acidose-dialise

Kidney International, Vol. 64, Supplement 88 (2003), pp. S13–S25

Metabolic acidosis in maintenance dialysis patients:Clinical considerations

RAJNISH MEHROTRA, JOEL D. KOPPLE, and MARSHA WOLFSON

Division of Nephrology and Hypertension and Research and Education Institute at Harbor-UCLA Medical Center; and DavidGeffen School of Medicine at UCLA and UCLA School of Public Health, Torrance, California; and Renal Division, BaxterHealthCare, McGaw Park, Illinois

Metabolic acidosis in maintenance dialysis patients: Clinicalconsiderations. Metabolic acidosis is a common consequenceof advanced chronic renal failure (CRF) and maintenance dial-ysis (MD) therapies are not infrequently unable to completelycorrect the base deficit. In MD patients, severe metabolic aci-dosis is associated with an increased relative risk for death. Thechronic metabolic acidosis of the severity commonly encoun-tered in patients with advanced CRF has two well-recognizedmajor systemic consequences. First, metabolic acidosis inducesnet negative nitrogen and total body protein balance, whichimproves upon bicarbonate supplementation. The data sug-gest that metabolic acidosis is both catabolic and antianabolic.Emerging data also indicate that metabolic acidosis may beone of the triggers for chronic inflammation, which may inturn promote protein catabolism among MD patients. In con-trast to these findings, metabolic acidosis may be associatedwith a decrease in hyperleptinemia associated with CRF. Sev-eral studies have shown that correction of metabolic acidosisamong MD patients is associated with modest improvementsin the nutritional status. Second, metabolic acidosis has severaleffects on bone, causing physicochemical dissolution of boneand cell-mediated bone resorption (inhibition of osteoblast andstimulation of osteoclast function). Metabolic acidosis is proba-bly also associated with worsening of secondary hyperparathy-roidism. Data on the effect of correction of metabolic acido-sis on renal osteodystrophy, however, are limited. Preliminaryevidence suggest that metabolic acidosis may play a role in b2-microglobulin accumulation, as well as the hypertriglyceridemiaseen in renal failure. Given the body of evidence pointing to theseveral systemic consequences of metabolic acidosis, a moreaggressive approach to the correction of metabolic acidosis isproposed.

Metabolic acidosis is a common accompaniment ofchronic renal failure (CRF) and it results from an inabilityto excrete nonvolatile acid in the face of reduced renalbicarbonate synthesis. The severity of metabolic acido-sis can vary widely among uremic patients with a similardegree of renal dysfunction [1, 2]; at least two studies

Key words: metabolic acidosis, nutrition, catabolism, bone, osteodys-trophy.

C© 2003 by the International Society of Nephrology

suggest that for a given level of renal function, diabeticindividuals may have a less severe degree of metabolicacidosis [3, 4]. One of the goals of dialysis therapy is tocorrect the metabolic abnormalities of uremia, includ-ing metabolic acidosis. Dialysis therapies, as practicedtoday, are unable to completely correct metabolic aci-dosis in a substantial proportion of patients undergoingmaintenance hemodialysis (MHD). Moreover, the serumbicarbonate levels in patients undergoing MHD follow a“saw-tooth pattern,” with the lowest bicarbonate levels inthe immediate predialysis period. Treatment with chronicperitoneal dialysis (CPD), on the other hand, appearsto maintain stable serum bicarbonate within the normalrange in the majority of patients, without the fluctuationsseen among patients undergoing MHD [5]. Even thoughCPD therapy is successful in normalizing the serum CO2

levels in almost 90% of patients, the anion gap remainswide in over 95% of patients [5]. The magnitude of aniongap in CPD patients is associated with higher serum ureanitrogen and phosphorus concentration, suggesting an in-adequate metabolic control by the dialysis prescription.The relevance of these findings is addressed below.

Increasing evidence points to a role, at least in part, formetabolic acidosis in the genesis, of several uremic mani-festations (Table 1). Moreover, in a retrospective analysisof a large cohort of patients, Lowrie et al [6] demonstratethat total serum CO2 was associated with a J-shapedrisk for death: increasing risk for death was observedwhen the total serum level was less than 17.5 mmol/L or greater than 25 mmol/L. The magnitude of the an-ion gap has sometimes been used as a surrogate for theseverity of metabolic acidosis. The available data suggestthat this assumption may be erroneous at least amongpatients undergoing CPD—the vast majority of patientswith a widened anion gap have normal serum bicarbonateconcentrations [5]. When the data are adjusted for case-mix, a high anion gap is associated with lower odds fordeath in MHD patients [7]. However, when the data areadjusted for serum albumin and creatinine levels alongwith case-mix, an increase in anion gap is associated with

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S-14 Mehrotra, Kopple, and Wolfson: Metabolic acidosis in maintenance dialysis patients

Table 1. Adverse systemic consequences of metabolic acidosis

Nutritional consequencesCatabolic effects—Increased proteolysisAntianabolic effects—Decreased protein synthesisInsulin resistanceSystemic inflammationDecreased serum leptin levels

Bone diseaseDirect effects

Physicochemical dissolution of boneDecreased function of osteoblastIncreased function of osteoclast

Indirect effectsIncreased release of parathyroid hormoneIncreased number of parathyroid hormone receptorsIncreased binding of parathyroid hormone to its receptorReduced activity of 1-a hydroxylase

Other systemic effectsIncreased generation and release of b2-microglobulinHypertriglyceridemia

a progressive increase in the risk for death [7]. The directassociation of a widened anion gap with the risk for deathis consistent with the thesis that a persistent increase inanion gap may reflect inadequate dialysis with respect tometabolic control. It is not clear, however, if an increasein dialysis dose can normalize the anion gap, or what theeffect of the normalization of the anion gap would haveon morbidity and mortality.

In this review, we present a brief overview of some ofthe systemic consequences of metabolic acidosis in indi-viduals with advanced CRF or undergoing MHD. Thereare many other consequences of metabolic acidosis, espe-cially if very severe, (e.g., malaise, weakness, hypotension,resistance to catecholamines). However, we shall limitthe discussion herein to metabolic acidosis that resultsfrom CRF and consequences from the range of severitythat usually occurs in nondialyzed CRF and MHD pa-tients. Even though it is assumed that the systemic conse-quences arise from an increase in the total hydrogen ionconcentration in the blood (acidemia), some of the datapresented here are based only upon a measurement ofplasma bicarbonate or serum total CO2.

GENERAL CONSIDERATIONS

There are two major considerations to take into ac-count while assessing the acid-base status of patients un-dergoing MHD: factors related to the measurement oftotal serum CO2 levels; and the effect of changing pat-terns of use of phosphate binders on the acid-base status.

Factors related to measurement of serum total CO2 levels

Close attention needs to be paid to two variables withrespect to measurement of total CO2 levels. First, un-derfilling of sample tubes should be avoided becauseevanescence of carbon dioxide may result in falsely low

measurements [8]. Second, shipping blood samples byovernight airfreight to laboratories several hundred milesaway is a standard practice in a large number of dial-ysis units in the United States. This practice has beenshown to be associated with a frequent occurrence ofspurious metabolic acidosis; the mean total CO2 contentof blood samples thus shipped is 5 mEq/L lower thansamples that undergo more immediate processing [9, 10].This decrease in total CO2 content cannot be accountedfor by an increase in lactate content or by the interval be-tween sample collection and processing. It is likely thatchanges in atmospheric pressure in the pressurized air-liner cabin or in a cargo hold lead to the escape of CO2

from the tube [11]. Indeed, if the sample is stored eitherat room temperature or refrigerated for 24 hours withoutair transport, the change in total CO2 is only 1 mEql/L[9, 12]. Thus, in MD patients, caution needs to be exer-cised in interpreting serum chemistry measurements thatindicate metabolic acidosis.

The effect of changing patterns of use of phosphatebinders on the acid-base status

Until recently, almost all MHD patients were treatedwith calcium-based phosphate binders, calcium acetateand calcium carbonate. Both of these calcium salts arealkalies and these medications have a salutary effect onmetabolic acidosis. However, one recent study suggeststhat a high dose of calcium-based phosphate binders isassociated with the presence of coronary artery calcifica-tion in MHD patients [13]. In a randomized control trialinvolving 200 MHD patients, the median percent changein coronary artery (25% vs. 6%) and aortic (28% vs. 5%)calcium scores was significantly greater with calcium-based phosphate binders, compared with sevalemerhydrochloride [14]. These findings have engendered anincreasing use of sevalemer hydrochloride as a phosphatebinder. However, sevalemer hydrochloride acts like anion-exchange resin in the gastrointestinal tract—it re-leases one mole of chloride for every mole of phosphorusthat it binds. Because 17% of sevalemer hydrochloride ischloride by weight, treatment with four 800 mg tablets ofsevalemer hydrochloride three times per day with mealsprovides 46 mEq of chloride load per day. The chloridethus released is buffered by bicarbonate, leading to a non-gap metabolic acidosis. These considerations suggest thata change from widespread use of alkalies for phosphatebinding to the use of an agent that fosters chloride loadingmay lead to a greater prevalence of persistent metabolicacidosis among MHD patients [15–17].

