Carbonic anhydrase II (CA-II) knockout mice (Car2)have depleted numbers of renal intercalated cells which are increasingly recognized to be innate immune effectors. We compared pyelonephritis susceptibility following reciprocal renal transplantations between Car2and wild type mice. We examined the effect of pharmacological CA suppression using acetazolamide in an experimental murine UTI model. Car2 vs wild type mice were compared for differences in renal innate immunity. In our transplant scheme, mice only lacking CA-II in the kidney had increased pyelonephritis risk. Mice treated with acetazolamide had lower kidney bacterial burdens at 6-hours post-infection which appeared to be due to tubular flow from diuresis because comparable results were obtained when furosemide was substituted for acetazolamide. Isolated Car2kidney cells enriched for intercalated cells demonstrate altered intercalated cell innate immune gene expression, notably increased Calgizzarin and Insulin receptor expression. Intercalated cell number and function along with renal tubular flow are determinants of pyelonephritis risk.