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To discuss whether the recently described relationship between proton pump inhibitor (PPI) use and the risk of adverse kidney outcomes represents a causal relationship or is merely the result of confounding.A wave of observational studies has described an association between PPI use and the risk of development of chronic kidney disease and its progression to end-stage renal disease. The results are generally robust and remarkably consistent across different studies. The application of modern pharmacoepidemiologic methods to estimate the effect of a putative unmeasured or unknown confounder or set of confounders on the relationship of PPI use and risk of adverse renal outcomes suggests that confounding is unlikely to explain away the reported association.The constellation of evidence from all available studies suggests that PPI use is associated with increased risk of adverse kidney outcomes. Exercising vigilance in the use of PPI is warranted.