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Abstract

Metabolic acidosis is a frequent complication when chronic kidney disease (CKD) develops, plus it is linked to adverse outcomes such as muscle wasting, inflammation, and progression of kidney disease. This article is intended to evaluate how correcting metabolic acidosis affects adult CKD patients via summarizing evidence from systematic reviews with meta-analyses. We conducted an umbrella review. Systematic reviews with meta-analyses assessing alkali therapy in CKD patients were included. Methodological quality was assessed using a Measurement Tool to Assess Systematic Reviews (AMSTAR 2). The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) certainty of evidence approach was used for rating the certainty of evidence. Twelve meta-analyses that were published between 2007 and 2024 were analyzed, and these included 169 associations, out of which 128 remained after excluding single-study outcomes. Only 8 (6.2%) of these associations were supported by high-certainty evidence, which included a slower decline in glomerular filtration rate, reduced hospitalization rates, lower diastolic blood pressure, increased serum bicarbonate after short-term therapy, and reduced use of β-blockers and vasodilators. However, most associations (52.3%) were rated as having very low certainty. Less than 10% of the associations analyzed in the selected systematic reviews have high certainty of evidence, which underscores a significant gap between common clinical practices and the strength of the supporting evidence.

Trial registration:

PROSPERO CRD42024548458.

Keywords

metabolic acidosis chronic kidney disease umbrella review

Introduction

In patients with chronic kidney disease (CKD), as the Glomerular Filtration Rate (GFR) declines, so does the kidney’s ability to excrete hydrogen ions and generate bicarbonate, leading to the development of chronic metabolic acidosis.¹ This typically occurs when GFR falls below 60 mL/min/1.73 m², with more pronounced reductions when it is less than 30 and 15 mL/min, that is, in CKD stages G4 and G5. The adjusted prevalence in adults with serum bicarbonate less than 22 mmol/L is 7.7% and 6.7% in those with and without diabetes in stages G3 and A1, respectively, increasing to 38.3% and 35.9% in CKD stages G5 and A3.¹

Metabolic acidosis is associated with an increased risk of protein catabolism, muscle wasting, inflammation, and other complications, such as impaired cardiac function and mortality, which are also associated with decreased GFR.^1–3 Although causality between metabolic acidosis and these outcomes has not been determined, treatment of acidosis with bicarbonate has been recommended.¹ The KDIGO 2024 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease recommends that, in individuals with CKD, pharmacologic therapy with or without dietary intervention should be considered to prevent the development of acidosis with potential clinical implications (e.g., serum bicarbonate <18 mmol/L in adults).¹ However, this recommendation is not without adverse effects, which is why monitoring treatment for metabolic acidosis is also recommended to ensure that it does not cause serum bicarbonate concentrations above the upper limit of normal or adversely affect blood pressure control, serum potassium, or fluid status.¹

The working group that developed this Clinical Practice Guideline did not issue a graded recommendation for the treatment of acidosis due to the lack of large-scale randomized clinical trials supporting its use, so the overall evidence remains limited.¹ The results of small- to medium-sized clinical trials in people with subclinical metabolic acidosis have also been inconclusive, so well-designed clinical trials are needed to determine the efficacy and safety of sodium bicarbonate and determine whether this intervention improves patient outcomes.^1,2 To summarize the evidence from these primary studies, several systematic reviews have been published.^4–8 However, to the best of our knowledge, there is no umbrella review on this topic.⁹ Accordingly, the objective of this study was to conduct an umbrella review evaluating the effects of correcting metabolic acidosis in patients with CKD.

Methods

Protocol registration

This umbrella review was conducted in accordance with the recommendations outlined in the Cochrane Handbook¹⁰ and is reported following the Preferred Reporting Items for Overviews of Reviews (PRIOR) statement (Table S1).¹¹ The protocol for this review was registered in the International Prospective Register of Systematic Reviews (PROSPERO) under the code CRD42024548458.

Search strategy

Three authors independently reviewed published meta-analytic systematic reviews by searching PubMed, Scopus, Embase, Web of Science, and Ovid Medline databases from their inception to December 2024.

The search strategy is presented in Table S2. We reviewed the studies of bibliographies to verify referenced sources and ensure the inclusion of relevant studies.

Eligibility criteria

Eligible studies for this umbrella review included systematic reviews with meta-analyses published in peer-reviewed journals. The target population comprised adults diagnosed with CKD at any stage and presenting with metabolic acidosis. Studies were considered if they evaluated the effects of correcting metabolic acidosis, including interventions with oral or dialysis bicarbonate supplementation, compared to no correction or other treatment strategies. If multiple systematic reviews addressed the exact same intervention(s) and outcome(s), we prioritized the inclusion of the review with the largest number of primary studies and highest methodological quality, as assessed by A Measurement Tool to Assess Systematic Reviews (AMSTAR 2)¹² assessment tool. Additionally, we performed an overlap analysis of the primary studies included in the meta-analyses using the Corrected Covered Area (CCA) method to identify potential duplication of evidence that could bias the results.¹³

Eligible outcomes included primary parameters such as nutritional status, bone turnover, blood pressure, quality of life, hospitalization rates, and mortality. Additional outcomes considered were uremia, antihypertensive agent use, GFR, proteinuria, and the development of cardiovascular disease. There were no restrictions on language, sex, or CKD stage for inclusion in this review. Studies were excluded if they did not include a meta-analytical component or if the population did not consist of CKD patients with metabolic acidosis.

Data extraction

Two reviewers independently extracted data using a predefined protocol, with any discrepancies resolved by a third reviewer. Information collected included study details (author, year, number of primary studies, sample size), type of intervention, outcomes assessed, and effect measures (risk ratio (RR), odds ratio (OR), mean difference (MD), or Standardized Mean Difference (SMD) with 95% confidence intervals (CIs)).

Outcomes were classified as primary (blood pressure, bone turnover, hospitalization, mortality) and secondary (uremia, use of antihypertensives, GFR, proteinuria, and cardiovascular disease). Statistical methods used, such as random-effects models, heterogeneity (I²), and the use of subgroup analyses, were also recorded to ensure analytical consistency.

Quality assessment of evidence and certainty of evidence

The methodological quality of the included meta-analyses was assessed using the AMSTAR 2 tool.¹² The certainty of the evidence was evaluated using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) framework,¹⁴ which classifies confidence in effect estimates into four levels: high, moderate, low, and very low.

Results

Selection of studies

A total of 2822 articles were retrieved from the PubMed, Scopus, Embase, Web of Science, and OVID-Medline databases. After eliminating duplicates, 2328 unique articles remained. Screening titles and abstracts led to the exclusion of 2314 records. Two additional articles^15,16 were removed after full-text evaluation because they did not include meta-analysis. Ultimately, 12 articles^{4,5,7,17–25} met the criteria for inclusion in this umbrella review (Figure 1).

Figure 1.

PRISMA flow diagram of the identification, screening, eligibility, and inclusion of systematic reviews and meta-analyses in this umbrella review.

Characteristics of the included meta-analyses

The 12 eligible articles, published between 2007 and 2024, evaluated 169 associations examining the correction of metabolic acidosis in relation to both clinical outcomes (e.g., systolic blood pressure) and laboratory parameters (e.g., proteinuria). The general characteristics of the included studies are summarized in Table 1. The number of outcomes assessed per study ranged from 4 to 30, with a median of 562 participants per outcome (range: 12–2746). Notably, aside from Hultin et al.,¹⁷ none of the studies conducted a GRADE assessment of their findings. Although some outcomes were similar across studies, differences in intervention types and/or participant populations ensured that no identical outcomes had to be excluded in this review. Additionally, the CCA overlap analysis yielded a value of 0.18%, indicating a slight degree of overlap.¹³

Table 1.

Summary characteristics of included systematic reviews and meta-analyses.

