Kidney International, Vol. 67, Supplement 95 (2005), pp. S21–S27

Risks of chronic metabolic acidosis in patients with chronickidney disease

JOEL D. KOPPLE, KAMYAR KALANTAR-ZADEH, and RAJNISH MEHROTRA

Division of Nephrology and Hypertension, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center; and theDavid Geffen School of Medicine at UCLA and UCLA School of Public Health, Los Angeles, California

Risks of chronic metabolic acidosis in patients with chronic kid-ney disease. Metabolic acidosis is associated with chronic renalfailure (CRF). Often, maintenance dialysis therapies are notable to reverse this condition. The major systemic consequencesof chronic metabolic acidosis are increased protein catabolism,decreased protein synthesis, and a negative protein balance thatimproves after bicarbonate supplementation. Metabolic acido-sis also induces insulin resistance and a decrease in the elevatedserum leptin levels associated with CRF. These three factorsmay promote protein catabolism in maintenance dialysis pa-tients. Available data suggest that metabolic acidosis is bothcatabolic and anti-anabolic. Several clinical studies have shownthat correction of metabolic acidosis in maintenance dialysispatients is associated with modest improvements in nutritionalstatus. Preliminary evidence indicates that metabolic acidosismay play a role in b2-microglobulin accumulation, as well asthe hypertriglyceridemia seen in renal failure. Interventionalstudies for metabolic acidosis have yielded inconsistent resultsin CRF and maintenance hemodialysis patients. In chronic peri-toneal dialysis patients, the mitigation of acidemia appears moreconsistently to improve nutritional status and reduce hospi-talizations. Large-scale, prospective, randomized interventionalstudies are needed to ascertain the potential benefits of correct-ing acidemia in maintenance hemodialysis patients. To avoidadverse events, an aggressive management approach is neces-sary to correct metabolic acidosis. Clinicians should attemptto adhere to the National Kidney Foundation Kidney DiseaseOutcome Quality Initiative (K/DOQI) guidelines for mainte-nance dialysis patients. The guidelines recommend maintenanceof serum bicarbonate levels at 22 mEq/L or greater.

Advanced chronic renal failure (CRF) often results inmetabolic acidosis, a process that promotes an increase inhydrogen ions in the body. Metabolic acidosis in CRF isthe result of a decreased ability to excrete nonvolatile acidand the reduced renal synthesis of bicarbonate. Mainte-nance dialysis therapies are often not able to completelycorrect the base deficit. In patients on maintenance dial-ysis, severe metabolic acidosis is associated with an in-creased relative risk for death. However, many epidemi-

Key words: metabolic acidosis, chronic renal failure, maintenance dial-ysis.

C© 2005 by the International Society of Nephrology

ologic studies on patients undergoing maintenance dialy-sis have indicated a paradoxically inverse association be-tween mildly decreased serum bicarbonate and improvedmarkers of protein-energy nutritional state. This reviewwill discuss the risk of chronic metabolic acidosis in pa-tients with CRF, with regard to its effect on nutritionalstatus and bone metabolism.

METABOLIC ACIDOSIS

Severe chronic metabolic acidosis (i.e., the presence ofexcess hydrogen ions in blood) has two well-recognizedmajor systemic consequences. First, metabolic acidosis,or acidemia, induces increased protein catabolism, de-creased protein synthesis, and negative nitrogen andtotal body protein balance, which improve upon bi-carbonate supplementation. Second, metabolic acidosiscauses physicochemical dissolution of bone and cell-mediated bone resorption (inhibition of osteoblast andstimulation of osteoclast function).

To avoid a misdiagnosis of metabolic acidosis, it is im-portant to handle blood specimens with utmost care. Un-derfilling of sample tubes may lead to evanescence of car-bon dioxide, which results in falsely low values [1]. Thetransportation of blood specimens—particularly via air—to distant laboratories, could lead to loss of total CO2 andoverestimation of the magnitude of acidosis. The meanCO2 level of shipped blood samples is 5 mEq/L lowerthan that of blood samples processed immediately [2].Also, serum bicarbonate measurements may suggest aninaccurately increased bicarbonate level, because the to-tal serum CO2 measurement usually overestimates theserum bicarbonate concentration. Thus, it is importantto exercise caution when interpreting serum chemistrymeasurements that indicate metabolic acidosis in main-tenance dialysis patients.