METABOLIC ACIDOSIS AND NUTRITION

In 1931, Lyon et al [18] first suggested that there may bea link between metabolic acidosis and nutritional status

Mehrotra, Kopple, and Wolfson: Metabolic acidosis in maintenance dialysis patients S-15

Metabolic acidosisMechanisms yet to be elucidated

Insulin resistance

Increased activity ofbranched chain ketoacid

dehydrogenase

Increased activity ofATP-dependentubiquitin-proteasomesystem

Increased muscle proteinbreakdown

InflammationReduced

serum leptin

Decreased muscle protein synthesisDecreased albumin synthesis

Protein energymalnutrition

Fig. 1. The mechanisms by which metabolic acidosis may induce protein-energy malnutrition. Of the various pathways, the stimulation of theATP-dependent ubiquitin-proteasome system by metabolic acidosis is the most well defined. Dotted lines indicate that the data supporting the roleof these pathways are less well documented at this time.

of patients with CRF. A large body of literature has subse-quently accumulated that suggests that metabolic acido-sis may play an important role in the pathogenesis of thenutritional abnormalities associated with uremia. Thereare five potential mechanisms by which metabolic acido-sis contributes to these nutritional abnormalities. One ofthese is well-researched and understood (increased pro-tein catabolism); more is being learned about two others(decreased protein synthesis and increased insulin resis-tance); and research has only begun to explore the role oftwo others (inflammation and reduction in serum leptinlevels) (Fig. 1).

Increased protein breakdown (catabolic effectsof metabolic acidosis)

Evidence for proteolysis. Evidence derived from ani-mal and human studies suggests that acidosis, includingthat associated with CRF, is associated with proteolysis,and correction of this acidosis leads to a decrease in pro-tein breakdown.

Acute metabolic acidosis in dogs leads to increasedtotal-body leucine oxidation, which is reduced withmetabolic alkalosis [19]. Studies in rats with normal renalfunction demonstrate that ammonium chloride–inducedmetabolic acidosis leads to an increase in skeletal mus-

cle protein degradation and amino acid oxidation [20–23]. Increased muscle protein degradation has also beenreported in rats with experimental renal failure; this in-creased protein breakdown was ameliorated by addingsodium bicarbonate to their diet [24].

In both healthy humans and individuals with CRF,metabolic acidosis may also engender negative N bal-ance [25–27]. A large number of investigations in humanswith various stages of renal failure have demonstratedthat metabolic acidosis promotes proteolysis (Table 2)[28–35].

Pathophysiologic mechanisms for the increased proteol-ysis associated with metabolic acidosis. Two key mech-anisms have been identified that mediate the cataboliceffects of metabolic acidosis.

Increased activity of branched-chain ketoacid dehydro-genase (BCKAD). Studies in intact rats and in isolatedmuscles demonstrate that acidosis stimulates the break-down of branched-chain amino acids (BCAA) [36].This catabolic response in muscle is associated with in-creased mRNAs and activity of the rate-limiting enzymebranched-chain ketoacid dehydrogenase (BCKAD)[21, 37]. The plasma and muscle levels of BCAA aresignificantly lower in animal models of metabolic acido-sis, as well as in humans undergoing MD therapy [21,38, 39]. Moreover, in MHD patients, the free valine


Table 2. Summary of controlled metabolic studies in humans that suggest that metabolic acidosis promotes catabolism

No. of Stage of renal Baseline Final Biologic phenomena Results of correction ofAuthor subjects failure pH pH studied metabolic acidosis

Papadoynnakis [27] 6 Nondialyzed a a N and K balance Both N and K balance improvedWilliams [28] 6 Nondialyzed 7.28 7.35 3-methyl histidine:creatinine ratio In patients on low protein diets,

increased urinary excretion in thepresence of metabolic acidosis,reduced with NaHCO3supplementation

Reaich [29] 9 Nondialyzed 7.31 7.38 L[1-13C]leucine kinetics Reduced protein degradation andsynthesis and leucine oxidation

Garibotto [30] 9 Nondialyzed a a 3H-phenylalanine kinetics Net phenylalanine release inverselyrelated to degree of acidosis

Graham [31] 7 CPD 7.39 7.41 L[1-13C]leucine kinetics Reduced whole body proteindegradation and synthesis; noeffect on leucine oxidation

Graham [32] 6 MHD 7.36 7.40 L[1-13C]leucine kinetics Reduced whole body proteindegradation and synthesis; noeffect on leucine oxidation

Lofberg [33] 9 MHD a a Intracellular branched amino acids Increased intracellularconcentrations of branched-chainamino acids

Lim [34] 8 Nondialyzed 7.29 7.39 L[1-13C]leucine kinetics Significant increase in leucineoxidation, insignificant increase inprotein degradation and synthesis

Boirie [35] 10 Nondialyzed a a L[1-13C]leucine kinetics Acidotic children had higher ratesof protein degradation

CPD, chronic peritoneal dialysis; MHD, maintenance hemodialysis.aData not available.

concentrations in the muscle correlate with both thepre- and postdialysis plasma bicarbonate levels [38].Correction of metabolic acidosis in MHD patients isassociated with an increase in plasma BCAA (leucine,isoleucine, and valine) levels [40]. Thus, it is likely thatin humans, the metabolic acidosis associated with renalfailure engenders an increased activity of BCKAD,which in turn leads to increased catabolism of BCAA.

Increased activity of the ATP-dependent ubiquitin-proteasome pathway. There are several lines of evidencethat establish the role of this pathway in mediating thecatabolic effects of metabolic acidosis in CRF. First,metabolic acidosis in rats with CRF is associated with anincrease in the muscle content of the mRNAs encodingthe ATP-dependent ubiquitin, as well as the subunits ofthe proteasome [41]. Feeding chow mixed with sodiumbicarbonate reversed these responses. This increase inmRNA is secondary to increased gene transcription [41,42]. Second, when isolated rat muscles are either depletedof ATP or exposed to an inhibitor of the proteasome inthe presence of metabolic acidosis, the increase in proteindegradation is abolished [20, 23, 41]. Third, incubatingskeletal muscle from CRF rats with metabolic acidosiswith an inhibitor of the proteasome suppresses proteoly-sis [41]. Finally, in a recent study involving CPD patients,Pickering et al [43] demonstrated that an increasein serum total CO2 was associated with a significantreduction in the muscle content of ubiquitin mRNA. Incontrast, there was no demonstrable increase in the

muscle ubiquitin mRNA levels in eight MHD patientswith only mild metabolic acidosis as compared tohealthy control patients [44]. These data suggest that theubiquitin-proteasome pathway plays an important rolein protein catabolism associated with metabolic acidosis.

Triggers for acidosis-induced enhancement of proteoly-sis in skeletal muscle. Despite the impressive progressin understanding the molecular mechanisms involvedin proteolysis in the setting of metabolic acidosis, thetriggers that activate these molecular mechanisms arepoorly understood. It appears unlikely to be the pH it-self, because metabolic acidosis in CRF does not causea sustained alteration in the intracellular pH of muscle[45]. Several hormonal triggers have been proposed andstudied.

Ammonium chloride–induced metabolic acidosis inadrenalectomized rats does not induce protein degrada-tion, an increase in the gene expression of BCKAD orits activity, or an elevation in any of the mRNAs of theubiquitin-proteasome system in muscle [20, 42, 46]. More-over, the urinary excretion of corticosterone in rats withacidotic experimental renal failure is significantly higherthan of pair-fed control rats [21]. These data suggest thatglucocorticoids may play a facilitative role in inducingthe catabolic pathways in the setting of metabolic acido-sis. Indeed, a glucocorticoid responsive element in thepromoter region of BCKAD has recently been discov-ered [47]. Increased urinary cortisol excretion has alsobeen reported in one experimental study of ammonium


chloride–induced metabolic acidosis of eight days’ dura-tion [48]. The role of glucocorticoids, however, in trig-gering the catabolic pathways in metabolic acidosis withCRF is less clear. Garibotto et al [30] found that mus-cle protein degradation correlated directly with plasmalevels of cortisol and negatively with serum bicarbonate,suggesting that both acidosis and glucocorticoids may beneeded to stimulate muscle protein degradation. Otherinvestigators have been unable to demonstrate elevatedcortisol concentrations in the setting of chronic metabolicacidosis [26, 49–51]. These observations, however, do notexclude the possibility that corticosteroids may need to bepresent for acidemia to stimulate skeletal muscle proteindegradation.

