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Siddiqui AH, Batool F, Khan S, Rizvi SS, Usman S, Jawed H, Ali MH, Zehra T, Adil AR, Anwar M, Hanif A, Hassan SK, Noble MW, Moeed A, Surani S. Safety and efficacy of sodium bicarbonate for treating metabolic acidosis in chronic kidney disease: A systematic review and meta-analysis. World J Nephrol 2025; 14:101078. [DOI: 10.5527/wjn.v14.i1.101078] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2024] [Revised: 12/14/2024] [Accepted: 01/07/2025] [Indexed: 01/20/2025] Open
Abstract
BACKGROUND Kidney dysfunction and reduced filtration capacity due to chronic kidney disease (CKD) lead to a shift in the body's acid-base balance, ultimately causing metabolic acidosis (MA). Sodium bicarbonate has been used as a supplement to alleviate the symptoms and reverse the acidosis, and it may even slow the progression of CKD. However, its safety profile and overall effectiveness are uncertain.
AIM To conduct a systematic review and meta-analysis of clinical trials assessing sodium bicarbonate's safety and efficacy for treating CKD-induced MA.
METHODS Medline, Scopus, EMBASE, and Cochrane Central were systematically searched from inception until May 2024 to select all relevant randomized control trials (RCTs) and non-RCT (NRCTs) evaluating the effectiveness of sodium bicarbonate in correcting MA in end-stage renal disease patients. In addition, ClinicalTrials.gov, Medrxiv.org, and Google Scholar were searched for other literature. A random-effects meta-analysis was performed to derive mean differences (MD) and risk ratios (RR) with their 95%CI for continuous and dichotomous outcomes respectively.
RESULTS Following a systematic search of the databases, 20 RCTs and 2 and NRCTs comprising 2932 patients were included in our study. The results revealed that sodium bicarbonate significantly increased serum bicarbonate in CKD patients (MD: 2.59, 95%CI: 0.95-4.22; P = 0.02; I2 = 95%). However, there was a non-significant increase in estimated glomerular filtration rate (eGFR) in patients on sodium bicarbonate therapy (MD: 0.93, 95%CI: -1.88-3.75; P = 0.52; I2 = 93%). Upon assessment of the safety profile of sodium bicarbonate, no significant association was found in the outcomes of death/prolonged hospitalization (RR: 1.05, 95%CI: 0.84-1.32; P = 0.66; I2 = 0%), or gastrointestinal disorders (RR: 1.64, 95%CI: 0.35-7.66; P = 0.53; I2 = 76%), or worsening edema (RR: 1.26, 95%CI: 0.94-1.68; P = 0.12; I2 = 37%) when compared to control.
CONCLUSION Sodium bicarbonate therapy may halt worsening kidney function by correcting serum bicarbonate levels and treating MA. Although sodium bicarbonate does not significantly improve the eGFR, it may potentially prevent CKD progression while maintaining an overall favorable safety profile.
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Affiliation(s)
- Abdul Hannan Siddiqui
- Department of Internal Medicine, Dow University of Health Sciences, Karachi 74200, Sindh, Pakistan
| | - Fizzah Batool
- Department of Internal Medicine, Dow University of Health Sciences, Karachi 74200, Sindh, Pakistan
| | - Shayan Khan
- Department of Internal Medicine, Dow University of Health Sciences, Karachi 74200, Sindh, Pakistan
| | - Syed Shabbeer Rizvi
- Department of Internal Medicine, Dow University of Health Sciences, Karachi 74200, Sindh, Pakistan
| | - Saad Usman
- Department of Internal Medicine, Dow University of Health Sciences, Karachi 74200, Sindh, Pakistan
| | - Huzaifa Jawed
- Department of Internal Medicine, United Medical and Dental College, Karachi 74200, Sindh, Pakistan
| | - Muhammad Hammad Ali
- Department of Internal Medicine, Jinnah Sindh Medical University, Karachi 74200, Sindh, Pakistan
| | - Tatheer Zehra
- Department of Internal Medicine, Dow University of Health Sciences, Karachi 74200, Sindh, Pakistan
| | - Abdul Rafay Adil
- Department of Internal Medicine, Karachi Medical and Dental College, Karachi 74200, Sindh, Pakistan
| | - Masifah Anwar
- Department of Internal Medicine, Dow University of Health Sciences, Karachi 74200, Sindh, Pakistan
| | - Areeba Hanif
- Department of Internal Medicine, Dow University of Health Sciences, Karachi 74200, Sindh, Pakistan
| | - Saad Khalid Hassan
- Department of Internal Medicine, Jinnah Medical and Dental College, Karachi 74200, Sindh, Pakistan
| | - Mark William Noble
- Department of Medicine, Kings College Hospital London, Dubai 25314, Dubayy, United Arab Emirates
| | - Abdul Moeed
- Department of Internal Medicine, Dow University of Health Sciences, Karachi 74200, Sindh, Pakistan
| | - Salim Surani
- Department of Medicine and Pharmacology, Texas A and M University, College Station, TX 77843, United States
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Ritter A, Kuhn C, Mohebbi N. [What is confirmed in the treatment of metabolic acidosis in chronic kidney disease?]. INNERE MEDIZIN (HEIDELBERG, GERMANY) 2024; 65:1209-1215. [PMID: 39514096 PMCID: PMC11632079 DOI: 10.1007/s00108-024-01806-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 09/26/2024] [Indexed: 11/16/2024]
Abstract
Precise regulation of the acid-base balance is essential for the functioning of various organs and physiological processes. Acid retention and metabolic acidosis (MA) are frequent complications of chronic kidney disease (CKD) and can also occur following kidney transplantation. In addition to dietary modifications, pharmacological interventions, most notably sodium bicarbonate, are employed to correct MA. While several studies have reported a beneficial effect of MA correction on the progression of CKD, the results remain inconsistent and the magnitude of the treatment effect may be limited. Importantly, no beneficial effect on graft function has been demonstrated after kidney transplantation. The MA is associated with impaired bone quality and although alkali treatment has generally shown positive effects on markers of bone metabolism, consistent changes in bone density have not been observed. Additionally, MA is linked to an increased incidence of cardiovascular events but so far there is a lack of interventional studies with definitive cardiovascular endpoints. Sodium bicarbonate may lead to sodium retention, potentially increasing blood pressure, although the data on this are inconclusive. One interventional study with notable limitations reported a positive effect of alkali treatment on mortality. Correction of MA has been suggested to positively impact protein and muscle catabolism, although no improvement in physical performance was observed in a geriatric population. Limited studies exist on the endocrinological effects of alkali treatment but these indicate a favorable impact on glucose metabolism and potential benefits for thyroid function in predialysis CKD patients. Given the overall low to moderate level of evidence supporting the benefits of alkali treatment, the current guidelines from Kidney Disease: Improving Global Outcomes (KDIGO) propose alkali treatment to prevent serum bicarbonate levels < 18 mmol/l (prior < 22 mmol/l) in adults and the resulting complications.
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Affiliation(s)
- Alexander Ritter
- Klinik für Nephrologie und Transplantationsmedizin, Kantonsspital St. Gallen, St. Gallen, Schweiz
- Klinik für Nephrologie, Universitätsspital Zürich, Zürich, Schweiz
| | - Christian Kuhn
- Klinik für Nephrologie und Transplantationsmedizin, Kantonsspital St. Gallen, St. Gallen, Schweiz
| | - Nilufar Mohebbi
- Praxis und Dialysezentrum Zürich-City, Stockerstrasse 50, Zürich, Schweiz.
- Universität Zürich, Zürich, Schweiz.
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Abe M, Yamaguchi T, Koshiba S, Takayama S, Nakai T, Nishioka K, Yamasaki S, Kawaguchi K, Umeyama M, Masaura A, Ishizawa K, Arita R, Kanno T, Akaishi T, Miyazaki M, Abe T, Tanaka T, Ishii T. Oral alkalinizing supplementation suppressed intrarenal reactive oxidative stress in mild-stage chronic kidney disease: a randomized cohort study. Clin Exp Nephrol 2024; 28:1134-1154. [PMID: 38872014 PMCID: PMC11568046 DOI: 10.1007/s10157-024-02517-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Accepted: 05/15/2024] [Indexed: 06/15/2024]
Abstract
BACKGROUND The beneficial effects of oral supplements with alkalinizing agents in patients with chronic kidney disease (CKD) have been limited to the severe stages. We investigated whether two types of supplements, sodium bicarbonate (SB) and potassium citrate/sodium citrate (PCSC), could maintain renal function in patients with mild-stage CKD. METHODS This was a single-center, open-labeled, randomized cohort trial. Study participants with CKD stages G2, G3a, and G3b were enrolled between March 2013 and January 2019 and randomly assigned by stratification according to age, sex, estimated glomerular filtration rate (eGFR), and diabetes. They were followed up for 6 months (short-term study) for the primary endpoints and extended to 2 years (long-term study) for the secondary endpoints. Supplementary doses were adjusted to achieve an early morning urinary pH of 6.8-7.2. We observed renal dysfunction or new-onset cerebrovascular disease and evaluated urinary surrogate markers for renal injury. RESULTS Overall, 101 participants were registered and allocated to three groups: standard (n = 32), SB (n = 34), and PCSC (n = 35). Two patients in the standard group attained the primary endpoints (renal stones and overt proteinuria) but were not statistically significant. There was one patient in the standard reduced eGFR during the long-term study (p = 0.042 by ANOVA). SB increased proteinuria (p = 0.0139, baseline vs. 6 months), whereas PCSC significantly reduced proteinuria (p = 0.0061, baseline vs. 1 year, or p = 0.0186, vs. 2 years) and urinary excretion of 8-hydroxy-2'-deoxyguanosine (p = 0.0481, baseline vs. 6 months). CONCLUSION This study is the first to report supplementation of PCSC reduced intrarenal oxidative stress in patients with mild-stage CKD.
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Affiliation(s)
- Michiaki Abe
- Department of Education and Support for Regional Medicine, Tohoku University Hospital, 1-1 Seiryo-Machi, Sendai, Miyagi, 9808574, Japan.
- Tohoku Medical Megabank Organization, Tohoku University, Sendai, Miyagi, Japan.
- Department of Nephrology, Rheumatology and Endocrinology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan.
| | - Takuhiro Yamaguchi
- Clinical Research Data Center, Tohoku University Hospital, Sendai, Miyagi, Japan
| | - Seizo Koshiba
- Tohoku Medical Megabank Organization, Tohoku University, Sendai, Miyagi, Japan
| | - Shin Takayama
- Department of Education and Support for Regional Medicine, Tohoku University Hospital, 1-1 Seiryo-Machi, Sendai, Miyagi, 9808574, Japan
| | - Toshiki Nakai
- Medical Affairs Department, Nippon Chemiphar Co., Ltd, Chiyoda-Ku, Tokyo, Japan
| | - Koichiro Nishioka
- Medical Affairs Department, Nippon Chemiphar Co., Ltd, Chiyoda-Ku, Tokyo, Japan
| | - Satomi Yamasaki
- Medical Affairs Department, Nippon Chemiphar Co., Ltd, Chiyoda-Ku, Tokyo, Japan
| | - Kazuhiko Kawaguchi
- Medical Affairs Department, Nippon Chemiphar Co., Ltd, Chiyoda-Ku, Tokyo, Japan
| | - Masanori Umeyama
- Development Planning Department, Nippon Chemiphar Co., Ltd, Chiyoda-Ku, Tokyo, Japan
| | - Atsuko Masaura
- Department of Education and Support for Regional Medicine, Tohoku University Hospital, 1-1 Seiryo-Machi, Sendai, Miyagi, 9808574, Japan
| | - Kota Ishizawa
- Department of Education and Support for Regional Medicine, Tohoku University Hospital, 1-1 Seiryo-Machi, Sendai, Miyagi, 9808574, Japan
- Tohoku Medical Megabank Organization, Tohoku University, Sendai, Miyagi, Japan
| | - Ryutaro Arita
- Department of Education and Support for Regional Medicine, Tohoku University Hospital, 1-1 Seiryo-Machi, Sendai, Miyagi, 9808574, Japan
| | - Takeshi Kanno
- Department of Education and Support for Regional Medicine, Tohoku University Hospital, 1-1 Seiryo-Machi, Sendai, Miyagi, 9808574, Japan
| | - Tetsuya Akaishi
- Department of Education and Support for Regional Medicine, Tohoku University Hospital, 1-1 Seiryo-Machi, Sendai, Miyagi, 9808574, Japan
| | - Mariko Miyazaki
- Department of Nephrology, Rheumatology and Endocrinology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
| | - Takaaki Abe
- Department of Nephrology, Rheumatology and Endocrinology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
- Department of Clinical Biology and Hormonal Regulation, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
| | - Tetsuhiro Tanaka
- Department of Nephrology, Rheumatology and Endocrinology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
| | - Tadashi Ishii
- Department of Education and Support for Regional Medicine, Tohoku University Hospital, 1-1 Seiryo-Machi, Sendai, Miyagi, 9808574, Japan
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Wu Y, Wang Y, Huang W, Guo X, Hou B, Tang J, Wu Y, Zheng H, Pan Y, Liu WJ. Efficacy and safety of oral sodium bicarbonate in kidney-transplant recipients and non-transplant patients with chronic kidney disease: a systematic review and meta-analysis. Front Pharmacol 2024; 15:1411933. [PMID: 39253380 PMCID: PMC11381255 DOI: 10.3389/fphar.2024.1411933] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2024] [Accepted: 08/14/2024] [Indexed: 09/11/2024] Open
Abstract
Introduction We investigated the efficacy and safety of oral sodium bicarbonate in kidney-transplant recipients and non-transplant patients with chronic kidney disease (CKD), which are currently unclear. Methods PubMed, Cochrane Library, Embase, and Web of Science were searched for randomized controlled trials investigating the efficacy and safety of sodium bicarbonate versus placebo or standard treatment in kidney-transplant and non-transplant patients with CKD. Results Sixteen studies of kidney-transplant recipients (two studies, 280 patients) and non-transplant patients with CKD (14 studies, 1,380 patients) were included. With non-transplant patients, sodium bicarbonate slowed kidney-function declines (standardized mean difference [SMD]: 0.49, 95% confidence interval [CI]: 0.14-0.85, p = 0.006) within ≥12 months (SMD: 0.75 [95% CI: 0.12-1.38], p = 0.02), baseline-serum bicarbonate <22 mmol/L (SMD: 0.41 [95% CI: 0.19-0.64], p = 0.0004) and increased serum-bicarbonate levels (mean difference [MD]: 2.35 [95% CI: 1.40-3.30], p < 0.00001). In kidney-transplant recipients, sodium bicarbonate did not preserve graft function (SMD: -0.07 [95% CI: -0.30-0.16], p = 0.56) but increased blood pH levels (MD: 0.02 [95% CI: 0.00-0.04], p = 0.02). No significant adverse events occurred in the kidney-transplant or non-transplant patients (risk ratio [RR]: 0.89, [95% CI: 0.47-1.67], p = 0.72; and RR 1.30 [95% CI: 0.84-2.00], p = 0.24, respectively). However, oral sodium bicarbonate correlated with increased diastolic pressure and worsened hypertension and edema (MD: 2.21 [95% CI: 0.67-3.75], p = 0.005; RR: 1.44 [95% CI: 1.11-1.88], p = 0.007; and RR: 1.28 [95% CI: 1.00-1.63], p = 0.05, respectively). Discussion Oral sodium bicarbonate may slow kidney-function decline in non-transplant patients with CKD taking sodium bicarbonate supplementation for ≥12 months or a baseline serum bicarbonate level of <22 mmol/L, without preserving graft function in kidney-transplant recipients. Sodium bicarbonate may increase diastolic pressure, and elevate a higher incidence of worsening hypertension and edema. Systematic Review Registration https://www.crd.york.ac.uk/prospero/, identifier CRD42023413929.
