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Correction of Metabolic Acidosis to Ameliorate Wasting in Chronic Kidney Disease: Goals and Strategies
Correction of Metabolic Acidosis to Ameliorate Wasting in Chronic Kidney Disease: Goals and Strategies Yi-Wen Chiu, MD,* Joel D. Kopple, MD,†,‡,§ and Rajnish Mehrotra, MD†,‡ Summary: Metabolic acidosis is an important cause of protein-energy wasting, commonly observed in chronic kidney disease (CKD). This wasting is, in part, a result of the imbalance between protein degradation and synthesis induced by metabolic acidosis. The increase in protein degradation seen with metabolic acidosis is largely secondary to increased activities of the adenosine triphosphate– dependent, ubiquitin-proteasome system and branched-chain ketoacid dehydrogenase. Studies consistently have shown increased protein degradation with lower serum bicarbonate levels and/or arterial pH; however, the evidence for the anti-anabolic effects of metabolic acidosis is less consistent. In contrast to these metabolic studies, many cross-sectional studies have shown a direct relationship between the severity of metabolic acidosis and the adequacy of nutritional status in CKD patients. Moreover, lower serum bicarbonate levels have been associated with better survival in some epidemiologic studies of patients undergoing maintenance hemodialysis. It is likely that these relationships are confounded by the direct association of dietary protein intakes with metabolic acidosis— controlling the survival data for measures of dietary protein intakes, malnutrition, and inflammation shows a rather steep increase in the risk of death with lower serum bicarbonate levels. Two randomized controlled studies have shown that correction of metabolic acidosis is associated with reduction in risk for hospitalization in chronic peritoneal dialysis patients; the studies in maintenance hemodialysis patients have been small and inconsistent. For now, metabolic studies and data from clinical trials lend support to the recommendations made by the Nutrition Workgroup of the Kidney Disease Outcomes Quality Initiative to maintain serum bicarbonate levels of 22 mEq/L or greater in all CKD patients. Limited data suggest that a higher serum bicarbonate level (around 24 mEq/L) may be even more beneficial, particularly in chronic peritoneal dialysis patients. Semin Nephrol 29:67-74. © 2009 Published by Elsevier Inc. Keywords: Metabolic acidosis, protein-energy wasting, chronic kidney disease, dialysis
etabolic acidosis frequently is present in patients with chronic kidney disease (CKD) and has been associated with several complications of uremia.1,2 These com-
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*Division of Nephrology, Department of Internal Medicine, at Kaohsiung Medical University Hospital, Kaohsiung, Taiwan. †Division of Nephrology and Hypertension, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Los Angeles, CA. ‡David Geffen School of Medicine at UCLA, Los Angeles, CA. §UCLA School of Public Health, Los Angles, CA. Rajnish Mehrotra is supported by grants from the National Institutes of Health (RR18298), Satellite Health, and DaVita, Inc.; and has received research support from Amgen, Baxter Health Care, and Shire, honoraria from Baxter Health Care and Shire, and has served as a consultant for Novartis. Address reprint requests to Rajnish Mehrotra, MD, Division of Nephrology and Hypertension, Harbor-UCLA Medical Center, 1124 W. Carson St, Torrance, CA 90509. E-mail: [email protected] 0270-9295/09/$ - see front matter © 2009 Published by Elsevier Inc. doi:10.1016/j.semnephrol.2008.10.009
plications mainly include clinical wasting with loss of lean body mass and adverse effects on bone health.3 These adverse consequences probably underlie the association of low predialysis bicarbonate with higher morbidity and mortality in maintenance dialysis patients.4-6 Clinical Practice Guidelines for Nutrition in Chronic Renal Failure of the Kidney Disease Outcomes Quality Initiative of the National Kidney Foundation has recommended that the predialysis serum bicarbonate of maintenance hemodialysis (MHD) patients and the steady state serum bicarbonate levels of chronic peritoneal dialysis (CPD) patients and those with stage 3 and 4 CKD should be 22 mEq/L or greater.7 The clinical practice guidelines for bone metabolism and disease in CKD suggest similar target
Seminars in Nephrology, Vol 29, No 1, January 2009, pp 67-74
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serum bicarbonate levels.8 Since the initial publication, more data have accumulated that lend further support to these guidelines. In this article, we will limit the discussion to review the evidence that provides support for the correction of metabolic acidosis to prevent proteinenergy wasting in patients with CKD. Through this review of mechanisms of how metabolic acidosis causes wasting and the related crosssectional and interventional studies, we will try to suggest the optimal goals and strategies to ameliorate wasting in CKD. The issue of the best way to diagnose metabolic acidosis for day-to-day management of CKD patients is outside the scope of this discussion; measurement of serum bicarbonate remains the most widely used test. However, attention needs to be given to 2 important issues: optimal handling of blood specimens and effects of different phosphate binders on a patient’s acid-base status. Underfilling of the blood tube and shipping the specimen by flight overnight, as often is done in patients cared for in units owned by large dialysis organizations in the United States, decreases the total CO2 level and would result in overestimation of acidosis.9,10 Second, all phosphate binders available in the United States, other than sevelamer hydrochloride, are alkalis. Furthermore, sevelamer hydrochloride is an ion-exchange resin; binding with different anions results in the release of chloride and can lead to the development of a non– gap metabolic acidosis.11 For both of these reasons, patients treated with sevelamer hydrochloride are more likely to develop a metabolic acidosis with significantly lower serum bicarbonate levels.12,13 In patients
Y.-W. Chiu, J.D. Kopple, and R. Mehrotra
with persistent metabolic acidosis, it often is more appropriate to use phosphate binders other than sevelamer hydrochloride. MECHANISMS OF METABOLIC ACIDOSIS–INDUCED WASTING IN CKD Protein-energy wasting is manifested clinically as loss of body mass— both fat-free, edema-free mass (or lean body mass), and fat mass.14 A large body of laboratory and clinical evidence indicates that metabolic acidosis leads to wasting via the increased protein breakdown and possibly decreased protein synthesis (Fig. 1).15-18 Two major pathways have been identified to explain the higher protein breakdown associated with metabolic acidosis—increased activities of both the adenosine triphosphate–dependent ubiquitin-proteasome system and of the branched-chain ketoacid dehydrogenase. Ubiquitin, a small protein expressed ubiquitously in eukaryotes, plays an important role in protein turnover. When conjugated (usually 4-5 in a chain) to a protein in an adenosine triphosphate– dependent process, it is recognized by the 26S proteasome, which degrades the protein. Bailey et al19 reported that proteolysis in acidotic rats with CKD was associated with increased amounts of ubiquitin messenger RNA and subunits of the proteasome in skeletal muscle, and these changes could be reversed by feeding sodium bicarbonate. Inhibition of either adenosine triphosphate or the proteasome was noted to slow the degradation of protein induced by acidosis in rat muscle.19,20 In addition, activation of caspase-3, an enzyme involved with protein degradation and apoptosis,
Figure 1. Mechanisms whereby metabolic acidosis may induce protein-energy wasting in patients with CKD. The thick line indicates that there is strong evidence supporting the potential pathophysiologic mechanism.