Insulin resistance may play a role in the activation ofthe ubiquitin-proteasome system. The high rate of proteindegradation in rats with acute onset of diabetic mellitusis not reduced by correction of the diabetic ketoacido-sis, but administration of insulin for 12 hours eliminatedthe excess proteolysis and higher ubiquitin mRNAs [52].Moreover, insulin-stimulated phosphorylation of insulin-receptor substrate-1 phosphatidylinositol 3 kinase acti-vity is significantly reduced in the muscle of rats withrenal failure [53]. It is possible, then, that suppressedphosphatidylinositol 3 kinase activity may lead to acti-vation of the ubiquitin-proteasome pathway and muscleprotein degradation [53].

Reduced tissue levels of or increased resistance toother anabolic hormones may also play a role in stim-ulating the catabolic pathways (see below).

Decreased muscle protein synthesis (antianaboliceffects of metabolic acidosis)

Cell culture studies using BC3H1 myocytes have showna significant reduction in protein synthesis in an acidicmedium [abstract; Ding et al, J Am Soc Nephrol 9:607A,1998] [54]. Increases in the pH of the medium (up to 7.70),even above normal physiologic pH, were associated withprogressively higher rates of protein synthesis [abstract;Ding et al, J Am Soc Nephrol, 9:607A, 1998]. Similarly,protein synthesis is significantly reduced in L6 musclecells cultured in an acidic medium [55]. Finally, acidic cul-ture medium significantly reduces the albumin and trans-ferrin concentrations in the supernatant of HepG2 cellcultures [56].

Rather analogous results have been observed in somebut not all studies of metabolic acidosis in humans. Acuteammonium chloride–induced metabolic acidosis in nor-mal individuals is associated with a significant reduc-tion in the fractional synthetic rate of muscle protein;the fractional, as well as the absolute, rate of albuminsynthesis remained unchanged [50]. On the other hand,chronic ammonium chloride–induced metabolic acido-sis is reported to significantly reduce the fractional syn-

thetic rate of albumin [25]. The applicability of thesefindings to metabolic acidosis in CRF is uncertain. Somestudies in MHD patients, using L-(13C)-leucine kinetics,demonstrate an increased total body protein synthesiswith metabolic acidosis, which decreases upon correc-tion of acidosis [29, 31, 32]. In these studies, however, thepresence of metabolic acidosis was also associated with asignificantly greater increase in the rate of protein degra-dation, resulting in a net negative protein balance [29, 31,32]. Thus, additional data are needed to determine the ef-fects on protein synthesis of metabolic acidosis associatedwith CRF in humans.

Alterations in one or more of three hormonal sys-tems may be responsible for the antianabolic effects ofammonium chloride–induced metabolic acidosis. First,metabolic acidosis may reduce the release of growthhormone; experimental data also suggest that metabolicacidosis may lead to peripheral resistance to growth hor-mone [57, 58]. Second, animal and human studies showthat metabolic acidosis is associated with a significant re-duction in the plasma levels of insulin-like growth fac-tor (IGF) and the hepatic content of IGF-I mRNA [25,58–60]. Third, thyroid hormones exert anabolic effects,and decreased thyroid function induced by metabolic aci-dosis might contribute to reduced synthesis of muscleprotein. In acute metabolic acidosis, there is a slight butsignificant increase in thyroid-stimulating hormone levelswithout any change in free triiodothyronine levels [50].In chronic metabolic acidosis, the same investigators re-ported a significant reduction in triiodothyronine levelswithout any change in thyroid-stimulating hormone lev-els [25]. Brungger et al [60] have reported similar resultsin an experimental study of chronic acidosis in humans.The relative contributions of these hormonal systems tothe altered anabolic and catabolic pathways induced bymetabolic acidosis, however, needs to be defined moreprecisely.

Insulin resistance

Insulin resistance is a known complication of CRF [61].Evidence suggests that this insulin resistance may in partbe secondary to metabolic acidosis [62]. In the presence ofacidosis, insulin binding in rat adipocytes is reduced by upto 30%. Hyperglycemic and euglycemic clamp studies inthe presence of ammonium chloride–induced metabolicacidosis revealed impaired glucose metabolism due to re-duced tissue sensitivity to insulin [62]. Indeed, correctionof metabolic acidosis in nondialyzed patients with CRFenhances insulin-stimulated glucose uptake.

Metabolic acidosis and inflammation: Is there a link?

Incubation of peritoneal macrophages in an acidic cellculture medium results in an increased production of


Table 3. Epidemiologic cross-sectional studies evaluating relationship between nutritional status and metabolic acidosis in MHD patients

No. of Dialysis Key findings suggesting that metabolic acidosis may not be associatedAuthor [ref.] subjects type with impaired nutritional status

Kang [73] 106 CPD Patients with serum total CO2 <22, compared to with total CO2 ≥26, had higher relative body weight,SUN, serum albumin, nPNA, and ultrafiltration volume

Uribarri [74] 23 MHD Patients with serum total CO2 ≤21 vs. total CO2 ≥25 had higher serum creatinine and SUN; significantinverse relationship between total CO2 and nPNA

Dumler [75] 50 CPD No difference in body cell mass or fat-free, edema-free mass between acidotic and nonacidotic groups;BMI higher in acidotic group

Ge [76] 75 MHD Lower relative body weight, triceps skin-fold thickness, midarm muscle circumference, serum albumin,transferrin, and fibronectin levels in patients with severe metabolic acidosis

Movilli [77] 81 MHD Direct association between serum bicarbonate and albumin levelsDumler [78] 124 Higher serum albumin, creatinine, and nPNA2 in acidotic group; no difference in body cell mass, fat-free

edema-free mass or mid-arm circumference between acidotic and non-acidotic groupUribarri [79] 995 MHD Serum total CO2 inversely associated with DPI4, nPNA2 and predialysis serum potassium, phosphorus,

creatinine, SUN1; no relationship with BMI3 or skinfold thicknessGao [80] 50 MHD Serum total CO2 inversely related to SUN, serum phosphorus, and uric acidLeavey [81] 3891 MHD Significant inverse relationship with serum albuminChauveau [82] 7123 MHD Plasma HCO3 inversely associated with nPNA2, serum albumin, prealbumin, BMI, and fat-free,

edema-free massKung [83] 43 CPD Malnourished subjects determined by subjective global assessment, had higher serum total CO2 than

well-nourished subjectsLin [64] 120 MHD Higher BMI, triceps skin-fold thickness, DPI, nPNA, serum creatinine, and potassium in acidemic

patients

Abbreviations are: SUN, serum urea nitrogen; nPNA, normalized protein equivalent of nitrogen appearance; BMI, body mass index; DPI, dietary protein intake;CPD, chronic peritoneal dialysis; MHD, maintenance hemodialysis.

tumor necrosis factor a (TNFa), suggesting a possiblelink between metabolic acidosis and the inflammatorycascade [63]. Two recent studies have investigated the linkbetween metabolic acidosis and inflammation. In a cross-sectional study of MHD patients, there was no significantdifference in the serum levels of C-reactive protein andinterleukin-6 in three groups of patients, divided on thebasis of their serum total CO2 levels (mean total CO2 inthe three groups, 19.2, 24.4, and 27.5 mmol/L) [64]. On theother hand, the correction of metabolic acidosis in eightCPD patients was associated with a significant decreasein TNFa levels [43]. Future studies need to define therelationship between metabolic acidosis associated withCRF and inflammation.

Leptin and metabolic acidosis

Leptin, a product of the ob gene, has been studiedas a potential mediator of protein-energy malnutrition.Serum leptin is elevated in CRF. Even though the preciserole of leptin in human renal disease remains to be de-fined, three longitudinal studies have demonstrated thatindividuals with high serum leptin levels are more likelyto lose weight [65–67]. Several recent studies have ex-plored the interaction between metabolic acidosis andhyperleptinemia, two frequent consequences of CRF.

Adipocytes exposed to a low pH (pH 7.1) in a culturemedium exhibit decreased leptin secretion [68]. In ratswith renal failure treated with sodium bicarbonate, theserum leptin is significantly lower than in those not sup-plemented with bicarbonate [68]. Furthermore, plasmaleptin concentrations are lower in patients with diabetic

ketoacidosis than in healthy subjects, and the leptin levelsincrease after initiation of insulin therapy [69, 70]. How-ever, diabetic ketoacidosis is associated with insulinope-nia, ketonemia, and increased sympathetic nervous ac-tivity and these factors may independently affect serumleptin levels. Among nondialyzed individuals with CRF,correction of metabolic acidosis is associated with an in-crease in serum leptin levels [71]. In a cross-sectionalstudy of 94 MHD patients, Kokot et al [72] were unable todemonstrate any correlation between blood hydrogen ionconcentration and serum leptin levels; there was a trend,not statistically significant, toward a progressively lowermedian leptin concentration with progressively higherblood hydrogen concentration.

