Proton-pump inhibitors up risk of mortality after kidney transplantation

Use of proton-pump inhibitors (PPIs) may increase the risk of mortality in kidney transplant recipients (KTRs), independent of potential confounders, reveals a study.

“Moreover, our data suggest that this risk is highest among KTRs taking high PPI dosages,” the researchers said. “[O]ur results require further corroboration before it can be recommended to avoid the long-term use of PPIs in KTRs.”

Multivariable Cox proportional hazard regression analyses were carried out to examine the association of PPI use with mortality risk in a single-centre prospective cohort of 703 stable outpatient KTRs, who visited the outpatient clinic of the University Medical Center Groningen between November 2008 and March 2011.

The researchers performed independent replication of the results in a prospective cohort of 656 KTRs (mean age, 53±13 years; 57 percent male) from the University Hospitals Leuven. Of the recipients, 56.6 percent used PPIs.

A total of 194 KTRs succumbed to death during a median follow-up of 8.2 (range, 4.7–9.0) years. Univariable Cox regression analyses revealed an almost twofold increased mortality risk (hazard ratio [HR], 1.86, 95 percent confidence interval [CI], 1.38–2.52; p<0.001) with PPI use compared with no use. [PLoS Med 2020;17:e1003140]

This association persisted even after adjustment for potential confounders (HR, 1.68, 95 percent CI, 1.21–2.33; p=0.002). Furthermore, the mortality risk in KTRs taking a high PPI dose (>20 mg omeprazole equivalents/day) compared with those taking no PPIs (HR, 2.14, 95 percent CI, 1.48–3.09; p<0.001) was higher than in KTRs on a low PPI dose (HR, 1.72, 95 percent CI, 1.23–2.39; p=0.001).

These results were replicated in the Leuven Renal Transplant Cohort.

The association between PPI use and mortality could be driven by several physiological mechanisms. In earlier studies, PPIs were shown to influence absorption of micronutrients, leading to deficiencies of important electrolytes, including iron and magnesium. [Am J Kidney Dis 2010;56:168-174; Gastroenterology 2017;152:821-829.e1; Curr Gastroenterol Rep 2010;12:448-457]

“Indeed, we previously found that PPI use was associated with iron deficiency and hypomagnesemia in KTRs,” the researchers said. “Iron deficiency can in turn lead to iron deficiency anaemia, which has been linked to a higher graft failure risk and mortality risk in KTRs.” [J Clin Med 2019;8:1382; J Clin Med 2019;8:2162; Transpl Int 2016;29:1176-1183; J Am Soc Nephrol 2006;17:3240-3247; Clin J Am Soc Nephrol 2008;3:1168-1174]

In addition, PPI use has been shown to increase the risk of cardiovascular mortality in the general population in a previous research, and this was also seen in the current study. [PLoS ONE 2015;10:e0124653]

“Another explanation might be that other adverse effects related to PPI use, such as an increased risk of gastrointestinal infections, community-acquired pneumonia, and acute and chronic kidney disease, collectively carry an increased mortality risk,” the researchers said. [JAMA Intern Med 2016;176:172-174; Am J Gastroenterol 2007;102:2047-2056; PLoS ONE 2015;10:e0128004; JAMA Intern Med 2016;176:238-246; Kidney Int 2017;91:1482-1494]

“Unfortunately, data on gastrointestinal infections and community-acquired pneumonia were unavailable in our study. Therefore, we were unable to investigate this hypothesis,” they added.

The current study was limited by its observational design, which precluded conclusions regarding causation, according to the researchers.