METABOLIC ACIDOSIS AND NUTRITION

In 1931, Lyon et al were the first investigators to sug-gest a potential link between metabolic acidosis and thenutritional status of patients with CRF (reviewed by

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1Patient 2 3 4 5 66543210

−1−2

40

30

20

10

0

Nitrogenbalance

(gr/24 hrs)

Potassiumbalance

(mEq/24 hrs)

Control period

Sodiumbicarbonateperiod

Fig. 1. Nitrogen and potassium balance in 6 nondialyzed uremic pa-tients pre- and postsupplementation with sodium bicarbonate. (From[4]).

Mehrotra et al [3]). Additional literature has subse-quently suggested that metabolic acidosis may play animportant role in the pathogenesis of nutritional ab-normalities associated with uremia. Increased proteincatabolism, decreased protein synthesis, increased insulinresistance, inflammation, and reduced serum leptin levelsare 5 potential mechanisms by which metabolic acidosiscould contribute to these nutritional abnormalities.

Catabolic effects: The ubiquitin-proteosome system

Multiple studies suggest that metabolic acidosis couldcause negative nitrogen balance in CRF patients, as wellas in healthy individuals. Papadoyannakis et al measurednitrogen and potassium levels in 6 nondialyzed uremic in-dividuals before and after supplementation with sodiumchloride and sodium bicarbonate [4]. A significant de-crease in blood urea nitrogen and a positive nitrogen andpotassium balance were detected during bicarbonate sup-plementation (Fig. 1).

There are several studies that have investigated theeffect of metabolic acidosis on protein metabolism [5–8], and all but one study [5] have shown that metabolicacidosis promotes proteolysis. In general, treatment toincrease blood pH from acidemic levels to normal levelsresulted in a decrease in protein degradation. Table 1summarizes data from these studies, obtained frompatients with varying stages of renal failure [5–8].Researchers believe that metabolic acidosis promotesprotein degradation by stimulation of the ubiquitin-proteosome system, through which proteins are gener-ally targeted for digestion to peptides and amino acids.Acidemia causes an increase in gene transcription for theproteosome and increased ubiquitin synthesis. Increasedactivity of the proteolytic enzyme caspase-3 and the ATP-dependent ubiquitin-proteosome pathway has been im-

plicated in mediating the catabolic effects of metabolicacidosis in CRF in both human and animal model sys-tems [9]. For example, Bailey et al observed that in uremicrats metabolic acidemia is associated with increased pro-tein degradation and amino acid oxidation. The mRNAfor proteosome and ubiquitin in skeletal muscle cells wasalso found to be elevated. The addition of sodium bicar-bonate to the diet of these animals resulted in a reversalof protein degradation [10].

Pickering et al made a similar observation in studiesof muscle mRNA from patients with CRF. A significantdecrease in ubiquitin mRNA abundance was seen after 4weeks of bicarbonate treatment [11]. In addition, studiesin isolated rat skeletal muscles exposed to an inhibitor ofthe proteosome, or depleted of ATP, in the presence ofmetabolic acidosis, have demonstrated that the increasedprotein degradation induced by metabolic acidemia wasabolished. These observations indicate that the ubiquitin-proteosome pathway is an important mechanism for pro-tein catabolism associated with metabolic acidemia.

Catabolic effects: Branched-chain aminoacids metabolism

Branched-chain amino acids (BCAA) are often alteredin pathologic conditions associated with metabolic acido-sis. Studies in rats, as well as in isolated skeletal musclecells, have shown that acidosis stimulates the breakdownof BCAA. Metabolic acidosis increases the gene tran-scription for an enzyme called branched chain keto-aciddehydrogenase (BCKAD). This enzyme degrades 3 es-sential branched chain amino acids: leucine, isoleucine,and valine [12].