Author	Year	Country of publication	Number of outcomes	Minimum participants per outcome	Maximum participants per outcome	Maximum number of primary studies included	Was GRADE performed by the authors?	Heterogeneity analysis
Hultin et al.¹⁷	2021	Australia	15	387	1932	13	Yes	Subgroup analysis, Meta-regression
Roderick et al.²⁵	2007	UK	30	18	332	3	No	NR
Beynon-Cobb et al.²⁴	2023	UK	27	52	2059	14	No	Subgroup analysis, Meta-regression
Visser et al.⁴	2023	Netherlands	7	115	1442	7	No	NR
Shi et al.²⁰	2022	China	6	404	2746	16	No	Subgroup analysis
Navab et al.²¹	2023	Iran	4	309	1484	13	No	Subgroup analysis
Cheng et al.¹⁸	2021	China	15	88	1781	10	No	NR
Yang et al.²²	2024	Taiwan	11	664	1945	12	No	Subgroup analysis, Meta-regression
Mahboobi et al.⁷	2024	Canada	10	62	644	6	No	Subgroup analysis
Hu et al.¹⁹	2019	UK	7	347	707	7	No	Subgroup analysis
Navaneethan et al.⁵	2019	USA	11	58	1378	14	No	Subgroup analysis
Susantitaphong et al.²³	2012	USA	26	0	288	4	No	NR

GRADE: Grading of Recommendations Assessment, Development, and Evaluation; NR: not reported.

Methodological quality of included meta-analyses

The AMSTAR 2 (Table S3) confidence assessment indicated that all 12 articles were rated as having critically low confidence. Among the critical domains, questions 2 and 4 most frequently received “No” or “Partial Yes” responses (10 out of 12 articles), whereas question 11 received these responses less frequently (2 out of 12 articles).

Summary findings and heterogeneity of the included meta-analyses

The summary of findings is displayed in Table 2. Among the 169 associations, the summary of random-effects estimates ranged from −1872 to 77. A total of 56 associations (33%) were statistically significant at p < 0.05 based on the random-effects model. Regarding heterogeneity, 59 associations (34.9%) had low heterogeneity (I² < 30%); 26 (15.3%) showed high heterogeneity (I² = 30%–60%); and 43 (25.4%) exhibited very high heterogeneity (I² > 60%). The remaining 41 associations (24.2%) included only one or no studies, preventing the calculation of statistical heterogeneity.

Table 2.

Summary of meta-analysis results and certainty of evidence (GRADE).