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Affiliation(s)
- Yun Wu
- Renal Research Institution of Beijing University of Chinese Medicine, and Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
- Department of Chinese Medicine, the Affiliated Hospital of Guizhou Medical University, Guiyang, China
| | - Ying Wang
- Renal Research Institution of Beijing University of Chinese Medicine, and Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Weijun Huang
- Renal Research Institution of Beijing University of Chinese Medicine, and Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Xi Guo
- Renal Research Institution of Beijing University of Chinese Medicine, and Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Baoluo Hou
- Renal Research Institution of Beijing University of Chinese Medicine, and Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Jingyi Tang
- Renal Research Institution of Beijing University of Chinese Medicine, and Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Yuqi Wu
- Renal Research Institution of Beijing University of Chinese Medicine, and Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Huijuan Zheng
- Renal Research Institution of Beijing University of Chinese Medicine, and Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Yanling Pan
- Department of Chinese Medicine, the Affiliated Hospital of Guizhou Medical University, Guiyang, China
| | - Wei Jing Liu
- Renal Research Institution of Beijing University of Chinese Medicine, and Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
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Yang TY, Lin HM, Wang HY, Chuang MH, Hsieh CC, Tsai KT, Chen JY. Sodium Bicarbonate Treatment and Clinical Outcomes in Chronic Kidney Disease with Metabolic Acidosis: A Meta-Analysis. Clin J Am Soc Nephrol 2024; 19:959-969. [PMID: 38980732 PMCID: PMC11321727 DOI: 10.2215/cjn.0000000000000487] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2023] [Accepted: 06/11/2024] [Indexed: 07/11/2024]
Abstract
Key Points Sodium bicarbonate for patients with CKD and metabolic acidosis leads to a significant improvement in kidney function. Treatment with sodium bicarbonate increases in mid-arm muscle circumference, indicating a positive effect on enhancing muscle mass. Sodium bicarbonate supplementation is associated with a higher risk of elevated systolic BP, marking a potential side effect. Background In patients with CKD, impaired kidney acid excretion leads to the onset of metabolic acidosis (MA). However, the evidence is not yet conclusive regarding the effects of sodium bicarbonate in treating CKD with MA. Methods Databases with PubMed, Embase, and the Cochrane Library were used to search for randomized controlled trials (RCTs) from the inception until November 11, 2023, to identify RCTs investigating the effect of sodium bicarbonate in participants with CKD and MA. The primary outcome was the change in eGFR. Secondary outcomes included hospitalization rates, change in systolic BP, all-cause mortality, and mid-arm muscle circumference. A random-effects model was applied for analysis, and subgroup, sensitivity analyses were also performed. Results Fourteen RCTs comprising 2037 patients demonstrated that sodium bicarbonate supplementation significantly improved eGFR (standardized mean difference [SMD], 0.33; 95% confidence interval [CI], 0.03 to 0.63; P = 0.03). The group receiving sodium bicarbonate had a lower hospitalization rate (odds ratio, 0.37; 95% CI, 0.25 to 0.55; P < 0.001). Higher mid-arm muscle circumference was observed with sodium bicarbonate treatment compared with those without (SMD, 0.23; 95% CI, 0.08 to 0.38; P = 0.003, I2<0.001). However, higher risk of elevated systolic BP was found with sodium bicarbonate treatment (SMD, 0.10; 95% CI, 0.01 to 0.20; P = 0.03). No significant difference in all-cause mortality was noted. Conclusions In patients with CKD and MA, sodium bicarbonate supplementation may provide potential benefits in preventing the deterioration of kidney function and increasing muscle mass. However, treatment may be associated with higher BP. Owing to the risk of bias stemming from the absence of double-blinded designs and inconsistencies in control group definitions across the studies, further research is crucial to verify these findings.
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Affiliation(s)
- Ting-Ya Yang
- Department of Family Medicine, Chi Mei Medical Center, Tainan, Taiwan
| | - Hong-Min Lin
- Department of Family Medicine, Chi Mei Medical Center, Tainan, Taiwan
| | - Hsien-Yi Wang
- Division of Nephrology, Department of Internal Medicine, Chi-Mei Medical Center, Tainan, Taiwan
- Department of Sport Management, College of Leisure and Recreation Management, Chia Nan University of Pharmacy and Science, Tainan, Taiwan
| | - Min-Hsiang Chuang
- Division of Nephrology, Department of Internal Medicine, Chi-Mei Medical Center, Tainan, Taiwan
| | - Chia-Chen Hsieh
- Department of Family Medicine, Chi Mei Medical Center, Tainan, Taiwan
| | - Kang-Ting Tsai
- Department of Family Medicine, Chi Mei Medical Center, Tainan, Taiwan
- Department of Senior Welfare and Services, Southern Taiwan University of Science and Technology, Tainan, Taiwan
| | - Jui-Yi Chen
- Division of Nephrology, Department of Internal Medicine, Chi-Mei Medical Center, Tainan, Taiwan
- Department of Health and Nutrition, Chia Nan University of Pharmacy and Science, Tainan, Taiwan
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Bullen AL, Katz R, Seegmiller J, Garimella PS, Ascher SB, Rifkin DE, Raphael KL, Shlipak MG, Ix JH. Urine Ammonium Concentrations and Cardiovascular and Kidney Outcomes in Systolic Blood Pressure Intervention Trial Participants with CKD. KIDNEY360 2024; 5:1077-1086. [PMID: 39037801 PMCID: PMC11371348 DOI: 10.34067/kid.0000000000000501] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/22/2024] [Accepted: 07/02/2024] [Indexed: 07/24/2024]
Abstract
Key Points Among nondiabetic individuals with hypertension and CKD, higher urine ammonium concentration is associated with higher risk of cardiovascular disease. Urine ammonium was not associated with all-cause mortality or CKD progression, AKI, or linear eGFR decline in the Systolic Blood Pressure Intervention Trial cohort. Background Impaired urine ammonium excretion is common in CKD and may identify risk of metabolic acidosis earlier than reductions in serum bicarbonate or pH and thus may have associations with cardiovascular disease (CVD) outcomes. We evaluated the association of urine ammonium with CVD and kidney outcomes among persons with hypertension and nondiabetic CKD enrolled in a trial of BP reduction. Methods We measured urine ammonium concentration in spot urine specimens collected at baseline among 2092 participants of the Systolic Blood Pressure Intervention Trial (SPRINT) with an eGFR <60 ml/min per 1.73 m2. We used multivariable-adjusted Cox models to evaluate associations of urine ammonium concentration with the SPRINT CVD composite outcome (myocardial infarction, acute coronary syndrome, stroke, heart failure, or CVD death), all-cause mortality, the SPRINT kidney composite outcome (50% kidney function decline, ESKD, or transplant), and AKI. Results At baseline, the mean (SD) age was 73 (9) years; 40% were female; and 25% were Black participants. The mean (SD) serum bicarbonate was 25.6 (2.8) mmol/L, median (interquartile range) urine ammonium concentration was 14.4 (9.5–23.1) mmol/L, and median (interquartile range) eGFR was 49 (39–55) ml/min per 1.73 m2. There were 255 CVD composite events, 143 deaths, 63 kidney composite events, and 146 AKI events during a median follow-up of 3.8 years. In multivariable models, each two-fold higher urinary ammonium concentration was associated with a 26% (95% confidence interval, 1.05 to 1.52) higher risk of the CVD composite, whereas there was no association with all-cause mortality, the SPRINT kidney composite outcome, or AKI. Conclusions Among nondiabetic individuals with hypertension and CKD, higher urine ammonium concentration is associated with higher risk of CVD. Further studies are needed to evaluate this association in other cohorts.
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Affiliation(s)
- Alexander L. Bullen
- Nephrology Section, Veterans Affairs San Diego Healthcare System, La Jolla, California
- Division of Nephrology and Hypertension, Department of Medicine, University of California San Diego, San Diego, California
| | - Ronit Katz
- Department of Obstetrics and Gynecology, University of Washington, Seattle, Washington
| | - Jesse Seegmiller
- Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota
| | - Pranav S. Garimella
- Division of Nephrology and Hypertension, Department of Medicine, University of California San Diego, San Diego, California
| | - Simon B. Ascher
- Kidney Health Research Collaborative, Department of Medicine, University of California, San Francisco, California
- Division of Hospital Medicine, University of California Davis, Sacramento, California
| | - Dena E. Rifkin
- Nephrology Section, Veterans Affairs San Diego Healthcare System, La Jolla, California
- Division of Nephrology and Hypertension, Department of Medicine, University of California San Diego, San Diego, California
| | - Kalani L. Raphael
- Division of Nephrology and Hypertension, Department of Internal Medicine, University of Utah, Salt Lake City, Utah
- VA Salt Lake City Health Care System, Salt Lake City, Utah
| | - Michael G. Shlipak
- Kidney Health Research Collaborative, Department of Medicine, University of California, San Francisco, California
- Department of Medicine, San Francisco VA Medical Center, San Francisco, California
| | - Joachim H. Ix
- Nephrology Section, Veterans Affairs San Diego Healthcare System, La Jolla, California
- Division of Nephrology and Hypertension, Department of Medicine, University of California San Diego, San Diego, California
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Raphael KL. Metabolic Acidosis in CKD: Pathogenesis, Adverse Effects, and Treatment Effects. Int J Mol Sci 2024; 25:5187. [PMID: 38791238 PMCID: PMC11121226 DOI: 10.3390/ijms25105187] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2023] [Revised: 04/28/2024] [Accepted: 05/05/2024] [Indexed: 05/26/2024] Open
Abstract
Metabolic acidosis is a frequent complication of chronic kidney disease and is associated with a number of adverse outcomes, including worsening kidney function, poor musculoskeletal health, cardiovascular events, and death. Mechanisms that prevent metabolic acidosis detrimentally promote further kidney damage, creating a cycle between acid accumulation and acid-mediated kidney injury. Disrupting this cycle through the provision of alkali, most commonly using sodium bicarbonate, is hypothesized to preserve kidney function while also mitigating adverse effects of excess acid on bone and muscle. However, results from clinical trials have been conflicting. There is also significant interest to determine whether sodium bicarbonate might improve patient outcomes for those who do not have overt metabolic acidosis. Such individuals are hypothesized to be experiencing acid-mediated organ damage despite having a normal serum bicarbonate concentration, a state often referred to as subclinical metabolic acidosis. Results from small- to medium-sized trials in individuals with subclinical metabolic acidosis have also been inconclusive. Well-powered clinical trials to determine the efficacy and safety of sodium bicarbonate are necessary to determine if this intervention improves patient outcomes.
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Affiliation(s)
- Kalani L. Raphael
- Division of Nephrology & Hypertension, Department of Internal Medicine, University of Utah, Salt Lake City, UT 84112, USA;
- Medicine Section, Veterans Affairs Salt Lake City Health Care System, Salt Lake City, UT 84148, USA
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Raju S, Manoharan K, Ramachandran N, Sahoo J, Vairappan B, Subramaniyam V, Parameswaran S, Priyamvada P. Randomized Trial on the Efficacy and Safety of Standard Versus Higher Bicarbonate Supplementation in CKD of Unknown Etiology. Kidney Int Rep 2024; 9:1504-1507. [PMID: 38707819 PMCID: PMC11068943 DOI: 10.1016/j.ekir.2024.02.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2023] [Revised: 01/24/2024] [Accepted: 02/05/2024] [Indexed: 05/07/2024] Open
Affiliation(s)
- Swathy Raju
- Department of Nephrology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India
| | - Karthikeyan Manoharan
- Department of Nephrology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India
| | - Natarajan Ramachandran
- Department of Nephrology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India
| | - Jayaprakash Sahoo
- Department of Endocrinology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India
| | - Balasubramanian Vairappan
- Department of Biochemistry, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India
| | - Velkumary Subramaniyam
- Department of Physiology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India
| | - Sreejith Parameswaran
- Department of Nephrology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India
| | - P.S. Priyamvada
- Department of Nephrology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India
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9
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Kuhn C, Mohebbi N, Ritter A. Metabolic acidosis in chronic kidney disease: mere consequence or also culprit? Pflugers Arch 2024; 476:579-592. [PMID: 38279993 PMCID: PMC11006741 DOI: 10.1007/s00424-024-02912-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2023] [Revised: 01/11/2024] [Accepted: 01/12/2024] [Indexed: 01/29/2024]
Abstract
Metabolic acidosis is a frequent complication in non-transplant chronic kidney disease (CKD) and after kidney transplantation. It occurs when net endogenous acid production exceeds net acid excretion. While nephron loss with reduced ammoniagenesis is the main cause of acid retention in non-transplant CKD patients, additional pathophysiological mechanisms are likely inflicted in kidney transplant recipients. Functional tubular damage by calcineurin inhibitors seems to play a key role causing renal tubular acidosis. Notably, experimental and clinical studies over the past decades have provided evidence that metabolic acidosis may not only be a consequence of CKD but also a driver of disease. In metabolic acidosis, activation of hormonal systems and the complement system resulting in fibrosis have been described. Further studies of changes in renal metabolism will likely contribute to a deeper understanding of the pathophysiology of metabolic acidosis in CKD. While alkali supplementation in case of reduced serum bicarbonate < 22 mmol/l has been endorsed by CKD guidelines for many years to slow renal functional decline, among other considerations, beneficial effects and thresholds for treatment have lately been under intense debate. This review article discusses this topic in light of the most recent results of trials assessing the efficacy of dietary and pharmacological interventions in CKD and kidney transplant patients.
