Skip to main content

Main menu

  • Home
  • Content
    • Published Ahead of Print
    • Current Issue
    • Podcasts
    • Subject Collections
    • Archives
    • Kidney Week Abstracts
    • Saved Searches
  • Authors
    • Submit a Manuscript
    • Author Resources
  • Trainees
    • Peer Review Program
    • Prize Competition
  • About CJASN
    • About CJASN
    • Editorial Team
    • CJASN Impact
    • CJASN Recognitions
  • More
    • Alerts
    • Advertising
    • Feedback
    • Reprint Information
    • Subscriptions
  • ASN Kidney News
  • Other
    • ASN Publications
    • JASN
    • Kidney360
    • Kidney News Online
    • American Society of Nephrology

User menu

  • Subscribe
  • My alerts
  • Log in
  • My Cart

Search

  • Advanced search
American Society of Nephrology
  • Other
    • ASN Publications
    • JASN
    • Kidney360
    • Kidney News Online
    • American Society of Nephrology
  • Subscribe
  • My alerts
  • Log in
  • My Cart
Advertisement
American Society of Nephrology

Advanced Search

  • Home
  • Content
    • Published Ahead of Print
    • Current Issue
    • Podcasts
    • Subject Collections
    • Archives
    • Kidney Week Abstracts
    • Saved Searches
  • Authors
    • Submit a Manuscript
    • Author Resources
  • Trainees
    • Peer Review Program
    • Prize Competition
  • About CJASN
    • About CJASN
    • Editorial Team
    • CJASN Impact
    • CJASN Recognitions
  • More
    • Alerts
    • Advertising
    • Feedback
    • Reprint Information
    • Subscriptions
  • ASN Kidney News
  • Visit ASN on Facebook
  • Follow CJASN on Twitter
  • CJASN RSS
  • Community Forum
Editorials
You have accessRestricted Access

Acid-Base Balance and Physical Function

Matthew K. Abramowitz
CJASN December 2014, 9 (12) 2030-2032; DOI: https://doi.org/10.2215/CJN.10371014
Matthew K. Abramowitz
Department of Medicine, Division of Nephrology and
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • Article
  • Info & Metrics
  • View PDF
Loading
  • acidosis
  • CKD
  • lean body mass

Physical disability is common among people with CKD and is a major cause of morbidity. Reduced cardiorespiratory fitness, impaired physical performance, and severely diminished physical activity have been well documented in the ESRD population and in earlier stages of CKD as well (1,2). Multiple factors have been proposed to account for the increased risk of functional deterioration, including the high burden of comorbid disease, microvascular dysfunction, and inflammation (1,2). Ultimately, to cause disability, these would need to cause some systemic impairment—for example, in neurologic function, the cardiopulmonary system, or skeletal muscle.

Skeletal muscle turnover occurs continuously in a tightly regulated cycle of synthesis and degradation. Over time, even a mild perturbation of this balance in favor of degradation can cause a net loss of muscle mass (3). Thus, muscle wasting is seen in catabolic states. The major pathway responsible for muscle protein degradation in catabolic conditions is the ATP-dependent ubiquitin-proteasome system (UPS). The UPS may be upregulated in skeletal muscle by a number of factors, including inflammation, uremia, alterations in the insulin/IGF-1 signaling pathway, and metabolic acidosis (4).

Animal models and human physiologic studies have clearly linked acidosis with skeletal muscle protein metabolism. Acidemia in rodent models induces an insulin/IGF-1 signaling defect in skeletal muscle, stimulating proteolysis by upregulation of caspase-3, which degrades actomyosin, and the UPS (4). Other mechanisms, including increased activity of branched-chain ketoacid dehydrogenase and increased amino acid oxidation, have also been implicated (5). Several studies in patients with ESRD and advanced predialysis CKD have found that correcting acidosis reduces protein breakdown (6–9). Even a mild decrease in extracellular pH is sufficient to activate proteolysis. Administration of ammonium chloride to healthy individuals without kidney disease lowered the pH from 7.42 to 7.35 and stimulated muscle protein degradation (10). Similarly, in a study of eight patients on peritoneal dialysis, achieving a pH of 7.44 was associated with more positive nitrogen balance than a pH of 7.37 (11).

