Antihypertensive Drug Combinations Modify Cisplatin-induced Acute Kidney Injury

Abstract

Background/Aim: There is limited evidence about the nephrotoxicity of calcium channel blockers (CCBs) and renin-angiotensin system (RAS) inhibitors with concomitant cisplatin (CDDP). We investigated whether combinations of antihypertensive drugs are associated with CDDP-related acute kidney injury (AKI) using the Japanese Adverse Drug Event Report database. Patients and Methods: We analysed 544,864 reports in the database from 2004 to 2020. A reporting odds ratio (ROR) and confidence interval (CI) with adjustment for potential confounding factors was calculated for AKI for each drug and the combined use of the drugs and CDDP. Results: CDDP, CCBs, and RAS inhibitors were all detected signals for AKI. The ROR in cases with concomitant use of CCBs, RAS inhibitors, and CDDP (adjusted ROR 7.28;) was higher than that in cases with use of each drug. Conclusion: AKI may require more attention when patients receiving CDDP take CCBs and RAS inhibitors together.Cisplatin (CDDP) is a platinum-based anticancer drug with many indications, and is positioned as a key drug for a wide range of cancer types including head and neck (1), lung (2, 3), oesophageal (4), and gastric (5) cancers. However, CDDPbased therapies can cause severe and life-threatening adverse events, typically mucosal injury in the gastrointestinal tract and myelosuppression. Acute kidney injury (AKI) is another adverse event of CDDP administration, with a reported incidence of 30-40% (6). Because CDDP-induced AKI is dosedependent, large fluid volumes, diuretics, and magnesium are often administered to prevent its development. Despite these measures, it is difficult to completely prevent AKI in patients receiving CDDP, and it often becomes a problem with advancing treatment. Identified risk factors for CDDP-induced AKI include older age, total CDDP dose, hypoalbuminaemia, hypokalaemia, diabetes, and cardiovascular disease (7-9). Hypertension (HT) was also identified as a risk factor for CDDP-induced AKI (10, 11), but studies have evaluated the presence or absence of a diagnosis of HT and did not clarify whether there were differences in AKI development depending on the antihypertensive drugs taken.Antihypertensive drugs are classified into several types, including calcium channel blockers (CCBs), renin-angiotensin system (RAS) inhibitors, and beta blockers. The prescription ratios of CCBs and RAS inhibitors were reported to be high among antihypertensive drugs in Japan (12). In animal studies, combined use of CCBs and CDDP was shown to increase the risk of nephrotoxicity development in rats (13,14). Use of RAS inhibitors was further identified as an independent risk factor for CDDP-induced AKI in elderly patients (15). However, the relationship between these combinations and the expression of AKI have not been clarified.Adverse event reports compiled during the post-marketing stages of drugs are provided by the Japanese regulatory authorities in a database and act as valuable tools for postmarketing surveillance to reflect the realities of clinical practice. T...

Evaluation of a new score associated with acute kidney injury in patients treated with cisplatin based EXTREME regimen

“…These cardiac treatments are known to affect afferent or efferent renal arterioles tonus and many interfere with OCT2 and MATE [ 57 ] which may alter with cisplatin elimination. In this sense, Takeuchi et al [ 54 ] reported a cumulative cisplatin related AKI-risk with the concomitant administration of several classes of antihypertensive treatments. However, the administration of antihypertensive therapies implies patient is suffering from an underlying hypertensive or cardiovascular disease, and the addition of extra cardiac treatment suggest a more serious trouble.…”