Intradialytic Oral Nutrition Improves Protein Homeostasis in Chronic Hemodialysis Patients with Deranged Nutritional Status
Lara B. Pupim*,,
Karen M. Majchrzak*,
Paul J. Flakolla and
T. Alp Ikizler*
* Department of Medicine, Division of Nephrology, Vanderbilt University Medical Center, Nashville, Tennessee; and General Medicine Therapeutic Area, Nephrology, Amgen Inc., Thousand Oaks, California
Address correspondence to: Dr. T. Alp Ikizler, Vanderbilt University Medical Center, 1161 21st Avenue South & Garland, Division of Nephrology, S-3223 MCN, Nashville, TN 37232-2372. Phone: 615-343-6104; Fax: 615-343-7156; alp.ikizler{at}vanderbilt.edu
Received for publication April 28, 2006.
Accepted for publication August 21, 2006.
Decreased dietary protein intake and hemodialysis (HD)-associatedprotein catabolism predispose chronic HD (CHD) patients to derangednutritional status, which is associated with poor clinical outcomein this population. Intradialytic parenteral nutrition (IDPN)reverses the net negative whole-body and skeletal muscle proteinbalance during HD. IDPN is costly and restricted by Medicareand other payers. Oral supplementation (PO) is a more promising,physiologic, and affordable intervention in CHD patients. Proteinturnover studies were performed by primed-constant infusionof l-(1-13C) leucine and l-(ring-2H5) phenylalanine in eightCHD patients with deranged nutritional status before, during,and after HD on three separate occasions: (1) with IDPN infusion,(2) with PO administration, and (3) with no intervention (control).Results showed highly positive whole-body net balance duringHD for both IDPN and PO (4.43 ± 0.7 and 5.71 ±1.2 mg/kg fat-free mass per min, respectively), compared witha neutral balance with control (0.25 ± 0.5 mg/kg fat-freemass per min; P = 0.002 and <0.001 for IDPN versus controland PO versus control, respectively). Skeletal muscle proteinhomeostasis during HD also improved with both IDPN and PO (50± 19 and 42 ± 17 µg/100 ml per min) versuscontrol (–27 ± 13 µg/100 ml per min; P =0.005 and 0.009 for IDPN versus control and PO versus control,respectively). PO resulted in persistent anabolic benefits inthe post-HD phase for muscle protein metabolism, when anabolicbenefits of IDPN dissipated (–53 ± 25 µg/100ml per min for control, 47 ± 41 µg/100 ml per minfor PO [P = 0.039 versus control], and –53 ± 24µg/100 ml per min for IDPN [P = 1.000 versus control and0.039 versus PO]). Long-term studies using intradialytic oralsupplementation are needed for CHD patients with deranged nutritionalstatus.
Poor nutritional status and muscle wasting are common in patientswith ESRD and are associated with increased hospitalizationand death (1,2). Among the many different causes that are associatedwith altered nutritional status in ESRD, the hemodialysis (HD)procedure has been associated clearly with net whole-body (WB)protein and skeletal muscle (SM) protein loss (3). This catabolicprocess can be reversed acutely by administration of intradialyticparenteral nutrition (IDPN) (4). Despite its shown anaboliceffects, IDPN administration is costly, and patient eligibilityfor this type of nutrition support is widely restricted. Inaddition, the anabolic effects of IDPN seem to be limited tothe period of administration, with no evidence of persistentanabolism once its infusion is shut off (4).
Oral nutritional supplementation (PO) is a promising anabolicintervention in chronic HD (CHD) patients because of its potentiallymore physiologic and affordable characteristics. Despite itspotential benefits, only limited studies have evaluated theeffects of intradialytic PO administration on protein metabolismin CHD patients, and none to our knowledge has compared itsmetabolic effects with those of IDPN in CHD patients with derangednutritional status.
In this study, we hypothesized that administration of intradialyticPO supplementation would compensate WB and SM protein derangementsas a result of the HD procedure, resulting in net protein anabolism.We further hypothesized that these beneficial effects wouldbe less than what is observed with IDPN administration. To testthese hypotheses, we studied protein metabolism in eight CHDpatients with deranged nutritional status during three separateHD sessions—with PO, with IDPN, and with no intervention(control)—using stable isotope infusion techniques.