Lower levels of plasma and muscle BCAA are re-ported in patients undergoing maintenance dialysis ther-apy, as well as in animal models of metabolic acidosis[13, 14]. Correction of metabolic acidosis in patients onmaintenance hemodialysis results in an increase in theplasma BCAA levels, as seen in Figure 2 [14]. Theseobservations suggest that patients suffering from CRFassociated with metabolic acidosis experience increasedactivity of BCKAD, which causes increased catabolismof BCAA. Thus, increased activity of caspase-3, theATP-dependent ubiquitin-proteasome and BCKAD ap-pears to contribute significantly to the negative nitro-gen balance observed in uremic patients with metabolicacidemia.

Anti-anabolic effects of metabolic acidosis

Metabolic acidosis possibly may decrease protein syn-thesis and produce anti-anabolic effects. Cell culture stud-ies of myocytes in an acidic medium have shown reducedprotein synthesis, and some studies of metabolic acido-sis in humans demonstrate analogous results. Induction ofmetabolic acidosis in normal individuals with ammonium

Kopple et al: Risks of chronic metabolic acidosis in CKD patients S-23

Table 1. Improvement in metabolic acidosis and protein turnover: Summary of controlled studies in CRF patients

First No. of Stage of Baseline Final Protein Protein Amino acidauthor subjects renal failure pH pH synthesis degradation oxidation

Reaich [6] 9 Nondialyzed 7.31 7.38 Decreased Decreased DecreasedGraham [7] 7 CPD 7.39 7.41 Decreased Decreased No changeGraham [8] 6 MHD 7.36 7.4 Decreased Decreased No changeLim [5] 8 Nondialyzed 7.29 7.39 No change No change Increased

Abbreviations: CPD, chronic peritoneal dialysis; MHD, maintenance hemodialysis.

0

20

40

60

80

100

120

% o

f con

trol

Before

After

Fig. 2. Branched chain amino acid levels measured in 9 hemodialysispatients before and after 6 months of bicarbonate treatment. A signifi-cant increase in the concentration of valine, leucine, and isoleucine wasseen on correction of the metabolic acidosis. (From [4]).

chloride caused a significant reduction in the fractionalsynthetic rate of muscle protein, while the fractional andabsolute rate of albumin synthesis remained unchanged[15]. Conversely, in another study, chronic ammoniumchloride-induced metabolic acidosis was reported to sig-nificantly reduce the fractional synthetic rate of albumin[16]. In light of these conflicting findings, the applicabil-ity of these observations to metabolic acidosis in CRF isuncertain, and additional data are needed to determinethe effects of metabolic acidosis associated with CRF onprotein synthesis. Figure 3 summarizes the mechanismsby which metabolic acidosis could induce protein energymalnutrition [3].

The anti-anabolic effects of ammonium chloride-induced metabolic acidosis could arise from possible al-terations in 1 or more of 4 hormonal systems. First,metabolic acidosis could reduce the release of growthhormone. Experimental data suggest that peripheral re-sistance to growth hormone could result from metabolicacidosis. Second, metabolic acidemia may induce insulinresistance (see below). Third, in both human subjects andanimal studies, plasma levels of insulin-like growth factor(IGF) and the hepatic content of IGF-1 mRNA, are sig-nificantly reduced in metabolic acidosis. Fourth, the an-abolic effects of thyroid hormone and the reduced thyroidfunction induced by metabolic acidosis could contributeto decreased synthesis of muscle protein.

A modest, though significant, increase in the levelsof thyroid-stimulating hormone has been reported inacute metabolic acidosis, without any change in the lev-

els of free triiodothyronine (T3). Chronic acidosis inhuman subjects, however, is associated with significantlyreduced T3 levels, with no change in the levels of thyroid-stimulating hormone. Additional studies are required todetermine the relative contributions of these hormonalsystems to the altered anabolic and catabolic pathways inCRF (reviewed by Mehrotra et al in [3]). In sum, thesedata suggest that metabolic acidosis has both catabolicand anti-anabolic effects on nutritional status of patientswith CRF. Figure 3 summarizes the catabolic and anti-anabolic effects of metabolic acidosis.

