Urine Nephrology Now: A Primer for Students in Nephrology
The relationship between proton pump inhibitor (PPI) use and kidney disease represents one of the most controversial topics in contemporary nephrology and gastroenterology. PPIs have become among the most widely prescribed medications globally since their introduction in 1989, with widespread use often for inappropriate indications or excessive duration.
While large observational studies have consistently demonstrated associations between PPI use and both acute kidney injury (AKI) and chronic kidney disease (CKD), establishing definitive causation remains challenging due to inherent limitations in observational study design. This chapter examines the current evidence base, addresses methodological limitations, and provides evidence-based guidance for clinical practice.
By irreversibly inhibiting the H+/K+-ATPase enzyme in gastric parietal cells, PPIs effectively reduce gastric acid secretion and are highly effective in treating peptic ulcer disease, gastroesophageal reflux disease, and preventing NSAID-induced gastropathy. However, concerns regarding long-term safety have emerged, particularly regarding potential nephrotoxicity.
Acute interstitial nephritis represents an important cause of acute renal failure, accounting for approximately 5 to 15 percent of patients hospitalized for acute renal failure. In a large single-center case series of 133 patients with biopsy-proven AIN from 1993 through 2011, proton pump inhibitors accounted for 14% of drug-induced cases, representing the second most common cause after antibiotics (49%).
PPI-induced acute interstitial nephritis represents an immune-mediated reaction involving the interstitium and renal tubules. Initially, tubule epithelial cells are injured, followed by a lymphocytic inflammatory infiltrate containing predominantly T cells. Renal scarring may initiate as a consequence of the spread of the infiltrate, followed by decrease in renal function.
There is strong evidence that AIN is immunologically mediated. The precise disease mechanism is unclear, but antigen-driven immunopathology is the key mechanism. The presence of helper-inducer and suppressor-cytotoxic T lymphocytes in the inflammatory infiltrate suggests that T-cell mediated hypersensitivity reactions and cytotoxic T-cell injury are involved in pathogenesis of AIN.
The clinical diagnosis of acute interstitial nephritis presents significant challenges for practicing physicians. Classic findings of fever, rash, and arthralgias may be absent in up to two thirds of patients, making clinical recognition difficult.
Patients with PPI-induced AIN were older, were less symptomatic, and had longer durations of drug exposure and longer delays in getting kidney biopsy and steroids than for antibiotic-induced or NSAID-induced AIN. This delayed recognition can negatively impact outcomes.
Despite historical emphasis on urine eosinophilia as a diagnostic marker, diagnostic studies such as urine eosinophils provide suggestive evidence, but they are unable to reliably confirm or exclude the diagnosis of acute interstitial nephritis. The sensitivity and specificity of urine eosinophilia are insufficient for definitive diagnosis, with many cases of confirmed AIN lacking this finding.
Novel biomarkers such as urine TNF-α and interleukin-9 may be able to differentiate AIN from acute tubular injury. For example, if the prebiopsy probability of AIN is 0.25:
Renal biopsy remains the gold standard for diagnosis, but it may not be required in mild cases or when clinical improvement is rapid after removal of an offending agent or medication.
Renal biopsy revealed AIN with dense lymphocyte and eosinophilic infiltrates in the interstitium. All cases showed almost uniform renal biopsy findings of extensive lymphoplasmacytic infiltrations involving the interstitium with sparing of the glomeruli. Eosinophils were seen in only some cases, highlighting that their absence does not exclude the diagnosis.
In a prospective community-based cohort of over 10,000 adults, baseline use of PPIs was independently associated with a 20–50% higher risk of incident chronic kidney disease, after adjusting for several potential confounding variables, including demographics, socioeconomic status, clinical measurements, prevalent comorbidities and concomitant use of medications.
A comprehensive meta-analysis of 6,829,905 participants from 10 observational studies found that compared with non-PPI use, PPI use was significantly associated with an increased risk of CKD (RR 1.72, 95% CI: 1.02–2.87, p = 0.03).
Analysis of the US FDA Adverse Event Reporting System from 2004 to 2019 identified:
The ELSA-Brasil prospective study of 13,909 participants found that after adjustments, PPI users for more than six months had an increased risk of CKD compared to non-users. Compared to non-users, users of PPIs for up to six months and above six months had greater decline in kidney function over time during a mean interval of 3.9 years.