These short-term effects of acid-base balance on protein metabolism seem to translate to long-term effects on skeletal muscle mass. Among 200 patients on peritoneal dialysis randomized to high- versus low-alkali dialysate, the high-alkali group experienced greater weight gain, increased muscle mass, and fewer hospitalizations after 1 year, despite a modest difference in acid-base status: the mean pH and serum bicarbonate values in the two groups were 7.44 and 27.2 mEq/L and 7.40 and 23.0 mEq/L, respectively, at the end of the study (12). In another year-long trial of 60 patients on peritoneal dialysis, the group randomized to oral sodium bicarbonate had greater lean mass, higher Subjective Global Assessment scores (a nutritional assessment that includes muscle mass), and fewer days of hospitalization at the end of the study compared with placebo (13). Treatment with oral sodium bicarbonate for 2 years also improved mid-arm circumference and increased serum albumin in patients with stage 4 CKD (14). Thus, correction of acidosis seems to preserve muscle mass in patients with kidney disease.

Given this link with skeletal muscle, it seems natural to ask whether chronic metabolic acidosis affects muscle function and whether this contributes to impaired physical function in people with CKD. Indeed, alkali administration curbs exercise-induced acidosis (15) and enhances short-term endurance performance and lactate threshold (16). Epidemiologic data also support a role. Among older adults in the general United States population, lower serum bicarbonate levels were associated with slower gait speed and lower quadriceps strength (17). In addition, individuals with serum bicarbonate <23 mEq/L were nearly two times as likely to manifest self-reported disability compared with those who had serum bicarbonate ≥23 mEq/L. Lower bicarbonate levels were also associated with poorer cardiorespiratory fitness in younger adults, possibly mediated by differences in lean body mass, supporting the hypothesis that metabolic acidosis causes functional impairment through effects on skeletal muscle (18). At this time, only small interventional studies have further tested this hypothesis. In healthy persons 50 years of age and older, 3 months of oral bicarbonate (sodium or potassium) improved muscle strength in women but not men (19). In 20 patients with stage 3 or 4 CKD, oral sodium bicarbonate supplementation was associated with improved lower extremity muscle function after 6 weeks (20). Thus, the evidence to date suggests that chronic metabolic acidosis could adversely affect physical function.

In this issue of CJASN, Yenchek et al. (21) provide longitudinal data examining the association of acid-base status with physical function over time. Yenchek et al. (21) used data from the Healthy Aging and Body Composition Study, a longitudinal cohort study of adults 70–79 years old who had no functional limitation at baseline. For this analysis, a subgroup of patients in the cohort who had arterialized venous blood gases drawn during year 3 of the study was examined. Lower blood bicarbonate at baseline was associated with a greater risk of incident self-reported functional limitation and lower gait speed during follow-up. These results are strengthened by the use of persistent disability over 6 months as an outcome as opposed to a single report of functional limitation, which might be more subject to the effects of acute illness and other transient circumstances. Furthermore, the effect was graded—having a blood bicarbonate <23 mEq/L was associated with greater risk than having a blood bicarbonate=23–25 mEq/L, which was still associated with greater risk than having a bicarbonate level ≥26 mEq/L. Higher bicarbonate was monotonically associated with lower risk of functional limitation, although levels at the extreme high and low ends of the spectrum were not specifically examined. The association of bicarbonate level with functional limitation did not differ between participants with and without CKD, and it did not explain the greater likelihood of disability associated with CKD. In this respect, the small fraction of the cohort with an eGFR<60 ml/min per 1.73 m2—13.8% or 213 people—is an important limitation, which Yenchek et al. (21) acknowledge. The small sample of participants with CKD precludes any definitive conclusions.

This study by Yenchek et al. (21) has the particular strength of measures of acid–base status beyond bicarbonate. This enabled Yenchek et al. (21) to address a limitation of earlier research—that lower bicarbonate levels could represent respiratory alkalosis and simply be a marker for overt or subclinical cardiopulmonary disease. After excluding those with respiratory alkalosis (defined as pH>7.42 and pCO2<38 mmHg), the results were unchanged. The associations found with lower bicarbonate levels did reflect associations with metabolic acidosis, even if it was subclinical in many individuals.

Surprisingly, pH was associated less strongly than bicarbonate with functional limitation. If lower blood bicarbonate represents a greater degree of metabolic acidosis, one would expect lower pH to be associated as well. This unexpected finding may be related to the much narrower distribution of pH relative to other acid-base parameters—the coefficient of variation was an order of magnitude smaller than that for bicarbonate or pCO2 in this cohort. Because changes in pH caused by metabolic perturbations will be limited by respiratory compensation, serum bicarbonate could actually be a better marker of long-term risk than the pH.

