Chronic Kidney Disease Amplifies Gabapentin-Associated Dementia Risk: Evidence for a Renal Pharmacokinetic Mechanism

Gabapentin and pregabalin are renally cleared gabapentinoids with markedly different pharmacokinetic profiles in chronic kidney disease: gabapentin half-life extends from 5-7 hours to 52-132 hours in advanced chronic kidney disease, while pregabalin accumulation is more predictable. In an active comparator new-user cohort of 33,791 adults aged [&ge;]40 years with hypertension initiating gabapentinoids (2018-2024) from the Rutgers Clinical Research Data Warehouse, chronic kidney disease substantially amplified gabapentin-associated dementia risk (hazard ratio 7.39, 95% confidence interval 3.43 to 15.92, P<0.001), whereas patients without chronic kidney disease showed near-null effect (hazard ratio 1.09, 95% confidence interval 0.89 to 1.34; P=0.41; interaction P<0.001). This effect was independent of prescribed dose: within the low-dose stratum, chronic kidney disease patients showed hazard ratio 5.06 versus 1.27 in patients without chronic kidney disease. Pre-existing chronic kidney disease conferred significantly elevated risk (hazard ratio 1.78; P=0.001), while incident chronic kidney disease showed a nonsignificant trend (hazard ratio 1.32; P=0.16), consistent with cumulative pharmacokinetic burden. Independent replication in the NIH All of Us Research Program Controlled Tier (N=47,079; hazard ratio 1.593, 95% confidence interval 1.349 to 1.882; P<0.001) confirmed the overall gabapentin-pregabalin signal; eGFR-staged analysis showed the expected pharmacokinetic pattern (mild CKD [eGFR [&ge;]45]: hazard ratio 1.15, not significant; severe CKD [eGFR <45]: hazard ratio 1.77, directionally elevated but underpowered with 51 events). Food and Drug Administration Adverse Event Reporting System data corroborated the renal mechanism (odds ratio 1.642 for renal events in elderly co-exposed patients). These converging findings suggest that chronic kidney disease is a clinically important modifier of gabapentin-associated cognitive risk, and that gabapentinoid selection in chronic kidney disease patients should integrate renal function status into prescribing decisions. Significance StatementGabapentin is the most prescribed gabapentinoid in the United States, with approximately 59 million annual prescriptions, and is entirely dependent on renal clearance. In this active comparator cohort study of 33,791 gabapentinoid initiators, chronic kidney disease amplified gabapentin-associated dementia risk nearly 7-fold compared with pregabalin, an effect that was independent of prescribed dose and persisted even among patients receiving low-dose gabapentin. External replication in the NIH All of Us Research Program and FDA pharmacovigilance data corroborated the signal. These findings suggest that current dose-adjustment guidelines for gabapentin in CKD may be insufficient to prevent cognitive harm, and that renal function status should be incorporated into gabapentinoid selection decisions.