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Affiliation(s)
- Christian Kuhn
- Clinic for Nephrology and Transplantation Medicine, Cantonal Hospital St. Gallen, St. Gallen, Switzerland
| | | | - Alexander Ritter
- Clinic for Nephrology and Transplantation Medicine, Cantonal Hospital St. Gallen, St. Gallen, Switzerland.
- Clinic for Nephrology, University Hospital Zurich, Zurich, Switzerland.
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10
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Mannon EC, Muller PR, Sun J, Bush WB, Coleman A, Ocasio H, Polichnowski AJ, Brands MW, O'Connor PM. NaHCO3 loading causes increased arterial pressure and kidney damage in rats with chronic kidney disease. Clin Sci (Lond) 2024; 138:189-203. [PMID: 38300615 DOI: 10.1042/cs20231709] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2023] [Revised: 01/26/2024] [Accepted: 02/01/2024] [Indexed: 02/02/2024]
Abstract
Sodium bicarbonate (NaHCO3) is commonly utilized as a therapeutic to treat metabolic acidosis in people with chronic kidney disease (CKD). While increased dietary sodium chloride (NaCl) is known to promote volume retention and increase blood pressure, the effects of NaHCO3 loading on blood pressure and volume retention in CKD remain unclear. In the present study, we compared the effects of NaCl and NaHCO3 loading on volume retention, blood pressure, and kidney injury in both 2/3 and 5/6 nephrectomy remnant kidney rats, a well-established rodent model of CKD. We tested the hypothesis that NaCl loading promotes greater volume retention and increases in blood pressure than equimolar NaHCO3. Blood pressure was measured 24 h daily using radio telemetry. NaCl and NaHCO3 were administered in drinking water ad libitum or infused via indwelling catheters. Rats were housed in metabolic cages to determine volume retention. Our data indicate that both NaHCO3 and NaCl promote hypertension and volume retention in remnant kidney rats, with salt-sensitivity increasing with greater renal mass reduction. Importantly, while NaHCO3 intake was less pro-hypertensive than equimolar NaCl intake, NaHCO3 was not benign. NaHCO3 loading significantly elevated blood pressure and promoted volume retention in rats with CKD when compared with control rats receiving tap water. Our findings provide important insight into the effects of sodium loading with NaHCO3 in CKD and indicate that NaHCO3 loading in patients with CKD is unlikely to be benign.
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Affiliation(s)
- Elinor C Mannon
- Department of Physiology, Medical College of Georgia at Augusta University, Augusta, Georgia, U.S.A
| | - P Robinson Muller
- Department of Physiology, Medical College of Georgia at Augusta University, Augusta, Georgia, U.S.A
| | - Jingping Sun
- Department of Physiology, Medical College of Georgia at Augusta University, Augusta, Georgia, U.S.A
| | - Weston B Bush
- Department of Physiology, Medical College of Georgia at Augusta University, Augusta, Georgia, U.S.A
| | - Alex Coleman
- Department of Physiology, Medical College of Georgia at Augusta University, Augusta, Georgia, U.S.A
| | - Hiram Ocasio
- Department of Physiology, Medical College of Georgia at Augusta University, Augusta, Georgia, U.S.A
| | - Aaron J Polichnowski
- Department of Biomedical Sciences, Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee, U.S.A
| | - Michael W Brands
- Department of Physiology, Medical College of Georgia at Augusta University, Augusta, Georgia, U.S.A
| | - Paul M O'Connor
- Department of Physiology, Medical College of Georgia at Augusta University, Augusta, Georgia, U.S.A
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11
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Raphael KL, Katz R, Larive B, Kendrick C, Isakova T, Sprague S, Wolf M, Raj DS, Fried LF, Gassman J, Hoofnagle A, Cheung AK, Ix JH. Oral Sodium Bicarbonate and Bone Turnover in CKD: A Secondary Analysis of the BASE Pilot Trial. J Am Soc Nephrol 2024; 35:57-65. [PMID: 38170601 PMCID: PMC10786609 DOI: 10.1681/asn.0000000000000264] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2023] [Accepted: 10/18/2023] [Indexed: 01/05/2024] Open
Abstract
SIGNIFICANCE STATEMENT In CKD, metabolic acidosis is commonly treated with alkali in the hope that it will improve bone health. In a post hoc analysis of the Bicarbonate Administration to Stabilize eGFR Pilot Trial, we investigated whether sodium bicarbonate affects serum levels of bone turnover markers and other hormones related to bone health in individuals with CKD who have normal to slightly reduced total CO2 (20-28 mEq/L). Sodium bicarbonate increased serum levels of α-klotho but had no significant effect on other bone health markers, including intact fibroblast growth factor-23 (iFGF-23), intact parathyroid hormone (iPTH), and bone-specific alkaline phosphatase (B-SAP). Further study is needed to determine the effect of bicarbonate administration on clinical aspects of bone health. BACKGROUND Treatment with alkali has been hypothesized to improve bone health in CKD by mitigating adverse effects of acid on bone mineral. We investigated the effect of treatment with sodium bicarbonate on bone turnover markers and other factors related to bone metabolism in CKD. METHODS This is a post hoc analysis of the Bicarbonate Administration to Stabilize eGFR Pilot Trial in which 194 individuals with CKD and serum total CO2 20-28 mEq/L were randomly assigned to placebo or one of two doses of sodium bicarbonate (0.5 or 0.8 mEq/kg lean body weight per day) for 28 weeks. The following serum measurements were performed at baseline, week 12, and week 28: B-SAP, c-telopeptide, procollagen type I intact N-terminal propeptide, iPTH, iFGF-23, soluble klotho, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, and tartrate-resistant acid phosphatase 5b. The difference (sodium bicarbonate versus placebo) in mean change of each bone biomarker from baseline was determined using linear mixed models. RESULTS One hundred sixty-eight participants submitted samples for post hoc investigations. Mean eGFR was 37±10 ml/min per 1.73 m2 and mean total CO2 was 24±3 mEq/L at baseline. Sodium bicarbonate induced a dose-dependent increase in soluble klotho levels compared with placebo. There was no significant effect of treatment with either dose of sodium bicarbonate on any of the other bone biomarkers, including iFGF-23, iPTH, and B-SAP. Effects on bone biomarkers were similar in those with baseline serum total CO2 <24 mEq/L compared with those with total CO2 ≥24 mEq/L. CONCLUSIONS In this pilot trial of individuals with CKD and total CO2 20-28 mEq/L, sodium bicarbonate treatment increased serum klotho levels but did not affect other bone health markers over 28 weeks. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER ClinicalTrials.gov, NCT02521181.
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Affiliation(s)
- Kalani L. Raphael
- University of Utah Health and VA Salt Lake City Health Care System, Salt Lake City, Utah
| | - Ronit Katz
- Department of Obstetrics & Gynecology, University of Washington, Seattle, Washington
| | | | | | - Tamara Isakova
- Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Stuart Sprague
- Division of Nephrology & Hypertension, Northshore University Health System-University of Chicago, Evanston, Illinois
| | - Myles Wolf
- Division of Nephrology, Department of Medicine, Duke Clinical Research Institute, Duke University School of Medicine, Durham, North Carolina
| | - Dominic S. Raj
- George Washington University School of Medicine, Washington, DC
| | - Linda F. Fried
- University of Pittsburgh and VA Pittsburgh Health Care System, Pittsburgh, Pennsylvania
| | | | - Andy Hoofnagle
- Department of Obstetrics & Gynecology, University of Washington, Seattle, Washington
| | - Alfred K. Cheung
- University of Utah Health and VA Salt Lake City Health Care System, Salt Lake City, Utah
| | - Joachim H. Ix
- University of California San Diego and VA San Diego Health Care System, San Diego, California
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12
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Ortiz A, Galán CDA, Carlos Fernández-García J, Cerezo JG, Ochoa RI, Núñez J, Gutiérrez FP, Navarro-González JF. Consensus document on the management of hyperkalemia. Nefrologia 2023; 43:765-782. [PMID: 38169239 DOI: 10.1016/j.nefroe.2023.12.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2023] [Accepted: 05/08/2023] [Indexed: 01/05/2024] Open
Abstract
Hyperkalaemia is a common electrolyte imbalance with potentially serious short-, medium- and long-term consequences on morbidity and mortality rates and the use of national health service resources. The fact that different medical specialities can manage hyperkalaemia makes it important to have a unified approach, and the recent availability of new specific drug treatments means that the approach needs to be updated. This consensus document from the scientific societies most directly involved in the management of hyperkalaemia (Sociedad Española de Cardiología [Spanish Society of Cardiology], Sociedad Española de Endocrinología y Nutrición [Spanish Society of Endocrinology and Nutrition], Sociedad Española de Medicina Interna [Spanish Society of Internal Medicine], Sociedad Española de Medicina de Urgencias y Emergencias [Spanish Society of Accident and Emergency Medicine] and Sociedad Española de Nefrología [Spanish Society of Nephrology]) first of all reviews basic aspects of potassium balance and blood potassium. Then it goes on to focus on the concept, epidemiology, pathophysiology and diagnostic and therapeutic approaches to hyperkalaemia. The available evidence and the main published studies have been reviewed with the aim of providing a useful tool in the multidisciplinary approach to patients with hyperkalaemia.
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Affiliation(s)
| | | | | | | | - Rosa Ibán Ochoa
- Sociedad Española de Medicina de Urgencias y Emergencias (SEMES), Spain
| | - Julio Núñez
- Sociedad Española de Cardiología (SEC), Spain
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13
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Navab F, Rouhani MH, Moeinzadeh F, Clark CCT, Ziaei R. The effects of oral sodium bicarbonate supplementation on anthropometric measures in patients with chronic kidney disease: A systematic review and meta-analysis of randomized clinical trials. Food Sci Nutr 2023; 11:6749-6760. [PMID: 37970385 PMCID: PMC10630834 DOI: 10.1002/fsn3.3627] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2023] [Revised: 08/01/2023] [Accepted: 08/04/2023] [Indexed: 11/17/2023] Open
Abstract
Metabolic acidosis (MA) may play a key role in the pathogenesis of protein-energy wasting (PEW) in patients with chronic kidney disease (CKD). To present a comprehensive synthesis of the effect of oral sodium bicarbonate (SB) supplementation on anthropometric measures in patients with CKD, a systematic review was undertaken in PubMed/MEDLINE, Web of Science, Cochrane CENTRAL, and Google Scholar, of relevant articles published prior to September 2022. The summary statistics of effect size, nonstandardized weighted mean difference (WMD), and 95% confidence interval (CI) were used to compare the effects of SB supplementation on anthropometric parameters vs. control group. To detect probable sources of heterogeneity, a series of predefined subgroup analyses were conducted. In total, 17 studies with 21 treatment arms, including 2203 participants (1149 cases, 1054 controls), met our inclusion criteria and were included in the meta-analysis. SB supplementation had no significant effect on body weight (BW), midarm muscle circumference (MAMC), or lean body mass (LBM) in patients with CKD. There was a significant increase in body mass index (BMI) (MD: 0.59 kg/m2, 95% CI: 0.25 to 0.93, p = 0.001) after SB supplementation in the overall analysis. In subgroup analysis, LBM was increased in studies that were ≥ 24-week duration (MD: 1.81 kg, 95% CI: 0.81 to 2.81) and in participants with BMI lower than 27 kg/m2 (MD: 1.81 mg/L, 95% CI: 0.81 to 2.81). SB supplementation may yield increases in BMI in predialysis CKD patients. However, our findings did not support the beneficial effects of SB supplementation on other anthropometric outcomes. There is an evident need for long-term high-quality interventions to confirm these findings.
