Chronic kidney disease (CKD) is a long-term structural or functional disorder of the kidneys, manifested by elevated serum levels of creatinine, cystatin C, or blood urea nitrogen (Drawz and Rahman, 2015). The estimated prevalence rate for all stages of CKD was 13% (Hill et al., 2016). Most patients with CKD are at risk for accelerated cardiovascular disease and death, with significantly impaired life expectancy and quality of life.

Metabolic acidosis is a common and persistent complication of CKD, which contributes to the continued progression of CKD. It is associated with a decrease in total renal ammonium excretion, titratable acid excretion, and bicarbonate reabsorption as a result of a decline in glomerular filtration rate (GFR) (Kraut and Madias, 2016). Previous studies have shown that chronic disturbances in serum acid excretion with increased serum bicarbonate are related to increased risk for renal disease progression, heart failure, and all-cause mortality (Shah et al., 2009; Menon et al., 2010; Raphael et al., 2011; Dobre et al., 2013).

Traditional treatments of metabolic acidosis mainly involve oral alkali supplementation. However, previous evidence demonstrated that oral alkali supplementation might result in edema, atherosclerosis progression (Lomashvili et al., 2006). In addition, the management of dietary interventions was proved difficult to fulfill, resulting in suboptimal treatment outcomes.

Veverimer (TRC101) is a novel oral and nonabsorbable hydrochloric acid adhesive. It is not an ion exchanger and does not introduce sodium ions. The structure and nature of veverimer dictate that it is protonated upon ingestion and selectively binds to anions, resulting in a reduction and removal of hydrochloric acid from the gastrointestinal tract (Wesson et al., 2019b; Adrogué and Madias, 2020). Data obtained from clinical trials (Bushinsky et al., 2018; Wesson et al., 2019a; Wesson et al., 2019b) have revealed that veverimer was effective against acidosis related to CKD, thereby improving patients’ bicarbonate level. The endogenous increase in serum bicarbonate without sodium retention is a unique feature of veverimer. However, some researchers have found that the mechanism of veverimer parallels the persistent vomiting to remove gastric acid. The difference is that add bicarbonate level of persistent vomiting is accompanied by the loss of endogenous fluid and ions; whereas the increased endogenous bicarbonate with veverimer does not lose fluid, sodium and potassium, etc. (Adrogué and Madias, 2020). No systematic approach has been conducted to evaluate the safety and efficacy of veverimer for the treatment of metabolic acidosis associated with CKD. Therefore, we conducted a meta-analysis to analyze the efficacy and safety veverimer.

Our study pooled 548 individuals with acidosis associated with CKD from three high quality RCTs. The analysis demonstrated that veverimer use was effective against acidosis in patients with CKD, with a mean increase in serum bicarbonate level of by an average of 3.08 mmol/L compared with placebo, and was related to improved physical function. Besides, the pooled results indicated that veverimer use was not associated with an increased risk of developing adverse events. Heterogeneity analysis of all the included outcomes was low, indicating a high level of clinical evidence. The observed outcomes strongly support the use of veverimer is beneficial for the treatment of acidosis related to CKD.

Patients with acidosis usually have no obvious clinical symptoms and are aware of their acid-base disorder through a chemistry panel. In the chronic renal insufficiency cohort study, it was shown that patients with less than 22 mmol/L had an almost 2-fold increased risk of CKD progression (Dobre et al., 2015). Notably, it is well known that eGFR is a critical diagnostic criterion for the diagnosis of CKD (Goldenstein et al., 2014). Extensive research has provided clinical evidence that patients with CKD with impaired GFR are likely to develop metabolic acidosis. Moreover, studies have revealed that an increase in bicarbonate concentration to the normal range can delay renal replacement therapy in patients with CKD and slow down the decline in the eGFR (Di Iorio et al., 2019).

