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Correction of Metabolic Acidosisto Ameliorate Wasting in Chronic

Kidney Disease: Goals and StrategiesYi-Wen Chiu, MD,* Joel D. Kopple, MD,†,‡,§ and Rajnish Mehrotra, MD†,‡

Summary: Metabolic acidosis is an important cause of protein-energy wasting, commonly ob-served in chronic kidney disease (CKD). This wasting is, in part, a result of the imbalance betweenprotein degradation and synthesis induced by metabolic acidosis. The increase in protein degra-dation seen with metabolic acidosis is largely secondary to increased activities of the adenosinetriphosphate–dependent, ubiquitin-proteasome system and branched-chain ketoacid dehydroge-nase. Studies consistently have shown increased protein degradation with lower serum bicarbon-ate levels and/or arterial pH; however, the evidence for the anti-anabolic effects of metabolicacidosis is less consistent. In contrast to these metabolic studies, many cross-sectional studies haveshown a direct relationship between the severity of metabolic acidosis and the adequacy ofnutritional status in CKD patients. Moreover, lower serum bicarbonate levels have been associatedwith better survival in some epidemiologic studies of patients undergoing maintenance hemodi-alysis. It is likely that these relationships are confounded by the direct association of dietaryprotein intakes with metabolic acidosis—controlling the survival data for measures of dietaryprotein intakes, malnutrition, and inflammation shows a rather steep increase in the risk of deathwith lower serum bicarbonate levels. Two randomized controlled studies have shown thatcorrection of metabolic acidosis is associated with reduction in risk for hospitalization in chronicperitoneal dialysis patients; the studies in maintenance hemodialysis patients have been small andinconsistent. For now, metabolic studies and data from clinical trials lend support to the recom-mendations made by the Nutrition Workgroup of the Kidney Disease Outcomes Quality Initiativeto maintain serum bicarbonate levels of 22 mEq/L or greater in all CKD patients. Limited datasuggest that a higher serum bicarbonate level (around 24 mEq/L) may be even more beneficial,particularly in chronic peritoneal dialysis patients.Semin Nephrol 29:67-74. © 2009 Published by Elsevier Inc.Keywords: Metabolic acidosis, protein-energy wasting, chronic kidney disease, dialysis

plbpamCCOndmsdac

etabolic acidosis frequently is presentin patients with chronic kidney disease(CKD) and has been associated with

everal complications of uremia.1,2 These com-

Division of Nephrology, Department of Internal Medicine, at KaohsiungMedical University Hospital, Kaohsiung, Taiwan.

Division of Nephrology and Hypertension, Los Angeles Biomedical ResearchInstitute at Harbor-UCLA Medical Center, Los Angeles, CA.

David Geffen School of Medicine at UCLA, Los Angeles, CA.

UCLA School of Public Health, Los Angles, CA.ajnish Mehrotra is supported by grants from the National Institutes of Health(RR18298), Satellite Health, and DaVita, Inc.; and has received researchsupport from Amgen, Baxter Health Care, and Shire, honoraria from BaxterHealth Care and Shire, and has served as a consultant for Novartis.

ddress reprint requests to Rajnish Mehrotra, MD, Division of Nephrology andHypertension, Harbor-UCLA Medical Center, 1124 W. Carson St, Torrance,CA 90509. E-mail: rmehrotra@labiomed.org

270-9295/09/$ - see front matter

l2009 Published by Elsevier Inc. doi:10.1016/j.semnephrol.2008.10.009

eminars in Nephrology, Vol 29, No 1, January 2009, pp 67-74

lications mainly include clinical wasting withoss of lean body mass and adverse effects onone health.3 These adverse consequencesrobably underlie the association of low predi-lysis bicarbonate with higher morbidity andortality in maintenance dialysis patients.4-6

linical Practice Guidelines for Nutrition inhronic Renal Failure of the Kidney Diseaseutcomes Quality Initiative of the National Kid-ey Foundation has recommended that the pre-ialysis serum bicarbonate of maintenance he-odialysis (MHD) patients and the steady state

erum bicarbonate levels of chronic peritonealialysis (CPD) patients and those with stage 3nd 4 CKD should be 22 mEq/L or greater.7 Thelinical practice guidelines for bone metabo-

ism and disease in CKD suggest similar target

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68 Y.-W. Chiu, J.D. Kopple, and R. Mehrotra

erum bicarbonate levels.8 Since the initial pub-ication, more data have accumulated that lendurther support to these guidelines. In this arti-le, we will limit the discussion to review thevidence that provides support for the correc-ion of metabolic acidosis to prevent protein-nergy wasting in patients with CKD. Throughhis review of mechanisms of how metaboliccidosis causes wasting and the related cross-ectional and interventional studies, we will tryo suggest the optimal goals and strategies tomeliorate wasting in CKD.