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Affiliation(s)
- Fatemeh Navab
- Student Research Committee, Nutrition and Food Security Research Center and Department of Community Nutrition, School of Nutrition and Food ScienceIsfahan University of Medical SciencesIsfahanIran
| | - Mohammad Hossein Rouhani
- Nutrition and Food Security Research Center, Department of Community Nutrition, School of Nutrition and Food ScienceIsfahan University of Medical SciencesIsfahanIran
| | - Firouzeh Moeinzadeh
- Isfahan Kidney Diseases Research CenterIsfahan University of Medical SciencesIsfahanIran
| | | | - Rahele Ziaei
- Nutrition and Food Security Research Center, Department of Community Nutrition, School of Nutrition and Food ScienceIsfahan University of Medical SciencesIsfahanIran
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14
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Kendrick J, You Z, Andrews E, Farmer-Bailey H, Moreau K, Chonchol M, Steele C, Wang W, Nowak KL, Patel N. Sodium Bicarbonate Treatment and Vascular Function in CKD: A Randomized, Double-Blind, Placebo-Controlled Trial. J Am Soc Nephrol 2023; 34:1433-1444. [PMID: 37228030 PMCID: PMC10400105 DOI: 10.1681/asn.0000000000000161] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2023] [Accepted: 04/18/2023] [Indexed: 05/27/2023] Open
Abstract
SIGNIFICANCE STATEMENT Lower serum bicarbonate levels, even within the normal range, are strongly linked to risks of cardiovascular disease in CKD, possibly by modifying vascular function. In this randomized, controlled trial, treatment with sodium bicarbonate (NaHCO 3 ) did not improve vascular endothelial function or reduce arterial stiffness in participants with CKD stage 3b-4 with normal serum bicarbonate levels. In addition, NaHCO 3 treatment did not reduce left ventricular mass index. NaHCO 3 did increase plasma bicarbonate levels and urinary citrate excretion and reduce urinary ammonium excretion, indicating that the intervention was indeed effective. NaHCO 3 therapy was safe with no significant changes in BP, weight, or edema. These results do not support the use of NaHCO 3 for vascular dysfunction in participants with CKD. BACKGROUND Lower serum bicarbonate levels, even within the normal range, are strongly linked to risks of cardiovascular disease in CKD, possibly by modifying vascular function. Prospective interventional trials with sodium bicarbonate (NaHCO 3 ) are lacking. METHODS We conducted a randomized, double-blind, placebo-controlled trial examining the effect of NaHCO 3 on vascular function in 109 patients with CKD stage 3b-4 (eGFR 15-44 ml/min per 1.73 m 2 ) with normal serum bicarbonate levels (22-27 mEq/L). Participants were randomized 1:1 to NaHCO 3 or placebo at a dose of 0.5 mEq/lean body weight-kg per day for 12 months. The coprimary end points were change in brachial artery flow-mediated dilation (FMD) and change in aortic pulse wave velocity over 12 months. RESULTS Ninety patients completed this study. After 12 months, plasma bicarbonate levels increased significantly in the NaHCO 3 group compared with placebo (mean [SD] difference between groups 1.35±2.1, P = 0.003). NaHCO 3 treatment did not result in a significant improvement in aortic pulse wave velocity from baseline. NaHCO 3 did result in a significant increase in flow-mediated dilation after 1 month; however, this effect disappeared at 6 and 12 months. NaHCO 3 resulted in a significant increase in 24-hour urine citrate and pH and a significant decrease in 24-hour urine ammonia. There was no significant change in left ventricular mass index, ejection fraction, or eGFR with NaHCO 3 . NaHCO 3 treatment was safe and well-tolerated with no significant changes in BP, antihypertensive medication, weight, plasma calcium, or potassium levels. CONCLUSION Our results do not support the use of NaHCO 3 for vascular dysfunction in participants with CKD and normal serum bicarbonate levels.
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Affiliation(s)
- Jessica Kendrick
- Division of Renal Disease and Hypertension, University of Colorado Anschutz Medical Campus, Aurora, Colorado
| | - Zhiying You
- Division of Renal Disease and Hypertension, University of Colorado Anschutz Medical Campus, Aurora, Colorado
| | - Emily Andrews
- Division of Renal Disease and Hypertension, University of Colorado Anschutz Medical Campus, Aurora, Colorado
| | - Heather Farmer-Bailey
- Division of Renal Disease and Hypertension, University of Colorado Anschutz Medical Campus, Aurora, Colorado
| | - Kerrie Moreau
- Division of Geriatrics, University of Colorado Anschutz Medical Campus, Aurora, Colorado
| | - Michel Chonchol
- Division of Renal Disease and Hypertension, University of Colorado Anschutz Medical Campus, Aurora, Colorado
| | - Cortney Steele
- Division of Renal Disease and Hypertension, University of Colorado Anschutz Medical Campus, Aurora, Colorado
| | - Wei Wang
- Division of Renal Disease and Hypertension, University of Colorado Anschutz Medical Campus, Aurora, Colorado
| | - Kristen L. Nowak
- Division of Renal Disease and Hypertension, University of Colorado Anschutz Medical Campus, Aurora, Colorado
| | - Nayana Patel
- Division of Radiology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico
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15
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Pao AC, Shahzad SR, Song S, Ganesan C, Conti S, Leppert J, Cheung AK, Ix JH, Isakova T, Wolf M, Raj DS, Sprague SM, Fried LF, Gassman J, Fong P, Koike S, Raphael KL. Response to Alkali Administration in Women and Men With and Without CKD. Kidney Med 2023; 5:100670. [PMID: 37492113 PMCID: PMC10363557 DOI: 10.1016/j.xkme.2023.100670] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/27/2023] Open
Affiliation(s)
- Alan C. Pao
- Division of Nephrology, Department of Medicine, Stanford University School of Medicine, Palo Alto, California
- Department of Urology, Stanford University School of Medicine, Palo Alto, California
| | - Sheikh R. Shahzad
- Division of Nephrology, Department of Medicine, Stanford University School of Medicine, Palo Alto, California
| | - Shen Song
- Division of Nephrology, Department of Medicine, Stanford University School of Medicine, Palo Alto, California
| | - Calyani Ganesan
- Division of Nephrology, Department of Medicine, Stanford University School of Medicine, Palo Alto, California
| | - Simon Conti
- Department of Urology, Stanford University School of Medicine, Palo Alto, California
| | - John Leppert
- Division of Nephrology, Department of Medicine, Stanford University School of Medicine, Palo Alto, California
- Department of Urology, Stanford University School of Medicine, Palo Alto, California
| | - Alfred K. Cheung
- Division of Nephrology and Hypertension, Department of Medicine, University of Utah School of Medicine, Salt Lake City, Utah
| | - Joachim H. Ix
- Division of Nephrology and Hypertension, Department of Medicine, University of California San Diego School of Medicine, San Diego, California
| | - Tamara Isakova
- Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
| | - Myles Wolf
- Division of Nephrology, Department of Medicine, Duke Clinical Research Institute, Duke University, Durham, North Carolina
| | - Dominic S. Raj
- Division of Renal Diseases and Hypertension, Department of Medicine, George Washington University School of Medicine, Washington, DC
| | - Stuart M. Sprague
- Department of Medicine, Northshore University Health System, University of Chicago, Evanston, Illinois
| | - Linda F. Fried
- Department of Medicine, University of Pittsburgh and Renal Section, Veterans Affairs Pittsburgh Health Care System, Pittsburgh, Pennsylvania
| | - Jennifer Gassman
- Department of Quantitative Health Sciences, Cleveland Clinic Foundation, Cleveland, Ohio
| | - Peter Fong
- Division of Nephrology and Hypertension, Department of Medicine, Oregon Health and Science University School of Medicine, Portland, Oregon
| | - Seiji Koike
- Biostatistics and Design Program, Oregon Health and Science University, Portland, Oregon
| | - Kalani L. Raphael
- Division of Nephrology and Hypertension, Department of Medicine, University of Utah School of Medicine, Salt Lake City, Utah
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16
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Koh ES. Hidden Acid Retention with Normal Serum Bicarbonate Level in Chronic Kidney Disease. Electrolyte Blood Press 2023; 21:34-43. [PMID: 37434806 PMCID: PMC10329907 DOI: 10.5049/ebp.2023.21.1.34] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2023] [Revised: 04/06/2023] [Accepted: 04/16/2023] [Indexed: 07/13/2023] Open
Abstract
Management of metabolic acidosis is crucial for preserving bone, muscle, and renal health, as evidenced by the results of several interventional studies conducted on patients with chronic kidney disease (CKD). Considering the continuity of CKD progression over time, it is reasonable to deduce that a subclinical form of metabolic acidosis may exist prior to the manifestation of overt metabolic acidosis. Covert H+ retention with normal serum bicarbonate level in patients with CKD may result in maladaptive responses that contribute to kidney function deterioration, even in the early stages of the disease. The loss of adaptive compensatory mechanisms of urinary acid excretion may be a key factor in this process. Early modulation of these responses could be an important therapeutic strategy in preventing CKD progression. However, to date, the optimal approach for alkali therapy in subclinical metabolic acidosis in CKD remains uncertain. There is a lack of established guidelines on when to initiate alkali therapy, potential side effects of alkali agents, and the optimal blood bicarbonate levels based on evidence-based practices. Therefore, further research is necessary to address these concerns and establish more robust guidelines for the use of alkali therapy in patients with CKD. Herein, we provide an overview of recent developments on this subject and examine the potential therapeutic approaches that interventional treatments may present for patients with hidden H+ retention, exhibiting normal serum bicarbonate levels - commonly described as subclinical or eubicarbonatemic metabolic acidosis in patients with CKD.
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Affiliation(s)
- Eun Sil Koh
- Division of Nephrology, Department of Internal Medicine, Yeouido St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
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17
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Beynon-Cobb B, Louca P, Hoorn EJ, Menni C, Padmanabhan S. Effect of Sodium Bicarbonate on Systolic Blood Pressure in CKD: A Systematic Review and Meta-Analysis. Clin J Am Soc Nephrol 2023; 18:435-445. [PMID: 36758154 PMCID: PMC10103210 DOI: 10.2215/cjn.0000000000000119] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2022] [Accepted: 01/24/2023] [Indexed: 02/11/2023]
Abstract
BACKGROUND Individuals with CKD are at a higher risk of cardiovascular morbidity and mortality. Acidosis is positively correlated with CKD progression and elevated systolic BP. Sodium bicarbonate is an efficacious treatment of acidosis, although this may also increase systolic BP. In this systematic review and meta-analysis, we summarize the evidence evaluating systolic BP and antihypertensive medication change (which may indicate systolic BP change) in response to sodium bicarbonate therapy in individuals with CKD. METHODS Medical Literature Analysis and Retrieval System Online, Excerpta Medica database, Cumulative Index to Nursing and Allied Health Literature, Allied and Complementary Medicine Database, Cochrane Central Register of Controlled Trials, and World Health Organization (WHO) trials registry databases were searched for randomized control trials where sodium bicarbonate was compared with placebo/usual care in CKD stage G1-5 non-dialysis-dependent populations. Random effects meta-analyses were used to evaluate changes in systolic BP and BP-modifying drugs after sodium bicarbonate intervention. RESULTS Fourteen randomized control trials (2110 individuals, median follow-up 27 [interquartile range 97] weeks, mean age 60 [SD 10] years, mean systolic BP 136 [SD 17] mm Hg, mean eGFR 38 [SD 10] ml/min, mean serum bicarbonate 22 [SD 4] mmol/L) were eligible for inclusion. Meta-analysis suggested that sodium bicarbonate did not influence systolic BP in individuals with CKD stage G1-5. Results were consistent when stratifying by dose of sodium bicarbonate or duration of intervention. Similarly, there was no significant increase in the use of antihypertensive medication or diuretics in individuals taking sodium bicarbonate, whereas there was a greater decrease in antihypertensive medication use in individuals taking sodium bicarbonate compared with controls. CONCLUSIONS Our results suggest, with moderate certainty, that sodium bicarbonate supplementation does not adversely affect systolic BP in CKD or negatively influence antihypertensive medication requirements.
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Affiliation(s)
- Beverley Beynon-Cobb
- Department of Nutrition & Dietetics, University Hospitals Coventry & Warwickshire NHS Trust, Coventry, United Kingdom
- Department of Twin Research and Genetic Epidemiology, King's College London, London, United Kingdom
| | - Panayiotis Louca
- Department of Twin Research and Genetic Epidemiology, King's College London, London, United Kingdom
| | - Ewout J. Hoorn
- Department of Internal Medicine, Divisions of Nephrology and Transplantation, Erasmus Medical Center, University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Cristina Menni
- Department of Twin Research and Genetic Epidemiology, King's College London, London, United Kingdom
| | - Sandosh Padmanabhan
- BHF Glasgow Cardiovascular Research Centre, School of Cardiovascular & Metabolic Health, University of Glasgow, Glasgow, United Kingdom
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18
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Abstract
Metabolic acidosis is a common complication in patients with chronic kidney disease that occurs when the daily nonvolatile acid load produced in metabolism cannot be excreted fully by the kidney. A reduction in urine net acid excretion coupled with a high nonvolatile acid load may play a role in its pathogenesis. Diet is important in generation of the nonvolatile acid load. Acids are produced from metabolism of dietary protein and from the endogenous production of organic anions from neutral precursors. Acids can be balanced by alkali precursors ingested in the diet in the form of combustible organic anions. These typically are reflected indirectly by the excess of mineral cations to mineral anions in a food or diet. These principles underscore widely used methods to estimate the nonvolatile acid load from dietary intake using formulas such as the net endogenous acid production equation and the potential renal acid load equation. Empiric data largely validate these paradigms with high net endogenous acid production and potential renal acid load contributed by foods such as protein, grains, and dairy, and low net endogenous acid production and potential renal acid load contributed by fruits and vegetables along with corresponding dietary patterns. Although further studies are needed to understand the health benefits of altering nonvolatile acid load via diet, this review provides a detailed assessment on our current understanding of the role of diet in chronic kidney disease-related acidosis, providing an updated resource for researchers and clinicians.
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Affiliation(s)
- Anita Vincent-Johnson
- Department of Medicine, University of Virginia School of Medicine, Charlottesville, VA
| | - Brenda Davy
- Department of Human Nutrition, Foods and Exercise, Virginia Polytechnic Institute and State University, Blacksburg, VA
| | - Julia J Scialla
- Department of Medicine, University of Virginia School of Medicine, Charlottesville, VA; Department of Public Health Sciences, University of Virginia School of Medicine, Charlottesville, VA.
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19
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Sodium zirconium cyclosilicate and metabolic acidosis: Potential mechanisms and clinical consequences. Biomed Pharmacother 2023; 158:114197. [PMID: 36916426 DOI: 10.1016/j.biopha.2022.114197] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Revised: 12/23/2022] [Accepted: 12/29/2022] [Indexed: 01/05/2023] Open
Abstract
Metabolic acidosis is frequent in chronic kidney disease (CKD) and is associated with accelerated progression of CKD, hypercatabolism, bone disease, hyperkalemia, and mortality. Clinical guidelines recommend a target serum bicarbonate ≥ 22 mmol/L, but metabolic acidosis frequently remains undiagnosed and untreated. Sodium zirconium cyclosilicate (SZC) binds potassium in the gut and is approved to treat hyperkalemia. In clinical trials with a primary endpoint of serum potassium, SZC increased serum bicarbonate, thus treating CKD-associated metabolic acidosis. The increase in serum bicarbonate was larger in patients with more severe pre-existent metabolic acidosis, was associated to decreased serum urea and was maintained for over a year of SZC therapy. SZC also decreased serum urea and increased serum bicarbonate after switching from a potassium-binding resin in normokalemic individuals. Mechanistically, these findings are consistent with SZC binding the ammonium ion (NH4+) generated from urea by gut microbial urease, preventing its absorption and, thus, preventing the liver regeneration of urea and promoting the fecal excretion of H+. This mechanism of action may potentially result in benefits dependent on corrected metabolic acidosis (e.g., improved well-being, decreased catabolism, improved CKD mineral bone disorder, better control of serum phosphate, slower progression of CKD) and dependent on lower urea levels, such as decreased protein carbamylation. A roadmap is provided to guide research into the mechanisms and clinical consequences of the impact of SZC on serum bicarbonate and urate.