Since metabolic acidosis can lead to low function of multiple organs in the body, we need to focus on the treatment of acidosis. The National Kidney Foundation guidelines recommend maintaining the value of serum bicarbonate concentration to ≥22 mmol/L (Bailie and Massry, 2005). First-line therapy of metabolic acidosis includes reducing acidic foods intakes or using alkalization treatments that maintain total serum carbon dioxide (Susantitaphong et al., 2012). In available data from 20 patients with metabolic acidosis, Matthew K. et al. found that for every 0.1 mmol/kg increase in the daily dose of oral sodium bicarbonate treatment during two week periods, serum bicarbonate increased by 0.33 mmol/L (Abramowitz et al., 2013). Besides, Lambers et al. showed the dietary intervention also reduced the renal acid load of the patients to varying degrees (Lambers Heerspink et al., 2012). However, studies revealed that sodium bicarbonate therapy had been found to introduce additional sodium into the body, which may increase the potential risk of sodium-sensitive comorbidities such as edema and hypertension, making it necessary for patients to take diuretics and antihypertensives to mitigate the inevitable complications. Furthermore, previous studies revealed an undesirable effect of alkalinization therapy on cardiovascular events (Kendrick et al., 2018; Raphael, 2019; Klaerner et al., 2020). Moreover, alkalization treatments may reduce the effect of nephroprotective agents, indicating that traditional treatments may aggravate the deterioration of renal function (Lambers Heerspink et al., 2012; Chen and Abramowitz, 2019; Navaneethan et al., 2019).

Veverimer, as a hydrochloric acid adhesive, can effectively combine with and remove hydrochloric acid from the gastrointestinal tract, thereby increasing the concentration of bicarbonate without causing hypervolemia and fluid loss. Therefore, chloride removal by veverimer may be more suitable for CKD patients with various organic diseases. KDQoL-PFD is a widely used questionnaire based on the quality of daily life and the physical function of patients with kidney disease. It was demonstrated that both alkalization therapy and veverimer could improve KDQoL-PFD (Abramowitz et al., 2013; Witham et al., 2015). According to the report, the clinical difference of KDQoL subscales is at least 3–5 points before and after treatment (Samsa et al., 1999; Clement et al., 2009; Collister et al., 2016). In our pooled analysis, the average change in the veverimer group was 6.4 points, and that in the placebo group was only 1.1 points, with a significant intergroup difference of 5.25 (95% CI [1.58, 8.92], p < 0.01).

Nevertheless, the treatment group improved by 1.8 s on average in the repeated chair stand test, which was also used to assess physical function. This test score was similar to the minimum clinical difference value, indicating that veverimer cannot significantly extend the time of repeating chair stand test (WMD 0.84, 95% CI [−0.73, 2.40], p = 0.29). Based on the current clinical score, we speculate that this finding may be related to the sample size and the fact that the repeated chair stand test was in only two trials, thereby limiting the judgment regarding the effect of veverimer treatment on physical function. Notably, because of the lack of trials comparing alkalization and veverimer interventions, further clinical trials are needed to evaluate the clinical advantage of veverimer over traditional treatments.

We also further analyzed safety outcomes. Most often, primary attention is given to the diagnosis and treatment of diseases in clinical practice, but the possibility of adverse events is neglected, resulting in complications and severe harm to patients. Diarrhea, headache, flatulence, and hyperkalemia are common clinical adverse reactions and therefore were considered the safety endpoints of our assessment as well. Some studies have revealed that veverimer may cause severe gastrointestinal reactions, especially diarrhea (Klaerner et al., 2020). In our study, the veverimer treatment group did not exhibit any significant adverse reactions compared with the control group.

This is the first meta-analysis study regarding veverimer treatment in patients with CKD and metabolic acidosis to the best of our knowledge. The heterogeneity yielded low for all the included outcomes, indicating a high level of clinical evidence. Nonetheless, it still had shortcomings. First, there was a difference in traits (such as appearance) between the veverimer and placebo groups, and the site staff members could not fully implement the double-blind method. Second, the baseline bicarbonate level and eGFR in the veverimer group were slightly higher than those in the placebo group (Chen and Abramowitz, 2019). However, as a risk element for metabolic acidosis, the eGFR may make it easier for patients in the veverimer group with a slightly higher baseline to achieve the outcome of the evaluation, thereby increasing the heterogeneity of the study. Finally, the trial period of this study was relatively short, and the completed long-term clinical trial was only extended to 52 weeks. Therefore, further studies that could improve on the current data are warranted to evaluate the efficacy and safety of veverimer.

The available clinical evidence indicates that veverimer treatment can be effective and safe in patients with CKD and may correct metabolic acidosis. Nonetheless, multicenter RCTs and large-scale trials are still needed to support this clinical evidence.