Skip to main content
Top
Published in: BMC Nephrology 1/2021

Open Access 01-12-2021 | Metabolic Acidosis | Research

Metabolic acidosis is associated with increased risk of adverse kidney outcomes and mortality in patients with non-dialysis dependent chronic kidney disease: an observational cohort study

Authors: Navdeep Tangri, Nancy L. Reaven, Susan E. Funk, Thomas W. Ferguson, David Collister, Vandana Mathur

Published in: BMC Nephrology | Issue 1/2021

Login to get access

Abstract

Background

Management of chronic kidney disease (CKD) requires the management of risk factors, such as hypertension and albuminuria, that affect CKD progression. Identification of additional modifiable risk factors is necessary to develop new treatment strategies for CKD. We sought to quantify the association of metabolic acidosis with CKD progression and mortality in a large U.S. community-based cohort.

Methods

In this longitudinal, retrospective cohort study we identified non-dialysis-dependent patients with stage 3‒5 CKD from Optum’s de-identified integrated electronic health records. We selected cohorts of patients with confirmed metabolic acidosis or normal serum bicarbonate levels based on 2 consecutive serum bicarbonate values: 12 to < 22 mEq/L or 22-29 mEq/L, respectively, 28‒365 days apart. The primary composite outcome was ≥ 40 % decline in estimated glomerular filtration rate (eGFR), renal replacement therapy (chronic dialysis or kidney transplant), or all-cause mortality (DD40). Secondary outcomes included each component of the composite outcome. Cox proportional hazards models were used for the DD40 outcome and secondary outcomes, while logistic regression models were used for the DD40 outcome at 2 years.

Results

A total of 51,558 patients qualified for the study. The unadjusted 2-year incidence of adverse renal and fatal outcomes was significantly worse among patients in the metabolic acidosis group vs. those who had normal serum bicarbonate levels: 48 % vs. 17 % for DD40, 10 % vs. 4 % for ≥ 40 % decline in eGFR, 20 % vs. 6 % for renal replacement therapy, and 31 % vs. 10 % for all-cause mortality (all P < 0.001). Over a ≤ 10-year period, for each 1-mEq/L increase in serum bicarbonate, the adjusted hazard ratio for DD40 was 0.926 (95 % confidence interval [CI], 0.922–0.930; P < 0.001); over a ≤ 2-year period, the adjusted odds ratio for DD40 was 0.873 (95 % CI, 0.866–0.879; P < 0.001).