Metabolic acidosis and protein-energy wasting
is activated by acidemic rats with chronic kidney failure and suppressed in these rats by feeding bicarbonate.21,22 Glucocorticoids may play a permissive role in inducing the catabolic effects of metabolic acidosis in skeletal muscle. In adrenalectomized rats with metabolic acidosis induced by NH4Cl, the increase in protein breakdown and higher messenger RNA of the ubiquitin proteasome system were abolished in these glucocorticoiddeficient animals and reappeared when glucocorticoids were given to the rats.23 Insulin has a direct effect on protein synthesis and degradation. Insulin resistance induced by acidosis may contribute to protein catabolism. Infusion of insulin, without correction of the ketoacidosis by feeding sodium bicarbonate, improved proteolysis and induced lesser up-regulation of the messenger RNA encoding for ubiquitin in rats with acute onset of diabetic ketoacidosis.24 The activity of insulin-receptor-substrate–associated phosphatidylinositol 3-kinase has been shown to be decreased in rats with CKD, which was normalized by insulin therapy and partially returned to control levels by correction of acidosis.22 These findings suggest that glucocorticoids and insulin resistance both play an important role in protein degradation. CKD also is associated with alternations of branched-chain amino acid (BCAA) metabolism. BCAAs account for more than 50% of the amino acid uptake in muscles and plays an important role in brain physiology and nutritional status. Uremic encephalopathy as well as protein-energy wasting in CKD are associated with abnormalities in BCAA metabolism.25 In CKD rats, metabolic acidosis is associated with lower serum and muscle levels of BCAA, suggesting higher rates of BCAA degradation.26 This increase in breakdown of BCAAs seems to be a result of an increase in the activity of branched-chain ketoacid dehydrogenase, a ratelimiting enzyme that is induced by metabolic acidosis.17 Finally, correction of acidosis is associated with higher plasma and intracellular BCAA levels in MHD patients.27,28 Decreased protein synthesis also might contribute to the protein-energy wasting induced by metabolic acidosis. In cell culture studies (L6 muscle cell), lower pH in the culture medium is
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associated with lower rates of protein synthesis, as ascertained by 14C-phenylalanine incorporation.29 Concentrations of albumin and transferrin also decreased in the supernatant of liver cell (HepG2) cultured in acid medium.30 Studies in human beings in which the effect of metabolic acidosis, and its correction, were evaluated using either N-balances or protein turnover using kinetic studies are summarized in Table 1.27,28,31-38 Virtually all of these studies show that acidosis is associated with increased protein degradation in patients with CKD. Furthermore, the correction of acidosis is associated with lower protein degradation in most studies. However, the effects of metabolic acidosis on protein synthesis in human studies are less consistent. CROSS-SECTIONAL AND LONGITUDINAL COHORT STUDIES OF THE EFFECTS OF METABOLIC ACIDOSIS ON NUTRITIONAL STATUS AND CLINICAL OUTCOMES IN CKD PATIENTS Despite the compelling laboratory evidence linking metabolic acidosis to protein-energy wasting, some epidemiologic studies have shown an inverse relationship between metabolic acidosis and nutritional status in CKD patients. Uribarri et al39 studied 995 MHD patients and reported an inverse relationship between serum total CO2 levels and dietary protein intake, normalized protein equivalent of total nitrogen appearance (nPNA), and predialysis serum potassium, phosphorus, and creatinine. Similar findings were observed, along with an inverse association between predialysis serum bicarbonate levels and albumin, in 2 larger cross-sectional studies of MHD patients (n ⫽ 3,891 and 7,123, respectively).40,41 However, if one accounts for the higher dietary protein intakes in patients with metabolic acidosis (by multivariate adjustment for nPNA), the inverse association between albumin and bicarbonate is reduced to a nonsignificant level.40 Consistent with these observations, post hoc analyses of the data from the Modification of Diet in Renal Disease study also showed an inverse association between serum total CO2 and dietary protein intakes.42 These studies allow us to make a few simple observations and inferences. First, higher protein intakes gener-
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Y.-W. Chiu, J.D. Kopple, and R. Mehrotra
Table 1. Summaries of Controlled, Metabolic Studies in Human Beings With CKD That Suggest That Metabolic Acidosis Promotes Catabolism Study
No. of Stage of Renal Subjects Failure
Papadoynnakis et al,31 1984
6
Williams et al,33 1991
6
Reaich et al,32 1993
9
Garibotto et al,34 1994
9
Graham et al,35 1996
7
Graham et al,36 1997
6
Lofberg et al,28 1997
9
Lim et al,37 1998
9
Boirie et al,38 2000
10
Lofberg et al,27 2006
16
Nondialyzed (SB)
Baseline pH/HCO3 */15.8
Final pH/HCO3 */23.4
Biologic Phenomena Studied
Results of Correction of Metabolic Acidosis
N- and K-balance
Both N- and K-balances improved Nondialyzed (SB) 7.28/17.0 7.35/24.3 Urine 3-methyl histidine: In patients on low-protein creatinine ratio (index diets, ratio increased in of skeletal muscle the presence of catabolism) metabolic acidosis; reduced with NaHCO3 supplementation Nondialyzed (SB) 7.31/15 7.38/21 L[1-13C]leucine kinetics Reduced protein degradation, synthesis, and leucine oxidation Net phenylalanine release Nondialyzed */20 *(Not corrected) 3H-phenylalanine kinetics inversely related to degree of acidosis CPD (SB) 7.39/19.3† 7.41/26.2† L[1-13C]leucine kinetics Reduced whole-body protein degradation and synthesis; no effect on leucine oxidation MHD (D) 7.36/18.5† 7.40/24.8† L[1-13C]leucine kinetics Reduced whole-body protein degradation and synthesis; no effect on leucine oxidation MHD (D) */20.6 */25.9 Intracellular BCAAs Increased intracellular concentrations of BCAAs Nondialyzed (SB) 7.29/19.0† 7.39/25.5† L[1-13C]leucine kinetics Significant decrease in leucine oxidation, insignificant decrease in protein degradation, and increase in synthesis Nondialyzed */19.2 *(Not corrected) L[1-13C]leucine kinetics Acidotic children had higher rates of protein degradation 3H-phenylalanine Decreased net amino acid MHD (D) 7.33/18.2 7.44/26.8 kinetics efflux and appearance; unchanged disposal (oxidation ⫹ synthesis)
