Successful treatment of hypoalbuminemic hemodialysis patients with a modified regimen of oral essential amino acids

Successful treatment of hypoalbuminemic hemodialysis patients with a modified regimen of oral essential amino acids

ORIGINAL RESEARCH Successful Treatment of Hypoalbuminemic Hemodialysis Patients With a Modified Regimen of Oral Essential Amino Acids Lauren Bronich,...

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ORIGINAL RESEARCH

Successful Treatment of Hypoalbuminemic Hemodialysis Patients With a Modified Regimen of Oral Essential Amino Acids Lauren Bronich, RE), LD,* Tite Te, RD, LD, ~-Kedar Shetye, MD,5~ Tara Stewart, RD, LD,* and Joseph A. Eustace, MB, MRCPI, MHS~ Objective: To evaluate compliance and the change in serum albumin associated with essential amino acid (EAA) therapy in hypoalbuminemic hemodialysis subjects. Design and Setting: Open label, single intervention, pilot study conducted at 2 outpatient hemodialysis centers located in Baltimore, Maryland. Subjects: Eighteen patients with a mean 3-month prestudy serum albumin of <3.8 g/alL and a mean Kt/V of ->1.0, without any recent hospitalizations or infections, who provided informed consent, and who demonstrated ->90% compliance rate during a 2 week run-in period, were enrolled in the study. The mean age was 61.3 years, 44% were male, 78% were black, and 50% were diabetic. Intervention: Subjects were instructed to take 3 Aminess N tablets (Recip AB, Stockholm, Sweden) 3 times each day with meals (total of 6.8 g of EAA per day) for 4 months. Main outcome measure: Median 4-month compliance and the change in mean follow-up serum albumin levels (mean of the serum albumin levels at day 30, day 60, day 90, and day 120 after the start of therapy) compared with mean baseline serum albumin levels (mean of the serum albumin levels at day -90, day -60, day -30, and day 0 before therapy). Secondary outcomes included changes in grip strength and body weight. Data was also collected on C-reactive protein levels, dialysis adequacy (Kt/V), and serum bicarbonate. A 2-day dietary recall was obtained at both the start and finish of the study. Results: Monthly compliance with EAA tablets remained relatively stable over the study period, with median compliance rates of 86%, 88%, 82%, and 82% at months 1 through 4, and an overall median compliance of 82%. Seventy-eight percent of patients had an overall compliance rate of 70% or greater. Serum albumin improved from baseline to follow-up by a mean (95% confidence interval) of 0.20 g/alL (95% confidence interval, 0.04 to 0.30; P = .001). Lowest postdialysis weight increased from a mean of 74.5 kg to 77.1 kg (P = .05), and there was a nonsignificant increase in grip strength. C-reactive protein levels increased in 33%, remained constant in 11%, and decreased in 56% of subjects, and there was no significant correlation between change in C-reactive protein levels and improvement in serum albumin. Dietary recalls did not show any significant change in the spontaneous protein or caloric intakes in association with the use of the EAA tablets. Conclusion: Although uncontrolled, these results support the feasibility and benefits of moderate dose oral EAA supplementation in hypoalbuminemic hemodialysis subjects. 2001 by the Nationa/ Kidney Foundation, Inc.

*Renal Dietitian, Gambro Healthcare,J. B. Zachary Dialysis Unit, Johns Hopkins Bayview Hospital, Baltimore, MD. "~Renal Dietitian, Gambro Healthcare, Band St. Dialysis Unit, Johns Hopkins University Hospital, Baltimore, MD. ~Renal Fellow,Johns Hopkins Bayview Hospital, Baltimore, MD. .~dssistant ProfessorDepartment of Medicine, Dqvision of Nephrology,Johns Hopkins University, Baltimore, MD. Supported by aJohns Hopkins clinicalscientistcareerdevelopment award, and an unconditionalresearchgirlfrom Recip AB and GambroAB, Stockholm, Sweden. Presented at the National Kidney Foundation Professional Councils Conference, October 12-15, 2000, Toronto, Canada. Address reprint requests to Joseph A. Eustace, MB, MRCPI, MHS, Division of Nephrotogy, Johns Hopkins University, Room 416, I830 Building, I830 East Monument .St, Baltimore, MD 21205. E-mait: [email protected] © 2001 by the National Kidney Foundation, Inc. 1051-2276/01 / 1104-0003535.00/0 doi: 10.1053/jren.2001.26978