Patients
Patients were recruited from the Vanderbilt University OutpatientDialysis Unit. Inclusion criteria consisted of patients whowere on CHD for >6 mo, were using a biocompatible HD membrane(Fresenius F80; Fresenius USA, Lexington, MA), had double-poolKt/V 1.4, were on a thrice-weekly HD program, and had signsof deranged nutrition status, as defined by levels of severalserum proteins below National Kidney Foundation Kidney DiseaseOutcomes Quality Initiative (K/DOQI) Nutritional Guidelinesrecommended targets, including serum albumin <4 g/dl, serumprealbumin <30 mg/dl, cholesterol <150 mg/dl, and serumtransferrin <150 mg/dl for 3 consecutive months before enrollment.b
Active infectious disease, hospitalization within the last3 mo, recirculation in the vascular access and/or vascular accessblood flow <750 ml/min, and use of steroids and/or immunosuppressiveagents were exclusion criteria. The Institutional Review Boardof Vanderbilt University approved the study protocol, and writteninformed consent was obtained from all study patients. Patientcharacteristics are shown in Tables 1 and 2.
Table 2. Biochemical parameters of the study population (n = 8)a
Design
This was a randomized, prospective, crossover study. After writteninformed consent was obtained and the inclusion and exclusioncriteria were reviewed, eligible patients were assigned a randomcomputer-generated sequence of study protocols that includedIDPN, control, and PO combinations. All patients who participatedin this study were randomly assigned and participated in allprotocols, with at least 4 wk between each study, to allow fortotal clearance of the stable isotopes. Within 1 wk before eachstudy, dual-energy x-ray absorptiometry was performed to estimatelean and fat body masses.
The patients were admitted to the General Clinical ResearchCenter (GCRC) the day before the study at approximately 7 p.m.,received a meal from the GCRC bionutrition services upon admission,and remained fasting after that. The last meal was given atleast 10 h before the initiation of the study for all patientsand consisted of 18% protein and 30% lipids. Energy intake waskept at maintenance levels on the basis of the Harris-Benedictequation and each patient’s gender, height, weight, andactivity levels.
A schematic diagram of the metabolic study day protocol is depictedin Figure 1. Each metabolic study consisted of a pre-HD phase(a 2-h equilibration phase followed by a 0.5-h basal samplingphase), a 4-h HD phase, and a 2-h post-HD phase. A dialysiscatheter was placed at the venous site of the arteriovenous(AV) shunt of the forearm at 6 a.m. to collect a baseline bloodsample (to assess baseline biochemical nutritional markers andisotopic backgrounds) and then to initiate the isotope infusion.Arterial vascular access that was obtained through the arterialside of the AV shunt was used to perform HD and to sample arterialblood. The venous site of the AV shunt was used to infuse theisotopes. Another catheter was placed in a deep vein (with aretrograde insertion) of the contralateral forearm to sampleblood draining the forearm muscle bed. At the start of the infusion,patients received a bolus injection of NaH13CO3 (0.12 mg/kg),l-(1-13C) leucine (7.2 µmol/kg), and l-(ring-2H5) phenylalanine(7.2 µmol/kg) to prime the CO2, leucine, and phenylalaninepools, respectively. A continuous infusion of leucine (0.12µmol/kg per min) and phenylalanine (0.12 µmol/kgper min) isotopes then was started and continued throughoutthe remainder of the study. Constant infusion of isotopes continuedthroughout the study. Blood samples were collected once beforethe start of the study, three times during the basal samplingphase, six times during HD, and three times during the post-HDphase. Simultaneous with each blood sample, breath samples werecollected from the patients via a Douglas bag with duplicate20-ml samples placed into nonsiliconized glass Vacutainer tubesfor measurement of breath 13CO2 enrichment. Patients were askedto breathe through a mask for 1 min each time blood was collected.In addition, forearm blood flow was estimated using capacitanceplethysmography (D.E. Hokanson, Inc., Bellevue, WA).