Abbreviations: SB, acidosis corrected by oral sodium bicarbonate; D, acidosis corrected through dialysate. *Data not available or applicable. †Total CO2 value.
ally are associated with a higher acid generation that, in turn, is associated with lower predialysis bicarbonate levels. Patients with higher protein intakes tend to be healthier and thus have higher values for serum albumin and other measures of nutritional status. The inverse association between metabolic acidosis and nutritional status therefore probably is secondary to the confounding influence of dietary protein intakes. Thus, the inverse association seen in these epidemiologic studies does not imply that the outcome of patients cannot be improved by correction of metabolic acidosis, nor should it engender therapeutic nihilism.
With regard to mortality, in MHD patients enrolled in the Dialysis Outcomes and Practice Patterns Study, a U-shaped association was observed between the serum predialysis bicarbonate level and mortality.5 The lowest risk for death and hospitalization was found in the group of patients with serum predialysis bicarbonate levels between 20.1 and 21.0 mEq/L. Similar findings had been shown in analyses of about 12,000 patients treated in Fresenius Medical Care clinics (Waltham, MA), wherein the lowest risk was seen in patients with serum bicarbonate levels between 20.0 and 22.5 mmol/L.4 The higher risk for death in patients with the highest
Metabolic acidosis and protein-energy wasting
predialysis bicarbonate levels (⬎27 mEq/L) was reduced to a nonsignificant level after adjusting for comorbidities, measures of nutrition, and small solute clearances as measured by eKt/V. However, despite adjustment for patient characteristics, case-mix, and laboratory measurements, low predialysis serum bicarbonate levels (⬍17 mEq/L) were associated independently with a significantly higher risk for death. These findings have been corroborated recently in a large study of patients being treated in clinics owned by DaVita Inc. (El Segundo, CA) (n ⫽ 56,385), wherein the lowest adjusted risk for death was observed in patients with predialysis serum bicarbonate levels higher than 22 mEq/L. Without adjusting for the malnutrition-inflammation complex syndrome, the lowest risk for death was found in patients with predialysis serum bicarbonate levels between 17 and 23 mEq/L. These findings imply that inflammation possibly might be another factor contributing to this inverse relationship.6 INTERVENTIONAL STUDIES OF THE EFFECT OF CORRECTION OF METABOLIC ACIDOSIS ON PROTEINENERGY WASTING IN CKD PATIENTS Epidemiologic analyses only allow us to determine associations, and causal relationships can be determined definitively by interventional studies. In 1931, Lyon and Stewart43 were the first to test the hypothesis that correction of metabolic acidosis with alkali treatment will result in the improvement of protein-energy wasting seen with CKD. Since then, several controlled and uncontrolled observational and randomized clinical studies have tested the effect of metabolic acidosis correction on the nutrition status of dialysis-dependent patients (Table 2).44-55 As is evident, the data documenting the beneficial effects of correction of metabolic acidosis in MHD patients have been inconsistent. However, some of the studies were uncontrolled. Moreover, the sample sizes of the studies were small and may have been underpowered to detect significant changes. Furthermore, some studies enrolled patients with only mild, if any, protein-energy wasting at baseline. Thus, the evi-
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dence for the benefits of the correction of metabolic acidosis on protein-energy wasting in MHD patients is presently inconclusive. It has, however, been reassuring that no serious adverse events—neither fluid overload, nor worsened blood pressure control— have been reported with alkali therapy. In contrast to the findings in MHD patients, 2 randomized controlled studied in CPD patients have shown beneficial effects of the correction of metabolic acidosis on nutrition status. Furthermore, in both of these studies, the correction of acidosis was associated with a reduction of hospitalization rates. The Cochrane collaboration recently has reported a systematic review of studies of correction of chronic metabolic acidosis for CKD patients; only 2 randomized clinical studies performed to correct protein-energy wasting met the criteria for patient selection and quality to be included.56 Brady and Hasbargen52 were unable to show any beneficial effects on the nutritional status of MHD patients after 4 months of follow-up evaluation. The second study was a double-blind study undertaken in CPD patients with a follow-up duration of 1 year. In this study, Szeto et al54 showed significant improvement in the subjective global assessment score, nPNA, and hospitalization after 1 year of oral sodium bicarbonate supplementation. Consistent with the findings reported in this study, Stein et al53 reported greater weight gain and mid–arm-muscle circumference and lower rates of hospitalization in a randomized controlled trial of 200 CPD patients. RECOMMENDATIONS Based on the current evidence, what should be the goal of a clinician to ensure optimal acidbase status and thus minimize the protein-energy wasting associated with metabolic acidosis? Modern dialysis therapy usually corrects the metabolic acidosis in most patients; thus causes other than kidney failure should be sought to explain severe metabolic acidosis when it occurs in well-dialyzed maintenance dialysis patients.57 In the absence of controlled trials in which patients are randomized to 2 different levels of serum bicarbonate levels, it is reasonable to maintain serum bicarbonate levels of 22 mEq/L or greater, as recommended by the Kid-