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Journal of Renal Nutrition, Vol 11, No 4 (October), 2001: pp 194-201

O R A L EEA T H E R A P Y IN" D I A L Y S I S H Y P O A L B U M I N E M I A

Y P O A L B U M I N E M I A is a common complication of maintenance hemodialysis and is significantly associated with poor patient outcome. 1-6 The cause of dialysis-associated hypoalbuminemia is controversial; in particular, the relative contribution of poor oral intake as compared with inflammation-related hypercatabolism is unclear. 7 Inflammation directly increases proteolysis but it also exacerbates anorexia, which in turn limits the body's ability to appropriately compensate for increased levels of catabolism. Several other factors also limit the spontaneous oral intake of dialysis patients, including inadequate dialysis, uncontrolled acidosis, comorbid conditions, such as diabetic gastroparesis, financial and socioeconomic constraints, and medically imposed dietary restrictions. 7-1° Although a negative nitrogen balance has traditionally been treated by encouraging an increased protein intake, this approach simultaneously results in the provision of additional potentially toxic protein degradation products, which may counteract some o f the potential benefits o f the increased nitrogen intake. The use of oral essential amino acid (EAA) supplements in this setting provides a potent nitrogen source while avoiding the generation o f potential uremic toxins and the addition of unwanted potassium and phosphate. For these reasons, we recently conducted a randomized double-blind, placebo-controlled trial investigating the use of oral supplementation with 10.8 g/d of EAA in a population of persistently hypoalbuminemic maintenance dialysis patients. 11 The mean increase in serum albumin over 3 months of follow-up was 0.22 g/dL (95% confidence interval [CI], 0.03 to 0.40) better in the EAA group as compared with the control group (P = .02). However, one limitation of this trial was a progressive decline in compliance with a mean overall compliance rate of 65%, making uncertain the feasibility of using this as a more long-term intervention. Nevertheless, compliance in the EAA group was almost identical to that o f the placebo group, suggesting that the limited compliance was not related to use of EAA tablets per se, but rather to the participation burden associated with taking 15 extra tablets, in addition to the patients' numerous routine medications. In view of these results, and in anticipation of conducting a larger randomized trial examining the beneficial effects of oral EAA supplementation on actual patient outcomes, we conducted the following pilot study

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with the specific aim o f evaluating patients' compliance and the change in serum albumin using a modified EAA regimen of 9 EAA tablets per day, a dose equivalent to the average daily amount of EAA actually consumed in our original trial.

Materials and Methods Subjects The study was conducted at 2 university-associated hemodialysis units in downtown Baldmore, MD. T o be eligible, subjects had to be at least 18 years old, had to have undergone maintenance hemodialysis for at least 3 months, and had to provide written infomaed consent. In addition, patients were required to have had a mean serum albumin level of <3.8 g/dL, as well as a mean Kt/V of ~1.0, over the 3-month period before entry into the study. Patients were excluded if, in the opinion o f their primary nephrologist or the dialysis staff, they were unlikely to comply with the study protocol or had an estimated life expectancy o f < 2 months, if they received nontopical antibiotics or had a nonelective hospitalization in the month before starting the study, or if they had uncontrolled hyperphosphatemia because o f suspected noncompliance with phosphate binders.