Figure 1. Metabolic study day protocol. Arrowheads denote time points for blood draws, breath sample collections, and muscle plasma flow measurements. A primed-constant infusion of l-(1-13C) leucine and l-(ring-2H5) phenylalanine was maintained throughout the entire study (510 min).
In the protocol using IDPN, its administration was started 30min after HD initiation and continued through the end of HD.Administration of PO was divided into three equal doses; thefirst dose was administered 30 min after the start of HD, thesecond dose was administered 1.5 h after the start of HD, andthe third dose was administered 2.5 h after HD was initiated.During the control protocol, no nutrition was given throughoutthe study. The IDPN treatment was based on existing recommendations(8). The solution consisted of amino acids (AA) at a concentrationof 15%, dextrose at a concentration of 50%, and lipids at aconcentration of 20%. The AA and dextrose solutions were infusedat a rate of 113 ml/h, and the lipids solution was infused ata rate of 37 ml/h, delivering approximately 525 ml and 188 kcal/h,and consisted of 59 g of AA, 26 g of lipids, and 197 g of carbohydrates.Intradialytic PO supplementation was designed in attempts tomatch the volume and protein content provided with IDPN, consistingof two cans of a specialized complete nutrition for electrolyteand fluid restrictions (NEPRO, Ross Products Division, AbbottLaboratories Inc., Columbus, OH) with the addition of 5 spoonsof powder protein (PROMOD, Ross Products Division) to prescribethe same protein amount provided by IDPN. The PO mixture contained474 ml and 1090 kcal and consisted of 57 g of AA, 48 g of lipids,and 109 g of carbohydrates. During the control study, no nutritionalsupplementation was given.
The following were the composition of essential AA providedwith IDPN and PO in grams, respectively: isoleucine (2.962 and3.011), leucine (4.113 and 5.754), valine (3.797 and 3.459),lysine (4.667 and 4.815), phenylalanine (4.113 and 2.560), histidine(3.536 and 1.305), methionine (2.962 and 1.513), threonine (2.962and 3.286), and tryptophan (0.989 and 0.873). Isoleucine, leucine,and valine are branched-chain AA (BCAA).
During each study, patients were dialyzed for 4 h with bloodflow of 400 ml/min and dialysate flow of 500 ml/min. Ultrafiltrationrates were determined by the patients’ needs and estimateddry weight and were similar during all studies. The compositionof the dialysate used during the study was identical for alltreatments and consisted of 139 mEq/L sodium, 2 mEq/L potassium,2.5 mEq/L calcium, 200 mg/dl glucose, and 39 mEq/L bicarbonate.Once HD was finished, dialysis lines were disconnected and the2-h post-HD phase ensued. After the post-HD phase, all catheterswere removed, and the patients were given a meal and observedat the GCRC until stable, upon which they were discharged.
Analytical Procedures
Blood samples were collected into Venoject tubes that contained15 mg of Na2EDTA (Terumo Medical Corp., Elkton, MD). All analyticalprocedures, including nutritional biochemical markers, wereperformed as described previously (3,4). Individual AA wereplaced into groups for analysis purposes. These groups includedessential AA (EAA; the sum of arginine, histidine, isoleucine,leucine, lysine, methionine, phenylalanine, threonine, tryptophan,and valine), total AA (TAA; the sum of all individual AA), andnonessential AA (NEAA; the difference between TAA and EAA).
Plasma enrichments of (13C) leucine, (13C)ketoisocaproate, and(ring-2H5) phenylalanine were determined using gas chromatography/massspectrometry (Hewlett-Packard 5890a GC and 5970 MS, San Fernando,CA), as described previously (3,4). The plasma enrichments of(ring-2H5) phenylalanine and, therefore, the muscle calculationswere available for only six of the eight studied patients.
Calculations
Net SM protein balance (synthesis – breakdown) was determinedby dilution and enrichment of phenylalanine across the forearmas described by Gelfand and Barrett (9) and as previously reported(3,4). The steady-state rates of total WB leucine appearance(Ra) were calculated by dividing the (13C)leucine infusion rateby the plasma (13C)ketoisocaproate enrichment (10) as describedpreviously (3,4).
