This report summarizes morbidity in 151 patients in a cooperative trial designed to evaluate the clinical effects of different dialysis prescriptions. Four treatment groups were divided along two dimensions: dialysis treatment time (long or short), and blood urea nitrogen (BUN) concentration averaged with respect to time (TACurea) (high or low). Dietary protein was not restricted. There was no difference in mortality between the groups. Withdrawal of patients from the high-BUN groups for medical reasons was significantly greater than withdrawal from the low-BUN groups. Hospitalization was also greater in the high-BUN groups, but dialysis treatment time had no significant effects. The data indicate that the occurrence of morbid events is affected by the dialysis prescription. Increased morbidity appears to accompany prescriptions associated with a relatively high BUN. Conversely, morbidity may be decreased by prescriptions associated with more efficient removal of urea if the dietary intake of protein and other nutrients is adequate.

This is the first randomized control trial in hemodialysis therapy relating patients’ outcomes and surrogates of dialysis dose (BUN level and treatment time). Its mechanistic interpretation [9] has opened the track for dialysis quantification with the K _t/V concept, allowing physician to quantify small-molecule clearance. The dialysis adequacy was born and has influenced dialysis prescriptions for the following decades. However, the interpretation of the NCDS has since been largely criticized. Treatment time was not retained as significantly influencing outcomes. In the subgroups with high BUN, the P value comparing outcomes according to treatment times (3 h versus 4.5 h) was 0.056. Ignoring this important factor was questionable [10, 11], leading to the idea that increasing K with a fixed T could reach dialysis adequacy. This approach has focused the prescription on small-molecule clearance, whereas important factors more “T dependent” have since emerged such as phosphate balance [12], fluid management [13], or middle-molecule removal [14]. Moreover, BUN as a marker of uremic toxicity reflects the protein intake. The range of protein intake in the study was wide, from 0.8 to 1.4 g/kg/day and then a source of confounding factor.

The implementation of new trials on alternative dialysis strategy on time and frequency (see elsewhere) is the evidence that the NCDS conclusions did not solve all aspects of dialysis adequacy. However, it has given the practitioner the key of the minimum requirements of dialysis treatment.

Background: The effects of the dose of dialysis and the level of flux of the dialyzer membrane on mortality and morbidity among patients undergoing maintenance hemodialysis are uncertain.

Methods: We undertook a randomized clinical trial in 1,846 patients undergoing thrice-weekly dialysis, using a two-by-two factorial design to assign patients randomly to a standard or high dose of dialysis and to a low-flux or high-flux dialyzer.

Results: In the standard-dose group, the mean (±SD) urea-reduction ratio was 66.3 ± 2.5 %, the single-pool K _t/V was 1.32 ± 0.09, and the equilibrated K _t/V was 1.16 ± 0.08; in the high-dose group, the values were 75.2 ± 2.5 %, 1.71 ± 0.11, and 1.53 ± 0.09, respectively. Flux, estimated on the basis of beta₂-microglobulin clearance, was 3 ± 7 ml/min in the low-flux group and 34 ± 11 ml/min in the high-flux group. The primary outcome, death from any cause, was not significantly influenced by the dose or flux assignment: the relative risk of death in the high-dose group as compared with the standard-dose group was 0.96 (95 % confidence interval, 0.84–1.10; P = 0.53), and the relative risk of death in the high-flux group as compared with the low-flux group was 0.92 (95 % confidence interval, 0.81–1.05; P = 0.23). The main secondary outcomes (first hospitalization for cardiac causes or death from any cause, first hospitalization for infection or death from any cause, first 15 % decrease in the serum albumin level or death from any cause, and all hospitalizations not related to vascular access) also did not differ significantly between either the dose groups or the flux groups. Possible benefits of the dose or flux interventions were suggested in two of seven prespecified subgroups of patients.

Conclusion: Patients undergoing hemodialysis thrice weekly appear to have no major benefit from a higher dialysis dose than that recommended by current US guidelines or from the use of a high-flux membrane.

The HEMO study was well designed, with an acceptable dropout rate and a substantial follow-up. This trial has shaken the thoughts of many nephrologists, providing no support for better survival with higher small-molecule clearance and for high-flux membrane (and then increased middle-molecule clearance). Interactions with baseline characteristics found a benefit of high-flux membrane in patients treated for more than 3.7 years and that women benefited of higher K _t/V [16]. Regarding this last finding, the in-depth analysis of the dialysis dose according to gender has pointed out that when K _t was related to body surface area rather than to “V,” women were receiving a lower dialysis dose than men [17]. This might explain the better outcome of women in the high-dose group. It also questions the K _t/V paradigm and the way to normalize K _t. This study also highlights the fact that survival is multifactorial in hemodialysis patients and cannot be limited to small- and middle-molecule clearances. Especially bone mineral metabolism and fluid balance are important factors for outcome and were not covered by the HEMO trial. This has been well underlined by Twardowski and Misra [18], pointing a type III statistical error (wrong hypothesis and correct answer): the beneficial effect of the increase in K _t/V may be blunted when obtained only from its “K” component.

