As illustrated in Figure 1, we identified 1534 records (613 from the Medline, 521 from the Web of Science, and 400 from the Scopus) through literature searches. After removing duplicate reports, 1217 studies were screened against inclusion and exclusion criteria. Subsequently, 1167 reports were excluded because they were animal studies (n=139), editorial letter (n=8), review/systematic review studies (n=23), or not relevant (n=997). Fifty remaining studies were scrutinized in detail, and 37 articles were excluded because of: 1) using intravenous sodium bicarbonate, 2) co-supplementation of sodium bicarbonate with vitamin C, 3) using vegetables and fruits as an intervention in control group, 4) not reporting relevant data, or 5) enrolling subjects with acute kidney injury. Finally, 13 studies met all inclusion and exclusion criteria were included in this systematic review and meta-analysis (3, 4, 11-21)
Characteristics of the included studies are presented in Table 1. Participants were from Hong Kong, Israel, Thailand, Chinese, Brazil, Italy, South Korea, England, Thailand, and the USA. All studies enrolled both genders. Participants in all studies were pre-dialysis patients, except for two studies that recruited peritoneal dialysis patients (1, 7). The mean age ranged from 54 to 72 years old. The design of three studies was pre-post (3, 5, 6) and the remaining studies were parallel randomized clinical trials. Five studies administered an increasing dose of sodium bicarbonate (3,4,8,12,13) and the remaining trials used a fixed dose.
Table 1: Characteristics and details of included studies
First author
(publication year)
|
Country
|
Sample
size
(male/female)
|
Participants
|
Age (y)
|
Reported data
|
Design
|
Duration
(week)
|
Dose of intervention
|
Comparison
|
Results
|
score
|
Szeto (2003)
|
Hong Kong
|
60
(35/25)
|
PD
|
55
|
GFR
|
Parallel
|
52 weeks
|
0.9 g thrice daily
|
Placebo
|
No significant effect
|
High
|
Ori (2015)
|
Israel
|
13
(12/1)
|
Pre-dialysis
|
65
|
Serum Creatinine,
GFR
Urea
|
Before after
|
4 weeks
|
1 to 3 gr
|
-------------
|
No significant effect
|
Low
|
de Brito-Ashurst (2009)
|
England
|
134
(68/66)
|
Pre-dialysis
|
54
|
Creatinine clearance
|
Parallel
|
52 weeks
|
1.82 g+-0.8
|
Standard care
|
Significant reduction in loss of creatinine clearance
|
High
|
Disthabanchong (2010)
|
Thailand
|
41
(21/20)
|
Pre-dialysis
|
70
|
GFR
Serum Creatinine
|
Before after
|
10 weeks
|
increasing dose
|
--------
|
Significant reduction in serum creatinine and increase in GFR
|
High
|
Liu (2017)
|
Chinese
|
40
)20/20(
|
PD
|
56
|
Creatinine clearance
|
Parallel
|
104weeks
|
1.0 g/day
|
Placebo
|
No significant effect
|
High
|
Rizzetto (2017)
|
Brazil
|
31
(21/10)
|
Pre-dialysis
|
59
|
Serum Creatinine
Bun
Creatinine clearance
|
Before After
|
60 weeks
|
1.0 mmol/kg
|
-------------
|
Significant reduction in BUN
|
Low
|
Di Iorio (2019)
|
Italy
|
740
(458/282)
|
Pre-dialysis
|
68
|
Creatinine clearance
|
Parallel
|
154 weeks
|
Increasing dose
|
Standard care
|
Significant reduction in loss of creatinine clearance
|
High
|
Jeong (2014)
|
South Korea
|
80
(47/33)
|
Pre-dialysis
|
55
|
GFR,
Serum Creatinine
BUN
|
Parallel
|
52 weeks
|
Increasing dose
|
Standard care
|
Significant increase in GFR
|
High
|
The BiCARB study group
(2020)
|
England
|
300
(214/86)
|
Pre-dialysis
|
70
|
GFR
Serum Creatinine
|
Parallel
|
104 weeks
|
Increasing dose
|
Placebo
|
No significant effect
|
High
|
Kittiskulnam (2020)
|
Thailand
|
42
(24/18)
|
Pre-dialysis
|
61
|
Serum Creatinine
GFR
|
Parallel
|
17 weeks
|
Increasing dose
|
Standard care
|
Significant reduction in loss of in GFR
|
High
|
Melamed (2020)
|
US
|
224
(102/122)
|
Pre-dialysis
|
61
|
GFR
|
Parallel
|
104 weeks
|
0.4 mEq/kg
|
Placebo
|
No significant effect
|
High
|
Raphael (2020)
|
US
|
74
(72/2)
|
Pre-dialysis
|
72
|
Bun
Creatinine clearance
GFR
|
Parallel
|
26 weeks
|
0.5 meq/kg
|
Placebo
|
Significant reduction in BUN
|
High
|
Raphael (2020)
|
US
|
194
9131/63)
|
Pre-dialysis
|
67
|
GFR
Creatinine clearance
|
Parallel
|
28 weeks
|
0.8 meq/kg
|
Placebo
|
No significant effect
|
High
|
BUN: Blood urea nitrogen, GFR: Glomerular filtration rate, PD: Peritoneal dialysis
The results of quality scores allocation showed that all studies were high-quality, except for two studies that received low scores (5,6).
Meta-analysis
Four studies reported the effect of sodium bicarbonate on BUN (4-6, 9). In comparison with control treatment, BUN was significantly decreased (WMD: - 8.63 mg/dL; 95% CI: -11.08, -6.19) after sodium bicarbonate administration (Figure 2). No significant heterogeneity was observed between studies (I2=0.0%, p=0.447).
The effect of sodium bicarbonate administration of serum creatinine was reported in six studies (3-6, 12, 13). We observed a significant reduction in serum creatinine (WMD: -0.19 mg/dL; 95% CI: -0.36, -0.02) after sodium bicarbonate supplementation compared with control treatment (Figure 3). There was no significant heterogeneity between studies (I2= 10.0%, p = 0.353).
As illustrated in Figure 4, five clinical trials (2, 6-9) reported that sodium bicarbonate had a beneficial effect on creatinine clearance compared with control treatment (WMD: 4.82 mL/min; 95% CI: 2.68, 6.96(. We do not find any significant heterogeneity between studies (I2=50.5%, P=0.089).
The forest plot from nine trials (1,3,4,5,9,10,11,12,13) of GFR response to sodium bicarbonate supplementation is shown in Figure 5. GFR was significantly increased following sodium bicarbonate administration in comparison with control treatment (WMD: 0.75 ml/min/1.73 m2; 95% CI: 0.14, 1.35). There was no significant heterogeneity between studies (I2=14.6%, P=0.308).
We did not find any evidence of publication bias for BUN (Begg’s P=0.497, Eggers’s P=0.491), serum creatinine (Begg’s P=0.573, Eggers’s P=0.353), creatinine clearance (Begg’s P=0.573, Eggers’s P=0.378), and GFR (Begg’s P=0.297, Eggers’s P=0.524).
The results of the sensitivity analysis showed that, in the case of GFR, results were insignificant when the Jeong et al. study was eliminated (WMD: 0.402 ml/min/1.73 m2; 95% CI: -0.187, 0.991). A similar finding was observed for serum creatinine after omitting the Rizzetto et al. study (WMD: -0.053 mg/dL; 95% CI: -0.297, 0.190). In the case of BUN and creatinine clearance, the omission of any study did not significantly alter the results.