Conclusions

In this large community cohort of patients with stage 3‒5 CKD, the presence of metabolic acidosis was a significant, independent risk factor for the composite adverse outcome of CKD progression, renal replacement therapy, and all-cause mortality (DD40).
Appendix
Available only for authorised users
Literature
1.
go back to reference United States Renal Data System. 2018 USRDS annual data report: Epidemiology of kidney disease in the United States. Bethesda: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases. 2018. United States Renal Data System. 2018 USRDS annual data report: Epidemiology of kidney disease in the United States. Bethesda: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases. 2018.
3.
go back to reference Kopple JD, Kalantar-Zadeh K, Mehrotra R. Risks of chronic metabolic acidosis in patients with chronic kidney disease. Kidney Int Suppl. 2005;67:S21–7. Kopple JD, Kalantar-Zadeh K, Mehrotra R. Risks of chronic metabolic acidosis in patients with chronic kidney disease. Kidney Int Suppl. 2005;67:S21–7.
4.
go back to reference Chen W, Abramowitz MK. Metabolic acidosis and the progression of chronic kidney disease. BMC Nephrol. 2014;15:55.CrossRef Chen W, Abramowitz MK. Metabolic acidosis and the progression of chronic kidney disease. BMC Nephrol. 2014;15:55.CrossRef
5.
go back to reference Kraut JA, Madias NE. Consequences and therapy of the metabolic acidosis of chronic kidney disease. Pediatr Nephrol. 2011;26:19–28.CrossRef Kraut JA, Madias NE. Consequences and therapy of the metabolic acidosis of chronic kidney disease. Pediatr Nephrol. 2011;26:19–28.CrossRef
6.
go back to reference Dobre M, Yang W, Chen J, Drawz P, Hamm LL, Horwitz E, et al. Association of serum bicarbonate with risk of renal and cardiovascular outcomes in CKD: a report from the Chronic Renal Insufficiency Cohort (CRIC) study. Am J Kidney Dis. 2013;62:670–8.CrossRef Dobre M, Yang W, Chen J, Drawz P, Hamm LL, Horwitz E, et al. Association of serum bicarbonate with risk of renal and cardiovascular outcomes in CKD: a report from the Chronic Renal Insufficiency Cohort (CRIC) study. Am J Kidney Dis. 2013;62:670–8.CrossRef
7.
go back to reference Shah SN, Abramowitz M, Hostetter TH, Melamed ML. Serum bicarbonate levels and the progression of kidney disease: a cohort study. Am J Kidney Dis. 2009;54:270–7.CrossRef Shah SN, Abramowitz M, Hostetter TH, Melamed ML. Serum bicarbonate levels and the progression of kidney disease: a cohort study. Am J Kidney Dis. 2009;54:270–7.CrossRef
8.
go back to reference Menon V, Tighiouart H, Vaughn NS, Beck GJ, Kusek JW, Collins AJ, et al. Serum bicarbonate and long-term outcomes in CKD. Am J Kidney Dis. 2010;56:907–14.CrossRef Menon V, Tighiouart H, Vaughn NS, Beck GJ, Kusek JW, Collins AJ, et al. Serum bicarbonate and long-term outcomes in CKD. Am J Kidney Dis. 2010;56:907–14.CrossRef
9.
go back to reference Kovesdy CP, Anderson JE, Kalantar-Zadeh K. Association of serum bicarbonate levels with mortality in patients with non-dialysis-dependent CKD. Nephrol Dial Transplant. 2009;24:1232–7.CrossRef Kovesdy CP, Anderson JE, Kalantar-Zadeh K. Association of serum bicarbonate levels with mortality in patients with non-dialysis-dependent CKD. Nephrol Dial Transplant. 2009;24:1232–7.CrossRef
10.
go back to reference Raphael KL, Wei G, Baird BC, Greene T, Beddhu S. Higher serum bicarbonate levels within the normal range are associated with better survival and renal outcomes in African Americans. Kidney Int. 2011;79:356–62.CrossRef Raphael KL, Wei G, Baird BC, Greene T, Beddhu S. Higher serum bicarbonate levels within the normal range are associated with better survival and renal outcomes in African Americans. Kidney Int. 2011;79:356–62.CrossRef
11.