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20
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Goraya N, Narayanan M, Wesson DE. Management of Metabolic Acidosis in Chronic Kidney Disease: Past, Present, and Future Direction. Adv Chronic Kidney Dis 2022; 29:416-423. [PMID: 36175079 DOI: 10.1053/j.ackd.2022.02.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Revised: 02/20/2022] [Accepted: 02/28/2022] [Indexed: 01/25/2023]
Abstract
Chronic kidney disease (CKD) is a major global epidemic associated with increased morbidity and mortality. Despite the effectiveness of kidney protection strategies of hypertension, diabetes, and lipid control and use of newer hypoglycemic agents and anti-angiotensin II drugs, the nephropathy in CKD continues unabated toward irreversible kidney failure. Thus, interventions targeting modifiable risk factors in CKD such as metabolic acidosis (MA) are needed. Acid reduction with sodium-based alkali has been shown to be an effective kidney-protection strategy for patients with CKD and reduced glomerular filtration rate (GFR). Small-scale studies reveal diets emphasizing ingestion of plant-sourced over animal-sourced protein reduce dietary acid, improve MA, and slow further nephropathy progression in patients with CKD and reduced GFR. Additionally, veverimer, an investigational, nonabsorbed polymer that binds and removes gastrointestinal hydrochloric acid, is being developed as a novel treatment for MA. As further studies define how to best use these interventions for kidney protection, clinicians must become aware of their potential utility in the management of patients with CKD. The aim of the present review is to explore the various intervention strategies that increase or normalize serum [HCO3-] in patients with CKD-associated MA or low normal serum [HCO3-] that may further slow progression of CKD.
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Affiliation(s)
- Nimrit Goraya
- Scott & White Medical Center-Temple, Division of Nephrology and Hypertension, Department of Medicine, Temple, TX.
| | - Mohanram Narayanan
- Scott & White Medical Center-Temple, Division of Nephrology and Hypertension, Department of Medicine, Temple, TX
| | - Donald E Wesson
- Dell Medical School, The University of Texas at Austin, Austin, TX
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21
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Ravikumar NPG, Pao AC, Raphael KL. Acid-Mediated Kidney Injury Across the Spectrum of Metabolic Acidosis. Adv Chronic Kidney Dis 2022; 29:406-415. [PMID: 36175078 DOI: 10.1053/j.ackd.2022.04.009] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Revised: 04/15/2022] [Accepted: 04/25/2022] [Indexed: 01/25/2023]
Abstract
Metabolic acidosis affects about 15% of patients with chronic kidney disease. As kidney function declines, the kidneys progressively fail to eliminate acid, primarily reflected by a decrease in ammonium and titratable acid excretion. Several studies have shown that the net acid load remains unchanged in patients with reduced kidney function; the ensuing acid accumulation can precede overt metabolic acidosis, and thus, indicators of urinary acid or potential base excretion, such as ammonium and citrate, may serve as early signals of impending metabolic acidosis. Acid retention, with or without overt metabolic acidosis, initiates compensatory responses that can promote tubulointerstitial fibrosis via intrarenal complement activation and upregulation of endothelin-1, angiotensin II, and aldosterone pathways. The net effect is a cycle between acid accumulation and kidney injury. Results from small- to medium-sized interventional trials suggest that interrupting this cycle through base administration can prevent further kidney injury. While these findings inform current clinical practice guidelines, large-scale clinical trials are still necessary to prove that base therapy can limit chronic kidney disease progression or associated adverse events.
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Affiliation(s)
- Naveen P G Ravikumar
- Division of Nephrology & Hypertension, Department of Medicine, Oregon Health & Science University, Portland, OR; Veterans Affairs Portland Health Care System, Portland, OR
| | - Alan C Pao
- Division of Nephrology, Department of Medicine, Stanford University School of Medicine, Stanford, CA; Veterans Affairs Palo Alto Health Care System, Palo Alto, CA
| | - Kalani L Raphael
- Division of Nephrology & Hypertension, Department of Medicine, Oregon Health & Science University, Portland, OR; Veterans Affairs Portland Health Care System, Portland, OR.
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22
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Vincent-Johnson A, Scialla JJ. Importance of Metabolic Acidosis as a Health Risk in Chronic Kidney Disease. Adv Chronic Kidney Dis 2022; 29:329-336. [PMID: 36175070 DOI: 10.1053/j.ackd.2022.05.002] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2022] [Revised: 05/09/2022] [Accepted: 05/25/2022] [Indexed: 01/25/2023]
Abstract
Human kidneys are well adapted to excrete the daily acid load from diet and metabolism in order to maintain homeostasis. In approximately 30% of patients with more advanced stages of CKD, these homeostatic processes are no longer adequate, resulting in metabolic acidosis. Potential deleterious effects of chronic metabolic acidosis in CKD, including muscle wasting, bone demineralization, hyperkalemia, and more rapid progression of CKD, have been well cataloged. Based primarily upon concerns related to nutrition and bone disease, early Kidney Disease Outcomes Quality Initiative guidelines recommended treating metabolic acidosis with alkali therapy targeting a serum bicarbonate ≥22 mEq/L. More recent guidelines have suggested similar targets based upon potential slowing of CKD progression. However, appropriately powered, long-term, randomized controlled trials to study efficacy and safety of alkali therapy for these outcomes are largely lacking. As a result, practice among physicians varies, underscoring the complexity of treatment of chronic metabolic acidosis in real-world CKD practice. Novel treatment approaches and rigorous phase 3 trials may resolve some of this controversy in the coming years. Metabolic acidosis is an important complication of CKD, and where it "falls" in the priority schema of CKD care will depend upon the generation of strong clinical evidence.
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Affiliation(s)
- Anita Vincent-Johnson
- Department of Medicine, University of Virginia School of Medicine, Charlottesville, VA
| | - Julia J Scialla
- Department of Medicine, University of Virginia School of Medicine, Charlottesville, VA; Department of Public Health Sciences, University of Virginia School of Medicine, Charlottesville, VA.
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23
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Cheng F, Li Q, Wang J, Wang Z, Zeng F, Zhang Y. The Effects of Oral Sodium Bicarbonate on Renal Function and Cardiovascular Risk in Patients with Chronic Kidney Disease: A Systematic Review and Meta-Analysis. Ther Clin Risk Manag 2021; 17:1321-1331. [PMID: 34908841 PMCID: PMC8665881 DOI: 10.2147/tcrm.s344592] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Accepted: 11/30/2021] [Indexed: 11/23/2022] Open
Abstract
OBJECTIVE Oral sodium bicarbonate is often used to correct acid-base disturbance in patients with chronic kidney disease (CKD). However, there is little evidence on patient-level benign outcomes to support the practice. METHODS We conducted a systematic review and meta-analysis to examine the efficacy and safety of oral sodium bicarbonate in CKD patients. A total of 1853 patients with chronic metabolic acidosis or those with low-normal serum bicarbonate (22-24 mEq/L) were performed to compare the efficacy and safety of oral sodium bicarbonate in patients with CKD. RESULTS There was a significant increase in serum bicarbonate level (MD 2.37 mEq/L; 95% CI, 1.03 to 3.72) and slowed the decline in estimated glomerular filtration rate (eGFR) (MD -4.44 mL/min per 1.73 m2, 95% CI, -4.92 to -3.96) compared with the control groups. The sodium bicarbonate lowered T50-time, an indicator of vascular calcification (MD -20.74 min; 95% CI, -49.55 to 8.08); however, there was no significant difference between the two groups. In addition, oral sodium bicarbonate dramatically reduced systolic blood pressure (MD -2.97 mmHg; 95% CI, -5.04 to -0.90) and diastolic blood pressure (MD -1.26 mmHg; 95% CI, -2.33 to -0.19). There were no statistically significant body weight, urine pH and mean mid-arm muscle circumference. CONCLUSION Treatment of metabolic acidosis with sodium bicarbonate may slow the decline rate of kidney function and potentially significantly improve vascular endothelial function in patients with CKD. PROSPERO REGISTRATION NUMBER CRD42020207185.
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Affiliation(s)
- Fang Cheng
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China
- Hubei Province Clinical Research Center for Precision Medicine for Critical Illness, Wuhan, People’s Republic of China
| | - Qiang Li
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China
- Hubei Province Clinical Research Center for Precision Medicine for Critical Illness, Wuhan, People’s Republic of China
| | - Jinglin Wang
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China
- Hubei Province Clinical Research Center for Precision Medicine for Critical Illness, Wuhan, People’s Republic of China
| | - Zhendi Wang
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China
| | - Fang Zeng
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China
- Hubei Province Clinical Research Center for Precision Medicine for Critical Illness, Wuhan, People’s Republic of China
| | - Yu Zhang
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China
- Hubei Province Clinical Research Center for Precision Medicine for Critical Illness, Wuhan, People’s Republic of China
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Kim HJ. Metabolic Acidosis in Chronic Kidney Disease: Pathogenesis, Clinical Consequences, and Treatment. Electrolyte Blood Press 2021; 19:29-37. [PMID: 35003283 PMCID: PMC8715222 DOI: 10.5049/ebp.2021.19.2.29] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Revised: 12/03/2021] [Accepted: 12/06/2021] [Indexed: 12/13/2022] Open
Abstract
The kidneys play an important role in regulating the acid-base balance. Metabolic acidosis is common in chronic kidney disease (CKD) patients and can lead to poor outcomes, such as bone demineralization, muscle mass loss, and worsening of renal function. Metabolic acidosis is usually approached with evaluating the serum bicarbonate levels but should be assessed by counting blood pH. Current guidelines recommend oral bicarbonate supplementation to maintain the serum bicarbonate levels within the normal range. However, a slow decline in the glomerular filtration rate might occur, even though the serum bicarbonate levels were in the normal range. Because the serum bicarbonate levels decrease when metabolic acidosis advances, other biomarkers are necessary to indicate acid retention for early diagnosis of metabolic acidosis. For this, urine citrate and ammonium excretion may be used to follow the course of CKD patients. Metabolic acidosis can be treated with an increased fruit and vegetable intake and oral alkali supplementation. Previous studies have suggested that administration of oral sodium bicarbonate may preserve kidney function without significant increases in blood pressure and body weight. Veverimer, a non-absorbed, counterion-free, polymeric drug, is emerging to treat metabolic acidosis, but further researches are awaited. Further studies are also needed to clarify the target therapeutic range of serum bicarbonate and the drugs used for metabolic acidosis.
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Affiliation(s)
- Hyo Jin Kim
- Department of Internal Medicine, Pusan National University School of Medicine, Busan, Republic of Korea.,Biomedical Research Institute, Pusan National University Hospital, Busan, Republic of Korea
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25
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Collister D, Ferguson TW, Funk SE, Reaven NL, Mathur V, Tangri N. Metabolic Acidosis and Cardiovascular Disease in CKD. Kidney Med 2021; 3:753-761.e1. [PMID: 34746740 PMCID: PMC8551483 DOI: 10.1016/j.xkme.2021.04.011] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022] Open
Abstract
Rationale & Objective Metabolic acidosis related to chronic kidney disease (CKD) is associated with an accelerated decline in glomerular filtration rate (GFR) and the development of end-stage kidney disease. Whether metabolic acidosis is associated with cardiovascular (CV) events in patients with CKD is unclear. Study Design Retrospective cohort study. Setting & Participants The Optum De-identified Electronic Health Records Dataset, 2007–2017, was used to generate a cohort of patients with non-dialysis-dependent CKD who had at least 3 estimated GFR < 60 mL/min/1.73 m2. Patients with metabolic acidosis (serum bicarbonate 12 to <22 mEq/L) or normal serum bicarbonate (22‒29 mEq/L) at baseline were identified by 2 consecutive measurements 28‒365 days apart. Predictor Serum bicarbonate as a continuous variable. Outcome Primary outcome was a composite of major adverse cardiovascular events (MACE+). Secondary outcomes included individual components of the composite outcome. Analytical Approach Cox proportional hazards models to evaluate the association between 1-mEq/L increments in serum bicarbonate and MACE+. Results A total of 51,558 patients were evaluated, 34% had metabolic acidosis. The median follow-up period was 3.9–4.5 years, depending on the outcome assessed. The adjusted hazard ratio (HR) for MACE+ was 0.964 (95% CI, 0.961–0.968). For the individual components of incident heart failure (HF), stroke, myocardial infarction (MI), and CV death, HRs were 0.98 (95% CI, 0.97–0.98), 0.98 (95% CI, 0.97–0.99), 0.96 (95% CI, 0.96–0.97), and 0.94 (95% CI, 0.93–0.94), respectively, for every 1-mEq/L increase in serum bicarbonate. Limitations Possible residual confounding. Conclusions Metabolic acidosis in CKD is associated with an increased risk of MACE+ as well as the individual components of incident HF, stroke, MI, and CV death. Randomized controlled trials evaluating treatments for the correction of metabolic acidosis in CKD to prevent CV events are needed.
