June 1, 2016

Proton Pump Inhibitors Associated with Chronic Kidney Disease

Widely prescribed medications for stomach upset are not risk-free
Recent evidence demonstrates a clear association between proton pump inhibitors and kidney disease.


Lazarus B, Chen Y, Wilson F, et al. Proton pump inhibitor use and the risk of chronic kidney disease. JAMA Intern Med. 2016;176(2):238-246.

Study Objective

To assess a potential correlation between proton pump inhibitor (PPI) use and incidence of chronic kidney disease (CKD). 


Observational study tracking glomerular filtration rate (GFR) of PPI users compared to nonusers. 


The study included 10,482 subjects participating in the Atherosclerosis Risk in Communities (ARIC) study. All subjects had a baseline GFR greater than 60 mL/min/1.73 m2. The mean age was 63.0 years; 43.9% were male, and 3,229 (3.1%) were taking PPIs at baseline. Median follow-up was 13.9 years. 
Separately, a replication cohort of 248,751 subjects in the Geisinger Health System in Pennsylvania were followed for a median of 6.2 years. All participants had a normal (>60 mL/min/1.73m2) GFR at recruitment. At baseline, 16,900 (6.8%) were taking PPIs. 

Study parameters assessed

Incidence of CKD was defined by a GFR less than 60 mL/min/1.73 m2 or by diagnostic codes at hospital discharge or death. 

Primary outcome measures

The baseline visits were between February 1, 1996 and January 30, 1999. Patients were tracked until December 31, 2011. For the ARIC cohort, participants who used PPIs at baseline had a 45% higher risk of developing CKD [HR (hazard ratio): 1.45; 95% CI (confidence interval): 1.11-1.90)] than nonusers. When adjusted for demographic, socioeconomic, and clinical variables the risk was similar, with a 50% higher risk of CKD in PPI users compared to nonusers (HR: 1.50; 95% CI: 1.14-1.96). When baseline PPI users were compared to H2 antagonist users, the association persisted; PPI users had a 39% increased risk of developing CKD compared to users of H2 antagonists (HR: 1.39; 95% CI: 1.01-1.91). 
The Geisinger Health System cohort corroborated the ARIC cohort. Use of PPIs was associated with CKD, with a dose-dependent increase in association. Those who took PPIs twice a day (adjusted HR:1.46; 95% CI: 1.28-1.67) had a higher risk of CKD than those who took PPIs once a day (adjusted HR: 1.15; 95% CI: 1.09-1.21). 

Key findings

Proton pump inhibitor use is a risk factor for CKD; in this study, baseline PPI users had a greater incidence of CKD than nonusers. However, PPI users were also more likely to be obese and take antihypertensive medication, indicating other risk factors. When data was analyzed adjusting for hazard ratio, comparing users and nonusers with similar risk for CKD, the association between PPI use and incidence persisted. The risk was also dose-dependent: twice- daily dosing was associated with a higher risk of incident CKD than once-daily dosing. 