Design This study was an open-label, single-intervention, feasibility study. Eligible patients who were willing to participate initially entered a 2-week placebo compliance-assessment period, and if sufficiently compliant, entered a 4-month, openlabel, active intervention period. During the initial compliance-assessment period, subjects received placebo tablets using a schedule identical to that o f the actual study. The returned pill container was weighed and the patients' compliance was estimated. To help detect patients who may have simply discarded their medication, additional tablets were present in the container in excess of those required for 2 weeks of full compliance. Patients received a pill holder capable of holding the daily dose of 9 EAA tablets, as well as a monthly study calendar. Patients were instructed to refill the pill holder from the study bottle each night and to record the number of tablets taken that day on the study calendar. Any reason for incomplete compliance was to be noted on the calendar, which also served to

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remind participants to take their tablets. Patients with a 90% or greater compliance rate during the run-in trial began the study the morning after their next monthly blood drawing. Patients were instructed to take 3 tablets 3 times each day, with meals when possible. Patients continued to use their pill holders and study calendars as described above for the duration of the study.

Study Intervention The oral EAA tablet used in the study was Aminess N (Recip AB, Stockholm, Sweden). Each tablet contained 720 mg of amino acids, including 45 mg histidine, 60 mg isoleucine, 90 mg leucine, 65 mg lysine, 90 mg methionine, 70 mg phenylalanine, 65 mg threonine, 25 mg tryptophan, 135 mg valine, and 75 mg L-tyrosine. This preparation was designed with specific reference to the abnormal serum amino acid profile found in chronic renal patients, namely elevated levels of many of the nonessential amino acids and depressed levels of most of the EAAs, as well as L-tyrosine. 12 As in the compliance period, each pill bottle contained more tablets than required for maximal compliance.

Laboratory Measurements On a monthly basis, blood chemistries were routinely taken in the dialysis units. Both dialysis units used the same dialysis provider (Gambro Healthcare) and followed identical laboratory monitoring procedures. The same central laboratory analyzed all blood tests from the 2 dialysis units and laboratory tests analyzed elsewhere were excluded from the primary analysis. Serum albumin was assayed using the bromocresol green method. Dialysis adequacy was quantitated using the urea reduction ratio (UPdL), and Kt/V was estimated by single-pool urea kinetic modeling. 13 The normalized protein nitrogen appearance (nPNA) was also calculated by using the urea kinetic model. C-reactive protein (C1LP) levels were measured at months 0, 2, 3, and 4 by nephelemetery.

Dietary and Clinical Measurements During the first and last weeks of the study, patients recorded their dietary intake for 2 days. An experienced renal dietitian collected, reviewed, and analyzed these data using Nutritionist IV software (First Data Bank, San Bruno, CA) to estimate the patients' protein and caloric in-

takes. Dietary intakes were indexed to body mass using the patients' actual postdialysis dry weight. Each month, the renal dietitian specifically questioned the subject regarding any adverse effects or complications possibly associated with the ingestion of the EAA supplement and measured their grip strength with a Jamar hydraulic dynamometer (Sammons Preston, Bolingbrook, IL) by using a standardized protocol. The patient's lowest postdialysis weight was determined by the lowest weight achieved on the day of the monthly blood drawing or from either of the previous 2 dialysis treatments. This weight was defined as the patient's weight at the time of leaving the dialysis unit and after the administration of all intravenous fluids. The patients' primary nephrologist remained solely responsible for the clinical treatment of the patient throughout the study period.

Patient Consent and Compensation Study participants were compensated for their time and commitment to the study, and received $5 for the return of both the monthly pill bottle and calendar, and $10 for each of the 2-day dietary recalls. Compensation was available independent of the actual degree of compliance with the EAA tablets or the completeness of the study calendar. The Institutional Review Board of both participating hospitals reviewed the study, and informed written consent was obtained from each patient by a study investigator other than the patient's primary nephrologist.

Outcome Measures The primary study outcome measures were compliance with intervention over the 4-month study period as assessed by returned pill bottle weights and the change in mean serum albumin. Change in mean serum albumin was calculated as the mean follow-up serum albumin levels (mean of the serum albumin levels measured at day 30, day 60, day 90, and day 120 after the start of therapy) compared with the mean baseline serum albumin levels (mean of the serum albumin levels measured at day - 9 0 , day - 6 0 , day - 3 0 , and day 0 before therapy). If a serum albumin level was not available, the mean of the available levels from previous tests was used. For the other examined variables, values at study entry were compared with those at month 4, or with the last available result.