Outcomes	Definition of outcome	Author, year	Type of participants	Type of intervention	Random effects (95% CI)	Random p-value	I ²	RCT or non RCT	GRADE score
Change in eGFR or creatinine clearance	–	Hultin et al., 2021¹⁷	CKD patients with MA	Oral bicarbonate vs placebo or no intervention	SMD 0.26 (0.13 to −0.40)	NR	50	RCT	Low
Change in eGFR	–	Hultin et al., 2021¹⁷	CKD patients with MA	Oral bicarbonate vs placebo or no intervention	MD 2.63 (0.70–4.55)	NR	66	RCT	Very low
Change in creatinine clearance	–	Hultin et al., 2021¹⁷	CKD patients with MA	Oral bicarbonate vs placebo or no intervention	MD 5.78 (3.56–7.99)	NR	0	RCT	Low
Change in serum creatinine from baseline	–	Hultin et al., 2021¹⁷	CKD patients with MA	Oral bicarbonate vs placebo or no intervention	MD −0.20 (−0.46 to 0.06)	NR	56	RCT	Very low
Progression to kidney failure	–	Hultin et al., 2021¹⁷	CKD patients with MA	Oral bicarbonate vs placebo or no intervention	RR 0.53 (0.30–0.89)	NR	64	RCT	Low
Rapid decline in kidney function	Annual decline in GFR or CrCl >3 mL/min/1.73 m²	Hultin et al., 2021¹⁷	CKD patients with MA	Oral bicarbonate vs placebo or no intervention	RR 0.32 (0.20–0.52)	NR	58	RCT	Low
Proteinuria	–	Hultin et al., 2021¹⁷	CKD patients with MA	Oral bicarbonate vs placebo or no intervention	SMD −0.09 (−0.27 to 0.09)	NR	16	RCT	Very low
Serum bicarbonate concentration	–	Hultin et al., 2021¹⁷	CKD patients with MA	Oral bicarbonate vs placebo or no intervention	MD 2.59 (1.51–3.66)	NR	95	RCT	Very low
SBP	–	Hultin et al., 2021¹⁷	CKD patients with MA	Oral bicarbonate vs placebo or no intervention	MD −0.57 (−2.32 to 1.18)	NR	0	RCT	Low
Diastolic BP	–	Hultin et al., 2021¹⁷	CKD patients with MA	Oral bicarbonate vs placebo or no intervention	MD 0.88 (−0.61 to 2.38)	NR	27	RCT	Low
Worsening BP	–	Hultin et al., 2021¹⁷	CKD patients with MA	Oral bicarbonate vs placebo or no intervention	RR 1.36 (1.05–1.77)	NR	58	RCT	Low
Edema	–	Hultin et al., 2021¹⁷	CKD patients with MA	Oral bicarbonate vs placebo or no intervention	RR 1.16 (0.90–1.50)	NR	28	RCT	Low
Change in weight	–	Hultin et al., 2021¹⁷	CKD patients with MA	Oral bicarbonate vs placebo or no intervention	MD −0.11 (−0.93 to 0.70)	NR	0	RCT	Low
Death events	–	Hultin et al., 2021¹⁷	CKD patients with MA	Oral bicarbonate vs placebo or no intervention	RR 0.81 (0.39–1.68)	NR	30	RCT	Very low
Hospitalizations for heart failure	–	Hultin et al., 2021¹⁷	CKD patients with MA	Oral bicarbonate vs placebo or no intervention	RR 1.19 (0.30–4.67)	NR	9	RCT	Very low
Bicarbonate level	–	Roderick et al., 2007²⁵	CKD patients with MA	Oral or dialysis bicarbonate vs placebo, control, or usual dialysis bicarbonate	MD 4.63 (1.06–8.20)	NR	87.51	RCT	Very low
Sodium level	–	Roderick et al., 2007²⁵	CKD patients with MA	Oral or dialysis bicarbonate vs placebo, control, or usual dialysis bicarbonate	MD −3.40 (−5.53 to −1.27)	NR	NA^a	RCT	NA^a
SBP	–	Roderick et al., 2007²⁵	CKD patients with MA	Oral or dialysis bicarbonate vs placebo, control, or usual dialysis bicarbonate	MD 8.60 (−7.72 to 24.92)	NR	NA^a	RCT	NA^a
Diastolic BP	–	Roderick et al., 2007²⁵	CKD patients with MA	Oral or dialysis bicarbonate vs placebo, control, or usual dialysis bicarbonate	MD −0.70 (−10.26 to 8.86)	NR	NA ^a	RCT	NA ^a
Kt/V	–	Roderick et al., 2007²⁵	CKD patients with MA	Oral or dialysis bicarbonate vs placebo, control, or usual dialysis bicarbonate	MD −0.07 (−0.2 to 0.07)	NR	11.55	RCT	Very low
SGA at 12 months	–	Roderick et al., 2007²⁵	CKD patients with MA	Oral or dialysis bicarbonate vs placebo, control, or usual dialysis bicarbonate	MD 0.61 (0.07–1.15)	NR	NA^a	RCT	NA^a
NPNA at 12 months	–	Roderick et al., 2007²⁵	CKD patients with MA	Oral or dialysis bicarbonate vs placebo, control, or usual dialysis bicarbonate	MD 0.21 (0.07–0.35)	NR	NA^a	RCT	NA^a
PCR	–	Roderick et al., 2007²⁵	CKD patients with MA	Oral or dialysis bicarbonate vs placebo, control, or usual dialysis bicarbonate	MD 0.08 (−0.08 to 0.24)	NR	NA^a	RCT	NA^a
Albumin	–	Roderick et al., 2007²⁵	CKD patients with MA	Oral or dialysis bicarbonate vs placebo, control, or usual dialysis bicarbonate	MD 2.23 (−2.71 to 7.17)	NR	93.29	RCT	Very low
Edema	–	Roderick et al., 2007²⁵	CKD patients with MA	Oral or dialysis bicarbonate vs placebo, control, or usual dialysis bicarbonate	MD −0.29 (−0.75 to 0.17)	NR	NA^a	RCT	NA^a
Fat-free edema-free body mass	–	Roderick et al., 2007²⁵	CKD patients with MA	Oral or dialysis bicarbonate vs placebo, control, or usual dialysis bicarbonate	MD 2.8 (−0.82 to 6.42)	NR	NA^a	RCT	NA^a
LBM	–	Roderick et al., 2007²⁵	CKD patients with MA	Oral or dialysis bicarbonate vs placebo, control, or usual dialysis bicarbonate	MD 0.7 (−4.2 to 5.6)	NR	NA^a	RCT	NA^a
Phosphorus	–	Roderick et al., 2007²⁵	CKD patients with MA	Oral or dialysis bicarbonate vs placebo, control, or usual dialysis bicarbonate	MD −0.9 (−2.22 to 0.42)	NR	NA^a	RCT	NA^a
Pre-dialysis calcium (mg/dL)	–	Roderick et al., 2007²⁵	CKD patients with MA	Oral or dialysis bicarbonate vs placebo, control, or usual dialysis bicarbonate	MD −0.18 (−0.55 to 0.19)	NR	0	RCT	Very low
Osteocalcin (ng/mL)	–	Roderick et al., 2007²⁵	CKD patients with MA	Oral or dialysis bicarbonate vs placebo, control, or usual dialysis bicarbonate	MD −25 (−76.93 to 26.93)	NR	NA^a	RCT	NA^a
PTH (1–84 pg/mL)	–	Roderick et al., 2007²⁵	CKD patients with MA	Oral or dialysis bicarbonate vs placebo, control, or usual dialysis bicarbonate	MD −74.99 (−207.55 to 57.57)	NR	0	RCT	Very low
PTH (53–84 pg/mL)	–	Roderick et al., 2007²⁵	CKD patients with MA	Oral or dialysis bicarbonate vs placebo, control, or usual dialysis bicarbonate	MD −38 (−250.9 to 174.9)	NR	NA^a	RCT	NA^a
PTH (44–68 pg/mL)	–	Roderick et al., 2007²⁵	CKD patients with MA	Oral or dialysis bicarbonate vs placebo, control, or usual dialysis bicarbonate	MD −1872 (−5486.99 to 1742.99)	NR	NA^a	RCT	NA^a
Bone volume (%)	–	Roderick et al., 2007²⁵	CKD patients with MA	Oral or dialysis bicarbonate vs placebo, control, or usual dialysis bicarbonate	MD 1.55 (−5.93 to 9.03)	NR	NA^a	RCT	NA^a
Osteoid volume (%)	–	Roderick et al., 2007²⁵	CKD patients with MA	Oral or dialysis bicarbonate vs placebo, control, or usual dialysis bicarbonate	MD −2.57 (−9.23 to 4.09)	NR	NA^a	RCT	NA^a
Osteoid surfaces (%)	–	Roderick et al., 2007²⁵	CKD patients with MA	Oral or dialysis bicarbonate vs placebo, control, or usual dialysis bicarbonate	MD −2.78 (−17.4 to 11.84)	NR	NA^a	RCT	NA^a
Osteoblast surfaces (%)	–	Roderick et al., 2007²⁵	CKD patients with MA	Oral or dialysis bicarbonate vs placebo, control, or usual dialysis bicarbonate	MD −4.55 (−9.88 to 0.78)	NR	NA^a	RCT	NA^a
Osteoclast surfaces (%)	–	Roderick et al., 2007²⁵	CKD patients with MA	Oral or dialysis bicarbonate vs placebo, control, or usual dialysis bicarbonate	MD −0.69 (−1.97 to 0.59)	NR	NA^a	RCT	NA^a
Osteoclasts sq/mm	–	Roderick et al., 2007²⁵	CKD patients with MA	Oral or dialysis bicarbonate vs placebo, control, or usual dialysis bicarbonate	MD −0.51 (−1.74 to 0.72)	NR	NA^a	RCT	NA^a
Bone formation rate (cubic µm/sq µm/d)	–	Roderick et al., 2007²⁵	CKD patients with MA	Oral or dialysis bicarbonate vs placebo, control, or usual dialysis bicarbonate	MD −0.1 (−0.21 to 0.01)	NR	NA^a	RCT	NA^a
Osteoid thickness (µm)	–	Roderick et al., 2007²⁵	CKD patients with MA	Oral or dialysis bicarbonate vs placebo, control, or usual dialysis bicarbonate	MD 1.6 (−1.07 to 4.27)	NR	NA^a	RCT	NA^a
Hospitalization	–	Roderick et al., 2007²⁵	CKD patients with MA	Oral or dialysis bicarbonate vs placebo, control, or usual dialysis bicarbonate	RR 0.76 (0.51–1.15)	NR	NA^a	RCT	NA^a
All-cause mortality	–	Roderick et al., 2007²⁵	CKD patients with MA	Oral or dialysis bicarbonate vs placebo, control, or usual dialysis bicarbonate	RR 0.4 (0.08–1.90)	NR	NA^a	RCT	NA^a