It is also worth considering that blood acid-base parameters may simply be insufficient for determining a person’s risk of chronic complications related to metabolic acidosis. Acid retention seems to occur in people with CKD even before changes in acid-base parameters manifest (22), which may increase tissue interstitial acidity (23,24). The reduction in interstitial pH could be sufficient to activate proteolytic mechanisms in skeletal muscle. In healthy postmenopausal women without overt acidosis, oral potassium bicarbonate in doses sufficient to reduce net acid excretion to near zero reduced urinary nitrogen excretion, suggesting an improvement in muscle protein breakdown (25). Therefore, the serum bicarbonate level may not be a sufficiently sensitive measure of the acid load—mostly caused by diet but modulated by age and kidney function—to which a person is exposed.

An understanding of the mechanisms underlying the findings by Yenchek et al. (21) would also be useful. If explained by a causal pathway between acid-base status and skeletal muscle, was it because of better preserved muscle mass in the highest bicarbonate category or better muscle contractile function? Could the effects relate to endurance and fatigability and not muscle strength? If so, might alkali ingestion have a synergistic effect with exercise interventions in the elderly and patients with CKD? Did people with higher bicarbonate levels have greater protein intake (14) with accompanying anabolic effects? Although the dietary acid load was lowest in the highest bicarbonate category, both protein and potassium intake could have been high and still resulted in a lower protein-to-potassium ratio than in the lower bicarbonate categories.

Finally, there is now quite a bit of data suggesting that higher bicarbonate is better, for kidney disease progression and for preservation of muscle mass and physical function. We should keep in mind, however, that nearly all of these data comes from observational studies and small interventional studies. Although treating chronic acidosis with oral alkali seems generally safe and well tolerated, it is not without risk (26). Those at the greatest risk for possible complications have been excluded from the published interventions, possibly resulting in an exaggerated sense of reassurance regarding tolerability. We should also recall the numerous occasions on which conventional wisdom backed by biologic plausibility was not borne out by large randomized clinical trials. Fortunately, several randomized trials of oral alkali are currently underway and should provide us with important new data in the coming years. We might do well to be cautious about extrapolating these findings to clinical practice just yet.

Disclosures

None.

Acknowledgments

This work was supported by an American Society of Nephrology Carl W. Gottschalk Research Scholar Grant and National Institutes of Health (NIH) Grant DK099438.

Its contents are solely the responsibility of the author and do not necessarily represent the official views of the NIH.

Footnotes

  • Published online ahead of print. Publication date available at www.cjasn.org.

  • See related article, “Association of Serum Bicarbonate with Incident Functional Limitation in Older Adults,” on pages 2111–2116.