go back to reference Tangri N, Stevens LA, Griffith J, Tighiouart H, Djurdjev O, Naimark D, et al. A predictive model for progression of chronic kidney disease to kidney failure. JAMA. 2011;305:1553–9.CrossRef Tangri N, Stevens LA, Griffith J, Tighiouart H, Djurdjev O, Naimark D, et al. A predictive model for progression of chronic kidney disease to kidney failure. JAMA. 2011;305:1553–9.CrossRef
12.
go back to reference Levey AS, Inker LA, Matsushita K, Greene T, Willis K, Lewis E, et al. GFR decline as an end point for clinical trials in CKD: a scientific workshop sponsored by the National Kidney Foundation and the US Food and Drug Administration. Am J Kidney Dis. 2014;64:821–35.CrossRef Levey AS, Inker LA, Matsushita K, Greene T, Willis K, Lewis E, et al. GFR decline as an end point for clinical trials in CKD: a scientific workshop sponsored by the National Kidney Foundation and the US Food and Drug Administration. Am J Kidney Dis. 2014;64:821–35.CrossRef
13.
go back to reference Wallace PJ, Shah ND, Dennen T, Bleicher PA, Crown WH. Optum Labs: building a novel node in the learning health care system. Health Aff (Millwood). 2014;33:1187–94.CrossRef Wallace PJ, Shah ND, Dennen T, Bleicher PA, Crown WH. Optum Labs: building a novel node in the learning health care system. Health Aff (Millwood). 2014;33:1187–94.CrossRef
14.
go back to reference Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF, 3rd, Feldman HI, et al. A new equation to estimate glomerular filtration rate. Ann Intern Med. 2009;150:604–12.CrossRef Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF, 3rd, Feldman HI, et al. A new equation to estimate glomerular filtration rate. Ann Intern Med. 2009;150:604–12.CrossRef
15.
go back to reference Quan H, Sundararajan V, Halfon P, Fong A, Burnand B, Luthi JC, et al. Coding algorithms for defining comorbidities in ICD-9-CM and ICD-10 administrative data. Med Care. 2005;43:1130–9.CrossRef Quan H, Sundararajan V, Halfon P, Fong A, Burnand B, Luthi JC, et al. Coding algorithms for defining comorbidities in ICD-9-CM and ICD-10 administrative data. Med Care. 2005;43:1130–9.CrossRef
16.
go back to reference Inker LA, Lambers Heerspink HJ, Mondal H, Schmid CH, Tighiouart H, Noubary F, et al. GFR decline as an alternative end point to kidney failure in clinical trials: a meta-analysis of treatment effects from 37 randomized trials. Am J Kidney Dis. 2014;64:848–59.CrossRef Inker LA, Lambers Heerspink HJ, Mondal H, Schmid CH, Tighiouart H, Noubary F, et al. GFR decline as an alternative end point to kidney failure in clinical trials: a meta-analysis of treatment effects from 37 randomized trials. Am J Kidney Dis. 2014;64:848–59.CrossRef
17.
go back to reference Schutte E, Lambers Heerspink HJ, Lutgers HL, Bakker SJ, Vart P, Wolffenbuttel BH, et al. Serum bicarbonate and kidney disease progression and cardiovascular outcome in patients with diabetic nephropathy: a post Hoc analysis of the RENAAL (Reduction of End Points in Non-Insulin-Dependent Diabetes With the Angiotensin II Antagonist Losartan) study and IDNT (Irbesartan Diabetic Nephropathy Trial). Am J Kidney Dis. 2015;66:450–8.CrossRef Schutte E, Lambers Heerspink HJ, Lutgers HL, Bakker SJ, Vart P, Wolffenbuttel BH, et al. Serum bicarbonate and kidney disease progression and cardiovascular outcome in patients with diabetic nephropathy: a post Hoc analysis of the RENAAL (Reduction of End Points in Non-Insulin-Dependent Diabetes With the Angiotensin II Antagonist Losartan) study and IDNT (Irbesartan Diabetic Nephropathy Trial). Am J Kidney Dis. 2015;66:450–8.CrossRef
18.
go back to reference Vittinghoff E, McCulloch CE. Relaxing the rule of ten events per variable in logistic and Cox regression. Am J Epidemiol. 2007;165:710–8.CrossRef Vittinghoff E, McCulloch CE. Relaxing the rule of ten events per variable in logistic and Cox regression. Am J Epidemiol. 2007;165:710–8.CrossRef
19.