Statistical Analyses
For each protocol, mean variables across all time points foreach study phase (before, during, and after HD) were averagedto represent each study phase average per patient. Values thatare presented in the text and figures are means ± SEM,unless otherwise noted. The goal of this study was to comparethe two modes of nutritional supplementation (IDPN and PO) withno intervention (control) at each study phase separately, ratherthan to examine time trends for each variable and their interactionthroughout the study phases. Therefore, for comparisons of variablesamong study protocols at each study phase, a general linearmodel ANOVA was performed, selecting study protocol as a fixedfactor and repeated contrast. Post hoc analyses of multiplecomparisons were completed by using the least significant differencetest, which is the equivalent to multiple t test between allpaired groups. Comparisons of baseline biochemical variablesamong the three groups were completed by a one-way ANOVA test.P < 0.05 was required to reject the null hypothesis of nodifference between the means. The software SPSS (version 14;SPSS Inc., Chicago, IL) was used for all analyses.
Blood Chemistries Table 2 depicts baseline biochemical nutritional markers forthe three study protocols: control, PO, and IDPN. As can beseen, these measurements were similar among the protocols, andthere were no statistical differences. As suggested by the biochemicalmarkers in Table 2, the population studied was in an overallderanged nutritional status. Measurement of pre- and post-HDblood chemistries, including BUN, showed expected changes afterHD treatment without any significant difference among the threeHD sessions within patients (data not shown).
Glucose and Metabolic Hormones Table 3 shows the results for glucose and metabolic hormonesfor the three study protocols. In the pre-HD phase, there wereno statistically significant differences in glucose or any ofthe metabolic hormones among protocols. During HD, plasma insulinconcentrations were significantly higher with both PO and IDPNcompared with control (P = 0.027 for IDPN versus control and0.001 for PO versus control). Insulin concentration remainedsignificantly elevated in the post-HD phase for the PO protocolbut not for the IDPN protocol, compared with control (P = 0.008and 0.590, respectively). As a result, insulin levels were statisticallysignificantly higher when PO and IDPN protocols were comparedin the post-HD phase (P = 0.025). Plasma glucose levels weresignificantly higher during HD for IDPN and PO compared withcontrol although at a higher extent with IDPN (P < 0.001and 0.037, respectively). In the post-HD phase, glucose levelsremained significantly higher in the PO protocol compared withIDPN and control (P = 0.002 and 0.007, respectively), but glucoselevels were not different between IDPN and control. There wereno statistically significant differences among protocols inany of the other metabolic hormones throughout the entire studyperiod.
Table 3. Plasma metabolic hormones and glucose concentrationsa
Plasma AA
There were no statistically significant differences among studyprotocols during the pre-HD phase for all plasma AA concentrations.Specifically, pre-HD plasma AA concentrations by functionalgroups for control, IDPN, and PO, respectively, were as follows:BCAA 313 ± 26 µmol/L, 353 ± 26 µmol/L,347 ± 28 µmol/L (P = 0.288 for IDPN versus controland 0.384 for PO versus); EAA 794 ± 52 µmol/L,834 ± 52 µmol/L, 849 ± 55 µmol/L (P= 0.595 for IDPN versus control and 0.478 for PO versus control);NEAA 1278 ± 75 µmol/L, 1364 ± 75 µmol/L,1314 ± 80 µmol/L (P = 0.427 for IDPN versus controland 0.743 for PO versus control); TAA 2072 ± 92 µmol/L,2197 ± 92 µmol/L, 2163 ± 99 µmol/L(P = 0.344 for IDPN versus control and 0.503 for PO versus control.However, plasma concentrations of all groups of AA were significantlyhigher during HD for both IDPN and PO compared with control(P < 0.001 for all comparisons), as shown in Figure 2. Thedifferences between IDPN and PO were numerically but not statisticallysignificantly higher for IDPN than PO for BCAA (P = 0.072),EAA (P = 0.067), and NEAA (P = 0.065) and were statisticallysignificantly higher only for the TAA group (P = 0.001). Duringthe post-HD phase, the concentrations of all groups of AA weresignificantly higher in the PO protocol compared with both controland IDPN. Specifically, the post-HD plasma concentrations ofthe grouped AA for control, IDPN, and PO were, respectively,as follows: BCAA 270 ± 31 µmol/L, 349 ±31 µmol/L, 585 ± 31 µmol/L (P 0.001 forPO versus control and <0.001 for PO versus IDPN); EAA 664± 59 µmol/L, 858 ± 59 µmol/L, 1230± 59 µmol/L (P < 0.001 for PO versus controland <0.001 for PO versus IDPN); NEAA 996 ± 66 µmol/L,1158 ± 66 µmol/L, 1500 ± 110 µmol/L(P < 0.001 for PO versus control and 0.002 for PO versusIDPN); TAA 1661 ± 110 µmol/L, 2017 ± 110µmol/L, 2730 ± 110 µmol/L (P < 0.001 forPO versus control and <0.001 for PO versus IDPN).