  • Copyright © 2014 by the American Society of Nephrology

References

  1. 1.↵
    1. Anand S,
    2. Johansen KL,
    3. Kurella Tamura M
    : Aging and chronic kidney disease: The impact on physical function and cognition. J Gerontol A Biol Sci Med Sci 69: 315–322, 2014
    OpenUrlPubMed
  2. 2.↵
    1. Weiner DE,
    2. Seliger SL
    : Cognitive and physical function in chronic kidney disease. Curr Opin Nephrol Hypertens 23: 291–297, 2014
    OpenUrlCrossRefPubMed
  3. 3.↵
    1. Mitch WE,
    2. Du J
    : Cellular mechanisms causing loss of muscle mass in kidney disease. Semin Nephrol 24: 484–487, 2004
    OpenUrlCrossRefPubMed
  4. 4.↵
    1. Workeneh BT,
    2. Mitch WE
    : Review of muscle wasting associated with chronic kidney disease. Am J Clin Nutr 91: 1128S–1132S, 2010
    OpenUrlAbstract/FREE Full Text
  5. 5.↵
    1. Mehrotra R,
    2. Kopple JD,
    3. Wolfson M
    : Metabolic acidosis in maintenance dialysis patients: Clinical considerations. Kidney Int Suppl 88: S13–S25, 2003
    OpenUrlPubMed
  6. 6.↵
    1. Graham KA,
    2. Reaich D,
    3. Channon SM,
    4. Downie S,
    5. Gilmour E,
    6. Passlick-Deetjen J,
    7. Goodship TH
    : Correction of acidosis in CAPD decreases whole body protein degradation. Kidney Int 49: 1396–1400, 1996
    OpenUrlCrossRefPubMed
  7. 7.
    1. Graham KA,
    2. Reaich D,
    3. Channon SM,
    4. Downie S,
    5. Goodship TH
    : Correction of acidosis in hemodialysis decreases whole-body protein degradation. J Am Soc Nephrol 8: 632–637, 1997
    OpenUrlAbstract
  8. 8.
    1. Lim VS,
    2. Yarasheski KE,
    3. Flanigan MJ
    : The effect of uraemia, acidosis, and dialysis treatment on protein metabolism: A longitudinal leucine kinetic study. Nephrol Dial Transplant 13: 1723–1730, 1998
    OpenUrlCrossRefPubMed
  9. 9.↵
    1. Reaich D,
    2. Channon SM,
    3. Scrimgeour CM,
    4. Daley SE,
    5. Wilkinson R,
    6. Goodship TH
    : Correction of acidosis in humans with CRF decreases protein degradation and amino acid oxidation. Am J Physiol 265: E230–E235, 1993
    OpenUrl
  10. 10.↵
    1. Reaich D,
    2. Channon SM,
    3. Scrimgeour CM,
    4. Goodship TH
    : Ammonium chloride-induced acidosis increases protein breakdown and amino acid oxidation in humans. Am J Physiol 263: E735–E739, 1992
    OpenUrlPubMed
  11. 11.↵
    1. Mehrotra R,
    2. Bross R,
    3. Wang H,
    4. Appell M,
    5. Tso L,
    6. Kopple JD
    : Effect of high-normal compared with low-normal arterial pH on protein balances in automated peritoneal dialysis patients. Am J Clin Nutr 90: 1532–1540, 2009
    OpenUrlAbstract/FREE Full Text
  12. 12.↵
    1. Stein A,
    2. Moorhouse J,
    3. Iles-Smith H,
    4. Baker F,
    5. Johnstone J,
    6. James G,
    7. Troughton J,
    8. Bircher G,
    9. Walls J
    : Role of an improvement in acid-base status and nutrition in CAPD patients. Kidney Int 52: 1089–1095, 1997
    OpenUrlCrossRefPubMed
  13. 13.↵
    1. Szeto CC,
    2. Wong TY,
    3. Chow KM,
    4. Leung CB,
    5. Li PK
    : Oral sodium bicarbonate for the treatment of metabolic acidosis in peritoneal dialysis patients: A randomized placebo-control trial. J Am Soc Nephrol 14: 2119–2126, 2003
    OpenUrlAbstract/FREE Full Text
  14. 14.↵
    1. de Brito-Ashurst I,
    2. Varagunam M,
    3. Raftery MJ,
    4. Yaqoob MM
    : Bicarbonate supplementation slows progression of CKD and improves nutritional status. J Am Soc Nephrol 20: 2075–2084, 2009
    OpenUrlAbstract/FREE Full Text
  15. 15.↵
    1. Street D,
    2. Nielsen JJ,
    3. Bangsbo J,
    4. Juel C
    : Metabolic alkalosis reduces exercise-induced acidosis and potassium accumulation in human skeletal muscle interstitium. J Physiol 566: 481–489, 2005
    OpenUrlCrossRefPubMed
  16. 16.↵
    1. Edge J,
    2. Bishop D,
    3. Goodman C
    : Effects of chronic NaHCO3 ingestion during interval training on changes to muscle buffer capacity, metabolism, and short-term endurance performance. J Appl Physiol (1985) 101: 918–925, 2006
    OpenUrlCrossRefPubMed
  17. 17.↵
    1. Abramowitz MK,
    2. Hostetter TH,
    3. Melamed ML
    : Association of serum bicarbonate levels with gait speed and quadriceps strength in older adults. Am J Kidney Dis 58: 29–38, 2011
    OpenUrlCrossRefPubMed
  18. 18.↵
    1. Abramowitz MK,
    2. Hostetter TH,
    3. Melamed ML
    : Lower serum bicarbonate and a higher anion gap are associated with lower cardiorespiratory fitness in young adults. Kidney Int 81: 1033–1042, 2012
    OpenUrlCrossRefPubMed
  19. 19.↵
    1. Dawson-Hughes B,
    2. Castaneda-Sceppa C,
    3. Harris SS,
    4. Palermo NJ,
    5. Cloutier G,
    6. Ceglia L,
    7. Dallal GE
    : Impact of supplementation with bicarbonate on lower-extremity muscle performance in older men and women. Osteoporos Int 21: 1171–1179, 2010
    OpenUrlCrossRefPubMed
  20. 20.↵
    1. Abramowitz MK,
    2. Melamed ML,
    3. Bauer C,
    4. Raff AC,
    5. Hostetter TH
    : Effects of oral sodium bicarbonate in patients with CKD. Clin J Am Soc Nephrol 8: 714–720, 2013
    OpenUrlAbstract/FREE Full Text
  21. 21.↵
    1. Yenchek R,
    2. Ix JH,
    3. Rifkin DE,
    4. Shlipak MG,
    5. Sarnak MJ,
    6. Garcia M,
    7. Patel KV,
    8. Satterfield S,
    9. Harris TB,
    10. Newman AB,
    11. Fried LF
    for the Health, Aging, and Body Composition Study: Association of serum bicarbonate with incident functional limitation in older adults. Clin J Am Soc Nephrol 9: 2111–2116, 2014
    OpenUrlAbstract/FREE Full Text
  22. 22.↵
    1. Wesson DE,
    2. Simoni J,
    3. Broglio K,
    4. Sheather S
    : Acid retention accompanies reduced GFR in humans and increases plasma levels of endothelin and aldosterone. Am J Physiol Renal Physiol 300: F830–F837, 2011
    OpenUrlCrossRefPubMed
  23. 23.↵
    1. Wesson DE
    : Dietary acid increases blood and renal cortical acid content in rats. Am J Physiol 274: F97–F103, 1998
    OpenUrl
  24. 24.↵
    1. Wesson DE,
    2. Simoni J
    : Increased tissue acid mediates a progressive decline in the glomerular filtration rate of animals with reduced nephron mass. Kidney Int 75: 929–935, 2009
    OpenUrlCrossRefPubMed
  25. 25.↵
    1. Frassetto L,
    2. Morris RC Jr..,
    3. Sebastian A
    : Potassium bicarbonate reduces urinary nitrogen excretion in postmenopausal women. J Clin Endocrinol Metab 82: 254–259, 1997
    OpenUrlCrossRefPubMed
  26. 26.↵
    1. Chen W,
    2. Abramowitz MK
    : Treatment of metabolic acidosis in patients with CKD. Am J Kidney Dis 63: 311–317, 2014
    OpenUrlCrossRefPubMed
PreviousNext
Back to top