go back to reference Wesson DE, Mathur V, Tangri N, Stasiv Y, Parsell D, Li E, et al. Veverimer versus placebo in patients with metabolic acidosis associated with chronic kidney disease: a multicentre, randomised, double-blind, controlled, phase 3 trial. Lancet. 2019;393:1417–27.CrossRef Wesson DE, Mathur V, Tangri N, Stasiv Y, Parsell D, Li E, et al. Veverimer versus placebo in patients with metabolic acidosis associated with chronic kidney disease: a multicentre, randomised, double-blind, controlled, phase 3 trial. Lancet. 2019;393:1417–27.CrossRef
20.
go back to reference Garneata L, Stancu A, Dragomir D, Stefan G, Mircescu G. Ketoanalogue-supplemented vegetarian very low-protein diet and CKD progression. J Am Soc Nephrol. 2016;27:2164–76.CrossRef Garneata L, Stancu A, Dragomir D, Stefan G, Mircescu G. Ketoanalogue-supplemented vegetarian very low-protein diet and CKD progression. J Am Soc Nephrol. 2016;27:2164–76.CrossRef
21.
go back to reference de Brito-Ashurst I, Varagunam M, Raftery MJ, Yaqoob MM. Bicarbonate supplementation slows progression of CKD and improves nutritional status. J Am Soc Nephrol. 2009;20:2075–84.CrossRef de Brito-Ashurst I, Varagunam M, Raftery MJ, Yaqoob MM. Bicarbonate supplementation slows progression of CKD and improves nutritional status. J Am Soc Nephrol. 2009;20:2075–84.CrossRef
22.
go back to reference Di Iorio BR, Bellasi A, Raphael KL, Santoro D, Aucella F, Garofano L, et al. Treatment of metabolic acidosis with sodium bicarbonate delays progression of chronic kidney disease: the UBI Study. J Nephrol. 2019;32:989–1001.CrossRef Di Iorio BR, Bellasi A, Raphael KL, Santoro D, Aucella F, Garofano L, et al. Treatment of metabolic acidosis with sodium bicarbonate delays progression of chronic kidney disease: the UBI Study. J Nephrol. 2019;32:989–1001.CrossRef
23.
go back to reference Dubey AK, Sahoo J, Vairappan B, Haridasan S, Parameswaran S, Priyamvada PS. Correction of metabolic acidosis improves muscle mass and renal function in chronic kidney disease stages 3 and 4: a randomized controlled trial. Nephrol Dial Transplant. 2020;35:121–9.PubMed Dubey AK, Sahoo J, Vairappan B, Haridasan S, Parameswaran S, Priyamvada PS. Correction of metabolic acidosis improves muscle mass and renal function in chronic kidney disease stages 3 and 4: a randomized controlled trial. Nephrol Dial Transplant. 2020;35:121–9.PubMed
24.
go back to reference Goraya N, Simoni J, Jo CH, Wesson DE. A comparison of treating metabolic acidosis in CKD stage 4 hypertensive kidney disease with fruits and vegetables or sodium bicarbonate. Clin J Am Soc Nephrol. 2013;8:371–81.CrossRef Goraya N, Simoni J, Jo CH, Wesson DE. A comparison of treating metabolic acidosis in CKD stage 4 hypertensive kidney disease with fruits and vegetables or sodium bicarbonate. Clin J Am Soc Nephrol. 2013;8:371–81.CrossRef
25.
go back to reference Goraya N, Simoni J, Jo CH, Wesson DE. Treatment of metabolic acidosis in patients with stage 3 chronic kidney disease with fruits and vegetables or oral bicarbonate reduces urine angiotensinogen and preserves glomerular filtration rate. Kidney Int. 2014;86:1031–8.CrossRef Goraya N, Simoni J, Jo CH, Wesson DE. Treatment of metabolic acidosis in patients with stage 3 chronic kidney disease with fruits and vegetables or oral bicarbonate reduces urine angiotensinogen and preserves glomerular filtration rate. Kidney Int. 2014;86:1031–8.CrossRef
Metadata
Title
Metabolic acidosis is associated with increased risk of adverse kidney outcomes and mortality in patients with non-dialysis dependent chronic kidney disease: an observational cohort study
Authors
Navdeep Tangri
Nancy L. Reaven
Susan E. Funk
Thomas W. Ferguson
David Collister
Vandana Mathur
Publication date
01-12-2021
Publisher
BioMed Central
Published in
BMC Nephrology / Issue 1/2021
Electronic ISSN: 1471-2369
DOI
https://doi.org/10.1186/s12882-021-02385-z

Other articles of this Issue 1/2021

BMC Nephrology 1/2021 Go to the issue
Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.