Figure 2. Total plasma amino acid concentrations by functional groups during hemodialysis (HD), comparing control (), intradialytic parenteral nutrition (IDPN;
), and oral supplementation (PO; ). Units are µmol/L. *P < 0.05 versus control; P < 0.05 versus IDPN. BCAA, branched-chain amino acids; EAA, essential amino acids; NEAA, nonessential amino acids; TAA, total amino acids.
Forearm AA Uptake Table 4 shows the forearm uptake of AA by functional groups.In the pre-HD phase, no statistically significant differenceswere observed among protocols for BCAA (P = 0.488 for both IDPNand PO versus control), EAA (P = 0.862 for IDPN versus controland 0.884 for PO versus control), NEAA (P = 0.537 for IDPN versuscontrol and 0.750 for PO versus control), and TAA (P = 0.538for IDPN versus control and P = 0.815 for PO versus control).During HD, however, forearm uptake of all grouped AA were significantlyimproved, changing from AA muscle loss to accretion, with bothPO and IDPN compared with control (BCAA [P = 0.004 for IDPNversus control and <0.001 for PO versus control], EAA [P= 0.001 for IDPN versus control and <0.001 for PO versuscontrol], NEAA [P < 0.001 for IDPN versus control and 0.001for PO versus control], and TAA [P < 0.001 for both IDPNand PO versus control]). The only significant difference betweenPO and IDPN was the functional group BCAA (P = 0.025). In thepost-HD phase, the benefits of IDPN, as compared with control,were dissipated (BCAA [P = 0.973], EAA [P = 0.699], NEAA [P= 0.570], and TAA [P = 0.484]), whereas the benefits of PO comparedwith both control and IDPN still were present for the uptakeof all grouped AA (BCAA [P = 0.001 for both PO versus controland PO versus IDPN], EAA [P < 0.001 for both PO versus controland PO versus IDPN], NEAA [P = 0.001 for PO versus control and<0.001 for PO versus IDPN], and TAA [P < 0.001 for bothPO versus control and PO versus IDPN]).
Table 4. Grouped amino acid uptake by the forearma
WB Protein Metabolism Table 5 shows the dynamic components of WB protein homeostasisfor the three study protocols at pre, during, and post-HD phases.In the pre-HD phase, there were no statistically significantdifferences among protocols for synthesis (P = 0.730 for IDPNversus control and 0.626 for PO versus control), proteolysis(P = 0.947 for IDPN versus control and 0.655 for PO versus control),and net balance (P = 0.662 for IDPN versus control and 0.722for PO versus control). Figure 3 depicts data during HD. Asseen, the infusion of IDPN and administration of PO during HDresulted in significantly higher protein synthesis comparedwith control (P = 0.012 for IDPN versus control and 0.001 forPO versus control). Whereas proteolysis was numerically lowerfor both IDPN and PO compared with control, it was only statisticallysignificantly lower, albeit slightly, for the IDPN versus controlcomparison (P = 0.040 for IDPN versus control and 0.218 forPO versus control). As a result, the net WB protein balancewas highly positive (anabolism) with both modes of nutritionsupport therapies as compared with control (P = 0.002 for IDPNversus control and <0.001 for PO versus control). In thepost-HD phase, protein synthesis remained statistically significantlyhigher, although slightly, for PO compared with both IDPN andcontrol (P = 0.012 for PO versus control and 0.022 for PO versusIDPN). In the post-HD phase, proteolysis also was higher forthe PO protocol compared with both IDPN and control, althoughthese differences did not reach statistical significance (P= 0.061 for PO versus control and 0.059 for PO versus IDPN).The net result therefore was a trend toward pre-HD values forboth control and IDPN protocols but not for PO, for which thenet balance was significantly more negative compared with controland IDPN (P = 0.012 for PO versus control and 0.039 for PO versusIDPN).