Hospital admission/patient	–	Roderick et al., 2007²⁵	CKD patients with MA	Oral or dialysis bicarbonate vs placebo, control, or usual dialysis bicarbonate	MD −0.68 (−1.83 to 0.47)	NR	NA^a	RCT	NA^a
Average length of hospital stay	–	Roderick et al., 2007²⁵	CKD patients with MA	Oral or dialysis bicarbonate vs placebo, control, or usual dialysis bicarbonate	MD −8.4 (−18.42 to 1.62)	NR	NA^a	RCT	NA^a
Mean systolic BP	–	Beynon-Cobb et al., 2023²⁴	13 studies + Raphael et al. high dose^b	Sodium bicarbonate or sodium citrate vs placebo or no intervention	MD 1.23 (−0.20 to 2.60)	0.09	39	RCT	Low
Mean systolic BP	–	Beynon-Cobb et al., 2023²⁴	13 studies + Raphael et al. low dose^b	Sodium bicarbonate or sodium citrate vs placebo or no intervention	MD 0.91 (−0.61 to 2.44)	0.24	45	RCT	Low
Mean systolic BP	–	Beynon-Cobb et al., 2023²⁴	13 studies + Raphael et al. high dose^b	High dose (0.51 mEqM/kg) sodium bicarbonate vs placebo or no intervention	MD 2.82 (−1.58 to 7.23)	NR	83.89	RCT	Moderate
Mean systolic BP	–	Beynon-Cobb et al., 2023²⁴	13 studies + Raphael et al. high dose^b	Low dose (<0.25 mEqM/kg) sodium bicarbonate vs placebo or no intervention	MD 1.39 (−1.87 to 4.65)	NR	0	RCT	Moderate
Mean systolic BP	–	Beynon-Cobb et al., 2023²⁴	13 studies + Raphael et al. high dose^b	Medium dose (0.26–0.5 mEqm/kg) sodium bicarbonate vs placebo or no intervention	MD 0.41 (−0.97 to 1.78)	NR	0	RCT	Moderate
Mean systolic BP	–	Beynon-Cobb et al., 2023²⁴	13 studies + Raphael et al. low dose^b	High dose (⩽0.51 mEqM/kg) sodium bicarbonate vs placebo or no intervention	MD 2.98 (−2.90 to 8.85)	NR	91.94	RCT	Low
Mean systolic BP	–	Beynon-Cobb et al., 2023²⁴	13 studies + Raphael et al. low dose^b	Low dose (<0.25 mEqM/kg) sodium bicarbonate vs placebo or no intervention	MD 1.39 (−1.87 to 4.65)	NR	0	RCT	Moderate
Mean systolic BP	–	Beynon-Cobb et al., 2023²⁴	13 studies + Raphael et al. low dose^b	Medium dose (0.26–0.5 mEqm/kg) sodium bicarbonate vs placebo or no intervention	MD 0.20 (−1.13 to 1.54)	NR	0	RCT	Moderate
Mean systolic BP	–	Beynon-Cobb et al., 2023²⁴	13 studies + Raphael et al. high dose^b	Long term (104–520 weeks) sodium bicarbonate vs placebo or no intervention	MD 0.74 (−0.49 to 1.97)	0.24	0	RCT	Moderate
Mean systolic BP	–	Beynon-Cobb et al., 2023²⁴	13 studies + Raphael et al. high dose^b	Medium term (24–28 weeks) sodium bicarbonate vs placebo or no intervention	MD 0.15 (−3.97 to 4.27)	0.94	20.9	RCT	Low
Mean systolic BP	–	Beynon-Cobb et al., 2023²⁴	13 studies + Raphael et al. high dose^b	Short term (4–12 weeks) sodium bicarbonate vs placebo or no intervention	MD 2.35 (−2.36 to 7.06)	0.33	69.16	RCT	Low
Mean systolic BP	–	Beynon-Cobb et al., 2023²⁴	13 studies + Raphael et al. low dose^b	Long term (104–520 weeks) sodium bicarbonate vs placebo or no intervention	MD 0.74 (−0.49 to −1.97)	0.24	0	RCT	Moderate
Mean systolic BP	–	Beynon-Cobb et al., 2023²⁴	13 studies + Raphael et al. low dose^b	Medium term (24–28 weeks) sodium bicarbonate vs placebo or no intervention	MD −2.25 (−6.00 to 1.50)	0.24	0	RCT	High
Mean systolic BP	–	Beynon-Cobb et al., 2023²⁴	13 studies + Raphael et al. low dose^b	Short term (4–12 weeks) sodium bicarbonate vs placebo or no intervention	MD 2.29 (−2.45 to 7.02)	0.34	69.78	RCT	Low
Mean systolic BP	–	Beynon-Cobb et al., 2023²⁴	13 studies + Raphael et al. high dose^b	Sodium bicarbonate vs placebo or no intervention in patients with CKD type 1	MD −1.30 (−4.49 to 1.89)	NA^a	NA^a	RCT	NA^a
Mean systolic BP	–	Beynon-Cobb et al., 2023²⁴	13 studies + Raphael et al. high dose^b	Sodium bicarbonate vs placebo or no intervention in patients with CKD type 2	MD 1.50 (−2.03 to 5.03)	NA^a	NA^a	RCT	NA^a
Mean systolic BP	–	Beynon-Cobb et al., 2023²⁴	13 studies + Raphael et al. high dose^b	Sodium bicarbonate vs placebo or no intervention in patients with CKD type 3	MD 0.70 (−0.72 to 2.12)	0.33	0	RCT	Moderate
Mean systolic BP	–	Beynon-Cobb et al., 2023²⁴	13 studies + Raphael et al. high dose^b	Sodium bicarbonate vs placebo or no intervention in patients with CKD type 4	MD 1.86 (−1.21 to 4.93)	0.23	53.22	RCT	High
Mean systolic BP	–	Beynon-Cobb et al., 2023²⁴	13 studies + Raphael et al. low dose^b	Sodium bicarbonate vs placebo or no intervention in patients with CKD type 1	MD −1.30 (−4.46 to 1.86)	NA^a	NA^a	RCT	NA^a
Mean systolic BP	–	Beynon-Cobb et al., 2023²⁴	13 studies + Raphael et al. low dose^b	Sodium bicarbonate vs placebo or no intervention in patients with CKD type 2	MD 1.50 (−2.03 to 5.03)	NA^a	NA^a	RCT	NA^a
Mean systolic BP	–	Beynon-Cobb et al., 2023²⁴	13 studies + Raphael et al. low dose^b	Sodium bicarbonate vs placebo or no intervention in patients with CKD type 3	MD 0.35 (−1.07 to 1.78)	0.68	0	RCT	Moderate
Mean systolic BP	–	Beynon-Cobb et al., 2023²⁴	13 studies + Raphael et al. low dose^b	Sodium bicarbonate vs placebo or no intervention in patients with CKD type 4	MD 1.83 (−1.25 to 4.92)	0.04	53.55	RCT	Moderate
Decrease in antihypertensive medications use	–	Beynon-Cobb et al., 2023²⁴	CKD patients with MA	Sodium bicarbonate or sodium citrate vs placebo or no intervention	RR 1.30 (1.05–1.59)	0.01	0	RCT	Moderate
Increase in b-blockers use	–	Beynon-Cobb et al., 2023²⁴	CKD patients with MA	Sodium bicarbonate or sodium citrate vs placebo or no intervention	RR 0.39 (0.18–0.84)	0.02	0	RCT	High
Increase in vasodilators use	–	Beynon-Cobb et al., 2023²⁴	CKD patients with MA	Sodium bicarbonate or sodium citrate vs placebo or no intervention	RR 0.64 (0.45–0.92)	0.02	0	RCT	High
Increase in diuretic medications use	–	Beynon-Cobb et al., 2023²⁴	CKD patients with MA	Sodium bicarbonate or sodium citrate vs placebo or no intervention	RR 1.16 (0.89–1.51)	0.27	11	RCT	Moderate
Decrease in diuretic medications use	–	Beynon-Cobb et al., 2023²⁴	CKD patients with MA	Sodium bicarbonate or sodium citrate vs placebo or no intervention	RR 0.71 (0.44–1.12)	0.14	0	RCT	Moderate
Dietary protein intake	Assessed with a food diary	Visser et al., 2023⁴	CKD patients with MA	Any type of intervention focused on correcting MA vs a control group with or without placebo	SMD 0.22 (−0.23 to 0.68)	0.34	76	RCT and non RCT	Very low
MAMC	–	Visser et al., 2023⁴	CKD patients with MA	Any type of intervention focused on correcting MA vs a control group with or without placebo	SMD 0.35 (0.16–0.54)	0.0003	34	RCT and non RCT	Very low
HGS	–	Visser et al., 2023⁴	CKD patients with MA	Any type of intervention focused on correcting MA vs a control group with or without placebo	SMD −0.02 (−0.52 to 0.58)	0.94	83	RCT and non RCT	Very low
STS	–	Visser et al., 2023⁴	CKD patients with MA	Any type of intervention focused on correcting MA vs a control group with or without placebo	SMD −0.31 (−0.52 to −0.11)	0.0003	0	RCT and non-RCT	Very low
Difference in serum albumin concentrations	–	Visser et al., 2023⁴	CKD patients with MA	Any type of intervention focused on correcting MA vs a control group with or without placebo	SMD 0.19 (−0.05 to 0.42)	0.11	72	RCT and non RCT	Very low
Difference in serum prealbumin concentrations	–	Visser et al., 2023⁴	CKD patients with MA	Any type of intervention focused on correcting MA vs a control group with or without placebo	SMD 0.24 (−0.13 to 0.61)	0.2	0	RCT and non RCT	Very low
Difference in BUN	–	Visser et al., 2023⁴	CKD patients with MA	Any type of intervention focused on correcting MA vs a control group with or without placebo	SMD −0.41 (−0.83 to 0.01)	0.05	62	RCT and non RCT	Very low
Rate of change in eGFR or creatinine clearance	Rate of eGFR decline by 2.59 mL/min/1.73 m²	Shi et al., 2022²⁰	Pre-dialysis CKD adults	Oral alkali therapy vs usual care	MD 2.59 (0.88–4.31)	NR	97.6	RCT and non RCT	Very low