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ORAL EEA THERAPY IN DIALYSIS HYPOALBUMINEMIA

Statistical Analysis The internal consistency of the data was examined by using time-trend analysis. Outlying values for each variable were identified using box and whisker plots, and their accuracy was verified by comparison with the original clinical record. The normality of each distribution was assessed with the Shapiro-Wilk test and with quartilequartile plots. Continuous variables were summarized by using the mean and the 95% CI (if normally distributed), or otherwise by the use o f the median and range. Paired data from the start and finish of the study were compared by using the nonparametric Wilcoxon signed-rank test. Correlations were examined by using the nonparametric Spearman rank correlation. All analyses were performed by using SPSS Base 7.5 (SPSS, Chicago, IL), and a 2-tailed type I error rate o f 0.05.

Results Patient Demographics The 18 subjects had a mean age of 61.3 (SD, 11.7) years. Ten (56%) were female, 14 were black (78%), and the remaining subjects were white. The median duration o f end-stage renal disease was 12.3 months (intraquartile range, 63 months) and the attributed causes of renal failure were diabetes (44%), hypertensive nephrosclerosis (22.2%), human immunodeficiency virus (HIV)-associated nephropathy (17%), and miscellaneous causes (16.4%). One additional patient had diabetes, although this was not the cause o f kidney failure. Five patients (27.8%) suffered

from hepatitis C, 1 of whom also had hepatitis B; however, none of these patients had clinical evidence of cirrhosis. The median duration since last hospitalization was 5.5 months (range, 1.4 to 24 months). O f the 14 patients who had sustained an infection since the start of dialysis, the median duration since last infection was 3.2 months (range, 1.1 to 26.3 months).

Dialysis Prescription Fifteen patients (83%) used polysulfone dialysis membranes, 2 patients (11.1%) used substituted cellulose membranes, and 1 patient (5.6%) used a polyacrylonitrile membrane. Dialyzer reuse was practiced in 1 dialysis unit, with a maximum of 12 reuses. Sixteen patients (88.9%) used an arteriovenous dialysis access, with the remaining 2 patients using a dual lumen cuffed catheter. The median blood flow rate through the arteriovenous accesses was 450 mL/min (range, 300 to 500). The median prescribed dialysis time was 4 hours, and only 4 subjects were prescribed less than 3.5 hours o f dialysis.

Baseline Measurement As shown in Table 1, the baseline mean serum albumin level (mean of the serum albumin levels measured at day - 9 0 , day - 6 0 , day - 3 0 , and day 0 before therapy) was 3.57 g / d E The population underwent dialysis with a mean UI~R of 69.0%, and a Kt/V of 1.39. The median body mass index (BMI) was 24.6 k g / m 2 (range, 17.4 to 44.9), and 6 patients had a BMI of <21 kg/m 2. The spontaneous dietary protein intake, measured by dietary recall and by nPNA, was 0.90

Table 1. Baseline Laboratory and 2-Day Dietary Recall Results

Baseline serum albumin*g/dL Serum bicarbonate, mmol/L Serum urea nitrogen, mg/dL Serum creatinine, mg/dL Serum phosphate, mg/dL CRP, mg/dL URR, % Kt/V nPNA, g/kg/d Protein intake, g/d Total energy intake, kcal/d Protein intake, g/kg/dl Total energy intake, kcal/kg/dt

Mean (SD)

Median

Range

3.57 (0.19) 19.9 (4.5) 56.9 (13.9) 9.1 (3.3) 5.0 (1.3) 1.75 (1.57) 69.0 (6.2) 1.39 (0.23) 1.02 (0.19) 61.3 (18.7) 1434.1 (439.1) 0.90 (0.4) 20.3 (8.3)

3.59 20 56.5 8.6 5.0 0.95 69.8 1.37 1.06 61.4 1424.9 0.86 18.7

3.18-3.9 14-29 35-75 4.6-16.1 2.47-7.93 0.50-5.40 56.6-79.3 1.05-1.89 0.58-1.29 27.6, 91.5 726-2306 0.28, 1.61 9.8, 40.1

*Mean of the serum albumin levels measured at day -90, day -60, day -30, and day 0 before therapy. 1"Actual postdialysis body weight.