The COMPASS trial was a large, international, blinded, placebo-controlled, randomized trial. From March 2013 to May 2016, 17,598 individuals from 580 centers in 33 countries were randomized to pantoprazole or placebo. All participants had chronic coronary artery disease and/or peripheral arterial disease.
The COMPASS trial has produced seemingly contradictory findings depending on the specific analysis conducted:
There was a statistically significant 20% faster GFR loss with PPI use:
If the effect of pantoprazole is relative, an excess loss of 0.8 ml/min per 1.73 m² per year is roughly equivalent to, but in the opposite direction of, the beneficial effect of renin-angiotensin system blockade. This represents the largest and only RCT data which provides unconfounded data on the relationship between PPI use and subsequent CKD and GFR change.
The pooled evidence from observational studies cannot provide an interpretation regarding causation. The findings are prone to selection bias, confounding bias, and exaggeration of associations.
Despite multiple observational studies suggesting associations, several high-quality studies have found no significant increased risk:
AIN causes acute inflammation and tubulointerstitial damage, which in the long term lead to interstitial fibrosis and chronic interstitial nephritis. Chronic interstitial nephritis may ultimately lead to CKD and, in severe cases, to renal failure.
There is a hypothesis suggesting that chronic usage of PPIs may precipitate the onset of chronic kidney disease, potentially through repeated episodes of acute kidney injury. This persistent impairment in renal function, potentially coupled with ongoing chronic interstitial nephritis, constitutes a precursor for CKD.
A study found that three-week treatment with PPIs in rodents resulted in an increase in serum levels of indoxyl sulfate. The increased amounts of liver CYP2E1 protein, which promotes indoxyl sulfate production, are likely responsible for this effect. This process may help to explain the link between the use of PPIs and a higher risk of developing CKD.
Step 1: Immediate PPI discontinuation
Step 2: Assess severity of kidney injury and need for renal replacement therapy
Step 3: Consider corticosteroid therapy based on severity and timing
Step 4: Monitor for recovery of kidney function
Step 5: Plan long-term follow-up and alternative gastroprotection if needed
At 6 months postbiopsy, 49% of patients with drug-induced AIN treated with steroids achieved complete recovery; 39%, partial recovery; and 12%, no recovery. Correlates of poor recovery included:
When PPI discontinuation is necessary due to kidney injury, alternative approaches for gastroprotection should be considered based on the original indication for PPI therapy.
H2 receptor antagonists may be considered as alternatives in specific clinical scenarios:
Limitation: PPIs are significantly more effective than H2RAs for healing esophagitis and managing severe GERD (RR 1.59, 95% CI 1.44-1.75).
Until the association between PPI use and kidney disease is better clarified, it is reasonable to monitor estimated glomerular filtration rate annually in patients receiving long-term PPI therapy, based on CKD guidelines for monitoring patients taking potentially nephrotoxic medications.
When real-world evidence suggests potential harm, both the precautionary principle and the Hippocratic principle support use of a careful decision-making strategy, involving both patients and providers, that encourages careful weighing and balancing of potential benefit but also the realism of potential risks.
Once deprescribing eligibility is established, a deprescribing strategy that tapers PPI use is recommended, since abrupt PPI discontinuation could potentially result in rebound symptoms of acid hypersecretion. The majority of tapering strategies support a reduction of the PPI maintenance dose by 50% in 1- to 2-week intervals.
Until further randomized control trials and biological studies confirm these results, PPI therapy should not stop patients with gastroesophageal reflux disease. However, caution should be used when prescribing to patients with high-risk kidney disease. Patients should be informed about:
The principal limitation of current evidence is that it predominantly incorporates observational studies, which are inherently prone to confounding bias. Future research should aim to address gaps by focusing on detailed collection and analysis of variables to enhance understanding of the relationship between PPI use and CKD risk.
RCTs may not represent the most practical approach to examine serious but infrequent adverse events associated with long-term use of a medication because they require large number of enrollees to be followed up for an extended duration. However, the debate surrounding causation versus correlation will likely continue until larger, longer-term randomized controlled trials are conducted.