Practice implications

The use of proton pump inhibitors was once thought to be relatively harmless, and many patients recall being told that there were no side effects. These are some of the most heavily prescribed medications, with more than 15 million Americans using PPI medications. It is estimated that 70% of these prescriptions are unnecessary.1 This is not even counting the over-the-counter PPI medications available without a prescription. The author also sees many kidney patients treated with prednisone for glomerulonephritis who are also given PPI prophylactically for stomach irritation. 
Many patients take PPIs unnecessarily. For those who do in fact have GERD, there are many treatment alternatives to consider before resorting to PPI use.
It is unclear whether PPI use and associated risk of CKD is causal due to direct nephrotoxicity or if other risk factors associated with the use of PPI medications are responsible for the association. In the study under review, the statistical analysis accounted for age, obesity, socioeconomic status, and use of hypertensive medications. Overall, the association was little changed when these parameters were taken into account (45% increased risk of CKD vs 50%). Patients with gastroesophageal reflux (GERD) are also more likely to have metabolic syndrome and endocrine dysfunction, so these comorbidities may have contributed to the prevalence of CKD in PPI users. In addition, a high body mass index (BMI), high triglycerides, and low HDL are associated with GERD, so these too may have influenced the risk of kidney dysfunction.2 Because diabetes is by far the number one cause of renal failure, maintaining a normal BMI is important for all patients at risk. 
Another risk factor for CKD is hypothyroidism, and those with hypothyroidism have a higher incidence of GERD. This is thought to be due to motility issues and/or hiatal hernias rather than hyperacidity.3 Conversely, CKD patients have a higher incidence of low thyroid function. One study suggested that hypothyroidism increases incrementally with progressively lower glomerular filtration.4
Although the association between chronic kidney disease and PPI use is newly established, the link between acute kidney disease and PPI use is well-known. Of all biopsy cases with proven acute interstitial nephritis (AIN), 70% are caused by medication, including PPIs.5 In addition, longer duration of drug use was associated with a poorer recovery.5 Biopsies of AIN patients who were taking PPIs almost uniformly showed extensive lymphoplasmacytic infiltrations involving the interstitium, with sparing of the glomeruli.6 This suggests there is direct damage to the architecture of the kidney’s filtration system, providing a plausible causality in the association between CKD and long-term PPI use. 
One natural agent can have a profound impact in lowering symptoms of GERD while benefiting those with CKD: melatonin. An often-overlooked feature of CKD is insomnia, and melatonin production is impaired in CKD. Evidence suggests that administering exogenous melatonin may favorably alter the course of CKD.7 Melatonin also plays a role in the development of GERD; the enterochromaffin cells of the gastrointestinal tract secrete 400 times as much melatonin as the pineal gland. Melatonin has been part of successful natural protocols aimed at treating GERD without PPIs.8 This is most likely due to inhibition of nitric oxide synthesis which causes transient lower esophageal sphincter relaxation (TLESR).9
In conclusion, GERD and CKD have several risk factors in common. Those who use PPI treatment for GERD may already be at risk for CKD. However, there is evidence that use of PPIs may be detrimental in and of itself. Many patients take PPIs unnecessarily. For those who do in fact have GERD, there are many treatment alternatives to consider before resorting to PPI use. 

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  1. Kelly JC. Proton pump inhibitors may increase risk for kidney disease. Medscape Web site. http://www.medscape.com/viewarticle/857060#vp_2. Published January 11, 2016. Accessed March 9, 2016.
  2. Nomura M, Tashiro N, Watanabe T, et al. Association of symptoms of gastroesophageal reflux with metabolic syndrome parameters in patients with endocrine disease. ISRN Gastroenterol. 2014:863206. doi:10.1155/2014/863206.
  3. Savina LV, Semenikhina TM, Korochanskaia NV, Klitinskaia IS, Iakovenko MS. Hiatus hernia and gastroesophageal reflux disease as a manifestation of a newly revealed hypothyroidism [in Russian]. Klin Med (Mosk). 2006;84(2):71-74.
  4. Rhee CM, Kalantar-Zadeh K, Streja E, et al. The relationship between thyroid function and estimated glomerular filtration rate in patients with chronic kidney disease. Nephrol Dial Transplant. 2015;30(2):282-287.
  5. Muriithi AK, Leung N, Valeri AM, et al. Biopsy-proven acute interstitial nephritis, 1993-2011: a case series. Am J Kidney Dis. 2014;64(4):558-566.
  6. Sampathkumar K, Ramalingam R, Prabakar A, Abraham A. Acute interstitial nephritis due to proton pump inhibitors. Indian J Nephrol. 2013;23(4):304-307.
  7. Quiroz Y, Ferrebuz A, Romero F, Vaziri ND, Rodriguez-Iturbe B. Am J Physiol Renal Physiol. 2008;294(2):F336-344.
  8. Webach MR. Melatonin for the treatment of gastroesophageal reflux disease. Altern Ther Health Med. 2008;14(4):54-58.
  9. Pereira RS. Regression of gastroesophageal reflux disease symptoms using dietary supplementation with melatonin, vitamins and amino acids: comparison with omeprazole. J Pineal Res. 2006;41(3):195-200.