BRONICH ET AL

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g / k g / d and 1.02, respectively, and the estimated daily energy intake was 20.6 kcal/kg/d.

Compliance Compliance was well maintained throughout the study period, with median compliance rates at months 1 through 4 o f 86%, 88%, 82%, and 82%, respectively (Fig 1). The overall median compliance was 82%, with an intraquartile range of 22%. Forty-four percent of patients had overall median compliance rates of >90%, and 78% o f patients had at least a 70% compliance rate. Only 1 patient had a consistently poor compliance rate of <25% throughout the entire study period.

Change in Serum Albumin and ClIP There was a marked improvement in serum albumin levels, especially during the first 2 months of therapy (Fig 2). The mean 3-month 4°0 3.9 3.8

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serum albumin level was lower than either the 2-1nonth or 4-month value, in part because of a substantial drop in serum albumin level in 1 subject who developed an ischemic foot complicated by fatal septicemia during the third month of the study. As shown in Fig 3, the mean follow-up (+30, +60, +90, +120 day) serum albumin level improved, compared with the mean baseline ( - 9 0 , - 6 0 , - 3 0 , 0 day) serum albumin level in 14 o f the 18 subjects. Similarly, the mean serum albumin level improved significantly from baseline to follow-up with a mean increase of 0.2 g/dL (95% CI, 0.10 to 0.30; P = .001) (Table 2). There was no significant difference between the change in serum albumin level in those patients with hepatitis, HIV, or diabetes and those without. Over the course of the study, CRP levels increased in 6 patients (33%), remained unchanged in 2 patients (11%), and decreased in 10 patients (56%). The change in albumin in the 2 patients, whose CRP levels remained unchanged, was 0.2 and 0.4 g/dL. There was no significant correlation between the change in CP, P and the change in serum albumin (r = .33, P = .18).

Dietary and Clinical Outcomes The provision o f the study supplement was not accompanied by a decrease in the spontaneous dietary intake of either protein or energy. The

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O R A L EEA T H E R A P Y I N D I A L Y S I S H Y P O A L B U M I N E M I A

Table 2. Change in Laboratory and Clinical Parameters at Follow-up Compared with Baseline

Change in albumin, g/dL* Change in serum bicarbonate, mmol/L Change in serum creatinine, mg/dL Change in BUN, mg/dL Change in potassium, mEq/L Change in URR, % Change in KW Change in nPNA, g/kg/d Change in lowest postdialysis weight, kg Change in grip strength, kg force Change in total energy intake, kcal/d-iChange in protein intake, g/diChange in total energy intake, kcal/kg:~/dlChange in protein intake, g/kg:~/dl-

Mean

95% CI

P

0.20 -0.5 -0.22 1.0 0.02 0.04 0.05 0.02 2.55 1.07 123.0 2.6 1.24 0.00

0.1, 0.30 -1.9, 0.87 -0.95, 0.52 -6.8, 8.8 -0.25, 0.29 -0.01, 0.09 -0.17, 0.06 -0.06, 0.10 0.00, 5.1 -1.23, 3.38 -114.8, 360.7 -5.8, 11.0 -2.45, 4.92 -0.13, 0.12

.001 NS NS NS NS NS NS NS .05 NS NS NS NS NS

Abbreviations: NS, not significant. *Mean (-90, -60, -30, and 0 days prerandomization). 1-Excluding study supplement. :[:Actual postdialysis body weight.

mean change in daily protein and energy intake from the start to the end of the study was not significant at 0.00 g / k g / d (95% CI, - 0 . 1 3 to 0.12) and 1.6 kcal/kg/d (95% CI, - 2 . 1 to 5.3), respectively. There was a weak trend toward a negative correlation between change in protein intake and change in serum albumin (r = - . 4 6 , P = .08) (Fig 4). Over the 4-month study period, the lowest achieved postdialysis weight and mean BMI increased by 2.6 kg (95% CI, 0.0 to 5.1) and 0.97 k g / m 2 (95% CI, 0.0 to 1.9), respectively (both P = .05). The mean change in BMI for the 6 patients whose initial BMI was <21 kg/m 2 was