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Affiliation(s)
- David Collister
- Department of Medicine, McMaster University, Hamilton, ON, Canada
| | - Thomas W Ferguson
- Department of Internal Medicine, Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba, Winnipeg, MB, Canada
| | | | | | | | - Navdeep Tangri
- Department of Internal Medicine, Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba, Winnipeg, MB, Canada
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26
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Ix JH, Shlipak MG. The Promise of Tubule Biomarkers in Kidney Disease: A Review. Am J Kidney Dis 2021; 78:719-727. [PMID: 34051308 PMCID: PMC8545710 DOI: 10.1053/j.ajkd.2021.03.026] [Citation(s) in RCA: 73] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Accepted: 03/10/2021] [Indexed: 12/23/2022]
Abstract
For over 70 years, serum creatinine has remained the primary index for detection and monitoring of kidney disease. Tubulointerstitial damage and fibrosis are highly prognostic for subsequent kidney failure in biopsy studies, yet this pathology is invisible to the clinician in the absence of a biopsy. Recent discovery of biomarkers that reflect distinct aspects of kidney tubule disease have led to investigations of whether these markers can provide additional information on risk of chronic kidney disease (CKD) progression and associated adverse clinical end points, above and beyond estimated glomerular filtration rate and albuminuria. These biomarkers can be loosely grouped into those that mark tubule cell injury (eg, kidney injury molecule 1, monocyte chemoattractant protein 1) and those that mark tubule cell dysfunction (eg, α1-microglobulin, uromodulin). These kidney tubule biomarkers provide new opportunities to monitor response to therapeutics used to treat CKD patients. In this review, we describe results from some unique contributions in this area and discuss the current challenges and requirements in the field to bring these markers to clinical practice. We advocate for a broader assessment of kidney health that moves beyond a focus on the glomerulus, and we highlight how such tools can improve diagnostic accuracy and earlier assessment of therapeutic efficacy or harm in CKD patients.
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Affiliation(s)
- Joachim H Ix
- Division of Nephrology and Hypertension, Department of Medicine, University of California San Diego, San Diego, California; Nephrology Section, Veterans Affairs San Diego Healthcare System, La Jolla, California; Kidney Research Innovation Hub of San Diego, San Diego, California.
| | - Michael G Shlipak
- Kidney Health Research Collaborative, San Francisco Veterans Affairs Medical Center and University of California, San Francisco, California; Division of General Internal Medicine, San Francisco Veterans Affairs Medical Center, San Francisco, California
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27
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Beaume J, Figueres L, Bobot M, de Laforcade L, Ayari H, Dolley-Hitze T, Gueutin V, Braconnier A, Golbin L, Citarda S, Seret G, Belaïd L, Cohen R, Luque Y, Larceneux F, Seervai RNH, Overs C, Bertocchio JP. Sodium Bicarbonate Prescription and Extracellular Volume Increase: Real-world Data Results from the AlcalUN Study. Clin Pharmacol Ther 2021; 111:252-262. [PMID: 34564842 DOI: 10.1002/cpt.2427] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2021] [Accepted: 09/13/2021] [Indexed: 11/11/2022]
Abstract
Oral alkalization with sodium bicarbonate (NaHCO3 ) or citrate is prescribed for conditions ranging from metabolic acidosis to nephrolithiasis. Although most nephrologists/urologists use this method routinely, extracellular volume (ECV) increase is the main feared adverse event reported for NaHCO3 . Thus far, no trial has specifically studied this issue in a real-world setting. AlcalUN (NCT03035812) is a multicentric, prospective, open-label cohort study with nationwide (France) enrollment in 18 (public and private) nephrology/urology units. Participants were adult outpatients requiring chronic (>1 month) oral alkalization by either NaHCO3 -containing or no-NaHCO3 -containing agents. The ECV increase (primary outcome) was judged based on body weight increase (ΔBW), blood pressure increase (ΔBP), and/or new-onset edema at the first follow-up visit (V1). From February 2017 to February 2020, 156 patients were enrolled. After a median 106 days of treatment, 91 (72%) patients reached the primary outcome. They had lower systolic (135 (125, 141) vs. 141 (130, 150), P = 0.02) and diastolic (77 (67, 85) vs. 85 (73, 90), P = 0.03) BP values, a higher plasma chloride (106.0 (105.0, 109.0) vs. 105.0 (102.0, 107.0), P = 0.02) at baseline, and a less frequent history of nephrolithiasis (32 vs. 56%, P = 0.02). Patients experienced mainly slight ΔBP (< 10 mmHg). The primary outcome was not associated (P = 0.79) with the study treatment (129 received NaHCO3 and 27 received citrate). We subsequently developed three different models of propensity score matching; each confirmed our results. Chronic oral alkalization with NaHCO3 is no longer associated with an ECV increase compared to citrate in real-life settings.
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Affiliation(s)
- Julie Beaume
- AVODD, HIA Sainte-Anne, Toulon, France.,Club des Jeunes Néphrologues, Paris, France
| | - Lucile Figueres
- Club des Jeunes Néphrologues, Paris, France.,DIVAT Consortium, Nantes, France.,Service de Néphrologie et d'immunologie clinique, ITUN, CHU de Nantes, Université de Nantes, Nantes, France
| | - Mickaël Bobot
- Club des Jeunes Néphrologues, Paris, France.,Centre de Néphrologie et Transplantation Rénale, Assistance Publique Hôpitaux de Marseille, Hôpital de la Conception, Marseille, France.,C2VN, INSERM 1263, INRAE 1260, Aix-Marseille Université, Marseille, France
| | - Louis de Laforcade
- Club des Jeunes Néphrologues, Paris, France.,Service Endocrinologie-Néphrologie, Centre Hospitalier Pierre Oudot, Bourgoin-Jallieu, France
| | - Hamza Ayari
- Renal and Metabolic Diseases Unit, European Georges Pompidou Hospital, AP-HP, Paris, France
| | - Thibault Dolley-Hitze
- Club des Jeunes Néphrologues, Paris, France.,Unité de dialyse de Saint-Malo, Fondation AUB Santé, Saint-Malo, France
| | - Victor Gueutin
- Service de Néphrologie-Dialyse, AURA Paris Plaisance, Paris, France.,Service de Néphrologie, Hôpital de La Pitié-Salpêtrière, AP-HP, Paris, France
| | - Antoine Braconnier
- Club des Jeunes Néphrologues, Paris, France.,Service de Néphrologie, Dialyse et Transplantation Rénale, CHU Reims, Hôpital Maison Blanche, Reims, France
| | - Léonard Golbin
- Club des Jeunes Néphrologues, Paris, France.,Service de Néphrologie, Dialyse et Transplantation Rénale, CHU Rennes, Hôpital Pontchaillou, Rennes, France
| | - Salvatore Citarda
- Club des Jeunes Néphrologues, Paris, France.,Centre associatif lyonnais de dialyse (Calydial), Irigny, France
| | | | - Lisa Belaïd
- Unité de dialyse de Saint-Malo, Fondation AUB Santé, Saint-Malo, France
| | - Raphaël Cohen
- Renal and Metabolic Diseases Unit, European Georges Pompidou Hospital, AP-HP, Paris, France
| | - Yosu Luque
- Club des Jeunes Néphrologues, Paris, France.,Urgences Néphrologiques et Transplantation Rénale, Hôpital Tenon, AP-HP, UMR_S1155, Sorbonne Université, Paris, France
| | - Fabrice Larceneux
- CNRS, UMR (7088), DRM, (ERMES), Université Paris-Dauphine, PSL Research University, Paris, France
| | - Riyad N H Seervai
- Center for Precision Environmental Health, Baylor College of Medicine, Houston, Texas, USA.,Molecular & Cellular Biology Graduate Program, Medical Scientist Training Program, Baylor College of Medicine, Houston, Texas, USA
| | - Camille Overs
- Association Française des Urologues en Formation, Paris, France.,Service d'Urologie, Andrologie et transplantation Rénale, CHU de Grenoble, La Tronche, France
| | - Jean-Philippe Bertocchio
- Club des Jeunes Néphrologues, Paris, France.,Service de Néphrologie, Hôpital de La Pitié-Salpêtrière, AP-HP, Paris, France
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- Club des Jeunes Néphrologues, Paris, France
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28
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Gaggl M, Repitz A, Riesenhuber S, Aigner C, Sliber C, Fraunschiel M, Cejka D, Sunder-Plassmann G. Effect of Oral Sodium Bicarbonate Treatment on 24-Hour Ambulatory Blood Pressure Measurements in Patients With Chronic Kidney Disease and Metabolic Acidosis. Front Med (Lausanne) 2021; 8:711034. [PMID: 34552945 PMCID: PMC8450526 DOI: 10.3389/fmed.2021.711034] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Accepted: 08/09/2021] [Indexed: 11/25/2022] Open
Abstract
Background: Sodium bicarbonate supplementation is a mainstay in the treatment of metabolic acidosis in patients with chronic kidney disease (CKD). Recent studies showed reduction of progression of CKD and reduced all-cause mortality. However, additional sodium loading could worsen arterial hypertension, a well-known contributor to progression of CKD. This patient-relevant and economically negative side effect is under-studied in prospective studies up until now. Objective: The aim of this study was to analyze the effect of sodium bicarbonate treatment on arterial blood pressure at baseline and after 8 weeks. Methods: The SoBic study is an ongoing randomized controlled trial, in which patients with CKD receive either a high dose of oral sodium bicarbonate or a rescue treatment, if necessary. We used standardized office blood pressure and 24-hour ambulatory blood pressure monitoring (24h-ABPM). Regression models were adjusted for estimated glomerular filtration rate and change of antihypertensives. Results: 47 subjects were enrolled and the mean age was 57 (±14.6) years and 18 (38%) were female. In 43 randomized subjects with sufficiently performed 24h-ABPM neither systolic 24h-ABPM (2.522; 95%CI: −2.364, 7.408; mmHg) nor diastolic 24h-ABPM (0.868; 95%CI: −2.411, 4.147; mmHg) was affected by study group allocation. When looking at the effect of individual sodium bicarbonate dose on 24h-ABPM, the fully adjusted model suggested an increase of 0.047 (95%CI: −0.026, 0.119) mmHg by each mg/kg per day increase of sodium bicarbonate dose. Conclusion: Sodium bicarbonate supplementation over 8 weeks did not significantly increase blood pressure measured by 24h-ABPM in CKD patients. Trial Registration: EUDRACT Number: 2012-001824-36; 12/07/2012 (https://www.clinicaltrialsregister.eu).
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Affiliation(s)
- Martina Gaggl
- Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Alexandra Repitz
- Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Sonja Riesenhuber
- Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Christof Aigner
- Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Christopher Sliber
- Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria.,Department of Medicine, Sana Klinikum Offenbach, Offenbach, Germany
| | - Melanie Fraunschiel
- ITSC - IT Systems & Communications, Section IT4Science, Medical University of Vienna, Vienna, Austria
| | - Daniel Cejka
- Department of Medicine III, Nephrology, Hypertension, Transplantation and Rheumatology, Ordensklinikum Linz - Elisabethinen, Linz, Austria
| | - Gere Sunder-Plassmann
- Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria
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29
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Bohling R, Grafals M, Moreau K, You Z, Tommerdahl KL, Bjornstad P, Stenson EK, Andrews E, Ramirez-Renteria L, Kendrick J. A Pilot Study of the Safety and Efficacy of Alkali Therapy on Vascular Function in Kidney Transplant Recipients. Kidney Int Rep 2021; 6:2323-2330. [PMID: 34514193 PMCID: PMC8419116 DOI: 10.1016/j.ekir.2021.06.006] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Revised: 05/18/2021] [Accepted: 06/07/2021] [Indexed: 12/31/2022] Open
Abstract
Introduction Metabolic acidosis is associated with cardiovascular events, graft function, and mortality in kidney transplant recipients (KTRs). We examined the effect of alkali therapy on vascular endothelial function in KTRs. Methods We performed an 18-week, randomized, double-blind, placebo-controlled crossover pilot study examining the effect of sodium bicarbonate therapy versus placebo on vascular function in 20 adult KTRs at least 1 year from transplant with an estimated glomerular filtration rate (eGFR) ≥45 ml/min per 1.73 m2 and a serum bicarbonate level of 20 to 26 mEq/L. Each treatment period was 8 weeks in duration with a 2-week washout period between treatments. The primary outcome was change in brachial artery flow-mediated dilation (FMD) between sodium bicarbonate treatment and placebo. Results Twenty patients completed the study and were included in the primary analysis. The mean (SD) baseline eGFR of participants was 75 (22) ml/min per 1.73 m2, respectively. Serum bicarbonate levels did not increase significantly with treatment (0.3 [1.5] mEq/L, P = 0.37). Sodium bicarbonate therapy was not associated with worsening blood pressure, weight gain, or hypokalemia. There was no significant increase in FMD after 8 weeks of sodium bicarbonate therapy compared to placebo (mean change in FMD 2.2%, 95% CI -0.1 to 4.6, P = 0.06). There were no significant changes in high-sensitivity C-reactive protein, interleukin-6, eGFR, or urinary albumin-to-creatinine ratio during treatment. Urinary ammonium excretion decreased by 9 mmol/d (P=0.003), with sodium bicarbonate. Conclusions Sodium bicarbonate therapy is safe and feasible in KTRs, and our results strengthen the need for a larger randomized controlled trial.
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Affiliation(s)
- Rachel Bohling
- Division of Renal Disease and Hypertension, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Monica Grafals
- Division of Renal Disease and Hypertension, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Kerrie Moreau
- Division of Geriatrics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.,Eastern Colorado VA Geriatric Research, Education and Clinical Center, Aurora, Colorado, USA
| | - Zhiying You
- Division of Renal Disease and Hypertension, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Kalie L Tommerdahl
- Division of Renal Disease and Hypertension, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.,Department of Pediatrics, Section of Pediatric Endocrinology, Children's Hospital Colorado and University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Petter Bjornstad
- Division of Renal Disease and Hypertension, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.,Department of Pediatrics, Section of Pediatric Endocrinology, Children's Hospital Colorado and University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Erin K Stenson
- Department of Pediatrics, Section of Critical Care Medicine, Children's Hospital Colorado and University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Emily Andrews
- Division of Renal Disease and Hypertension, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Lorena Ramirez-Renteria
- Division of Renal Disease and Hypertension, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Jessica Kendrick
- Division of Renal Disease and Hypertension, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
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Shiizaki K, Tsubouchi A, Miura Y, Seo K, Kuchimaru T, Hayashi H, Iwazu Y, Miura M, Battulga B, Ohno N, Hara T, Kunishige R, Masutani M, Negishi K, Kario K, Kotani K, Yamada T, Nagata D, Komuro I, Itoh H, Kurosu H, Murata M, Kuro-o M. Calcium phosphate microcrystals in the renal tubular fluid accelerate chronic kidney disease progression. J Clin Invest 2021; 131:145693. [PMID: 34185705 PMCID: PMC8363285 DOI: 10.1172/jci145693] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Accepted: 06/25/2021] [Indexed: 12/19/2022] Open
Abstract
The Western pattern diet is rich not only in fat and calories but also in phosphate. The negative effects of excessive fat and calorie intake on health are widely known, but the potential harms of excessive phosphate intake are poorly recognized. Here, we show the mechanism by which dietary phosphate damages the kidney. When phosphate intake was excessive relative to the number of functioning nephrons, circulating levels of FGF23, a hormone that increases the excretion of phosphate per nephron, were increased to maintain phosphate homeostasis. FGF23 suppressed phosphate reabsorption in renal tubules and thus raised the phosphate concentration in the tubule fluid. Once it exceeded a threshold, microscopic particles containing calcium phosphate crystals appeared in the tubule lumen, which damaged tubule cells through binding to the TLR4 expressed on them. Persistent tubule damage induced interstitial fibrosis, reduced the number of nephrons, and further boosted FGF23 to trigger a deterioration spiral leading to progressive nephron loss. In humans, the progression of chronic kidney disease (CKD) ensued when serum FGF23 levels exceeded 53 pg/mL. The present study identified calcium phosphate particles in the renal tubular fluid as an effective therapeutic target to decelerate nephron loss during the course of aging and CKD progression.
