Reflections on the HEMO study: the American viewpoint

Nathan Levin1, and Roger Greenwood2

1 Renal Research Institute, New York, USA and 2 Lister Renal Unit, East and North Hertforshire NHS Trust, Stevenage, UK

Keywords: dialysis dose; haemodialysis; HEMO study; membrane flux; randomized controlled trials

When such a large study as the NIH sponsored HEMO trial reports, it is sobering to first ask if it was all worth it. After all, we know that randomized controlled trials (RCTs) tend to be hugely expensive, be lengthy in their execution and that they can explore causality for only a few parameters. Recognizing that at the outset the planners had a long list of issues which they had to prioritize (for example, they chose not to study membrane biocompatibility) most would probably agree that the final short list (dialysis dose and membrane flux) was wisely chosen as these issues remain central concerns for those engaged in day-to-day haemodialysis therapy. In particular, there is continuing worry that the convergence of practice worldwide—to much shorter, more aggressive schedules which has been brought about by economic pressures, improved patient tolerance and preference—is resulting in systematic under-dialysis. While many would probably have preferred dialysis time (as opposed to dose) as a study parameter an initial pilot study showed this to be impractical not least because the capacity implications for individual centres were prohibitive.

The HEMO study was an RCT in 1846 patients undergoing thrice-weekly haemodialysis in 15 centres encompassing 72 dialysis units in the US, with 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 dialyser. The subjects were enrolled and randomized between March 1995 and October 2000. Eligibility requirements included age between 18 and 80 years and having been on regular thrice-weekly haemodialysis for at least 3 months. Patients were excluded if the residual urea clearance (by urine collection) exceeded 1.5 ml/min per 35 l volume of urea distribution, if serum albumin was <2.6 g/dl and if there was a failure to achieve the high target dialysis dose in <=4.5 h on two of three consecutive monitored dialysis sessions. Further exclusions included the presence of serious co-morbid medical conditions, including active malignancy or infection, unstable angina or end-stage cardiac, pulmonary or hepatic disease, or if scheduled for a living-donor kidney transplant. The primary outcome was death from any cause. The main secondary outcomes were the rate of all hospitalizations not related to vascular access and three composite end points: the first hospitalization for cardiac causes or death from any cause, the first hospitalization for infection or death from any cause and the first decline of >15% from baseline in the serum albumin level or death from any cause.

The standard-dose group achieved a urea reduction ratio (URR) of 66.3±2.5%, the single pool (SP) Kt/V was 1.32±0.09 and the equilibrated Kt/V was 1.16±0.08. The high-dose equivalents were 75.2±2.5%, 1.71±0.11 and 1.53±0.09. It is worth noting that the standard group received a dose well within the current US guideline (SP Kt/V >=1.2) and approximately equivalent to the dose currently being received by the majority of European patients. Flux, quantified according to beta-2-microglobulin clearance (B2M), was 3±7 ml/min in the low-flux group and 34±11 ml/min in the high-flux group.

What were the trial's strengths and weaknesses? Reviews of the methodologies employed in the trial and in the pilot studies have already given rise to a wealth of important published material, which is one of the important legacies of the HEMO trial. The good separation of the groups with respect to dose was achieved by diligent overseeing from the Cleveland Clinic Data Coordinating Center and attention was paid to stratification according to clinical centre and the presence of diabetes. However, the requirement to deliver a high dialysis dose in a limited time led to the exclusion of heavy patients. Ninety seven per cent of the patients who underwent randomization weighed <100 kg. While the proportions of diabetics in the groups reflected their prevalence in the US dialysis population, African Americans, who tend to have the better haemodialysis survival, were over-represented in the final cohort compared with the US dialysis population (62 vs 37%). Separation of the flux groups could have been greater were it not for the confounding factor of reuse, which had a variable although limited deleterious influence on B2M clearances. Water quality, which many would argue is a major contributor to morbidity in haemodialysis patients, was not taken into account, although participating units were expected to comply with national standards. There were no clinical directives to achieve dry weight.