Renal failure events	50% decline in eGFR or progression to ESRD	Shi et al., 2022²⁰	Pre-dialysis CKD adults	Oral alkali therapy vs usual care	RR 0.45 (0.25–0.82)	NR	67.8	RCT and non RCT	Very low
All-cause mortality events	Death from any cause	Shi et al., 2022²⁰	Pre-dialysis CKD adults	Oral alkali therapy vs usual care	RR 0.90 (0.40–2.02)	NR	54.7	RCT and non RCT	Very low
CV events	Fatal or non-fatal CV events	Shi et al., 2022²⁰	Pre-dialysis CKD adults	Oral alkali therapy vs usual care	RR 1.03 (0.32–3.37)	NR	65.1	RCT and non RCT	Very low
Decline in eGFR events	Decline in eGFR >3 mL/min/1.73 m² per year	Shi et al., 2022²⁰	Pre-dialysis CKD adults	Oral alkali therapy vs usual care	RR 0.34 (0.09–1.23)	NR	54.1	RCT and non RCT	Very low
Proteinuria or albuminuria		Shi et al., 2022²⁰	Pre-dialysis CKD adults	Oral alkali therapy vs usual care	SMD −0.32 (−1.08 to 0.43)	NR	88.2	RCT and non RCT	Very low
BW	–	Navab et al., 2023²¹	Pre-dialysis CKD patients	Oral sodium bicarbonate vs control	MD 0.01 kg (−0.26 to 0.29)	0.84	19.2	RCT	Very low
BMI	–	Navab et al., 2023²¹	Pre-dialysis CKD patients	Oral sodium bicarbonate vs control	MD 0.59 kg/m² (0.25–0.93)	0.001	9.2	RCT	Very low
MAMC	–	Navab et al., 2023²¹	Pre-dialysis CKD patients	Oral sodium bicarbonate vs control	MD 0.63 cm (−0.21 to 1.47)	0.14	81.2	RCT	Very low
LBM	–	Navab et al., 2023²¹	Pre-dialysis CKD patients	Oral sodium bicarbonate vs control	MD 1.31 kg (−0.11 to 2.72)	0.07	65	RCT	Very low
Decline in eGFR (mL/min/1.73 m²)	Change in kidney function measured as eGFR decline	Cheng et al., 2021¹⁸	CKD patients with MA	Sodium bicarbonate vs no treatment, usual patient care, or placebo therapy	MD −4.44 (−4.92 to −3.96)	NR	9	RCT	High
Serum Bicarbonate (mEq/L)	–	Cheng et al., 2021¹⁸	CKD patients with MA	Sodium bicarbonate vs no treatment, usual patient care, or placebo therapy	MD 2.37 (1.03–3.72)	NR	98	RCT	Low
Creatinine (mg/dL)	–	Cheng et al., 2021¹⁸	CKD patients with MA	Sodium bicarbonate vs no treatment, usual patient care, or placebo therapy	MD −0.5 (−0.56 to −0.44)	NR	NA^a	RCT	NA^a
Urinary ACR, mg/g	–	Cheng et al., 2021¹⁸	CKD patients with MA	Sodium bicarbonate vs no treatment, usual patient care, or placebo therapy	MD −31.0 (−36.0 to −26.0)	NR	NA^a	RCT	NA^a
T50-time (min)	Vascular calcification propensity	Cheng et al., 2021¹⁸	CKD patients with MA	Sodium bicarbonate vs no treatment, usual patient care, or placebo therapy	MD −20.74 (−49.55 to 8.08)	NR	0	RCT	Low
Systolic BP (mmHg)	–	Cheng et al., 2021¹⁸	CKD patients with MA	Sodium bicarbonate vs no treatment, usual patient care, or placebo therapy	MD −2.97 (−5.04 to −0.90)	NR	56	RCT	Moderate
Diastolic BP (mmHg)	–	Cheng et al., 2021¹⁸	CKD patients with MA	Sodium bicarbonate vs no treatment, usual patient care, or placebo therapy	MD −1.26 (−2.33 to −0.19)	NR	0	RCT	High
Serum potassium, mEq/L	–	Cheng et al., 2021¹⁸	CKD patients with MA	Sodium bicarbonate vs no treatment, usual patient care, or placebo therapy	MD 0.01 (−0.06 to 0.07)	NR	0	RCT	Very low
Serum calcium, mg/dL	–	Cheng et al., 2021¹⁸	CKD patients with MA	Sodium bicarbonate vs no treatment, usual patient care, or placebo therapy	MD 0.12 (0.05–0.19)	NR	0	RCT	Low
Serum phosphate, mg/dL	–	Cheng et al., 2021¹⁸	CKD patients with MA	Sodium bicarbonate vs no treatment, usual patient care, or placebo therapy	MD 0.09 (0.04–0.15)	NR	57.4	RCT	Very low
Serum albumin, g/L	–	Cheng et al., 2021¹⁸	CKD patients with MA	Sodium bicarbonate vs no treatment, usual patient care, or placebo therapy	MD 0.12 (0.09–0.15)	NR	31.4	RCT	Low
BW (kg)	–	Cheng et al., 2021¹⁸	CKD patients with MA	Sodium bicarbonate vs no treatment, usual patient care, or placebo therapy	MD 0.25 (−1.12 to 1.61)	NR	0	RCT	Very low
24 h urinary sodium excretion (mEq/24 h)	–	Cheng et al., 2021¹⁸	CKD patients with MA	Sodium bicarbonate vs no treatment, usual patient care, or placebo therapy	MD 24.31 (21.74–26.89)	NR	92.8	RCT	Low
Urine pH	–	Cheng et al., 2021¹⁸	CKD patients with MA	Sodium bicarbonate vs no treatment, usual patient care, or placebo therapy	MD 0.23 (0.16–0.31)	NR	53.4	RCT	Very low
Mean MAMC (cm)	–	Cheng et al., 2021¹⁸	CKD patients with MA	Sodium bicarbonate vs no treatment, usual patient care, or placebo therapy	MD 0.14 (−0.46 to 0.74)	NR	0	RCT	Very low
Change in eGFR	–	Yang et al., 2024²²	CKD patients with MA	Sodium bicarbonate vs placebo, standard care, or rescue therapy	SMD 0.33 (0.03–0.63)	NR	74.7	RCT	Very low
Change in SBP	–	Yang et al., 2024²²	CKD patients with MA	Sodium bicarbonate vs placebo, standard care, or rescue therapy	SMD 0.10 (0.01–0.20)	NR	0	RCT	Moderate
Hospitalization rate	–	Yang et al., 2024²²	CKD patients with MA	Sodium bicarbonate vs placebo, standard care, or rescue therapy	OR 0.37 (0.25–0.55)	NR	0	RCT	High
All-cause mortality	Mortality from any cause	Yang et al., 2024²²	CKD patients with MA	Sodium bicarbonate vs placebo, standard care, or rescue therapy	OR 0.72 (0.40–1.31)	NR	12.16	RCT	Very low
MAMC	–	Yang et al., 2024²²	CKD patients with MA	Sodium bicarbonate vs placebo, standard care, or rescue therapy	SMD 0.23 (0.08–0.38)	NR	0	RCT	Moderate
Serum bicarbonate	–	Yang et al., 2024²²	CKD patients with MA	Sodium bicarbonate vs placebo, standard care, or rescue therapy	SMD 1.89 (1.10–2.68)	NR	97.68	RCT	Moderate
Serum albumin	–	Yang et al., 2024²²	CKD patients with MA	Sodium bicarbonate vs placebo, standard care, or rescue therapy	SMD 0.25 (0.14–0.36)	NR	2.74	RCT	Moderate
24-h urinary sodium excretion	–	Yang et al., 2024²²	CKD patients with MA	Sodium bicarbonate vs placebo, standard care, or rescue therapy	SMD 0.27 (0.13–0.41)	NR	0	RCT	Moderate
BW	–	Yang et al., 2024²²	CKD patients with MA	Sodium bicarbonate vs placebo, standard care, or rescue therapy	SMD 0.04 (−0.06 to 0.15)	NR	0	RCT	Very low
Serum calcium	–	Yang et al., 2024²²	CKD patients with MA	Sodium bicarbonate vs placebo, standard care, or rescue therapy	SMD 0.39 (0.18–0.60)	NR	38.1	RCT	Low
Phosphate levels	–	Yang et al., 2024²²	CKD patients with MA	Sodium bicarbonate vs placebo, standard care, or rescue therapy	SMD, 0.20 (0.05–0.35)	NR	1	RCT	Moderate
Acid–base balance	Increase in serum bicarbonate	Mahboobi et al., 2024⁷	CKD patients with MA	Dietary protein and phosphate restriction and no protein/phosphate restriction	MD 2.98 (0.77–5.19)	NR	91	RCT	Low
Serum SUN	–	Mahboobi et al., 2024⁷	CKD patients with MA	Dietary protein and phosphate restriction and no protein/phosphate restriction	MD −40.21 (−68.8 to −11.61)	NR	60	RCT	Low
Serum creatinine	–	Mahboobi et al., 2024⁷	CKD patients with MA	Dietary protein and phosphate restriction and no protein/phosphate restriction	MD −0.26 (−1.28 to 0.76)	NR	0	RCT	Very low
SBP	–	Mahboobi et al., 2024⁷	CKD patients with MA	Dietary protein and phosphate restriction and no protein/phosphate restriction	MD −13.10 (−18.27 to −7.94)	NR	0	RCT	Moderate
RRT initiation	–	Mahboobi et al., 2024⁷	CKD patients with MA	Dietary protein and phosphate restriction and no protein/phosphate restriction	RR 0.59 (0.24–1.45)	NR	69	RCT	Very low
Serum phosphate	–	Mahboobi et al., 2024⁷	CKD patients with MA	Dietary protein and phosphate restriction and no protein/phosphate restriction	MD −1.22 (−2.34 to −0.10)	NR	82	RCT	Very low
Serum calcium	–	Mahboobi et al., 2024⁷	CKD patients with MA	Dietary protein and phosphate restriction and no protein/phosphate restriction	MD 0.51 (0.30–0.73)	NR	0	RCT	Low
Serum potassium	–	Mahboobi et al., 2024⁷	CKD patients with MA	Dietary protein and phosphate restriction and no protein/phosphate restriction	MD −0.01 (−0.19 to 0.18)	NR	31	RCT	Very low
Serum albumin	–	Mahboobi et al., 2024⁷	CKD patients with MA	Dietary protein and phosphate restriction and no protein/phosphate restriction	MD 0.04 (−0.17 to 0.25)	NR	61	RCT	Very low
BMI	–	Mahboobi et al., 2024⁷	CKD patients with MA	Dietary protein and phosphate restriction and no protein/phosphate restriction	MD −0.84 (−2.09 to 0.41)	NR	49	RCT	Very low