In this issue

Clinical Journal of the American Society of Nephrology: 9 (12)
Clinical Journal of the American Society of Nephrology
Vol. 9, Issue 12
December 05, 2014
  • Table of Contents
  • Table of Contents (PDF)
  • Index by author
View Selected Citations (0)
Print
Download PDF
Sign up for Alerts
Email Article
Thank you for your help in sharing the high-quality science in CJASN.
Enter multiple addresses on separate lines or separate them with commas.
Acid-Base Balance and Physical Function
(Your Name) has sent you a message from American Society of Nephrology
(Your Name) thought you would like to see the American Society of Nephrology web site.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
Acid-Base Balance and Physical Function
Matthew K. Abramowitz
CJASN Dec 2014, 9 (12) 2030-2032; DOI: 10.2215/CJN.10371014

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Request Permissions
Share
Acid-Base Balance and Physical Function
Matthew K. Abramowitz
CJASN Dec 2014, 9 (12) 2030-2032; DOI: 10.2215/CJN.10371014
del.icio.us logo Digg logo Reddit logo Twitter logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like

Jump to section

  • Article
    • Disclosures
    • Acknowledgments
    • Footnotes
    • References
  • Info & Metrics
  • View PDF

More in this TOC Section

  • Should We Let Dialysis Patients Eat Their Fruits and Veggies?
  • Atrasentan: The Difficult Task of Integrating Endothelin A Receptor Antagonists into Current Treatment Paradigm for Diabetic Kidney Disease
  • APOL1 Kidney Risk Variants and Acute Kidney Injury in Those with COVID-19
Show more Editorials

Cited By...

  • Increase in branched-chain amino acids due to acidemia in neonatal calves with diarrhoea
  • Google Scholar

Similar Articles

Related Articles

  • Association of Serum Bicarbonate with Incident Functional Limitation in Older Adults
  • PubMed
  • Google Scholar

Keywords

  • acidosis
  • CKD
  • lean body mass

Articles

  • Current Issue
  • Early Access
  • Subject Collections
  • Article Archive
  • ASN Meeting Abstracts

Information for Authors

  • Submit a Manuscript
  • Trainee of the Year
  • Author Resources
  • ASN Journal Policies
  • Reuse/Reprint Policy

About

  • CJASN
  • ASN
  • ASN Journals
  • ASN Kidney News

Journal Information

  • About CJASN
  • CJASN Email Alerts
  • CJASN Key Impact Information
  • CJASN Podcasts
  • CJASN RSS Feeds
  • Editorial Board

More Information

  • Advertise
  • ASN Podcasts
  • ASN Publications
  • Become an ASN Member
  • Feedback
  • Follow on Twitter
  • Password/Email Address Changes
  • Subscribe to ASN Journals

© 2022 American Society of Nephrology

Print ISSN - 1555-9041 Online ISSN - 1555-905X

Powered by HighWire