Hormonal triggers in metabolic acidosis

Despite recent progress made in understanding themolecular mechanisms of proteolysis in the setting ofmetabolic acidosis, other triggers that activate these path-ways are not fully understood.

Cortisol

Ammonium chloride-induced metabolic acidosis inadrenalectomized rats does not cause induction of pro-tein degradation, or an increase in the gene expressionof BCKAD or its activity, and does not lead to increasesin mRNA for the ubiquitin-proteosome system in mus-cle. Additionally, in rats with acidotic experimental renalfailure, the urinary excretion of corticosterone was sig-nificantly elevated when compared with control animals.These observations implicate glucocorticoids as a majorfactor necessary for the induction of the catabolic path-ways in metabolic acidosis. A direct, positive correlationof muscle protein degradation with plasma levels of cor-tisol, and a negative correlation with serum bicarbonatelevels, suggests that a combination of acidosis and glu-cocorticoids may be needed to stimulate muscle proteindegradation. However, other investigators have not beenable to demonstrate increased concentrations of cortisolin the setting of chronic metabolic acidosis (reviewed byMehrotra et al in [3]). Hence, the involvement of corticos-teroids in stimulating skeletal muscle protein degradationneeds further investigation.

Insulin resistance

It has been suggested that insulin resistance, a com-plication of CRF, plays a role in the activation of the

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Metabolic acidemia

↑ Activity of branched chainketoacid dehydrogenase

↑ Activity of caspase-3and the ATP-dependent

ubiquitin proteasome system

Increased muscle breakdownDecreased muscle protein synthesisdecreased albumin synthesis

Insulin resistance Inflammation

Reducedserum leptin

? Protectiveeffect

Protein-energy malnutrition

Fig. 3. Mechanisms by which metabolic acidosis may induce protein energy malnutrition. (From [3]).

ubiquitin-proteosome system. Administration of insulinto rats with diabetic ketosis eliminated excess prote-olysis, as well as the increased ubiquitin mRNA [17].Additionally, insulin-stimulated phosphorylation of theinsulin-receptor substrate-1 (IRS-1) phosphoinostitol-3kinase (PI-3 kinase) activity is significantly reduced inrats with renal failure. The activation of the ubiquitin-proteosome pathway and muscle protein degradation arethought to result from suppressed PI-3 kinase activity.Thus, glucocorticoids and low insulin levels may act intandem to activate the ubiquitin-proteosome pathway.

Leptin

Leptin, a protein encoded by the obese (ob) gene, isinvolved with food intake, energy expenditure, and bodyweight. It has been studied as a potential mediator ofprotein energy malnutrition. Circulating leptin is partlycleared by the kidney, and is reported to increase 3-foldin individuals with CRF compared with healthy controlswith similar body mass index [18]. Metabolic acidosis andhyperleptinemia are 2 common clinical findings in pa-tients with CRF. In animal studies, decreased leptin secre-tion has been observed in adipocytes exposed to relativelyacidic environments (pH 7.1). Sodium bicarbonate treat-ment of rats with renal failure showed significantly re-duced leptin levels, compared with untreated rats. Plasmaleptin concentrations were also lower in patients with di-abetic ketoacidosis compared with healthy individuals.Initiation of insulin therapy resulted in increased leptinlevels. Correcting the metabolic acidosis in nondialyzedindividuals with CRF resulted in increased serum leptin

levels [19]. However, Kokot et al were unable to demon-strate a correlation between blood hydrogen concentra-tions and serum leptin levels in a cross-sectional study of94 patients on maintenance hemodialysis [20]. The studydid, however, reveal a trend toward progressively lowermedian leptin concentrations with progressively higherblood hydrogen concentrations. Because increased serumleptin levels are associated with weight loss, a decreasein serum leptin levels could adaptively ameliorate thecatabolic effects of metabolic acidosis.

