Kidney Injury Signals Flagged for Sacubitril/Valsartan in Japanese Adverse Event Database

A pharmacovigilance analysis of Japan’s national spontaneous reporting database has identified a disproportionate signal of acute kidney injury (AKI) among reports involving sacubitril/valsartan, the angiotensin receptor neprilysin inhibitor known as ARNI. The study, published in the journal Drugs – Real World Outcomes, also found that within reports involving ARNI, heart failure and chronic kidney disease were independently associated with higher odds of AKI reporting, and that reports involving ARNI carried higher odds of AKI reporting than reports involving valsartan alone, even after statistical adjustment. The authors stress that spontaneous reporting data cannot establish incidence or causal risk, but the work adds Japanese evidence to a safety question previously explored mainly in international databases.

Sacubitril/valsartan combines a neprilysin inhibitor with an angiotensin II type 1 receptor blocker. In Japan, prescriptions have risen since the drug launched in 2020 and gained an additional indication for hypertension in 2021, and the Japanese Circulation Society/Japanese Heart Failure Society 2025 heart failure guidelines recommend it as a class I option for switching from renin-angiotensin system inhibitors. Because ARNI suppresses the renin-angiotensin-aldosterone system and may influence renal hemodynamics and glomerular filtration, questions about kidney safety have persisted, particularly since some studies report reduced glomerular filtration rate compared with conventional renin-angiotensin system inhibitors.

JADER contains four linked tables covering patient demographics, drug information, adverse events, and primary diseases. Because ARNI launched in Japan in 2020, the study used reports published between April 2020 and August 2023, with the dataset accessed on 26 August 2023. After excluding reports with unavailable sex or age information and reports involving concomitant ARNI and other renin-angiotensin system inhibitors, the final dataset contained 180,971 reports, including 1,363 reports involving ARNI and 1,296 involving valsartan.

Acute kidney injury was identified using the narrow and broad scope Preferred Terms of the Standardized MedDRA Query for “acute renal failure” in MedDRA/J version 26.1. Overall, 7,901 reports in the dataset involved AKI, including 325 reports involving ARNI and 114 involving valsartan. The team calculated reporting odds ratios, a standard disproportionality measure defined as the odds of a particular adverse event with a particular drug divided by the odds with other drugs in the database, with a lower 95% confidence limit above 1 indicating a potential signal.

The central finding was a strong disproportionality signal for AKI in reports involving ARNI, with a reporting odds ratio of 7.11 (95% confidence interval 6.27-8.07). Reports involving valsartan also showed a signal, though a weaker one, at 2.13 (95% CI 1.75-2.58). Five sensitivity analyses, which included restricting the analysis to suspected drugs, excluding reports containing hyperkalemia or dehydration, excluding reports with concomitant diuretics or NSAIDs, and tightening the AKI definition to the narrow scope or to the single preferred term "acute kidney injury," produced results consistent with the primary analysis, with RORs ranging from 2.65 to 8.54 for ARNI and 1.73 to 2.96 for valsartan.

To explore which factors were associated with AKI reporting among ARNI reports, the researchers ran multivariable logistic regression adjusting for sex, age of 70 years or older, heart failure, diabetes mellitus, chronic kidney disease, and concomitant diuretics and NSAIDs. Heart failure (adjusted ROR 1.68, 95% CI 1.22-2.31; p = 0.002) and chronic kidney disease (adjusted ROR 2.17, 95% CI 1.60-2.93; p < 0.001) emerged as independently associated with increased AKI reporting. Sex, age, diabetes, concomitant diuretics, and concomitant NSAIDs were not significantly associated. In the valsartan group, concomitant diuretics were associated with increased AKI reporting (adjusted ROR 1.81, 95% CI 1.17-2.82), while chronic kidney disease showed only a borderline association (adjusted ROR 1.75, 95% CI 0.99-3.58; p = 0.0527), possibly reflecting the smaller number of valsartan reports involving chronic kidney disease.

