payment structure to motivate suitable subjects to at least try these otherwise costly therapies. Provision of financial incentives based on certain clinical outcomes is already incorporated in the bundled payment system. Some of these outcomes such as phosphorus and hemoglobin are already shown to be influenced positively by nocturnal hemodialysis in the study by Lacson et al. Finally, these studies provide a detailed description of the patients who have been exposed to, and potentially benefited from, more frequent and nocturnal hemodialysis. Clearly, not every hemodialysis patient is appropriate for these treatments, and these data may allow identification of these individuals for efficient resource allocation. In summary, convincing data are accumulating to indicate that more radical alterations in hemodialysis regimens are likely to improve patient outcomes. The excellent studies by Nesrallah et al. and Lacson et al. add further evidence to these observations. While indisputable evidence to show beneficial effect on survival can only be obtained by randomized clinical trials, it is unrealistic to expect such an initiative in the near future. Therefore, acquisition of reliable and comprehensive observational data is of the upmost importance to reliably examine the clinical consequences of more radical modifications in dialysis therapies. The International Quotidian Dialysis registry is an excellent example of such an effort.9 These initiatives must be expanded to include more granular data collection and extended to other subgroups for appropriate comparisons. In the meantime, clinicians should be encouraged to use the invaluable information gathered from these studies to apply to their practice to choose the right patient for the prescribed therapy. Concurrently, given the cost and inconvenience of these treatment choices, appropriate financial incentives should be incorporated within the payment system. Advances in hemodialysis treatment has been stagnant for decades, and it might be time to go back to the beginning—an era where more frequent and longer treatment was frequently provided compared with current practice.10 Disclosures T.A.I. received consultant fees from Renal Advantage Inc., Baxter Health Care, and Satellite Health Care.