INFLAMMATION AND METABOLIC ACIDOSIS

Emerging evidence suggests that metabolic acido-sis may induce chronic inflammation (reviewed byMehrotra et al [3]). Increased production of a key inflam-matory cytokine—tumor necrosis factor a (TNFa)—byperitoneal macrophages incubated in an acidic cell cul-ture medium suggests a potential link between the in-flammatory process and metabolic acidosis. Two recentstudies have analyzed the link between metabolic acidosisand inflammation. In the first study, markers of inflamma-tion, serum C-reactive protein (CRP) and interleukin-6(IL-6), were evaluated in maintenance hemodialysis pa-tients. No significant difference in serum levels of CRPor IL-6 was seen in 3 groups of patients subdivided onthe basis of their serum CO2 levels [21]. In the secondstudy, correction of metabolic acidosis in 8 chronic peri-toneal dialysis patients was associated with significantlyreduced levels of TNFa [11]. It is important to mentionthat the acidic pH in these studies is 7.39 and the alka-line pH is 7.42, and metabolic changes are seen within

Kopple et al: Risks of chronic metabolic acidosis in CKD patients S-25

Metabolicacidosis

Directeffects

Indirecteffects

Vitamin D

Decreased 1αhydroxylase

Increased bindingto receptor

Increased receptorexpression

Increasedcirculating levels

Stimulation ofosteoclasts

Inhibition ofosteoblasts

Physicochemicaldissolution of

bone

Bone disease

Parathyroid hormone

Fig. 4. The various mechanisms by which metabolic acidosis may contribute to bone disease. (From [3]).

this narrow pH range. These observations raise an im-portant question as to whether there is an optimal pH formaintaining healthy nutritional status. In various studies,an increase in the pH from 7.23 to 7.7 of the cell culturemedium results in a progressive increase in the rate of pro-tein synthesis. Interestingly, at increased pH levels (pH>7.4), protein synthesis by skeletal muscles is enhanced,possibly suggesting an increased pH to be optimal foranabolism.

METABOLIC ACIDOSIS AND BONE DISEASE

Metabolic acidosis exerts multiple effects on bone. Itcauses the physicochemical dissolution of bone and cell-mediated bone resorption through the inhibition of os-teoblast activity and stimulation of osteoclast function.These events are associated with a loss of calcium andphosphorus from the bone. Metabolic acidosis stimulatesosteoblasts to release prostaglandins. This stimulates os-teoclast function and inhibits osteoblast activity. Gluco-corticoids can inhibit the production of prostaglandins byosteoblasts.

Metabolic acidosis is also associated with a decrease inthe content of bone bicarbonate. Additionally, bicarbon-ate supplementation in postmenopausal women is associ-ated with decreases in urinary calcium, phosphorus, andincreased osteocalcin levels, indicating a beneficial effect.Figure 4 shows the mechanisms relating metabolic aci-dosis with bone disease [3]. These observations suggestthat uncorrected metabolic acidosis has adverse conse-quences on bone anatomy and physiology.

METABOLIC ACIDOSIS AND SECONDARYHYPERPARATHYROIDISM

Metabolic acidosis is probably also associated withworsening of secondary hyperparathyroidism. Metabolic

acidosis may decrease the sensitivity of PTH secretionto elevated ionized calcium [22]. The effect of metabolicacidemia on serum PTH level is rather variable [23]. Onthe other hand, Lefebvre et al studied the role of aci-dosis on hemodialysis osteodystrophy in a group of 21patients dialyzed with varying amounts of HCO3 over an18-month interval [24]. These data show no increase inserum PTH levels in patients treated with higher dialysatebicarbonate. However, serum PTH levels increased sig-nificantly in patients with persistent metabolic acidosiswho were treated with standard dialysate bicarbonate.Additionally, other investigators report a decrease inserum PTH levels after correcting metabolic acidosis inmaintenance hemodialysis patients.

