Individuals who use proton pump inhibitors (PPIs) regularly may be at risk for decreased urinary citrate excretion, which is a known risk factor for kidney stone formation, investigators reported at Kidney Week 2020 Reimagined, a virtual meeting of the American Society of Nephrology.

Parth M. Patel, MD, and colleagues from the Loyola University Health System in Maywood, Illinois, examined 24-hour urinary collection results from 88 patients with nephrolithiasis taking PPIs and 213 not taking the drugs. Patients taking PPIs were significantly older (age 56 vs 51 years; P <.01) and significantly more likely to have conditions associated with metabolic syndrome, such as hypertension (57% vs 41%; P =.01), diabetes (37% vs 17%; P <.01), and dyslipidemia (51% vs 35%; P =.01).

In a multivariable model, normotension, diabetes, high body mass index, and good renal function independently associated with higher urinary citrate. Dr Patel’s team found, however, that stone-forming patients taking PPIs had a significant 12% reduction in urinary citrate excretion (P =.04) even after adjustment. Despite previous research linking low serum magnesium to kidney stone formation, urinary magnesium excretion was not significantly lower among PPI users. The investigators observed no other differences in urinary composition between the groups.

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Citrate is a strong tricarboxylic acid with pKa values of 2.9, 4.8, and 5.6, the investigators explained. Patients requiring PPIs tend to have poor diets, avoiding healthy foods such as high-citrate fruits. The alkalinization of the intestinal lumen induced by PPIs might decrease the amount of the divalent form of citrate and its intestinal absorption, and thereby decrease alkaline load and urinary citrate excretion.

“The reduction in urinary citrate levels may be the mechanism behind the higher incidence of kidney stones in patients taking PPIs, though further studies are needed to definitively prove this,” Dr Patel said. “It may have clinical significance, particularly in patients with idiopathic hypocalciuria or other conditions associated with hypocitraturia such as genetic polymorphisms of the renal sodium-citrate transporter, chronic metabolic acidosis, use of carbonic anhydrase inhibitors, high animal protein diet intake, and incomplete distal renal tubular acidosis.”


Patel PM, Kandabarow A, Aiwerioghene E, et al. Proton-pump inhibitors are associated with decreased urinary citrate excretion. Presented at: Kidney Week 2020 Reimagined; October 19-25, 2020. Poster PO0410.