Serum bicarbonate	–	Hu et al., 2019¹⁹	CKD patients with MA	Oral bicarbonate	MD 3.4 (1.9–4.9)	<0.00001	97	RCT	Moderate
eGFR at the end of follow-up	–	Hu et al., 2019¹⁹	CKD patients with MA	Oral bicarbonate	MD 3.1 (1.3–4.9)	0.008	68	RCT	Low
Serum creatinine	–	Hu et al., 2019¹⁹	CKD patients with MA	Oral bicarbonate	MD −0.20 (−0.42 to 0.03)	0.09	69	RCT	Very low
SBP	–	Hu et al., 2019¹⁹	CKD patients with MA	Oral bicarbonate	MD 1.68 (−0.87 to 4.23)	0.2	73	RCT	Very low
Weight	–	Hu et al., 2019¹⁹	CKD patients with MA	Oral bicarbonate	MD 0.61 (−0.55 to 1.77)	0.3	87	RCT	Very low
Effects of oral bicarbonate therapy and control on eGFR at 1 year	–	Hu et al., 2019¹⁹	CKD patients with MA	Oral bicarbonate	MD 1.37 (−0.69 to 3.43)	0.19	46	RCT	Very low
Effects of oral bicarbonate therapy and control on serum bicarbonate levels at 1 year	–	Hu et al., 2019¹⁹	CKD patients with MA	Oral bicarbonate	MD 3.16 (2.02–4.29)	<0.00001	66	RCT	Low
eGFR decline, mL/min/1.72 m²	–	Navaneethan et al., 2019⁵	CKD patients with MA	Oral alkali supplementation or reduction of dietary acid intake	MD −3.3 (−4.4 to −2.1)	<0.001	39	RCT	Very low
eGFR decline per year, mL/min/1.72 m²/yr	–	Navaneethan et al., 2019⁵	CKD patients with MA	Oral alkali supplementation or reduction of dietary acid intake	MD −2.1 (−2.8 to −1.4)	<0.001	0	RCT	Very low
Progression to ESKD	–	Navaneethan et al., 2019⁵	CKD patients with MA	Oral alkali supplementation or reduction of dietary acid intake	RR 0.3 (0.2–0.6)	<0.001	17	RCT	Low
Urinary ACR, mg/g	–	Navaneethan et al., 2019⁵	CKD patients with MA	Oral alkali supplementation or reduction of dietary acid intake	MD −52 (−76 to −27)	<0.001	0	RCT	Very low
Serum bicarbonate	–	Navaneethan et al., 2019⁵	CKD patients with MA	Oral alkali supplementation or reduction of dietary acid intake	MD 3.3 (2.4–4.3)	<0.001	93	RCT	Very low
Serum potassium	–	Navaneethan et al., 2019⁵	CKD patients with MA	Oral alkali supplementation or reduction of dietary acid intake	MD −0.15 (−0.38 to 0.07)	0.17	88	RCT	Very low
Serum calcium	–	Navaneethan et al., 2019⁵	CKD patients with MA	Oral alkali supplementation or reduction of dietary acid intake	MD 0.04 (−0.26 to 0.35)	0.79	82	RCT	Very low
Serum phosphate	–	Navaneethan et al., 2019⁵	CKD patients with MA	Oral alkali supplementation or reduction of dietary acid intake	MD −0.30 (−0.62 to 0.02)	0.06	59	RCT	Very low
Serum albumin	–	Navaneethan et al., 2019⁵	CKD patients with MA	Oral alkali supplementation or reduction of dietary acid intake	MD 0.43 (−0.54 to 1.41)	0.39	68	RCT	Very low
Serum PTH	–	Navaneethan et al., 2019⁵	CKD patients with MA	Oral alkali supplementation or reduction of dietary acid intake	MD −22 (−126 to 81)	0.67	42	RCT	Very low
MAMC	–	Navaneethan et al., 2019⁵	CKD patients with MA	Oral alkali supplementation or reduction of dietary acid intake	MD 0.2 (−0.2 to 0.6)	0.29	0	RCT	Very low
GFR, mL/min or mL/min/1.73 m²	–	Susantitaphong et al., 2012²³	Short-term (⩽7 days) studies	Any form of alkali therapy vs standard-of-care or placebo	MD 0.4 (−2.8 to 3.6)	0.82	5	RCT	Very low
Serum creatinine, mg/dL	–	Susantitaphong et al., 2012²³	Short-term (⩽7 days) studies	Any form of alkali therapy vs standard-of-care or placebo	MD 0.2 (−1.1 to 1.5)	0.76	NA^a	RCT	NA^a
Serum SUN, mg/dL	–	Susantitaphong et al., 2012²³	Short-term (⩽7 days) studies	Any form of alkali therapy vs standard-of-care or placebo	MD 2.8 (−5.5 to 11.1)	0.51	NA^a	RCT	NA^a
Serum sodium, mEq/L	–	Susantitaphong et al., 2012²³	Short-term (⩽7 days) studies	Any form of alkali therapy vs standard-of-care or placebo	MD 1.2 (−1.4 to 3.9)	0.37	46	RCT	Very low
Serum potassium, mEq/L	–	Susantitaphong et al., 2012²³	Short-term (⩽7 days) studies	Any form of alkali therapy vs standard-of-care or placebo	MD −0.2 (−0.4 to 0.1)	0.12	0	RCT	Very low
Serum chloride, mEq/L	–	Susantitaphong et al., 2012²³	Short-term (⩽7 days) studies	Any form of alkali therapy vs standard-of-care or placebo	MD −8.0 (−10.4 to −5.6)	<0.001	0	RCT	Low
Serum bicarbonate, mEq/L	–	Susantitaphong et al., 2012²³	Short-term (⩽7 days) studies	Any form of alkali therapy vs standard-of-care or placebo	MD 5.4 (4.0–6.7)	<0.001	0	RCT	High
Serum albumin, g/dL	–	Susantitaphong et al., 2012²³	Short-term (⩽7 days) studies	Any form of alkali therapy vs standard-of-care or placebo	NA^a	NA^a	NA^a	RCT	NA^a
24 h urine sodium excretion, mEq/day	–	Susantitaphong et al., 2012²³	Short-term (⩽7 days) studies	Any form of alkali therapy vs standard-of-care or placebo	MD 77.0 (48.7–105.3)	<0.001	NA^a	RCT	NA^a
24 h urine protein excretion, mg/day	–	Susantitaphong et al., 2012²³	Short-term (⩽7 days) studies	Any form of alkali therapy vs standard-of-care or placebo	NA^a	NA^a	NA^a	RCT	NA^a
SBP, mm Hg	–	Susantitaphong et al., 2012²³	Short-term (⩽7 days) studies	Any form of alkali therapy vs standard-of-care or placebo	MD −1.3 (−15.4 to 12.8)	0.86	NA^a	RCT	NA^a
Diastolic BP, mm Hg	–	Susantitaphong et al., 2012²³	Short-term (⩽7 days) studies	Any form of alkali therapy vs standard-of-care or placebo	MD −5.6 (−16.0 to 4.7)	0.29	NA^a	RCT	NA^a
Weight change, kg	–	Susantitaphong et al., 2012²³	Short-term (⩽7 days) studies	Any form of alkali therapy vs standard-of-care or placebo	MD 0.5 (−6.6 to 7.7)	0.89	0	RCT	Very low
GFR, mL/min or mL/min/1.73 m²	–	Susantitaphong et al., 2012²³	Long-term (⩾2 months) studies	Any form of alkali therapy vs standard-of-care or placebo	MD 3.2 (1.6–4.7)	<0.001	0	RCT	Moderate
Serum creatinine, mg/dL	–	Susantitaphong et al., 2012²³	Long-term (⩾2 months) studies	Any form of alkali therapy vs standard-of-care or placebo	MD −0.07 (−0.09 to −0.05)	<0.001	0	RCT	Low
Serum SUN, mg/dL	–	Susantitaphong et al., 2012²³	Long-term (⩾2 months) studies	Any form of alkali therapy vs standard-of-care or placebo	MD −10.8 (−17.5 to −4.1)	0.002	32	RCT	Low
Serum sodium, mEq/L	–	Susantitaphong et al., 2012²³	Long-term (⩾2 months) studies	Any form of alkali therapy vs standard-of-care or placebo	MD −1.1 (−2.6 to 0.3)	0.14	NA^a	RCT	NA^a
Serum potassium, mEq/L	–	Susantitaphong et al., 2012²³	Long-term (⩾2 months) studies	Any form of alkali therapy vs standard-of-care or placebo	MD −0.7 (−1.3 to −0.1)	0.03	95	RCT	Very low
Serum chloride, mEq/L	–	Susantitaphong et al., 2012²³	Long-term (⩾2 months) studies	Any form of alkali therapy vs standard-of-care or placebo	MD −2.1 (−3.5 to −0.6)	0.006	NA^a	RCT	NA^a
Serum bicarbonate, mEq/L	–	Susantitaphong et al., 2012²³	Long-term (⩾2 months) studies	Any form of alkali therapy vs standard-of-care or placebo	MD 2.7 (0.6–4.8)	0.013	97	RCT	Very low
Serum albumin, g/dL	–	Susantitaphong et al., 2012²³	Long-term (⩾2 months) studies	Any form of alkali therapy vs standard-of-care or placebo	MD 0.001 (−0.41 to 0.42)	1	97	RCT	Very low
24 h urine sodium excretion, mEq/day	–	Susantitaphong et al., 2012²³	Long-term (⩾2 months) studies	Any form of alkali therapy vs standard-of-care or placebo	MD 24.3 (−7.1 to 55.7)	0.13	NA^a	RCT	NA^a
24 h urine protein excretion, mg/day	–	Susantitaphong et al., 2012²³	Long-term (⩾2 months) studies	Any form of alkali therapy vs standard-of-care or placebo	MD 34 (−223 to 292)	0.79	88	RCT	Very low
SBP, mm Hg	–	Susantitaphong et al., 2012²³	Long-term (⩾2 months) studies	Any form of alkali therapy vs standard-of-care or placebo	MD 0.5 (−1.3 to 2.3)	0.58	16	RCT	Very low
Diastolic BP, mm Hg	–	Susantitaphong et al., 2012²³	Long-term (⩾2 months) studies	Any form of alkali therapy vs standard-of-care or placebo	MD 2.8 (−0.1 to 5.7)	0.06	64	RCT	Very low
Weight change, kg	–	Susantitaphong et al., 2012²³	Long-term (⩾2 months) studies	Any form of alkali therapy vs standard-of-care or placebo	MD −0.4 (−0.9 to 0.1)	0.15	0	RCT	Very low

