Abstract Background and Aims Renin-angiotensin-aldosterone system inhibitors (RAASi) are well-established renoprotective agents, but can induce serum potassium (K) elevation and metabolic acidosis (MA). MA contributes to the progression of chronic kidney disease (CKD), thus the renoprotective potential of RAASi is unknown in advanced CKD with MA due to the use of RAASi. MA with elevated serum K may discourage the use of RAASi. In highly advanced CKD, besides factors such as age, proteinuria, and diabetes, it is still debatable under what conditions the continued use of RAASi is favorable for renal prognosis. Furthermore, no studies have focused on the relationship between the response to alkalizing therapy for MA and renal prognosis in advanced CKD with MA and serum K elevation under RAASi use. Method In this single-center retrospective observational study, CKDG4 or G5 outpatients with MA ([HCO3−] < 22 mM) and elevated K (serum [K]≥5.0 mEq/L) at our center and who had started alkalinizing therapy (i.e., sodium bicarbonate and/or low-dose trichlormethiazide plus fludrocortisone) for MA were included. A total of 45 patients were selected, excluding those who had already been prepared for renal replacement therapy at the start of treatment. The RAASi group (Ri group, N = 39) and the non-RAASi group (non-Ri group, N = 16) were divided by the presence or absence of continued RAASi use prior to alkalizing therapy for MA, and the two groups were followed and compared up to 2 years after treatment. Background factors including age, sex, cause of CKD, estimated glomerular filtration rate (eGFR), CKD stage, diabetes, urinary protein (g/gCr), serum [K]/ [HCO3−]/[Na]/[CL]/albumin/phosphate, hemoglobin levels, and the use of K binders, diuretics were investigated. The endpoints were rapid response to alkalizing therapy (i.e., changes in serum [HCO3−], [K], [Na]-[CL] levels 2 months after the start of alkalinizing therapy, and percentage of patients achieving [HCO3−] ≥22 mM at 2 months after the start of alkalizing therapy) and incidence of renal events (>30% reduction in eGFR or renal replacement therapy). Results In all 45 subjects, the mean age was 71.3±11.8 years, 84% were male, mean eGFR was 18.3 ± 5.6 mL/min/1.73 m2, G4 67%/G5 33%, primary disease was diabetic nephropathy 31%, nephrosclerosis 40%, K binders and diuretics use was 25% and 24%, respectively. Mean serum [HCO3−] was 17.9 ± 2.3 mM and mean serum [K] was 5.5 ± 0.4 mEq/L. Comparison of background factors showed no significant difference between the two groups. The changes in serum [K], [HCO3−], [Na]-[CL] 2 months after the start of alkalinizing therapy and the percentage of patients achieving [HCO3−] ≥22 mM after 2 months of starting alkalizing therapy did not differ at all between the Ri and non-Ri groups (Table 1). Cumulative renal survival (non-renal events) was significantly higher in the Ri group than in the non-Ri group(p = 0.010) (Figure 1). None of the rapid responses to alkalizing therapy (i.e., changes in serum[HCO3−], [K], [Na]-[CL], and the percentage of patients achieving [HCO3−] ≥22 mM) were significantly associated with cumulative renal survival (p = 0.186, p = 0.266, p = 0.65, p = 0.114). In a Cox proportional hazards multivariate model adjusted for age, sex, eGFR, cause of CKD, diabetes, urinary protein(g/gCr), method of alkalizing therapy, and rapid response to alkalizing therapy, the risk of renal events without RAASi use was significantly higher (Table 2). Conclusion In CKDG4/5 with MA with elevated serum K under RAASi use, renal function declines more slowly than with non-RAASi use, ensuring a rapid response to alkalizing therapy for MA.