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Y.-W. Chiu, J.D. Kopple, and R. Mehrotra
Table 2. Interventional Studies Evaluating the Nutritional Response to Correction of Metabolic
Acidosis in Chronic Dialysis Patients Study
No. of Subjects
Observational studies MHD patients Seyffart et al,44 1987
21 (D)
Duration of Treatment
Baseline pH/ HCO3
Final pH/HCO3
12-19 mo
*/14.4
*/20.2
Kooman et al,45 1997
12 (D ⫹ SB)
6 mo
*/18.7
*/23.1
Movilli et al,46 1998
12 (SB)
3 mo
7.34/19.3
7.40/24.4
Lin et al,47 2002
17 (D)
6 mo
7.34/18.4
7.41/24.2
Verove et al,48 2002
18 (SB)
6 mo
*/16
*/24
6 mo
*/21.7
*/23.1
1y
*/18.1
*/22.1
Blair et al,49 2003
199 (D)
Bossola et al,50 2007 CPD patients Feriani et al,55 2004
20 (SB)
34 (D) (HCO3 39 mmol/L)
2y
13 (D) (HCO3 34 mmol/L)
Randomized controlled studies MHD patients Williams et al,51 1997
Brady and Hasbargen,52 1998 CPD patients Stein et al,53 1997
Szeto et al,54 2003
46 (D)
6 mo (double cross-over)
7.31/23.45
7.33/25.70
7.34/27.77
7.32/27.06
Final pH/HCO3 in Control Group
Final pH/HCO3 in Study Group
Group A */20.4 Group B */19.8
Group B */26.7 Group A */23.3
*/17.3
*/20.2
36 (D ⫹ SB)
4 mo
200 (D ⫹ SB)
1y
7.40/23.0
7.44/27.2
1y
*/24.7
*/27.8
60 (SB)
Key Findings
Significant increase in dry body weight in 11 of 21 patients Increased plasma BCAA levels; no change in body composition, serum proteins, or dietary intake Increase in serum albumin, decrease in nPNA No change in any nutritional parameters Significant increase in serum albumin and prealbumin levels; decrease in nPNA; no change in dietary protein intake Significant decrease in nPCR; no change in albumin and SGA No change in any nutritional parameter Significant decrease of PNA in the subgroup (n⫽23) with complete acidosis correction
Increased triceps skinfold thickness; no change in serum albumin, nPNA, or mid–arm-muscle circumference No change in serum albumin or total lymphocyte count
Greater gain in body weight and mid–arm-muscle circumference; reduction in hospitalizations Significant improvements in SGA, nPNA, and hospitalization
Beneficial effects are italicized. SB, acidosis corrected by oral sodium bicarbonate; D, acidosis corrected through dialysate; SGA, subjective global assessment; nPCR, normalized protein catabolic rate. *Data not available or applicable.
ney Disease Outcome Quality Initiative guidelines. In patients undergoing CPD, evidence, particularly from the study by Szeto et al,54 seems to suggest that a higher serum bicarbonate level may be even more beneficial.
Several therapeutic strategies can be attempted in patients with persistent metabolic acidosis. In patients undergoing MHD, dialysate bicarbonate can be increased safely from 35 to 40 mEq/L. Care should be taken to avoid acid-gener-
Metabolic acidosis and protein-energy wasting
ating phosphate binders such as sevelamer hydrochloride. If acidosis is persistent, oral sodium bicarbonate supplementation should be considered because it generally is safe and effective.
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17.
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on acute phase protein metabolism in liver cells. Miner Electrolyte Metab. 1999;25:228-33. Papadoyannakis NJ, Stefanidis CJ, McGeown M. The effect of the correction of metabolic acidosis on nitrogen and potassium balance of patients with chronic renal failure. Am J Clin Nutr. 1984;40:623-7. Reaich D, Channon SM, Scrimgeour CM, et al. Correction of acidosis in humans with CRF decreases protein degradation and amino acid oxidation. Am J Physiol. 1993;265:E230-5. Williams B, Hattersley J, Lawyard E, et al. Metabolic acidosis and skeletal muscle adaptation to low protein diets in chronic uremia. Kidney Int. 1991;40:779-86. Garibotto G, Russo R, Sofia A, et al. Skeletal muscle protein synthesis and degradation in patients with chronic renal failure. Kidney Int. 1994;45:1432-9. Graham KA, Reaich D, Channon SM, et al. Correction of acidosis in CAPD decreases whole body protein degradation. Kidney Int. 1996;49:1396-400. Graham KA, Reaich D, Channon SM, et al. Correction of acidosis in hemodialysis decreases whole-body protein degradation. J Am Soc Nephrol. 1997;8:632-7. Lim VS, Yarasheski KE, Flanigan MJ. The effect of uraemia, acidosis, and dialysis treatment on protein metabolism: a longitudinal leucine kinetic study. Nephrol Dial Transplant. 1998;13:1723-30. Boirie Y, Broyer M, Gagnadoux MF, et al. Alterations of protein metabolism by metabolic acidosis in children with chronic renal failure. Kidney Int. 2000;58: 236-41. Uribarri J, Levin NW, Delmez J, et al. Association of acidosis and nutritional parameters in hemodialysis patients. Am J Kidney Dis. 1999;34:493-9. Leavey SF, Strawderman RL, Young EW, et al. Crosssectional and longitudinal predictors of serum albumin in hemodialysis patients. Kidney Int. 2000;58: 2119-28. Chauveau P, Fouque D, Combe C, et al. Acidosis and nutritional status in hemodialyzed patients. French Study Group for Nutrition in Dialysis. Semin Dial. 2000;13:241-6. Gennari FJ, Hood VL, Greene T, et al. Effect of dietary protein intake on serum total CO2 concentration in chronic kidney disease: Modification of Diet in Renal Disease study findings. Clin J Am Soc Nephrol. 2006; 1:52-57. Dunloup DM, DD, Stewart CP. The alkaline treatment of chronic nephritis. Lancet. 1931;2:1009-13. Seyffart G, Ensminger A, Scholz R. Increase of body mass during long-term bicarbonate hemodialysis. Kidney Int Suppl. 1987;22:S174-7.