Because elevated serum leptin levels lead to weightloss, a decrease in serum levels could adaptively amelio-rate the catabolic effects of metabolic acidosis. To theauthors’ knowledge, there are no published data regard-ing the interaction of metabolic acidosis with serum lep-tin levels and the relative contribution of each on thenutritional status of MHD patients.

Cross-sectional and interventional studies concerningpotential adverse effects of metabolic acidosison the nutritional status of MHD patients

Notwithstanding the preponderance of metabolic stud-ies that indicate an adverse catabolic response tometabolic acidosis, the vast majority of cross-sectionalstudies demonstrate an inverse relationship betweenmetabolic acidosis and the nutritional status of MHDpatients (Table 3) [64, 73–83]. The explanation for thisphenomenon may lie in the likelihood that healthy


Table 4. Interventional studies that have evaluated the nutritional response to correction of metabolic acidosis in MHD patients

No. of Duration of Randomized Baseline vs. final pH Final pH (control Key findings (beneficialAuthor [ref.] subjects treatment control trial in study group vs. study group) effects are italicized)

MHD patientsSeyffart [84] 21 12–19 months No a a Significant increase in dry body weight in

11 of 21 patientsRoberts [85] 8 Four weeks No 7.32 vs. 7.36 No change in nPNA or DPIKooman [40] 12 Six months No a a No change in body composition, serum

proteins or dietary intake; increasedplasma branched-chain amino acidlevels

Williams [86] 46 Six months Yes (doublecrossover)

7.38 vs. 7.43 a Increased triceps skin-fold thickness; nochange in serum albumin, nPNA, ormidarm muscle circumference

Brady [87] 36 Four months Yes a a No change in serum albumin or totallymphocyte count

Movilli [88] 12 Three months No 7.34 vs. 7.40 a Increase in serum albumin, decrease innPNA

Lin, ’02 [64] 17 Six months No 7.34 vs. 7.41 a No change in any nutritional parametersVerove [89] 18 Six months No a a Significant increase in serum albumin and

prealbumin levels; decrease in nPNA;no change in DPI

CPD patientsStein [90] 200 One year Yes a 7.40 vs. 7.44 Greater gain in body weight and midarm

muscle circumference

nPNA, normalized protein equivalent of nitrogen appearance; DPI, dietary protein intake.aData not available or applicable.

people tend to have greater appetite and, hence, ingestmore protein. Healthier people are not likely to showmanifestations of protein-energy malnutrition. More-over, a higher protein (and consequently higher energy)diet may reduce the risk of protein-energy malnutrition.Finally, a higher intake of dietary protein is associatedwith a higher dietary acid load and, thus, a lower serumtotal CO2 level. This, in turn, appears to confound theassociation of low serum total CO2 levels with increasedprotein catabolism. However, cross-sectional studies onlydemonstrate associations, and care must be exercised be-fore concluding that mild to moderate metabolic acido-sis has no deleterious effect on the nutritional status ofMD patients. In contrast to these findings, in a cross-sectional evaluation of 81 MHD patients, Movilli et al[77] demonstrated a direct association between serumbicarbonate and serum albumin. Similarly, Ge et al [76]demonstrated that MHD patients with severe metabolicacidosis had significantly lower relative body weight, tri-ceps skin-fold thickness, midarm muscle circumference,serum albumin, transferrin, and fibronectin levels whencompared to those with higher serum bicarbonate lev-els. It is also possible that the protein catabolic effectsassociated with metabolic acidosis may be rather tran-sient because in most studies, the metabolic acidosis orbicarbonate therapy was maintained for a relatively shortperiod of time.

Several investigators have prospectively evaluated theeffect of correcting metabolic acidosis on the nutritionalstatus of MD patients [40, 64, 84–90]. As is shown inTable 4, the beneficial results were inconsistent and usu-ally limited. There are two major limitations of these stud-

ies. First, the sample size in most of these studies was smalland, thus, underpowered to detect an improvement innutritional status. Indeed, the largest study reported todate successfully demonstrated an improvement in bodyweight and triceps skin-fold thickness upon correction ofmetabolic acidosis [90]. Second, a significant number ofthe individuals studied had either normal or only mildlyimpaired nutritional status.

These considerations suggest that there is a need fora large, controlled trial to evaluate the effects of correc-tion of metabolic acidosis on the nutritional status of MDpatients.

METABOLIC ACIDOSIS AND BONE DISEASE

Early studies in humans with advanced CRF nottreated by MHD indicate that a marked reduction in netacid excretion leads to daily net positive proton balance[91, 92]. It has been suggested that the cost of maintain-ing a stable serum total CO2 in the face of uncorrectedmetabolic acidosis was a constant dissolution of bonebuffers (Fig. 2) [92, 93]. Studies by Uribarri et al [94] have,however, demonstrated that early studies had method-ologic errors that may have led to an overestimation ofendogenous acid production and/or underestimation ofnet acid excretion. Thus, the magnitude of daily positiveproton balance in the presence of renal failure may havebeen significantly overestimated.

Direct effects of acidosis on bone

In vitro studies have shown that metabolic acidosis isassociated with net calcium efflux from bone [95]. The


Metabolic acidosis

Directeffects

Indirecteffects

Physicochemicaldissolution of

bone

Inhibition ofosteoblasts

Stimulation ofosteoclasts

Increasedcirculating levels

Increased receptorexpression

Increased bindingto receptor

Vitamin D

Decreased 1αhydroxylase

Bone disease

Parathyroid hormone

Fig. 2. The various mechanisms by which metabolic acidosis may contribute to bone disease. Dotted lines indicate that the data supporting therole of these pathways are less well documented at this time.

net calcium efflux is a result of direct physicochemicaldissolution of bone as well as cell-mediated bone resorp-tion (inhibition of osteoblast and stimulation of osteoclastfunction) [96–98]. Metabolic acidosis also stimulates os-teoblasts to release prostaglandins, which in turn in-hibits osteoblastic activity and stimulates osteoclasticfunction [99–102]. Glucocorticoids inhibit the productionof prostaglandins by osteoblasts, and this in turn inhibitsthe acidosis-induced bone resorption [103]. Furthermore,since acid loading in normal animals and humans is asso-ciated with hypercalciuria and phosphaturia, it has beensuggested that bone is a major site for the extracellu-lar buffering of the retained acid [92, 97, 104–109]. Con-sistent with this thesis is the observation that metabolicacidosis is associated with a decrease in the content ofbone bicarbonate [110, 111]. Finally, bicarbonate supple-mentation in postmenopausal women with normal renalfunction is associated with decreases in urinary cal-cium, phosphorus, and hydroxyproline, and increased os-teocalcin levels, suggesting an overall beneficial effect[112]. These observations also suggest that uncorrectedmetabolic acidosis has adverse consequences on boneanatomy and physiology.

Since acidosis in CRF is not associated with hypercalci-uria, the relevance of these findings to human renal failurehas been questioned [113, 114]. Several lines of evidencesupport a role for metabolic acidosis in the pathogene-sis of bone disease in CRF; most of these studies werepublished 20 to 35 years ago. First, advanced uremia in

humans is associated with a decrease in the content ofcalcium carbonate in bone [115–117]. Second, metabolicacidosis in CRF is associated with a net negative cal-cium balance; when metabolic acidosis is corrected, thecalcium balance becomes less negative [92, 106]. It isnot known if such acute effects of metabolic acidosison calcium balance will persist chronically. Third, stud-ies in nondialyzed individuals with CRF showed that se-vere metabolic acidosis is associated with impaired bonemineralization and an increased incidence of osteoma-lacia [106, 118–120]. Indeed, Mora Palma et al [119] re-ported that over one third of 327 nondialyzed patientswith renal failure who had undergone a bone biopsy hadevidence for osteomalacia; the individuals with osteo-malacia were characterized by a more severe degree ofmetabolic acidosis. Fourth, Cochran et al [106] demon-strated a significant increase in bone mineralization rateafter the correction of metabolic acidosis in nondialyzedindividuals with CRF. Fifth, cross-sectional analyses ofindividuals with a renal transplant demonstrate a signif-icant direct relationship between bone mineral densityand plasma bicarbonate levels, using Cox multivariateproportional hazard analysis [121]. Finally, acute correc-tion of metabolic acidosis in nondialyzed CRF patientsis associated with increased plasma levels of osteocal-cin and procollagen type 1 carboxyterminal propeptide,suggesting an improvement in osteoblast function [122,123]. Notwithstanding these findings, the precise con-tribution of metabolic acidosis to the bone disease in


nondialyzed individuals with CRF and MHD patientsremains uncertain.

