Proton Pump Inhibitors: Indigestion for nephrologists!

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Proton pump inhibitors (PPIs) are one of the most commonly prescribed medications, mostly because of their efficacy and their favorable safety profile. However, it has been estimated that between 25% and 70% of these prescriptions do not have an appropriate indication. The duration of PPI use also frequently extends beyond recommended guidelines. More than 15 million Americans used prescription PPIs in 2013, costing more than $10 billion. Specifically, in patients with kidney disease, a small study suggested a high consumption of AST (acid suppressing therapy, mostly PPIs) in patients on dialysis (compared to other chronic diseases) and the use of AST had, in the majority of cases, no adequate indication. DOPPS data showed a relatively consistent overall prescription rate of 36% to 38%, suggesting that prescription rates in this population are several times greater than in the general population. It is speculated that the overuse in patients with CKD may be related to polypharmacy, co-morbidities, hypergastrinaemia or the involvement of many physicians in their care.

In 1992, a sentinel case-report identified the PPI omeprazole, as a possible cause of acute interstitial nephritis (AIN) in an elderly woman. Since that time, a growing body of literature suggests that this class of drugs may be linked to AKI, which can potentially lead to chronic injury or kidney failure.

A large nested case–control study supported the association between renal disease and PPI exposure and found that patients with an incident renal disease diagnosis were nearly twice as likely (OR 1.72, p < 0.001) to have been exposed to PPIs, providing the first estimate of an effect size for this relationship

A subsequent Canadian population-based cohort study, involving nearly 600,000 patients, found that those who commenced treatment with PPIs had a more than twofold increase in rates of AKI (13.49 v. 5.46 per 1000 person-years; HR 2.52) and AIN (0.32 versus 0.11 per 1000 person-years; HR 3.00) in hospital admission diagnoses. Similar results were found in an analysis stratified by individual PPIs, substantiating the class effect. Indeed, more than half (59%) of the patients in this study, on discharge from the hospital, received another prescription for a PPI in the ensuing 100 days. Of these patients, 7.5% were re-admitted to hospital with AKI in the ensuing 120 days, consistent with a causal role of PPIs in some instances, providing the first estimate of the risk of drug rechallenge. This also highlights the lack of awareness among clinicians of the potential association between these drugs and renal disease.

In a recently published article in JAMA looking at PPI use and the risk of CKD in two large cohorts, (n=10,482 and n=248,751) PPI use was associated with incident CKD in analysis adjusted for demographic, socioeconomic, and clinical variables (HR, 1.50); and in analysis with PPI use modeled as a time-varying variable (adjusted HR 1.35). The association persisted when baseline PPI users were compared directly with H2 receptor antagonist users (adjusted HR 1.39) and with propensity score–matched non-users (HR 1.76). Twice-daily PPI dosing was associated with a higher risk than once-daily dosing, suggesting a biological gradient. Again, twice-daily PPI dosing was associated with a higher risk of AKI than once-daily dosing.

Of interest to the renal community, PPIs also cause hypomagnesaemia, the cause which is probably related to magnesium wasting via TRPM-6 and TRPM-7 inhibition. This phenomenon is also seen in dialysis patients. One may argue that all of these are observational studies which can only show an association and hence cannot prove causality (between PPI use and AKI/CKD or hypomagnesaemia). Many of the studies used hospital diagnosis code, which are less sensitive, and may underestimate the true incidence and association. In addition, they rely on administrative data and hence had no access to laboratory indices of clinical or medication data that may have influenced the risk of renal outcomes, including over-the-counter NSAID use (which might perhaps be one of the most common reasons for PPI use).

In conclusion, observational cohort studies represent one of the best methods to study adverse effects of medications used in real-world settings. Given the millions of individuals who take PPIs each year and the fact that more than half of such prescriptions may not be clinically indicated, even a small absolute increase in risk of AKI/CKD outweighs any benefits that might be derived from these drugs in many patients for whom they are prescribed. Although it should not deter clinicians from prescribing PPIs for patients with well-defined indications and durations, the current evidence underscores the importance of ongoing efforts to curtail the indiscriminate use of these drugs.

It also leaves us with some unanswered questions:
1. What is the mechanism of CKD due to PPI use? Is it due to repeated AKI, a hitherto unreported ‘chronic interstitial nephritis’, or related to hypomagnesaemia?
2. Will treatment of hypomagnesaemia change hard outcomes like mortality/hospital admissions? An interventional study in haemodialysis patients that reported a beneficial effect of oral Mg administration on decreasing carotid intima-media thickness and a recent small randomized pilot study showed that supplementation with Mg carbonate for 1 year in HD patients led to improved calcification scores in some patients. If yes, to what targets

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