GFR: glomerular filtration rate; eGFR: estimated glomerular filtration rate; PTH: parathyroid hormone; BP, blood pressure; BUN: blood urea nitrogen; ACR: albumin-to-creatinine ratio; SBP: systolic blood pressure; BMI: body mass index; ESKD: end stage kidney disease; CV: cardiovascular; CKD: chronic kidney disease; MA: metabolic acidosis; MD: mean difference; SMD: standardized mean difference; RR: risk ratio; OR: odds ratio; NA: not applicable; NR: not reported; RCT: randomized control trial; GRADE score: Grading of Recommendations Assessment, Development and Evaluation score; RRT: renal replacement therapy; BW: body weight; HGS: handgrip strength; LBM: lean body mass; MAMC: mid-arm muscle circumference; NPNA: normalized protein nitrogen appearance; PCR: protein catabolic rate; SGA: subjective global assessment; STS: sit-to-stand time.

NA, as those studies had less than two primary studies included in their analysis, so no association could be made.

The authors divided the studies into two groups: 13 studies plus Raphael et al. with high-dose IV bicarbonate and 13 studies plus Raphael et al. with low-dose IV bicarbonate, since Raphael et al. compared high and low doses versus a control group.

Certainty of evidence

As previously mentioned, 41 of the 169 associations analyzed in this review were based on a single study or none. The GRADE framework assessment (Table S4) of the remaining 128 associations found that only 8 (6.2%) were supported by high-quality evidence. These included a reduced use of β-blockers (intervention vs control, RR = 0.39, 95% CI: 0.18–0.84) and a reduced use of vasodilators (intervention vs control, RR = 0.64, 95% CI: 0.45–0.92); no change in mean systolic blood pressure in 14 primary studies after medium-term (24–28 weeks) sodium bicarbonate use (intervention vs control, MD = −2.25, 95% CI: −6.00 to 1.50); no change in mean systolic blood pressure in 14 primary studies in CKD stage 4 patients (intervention vs control, MD = 1.86, 95% CI: −1.21 to 4.93); a slower decline in GFR (mL/min/1.73 m²; intervention vs control, MD = −4.44, 95% CI: −4.92 to −3.96); a reduction in diastolic blood pressure (intervention vs control, MD = −1.26, 95% CI: −2.33 to −0.19); lower hospitalization rates (intervention vs control, OR = 0.37, 95% CI: 0.25–0.55); and increased serum bicarbonate levels in patients receiving short-term alkali therapy (⩽7 days; intervention vs control, MD = 5.4, 95% CI: 4.0–6.7).

All comparisons were made against placebo, no intervention, or standard therapy. The remaining associations were classified as moderate-quality evidence (n = 23; 17.9%), low-quality evidence (n = 30; 23.4%), and very low-quality evidence (n = 67; 52.3%).

Discussion

Our main results show that less than 10% of the associations evaluated in the included systematic reviews were supported by high certainty of evidence according to our independent GRADE assessment. These include that bicarbonate use is not associated with changes in mean systolic blood pressure, that its use is associated with a reduction in diastolic blood pressure compared to the control group, and that the control group has greater use of β-blockers and vasodilators than patients using bicarbonate. Likewise, there is high-quality evidence regarding the association of bicarbonate use with a slower decline in GFR, higher serum bicarbonate levels, and lower hospitalization rates.

Metabolic acidosis develops as CKD progresses due to a decreased acid excretory capacity and high daily endogenous and exogenous acid loads, resulting in a positive H+ balance.²⁶ As nephron mass decreases in CKD patients, the single-nephron GFR increases, which, in turn, increases acid excretion, especially ammoniagenesis.²⁷ However, net renal acid excretion decreases because the remaining nephrons do not excrete the acid load sufficiently.^26,27 Furthermore, there is a decreased renal capacity to produce ammonia to neutralize the daily acid load, resulting in a normal anion gap metabolic acidosis characteristic of patients with moderate CKD.²⁸ Despite this, titratable acid excretion is relatively preserved, in contrast to the reduced renal ammonia production, until the GFR falls below 15 mL/min/1.73 m² (G5).²⁸ When titratable acid excretion decreases, a high anion gap metabolic acidosis occurs secondary to the accumulation of phosphate and other anions.²⁸ Additionally, as CKD progresses, proximal tubule bicarbonate reabsorption also decreases, which is associated with an increase in the bicarbonate load per nephron that exceeds its reabsorption capacity.²⁹

The first data on the beneficial effects of alkalizing therapy on CKD progression were published in 1931.³⁰ Currently, sodium bicarbonate is the main pharmacological treatment for metabolic acidosis in patients with CKD, with a value below 22 mmol/L established as the diagnostic threshold, after some observational studies showed that plasma or venous blood concentrations below 21–23 mmol/L are characterized by greater CKD progression and higher mortality.³¹ However, despite numerous clinical trials testing its efficacy and systematic reviews attempting to synthesize their evidence, only 8 of the 169 associations evaluated in the systematic reviews that met the pre-established selection criteria were supported by high-quality evidence, including aspects related to blood pressure, CKD progression, and safety.