Indirect effects: Acidosis and parathyroid hormone

Among individuals with normal renal function,metabolic acidosis is associated with three physiologicchanges with varying effects on serum parathyroid hor-mone (PTH) concentrations: there is an increase in serumionized calcium, hypercalciuria, and a reduced sensitiv-ity of the PTH secretion in response to ionized calcium[124–126]. With decreased sensitivity of the parathyroidgland to calcium, the rise in ionized calcium may not besufficient to maintain the normal serum PTH levels. In-deed, early investigations among individuals with normalrenal function suggest that the hypercalciuria associatedwith metabolic acidosis leads to an increase in serum PTHlevels [125]. In nondialyzed individuals with CRF, there isan inverse relationship between plasma bicarbonate andserum PTH levels that is consistent with these observa-tions [127]. This relationship may have been secondary tothe bicarbonaturia that is associated with elevated serumPTH levels. However, the rapid correction of metabolicacidosis in this latter group of patients is associated witha decrease in serum PTH levels, arguing against a role forbicarbonaturia [123].

The available evidence, although not conclusive, sug-gests that metabolic acidosis is also associated with anincrease in serum PTH levels in MHD patients. In a ran-domized controlled study of 21 patients, Lefebvre et al[128] demonstrated that in MHD patients treated witha higher dialysate bicarbonate, there was no significantincrease in serum PTH levels over time; however, in thegroup of patients treated with standard dialysate bicar-bonate and persistent metabolic acidosis, serum PTH lev-els increased significantly. In addition, some (althoughnot all) investigators report a decrease in serum PTHlevels after correction of metabolic acidosis in MHD pa-tients [64, 86, 129, 130].

Early studies reported that PTH causes a greater in-crease in serum calcium in the presence of metabolicacidosis [131]. Moreover, using isolated perfused caninetibia, Martin et al [132] demonstrated that metabolic aci-dosis enhances the generation of cyclic AMP in responseto PTH, an event which may promote bone resorption.Two recent studies have shed greater light on this is-sue. First, using neonatal mouse calvariae, Bushinsky andNilsson [133] have demonstrated that in the presence ofmetabolic acidosis, PTH stimulates greater net efflux ofcalcium, inhibition of osteoblast activity, and enhance-ment of osteoclast function. Second, using UMR 106-01osteoblast-like cells, Disthabanchong et al [134] recentlydemonstrated that acid culture medium increases PTHreceptor mRNA, raises the binding of PTH to its receptor,and enhances the PTH-stimulated generation of cyclic

AMP. These findings suggest that metabolic acidosis mayenhance the peripheral actions of PTH on bone.

Thus, although the evidence cannot be consideredconclusive, the available data suggest that metabolicacidosis may lead to a worsening of secondary hyper-parathyroidism.

Indirect effects: Acidosis and vitamin D

Metabolic acidosis reduces activity of 1a-hydroxylasein the renal tubules of rats [135]. The data regarding theeffects of metabolic acidosis on serum levels of 1,25 di-hydroxycholecalciferol are difficult to interpret becausethey are confounded by the effects of acidosis on levelsof serum phosphorus and PTH. Thus, studies have in-dicated that metabolic acidosis may be associated withincreased, unchanged, or decreased levels of serum 1,25dihydroxycholecalciferol levels [108, 129, 136–139].

Does correction of metabolic acidosis increasethe risk for metastatic calcification?

It has been proposed that postdialysis alkalosis mayincrease the risk for metastatic calcification. However,Harris et al [140] treated nine MHD patients with a higherdialysate bicarbonate concentration of 40 mmol/L forfour weeks. They observed that the risk of metastatic cal-cification between standard and high dialysis bicarbonate,as determined by plasma inorganic phosphate, estimatedplasma tribasic inorganic phosphate (the phosphate com-ponent of hydroxyapatite), and magnitude of postdial-ysis phosphate rebound, was not significantly differentbetween the two groups with different dialysate bicar-bonate concentrations. This evidence, however, is indi-rect and the question needs further evaluation.

OTHER SYSTEMIC CONSEQUENCESOF ACIDOSIS

b2-microglobulin levels

Several lines of evidence suggest that metabolic aci-dosis may increase the serum levels of b2-microglobulin.First, cell culture studies suggest that metabolic acidosismay enhance cellular b2-microglobulin generation andrelease [141–143]. Second, ammonium chloride–inducedmetabolic acidosis in healthy adults is associated with a1.5-fold increase in the b2-microglobulin mRNA expres-sion in lymphocytes [143]. Third, in patients with CRF,a strong inverse relationship has been demonstrated be-tween serum total CO2 and b2-microglobulin levels [143].Finally, using acetate instead of bicarbonate as a bufferin dialysate is associated with a decrease in blood pH andtotal CO2 and an increase in plasma b2-microglobulinlevels [143]. Thus, even though reduced renal excretionof b2-microglobulin is the predominant mechanism for its


accumulation in MHD patients, these data suggest thatmetabolic acidosis may also play a role.

Hypertriglyceridemia

In a small, uncontrolled study of MHD patients, thecorrection of metabolic acidosis was associated withsignificant decrease in serum triglycerides, suggestingthat metabolic acidosis may contribute to hypertriglyc-eridemia seen in MHD patients [139]. However, giventhe limitations of study design, these data need to be con-firmed before any definitive conclusions are made.

CONCLUSION

A large body of evidence suggests that uncorrectedmetabolic acidosis is detrimental to the overall health andspecifically the nutritional status and bone disease amongMHD patients. Even though the relative contribution ofmetabolic acidosis to the development of protein-energymalnutrition or renal osteodystrophy remains to be de-fined, the correction of metabolic acidosis among MHDpatients appears to be a desirable goal.

ACKNOWLEDGMENTS

This work was supported in part by the following grants: SatelliteResearch grant, Harbor-UCLA General Clinical Research Center grantM01-RR00425 from the National Centers for Research Resources, anda grant from the NIDDK (1RO1 DK61389-0141). We are grateful toJack Coburn, M.D., for a critical review of the manuscript.

REFERENCES

1. WIDMER B, GERHARDT RE, HARRINGTON JT, COHEN JJ: Serum elec-trolyte and acid base composition. The influence of graded degreesof chronic renal failure. Arch Intern Med 139:1099–1102, 1979

2. HAKIM RM, LAZARUS JM: Biochemical parameters in chronic renalfailure. Am J Kidney Dis 11:238–247, 1988

3. CARAVACA F, ARROBAS M, PIZARRO JL, ESPARRAGO JF: Metabolicacidosis in advanced renal failure: Differences between diabeticand nondiabetic patients. Am J Kidney Dis 33:892–898, 1999

4. WALLIA R, GREENBERG A, PIRAINO B, et al: Serum electrolyte pat-terns in end-stage renal disease. Am J Kidney Dis 8:98–104, 1986

5. MUJAIS S: Acid-base profile in patients on PD. Kidney Int64(Suppl), 2003 (in press)

6. LOWRIE EG, LEW N: Death risk in hemodialysis patients: The pre-dictive value of commonly measured variables and an evaluation ofdeath rate differences between facilities. Am J Kidney Dis 15:458–482, 1990

7. LOWRIE EG, ZHU X, LEW NL: Primary associates of mortalityamong dialysis patients: Trends and reassessment of Kt/V and ureareduction ratio as outcome-based measures of dialysis dose. Am JKidney Dis 32:S16–31, 1998

8. HERR RD, SWANSON T: Serum bicarbonate declines with samplesize in vacutainer tubes. Am J Clin Pathol 97:213–216, 1992

9. BRAY SH, TUNG RL, JONES ER: The magnitude of metabolic acido-sis is dependent on differences in bicarbonate assays. Am J KidneyDis 28:700–703, 1996

10. KIRSCHBAUM B: Spurious metabolic acidosis in hemodialysis pa-tients. Am J Kidney Dis 35:1068–1071, 2000

11. LASKI ME: Penny wise and bicarbonate foolish. Am J Kidney Dis35:1224–1225, 2000

12. HOWSE ML, LEONARD M, VENNING M, SOLOMAN L: The effect ofdifferent methods of storage on the results of serum total CO2assays. Clin Sci (Lond) 100:609–611, 2001

13. GOODMAN WG, GOLDIN J, KUIZON BD, et al: Coronary-artery cal-cification in young adults with end-stage renal disease who areundergoing dialysis. N Engl J Med 342:1478–1483, 2000

14. CHERTOW GM, BURKE SK, RAGGI P: Sevelamer attenuates the pro-gression of coronary and aortic calcification in hemodialysis pa-tients. Kidney Int 62:245–252, 2002

15. GALLIENI M, COZZOLINO M, BRANCACCIO D: Transient decreaseof serum bicarbonate levels with Sevelamer hydrochloride as thephosphate binder. Kidney Int 57:1776–1777, 2000

16. SADEK T, MAZOUZ H, BAHLOUL H, et al: Sevelamer hydrochloridewith or without alphacalcidol or higher dialysate calcium vs cal-cium carbonate in dialysis patients: An open-label, randomizedstudy. Nephrol Dial Transplant 18:582–589, 2003

17. MARCO MP, MURAY S, BETRIU A, et al: Treatment with sevelamerdecreases bicarbonate levels in hemodialysis patients. Nephron92:499–500, 2002

