Maintenance hemodialysis patients with low albumin levels who received intradialytic oral nutritional supplementation had significantly longer survival than matched controls did, according to a non-randomized study published in the American Journal of Kidney Diseases (2012;60:591–600).
“Confirmation of our findings may require future clinical trials or similar findings by other providers who may opt to adopt the monitored oral nutritional supplement program,” wrote the study authors, who were led by Eduardo Lacson Jr., MD, MPH, of Fresenius Medical Care North America (FMCNA).
“In the meantime, until proved otherwise, we strongly recommend that intradialytic oral nutrition be offered as a treatment option to eligible hypoalbuminemic maintenance hemodialysis patients.”
This study, taken together with the results of short-term, mostly single-center studies that were previously conducted, indicates that this intervention should be a treatment for dialysis patients who are hypoalbuminemic and have no other obvious cause for their condition, agreed Joel D. Kopple, MD, Professor of Medicine and Public Health at the David Geffen School of Medicine at UCLA and the UCLA Fielding School of Public Health, who has worked in the field of renal nutrition for 40 years.
“I consider this a very exciting paper because it addresses a major problem, which is that there is a very high mortality among maintenance dialysis patients, and mortality is greatly exaggerated in patients who have low serum albumin levels,” he said in an interview.
“The idea that giving a nutritional supplement simply three times a week during hemodialysis treatments can reduce mortality in these patients is really exciting.”
Large Sample Size
In 2007, Fresenius Medical Care North America started a pilot program of monitored intradialytic oral nutritional supplements for incident maintenance hemodialysis patients. By late 2009, that pilot had matured into a standard nationally available program.
Patients qualified for oral nutritional supplement use for up to one year if their albumin level was 3.5 g/dL or less. If the target albumin level of 4.0 g/dL was reached, oral supplementation was discontinued.
The program encouraged physicians and patients to take part, but participation was not mandatory, and many attending nephrologists were unconvinced that monitored oral nutritional supplements were effective and opted to defer participation in the program until more outcome data became available.
In the current study, Dr. Lacson and his team followed up the outcome of patient deaths, including dialysis withdrawals, until Dec. 31, 2010.
They performed intention-to-treat (ITT) analyses and as-treated analyses, with the latter excluding as potential controls eligible patients who subsequently received supplements after Jan. 1, 2010.
One dose of monitored oral nutritional supplements was given per treatment three times a week. Patients were able to choose from up to four different products: Nepro with Carb Steady, Pro-Stat RC, ZonePerfect, and VitalProteinRX.
The intention-to-treat analysis included 5,227 oral nutritional supplement patients who were matched to 5,227 controls. Forty percent of the controls received supplements after Jan. 1, 2010, because of delayed physician participation. The as-treated analysis included 4,289 patients and matched controls.
All patients were similar in terms of age, sex, race, and diabetes status, but supplement patients in the intention-to-treat population had a slightly lower body mass index (30.4 vs. 30.8 kg/m2) and lower hemoglobin levels (11.2 vs. 11.3 g/dL) at baseline compared with study controls. In the as-treated cohort, supplement patients had slightly longer dialysis vintage (3.9 vs. 3.6 years) and lower baseline phosphorus levels (5.1 vs. 5.2 mg/dL).
Importantly, there was no significant difference in baseline albumin levels, with an overall mean of 3.3 g/dL in all groups.
There was lower mortality with oral nutritional supplementation in both the intention-to-treat and as-treated groups, the researchers found.
In the multivariate analysis, there was a 9% increase in survival among those who took the supplements compared with controls in the intention-to-treat group, and up to a 34% increase among supplement patients in the as-treated group.
“Although the as-treated analysis may represent the ‘upper limit’ of the potential survival effect of intradialytic oral nutritional supplements, the ITT analysis likely represents an underestimate of the true difference in outcomes, albeit a 9% (or greater) survival benefit in this sickest of maintenance hemodialysis patients is not trivial,” the authors commented in their discussion.
Dr. Lacson and his team pointed out that their study had several strengths, including a large sample size, the inclusion of multiple centers, a standardized program definition, and a national distribution.