Figure 3. Whole-body (WB) protein homeostasis dynamic components during HD, comparing control (), IDPN (
), and PO (). Units are mg/kg fat-free mass per min. *P < 0.05 versus control; P < 0.05 versus IDPN.
Forearm Muscle Protein Metabolism Table 6 depicts the dynamic components of the forearm muscleprotein homeostasis. At baseline, there were no statisticallysignificant differences among the study protocols. During HD,muscle protein synthesis was only numerically higher for bothIDPN and PO compared with control (P = 0.445 and 0.543, respectively),but because these numerically higher rates exceeded the ratesof proteolysis, the net result was positive muscle protein metabolism(protein accretion) for both IDPN and PO compared with control(P = 0.005 for IDPN versus control and 0.009 for PO versus control;Figure 4). In the post-HD phase, the positive net balance persistedfor PO but not for IDPN, resulting in significant improvementsin the net forearm muscle balance for PO compared with bothcontrol and IDPN (P = 0.039 for both comparisons).
Figure 4. Forearm muscle protein homeostasis dynamic components during HD, comparing control (), IDPN (
), and PO (). Units are µg/100 ml per min. *P < 0.05 versus control.
Our study was designed to examine the effectiveness of oralnutritional supplementation that is administered during theHD procedure in a selected group of CHD patients with findingsof deranged nutritional status. Our results indicate that intradialyticPO supplementation is capable of reversing the HD-associatednet WB and SM protein catabolism. Our results further indicatethat PO administration is similarly effective to IDPN at maintaininga positive WB and SM net protein balance during HD, consistentwith our study hypothesis. Because these findings are observedin a group of high-risk CHD patients with deranged nutritionalstatus, they have potential clinical relevance and need to beconfirmed by long-term nutritional studies in this patient population.
Most patients with ESRD experience some degree of a complexsyndrome that includes low concentrations of serum proteinsand/or lean body mass loss and often is associated with increasedserum concentrations of inflammatory markers. This occurs despitepreventive methods such as adequate dosage of dialysis and intensenutritional counseling. The well-established link between signsof deranged nutritional status and increased risk for hospitalizationand death in CHD patients (11,12) necessitates nutritional interventionsabove and beyond these traditional preventive methods. We previouslyreported that IDPN is highly effective in reversing HD-associatedcatabolism, at least in the acute setting. Although the logicalextension of these studies would be a long-term clinical trialto examine the prolonged use of IDPN, such an approach is notattractive primarily because of certain logistical barriersthat are associated with the use of IDPN, at least in the UnitedStates. Specifically, IDPN is costly, and its prescription requiresovercoming major regulatory hurdles. Furthermore, there areindications that IDPN might be associated with certain adverseeffects such as nausea, hypoglycemia, and hyperlipidemia andthat its beneficial effect on protein turnover is limited tothe period in which it is being administered (13,14). Overall,these drawbacks decrease the enthusiasm for the use of IDPNin the long term and suggest that alternative approaches ofnutrition support and the treatment of deranged nutritionalstatus should be explored.
Several small-scale, short-term studies, including a few controlledtrials, indicate that oral nutritional supplementation administrationcan be an effective approach to preventing deranged nutritionalstatus (15–17). In addition, a few studies indicated benefitsof PO given during HD to treat the HD-associated protein catabolism(4,18). A study by Veeneman et al. (18) examined the effectsof feeding during HD on WB protein balance in a group of well-nourishedCHD patients. The feeding was in the form of yogurt, cream,and protein-enriched milk powder, given as six equal portionsduring the HD procedure as well as on a nondialysis day. Theirresults showed that consumption of a protein- and energy-enrichedmeal during HD resulted in a positive protein balance to thesame extent as on a nondialysis day. Of note, the investigatorsdid not examine SM protein balance in this study. Although ourresults are in general agreement with that of Veeneman et al.,our study further extends these findings to a target patientpopulation with deranged nutritional status and provides criticalinformation regarding the different components of WB proteinmetabolism, namely SM.