What were the main messages? Looking at the whole study group who were receiving thrice-weekly haemodialysis for between 2.5 and 4.5 h neither a higher dose of dialysis nor the use of high-flux membranes significantly improved survival or reduced morbidity. However, in females a significant effect of dose was observed with a favourable effect on survival, even when adjusted for body size. Although dialysis duration was not a primary study parameter, within the limited range from 2.5 to 4.5 h no effect of time on survival was observed. In patients who had been on dialysis for >3.7 years compared with those on dialysis for <3.7 years, all-cause mortality was lower when patients used high-flux membranes. Also, the patients who benefited most from high flux were those who had been treated pre-trial with low-flux membranes. It is tempting to speculate that the favourable impact on this group, who would have had very little residual renal function, reflected the accumulation of toxins over a long period, which may have had higher clearance on high flux. Interestingly in the whole group there was a reduction in cardiac deaths (but not in all cause mortality) in high-flux patients.

Where does this leave us? The international dialysis community including practitioners and patients alike can probably breathe a moderate sigh of relief in the knowledge that current practice, within the constraints of thrice-weekly treatment, is delivering an adequate dose of dialysis to the majority. Fortuitously, despite the findings in women, most current patients are also likely to be in the safety zone as they tend to receive higher doses because of their smaller volumes when dialysis is not prescribed according to urea kinetic modelling (UKM). Mortality was inversely related to V, the volume of body water used in UKM. When gender was considered, the higher dose group had a lower mortality risk among females but not males. Since V is categorically smaller in females, it would seem prudent to deliver more dialysis for patients with a small V. In practice this will require relatively trivial and easily applied modifications to UKM formulae in current usage. In some ways the HEMO trial may draw a line under part of the adequacy debate as it has confirmed what we know from first principles that an intermittent therapy can only be pushed so far in what it can deliver and it looks as if thrice-weekly treatment is being driven about as hard as it can be. However, because of its convenience, relative economy and proven track record it is likely that it will remain the standard treatment for the majority. The trial reinforces the view that for highly motivated, particularly low-risk patients, more frequent dialysis, not more intense or longer sessions offers the best opportunity to optimize health prospects.

We also know that the broader the spectrum of molecules removed the closer dialysis approaches the functioning of the kidney and, provided there are no downsides, this remains a worthy therapeutic goal. Apart from cost differentials (which are decreasing) a significant obstacle to the adoption of high-flux membranes, certainly in Europe, has been the fear of adverse events in circumstances where water quality may not be stringently monitored. Here we have an RCT, which shows that high flux may be beneficial even when water quality is not actively monitored. The HEMO trial probably permits us, at last, to turn the question around—a rare luxury in this age of evidenced-based medicine. Is it justifiable to continue using tight membranes in the absence of demonstrable deleterious consequences and in the light of potential benefits of high flux? The absence of negative findings in this context may well boost the transition to high flux and indeed to haemodiafiltration, which fully exploits membrane porosity to consistently lower B2M levels in haemodialysis patients. In the last few years the technical problems of on-line filtration have been overcome. Haemodiafiltration, which can now be offered cost neutrally and which some argue is the natural evolutionary end point of dialytic therapy, is slowly being ingrained into routine therapy in Europe. This could accelerate and haemodiafiltration could ultimately find acceptance in the US.

Do we need another RCT of this type in haemodialysis? Probably not. Further clarification about the importance of flux will hopefully ensue from the Membrane Permeability Outcome (MPO) study currently underway in Europe. The HEMO trial may well herald a period of refinement rather than revolution in blood purification techniques and may well mark the time when efforts to establish frequent dialysis programmes gain momentum. The fact that the National Institutes of Diabetes and Digestive and Kidney Diseases (NIDDK) in the US has recently called for expressions of interest in a study of frequent dialysis compared with standard treatment may be partly explained by the outcomes of the HEMO trial. Taking a broader view it is likely that practice patterns and their relationship to healthcare systems will take centre stage for a period. The Dialysis Outcomes and Practice Patterns Study (DOPPS) has revealed large differences in outcomes between continents and between countries. For example the higher mortality in the UK compared with some other European countries is probably explained by poor vascular access services and the chronic planning blight within the National Health Service which has lead to inadequate expansion of haemodialysis with resulting precarious over-dependence on CAPD. The differences in mortality being observed are one order of magnitude greater than any differences shown in the HEMO trial. The reduction of these differences through reform of deficient service provision constitutes the biggest challenge currently facing services for patients with established renal failure.

Notes

Correspondence and offprint requests to: Dr Nathan Levin, Renal Research Institute, 207 East 94th Street, Suite 303, New York, NY 10128-3705, USA. Email: nlevin{at}rriny.com Back