The effects of sodium bicarbonate use on blood pressure were supported by conflicting evidence; however, there was a theoretical risk that its use could increase blood pressure. The KDIGO 2024 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease recommends monitoring its use due to the possibility that it may negatively affect blood pressure control.¹ This theoretical risk is related to the fact that sodium loading increases fluid retention; however, the evidence calls this claim into question. In a study that aimed to profile the fluid retention characteristics of sodium bicarbonate and sodium citrate to determine the efficacy of these buffer media as hyperhydrating agents, it was found that although plasma volume expansion was greater in both bicarbonate and citrate users compared to the control group using water alone, no increase in body mass was observed.³² Additionally, in animal models of hypertension, blood pressure was observed to increase only if sodium was coadministered with chloride, but not with other anions (including bicarbonate), suggesting that the effects of sodium on blood pressure only occur when chloride is the coadministered anion.² Indeed, human studies suggest that in patients with and without CKD, ingested sodium in the form of bicarbonate is completely excreted in the urine, while sodium in the form of chloride is retained, which potentiates its effect on systolic blood pressure.^33,34

Another result with high-quality evidence is that the use of beta-blockers and vasodilators is higher in the control group compared to patients who use bicarbonate. However, it is necessary to highlight the uncertainty in the medication findings due to the difficulty in comparing dose changes of antihypertensive medication and diuretics within and between the clinical trials included in the systematic review that found this association. This also diminishes the quality of the evidence that sodium bicarbonate treatment is not associated with an increase in the use of antihypertensives or diuretics²⁴ (Table 2). This is relevant because increased antihypertensive treatment was the argument used to explain the dramatic decrease in diastolic blood pressure in the systematic review that supports the high quality of evidence for this association.¹⁸

Regarding the high-quality evidence that bicarbonate use is associated with a slowing of the decline in GFR, this may be related to the fact that correcting metabolic acidosis reverses its effects on CKD progression.³¹ Indeed, metabolic acidosis contributes to the development of the inflammatory process in CKD patients and the vicious cycle initiated by acid retention leads to a cascade of events that contribute to the progression of CKD.³ Metabolic acidosis triggers increased ammoniagenesis in the remaining nephrons, the production of endothelin-1, and the activation of the renin–angiotensin system, which subsequently promotes complement activation by ammonium as well as the generation of proinflammatory and profibrotic mediators.³ As a result, interstitial fibrosis, tubular atrophy, and loss of podocyte integrity occur, culminating in the loss of functional nephrons.³ Despite this, the effect of sodium bicarbonate on renal fibrosis is not fully understood. In a study of diabetic patients, sodium bicarbonate use did not significantly reduce TGF-β1, KIM-1, fibronectin, NGAL, or urinary albuminuria during 6 months of treatment.³⁵

The CRIC observational study found that elevated serum bicarbonate levels above 24 mmol/L are associated with an increased risk of congestive heart failure; specifically, for every 1 mmol/L increase above this threshold, the risk increases by 14%.³⁶ Following this association, several studies evaluating bicarbonate use have considered hospitalizations as a surrogate measure of safety. Our findings show high-quality evidence that bicarbonate treatment successfully increases serum bicarbonate levels in patients who receive it. We also found high-quality evidence suggesting that bicarbonate use is associated with a lower rate of hospitalizations. However, it is important to note that this conclusion comes from a systematic review²² that, after excluding one study with a high risk of bias but with considerable statistical weight,³⁷ did not find a significant reduction in hospitalizations. This finding is consistent with evidence indicating that adverse effects related to fluid retention, such as weight gain, occur primarily when sodium is administered as chloride,^33,34 and not necessarily when it is administered as bicarbonate.

The present study is the first umbrella review to synthesize the published evidence on correcting metabolic acidosis in patients with CKD. The high certainty of evidence observed for some outcomes has important clinical implications. First, bicarbonate therapy effectively increases serum bicarbonate levels, supporting its use in treating metabolic acidosis. Second, it may slow CKD progression, although the exact mechanisms remain unclear. Third, no significant variations in blood pressure were observed, though monitoring systolic blood pressure is advisable due to potential unverified changes in concomitant medications. These results may guide physicians in using bicarbonate therapy to correct metabolic acidosis and mitigate CKD progression with relative safety.

Our findings should be interpreted in light of several limitations. The clinical and methodological heterogeneity of the primary studies included may have influenced the results. For example, trials enrolled patients with CKD at different stages, varying prevalence of metabolic acidosis, and baseline bicarbonate levels above 22 mmol/L. Variability in follow-up duration, intervention doses, and study designs—such as open-label, single-center trials with small sample sizes—may have affected the observed effects on key outcomes.

Despite these limitations, our GRADE evaluation indicated high-certainty evidence for several outcomes, even though most systematic reviews were rated as low or critically low in methodological quality according to AMSTAR 2. This apparent discrepancy reflects the different focus of these tools: AMSTAR 2 evaluates the methodological rigor of systematic reviews, whereas GRADE assesses the certainty of the underlying evidence. Nevertheless, the low AMSTAR 2 ratings caution against overinterpreting the comprehensiveness and reproducibility of the included reviews.

Conclusion

In conclusion, less than 10% of the associations analyzed in the included systematic reviews were supported by high certainty of evidence, particularly those related to the effects of sodium bicarbonate on the treatment of metabolic acidosis, blood pressure, CKD progression, and safety outcomes. However, our review highlights the need for new, well-designed clinical trials to address the methodological limitations observed in the existing studies. Future research should include patients with CKD stages in which metabolic acidosis is clinically relevant, enroll individuals with bicarbonate levels for which bicarbonate therapy is recommended, and recruit sufficiently large samples to yield robust and generalizable results, among other key aspects.

Supplemental Material

sj-docx-1-taj-10.1177_27558428251411463 – Supplemental material for Effects of correcting metabolic acidosis in chronic kidney disease patients: An umbrella review

Supplemental material, sj-docx-1-taj-10.1177_27558428251411463 for Effects of correcting metabolic acidosis in chronic kidney disease patients: An umbrella review by Percy Herrera-Añazco, Miguel A. Huayta-Cortez, Juan R. Ulloque-Badaracco, Christian N. Rojas, Nella Altamirano-Cabezas and Vicente A. Benites-Zapata in Therapeutic Advances in Chronic Disease

Footnotes

Acknowledgements

None to report.

ORCID iDs

Miguel A. Huayta-Cortez

Juan R. Ulloque-Badaracco

Christian N. Rojas

Nella Altamirano-Cabezas

Vicente A. Benites-Zapata

Author contributions

Miguel A. Huayta-Cortez: Conceptualization; Data curation; Investigation; Methodology; Project administration; Supervision; Validation; Writing—original draft; Writing—review & editing.

Percy Herrera-Añazco: Investigation; Writing—original draft.

Juan R. Ulloque-Badaracco: Investigation; Supervision; Writing—original draft.

Christian N. Rojas: Data curation; Investigation; Writing—original draft.

Nella Altamirano-Cabezas: Data curation; Investigation; Writing—original draft.

Vicente A. Benites-Zapata: Conceptualization; Investigation; Methodology; Project administration; Validation; Writing—original draft; Writing—review & editing.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Data availability statement

All data generated or used during our research are included in this published article and its Supporting Information Files.

Supplemental material

Supplemental material for this article is available online.

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