An additional novel aspect of our study is that we assessedthe relative protein metabolic effects of two modes of nutritionalsupport: PO and IDPN. Our results are consistent with our nullhypothesis, indicating that IDPN did not provide a significantlyhigher anabolic effect over intradialytic PO in reversing HD-associatedprotein catabolism, in both the WB and SM compartments. Furthermore,the beneficial effects of oral supplementation extended to thepost-HD period in the muscle compartment, providing an additionalpositive effect above and beyond of what is observed with IDPN.Taken together, these results strongly indicate that PO nutritionalsupplementation is an excellent strategy to prevent and potentiallytreat deranged nutritional status. When the financial advantagesof oral supplementation over IDPN are included in the finalanalysis, it is reasonable to suggest that PO supplementationwould be the treatment of choice for all CHD patients that requirenutritional intervention. Nonetheless, we acknowledge that ourfindings are from a small-scale metabolic study and as suchneed to be confirmed by long-term nutritional trials in theCHD population with deranged nutritional status. Furthermore,the results of this study may not be generalizable to nonblackCHD patients with low fat and lean body masses, because thesewere not characteristics of the population studied herein.
Our study clearly indicates that nutritional supplementation,administered either intravenously or orally, can compensateadequately for the catabolic effects of the HD procedure. Althoughwe did not specifically study the cellular and molecular mechanismsthat are associated with these responses, it is likely thatthe increased plasma concentrations of AA is one of the criticalcomponents that drive the positive protein balance as evidencedby increased plasma AA during IDPN and maintenance of AA levelsduring PO administration (19,20). Of note, these increases wereobserved despite potentially increased AA losses into the dialysate(21). However, studies that have examined nutrient supplementationunder many different conditions have demonstrated that muscleprotein stores are not determined by nutrient intake alone.Insulin action also plays an important role in controlling nutrientdeposition (22). Specifically, circulating insulin influencescarbohydrate homeostasis by altering muscle glucose transport(23,24) and utilization (25) and regulates protein dynamicsby stimulating AA transport, promoting WB and muscle proteinsynthesis, and inhibiting proteolysis (22). These effects areamplified when AA availability is increased simultaneously withinsulin (22). In our study, increased insulin concentrationand ample AA availability as a result of IDPN and PO decreasedWB proteolysis and increased WB protein synthesis, suggestingthat the effects likely are the result of both increased AAavailability and increased insulin action, at least in part.Another indication that insulin plays a critical role in themetabolic response that is associated with nutritional supplementationis that once the IDPN infusion was stopped, the insulin concentrationdecreased back to baseline values with a simultaneous reversalof the net protein balance to baseline levels, whereas insulinconcentrations remained elevated during the post-HD period inthe PO protocol with simultaneously increased SM net proteinbalance. However, the WB proteolysis also increased during thepost-HD period in the PO protocol without a clear explanation.It is possible that the characteristics of the patient populationstudied, such as deranged nutritional status, might have ledto certain unrecognized abnormalities in substrate metabolism.In addition, although speculative, it is possible that provisionof PO might have suppressed signaling for the production ofsome of the acute-phase reactants, which constitutes a significantportion of WB protein turnover. In any case, our results indicatethat PO provided clear benefits in the muscle protein homeostasiscompared with IDPN both during dialysis and postdialysis periods.
It also is important to note that in this study, oral and parenteralnutritional supplementations were not exactly matched for carbohydrate,lipid, and AA supplies. However, both protocols provided carbohydrateand lipid amounts well above the minimum level required foreach to provide any significant effect on protein metabolism.In these conditions, we believe that the differences in energysupplies would have little effect on protein metabolism. Similarly,there was minimal difference in the amount of EAA, includingBCAA, that was provided in the two nutritional regimens. Webelieve that these minimal differences were unlikely to haveaffected the results. This is consistent with the observationthat plasma EAA concentrations were not statistically significantlydifferent between IDPN and PO protocols.