1.8 kg/m 2, compared with 0.5 kg/m 2 for the remaining subjects (P = .19). In a post hoc analysis, the mean o f the average monthly change in lowest postdialysis weight per subject was 0.65 (95% CI, - 0 . 0 3 to 1.3; P = .06). The mean change in grip strength increased by 1.07 (95% CI, - 1 . 2 3 to 3.38; p = .34). As previously mentioned, 1 patient died before the 4-month evaluation as a result of septicemia. The only observed or reported potential side effect o f treatment was mild intermittent dyspepsia in 1 patient who, nevertheless, completed the study with an overall compliance rate of 94%.

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BRONICH ET AL

Discussion Several studies have reported a strong negative association between hypoalbuminemia and dialysis morbidity and mortality rates. 1-6 As shown by Lowrie et al I in a study of over 12,000 patients, the relative risk o f death increased 18-fold in patients with serum albumin levels <2.5 g/dL compared with those who had serum albumin levels in the 4.0 to 4.5 g/dL range. Even more importantly, the relative risk of death increased more than 2-fold in patients with serum albumin levels at 3.5 to 4.0 g/dL, which is the serum albumin level for more than 50% of the prevalent dialysis population. 1 Furthermore, Owen et al2 found serum albumin levels to be the single most powerful predictor o f patient survival, with a 0.2 g/dL decrease in serum albumin levels associated with a 25% decrease in survival. Given this strong association between hypoalbuminemia and patient outcomes, together with the high prevalence o f hemodialysis patients with low or lowto-normal serum albumin levels, an intervention that successfully improves serum albumin levels may exert substantial effects on overall patient health and survival. Although our earlier randomized placebo-controlled trial conf~med the efficacy of oral EAA supplementation, it was limited by a progressive decline in compliance. In the current study, the compliance rate was both improved and better maintained than the initial trial. This compliance rate was achieved through a reduction in the number of tablets prescribed and through a focused compliance program provided by an interdisciplinary team. The renal dietitian, the patient care technician, and the renal fellow regularly reinforced compliance and encouraged patients to return their pill bottles and to complete their calendars and dietary recalls. Although this degree of reinforcement is clearly impractical on a daily clinical basis, it should be possible in most formal research studies. These results support the feasibility of using such a protocol to examine the efficacy of EAA supplementation in a larger randomized trial. Our study subjects received financial reimbursement to help offset their time commitment for study-related activities (such as completing the study calendars and the 2-day dietary recalls); however, the level of reimbursement was completely independent of the degree of compliance. Although the reimbursement may have assisted in subject recruitment, we do not

believe that it played a substantial role in maintaining compliance. The 2-day dietary recalls estimated mean daily intakes of 0.90 g of protein/kg and 20.6 kcal/kg. These results are substantially below the National Kidney Foundation nutritional guidelines of 1.2 g of protein/kg/d and 35 kcal/kg/dfl 4 Similar suboptimal nutritional intakes have been reported in numerous studies of hemodialysis patients. 15-18 These findings illustrate the difficulty that hemodialysis patients have, especially if anorexic, in meeting their prescribed dietary requirements despite the extensive efforts of renal dietitians. Although oral protein-based supplementation is frequently used as a means to improve albumin, EAA tablets have the potential advantage of improving nitrogen balance without providing additional, possibly toxic, protein degradation products. Although the potential benefits of EAA and protein-based preparations have long been recognized, 19"2° the perception of oral EAA therapy as being poorly tolerated appears to have limited their widespread use. However, both our current study and our recent randomized trial show that, at least with the formulation used in our study, EAA preparations are well tolerated. The improved and relatively stable compliance observed over the 4-month study period makes this modified intervention much more suitable for use in a larger scale clinical trial than the 15-tablet-per-day protocol used in our original trial. In addition, the mean changes in serum albumin seen in the 2 studies, 0.20 (95% CI, 0.10 to 0.30) and 0.22 g/dL (95% CI, 0.03 to 0.40), are clearly comparable and support the potential benefits of EAA therapy. Our current study suffers from several important limitations. By virtue of its uncontrolled design, we cannot establish to what degree other secular trends may have influenced the observed improvements in serum albumin. However, in an attempt to limit such confounders, and especially the influence of regression to the mean, we required our subjects to have persistently low or low-to-normal mean serum albumin levels over the 3 months before to study entry, and we used the mean of the albumin level at study entry and during the previous 3 months to define the baseline level for our primary analysis. Although some regression to the mean effect may still be present despite these measures, we suspect that its magnitude is likely to be small and doubt that it can explain the majority of the observed beneficial effects of treatment. In addition, the improvements