45. Kooman JP, Deutz NE, Zijlmans P, et al. The influence of bicarbonate supplementation on plasma levels of branched-chain amino acids in haemodialysis patients with metabolic acidosis. Nephrol Dial Transplant. 1997;12:2397-401. 46. Movilli E, Zani R, Carli O, et al. Correction of metabolic acidosis increases serum albumin concentrations and decreases kinetically evaluated protein intake in haemodialysis patients: a prospective study. Nephrol Dial Transplant. 1998;13:1719-22. 47. Lin SH, Lin YF, Chin HM, et al. Must metabolic acidosis be associated with malnutrition in haemodialysed patients? Nephrol Dial Transplant. 2002;17:2006-10. 48. Verove C, Maisonneuve N, El Azouzi A, et al. Effect of the correction of metabolic acidosis on nutritional status in elderly patients with chronic renal failure. J Ren Nutr. 2002;12:224-8. 49. Blair D, Bigelow C, Sweet SJ. Nutritional effects of delivered bicarbonate dose in maintenance hemodialysis patients. J Ren Nutr. 2003;13:205-11. 50. Bossola M, Giungi S, Tazza L, et al. Long-term oral sodium bicarbonate supplementation does not improve serum albumin levels in hemodialysis patients. Nephron Clin Pract. 2007;106:c51-6. 51. Williams AJ, Dittmer ID, McArley A, et al. High bicarbonate dialysate in haemodialysis patients: effects on acidosis and nutritional status. Nephrol Dial Transplant. 1997;12:2633-7. 52. Brady JP, Hasbargen JA. Correction of metabolic acidosis and its effect on albumin in chronic hemodialysis patients. Am J Kidney Dis. 1998;31:35-40. 53. Stein A, Moorhouse J, Iles-Smith H, et al. Role of an improvement in acid-base status and nutrition in CAPD patients. Kidney Int. 1997;52:1089-95. 54. Szeto CC, Wong TY, Chow KM, et al. Oral sodium bicarbonate for the treatment of metabolic acidosis in peritoneal dialysis patients: a randomized placebocontrol trial. J Am Soc Nephrol. 2003;14:2119-26. 55. Feriani M, Passlick-Deetjen J, Jaeckle-Meyer I, et al. Individualized bicarbonate concentrations in the peritoneal dialysis fluid to optimize acid-base status in CAPD patients. Nephrol Dial Transplant. 2004;19: 195-202. 56. Roderick P, Willis NS, Blakeley S, et al. Correction of chronic metabolic acidosis for chronic kidney disease patients. Cochrane Database Syst Rev. 2007;1: CD001890. 57. Uribarri J. How should dialysis fluid be individualized for the chronic hemodialysis patient? Bicarbonate. Semin Dial. 2008;21:221-3.
etabolic acidosis frequently is present in patients with chronic kidney disease (CKD) and has been associated with several complications of uremia.1,2 These com-
M
*Division of Nephrology, Department of Internal Medicine, at Kaohsiung Medical University Hospital, Kaohsiung, Taiwan. †Division of Nephrology and Hypertension, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Los Angeles, CA. ‡David Geffen School of Medicine at UCLA, Los Angeles, CA. §UCLA School of Public Health, Los Angles, CA. Rajnish Mehrotra is supported by grants from the National Institutes of Health (RR18298), Satellite Health, and DaVita, Inc.; and has received research support from Amgen, Baxter Health Care, and Shire, honoraria from Baxter Health Care and Shire, and has served as a consultant for Novartis. Address reprint requests to Rajnish Mehrotra, MD, Division of Nephrology and Hypertension, Harbor-UCLA Medical Center, 1124 W. Carson St, Torrance, CA 90509. E-mail: [email protected] 0270-9295/09/$ - see front matter © 2009 Published by Elsevier Inc. doi:10.1016/j.semnephrol.2008.10.009
plications mainly include clinical wasting with loss of lean body mass and adverse effects on bone health.3 These adverse consequences probably underlie the association of low predialysis bicarbonate with higher morbidity and mortality in maintenance dialysis patients.4-6 Clinical Practice Guidelines for Nutrition in Chronic Renal Failure of the Kidney Disease Outcomes Quality Initiative of the National Kidney Foundation has recommended that the predialysis serum bicarbonate of maintenance hemodialysis (MHD) patients and the steady state serum bicarbonate levels of chronic peritoneal dialysis (CPD) patients and those with stage 3 and 4 CKD should be 22 mEq/L or greater.7 The clinical practice guidelines for bone metabolism and disease in CKD suggest similar target
Seminars in Nephrology, Vol 29, No 1, January 2009, pp 67-74
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serum bicarbonate levels.8 Since the initial publication, more data have accumulated that lend further support to these guidelines. In this article, we will limit the discussion to review the evidence that provides support for the correction of metabolic acidosis to prevent proteinenergy wasting in patients with CKD. Through this review of mechanisms of how metabolic acidosis causes wasting and the related crosssectional and interventional studies, we will try to suggest the optimal goals and strategies to ameliorate wasting in CKD. The issue of the best way to diagnose metabolic acidosis for day-to-day management of CKD patients is outside the scope of this discussion; measurement of serum bicarbonate remains the most widely used test. However, attention needs to be given to 2 important issues: optimal handling of blood specimens and effects of different phosphate binders on a patient’s acid-base status. Underfilling of the blood tube and shipping the specimen by flight overnight, as often is done in patients cared for in units owned by large dialysis organizations in the United States, decreases the total CO2 level and would result in overestimation of acidosis.9,10 Second, all phosphate binders available in the United States, other than sevelamer hydrochloride, are alkalis. Furthermore, sevelamer hydrochloride is an ion-exchange resin; binding with different anions results in the release of chloride and can lead to the development of a non– gap metabolic acidosis.11 For both of these reasons, patients treated with sevelamer hydrochloride are more likely to develop a metabolic acidosis with significantly lower serum bicarbonate levels.12,13 In patients