The combination of metabolic acidemia and elevatedserum levels of parathyroid hormone, such as is found inpatients with CRF, leads to a far greater efflux of Ca com-pared with either metabolic acidemia or hyperparathy-roidism alone (reviewed in Bushinsky and Frick [25] andBushinsky and Nilsson [26]). Correction of metabolicacidemia improves bone mineralization and histologyin maintenance hemodialysis patients. Thus, the avail-able data suggest that metabolic acidosis may lead toworsening of secondary hyperparathyroidism. Metabolicacidemia also reduces 1-alphahydroxylase activity in re-nal tubules of rats, but the effects on serum levels of 1,25-dihydroxycholecalciferol, the metabolic product of thisenzyme, are more difficult to ascertain [3, 27].

OTHER CLINICAL AND METABOLICALTERATIONS OF METABOLIC ACIDOSIS

Preliminary evidence also suggests that metabolicacidosis, in addition to its effects on protein andbone metabolism, may play a role in the accumula-tion of b-2 microglobulin, hypertriglyceridemia, malaise,

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hypotension, and in the resistance to catecholamines [28,29]. The small subunit of the MHC class I molecule, b-2microglobulin, is located on the cell membrane of manycells, including lymphocytes. Small amounts of b-2 mi-croglobulin are found in serum, plasma, and urine of nor-mal individuals, while elevated levels are often seen in theplasma and urine of patients with renal failure and kid-ney transplants. Studies using cell cultures as well as CRFpatients have shown increased mRNA, as well as serumlevels of b-2 microglobulin (reviewed by Mehrotra et alin [3]).

NATIONAL KIDNEY FOUNDATION KIDNEYDISEASE OUTCOME QUALITY INITIATIVEGUIDELINES FOR NUTRITION IN PATIENTSWITH CRF

The K/DQOI has developed guidelines for patientswith CRF. One is the monthly measuring of serum bi-carbonate levels in maintenance dialysis patients. It isrecommended that the predialysis or stabilized serum bi-carbonate should be maintained at ≥22 mEq/L in theseindividuals [30]. In patients with chronic kidney disease,stages 3, 4, and 5, the serum levels of total CO2 also shouldbe maintained at ≥22 mEq/L [31]. To achieve this goal,supplemental alkali should be given as required.

CONCLUSION

Uncorrected metabolic acidosis is detrimental to thenutritional status, may aggravate bone disease and, thus,may impact the overall health of maintenance hemodial-ysis patients. A small, persistent decrease in the rateof protein synthesis, or increase in protein degradation,could result in a substantial loss of muscle mass and de-velopment of more severe chronic bone disease, suchas that seen in patients with CRF and end-stage kid-ney disease. The caspase-3, ubiquitin-proteosome sys-tem targets proteins for degradation and may contributeto protein catabolism and negative protein balance inCRF. However, additional catabolic signals may con-tribute to this process. New information that identi-fies mechanisms involved in the complex pathways ofprotein catabolism is crucial with regard to developingnew therapies to prevent the loss of muscle mass inCRF. Based on currently available data, clinicians shouldadhere to the K/DOQI guidelines for maintenancedialysis patients and maintain predialysis bicarbonateconcentrations ≥22 mEq/L. Large-scale, prospective,randomized interventional studies are needed to as-certain the potential benefits of correcting acidemia inboth maintenance hemodialysis and chronic peritonealdialysis patients. An aggressive approach to correctingmetabolic acidosis seems indicated to help to prevent themultiple adverse consequences of this condition.