18. LYON DM, DUNLOP DM, STEWART CP: The alkaline treatment ofchronic nephritis. Lancet 2:1009–1013, 1931

19. RODRIGUEZ NR, MILES JM, SCHWENK WF, HAYMOND MW: Effectsof acute metabolic acidosis and alkalosis on leucine metabolism inconscious dogs. Diabetes 38:847–853, 1989

20. MAY RC, KELLY RA, MITCH WE: Metabolic acidosis stimulatesprotein degradation in rat muscle by a glucocorticoid-dependentmechanism. J Clin Invest 77:614–621, 1986

21. MAY RC, HARA Y, KELLY RA, et al: Branched-chain amino acidmetabolism in rat muscle: abnormal regulation in acidosis. Am JPhysiol 252:E712–718, 1987

22. MAY RC, MASUD T, LOGUE B, et al: Chronic metabolic acidosisaccelerates whole body proteolysis and oxidation in awake rats.Kidney Int 41:1535–1542, 1992

23. MITCH WE, MEDINA R, GRIEBER S, et al: Metabolic acidosis stim-ulates muscle protein degradation by activating the adenosinetriphosphate-dependent pathway involving ubiquitin and protea-somes. J Clin Invest 93:2127–2133, 1994

24. MAY RC, KELLY RA, MITCH WE: Mechanisms for defects in mus-cle protein metabolism in rats with chronic uremia. Influence ofmetabolic acidosis. J Clin Invest 79:1099–1103, 1987

25. BALLMER PE, MCNURLAN MA, HULTER HN, et al: Chronicmetabolic acidosis decreases albumin synthesis and induces nega-tive nitrogen balance in humans. J Clin Invest 95:39–45, 1995

26. REAICH D, CHANNON SM, SCRIMGEOUR CM, GOODSHIP TH: Ammo-nium chloride-induced acidosis increases protein breakdown andamino acid oxidation in humans. Am J Physiol 263:E735–739, 1992

27. PAPADOYANNAKIS NJ, STEFANIDIS CJ, MCGEOWN M: The effect ofthe correction of metabolic acidosis on nitrogen and potassium bal-ance of patients with chronic renal failure. Am J Clin Nutr 40:623–627, 1984

28. WILLIAMS B, HATTERSLEY J, LAYWARD E, WALLS J: Metabolic aci-dosis and skeletal muscle adaptation to low protein diets in chronicuremia. Kidney Int 40:779–786, 1991

29. REAICH D, CHANNON SM, SCRIMGEOUR CM, et al: Correction ofacidosis in humans with CRF decreases protein degradation andamino acid oxidation. Am J Physiol 265:E230–235, 1993

30. GARIBOTTO G, RUSSO R, SOFIA A, et al: Skeletal muscle proteinsynthesis and degradation in patients with chronic renal failure.Kidney Int 45:1432–1439, 1994

31. GRAHAM KA, REAICH D, CHANNON SM, et al: Correction of acidosisin CAPD decreases whole body protein degradation. Kidney Int49:1396–1400, 1996

32. GRAHAM KA, REAICH D, CHANNON SM, et al: Correction of acidosisin hemodialysis decreases whole-body protein degradation. J AmSoc Nephrol 8:632–637, 1997

33. LOFBERG E, WERNERMAN J, ANDERSTAM B, BERGSTROM J: Correc-tion of acidosis in dialysis patients increases branched-chain andtotal essential amino acid levels in muscle. Clin Nephrol 48:230–237, 1997

34. LIM VS, YARASHESKI KE, FLANIGAN MJ: The effect of uraemia,acidosis, and dialysis treatment on protein metabolism: a longitu-dinal leucine kinetic study. Nephrol Dial Transplant 13:1723–1730,1998


35. BOIRIE Y, BROYER M, GAGNADOUX MF, et al: Alterations of proteinmetabolism by metabolic acidosis in children with chronic renalfailure. Kidney Int 58:236–241, 2000

36. HARA Y, MAY RC, KELLY RA, MITCH WE: Acidosis, not azotemia,stimulates branched-chain, amino acid catabolism in uremic rats.Kidney Int 32:808–814, 1987

37. ENGLAND BK, GREIBER S, MITCH WE, et al: Rat muscle branched-chain ketoacid dehydrogenase activity and mRNAs increase withextracellular acidemia. Am J Physiol 268:C1395–1400, 1995

38. BERGSTROM J, ALVESTRAND A, FURST P: Plasma and muscle freeamino acids in maintenance hemodialysis patients without proteinmalnutrition. Kidney Int 38:108–114, 1990

39. MOCHIZUKI T: The effect of metabolic acidosis on amino acid andketo acid metabolism in chronic renal failure. Nippon Jinzo GakkaiShi 33:213–224, 1991

40. KOOMAN JP, DEUTZ NE, ZIJLMANS P, et al: The influence of bicar-bonate supplementation on plasma levels of branched-chain aminoacids in haemodialysis patients with metabolic acidosis. NephrolDial Transplant 12:2397–2401, 1997

41. BAILEY JL, WANG X, ENGLAND BK, et al: The acidosis of chronicrenal failure activates muscle proteolysis in rats by augmentingtranscription of genes encoding proteins of the ATP-dependentubiquitin-proteasome pathway. J Clin Invest 97:1447–1453, 1996

42. PRICE SR, ENGLAND BK, BAILEY JL, et al: Acidosis and glucocor-ticoids concomitantly increase ubiquitin and proteasome subunitmRNAs in rat muscle. Am J Physiol 267:C955–960, 1994

43. PICKERING WP, PRICE SR, BIRCHER G, et al: Nutrition in CAPD:Serum bicarbonate and the ubiquitin-proteasome system in mus-cle. Kidney Int 61:1286–1292, 2002

44. BOSSOLA M, MUSCARITOLI M, COSTELLI P, et al: Muscle ubiquitinm-rNA levels in patients with end-stage renal disease on mainte-nance hemodialysis. J Nephrol 15:552–557, 2002

45. BAILEY JL, ENGLAND BK, LONG RC, JR, et al: Experimentalacidemia and muscle cell pH in chronic acidosis and renal failure.Am J Physiol 269:C706–712, 1995

46. PRICE SR, WANG X, BAILEY JL: Tissue-specific responsesof branched-chain alpha-ketoacid dehydrogenase activity inmetabolic acidosis. J Am Soc Nephrol 9:1892–1898, 1998

47. PRICE SR, WANG X: Glucocorticoids and acidification indepen-dently increase transcription of branched-chain ketoacid dehy-drogenase subunit genes. Miner Electrolyte Metab 25:224–227,1999

48. SICURO A, MAHLBACHER K, HULTER HN, KRAPF R: Effect of growthhormone on renal and systemic acid-base homeostasis in humans.Am J Physiol 274:F650–657, 1998

49. SCHAMBELAN M, SEBASTIAN A, KATUNA BA, ARTEAGA E: Adreno-cortical hormone secretory response to chronic NH4Cl-inducedmetabolic acidosis. Am J Physiol 252:E454–460, 1987

50. KLEGER GR, TURGAY M, IMOBERDORF R, et al: Acute metabolic aci-dosis decreases muscle protein synthesis but not albumin synthesisin humans. Am J Kidney Dis 38:1199–1207, 2001

51. MANIAR S, LAOUARI D, DECHAUX M, et al: In vivo unaltered mus-cle protein synthesis in experimental chronic metabolic acidosis.Kidney Int 46:1705–1712, 1994

52. MITCH WE, BAILEY JL, WANG X, et al: Evaluation of signals activat-ing ubiquitin-proteasome proteolysis in a model of muscle wasting.Am J Physiol 276:C1132–1138, 1999

53. PRICE SR, DU JD, BAILEY JL, MITCH WE: Molecular mechanismsregulating protein turnover in muscle. Am J Kidney Dis 37:S112–114, 2001

54. ENGLAND BK, CHASTAIN JL, MITCH WE: Abnormalities in proteinsynthesis and degradation induced by extracellular pH in BC3H1myocytes. Am J Physiol 260:C277–282, 1991

55. BEVINGTON A, POULTER C, BROWN J, WALLS J: Inhibition of pro-tein synthesis by acid in L6 skeletal muscle cells: analogies withthe acute starvation response. Miner Electrolyte Metab 24:261–266,1998

56. ULRICH C, KRUGER B, KOHLER H, RIEGEL W: Effects of acidosison acute phase protein metabolism in liver cells. Miner ElectrolyteMetab 25:228–233, 1999

57. CHALLA A, KRIEG RJ, JR, THABET MA, et al: Metabolic acidosisinhibits growth hormone secretion in rats: mechanism of growthretardation. Am J Physiol 265:E547–553, 1993

58. MANIAR S, KLEINKNECHT C, ZHOU X, et al: Growth hormone actionis blunted by acidosis in experimental uremia or acid load. ClinNephrol 46:72–76, 1996