Y.-W. Chiu, J.D. Kopple, and R. Mehrotra
with persistent metabolic acidosis, it often is more appropriate to use phosphate binders other than sevelamer hydrochloride. MECHANISMS OF METABOLIC ACIDOSIS–INDUCED WASTING IN CKD Protein-energy wasting is manifested clinically as loss of body mass— both fat-free, edema-free mass (or lean body mass), and fat mass.14 A large body of laboratory and clinical evidence indicates that metabolic acidosis leads to wasting via the increased protein breakdown and possibly decreased protein synthesis (Fig. 1).15-18 Two major pathways have been identified to explain the higher protein breakdown associated with metabolic acidosis—increased activities of both the adenosine triphosphate–dependent ubiquitin-proteasome system and of the branched-chain ketoacid dehydrogenase. Ubiquitin, a small protein expressed ubiquitously in eukaryotes, plays an important role in protein turnover. When conjugated (usually 4-5 in a chain) to a protein in an adenosine triphosphate– dependent process, it is recognized by the 26S proteasome, which degrades the protein. Bailey et al19 reported that proteolysis in acidotic rats with CKD was associated with increased amounts of ubiquitin messenger RNA and subunits of the proteasome in skeletal muscle, and these changes could be reversed by feeding sodium bicarbonate. Inhibition of either adenosine triphosphate or the proteasome was noted to slow the degradation of protein induced by acidosis in rat muscle.19,20 In addition, activation of caspase-3, an enzyme involved with protein degradation and apoptosis,
Figure 1. Mechanisms whereby metabolic acidosis may induce protein-energy wasting in patients with CKD. The thick line indicates that there is strong evidence supporting the potential pathophysiologic mechanism.
Metabolic acidosis and protein-energy wasting
is activated by acidemic rats with chronic kidney failure and suppressed in these rats by feeding bicarbonate.21,22 Glucocorticoids may play a permissive role in inducing the catabolic effects of metabolic acidosis in skeletal muscle. In adrenalectomized rats with metabolic acidosis induced by NH4Cl, the increase in protein breakdown and higher messenger RNA of the ubiquitin proteasome system were abolished in these glucocorticoiddeficient animals and reappeared when glucocorticoids were given to the rats.23 Insulin has a direct effect on protein synthesis and degradation. Insulin resistance induced by acidosis may contribute to protein catabolism. Infusion of insulin, without correction of the ketoacidosis by feeding sodium bicarbonate, improved proteolysis and induced lesser up-regulation of the messenger RNA encoding for ubiquitin in rats with acute onset of diabetic ketoacidosis.24 The activity of insulin-receptor-substrate–associated phosphatidylinositol 3-kinase has been shown to be decreased in rats with CKD, which was normalized by insulin therapy and partially returned to control levels by correction of acidosis.22 These findings suggest that glucocorticoids and insulin resistance both play an important role in protein degradation. CKD also is associated with alternations of branched-chain amino acid (BCAA) metabolism. BCAAs account for more than 50% of the amino acid uptake in muscles and plays an important role in brain physiology and nutritional status. Uremic encephalopathy as well as protein-energy wasting in CKD are associated with abnormalities in BCAA metabolism.25 In CKD rats, metabolic acidosis is associated with lower serum and muscle levels of BCAA, suggesting higher rates of BCAA degradation.26 This increase in breakdown of BCAAs seems to be a result of an increase in the activity of branched-chain ketoacid dehydrogenase, a ratelimiting enzyme that is induced by metabolic acidosis.17 Finally, correction of acidosis is associated with higher plasma and intracellular BCAA levels in MHD patients.27,28 Decreased protein synthesis also might contribute to the protein-energy wasting induced by metabolic acidosis. In cell culture studies (L6 muscle cell), lower pH in the culture medium is
69
associated with lower rates of protein synthesis, as ascertained by 14C-phenylalanine incorporation.29 Concentrations of albumin and transferrin also decreased in the supernatant of liver cell (HepG2) cultured in acid medium.30 Studies in human beings in which the effect of metabolic acidosis, and its correction, were evaluated using either N-balances or protein turnover using kinetic studies are summarized in Table 1.27,28,31-38 Virtually all of these studies show that acidosis is associated with increased protein degradation in patients with CKD. Furthermore, the correction of acidosis is associated with lower protein degradation in most studies. However, the effects of metabolic acidosis on protein synthesis in human studies are less consistent. CROSS-SECTIONAL AND LONGITUDINAL COHORT STUDIES OF THE EFFECTS OF METABOLIC ACIDOSIS ON NUTRITIONAL STATUS AND CLINICAL OUTCOMES IN CKD PATIENTS Despite the compelling laboratory evidence linking metabolic acidosis to protein-energy wasting, some epidemiologic studies have shown an inverse relationship between metabolic acidosis and nutritional status in CKD patients. Uribarri et al39 studied 995 MHD patients and reported an inverse relationship between serum total CO2 levels and dietary protein intake, normalized protein equivalent of total nitrogen appearance (nPNA), and predialysis serum potassium, phosphorus, and creatinine. Similar findings were observed, along with an inverse association between predialysis serum bicarbonate levels and albumin, in 2 larger cross-sectional studies of MHD patients (n ⫽ 3,891 and 7,123, respectively).40,41 However, if one accounts for the higher dietary protein intakes in patients with metabolic acidosis (by multivariate adjustment for nPNA), the inverse association between albumin and bicarbonate is reduced to a nonsignificant level.40 Consistent with these observations, post hoc analyses of the data from the Modification of Diet in Renal Disease study also showed an inverse association between serum total CO2 and dietary protein intakes.42 These studies allow us to make a few simple observations and inferences. First, higher protein intakes gener-
