Kidney injury in chronic kidney disease (CKD) is likely multifactorial, but recent data support that a component is mediated by mechanisms used by the kidney to increase acidification in response to an acid challenge to systemic acid-base status. If so, systemic alkalization might attenuate this acid-induced component of kidney injury. An acid challenge to systemic acid-base status increases nephron acidification through increased production of endothelin, aldosterone, and angiotensin II, each of which can contribute to kidney inflammation and fibrosis that characterizes CKD. Systemic alkalization that ameliorates an acid challenge might attenuate the contributions of angiotensin II, endothelin, and aldosterone to kidney injury. Some small clinical studies support the efficacy of alkalization in attenuating kidney injury and slowing glomerular filtration rate decline in CKD. This review focuses on the potential that orally administered NaHCO₃ prevents CKD progression and additionally addresses its mechanism of action, side effects, possible complications, dosage, interaction, galenic form description, and contraindications. Current National Kidney Foundation guidelines recommend oral alkali, including NaHCO₃(-), in CKD patients with serum HCO₃(-) <22 mmol/l. Although oral alkali can be provided by other medications and by base-inducing dietary constituents, oral NaHCO₃ will be the focus of this review because of its relative safety and apparent efficacy, and its comparatively low cost.

Studies aimed at evaluating the effect of reduction in net endogenous acid production (NEAP) have been 2-fold; either directly reducing NEAP by administration of sodium bicarbonate or by dietary alteration using fruits and vegetables, which both decrease NEAP and alter the composition and quantity of dietary protein, partially confounding the effect of reduction of NEAP alone.
In adults with CKD, 4 RCTs, 1 NRCT, 2 noncontrolled studies, 2 prospective cohort studies, and 1 retrospective cohort study examined the effects of dietary fruit and vegetable or oral bicarbonate supplements on CKD progression. In patients with CKD stages 2-4 (20-65 mL/min/1.73 m2 in available studies), higher quartiles of NEAP were associated with greater I125iothalamate GFR decline (_P_ -trend = 0.02). In CKD stages 3-5 not receiving dialysis (≤60 mL/min/1.73 m2), higher NEAP is associated with CKD progression (_P_ < 0.05 for all quartile groups). In CKD stages 3-4 (≥15 or <60 mL/min/1.73 m2) compared with the lowest dietary acid load tertile, the highest dietary acid load had greater relative hazard of ESKD (_P_ = 0.05).
Studies reducing NEAP by the administration of oral sodium bicarbonate are not confounded by alteration in dietary protein composition and are easier to study in a randomized controlled prospective manner. In studies involving patients with CKD stages 4-5, the oral sodium bicarbonate group had significantly greater creatinine clearance after 18 and 24 months (_P_ < 0.05).

Sodium bicarbonate (NaHCO) has been recognized as a possible therapy to target chronic kidney disease (CKD) progression. Several small clinical trials have demonstrated that supplementation with NaHCO or other alkalizing agents slows renal functional decline in patients with CKD. While the benefits of NaHCO treatment have been thought to result from restoring pH homeostasis, a number of studies have now indicated that NaHCO or other alkalis may provide benefit regardless of the presence of metabolic acidosis. These data have raised questions as to how NaHCO protects the kidneys. To date, the physiological mechanism(s) that mediates the reported protective effect of NaHCO in CKD remain unclear. In this review, we first examine the evidence from clinical trials in support of a beneficial effect of NaHCO and other alkali in slowing kidney disease progression and their relationship to acid-base status. Then, we discuss the physiological pathways that have been proposed to underlie these renoprotective effects and highlight strengths and weaknesses in the data supporting each pathway. Finally, we discuss how answering key questions regarding the physiological mechanism(s) mediating the beneficial actions of NaHCO therapy in CKD is likely to be important in the design of future clinical trials. We conclude that basic research in animal models is likely to be critical in identifying the physiological mechanisms underlying the benefits of NaHCO treatment in CKD. Gaining an understanding of these pathways may lead to the improved implementation of NaHCO as a therapy in CKD and perhaps other disease states.

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.