59. CHALLA A, CHAN W, KRIEG RJ, JR, et al: Effect of metabolic aci-dosis on the expression of insulin-like growth factor and growthhormone receptor. Kidney Int 44:1224–1227, 1993

60. BRUNGGER M, HULTER HN, KRAPF R: Effect of chronic metabolicacidosis on the growth hormone/IGF-1 endocrine axis: New causeof growth hormone insensitivity in humans. Kidney Int 51:216–221,1997

61. MITCH WE, GOLDBERG AL: Mechanisms of muscle wasting. Therole of the ubiquitin-proteasome pathway. N Engl J Med 335:1897–1905, 1996

62. DEFRONZO RA, BECKLES AD: Glucose intolerance followingchronic metabolic acidosis in man. Am J Physiol 236:E328–334,1979

63. BELLOCQ A, SUBERVILLE S, PHILIPPE C, et al: Low environmen-tal pH is responsible for the induction of nitric-oxide synthase inmacrophages. Evidence for involvement of nuclear factor-kappaBactivation. J Biol Chem 273:5086–5092, 1998

64. LIN SH, LIN YF, CHIN HM, WU CC: Must metabolic acidosis beassociated with malnutrition in haemodialysed patients? NephrolDial Transplant 17:2006–2010, 2002

65. ODAMAKI M, FURUYA R, YONEYAMA T, et al: Association of theserum leptin concentration with weight loss in chronic hemodial-ysis patients. Am J Kidney Dis 33:361–368, 1999

66. HEIMBURGER O, LONNQVIST F, DANIELSSON A, et al: Serum im-munoreactive leptin concentration and its relation to the body fatcontent in chronic renal failure. J Am Soc Nephrol 8:1423–1430,1997

67. STENVINKEL P, LINDHOLM B, LONNQVIST F, et al: Increases in serumleptin levels during peritoneal dialysis are associated with inflam-mation and a decrease in lean body mass. J Am Soc Nephrol11:1303–1309, 2000

68. TETA D, BEVINGTON A, BROWN J, et al: Effects of acidosis on lep-tin secretion from 3T3-L1 adipocytes and on serum leptin in theuraemic rat. Clin Sci (Lond) 97:363–368, 1999

69. HATHOUT EH, SHARKEY J, RACINE M, et al: Changes in plasma leptinduring the treatment of diabetic ketoacidosis. J Clin EndocrinolMetab 84:4545–4548, 1999

70. FLUCK CE, KUHLMANN BV, MULLIS PE: Insulin increases serumleptin concentrations in children and adolescents with newly di-agnosed type I diabetes mellitus with and without ketoacidosis.Diabetologia 42:1067–1070, 1999

71. ZHENG F, QIU X, YIN S, LI Y: Changes in serum leptin levels inchronic renal failure patients with metabolic acidosis. J Ren Nutr11:207–211, 2001

72. KOKOT F, CHUDEK J, ADAMCZAK M, WIECEK A: Interrelationshipbetween plasma leptin concentration and severity of metabolicacidosis in haemodialysed patients with chronic renal failure. ExpClin Endocrinol Diabetes 109:370–373, 2001

73. KANG SW, LEE SW, LEE IH, et al: Impact of metabolic acidosison serum albumin and other nutritional parameters in long-termCAPD patients. Adv Perit Dial 13:249–252, 1997

74. URIBARRI J: Moderate metabolic acidosis and its effects on nutri-tional parameters in hemodialysis patients. Clin Nephrol 48:238–240, 1997

75. DUMLER F, FALLA P, BUTLER R, et al: Impact of peritoneal dialysismodality and acidosis on nutritional status in peritoneal dialysispatients. Adv Perit Dial 14:205–208, 1998

76. GE YQ, WU ZL, XU YZ, LIAO LT: Study on nutritional status ofmaintenance hemodialysis patients. Clin Nephrol 50:309–314, 1998

77. MOVILLI E, BOSSINI N, VIOLA BF, et al: Evidence for an independentrole of metabolic acidosis on nutritional status in haemodialysispatients. Nephrol Dial Transplant 13:674–678, 1998

78. DUMLER F, FALLA P, BUTLER R, et al: Impact of dialysis modalityand acidosis on nutritional status. Asaio J 45:413–417, 1999

79. URIBARRI J, LEVIN NW, DELMEZ J, et al: Association of acidosis andnutritional parameters in hemodialysis patients. Am J Kidney Dis34:493–499, 1999

80. GAO H, LEW SQ, BOSCH JP: Moderate metabolic acidosis and itseffects on serum parameters in hemodialysis patients. Nephron86:135–138, 2000


81. LEAVEY SF, STRAWDERMAN RL, YOUNG EW, et al: Cross-sectionaland longitudinal predictors of serum albumin in hemodialysis pa-tients. Kidney Int 58:2119–2128, 2000

82. CHAUVEAU P, FOUQUE D, COMBE C, et al: Acidosis and nutritionalstatus in hemodialyzed patients. French Study Group for Nutritionin Dialysis. Semin Dial 13:241–246, 2000

83. KUNG SC, MORSE SA, BLOOM E, RAJA RM: Acid-base balance andnutrition in peritoneal dialysis. Adv Perit Dial 17:235–237, 2001

84. SEYFFART G, ENSMINGER A, SCHOLZ R: Increase of body mass dur-ing long-term bicarbonate hemodialysis. Kidney Int Suppl 22:S174–177, 1987

85. ROBERTS RG, GILMOUR ER, GOODSHIP TH: The correction of aci-dosis does not increase dietary protein intake in chronic renal fail-ure patients. Am J Kidney Dis 28:350–353, 1996

86. WILLIAMS AJ, DITTMER ID, MCARLEY A, CLARKE J: High bi-carbonate dialysate in haemodialysis patients: Effects on acido-sis and nutritional status. Nephrol Dial Transplant 12:2633–2637,1997

87. BRADY JP, HASBARGEN JA: Correction of metabolic acidosis and itseffect on albumin in chronic hemodialysis patients. Am J KidneyDis 31:35–40, 1998

88. MOVILLI E, ZANI R, CARLI O, et al: Correction of metabolic acidosisincreases serum albumin concentrations and decreases kineticallyevaluated protein intake in haemodialysis patients: A prospectivestudy. Nephrol Dial Transplant 13:1719–1722, 1998

89. VEROVE C, MAISONNEUVE N, EL AZOUZI A, et al: Effect of the cor-rection of metabolic acidosis on nutritional status in elderly pa-tients with chronic renal failure. J Ren Nutr 12:224–228, 2002

90. STEIN A, MOORHOUSE J, ILES-SMITH H, et al: Role of an improve-ment in acid-base status and nutrition in CAPD patients. KidneyInt 52:1089–1095, 1997

91. GOODMAN AD, LEMANN JJ, LITZOW JR: Production, excretion andnet balance in patients with renal disease. J Clin Invest 44:495–506,1965

92. LITZOW JR, LEMANN J, JR, LENNON EJ: The effect of treatment ofacidosis on calcium balance in patients with chronic azotemic renaldisease. J Clin Invest 46:280–286, 1967

93. ALPERN RJ, SAKHAEE K: The clinical spectrum of chronic metabolicacidosis: Homeostatic mechanisms produce significant morbidity.Am J Kidney Dis 29:291–302, 1997

94. URIBARRI J, DOUYON H, OH MS: A re-evaluation of the urinary pa-rameters of acid production and excretion in patients with chronicrenal acidosis. Kidney Int 47:624–627, 1995

95. BUSHINSKY DA: Net calcium efflux from live bone during chronicmetabolic, but not respiratory, acidosis. Am J Physiol 256:F836–842, 1989

96. KRAUT JA, MISHLER DR, KUROKAWA K: Effect of colchicine andcalcitonin on calcemic response to metabolic acidosis. Kidney Int25:608–612, 1984

97. KRAUT JA, MISHLER DR, SINGER FR, GOODMAN WG: The effectsof metabolic acidosis on bone formation and bone resorption inthe rat. Kidney Int 30:694–700, 1986

98. FRICK KK, BUSHINSKY DA: Chronic metabolic acidosis reversiblyinhibits extracellular matrix gene expression in mouse osteoblasts.Am J Physiol 275:F840–847, 1998

99. GOLDHABER P, RABADJIJA L: H+ stimulation of cell-mediated boneresorption in tissue culture. Am J Physiol 253:E90–98, 1987

100. RABADJIJA L, BROWN EM, SWARTZ SL, et al: H(+)-stimulated re-lease of prostaglandin E2 and cyclic adenosine 3′,5′-monophos-phoric acid and their relationship to bone resorption in neonatalmouse calvaria cultures. Bone Miner 11:295–304, 1990