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Affiliation(s)
- Kazuhiro Shiizaki
- Division of Anti-aging Medicine, Center for Molecular Medicine, Jichi Medical University, Shimotsuke, Japan
- Yurina Medical Park, Shimotsuga, Japan
| | - Asako Tsubouchi
- Graduate School of Arts and Sciences, University of Tokyo, Tokyo, Japan
| | - Yutaka Miura
- Division of Anti-aging Medicine, Center for Molecular Medicine, Jichi Medical University, Shimotsuke, Japan
| | - Kinya Seo
- Division of Cell and Molecular Medicine
| | | | - Hirosaka Hayashi
- Division of Anti-aging Medicine, Center for Molecular Medicine, Jichi Medical University, Shimotsuke, Japan
| | - Yoshitaka Iwazu
- Division of Anti-aging Medicine, Center for Molecular Medicine, Jichi Medical University, Shimotsuke, Japan
- Division of Nephrology, Department of Internal Medicine
- Department of Clinical Laboratory Medicine, and
| | - Marina Miura
- Division of Anti-aging Medicine, Center for Molecular Medicine, Jichi Medical University, Shimotsuke, Japan
- Division of Nephrology, Department of Internal Medicine
| | - Batpurev Battulga
- Division of Histology and Cell Biology, Department of Anatomy, Jichi Medical University, Shimotsuke, Japan
| | - Nobuhiko Ohno
- Division of Histology and Cell Biology, Department of Anatomy, Jichi Medical University, Shimotsuke, Japan
- Division of Ultrastructural Research, National Institute for Physiological Sciences, Okazaki, Japan
| | - Toru Hara
- Electron Microscopy Analysis Station, Research Network and Facility Service Division, National Institute for Materials Science, Tsukuba, Japan
| | - Rina Kunishige
- Graduate School of Arts and Sciences, University of Tokyo, Tokyo, Japan
| | - Mamiko Masutani
- Healthcare Business Unit, Nikon Corporation, Yokohama, Japan
| | - Keita Negishi
- Division of Cardiovascular Medicine, Department of Internal Medicine, Jichi Medical University, Shimotsuke, Japan
| | - Kazuomi Kario
- Division of Cardiovascular Medicine, Department of Internal Medicine, Jichi Medical University, Shimotsuke, Japan
| | | | | | | | - Issei Komuro
- Department of Cardiovascular Medicine, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
| | - Hiroshi Itoh
- Division of Endocrinology, Metabolism and Nephrology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Hiroshi Kurosu
- Division of Anti-aging Medicine, Center for Molecular Medicine, Jichi Medical University, Shimotsuke, Japan
| | - Masayuki Murata
- Graduate School of Arts and Sciences, University of Tokyo, Tokyo, Japan
| | - Makoto Kuro-o
- Division of Anti-aging Medicine, Center for Molecular Medicine, Jichi Medical University, Shimotsuke, Japan
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31
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Cheung AK, Chang TI, Cushman WC, Furth SL, Hou FF, Ix JH, Knoll GA, Muntner P, Pecoits-Filho R, Sarnak MJ, Tobe SW, Tomson CR, Mann JF. KDIGO 2021 Clinical Practice Guideline for the Management of Blood Pressure in Chronic Kidney Disease. Kidney Int 2021; 99:S1-S87. [PMID: 33637192 DOI: 10.1016/j.kint.2020.11.003] [Citation(s) in RCA: 479] [Impact Index Per Article: 119.8] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Accepted: 11/02/2020] [Indexed: 12/19/2022]
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Abstract
Metabolic acidosis is fairly common in patients with chronic kidney disease (CKD). The prevalence of metabolic acidosis increases with worsening kidney function and is observed in ∼40% of those with stage 4 CKD. For the past 2 decades, clinical practice guidelines have suggested treatment of metabolic acidosis to counterbalance adverse effects of metabolic acidosis on bone and muscle. Studies in animal models of CKD also demonstrated that metabolic acidosis causes kidney fibrosis. During the past decade, results from observational studies identified associations between metabolic acidosis and adverse kidney outcomes, and results from interventional studies support the hypothesis that treating metabolic acidosis with sodium bicarbonate preserves kidney function. However, convincing data from large-scale, double-blinded, placebo-controlled, randomized trials have been lacking. This review discusses findings from recent interventional trials of alkali therapy in CKD and new findings linking metabolic acidosis with cardiovascular disease in adults and CKD progression in children. Finally, a novel agent that treats metabolic acidosis in patients with CKD by binding hydrochloric acid in the gastrointestinal tract is discussed.
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Affiliation(s)
- Michal L Melamed
- Department of Medicine, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY
| | - Kalani L Raphael
- Division of Nephrology & Hypertension, Department of Medicine, Oregon Health & Science University and Portland VA Medical Center, Portland, OR
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Shlipak MG, Tummalapalli SL, Boulware LE, Grams ME, Ix JH, Jha V, Kengne AP, Madero M, Mihaylova B, Tangri N, Cheung M, Jadoul M, Winkelmayer WC, Zoungas S. The case for early identification and intervention of chronic kidney disease: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference. Kidney Int 2021; 99:34-47. [PMID: 33127436 DOI: 10.1016/j.kint.2020.10.012] [Citation(s) in RCA: 263] [Impact Index Per Article: 65.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Revised: 10/05/2020] [Accepted: 10/13/2020] [Indexed: 02/06/2023]
Abstract
Chronic kidney disease (CKD) causes substantial global morbidity and increases cardiovascular and all-cause mortality. Unlike other chronic diseases with established strategies for screening, there has been no consensus on whether health systems and governments should prioritize early identification and intervention for CKD. Guidelines on evaluating and managing early CKD are available but have not been universally adopted in the absence of incentives or quality measures for prioritizing CKD care. The burden of CKD falls disproportionately upon persons with lower socioeconomic status, who have a higher prevalence of CKD, limited access to treatment, and poorer outcomes. Therefore, identifying and treating CKD at the earliest stages is an equity imperative. In 2019, Kidney Disease: Improving Global Outcomes (KDIGO) held a controversies conference entitled "Early Identification and Intervention in CKD." Participants identified strategies for screening, risk stratification, and treatment for early CKD and the key health system and economic factors for implementing these processes. A consensus emerged that CKD screening coupled with risk stratification and treatment should be implemented immediately for high-risk persons and that this should ideally occur in primary or community care settings with tailoring to the local context.
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Affiliation(s)
- Michael G Shlipak
- Kidney Health Research Collaborative, Department of Medicine, University of California San Francisco, San Francisco, California, USA; General Internal Medicine Division, Medical Service, San Francisco Veterans Affairs Health Care System, San Francisco, California, USA.
| | - Sri Lekha Tummalapalli
- Kidney Health Research Collaborative, Department of Medicine, University of California San Francisco, San Francisco, California, USA; General Internal Medicine Division, Medical Service, San Francisco Veterans Affairs Health Care System, San Francisco, California, USA
| | - L Ebony Boulware
- Department of General Internal Medicine, Duke University School of Medicine, Durham, North Carolina, USA
| | - Morgan E Grams
- Division of Nephrology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA; Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA
| | - Joachim H Ix
- Division of Nephrology-Hypertension, Department of Medicine, University of California San Diego, San Diego, California, USA; Nephrology Section, Veterans Affairs San Diego Healthcare System, La Jolla, California, USA; Division of Preventive Medicine, Department of Family Medicine and Public Health, University of California San Diego, San Diego, California, USA
| | - Vivekanand Jha
- George Institute for Global Health, University of New South Wales, New Delhi, India; University of Oxford, Oxford, UK; Department of Nephrology, Manipal Academy of Higher Education, Manipal, India
| | - Andre-Pascal Kengne
- Non-Communicable Diseases Research Unit, South African Medical Research Council, Cape Town, South Africa; Department of Medicine, University of Cape Town, Cape Town, South Africa
| | - Magdalena Madero
- Department of Medicine, Division of Nephrology, Instituto Nacional de Cardiología Ignacio Chávez, Mexico City, Mexico
| | - Borislava Mihaylova
- Health Economics Research Centre, Nuffield Department of Population Health, University of Oxford, Oxford, UK; Institute of Population Health Sciences, Blizard Institute, Queen Mary University of London, London, UK
| | - Navdeep Tangri
- Department of Community Health Services, Max Rady College of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Michael Cheung
- Kidney Disease: Improving Global Outcomes, Brussels, Belgium
| | - Michel Jadoul
- Cliniques Universitaires Saint Luc, Université Catholique de Louvain, Brussels, Belgium
| | - Wolfgang C Winkelmayer
- Selzman Institute for Kidney Health, Section of Nephrology, Department of Medicine, Baylor College of Medicine, Houston, Texas, USA
| | - Sophia Zoungas
- Diabetes and Vascular Medicine Unit, Monash Health, Clayton, Victoria, Australia; School of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, Australia.
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Effect of sodium bicarbonate supplementation on the renin-angiotensin system in patients with chronic kidney disease and acidosis: a randomized clinical trial. J Nephrol 2020; 34:1737-1745. [PMID: 33382448 PMCID: PMC8494695 DOI: 10.1007/s40620-020-00944-5] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2020] [Accepted: 11/30/2020] [Indexed: 12/21/2022]
Abstract
Background Acidosis-induced kidney injury is mediated by the intrarenal renin-angiotensin system, for which urinary renin is a potential marker. Therefore, we hypothesized that sodium bicarbonate supplementation reduces urinary renin excretion in patients with chronic kidney disease (CKD) and metabolic acidosis. Methods Patients with CKD stage G4 and plasma bicarbonate 15–24 mmol/l were randomized to receive sodium bicarbonate (3 × 1000 mg/day, ~ 0.5 mEq/kg), sodium chloride (2 × 1,00 mg/day), or no treatment for 4 weeks (n = 15/arm). The effects on urinary renin excretion (primary outcome), other plasma and urine parameters of the renin-angiotensin system, endothelin-1, and proteinuria were analyzed. Results Forty-five patients were included (62 ± 15 years, eGFR 21 ± 5 ml/min/1.73m2, plasma bicarbonate 21.7 ± 3.3 mmol/l). Sodium bicarbonate supplementation increased plasma bicarbonate (20.8 to 23.8 mmol/l) and reduced urinary ammonium excretion (15 to 8 mmol/day, both P < 0.05). Furthermore, a trend towards lower plasma aldosterone (291 to 204 ng/L, P = 0.07) and potassium (5.1 to 4.8 mmol/l, P = 0.06) was observed in patients receiving sodium bicarbonate. Sodium bicarbonate did not significantly change the urinary excretion of renin, angiotensinogen, aldosterone, endothelin-1, albumin, or α1-microglobulin. Sodium chloride supplementation reduced plasma renin (166 to 122 ng/L), and increased the urinary excretions of angiotensinogen, albumin, and α1-microglobulin (all P < 0.05). Conclusions Despite correction of acidosis and reduction in urinary ammonium excretion, sodium bicarbonate supplementation did not improve urinary markers of the renin-angiotensin system, endothelin-1, or proteinuria. Possible explanations include bicarbonate dose, short treatment time, or the inability of urinary renin to reflect intrarenal renin-angiotensin system activity. Graphic abstract ![]()
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35
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Hultin S, Hood C, Campbell KL, Toussaint ND, Johnson DW, Badve SV. A Systematic Review and Meta-Analysis on Effects of Bicarbonate Therapy on Kidney Outcomes. Kidney Int Rep 2020; 6:695-705. [PMID: 33732984 PMCID: PMC7938083 DOI: 10.1016/j.ekir.2020.12.019] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Revised: 11/16/2020] [Accepted: 12/17/2020] [Indexed: 12/22/2022] Open
Abstract
Aim Preclinical studies suggest treatment of metabolic acidosis may slow chronic kidney disease (CKD) progression. This systematic review aimed to summarize evidence from randomized controlled trials (RCTs) concerning the benefits and risks of bicarbonate therapy on kidney outcomes. Methods Medline, EMBASE, and Cochrane databases were searched for RCTs with ≥3 months’ follow-up in patients with CKD (estimated glomerular filtration rate [eGFR] ≤60 ml/min per 1.73 m2 and/or proteinuria) comparing the effects of sodium bicarbonate with placebo/no study medication on kidney outcomes. The primary outcome was change from baseline to last measurement in kidney function measured as either eGFR or creatinine clearance. Treatment effects were summarized using random-effects meta-analysis. Results Fifteen trials (2445 participants, median follow-up 12 months) were eligible for inclusion. Compared with placebo or no study medication, sodium bicarbonate retarded the decline in kidney function (standardized mean difference [SMD]: 0.26; 95% confidence interval [CI]: 0.13–0.40; I2 = 50%, low certainty evidence), and reduced the risk of end-stage kidney failure (risk ratio [RR]: 0.53; 95% CI 0.32–0.89; I2 = 69%, low certainty evidence). The effect of sodium bicarbonate on proteinuria (SMD: −0.09; 95% CI −0.27 to 0.09; I2 = 28%, very low certainty evidence), systolic blood pressure (weighted mean difference [WMD]: −0.57 mm Hg; 95% CI −2.32 to 1.18; I2 = 0%, low certainty evidence), all-cause death (RR: 0.81; 95% CI: 0.39–1.68; I2 = 30%; very low certainty evidence) and edema (RR: 1.16; 95% CI: 0.90–1.50; I2 = 28%; low certainty evidence) were uncertain. Conclusion Sodium bicarbonate may slow CKD progression. Adequately powered randomized trials are required to evaluate the benefits and risks of sodium bicarbonate in CKD.
