Recent Evidence on the Effect of Treatment of Metabolic Acid on the Progression of Kidney Disease

Sebastian Hultin; David W. Johnson; Sunil V. Badve


Curr Opin Nephrol Hypertens. 2021;30(5):467-473. 

In This Article

Abstract and Introduction


Purpose of Review: Preclinical and epidemiological studies have shown an association between acidosis and progression of chronic kidney disease (CKD) and kidney fibrosis. This review discusses the recent trials evaluating the effect of treatment of metabolic acidosis on kidney outcomes.

Recent Findings: The emerging evidence suggests that bicarbonate treatment may slow the progression of CKD and reduce the risk of kidney failure. However, high-certainty evidence on the efficacy and safety of alkali therapy is still lacking. Ongoing studies are evaluating the effect of veverimer, a novel nonabsorbable polymer, on clinical kidney outcomes.

Summary: Recent studies indicate a potential benefit from reduction in acid load in patients with CKD. Whilst it is reasonable that clinicians institute acid-lowering interventions in CKD patients with acidosis, adequately powered trials are required to evaluate the benefit of correction of metabolic acidosis to delay kidney disease progression.


As kidney function declines, the kidney's ability to excrete hydrogen ions, regenerate bicarbonate and excrete ammonia is impaired resulting in accumulation of dietary and metabolism-related nonvolatile acids, leading to acidosis.[1] Despite initial compensatory mechanisms with angiotensin-II and aldosterone-mediated upregulation of proton transport in the kidney and increase in ammoniagenesis,[2,3] biochemical derangement on routine serum monitoring can be observed as early as stage 3 chronic kidney disease (CKD).[4] Although the exact mechanism of acidosis-related CKD progression is not fully elucidated, multiple studies link the compensatory upregulation of angiotensin-II and aldosterone to interstitial fibrosis and tubular atrophy, inflammation and proteinuria.[5–7] Increased compensatory ammoniagenesis in residual nephrons may also lead to complement activation, inflammation and progressive tubular injury and TGF-beta-mediated fibrogenesis.[8–10] Even prior to detectable abnormal serum bicarbonate, patients with mild CKD demonstrate increased urinary endothelin-1 and aldosterone, both of which have been demonstrated to mediate CKD progression in animal models.[11]

There is a demonstrable association between metabolic acidosis and CKD progression, with notably the Chronic Renal Insufficiency Cohort (CRIC) Study showing a 3% lower risk of kidney failure or more than 50% reduction in estimated glomerular filtration rate (eGFR) for each 1 mmol/l increase in serum bicarbonate concentration in patients with CKD stages 2–4.[12] Similarly, in the Modification of Diet in Renal Disease (MDRD) Study, the lowest serum bicarbonate quartile was associated with increased risks of progression to kidney failure hazard ratio of 2.22 [95% confidence interval (CI) 1.83--2.68].[13]

Due to the physiological and metabolic abnormalities associated with acidosis, the Kidney Disease: Improving Global Outcomes (KDIGO) 2012 Clinical Practice Guidelines for the Evaluation and Management of CKD recommend bicarbonate supplementation to CKD patients with acidosis to normalize serum bicarbonate, unless contraindicated.[14] This recommendation is based on level 2B evidence. Systematic reviews and metanalyses have consistently reported lack of conclusive evidence and suggested that further randomized controlled trials (RCTs) were needed in all stages of CKD.[15,16] In this review, we will discuss recent randomized controlled trials (RCT) of bicarbonate supplementation with at least 24 months follow-up duration reporting kidney outcomes (Table 1).[17–22] We will also briefly discuss recent trials evaluating veverimer[23,24] and selected dietary interventions.[20,25–27]