Novel therapeutic targets for renal protection are imperative due to the escalating prevalence of end-stage kidney disease despite existing treatments for chronic kidney disease (CKD). We explored the reno-protective effects of D-serine and D-alanine, which have previously demonstrated efficacy in acute kidney injury against CKD. Female and male 5/6-nephrectomy mice were used as CKD models, receiving 20 mM D-serine or D-alanine supplementation, and their survival rates, renal function, and transcriptomic changes were examined. The proliferation of human tubular epithelial cells supplemented with D-serine or D-alanine was evaluated in vitro. A prospective cohort study involving 14 patients was conducted to examine the association between increased blood D-serine or D-alanine levels and long-term renal function decline. D-serine or D-alanine supplementation improved survival rates and renal function in female 5/6-nephrectomy mice. D-alanine supplementation was associated with the upregulation of mitochondrial pathway-related genes. Long-term supplementation (500 days) in normal mice did not induce nephrotoxicity, and promoted tubular epithelial cell proliferation. Although a trend toward a slower decline in eGFR was observed in patients with higher D-alanine levels, this association was limited and does not indicate a causal relationship. Further studies involving D-Ala interventions in patients with CKD are needed to confirm these findings.
Nakade et al. (2026) studied this question.