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Affiliation(s)
- Sebastian Hultin
- Australasian Kidney Trials Network, The University of Queensland, Brisbane, Australia.,University of Sydney, Sydney, Australia.,Department of Nephrology, St George Hospital, Sydney, Australia
| | - Chris Hood
- Australasian Kidney Trials Network, The University of Queensland, Brisbane, Australia.,Department of Nephrology, Middlemore Hospital, Auckland, New Zealand
| | - Katrina L Campbell
- Australasian Kidney Trials Network, The University of Queensland, Brisbane, Australia.,Healthcare Excellence and Innovation, Metro North Hospital and Health Service, Brisbane, Australia
| | - Nigel D Toussaint
- Australasian Kidney Trials Network, The University of Queensland, Brisbane, Australia.,Department of Nephrology, The Royal Melbourne Hospital, Parkville, Australia
| | - David W Johnson
- Australasian Kidney Trials Network, The University of Queensland, Brisbane, Australia.,Department of Nephrology, Princess Alexandra Hospital, Brisbane, Australia.,Translational Research Institute, Brisbane, Australia
| | - Sunil V Badve
- Australasian Kidney Trials Network, The University of Queensland, Brisbane, Australia.,Department of Nephrology, St George Hospital, Sydney, Australia.,The George Institute for Global Health, University of New South Wales Medicine, Sydney, Australia
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Klaerner G, Shao J, Biyani K, Kade M, Kierstead P, Gbur R, Tabakman S, Nguyen S, Buysse J. Mechanism of Action of Veverimer: A Novel, Orally Administered, Nonabsorbed, Counterion-Free, Hydrochloric Acid Binder under Development for the Treatment of Metabolic Acidosis in Chronic Kidney Disease. J Pharmacol Exp Ther 2020; 375:439-450. [PMID: 33033169 DOI: 10.1124/jpet.120.000190] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Accepted: 08/31/2020] [Indexed: 12/14/2022] Open
Abstract
Current management of metabolic acidosis in patients with chronic kidney disease (CKD) relies on dietary intervention to reduce daily endogenous acid production or neutralization of retained acid with oral alkali (sodium bicarbonate, sodium citrate). Veverimer is being developed as a novel oral treatment for metabolic acidosis through removal of intestinal acid, resulting in an increase in serum bicarbonate. Veverimer is a free-amine polymer that combines high capacity and selectivity to bind and remove hydrochloric acid (HCl) from the gastrointestinal (GI) tract. In vitro studies demonstrated that veverimer had a binding capacity of 10.7 ± 0.4 mmol HCl per gram of polymer with significant binding capacity (>5 mmol/g) across the range of pH values found in the human GI tract (1.5-7). Upon protonation, veverimer bound chloride with high specificity but showed little or no binding of phosphate, citrate, or taurocholate (<1.5 mmol/g), which are all anions commonly found in the human GI tract. Administration of veverimer to rats with adenine-induced CKD and metabolic acidosis resulted in a significant increase in fecal chloride excretion and a dose-dependent increase in serum bicarbonate to within the normal range compared with untreated controls. Absorption, distribution, metabolism, and excretion studies in rats and dogs dosed with 14C-labeled veverimer showed that the polymer was not absorbed from the GI tract and was quantitatively eliminated in the feces. Acid removal by veverimer, an orally administered, nonabsorbed polymer, may provide a potential new treatment for metabolic acidosis in patients with CKD. SIGNIFICANCE STATEMENT: Metabolic acidosis is a complication of chronic kidney disease (CKD) as well as a cause of CKD progression. Veverimer is a high-capacity, selective, nonabsorbed, hydrochloric acid-binding polymer being developed as a treatment for metabolic acidosis. Veverimer binds and removes hydrochloric acid from the gastrointestinal tract, resulting in increased serum bicarbonate and the correction of metabolic acidosis. Veverimer is not an ion-exchange resin and does not deliver sodium or other counterions, and so it may be appropriate for patients with CKD with and without sodium-sensitive comorbidities.
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Affiliation(s)
- Gerrit Klaerner
- Tricida, Inc., South San Francisco, California (G.K., J.S., K.B., M.K., P.K., R.G., S.T., S.N.) and FFV Consulting, Los Altos, California (J.B.)
| | - Jun Shao
- Tricida, Inc., South San Francisco, California (G.K., J.S., K.B., M.K., P.K., R.G., S.T., S.N.) and FFV Consulting, Los Altos, California (J.B.)
| | - Kalpesh Biyani
- Tricida, Inc., South San Francisco, California (G.K., J.S., K.B., M.K., P.K., R.G., S.T., S.N.) and FFV Consulting, Los Altos, California (J.B.)
| | - Matthew Kade
- Tricida, Inc., South San Francisco, California (G.K., J.S., K.B., M.K., P.K., R.G., S.T., S.N.) and FFV Consulting, Los Altos, California (J.B.)
| | - Paul Kierstead
- Tricida, Inc., South San Francisco, California (G.K., J.S., K.B., M.K., P.K., R.G., S.T., S.N.) and FFV Consulting, Los Altos, California (J.B.)
| | - Randi Gbur
- Tricida, Inc., South San Francisco, California (G.K., J.S., K.B., M.K., P.K., R.G., S.T., S.N.) and FFV Consulting, Los Altos, California (J.B.)
| | - Scott Tabakman
- Tricida, Inc., South San Francisco, California (G.K., J.S., K.B., M.K., P.K., R.G., S.T., S.N.) and FFV Consulting, Los Altos, California (J.B.)
| | - Son Nguyen
- Tricida, Inc., South San Francisco, California (G.K., J.S., K.B., M.K., P.K., R.G., S.T., S.N.) and FFV Consulting, Los Altos, California (J.B.)
| | - Jerry Buysse
- Tricida, Inc., South San Francisco, California (G.K., J.S., K.B., M.K., P.K., R.G., S.T., S.N.) and FFV Consulting, Los Altos, California (J.B.)
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Adrogué HJ, Madias NE. Veverimer: An Emerging Potential Treatment Option for Managing the Metabolic Acidosis of CKD. Am J Kidney Dis 2020; 76:861-867. [PMID: 32920151 DOI: 10.1053/j.ajkd.2020.07.019] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2020] [Accepted: 07/05/2020] [Indexed: 11/11/2022]
Abstract
Sodium bicarbonate is the mainstay treatment of the metabolic acidosis of chronic kidney disease but associated concerns center on administering sodium to patients with hypertension and sodium-retentive states. Veverimer (formerly referred to as TRC101), a drug candidate for which Tricida, Inc is seeking approval from the US Food and Drug Administration, is a novel nonabsorbable polymer that binds hydrogen cations and chloride anions in the gastrointestinal tract and then is excreted fecally, thereby increasing serum bicarbonate concentration without administering sodium. We examine the published evidence on the investigational use of veverimer in patients with chronic kidney disease and metabolic acidosis. We highlight the achieved increase in serum bicarbonate concentration without coadministering sodium, effects on physical functioning, and the safety record of the drug. We also scrutinize certain unanticipated findings: a lack of dose dependency in the increase in serum bicarbonate concentration observed and that despite the presumed large hydrogen chloride losses in feces, veverimer induces an isochloremic increase in serum bicarbonate concentration that is accompanied by a decrease in serum anion gap. We propose likely explanations for these puzzling findings and raise questions about veverimer's mode of action and its potential interaction with colonic bacterial flora. Additional work is required to fill these knowledge gaps that could have important clinical implications.
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Affiliation(s)
- Horacio J Adrogué
- Department of Medicine, Baylor College of Medicine, Houston, TX; Division of Nephrology, Department of Medicine, Houston Methodist Hospital, Houston, TX
| | - Nicolaos E Madias
- Department of Medicine, Tufts University School of Medicine, Boston, MA; Division of Nephrology, Department of Medicine, St. Elizabeth's Medical Center, Boston, MA.
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Clinical and cost-effectiveness of oral sodium bicarbonate therapy for older patients with chronic kidney disease and low-grade acidosis (BiCARB): a pragmatic randomised, double-blind, placebo-controlled trial. BMC Med 2020; 18:91. [PMID: 32268897 PMCID: PMC7144058 DOI: 10.1186/s12916-020-01542-9] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2019] [Accepted: 02/25/2020] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Chronic kidney disease with metabolic acidosis is common in older people, but the effectiveness of oral sodium bicarbonate therapy in this group is unclear. We tested whether oral sodium bicarbonate provides net health benefit for older people with advanced chronic kidney disease and serum bicarbonate concentrations < 22 mmol/L. METHODS Pragmatic multicentre, parallel group, double-blind, placebo-controlled randomised trial. We recruited adults aged ≥ 60 years with estimated glomerular filtration rate of < 30 mL/min/1.73 m2, not receiving dialysis, with serum bicarbonate concentration < 22 mmol/L, from 27 nephrology and geriatric medicine departments in the UK. Participants received oral sodium bicarbonate (up to 3 g/day) or matching placebo given for up to 2 years, randomised in a 1:1 ratio. The primary outcome was between-group difference in the Short Physical Performance Battery (SPPB) at 12 months, adjusted for baseline values, analysed by intention to treat. Secondary outcomes included generic and disease-specific quality of life (EQ-5D and KDQoL tools), anthropometry, renal function, walk distance, blood pressure, bone and vascular health markers, and incremental cost per quality-adjusted life year gained. RESULTS We randomised 300 participants between May 2013 and February 2017, mean age 74 years, 86 (29%) female. At 12 months, 116/152 (76%) participants allocated to bicarbonate and 104/148 (70%) allocated to placebo were assessed; primary outcome data were available for 187 participants. We found no significant treatment effect for the SPPB: bicarbonate arm 8.3 (SD 2.5) points, placebo arm 8.8 (SD 2.2) and adjusted treatment effect - 0.4 (95% CI - 0.9 to 0.1, p = 0.15). We found no significant treatment effect for glomerular filtration rate (0.6 mL/min/1.73 m2, 95% CI - 0.8 to 2.0, p = 0.39). The bicarbonate arm showed higher costs and lower quality of life as measured by the EQ-5D-3L tool over 1 year (£564 [95% CI £88 to £1154]); placebo dominated bicarbonate under all sensitivity analyses. Adverse events were more frequent in those randomised to bicarbonate (457 versus 400). CONCLUSIONS Oral sodium bicarbonate did not improve physical function or renal function, increased adverse events and is unlikely to be cost-effective for use by the UK NHS for this patient group. TRIAL REGISTRATION European Clinical Trials Database (2011-005271-16) and ISRCTN09486651; registered 17 February 2012.
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Moore MC, Coate KC, Scott M, Kraft G, Vath JE, Hughes TE, Farmer B, Cherrington AD. MetAP2 inhibitor treatment of high-fat and -fructose-fed dogs: impact on the response to oral glucose ingestion and a hyperinsulinemic hyperglycemic clamp. Am J Physiol Endocrinol Metab 2020; 318:E514-E524. [PMID: 31990576 PMCID: PMC7191409 DOI: 10.1152/ajpendo.00451.2019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
We examined the methionine aminopeptidase 2 inhibitor fumagillin in dogs consuming a high-fat and -fructose diet (HFFD). In pilot studies (3 dogs that had consumed HFFD for 3 yr), 8 wk of daily treatment with fumagillin reduced food intake 29%, weight 6%, and the glycemic excursion during an oral glucose tolerance test (OGTT) 44%. A second group of dogs consumed the HFFD for 17 wk: pretreatment (weeks 0-4), treatment with fumagillin (FUM; n = 6), or no drug (Control, n = 8) (weeks 4-12), washout period (weeks 12-16), and fumagillin or no drug for 1 wk (week 17). OGTTs were performed at 0, 4, 11, and 16 wk. A hyperinsulinemic hyperglycemic clamp was performed in week 12; 4 chow-fed dogs underwent identical clamps. Kilocalories per day intake during the treatment period was 2,067 ± 50 (Control) versus 1,824 ± 202 (FUM). Body weights (kg) increased 1.9 ± 0.3 vs. 2.7 ± 0.8 (0-4 wk) and 1.2 ± 0.2 vs. -0.02 ± 0.9 (4-12 wk) in Control versus fumagillin. The OGTT glycemic response was 30% greater in Control versus fumagillin at 11 wk. Net hepatic glucose uptake (NHGU; mg·kg-1·min-1) in the Chow, Control, and fumagillin dogs was ~1.5 ± 0.6, -0.1 ± 0.1, and 0.3 ± 0.4 (with no portal glucose infusion) and 3.1 ± 0.6, 0.5 ± 0.3, and 1.5 ± 0.5 (portal glucose infusion at 4 mg·kg-1·min-1), respectively. Fumagillin improved glucose tolerance and NHGU in HFFD dogs, suggesting methionine aminopeptidase 2 (MetAP2) inhibitors have the potential for improving glycemic control in prediabetes and diabetes.
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Affiliation(s)
- Mary Courtney Moore
- Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee
| | - Katie C Coate
- Diabetes Research and Training Center, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Melanie Scott
- Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee
| | - Guillaume Kraft
- Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee
| | | | - Thomas E Hughes
- Zafgen, Incorporated, Boston, Massachusetts
- Navitor Pharmaceuticals, Incorporated, Cambridge, Massachusetts
| | - Ben Farmer
- Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee
| | - Alan D Cherrington
- Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee
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Neuen BL, Perkovic V. Pilot Trials in Nephrology: Establishing a BASE for Large-Scale Randomized Trials. J Am Soc Nephrol 2020; 31:4-6. [PMID: 31871251 PMCID: PMC6934990 DOI: 10.1681/asn.2019111196] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/22/2024] Open
Affiliation(s)
| | - Vlado Perkovic
- The George Institute for Global Health and
- Faculty of Medicine, University of New South Wales, Sydney, Australia
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