The issue of the best way to diagnose meta-olic acidosis for day-to-day management ofKD patients is outside the scope of this dis-ussion; measurement of serum bicarbonate re-ains the most widely used test. However, at-

ention needs to be given to 2 important issues:ptimal handling of blood specimens and ef-ects of different phosphate binders on a pa-ient’s acid-base status. Underfilling of thelood tube and shipping the specimen by flightvernight, as often is done in patients cared for

n units owned by large dialysis organizations inhe United States, decreases the total CO2 levelnd would result in overestimation of acido-is.9,10 Second, all phosphate binders availablen the United States, other than sevelamer hy-rochloride, are alkalis. Furthermore, sevel-mer hydrochloride is an ion-exchange resin;inding with different anions results in the re-

ease of chloride and can lead to the develop-ent of a non–gap metabolic acidosis.11 For

oth of these reasons, patients treated withevelamer hydrochloride are more likely to de-elop a metabolic acidosis with significantlyower serum bicarbonate levels.12,13 In patients

igure 1. Mechanisms whereby metabolic acidosis may

ine indicates that there is strong evidence supporting the pot

ith persistent metabolic acidosis, it often isore appropriate to use phosphate binders

ther than sevelamer hydrochloride.

ECHANISMS OF METABOLICCIDOSIS–INDUCED WASTING IN CKD

rotein-energy wasting is manifested clinically asoss of body mass—both fat-free, edema-free massor lean body mass), and fat mass.14 A large bodyf laboratory and clinical evidence indicates thatetabolic acidosis leads to wasting via the in-

reased protein breakdown and possibly de-reased protein synthesis (Fig. 1).15-18 Two majorathways have been identified to explain theigher protein breakdown associated withetabolic acidosis—increased activities of

oth the adenosine triphosphate–dependent ubiq-itin-proteasome system and of the branched-chainetoacid dehydrogenase.

Ubiquitin, a small protein expressed ubiqui-ously in eukaryotes, plays an important role inrotein turnover. When conjugated (usually 4-5

n a chain) to a protein in an adenosine triphos-hate–dependent process, it is recognized byhe 26S proteasome, which degrades the pro-ein. Bailey et al19 reported that proteolysis incidotic rats with CKD was associated withncreased amounts of ubiquitin messenger RNAnd subunits of the proteasome in skeletal mus-le, and these changes could be reversed byeeding sodium bicarbonate. Inhibition of ei-her adenosine triphosphate or the proteasomeas noted to slow the degradation of protein

nduced by acidosis in rat muscle.19,20 In addi-ion, activation of caspase-3, an enzyme in-olved with protein degradation and apoptosis,

e protein-energy wasting in patients with CKD. The thick

induc ential pathophysiologic mechanism.

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Metabolic acidosis and protein-energy wasting 69

s activated by acidemic rats with chronic kid-ey failure and suppressed in these rats by feed-

ng bicarbonate.21,22

Glucocorticoids may play a permissive rolen inducing the catabolic effects of metaboliccidosis in skeletal muscle. In adrenalectomizedats with metabolic acidosis induced by NH4Cl,he increase in protein breakdown and higheressenger RNA of the ubiquitin proteasome

ystem were abolished in these glucocorticoid-eficient animals and reappeared when glu-ocorticoids were given to the rats.23 Insulinas a direct effect on protein synthesis andegradation. Insulin resistance induced by aci-osis may contribute to protein catabolism. Infu-ion of insulin, without correction of the ketoac-dosis by feeding sodium bicarbonate, improvedroteolysis and induced lesser up-regulation ofhe messenger RNA encoding for ubiquitin in ratsith acute onset of diabetic ketoacidosis.24 The

ctivity of insulin-receptor-substrate–associatedhosphatidylinositol 3-kinase has been shown toe decreased in rats with CKD, which was nor-alized by insulin therapy and partially returned

o control levels by correction of acidosis.22 Thesendings suggest that glucocorticoids and insulinesistance both play an important role in proteinegradation.