101. KRIEGER NS, PARKER WR, ALEXANDER KM, BUSHINSKY DA:Prostaglandins regulate acid-induced cell-mediated bone resorp-tion. Am J Physiol Renal Physiol 279:F1077–1082, 2000

102. BUSHINSKY DA, PARKER WR, ALEXANDER KM, KRIEGER NS:Metabolic, but not respiratory, acidosis increases bone PGE(2)levels and calcium release. Am J Physiol Renal Physiol 281:F1058–1066, 2001

103. KRIEGER NS, FRICK KK, BUSHINSKY DA: Cortisol inhibits acid-induced bone resorption in vitro. J Am Soc Nephrol 13:2534–2539,2002

104. LEMANN J, JR, LITZOW JR, LENNON EJ: The effects of chronic acidloads in normal man: further evidence for the participation of bone

mineral in the defense against chronic metabolic acidosis. J ClinInvest 45:1608–1614, 1966

105. SUTTON RA, WONG NL, DIRKS JH: Effects of metabolic acidosisand alkalosis on sodium and calcium transport in the dog kidney.Kidney Int 15:520–533, 1979

106. COCHRAN M, WILKINSON R: Effect of correction of metabolic acido-sis on bone mineralisation rates in patients with renal osteomalacia.Nephron 15:98–110, 1975

107. LEVINE BS, HO K, KRAUT JA, et al: Effect of metabolic acido-sis on phosphate transport by the renal brush-border membrane.Biochim Biophys Acta 727:7–12, 1983

108. KRAPF R, VETSCH R, VETSCH W, HULTER HN: Chronicmetabolic acidosis increases the serum concentration of 1,25-dihydroxyvitamin D in humans by stimulating its production rate.Critical role of acidosis-induced renal hypophosphatemia. J ClinInvest 90:2456–2463, 1992

109. AMBUHL PM, ZAJICEK HK, WANG H, et al: Regulation of renalphosphate transport by acute and chronic metabolic acidosis inthe rat. Kidney Int 53:1288–1298, 1998

110. BUSHINSKY DA, LECHLEIDER RJ: Mechanism of proton-inducedbone calcium release: calcium carbonate-dissolution. Am J Physiol253:F998–1005, 1987

111. BUSHINSKY DA, LAM BC, NESPECA R, et al: Decreased bone carbon-ate content in response to metabolic, but not respiratory, acidosis.Am J Physiol 265:F530–536, 1993

112. SEBASTIAN A, HARRIS ST, OTTAWAY JH, et al: Improved min-eral balance and skeletal metabolism in postmenopausal womentreated with potassium bicarbonate. N Engl J Med 330:1776–1781,1994

113. OH MS: Irrelevance of bone buffering to acid-base homeostasis inchronic metabolic acidosis. Nephron 59:7–10, 1991

114. OH MS: New perspectives on acid-base balance. Semin Dial13:212–219, 2000

115. PELLEGRINO ED, BILTZ RM: The composition of human bonein uremia. Observations on the reservoir functions of bone anddemonstration of a labile fraction of bone carbonate. Medicine(Baltimore) 44:397–418, 1965

116. KAYE M, FRUEH AJ, SILVERMAN M, et al: A study of vertebralbone powder from patients with chronic renal failure. J Clin Invest49:442–453, 1970

117. PELLEGRINO ED, BILTZ RM, LETTERI JM: Inter-relationships ofcarbonate, phosphate, monohydrogen phosphate, calcium, mag-nesium and sodium in uraemic bone: Comparison of dialysed andnon-dialysed patients. Clin Sci Mol Med 53:307–316, 1977

118. INGHAM JP, KLEEREKOPER M, STEWART JH, POSEN S: Symptomaticskeletal disease in non-terminal renal failure. Med J Aust 1:873–876, 1974

119. MORA PALMA FJ, ELLIS HA, COOK DB, et al: Osteomalacia in pa-tients with chronic renal failure before dialysis or transplantation.Q J Med 52:332–348, 1983

120. COEN G, MANNI M, ADDARI O, et al: Metabolic acidosis and os-teodystrophic bone disease in predialysis chronic renal failure: Ef-fect of calcitriol treatment. Miner Electrolyte Metab 21:375–382,1995

121. HEAF J, TVEDEGAARD E, KANSTRUP IL, FOGH-ANDERSEN N: Boneloss after renal transplantation: Role of hyperparathyroidism, aci-dosis, cyclosporine and systemic disease. Clin Transplant 14:457–463, 2000

122. LIN YF, SHIEH SD, DIANG LK, et al: Influence of rapid correctionof metabolic acidosis on serum osteocalcin level in chronic renalfailure. Asaio J 40:M440–444, 1994

123. CHU P, LU KC, LIN YF: Acute correction of metabolic acidosisincreases serum procollagen type I carboxyterminal propeptide inpatients with chronic renal failure. J Formos Med Assoc 100:748–752, 2001

124. MOORE EW: Ionized calcium in normal serum, ultrafiltrates, andwhole blood determined by ion-exchange electrodes. J Clin Invest49:318–334, 1970

125. COE FL, FIRPO JJ, JR, HOLLANDSWORTH DL, et al: Effect of acute andchronic metabolic acidosis on serum immunoreactive parathyroidhormone in man. Kidney Int 8:263–273, 1975

126. GRAHAM KA, HOENICH NA, TARBIT M, et al: Correction of aci-dosis in hemodialysis patients increases the sensitivity of the


parathyroid glands to calcium. J Am Soc Nephrol 8:627–631,1997

127. ST JOHN A, THOMAS MB, DAVIES CP, et al: Determinants of intactparathyroid hormone and free 1,25-dihydroxyvitamin D levels inmild and moderate renal failure. Nephron 61:422–427, 1992

128. LEFEBVRE A, VERNEJOUL MC, GUERIS J, et al: Optimal correctionof acidosis changes progression of dialysis osteodystrophy. KidneyInt 36:1112–1118, 1989

129. LU KC, SHIEH SD, LI BL, et al: Rapid correction of metabolicacidosis in chronic renal failure: Effect on parathyroid hormoneactivity. Nephron 67:419–424, 1994

130. MOVILLI E, ZANI R, CARLI O, et al: Direct effect of the correc-tion of acidosis on plasma parathyroid hormone concentrations,calcium and phosphate in hemodialysis patients: A prospectivestudy. Nephron 87:257–262, 2001

131. BECK N, KIM HP, KIM KS: Effect of metabolic acidosis on renalaction of parathyroid hormone. Am J Physiol 228:1483–1488, 1975

132. MARTIN KJ, FREITAG JJ, BELLORIN-FONT E, et al: The effect of acuteacidosis on the uptake of parathyroid hormone and the productionof adenosine 3′,5′-monophosphate by isolated perfused bone. En-docrinology 106:1607–1611, 1980

133. BUSHINSKY DA, NILSSON EL: Additive effects of acidosis andparathyroid hormone on mouse osteoblastic and osteoclastic func-tion. Am J Physiol 269:C1364–1370, 1995

134. DISTHABANCHONG S, MARTIN KJ, MCCONKEY CL, GONZALEZ EA:Metabolic acidosis up-regulates PTH/PTHrP receptors in UMR106–01 osteoblast-like cells. Kidney Int 62:1171–1177, 2002

135. KRAUT JA: The role of metabolic acidosis in the pathogen-esis of renal osteodystrophy. Adv Ren Replace Ther 2:40–51,1995

136. LANGMAN CB: Calcitriol metabolism during chronic metabolic aci-dosis. Semin Nephrol 9:65–71, 1989

137. GAFTER U, KRAUT JA, LEE DB, et al: Effect of metabolic acidosisin intestinal absorption of calcium and phosphorus. Am J Physiol239:G480–484, 1980

138. LU KC, LIN SH, YU FC, et al: Influence of metabolic acidosis onserum 1,25(OH)2D3 levels in chronic renal failure. Miner Elec-trolyte Metab 21:398–402, 1995

139. MAK RH: Effect of metabolic acidosis on hyperlipidemia in uremia.Pediatr Nephrol 13:891–893, 1999

140. HARRIS DC, YUILL E, CHESHER DW: Correcting acidosis inhemodialysis: Effect on phosphate clearance and calcification risk.J Am Soc Nephrol 6:1607–1612, 1995

141. HOCHMAN JH, JIANG H, MATYUS L, et al: Endocytosis and disso-ciation of class I MHC molecules labeled with fluorescent beta-2microglobulin. J Immunol 146:1862–1867, 1991

142. POLAKOVA K, KARPATOVA M, RUSS G: Dissociation of beta 2-microglobulin is responsible for selective reduction of HLA classI antigenicity following acid treatment of cells. Mol Immunol30:1223–1230, 1993

143. SONIKIAN M, GOGUSEV J, ZINGRAFF J, et al: Potential ef-fect of metabolic acidosis on beta 2-microglobulin generation:in vivo and in vitro studies. J Am Soc Nephrol 7:350–356,1996

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