ORAL EEA THERAPY IN DIALYSIS HYPOALBUMINEMIA

in a l b u m i n did n o t correlate w i t h changes in the patients' inflammatory status, as s h o w n b y the absence o f any correlation b e t w e e n the change in serum a l b u m i n and the change in C R P levels, and w e did n o t identify any significant change in the patients' dialysis dose, spontaneous oral intake, or acid base status over the course o f the study. M o r e over, having s h o w n the efficacy o f oral E A A supplements in o u r earlier placebo-controlled r a n d o m ized trial, la o u r primary objective i n this study was to e x a m i n e compliance and any associated change i n s e r u m a l b u m i n w i t h a m o d i f i e d treatment regimen. Because all o f o u r patients w e r e r e q u i r e d to have stable h y p o a l b u m i n e m i a for the 3 - m o n t h p e r i o d before e n t e r i n g the study, a n d because patients w i t h r e c e n t infections o r hospitalizations w e r e excluded, it is likely that the u n d e r l y i n g cause o f h y p o a l b u m i n e m i a is related m o r e to decreased oral intakes, as e v i d e n c e d i n the p a tients' dietary recalls, t h a n it is to u n d e r l y i n g i n f l a m m a t i o n . W h e t h e r similar i m p r o v e m e n t s w i t h the m o d i f i e d p r o t o c o l w o u l d be seen i n a p o p u l a t i o n w i t h greater degrees o f i n f l a m m a t i o n remains undetermined. Although muscle function, w h i c h was assessed b y grip strength, i m p r o v e d d u r i n g the course o f the study, this i m p r o v e m e n t was n o t statistically significant. T h e l i m i t e d d u r a t i o n a n d sample size o f o u r study m a y have resulted i n o u r failure to detect a significant change. I n addition, b o t h o u r p r e v i o u s a n d o u r c u r r e n t study o n l y address changes i n s e r u m alb u m i n , a surrogate m a r k e r for p a t i e n t o u t c o m e s . I m p r o v i n g dietary intake a n d m a i n t a i n i n g a n e u t r a l n i t r o g e n balance is a c o n s t a n t challenge for renal dietitians. O r a l E A A t h e r a p y holds p o tential as a safe, w e l l tolerated, a n d relatively i n e x p e n s i v e m e t h o d to correct h y p o a l b u m i n e m i a a n d to i m p r o v e b o t h n i t r o g e n balance a n d o u t c o m e s i n a n o r e x i c dialysis patients. It has p o t e n tial advantages i n c o m p a r i s o n w i t h the use o f p r o t e i n - b a s e d supplements. T h e degree to w h i c h this p o t e n t i a l will b e realized r e m a i n s to b e established i n a n appropriately p o w e r e d r a n d o m ized p l a c e b o - c o n t r o l l e d trial.

Acknowledgment The authors thank Dr Josef Coresh, Dr Paul Scheel, Dr Gary Briefel, Professor Mackensie Walser, the staff of the Gambro Healthcare J. B. Zachary dialysis unit, and the Bond St. dialysis unit, Baltimore, MD for their advice and assistance in the conduct of this study.

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