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Y.-W. Chiu, J.D. Kopple, and R. Mehrotra
Table 1. Summaries of Controlled, Metabolic Studies in Human Beings With CKD That Suggest That Metabolic Acidosis Promotes Catabolism Study
No. of Stage of Renal Subjects Failure
Papadoynnakis et al,31 1984
6
Williams et al,33 1991
6
Reaich et al,32 1993
9
Garibotto et al,34 1994
9
Graham et al,35 1996
7
Graham et al,36 1997
6
Lofberg et al,28 1997
9
Lim et al,37 1998
9
Boirie et al,38 2000
10
Lofberg et al,27 2006
16
Nondialyzed (SB)
Baseline pH/HCO3 */15.8
Final pH/HCO3 */23.4
Biologic Phenomena Studied
Results of Correction of Metabolic Acidosis
N- and K-balance
Both N- and K-balances improved Nondialyzed (SB) 7.28/17.0 7.35/24.3 Urine 3-methyl histidine: In patients on low-protein creatinine ratio (index diets, ratio increased in of skeletal muscle the presence of catabolism) metabolic acidosis; reduced with NaHCO3 supplementation Nondialyzed (SB) 7.31/15 7.38/21 L[1-13C]leucine kinetics Reduced protein degradation, synthesis, and leucine oxidation Net phenylalanine release Nondialyzed */20 *(Not corrected) 3H-phenylalanine kinetics inversely related to degree of acidosis CPD (SB) 7.39/19.3† 7.41/26.2† L[1-13C]leucine kinetics Reduced whole-body protein degradation and synthesis; no effect on leucine oxidation MHD (D) 7.36/18.5† 7.40/24.8† L[1-13C]leucine kinetics Reduced whole-body protein degradation and synthesis; no effect on leucine oxidation MHD (D) */20.6 */25.9 Intracellular BCAAs Increased intracellular concentrations of BCAAs Nondialyzed (SB) 7.29/19.0† 7.39/25.5† L[1-13C]leucine kinetics Significant decrease in leucine oxidation, insignificant decrease in protein degradation, and increase in synthesis Nondialyzed */19.2 *(Not corrected) L[1-13C]leucine kinetics Acidotic children had higher rates of protein degradation 3H-phenylalanine Decreased net amino acid MHD (D) 7.33/18.2 7.44/26.8 kinetics efflux and appearance; unchanged disposal (oxidation ⫹ synthesis)
Abbreviations: SB, acidosis corrected by oral sodium bicarbonate; D, acidosis corrected through dialysate. *Data not available or applicable. †Total CO2 value.
ally are associated with a higher acid generation that, in turn, is associated with lower predialysis bicarbonate levels. Patients with higher protein intakes tend to be healthier and thus have higher values for serum albumin and other measures of nutritional status. The inverse association between metabolic acidosis and nutritional status therefore probably is secondary to the confounding influence of dietary protein intakes. Thus, the inverse association seen in these epidemiologic studies does not imply that the outcome of patients cannot be improved by correction of metabolic acidosis, nor should it engender therapeutic nihilism.
With regard to mortality, in MHD patients enrolled in the Dialysis Outcomes and Practice Patterns Study, a U-shaped association was observed between the serum predialysis bicarbonate level and mortality.5 The lowest risk for death and hospitalization was found in the group of patients with serum predialysis bicarbonate levels between 20.1 and 21.0 mEq/L. Similar findings had been shown in analyses of about 12,000 patients treated in Fresenius Medical Care clinics (Waltham, MA), wherein the lowest risk was seen in patients with serum bicarbonate levels between 20.0 and 22.5 mmol/L.4 The higher risk for death in patients with the highest
Metabolic acidosis and protein-energy wasting
predialysis bicarbonate levels (⬎27 mEq/L) was reduced to a nonsignificant level after adjusting for comorbidities, measures of nutrition, and small solute clearances as measured by eKt/V. However, despite adjustment for patient characteristics, case-mix, and laboratory measurements, low predialysis serum bicarbonate levels (⬍17 mEq/L) were associated independently with a significantly higher risk for death. These findings have been corroborated recently in a large study of patients being treated in clinics owned by DaVita Inc. (El Segundo, CA) (n ⫽ 56,385), wherein the lowest adjusted risk for death was observed in patients with predialysis serum bicarbonate levels higher than 22 mEq/L. Without adjusting for the malnutrition-inflammation complex syndrome, the lowest risk for death was found in patients with predialysis serum bicarbonate levels between 17 and 23 mEq/L. These findings imply that inflammation possibly might be another factor contributing to this inverse relationship.6 INTERVENTIONAL STUDIES OF THE EFFECT OF CORRECTION OF METABOLIC ACIDOSIS ON PROTEINENERGY WASTING IN CKD PATIENTS Epidemiologic analyses only allow us to determine associations, and causal relationships can be determined definitively by interventional studies. In 1931, Lyon and Stewart43 were the first to test the hypothesis that correction of metabolic acidosis with alkali treatment will result in the improvement of protein-energy wasting seen with CKD. Since then, several controlled and uncontrolled observational and randomized clinical studies have tested the effect of metabolic acidosis correction on the nutrition status of dialysis-dependent patients (Table 2).44-55 As is evident, the data documenting the beneficial effects of correction of metabolic acidosis in MHD patients have been inconsistent. However, some of the studies were uncontrolled. Moreover, the sample sizes of the studies were small and may have been underpowered to detect significant changes. Furthermore, some studies enrolled patients with only mild, if any, protein-energy wasting at baseline. Thus, the evi-