The results of this study indicate that intradialytic PO supplementationis similarly effective as IDPN in preventing HD-associated netWB and SM protein catabolism and has the additional benefitof persistent anabolic effects in the SM after the HD procedureis complete. Because these findings were observed in a groupof high-risk CHD patients with deranged nutritional status,they have significant implications for the nephrology clinicalpractice. Further studies to examine both the mechanisms ofaction in different patient populations and long-term effectsof PO supplementation are warranted, specifically in CHD patients,who are at additional risk for mortality and morbidity, partlyas a result of deranged nutritional status.
Acknowledgments
This study is supported in part by National Institutes of Healthgrants R01-DK45604 and K24-DK62849, Clinical Nutrition ResearchUnit grant DK26657, GCRC grant M01-RR00095, and Diabetes ResearchTraining Center grant DK20593, Food and Drug Administrationgrant 000943, and Satellite Health Norman Coplon ExtramuralGrant Program.
We express our appreciation to the patients and staff of VanderbiltUniversity Medical Center, Outpatient Dialysis Unit, for participationin the study. The excellent technical assistance of PhyllisEgbert, Jennifer Gresham, Suzan Vaughan, Janice Harvell, MuZheng, Wanda Snead, and the nursing staff on the VanderbiltGCRC is appreciated. Lara B. Pupim has been an employee of Amgen,Inc., since August 2005 and declares no conflict of interestwith the work presented here.
Footnotes
Published online ahead of print. Publication date availableat www.jasn.org.
a Deceased.
b Several terminologies have been proposed for this complex syndromeof low visceral and/or somatic protein stores that are associatedor not with inflammatory response. These include uremic malnutrition(5), malnutrition inflammation atherosclerosis syndrome (6),malnutrition inflammation complex syndrome (7), and, more recently,kidney disease wasting (Denis Fouque, personal communication,Dénutrition des Maladies Chroniques Hpital, Lyon, France, April 27, 2006). Although aconsensus on terminology is yet to be achieved, the term derangednutritional status is used as reference in this article.
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Abstract
Introduction
1.4, were on a thrice-weekly HD program, and had signs of deranged nutrition status, as defined by levels of several serum proteins below National Kidney Foundation Kidney Disease Outcomes Quality Initiative (K/DOQI) Nutritional Guidelines recommended targets, including serum albumin <4 g/dl, serum prealbumin <30 mg/dl, cholesterol <150 mg/dl, and serum transferrin <150 mg/dl for 3 consecutive months before enrollment. b
Active infectious disease, hospitalization within the last 3 mo, recirculation in the vascular access and/or vascular access blood flow <750 ml/min, and use of steroids and/or immunosuppressive agents were exclusion criteria. The Institutional Review Board of Vanderbilt University approved the study protocol, and written informed consent was obtained from all study patients. Patient characteristics are shown in Tables 1 and 2. 
0.001 for PO versus control and <0.001 for PO versus IDPN); EAA 664 ± 59 µmol/L, 858 ± 59 µmol/L, 1230 ± 59 µmol/L (P < 0.001 for PO versus control and <0.001 for PO versus IDPN); NEAA 996 ± 66 µmol/L, 1158 ± 66 µmol/L, 1500 ± 110 µmol/L (P < 0.001 for PO versus control and 0.002 for PO versus IDPN); TAA 1661 ± 110 µmol/L, 2017 ± 110 µmol/L, 2730 ± 110 µmol/L (P < 0.001 for PO versus control and <0.001 for PO versus IDPN). 
pital, Lyon, France, April 27, 2006). Although a consensus on terminology is yet to be achieved, the term deranged nutritional status is used as reference in this article. 
), intradialytic parenteral nutrition (IDPN;
), and oral supplementation (PO; 
). Units are µmol/L. *P < 0.05 versus control; 
P < 0.05 versus IDPN. BCAA, branched-chain amino acids; EAA, essential amino acids; NEAA, nonessential amino acids; TAA, total amino acids.