Reprint requests to Joel D. Kopple, M.D., Division of Nephrology& Hypertension, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, 1124 West Carson Street, C-1 Annex, Torrance,CA 90501–2052.E-mail: jkopple@labiomed.org

REFERENCES

1. HERR RD, SWANSON T: Serum bicarbonate declines with sample sizein vacutainer tubes. Am J Clin Pathol 97:213–216, 1992

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

3. MEHROTRA R, KOPPLE JD, WOLFSON M: Metabolic acidosis in main-tenance dialysis patients: Clinical considerations. Kidney Int (Suppl88):S13–S25, 2003

4. PAPADOYANNAKIS NJ, STEFANIDIS CJ, MCGEOWN M: The effect of thecorrection of metabolic acidosis on nitrogen and potassium balanceof patients with chronic renal failure. Am J Clin Nutr 40:623–627,1984

5. LIM VS, YARASHESKI KE, FLANIGAN MJ: The effect of uraemia, aci-dosis, and dialysis treatment on protein metabolism: A longitudi-nal leucine kinetic study. Nephrol Dial Transplant 13:1723–1730,1998

6. REAICH D, CHANNON SM, SCRIMGEOUR CM, et al: Correction of aci-dosis in humans with CRF decreases protein degradation and aminoacid oxidation. Am J Physiol 265:E230–E235, 1993

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

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

9. DU J, WANG X, MIERELES C, et al: Activation of caspase-3 is aninitial step triggering accelerated muscle proteolysis in catabolicconditions. J Clin Invest 113:115–123. 2004

10. BAILEY JL, WANG X, ENGLAND BK, et al: The acidosis of chronic renalfailure activates muscle proteolysis in rats by augmenting transcrip-tion of genes encoding proteins of the ATP-dependent ubiquitin-proteasome pathway. J Clin Invest 97:1447–1453, 1996

11. PICKERING WP, PRICE SR, BIRCHER G: Nutrition in CAPD: Serumbicarbonate and the ubiquitin-proteasome system in muscle. KidneyInt 61:1286–1292, 2002

12. 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

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

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

15. 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

16. BALLMER PE, MCNURLAN MA, HULTER HN, et al: Chronic metabolicacidosis decreases albumin synthesis and induces negative nitrogenbalance in humans. J Clin Invest 95:39–45, 1995

17. 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

18. 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

19. 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

20. KOKOT F, CHUDEK J, ADAMCZAK M, WIECEK A: Interrelationshipbetween plasma leptin concentration and severity of metabolic aci-dosis in haemodialysed patients with chronical renal failure. ExpClin Endocrinol Diabetes 109:370–373, 2001

Kopple et al: Risks of chronic metabolic acidosis in CKD patients S-27

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

22. GRAHAM KA, HOENICH NA, TARBIT M, et al: Correction of acidosisin hemodialysis patients increases the sensitivity of the parathyroidglands to calcium. J Am Soc Nephrol 8:627–631, 1997

23. COE FL, FIRPO JJ, Jr., HOLLANDSWORTH DL, et al: Effect of acute andchronic metabolic acidosis on serum immunoreactive parathyroidhormone in man. Kidney Int 8: 263–267, 1975

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

25. BUSHINSKY DA, FRICK KK: The effects of acid on bone. Curr OpinNephrol Hypertens. 9:369–379, 2000

26. BUSHINSKY DA, NILSSON EL: Additive effects of acidosis and

parathyroid hormone on mouse osteoblastic and osteoclastic func-tion. Am J Physiol 269:C1364–1370, 1995

27. KRAUT JA: The role of metabolic acidosis in the pathogenesis ofrenal osteodystrophy. Adv Ren Replace Ther 2:40–51, 1995

28. SONIKIAN M, GOGUSEV J, ZINGRAFF J, et al: Potential effect ofmetabolic acidosis on beta 2-microglobulin generation: In vivo andin vitro studies. J Am Soc Nephrol 7:350–356, 1996

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

30. NATIONAL KIDNEY FOUNDATION: K/DOQI clinical practice guidelinesfor nutrition in chronic renal failure. Am J Kidney Dis 35 (Suppl 2):S1–S140, 2000

31. NATIONAL KIDNEY FOUNDATION: K/DOQI clinical practice guidelinesfor bone metabolism and disease in chronic kidney disease. Am JKidney Dis 42 (Suppl 3):S1–S202, 2003