Alkali supplementation as a therapeutic in chronic kidney disease: what mediates protection?

Sodium bicarbonate (NaHCO₃) has been recognized as a possible therapy to target chronic kidney disease (CKD) progression. Several small clinical trials have demonstrated that supplementation with NaHCO₃ or other alkalizing agents slows renal functional decline in patients with CKD. While the benefits of NaHCO₃ treatment have been thought to result from restoring pH homeostasis, a number of studies have now indicated that NaHCO₃ or other alkalis may provide benefit regardless of the presence of metabolic acidosis. These data have raised questions as to how NaHCO₃ protects the kidneys. To date, the physiological mechanism(s) that mediates the reported protective effect of NaHCO₃ in CKD remain unclear. In this review, we first examine the evidence from clinical trials in support of a beneficial effect of NaHCO₃ 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 NaHCO₃ 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 NaHCO₃ treatment in CKD. Gaining an understanding of these pathways may lead to the improved implementation of NaHCO₃ as a therapy in CKD and perhaps other disease states.