CKD also is associated with alternations ofranched-chain amino acid (BCAA) metabo-

ism. BCAAs account for more than 50% of themino acid uptake in muscles and plays anmportant role in brain physiology and nutri-ional status. Uremic encephalopathy as well asrotein-energy wasting in CKD are associatedith abnormalities in BCAA metabolism.25 InKD rats, metabolic acidosis is associated with

ower serum and muscle levels of BCAA, sug-esting higher rates of BCAA degradation.26

his increase in breakdown of BCAAs seems toe a result of an increase in the activity ofranched-chain ketoacid dehydrogenase, a rate-

imiting enzyme that is induced by metaboliccidosis.17 Finally, correction of acidosis is as-ociated with higher plasma and intracellularCAA levels in MHD patients.27,28

Decreased protein synthesis also might con-ribute to the protein-energy wasting inducedy metabolic acidosis. In cell culture studies (L6

uscle cell), lower pH in the culture medium is i

ssociated with lower rates of protein synthesis,s ascertained by 14C-phenylalanine incorpora-ion.29 Concentrations of albumin and transferrinlso decreased in the supernatant of liver cellHepG2) cultured in acid medium.30

Studies in human beings in which the effectf metabolic acidosis, and its correction, werevaluated using either N-balances or proteinurnover using kinetic studies are summarizedn Table 1.27,28,31-38 Virtually all of these studieshow that acidosis is associated with increasedrotein degradation in patients with CKD. Fur-hermore, the correction of acidosis is associ-ted with lower protein degradation in mosttudies. However, the effects of metabolic aci-osis on protein synthesis in human studies are

ess consistent.

ROSS-SECTIONAL ANDONGITUDINAL COHORT STUDIESF THE EFFECTS OF METABOLICCIDOSIS ON NUTRITIONAL STATUS ANDLINICAL OUTCOMES IN CKD PATIENTS

espite the compelling laboratory evidence link-ng metabolic acidosis to protein-energy wasting,ome epidemiologic studies have shown an in-erse relationship between metabolic acidosisnd nutritional status in CKD patients. Uribarri etl39 studied 995 MHD patients and reported annverse relationship between serum total CO2 lev-ls and dietary protein intake, normalized proteinquivalent of total nitrogen appearance (nPNA),nd predialysis serum potassium, phosphorus,nd creatinine. Similar findings were observed,long with an inverse association between predi-lysis serum bicarbonate levels and albumin, in 2arger cross-sectional studies of MHD patientsn � 3,891 and 7,123, respectively).40,41 How-ver, if one accounts for the higher dietary pro-ein intakes in patients with metabolic acidosisby multivariate adjustment for nPNA), the in-erse association between albumin and bicar-onate is reduced to a nonsignificant level.40

onsistent with these observations, post hocnalyses of the data from the Modification ofiet in Renal Disease study also showed an

nverse association between serum total CO2

nd dietary protein intakes.42 These studies al-ow us to make a few simple observations and

nferences. First, higher protein intakes gener-

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70 Y.-W. Chiu, J.D. Kopple, and R. Mehrotra

lly are associated with a higher acid generationhat, in turn, is associated with lower predialy-is bicarbonate levels. Patients with higher pro-ein intakes tend to be healthier and thus haveigher values for serum albumin and other mea-ures of nutritional status. The inverse associa-ion between metabolic acidosis and nutritionaltatus therefore probably is secondary to theonfounding influence of dietary protein in-akes. Thus, the inverse association seen inhese epidemiologic studies does not imply thathe outcome of patients cannot be improved byorrection of metabolic acidosis, nor should it

Table 1. Summaries of Controlled, MetabolicThat Metabolic Acidosis Promotes Catabolism

StudyNo. of

SubjectsStage of Renal

FailureBaselin

pH/HCO

Papadoynnakis et al,31 1984 6 Nondialyzed (SB) */15.

Williams et al,33 1991 6 Nondialyzed (SB) 7.28/17.

Reaich et al,32 1993 9 Nondialyzed (SB) 7.31/15

Garibotto et al,34 1994 9 Nondialyzed */20

Graham et al,35 1996 7 CPD (SB) 7.39/19.

Graham et al,36 1997 6 MHD (D) 7.36/18.

Lofberg et al,28 1997 9 MHD (D) */20.

Lim et al,37 1998 9 Nondialyzed (SB) 7.29/19.

Boirie et al,38 2000 10 Nondialyzed */19.

Lofberg et al,27 2006 16 MHD (D) 7.33/18.