In a direct comparison treating AKI reporting as the outcome and drug group as the explanatory variable, reports involving ARNI had higher odds of AKI reporting than reports involving valsartan in the crude analysis (ROR 3.25, 95% CI 2.58-4.08), and the association remained significant after adjustment (adjusted ROR 2.03, 95% CI 1.50-2.74). The authors interpret this cautiously: the persistence of the difference after adjustment suggests it cannot be fully explained by the measured patient characteristics or concomitant medications, but it should not be read as evidence that ARNI confers a higher clinical risk of AKI than valsartan, because spontaneous reporting databases lack incidence rates and residual confounding may remain.

The study also examined the so-called “triple whammy” combination of a renin-angiotensin system inhibitor, a diuretic, and an NSAID, a combination previously shown in a study by Lapi and colleagues to increase AKI incidence (rate ratio 1.31, 95% CI 1.12-1.53) compared with a renin-angiotensin system inhibitor plus diuretic, with the highest risk within 30 days of starting the three-drug combination. Among 103 reports involving ARNI with both diuretics and NSAIDs, 22 (21.4%) involved AKI, and a disproportionality signal was detected (ROR 5.96, 95% CI 3.72-9.56). However, the proportion of AKI reports in this triple-combination group was not higher than the 23.8% seen across all ARNI reports, and the authors explicitly caution against interpreting the signal as evidence of an additional or synergistic effect of the triple combination.

Mechanistically, the authors note that ARNI’s neprilysin inhibition enhances natriuretic peptide activity, adding diuretic effects to the RAAS-inhibiting actions of valsartan, which could theoretically affect renal blood flow. They also observe that clinical trials have reported lower serum creatinine and potassium with ARNI than with enalapril, and that ARNI has been reported to reduce glomerular filtration rate decline compared with conventional renin-angiotensin system inhibitors, which may help explain why concomitant diuretics were not significantly associated with AKI reporting in the ARNI group after adjustment. The absence of a significant NSAID association may reflect cautious prescribing, since clinical recommendations advise avoiding NSAIDs in heart failure, and the aRORs below 1 should not be read as protective effects.

The limitations are substantial and the authors enumerate them in detail. JADER contains only submitted safety reports without a denominator of exposed patients, so incidence, risk differences, and numbers needed to harm could not be calculated. Reporting bias, missing demographic detail, the exclusion of mild-to-moderate renal deterioration, the lack of clinical information such as drug dosage, disease severity, volume status, and longitudinal renal function, and the inability to adjust for other renally relevant medications such as mineralocorticoid receptor antagonists or SGLT2 inhibitors all constrain interpretation. Low-dose aspirin could not be distinguished from anti-inflammatory-dose aspirin and was included in the NSAID category, potentially misclassifying exposure. The study period ended in August 2023, and the findings apply only to Japanese spontaneous reports. Within those bounds, the authors conclude that the signals provide complementary pharmacovigilance evidence and support careful renal monitoring in patients receiving ARNI, particularly those with heart failure or chronic kidney disease, while calling for confirmation in real-world clinical datasets.

Subject of Research: Disproportionality analysis of acute kidney injury reports associated with sacubitril/valsartan in the Japanese Adverse Drug Event Report database

Article Title: Disproportionality Analysis of Acute Kidney Injury Reports Associated with Sacubitril/Valsartan (ARNI) in the Japanese Adverse Drug Event Report Database

Article References: Urashima, K., Ueda, T., Urashima, Y., Tamura-Takaori, M., Fujimoto, A., Tanaka, S., Kohda, Y., Kitazawa, F., & Kato, R. (2026). Disproportionality Analysis of Acute Kidney Injury Reports Associated with Sacubitril/Valsartan (ARNI) in the Japanese Adverse Drug Event Report Database. Drugs – Real World Outcomes. https://doi.org/10.1007/s40801-026-00593-3

Image Credits: AI Generated

DOI: 10.1007/s40801-026-00593-3

Keywords: sacubitril/valsartan, ARNI, acute kidney injury, pharmacovigilance, JADER, disproportionality analysis, reporting odds ratio, heart failure, chronic kidney disease, triple whammy, drug safety, Japan