The MPO study is the second negative study on membrane flux after the HEMO study. It included incident patients, ruling out selection of survivors and the effects of previous treatment. The subgroup analysis has shown a survival advantage in patients with serum albumin(S-Alb) below 40 g/l and in diabetic patients. The main issue is that the design has changed during the study because of the slow pace of inclusions. Initially recruitment involved patients with S-Alb <40 g/l. Thereafter inclusion was widened to patients with normal S-Alb. The sample size calculation was adapted to this change. But it may explain the negative results and it has blurred the message. However, it confirms the beneficial effect of high-flux membranes reported in diabetic patients reported from the 4-D trial [19].

Background: In this randomized clinical trial, we aimed to determine whether increasing the frequency of in-center hemodialysis would result in beneficial changes in left ventricular mass, self-reported physical health, and other intermediate outcomes among patients undergoing maintenance hemodialysis.

Methods: Patients were randomly assigned to undergo hemodialysis six times per week (frequent hemodialysis, 125 patients) or three times per week (conventional hemodialysis, 120 patients) for 12 months. The two coprimary composite outcomes were death or change (from baseline to 12 months) in left ventricular mass, as assessed by cardiac magnetic resonance imaging, and death or change in the physical-health composite score of the RAND 36-item health survey. Secondary outcomes included cognitive performance; self-reported depression; laboratory markers of nutrition, mineral metabolism, and anemia; blood pressure; and rates of hospitalization and of interventions related to vascular access.

Results: Patients in the frequent-hemodialysis group averaged 5.2 sessions per week; the weekly standard K _t/V _urea (the product of the urea clearance and the duration of the dialysis session normalized to the volume of distribution of urea) was significantly higher in the frequent-hemodialysis group than in the conventional-hemodialysis group (3.54 ± 0.56 vs. 2.49 ± 0.27). Frequent hemodialysis was associated with significant benefits with respect to both coprimary composite outcomes (hazard ratio for death or increase in left ventricular mass, 0.61; 95 % confidence interval [CI], 0.46–0.82; hazard ratio for death or a decrease in the physical-health composite score, 0.70; 95 % CI, 0.53–0.92). Patients randomly assigned to frequent hemodialysis were more likely to undergo interventions related to vascular access than were patients assigned to conventional hemodialysis (hazard ratio, 1.71; 95 % CI, 1.08–2.73). Frequent hemodialysis was associated with improved control of hypertension and hyperphosphatemia. There were no significant effects of frequent hemodialysis on cognitive performance, self-reported depression, serum albumin concentration, or use of erythropoiesis-stimulating agents.

Conclusions: Frequent hemodialysis, as compared with conventional hemodialysis, was associated with favorable results with respect to the composite outcomes of death or change in left ventricular mass and death or change in a physical-health composite score but prompted more frequent interventions related to vascular access. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; ClinicalTrials.gov number, NCT00264758.)

The FHN daily trial has highlighted the benefits of daily dialysis after 1 year on composite coprimary outcomes, death and left ventricular mass, and death and physical-health composite score. The authors explained the choice of these end points in a preliminary article about the FHN methodology [20]. Analyzing mortality per se would have been a hard challenge, requiring 1,500 patients and several years of follow-up [20]. Several concerns have been raised after the study release. The death rate was unusually low in the two groups and the use of coprimary outcomes is questionable [21]. Moreover, the frequent group received a 23 % extra time of dialysis treatment, introducing a serious bias regarding the frequency benefit [22]. The high frequency of blood access complications and the economic issues make the finding not easily translatable. The FHN trial is a good illustration of the huge difficulties in implementing an RCT to compare standard and alternative dialysis techniques.

Prior small studies have shown multiple benefits of frequent nocturnal hemodialysis compared to conventional three times per week treatments. To study this further, we randomized 87 patients to three times per week conventional hemodialysis or to nocturnal hemodialysis six times per week, all with single-use high-flux dialyzers. The 45 patients in the frequent nocturnal arm had a 1.82-fold higher mean weekly std K _t/V _urea, a 1.74-fold higher average number of treatments per week, and a 2.45-fold higher average weekly treatment time than the 42 patients in the conventional arm. We did not find a significant effect of nocturnal hemodialysis for either of the two coprimary outcomes (death or left ventricular mass (measured by MRI) with a hazard ratio of 0.68, or of death or RAND Physical Health Composite with a hazard ratio of 0.91). Possible explanations for the left ventricular mass result include limited sample size and patient characteristics. Secondary outcomes included cognitive performance, self-reported depression, laboratory markers of nutrition, mineral metabolism and anemia, blood pressure and rates of hospitalization, and vascular access interventions. Patients in the nocturnal arm had improved control of hyperphosphatemia and hypertension, but no significant benefit among the other main secondary outcomes. There was a trend for increased vascular access events in the nocturnal arm. Thus, we were unable to demonstrate a definitive benefit of more frequent nocturnal hemodialysis for either coprimary outcome.