Abbreviations: SB, acidosis corrected by oral sodium bicarbonate; D,*Data not available or applicable.†Total CO2 value.

ngender therapeutic nihilism. h

With regard to mortality, in MHD patientsnrolled in the Dialysis Outcomes and Practiceatterns Study, a U-shaped association was ob-erved between the serum predialysis bicarbon-te level and mortality.5 The lowest risk foreath and hospitalization was found in theroup of patients with serum predialysis bicar-onate levels between 20.1 and 21.0 mEq/L.imilar findings had been shown in analyses ofbout 12,000 patients treated in Fresenius Med-cal Care clinics (Waltham, MA), wherein the low-st risk was seen in patients with serum bicarbon-te levels between 20.0 and 22.5 mmol/L.4 The

ies in Human Beings With CKD That Suggest

FinalH/HCO3

Biologic PhenomenaStudied

Results of Correctionof Metabolic Acidosis

*/23.4 N- and K-balance Both N- and K-balancesimproved

.35/24.3 Urine 3-methyl histidine:creatinine ratio (indexof skeletal musclecatabolism)

In patients on low-proteindiets, ratio increased inthe presence ofmetabolic acidosis;reduced with NaHCO3

supplementation.38/21 L[1-13C]leucine kinetics Reduced protein

degradation, synthesis,and leucine oxidation

ot corrected) 3H-phenylalaninekinetics

Net phenylalanine releaseinversely related todegree of acidosis

.41/26.2† L[1-13C]leucine kinetics Reduced whole-bodyprotein degradationand synthesis; no effecton leucine oxidation

.40/24.8† L[1-13C]leucine kinetics Reduced whole-bodyprotein degradationand synthesis; no effecton leucine oxidation

*/25.9 Intracellular BCAAs Increased intracellularconcentrations ofBCAAs

.39/25.5† L[1-13C]leucine kinetics Significant decrease inleucine oxidation,insignificant decreasein protein degradation,and increase insynthesis

ot corrected) L[1-13C]leucine kinetics Acidotic children hadhigher rates of proteindegradation

.44/26.8 3H-phenylalaninekinetics

Decreased net amino acidefflux and appearance;unchanged disposal(oxidation � synthesis)

corrected through dialysate.

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Metabolic acidosis and protein-energy wasting 71

redialysis bicarbonate levels (�27 mEq/L) waseduced to a nonsignificant level after adjustingor comorbidities, measures of nutrition, andmall solute clearances as measured by eKt/V.owever, despite adjustment for patient charac-

eristics, case-mix, and laboratory measurements,ow predialysis serum bicarbonate levels (�17

Eq/L) were associated independently with a sig-ificantly higher risk for death. These findingsave been corroborated recently in a large studyf patients being treated in clinics owned byaVita Inc. (El Segundo, CA) (n � 56,385),herein the lowest adjusted risk for death wasbserved in patients with predialysis serum bicar-onate levels higher than 22 mEq/L. Without ad-

usting for the malnutrition-inflammation com-lex syndrome, the lowest risk for death was

ound in patients with predialysis serum bicarbon-te levels between 17 and 23 mEq/L. These find-ngs imply that inflammation possibly might benother factor contributing to this inverse rela-ionship.6

NTERVENTIONALTUDIES OF THE EFFECTF CORRECTION OFETABOLIC ACIDOSIS ON PROTEIN-

NERGY WASTING IN CKD PATIENTS

pidemiologic analyses only allow us to deter-ine associations, and causal relationships can

e determined definitively by interventionaltudies. In 1931, Lyon and Stewart43 were therst to test the hypothesis that correction ofetabolic acidosis with alkali treatment will

esult in the improvement of protein-energyasting seen with CKD. Since then, several

ontrolled and uncontrolled observational andandomized clinical studies have tested the ef-ect of metabolic acidosis correction on theutrition status of dialysis-dependent patientsTable 2).44-55

As is evident, the data documenting the ben-ficial effects of correction of metabolic acido-is in MHD patients have been inconsistent.owever, some of the studies were uncon-

rolled. Moreover, the sample sizes of the stud-es were small and may have been underpoweredo detect significant changes. Furthermore, sometudies enrolled patients with only mild, if any,

rotein-energy wasting at baseline. Thus, the evi- m

ence for the benefits of the correction of meta-olic acidosis on protein-energy wasting in MHDatients is presently inconclusive. It has, how-ver, been reassuring that no serious adversevents—neither fluid overload, nor worsenedlood pressure control—have been reportedith alkali therapy. In contrast to the findings

n MHD patients, 2 randomized controlled stud-ed in CPD patients have shown beneficial ef-ects of the correction of metabolic acidosis onutrition status. Furthermore, in both of thesetudies, the correction of acidosis was associ-ted with a reduction of hospitalization rates.

