Increased Proton Pump Inhibitors-Induced Mortality Risk In Hemodialysis Patients Reply

de Francisco et al. carried out an interesting study showing an association between the use of proton pump inhibitors (PPIs) by hemodialysis patients and increased risk of all-cause and cardiovascular mortality.1de Francisco A.L.M. Varas J. Ramos R. et al.Proton pump inhibitor usage and the risk of mortality in hemodialysis patients.Kidney Int Rep. 2018; 3: 374-384Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar In addition to mechanisms that may explain the relationship between the use of PPIs and the increased risk of cardiovascular mortality discussed in their article, there is now compelling evidence for an additional mechanism that should be taken into account. The chronic use of PPIs may impair vascular function and increase the risk of adverse cardiovascular events by interfering with the nitrate−nitrite−nitric oxide (NO) pathway, which is accepted as a major alternative source of NO to the classical L-arginine−NO synthase pathway.2Pinheiro L.C. Montenegro M.F. Amaral J.H. et al.Increase in gastric pH reduces hypotensive effect of oral sodium nitrite in rats.Free Radic Biol Med. 2012; 53: 701-709Crossref PubMed Scopus (66) Google Scholar First, this mechanism involves the bioconversion of nitrate to nitrite in the entero-salivary circulation by the action of nitrate reductase enzymes from commensal bacteria in the oral cavity. Once saliva containing nitrite enters the acidic gastric lumen, nitrite is converted by nonenzymatic reduction to NO and other bioactive NO-related species, including S-nitrosothiols, which act as relatively stable NO donors and may promote cardiovascular protection.3Pinheiro L.C. Amaral J.H. Ferreira G.C. et al.Gastric S-nitrosothiol formation drives the antihypertensive effects of oral sodium nitrite and nitrate in a rat model of renovascular hypertension.Free Radic Biol Med. 2015; 87: 252-262Crossref PubMed Scopus (61) Google Scholar Proton pump inhibitors reduce the excess of protons in the gastric juice, which are necessary for the conversion of nitrite to NO, consequently disrupting the nitrate−nitrite−NO pathway. In addition, PPIs promote oxidative stress mediated by increased xanthine oxidase formation of superoxide, thus impairing endothelium-dependent vasodilation.4Pinheiro L.C. Oliveira-Paula G.H. Portella R.L. et al.Omeprazole impairs vascular redox biology and causes xanthine oxidoreductase-mediated endothelial dysfunction.Redox Biol. 2016; 9: 134-143Crossref PubMed Scopus (31) Google Scholar These results reported by de Francisco et al. may critically involve mechanisms associated with impaired nitrate–nitrite–NO pathway in patients taking PPIs, which add to the mechanisms mentioned in their article. All the authors declared no competing interests. Proton Pump Inhibitor Usage and the Risk of Mortality in Hemodialysis PatientsKidney International ReportsVol. 3Issue 2PreviewLong-term inappropriate proton pump inhibitors use (PPIs) is a matter of concern because of the risks associated with their long-term use in older patients with chronic conditions. The risk of PPI treatment in hemodialysis patients remains unexplored. Full-Text PDF Open AccessThe Authors ReplyKidney International ReportsVol. 4Issue 3PreviewWe thank Jonas T. Sertorio and Jose E. Tanus-Santos for their interest in our study “Proton Pump Inhibitor Usage and the Risk of Mortality in Hemodialysis Patients.”1 Full-Text PDF Open Access