71
dence for the benefits of the correction of metabolic acidosis on protein-energy wasting in MHD patients is presently inconclusive. It has, however, been reassuring that no serious adverse events—neither fluid overload, nor worsened blood pressure control— have been reported with alkali therapy. In contrast to the findings in MHD patients, 2 randomized controlled studied in CPD patients have shown beneficial effects of the correction of metabolic acidosis on nutrition status. Furthermore, in both of these studies, the correction of acidosis was associated with a reduction of hospitalization rates. The Cochrane collaboration recently has reported a systematic review of studies of correction of chronic metabolic acidosis for CKD patients; only 2 randomized clinical studies performed to correct protein-energy wasting met the criteria for patient selection and quality to be included.56 Brady and Hasbargen52 were unable to show any beneficial effects on the nutritional status of MHD patients after 4 months of follow-up evaluation. The second study was a double-blind study undertaken in CPD patients with a follow-up duration of 1 year. In this study, Szeto et al54 showed significant improvement in the subjective global assessment score, nPNA, and hospitalization after 1 year of oral sodium bicarbonate supplementation. Consistent with the findings reported in this study, Stein et al53 reported greater weight gain and mid–arm-muscle circumference and lower rates of hospitalization in a randomized controlled trial of 200 CPD patients. RECOMMENDATIONS Based on the current evidence, what should be the goal of a clinician to ensure optimal acidbase status and thus minimize the protein-energy wasting associated with metabolic acidosis? Modern dialysis therapy usually corrects the metabolic acidosis in most patients; thus causes other than kidney failure should be sought to explain severe metabolic acidosis when it occurs in well-dialyzed maintenance dialysis patients.57 In the absence of controlled trials in which patients are randomized to 2 different levels of serum bicarbonate levels, it is reasonable to maintain serum bicarbonate levels of 22 mEq/L or greater, as recommended by the Kid-
72
Y.-W. Chiu, J.D. Kopple, and R. Mehrotra
Table 2. Interventional Studies Evaluating the Nutritional Response to Correction of Metabolic
Acidosis in Chronic Dialysis Patients Study
No. of Subjects
Observational studies MHD patients Seyffart et al,44 1987
21 (D)
Duration of Treatment
Baseline pH/ HCO3
Final pH/HCO3
12-19 mo
*/14.4
*/20.2
Kooman et al,45 1997
12 (D ⫹ SB)
6 mo
*/18.7
*/23.1
Movilli et al,46 1998
12 (SB)
3 mo
7.34/19.3
7.40/24.4
Lin et al,47 2002
17 (D)
6 mo
7.34/18.4
7.41/24.2
Verove et al,48 2002
18 (SB)
6 mo
*/16
*/24
6 mo
*/21.7
*/23.1
1y
*/18.1
*/22.1
Blair et al,49 2003
199 (D)
Bossola et al,50 2007 CPD patients Feriani et al,55 2004
20 (SB)
34 (D) (HCO3 39 mmol/L)
2y
13 (D) (HCO3 34 mmol/L)
Randomized controlled studies MHD patients Williams et al,51 1997
Brady and Hasbargen,52 1998 CPD patients Stein et al,53 1997
Szeto et al,54 2003
46 (D)
6 mo (double cross-over)
7.31/23.45
7.33/25.70
7.34/27.77
7.32/27.06
Final pH/HCO3 in Control Group
Final pH/HCO3 in Study Group
Group A */20.4 Group B */19.8
Group B */26.7 Group A */23.3
*/17.3
*/20.2
36 (D ⫹ SB)
4 mo
200 (D ⫹ SB)
1y
7.40/23.0
7.44/27.2
1y
*/24.7
*/27.8
60 (SB)
Key Findings
Significant increase in dry body weight in 11 of 21 patients Increased plasma BCAA levels; no change in body composition, serum proteins, or dietary intake Increase in serum albumin, decrease in nPNA No change in any nutritional parameters Significant increase in serum albumin and prealbumin levels; decrease in nPNA; no change in dietary protein intake Significant decrease in nPCR; no change in albumin and SGA No change in any nutritional parameter Significant decrease of PNA in the subgroup (n⫽23) with complete acidosis correction
Increased triceps skinfold thickness; no change in serum albumin, nPNA, or mid–arm-muscle circumference No change in serum albumin or total lymphocyte count
Greater gain in body weight and mid–arm-muscle circumference; reduction in hospitalizations Significant improvements in SGA, nPNA, and hospitalization
Beneficial effects are italicized. SB, acidosis corrected by oral sodium bicarbonate; D, acidosis corrected through dialysate; SGA, subjective global assessment; nPCR, normalized protein catabolic rate. *Data not available or applicable.
ney Disease Outcome Quality Initiative guidelines. In patients undergoing CPD, evidence, particularly from the study by Szeto et al,54 seems to suggest that a higher serum bicarbonate level may be even more beneficial.
Several therapeutic strategies can be attempted in patients with persistent metabolic acidosis. In patients undergoing MHD, dialysate bicarbonate can be increased safely from 35 to 40 mEq/L. Care should be taken to avoid acid-gener-
Metabolic acidosis and protein-energy wasting
ating phosphate binders such as sevelamer hydrochloride. If acidosis is persistent, oral sodium bicarbonate supplementation should be considered because it generally is safe and effective.
73
16.
17.
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