The Cochrane collaboration recently has re-orted a systematic review of studies of correctionf chronic metabolic acidosis for CKD patients; onlyrandomized clinical studies performed to correctrotein-energy wasting met the criteria for patientelection and quality to be included.56 Brady andasbargen52 were unable to show any beneficialffects on the nutritional status of MHD patientsfter 4 months of follow-up evaluation. Theecond study was a double-blind study under-aken in CPD patients with a follow-up durationf 1 year. In this study, Szeto et al54 showedignificant improvement in the subjectivelobal assessment score, nPNA, and hospitaliza-ion after 1 year of oral sodium bicarbonateupplementation. Consistent with the findingseported in this study, Stein et al53 reportedreater weight gain and mid–arm-muscle cir-umference and lower rates of hospitalizationn a randomized controlled trial of 200 CPDatients.

ECOMMENDATIONS

ased on the current evidence, what should behe goal of a clinician to ensure optimal acid-ase status and thus minimize the protein-en-rgy wasting associated with metabolic acido-is? Modern dialysis therapy usually corrects theetabolic acidosis in most patients; thus causes

ther than kidney failure should be sought toxplain severe metabolic acidosis when it oc-urs in well-dialyzed maintenance dialysis pa-ients.57 In the absence of controlled trials inhich patients are randomized to 2 different

evels of serum bicarbonate levels, it is reason-ble to maintain serum bicarbonate levels of 22

Eq/L or greater, as recommended by the Kid-

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72 Y.-W. Chiu, J.D. Kopple, and R. Mehrotra

ey Disease Outcome Quality Initiative guide-ines. In patients undergoing CPD, evidence,articularly from the study by Szeto et al,54

eems to suggest that a higher serum bicarbon-

Table 2. Interventional Studies Evaluating theAcidosis in Chronic Dialysis Patients

Study No. of SubjectsDurationTreatme

Observational studiesMHD patients

Seyffart et al,44 1987 21 (D) 12-19 m

Kooman et al,45 1997 12 (D � SB) 6 mo

Movilli et al,46 1998 12 (SB) 3 mo

Lin et al,47 2002 17 (D) 6 mo

Verove et al,48 2002 18 (SB) 6 mo

Blair et al,49 2003 199 (D) 6 mo

Bossola et al,50 2007 20 (SB) 1 y

CPD patientsFeriani et al,55 2004 34 (D) (HCO3 39 mmol/L) 2 y

13 (D) (HCO3 34 mmol/L)

Randomized controlled studiesMHD patients

Williams et al,51 1997 46 (D) 6 mo(doublecross-o

Brady andHasbargen,52

1998

36 (D � SB) 4 mo

CPD patientsStein et al,53 1997 200 (D � SB) 1 y

Szeto et al,54 2003 60 (SB) 1 y

Beneficial effects are italicized.SB, acidosis corrected by oral sodium bicarbonate; D, acidosis correc

protein catabolic rate.*Data not available or applicable.

te level may be even more beneficial. m

Several therapeutic strategies can be at-empted in patients with persistent metaboliccidosis. In patients undergoing MHD, dialysateicarbonate can be increased safely from 35 to 40

ritional Response to Correction of Metabolic

Baseline pH/HCO3 Final pH/HCO3 Key Findings

*/14.4 */20.2 Significant increase in dry bodyweight in 11 of 21 patients

*/18.7 */23.1 Increased plasma BCAA levels;no change in bodycomposition, serumproteins, or dietary intake

7.34/19.3 7.40/24.4 Increase in serum albumin,decrease in nPNA

7.34/18.4 7.41/24.2 No change in any nutritionalparameters

*/16 */24 Significant increase in serumalbumin and prealbuminlevels; decrease in nPNA; nochange in dietary proteinintake

*/21.7 */23.1 Significant decrease in nPCR;no change in albumin andSGA

*/18.1 */22.1 No change in any nutritionalparameter

7.31/23.45 7.33/25.70 Significant decrease of PNA inthe subgroup (n�23) withcomplete acidosis correction

7.34/27.77 7.32/27.06

FinalpH/HCO3 in

ControlGroup

FinalpH/HCO3 inStudy Group

roup A */20.4roup B */19.8

Group B */26.7Group A */23.3

Increased triceps skinfoldthickness; no change inserum albumin, nPNA, ormid–arm-musclecircumference

*/17.3 */20.2 No change in serum albuminor total lymphocyte count

7.40/23.0 7.44/27.2 Greater gain in body weightand mid–arm-musclecircumference; reduction inhospitalizations

*/24.7 */27.8 Significant improvements inSGA, nPNA, andhospitalization

ugh dialysate; SGA, subjective global assessment; nPCR, normalized

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Metabolic acidosis and protein-energy wasting 73

ting phosphate binders such as sevelamer hydro-hloride. If acidosis is persistent, oral sodium bi-arbonate supplementation should be consideredecause it generally is safe and effective.

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3

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