They also stressed that they made an effort to adjust for potential confounding. Nevertheless, the observational design of their study is limited by the likelihood of residual confounding from unmeasured patient, facility, and treatment-related factors.
‘Don't See Any Harm’
In an accompanying editorial, Seth Wright, MD, and Daniel E. Weiner, MD, MS, of Tufts University School of Medicine, wrote that despite these limitations, it seems appropriate to suggest implementation of oral nutritional supplementation (Am J Kidney Dis 2012;60:507–509).
“Based on these data, if people want to start giving dialysis patients nutritional supplements, I can't see that that would be a bad decision, because I don't see any harm,” Dr. Weiner, who is Assistant Professor of Medicine at Tufts, said in an interview. “I see a potential benefit.”
For one thing, the supplements are inexpensive.
“For better or for worse, the reality of a bundle system is that we need to weigh patient benefit for a capitated dollar,” he said. “This presents a very attractive possibility.”
In terms of potential confounding, it is possible that there are differences between the patients who got the supplements and those who did not, and differences in the attitudes of the physicians who were treating the patients, since supplement use was left up to physician discretion, Dr. Weiner noted.
“There may have been something about these earlier doctors that was inherently different compared with the doctors who started nutritional supplements later,” he said. “But Lacson and colleagues tried to get at all of these differences by looking at other clinical characteristics. Still, you can never be certain you got them all.”
A randomized clinical trial could settle the question of supplement use once and for all, Dr. Weiner stressed.
“I wouldn't necessarily hold off on giving the intervention while waiting for the clinical trial, but I want to see whether this truly does work, and the only way you can do that is with a clinical trial.”
Rajnish Mehrotra, MD, MS, Professor of Medicine at the University of Washington, called the results of the study encouraging but also expressed caution.
“One has to be careful, as this was not a clinical trial, and in the absence of random assignment, there is always some doubt whether the differences in death risk are truly a result of the intervention or because of unrecognized differences in patients who received the intervention not captured by the study,” he said.
If the study premise is correct and the death risk of dialysis patients with low albumin levels can be reduced by providing oral nutritional supplements during dialysis treatment three times a week, the intervention will represent a simple, relatively inexpensive way to reduce the high death risk of dialysis patients, he added.
In the United States, it is unusual for patients to receive oral nutritional supplements. In contrast, in many European countries, patients are given a meal when they come in for dialysis, Dr. Mehrotra noted.
While the design of the study does not allow for exploration of the mechanisms behind the findings, there are two potential explanations, Dr. Mehrotra suggested.
“The first explanation may be that there is a direct relationship between low albumin, nutritional status, and death risk,” he said.
“In this regard, there is evidence, at least in peritoneal dialysis patients, that low serum albumin in and of itself can lead to volume expansion. So, there is a possibility that an increase in serum albumin may be directly beneficial. But this study was limited in that they did not have reliable follow-up measurements of serum albumin.
“The second potential explanation is that providing excess calories and protein to chronically ill people, irrespective of what the cause of debility is, may reduce their death risk by allowing them to better deal with the chronic illness. This could be from a better immune function, reduction in inflammation. The short answer is that we don't know, and all that I have mentioned is speculative.”
Need for Randomized Trial
Like Dr. Weiner, Dr. Kopple said that it is essential to confirm the findings of this study with a large-scale, randomized, prospective clinical trial.
“The main problem with the study is that it is not randomized,” he said. “We also don't really know who actually took or did not take the nutritional supplement. The monitoring of survival was excellent, but the monitoring of compliance to the nutritional supplement regimens was not.
“It would also be helpful to know when, in the course of the hemodialysis sessions, the supplement was taken. One could argue that the best time to take the supplement is at the beginning of the dialysis, but this was not specified in this paper. It may or may not be an important factor.”
Dr. Kopple said that for years he and others have advocated giving nutrition during dialysis.
“We know that peptides, very small proteins, and many amino acids are removed during the dialysis procedure. That is why we believe giving nutrition during dialysis is a way of not only providing nutrition but preventing this recurrent, three-times-weekly loss during dialysis of nutrients that the patient needs.
“I greatly hope that this study leads to government funding of a randomized, prospective clinical trial. That is really what is needed now.”