Chronic Kidney Disease Amplifies Gabapentin-Associated Dementia Risk in Non-Dialysis Patients: Findings Consistent with a Renal Pharmacokinetic Vulnerability.

Gabapentinoids are widely prescribed in patients with chronic kidney disease (CKD), yet whether routine renal dose adjustment is sufficient to mitigate cognitive safety risk remains unresolved. Gabapentin and pregabalin differ markedly in pharmacokinetic behavior under impaired clearance: gabapentin half-life extends from 5-7 hours to 52-132 hours in advanced CKD (a 10- to 20-fold increase), versus an approximately 4-fold extension for pregabalin. We examined whether CKD amplifies gabapentin-associated dementia risk relative to pregabalin in a real-world active comparator cohort, with external replication. Among 33,791 adults aged ≥40 years with hypertension initiating gabapentinoids in the Rutgers Clinical Research Data Warehouse (2018-2024), gabapentin was associated with substantially elevated dementia risk in patients with CKD (hazard ratio [HR] 7.39; 95% CI, 3.43-15.92; P<0.001) versus a near-null association in patients without CKD (HR 1.09; 95% CI, 0.89-1.34; P=0.41). The elevated risk in CKD persisted within the low-dose stratum (≤300 mg: HR 5.06 in CKD vs. 1.27 in non-CKD), suggesting that dose adjustment alone may not fully offset cognitive safety risk. The signal concentrated in non-dialysis CKD (KDIGO G3b-G4: HR 4.54; 95% CI, 1.62-12.76) and attenuated in CKD stage 5 (HR 1.57; P=0.18), a pattern consistent with renal pharmacokinetic exposure as the dominant driver. External replication in the NIH All of Us Research Program (N=47,079) confirmed the gabapentin-pregabalin signal (HR 1.59; 95% CI, 1.35-1.88; P<0.001) with a directionally consistent eGFR gradient. FAERS pharmacovigilance analysis showed disproportionately higher renal adverse event reporting for gabapentin versus pregabalin (chronic kidney disease ROR 5.98; renal failure ROR 2.43). These findings are consistent with the interpretation that CKD may transform routine gabapentin prescribing into a renal pharmacokinetic cognitive safety problem, with risk concentrated in the non-dialysis CKD population and persisting even at low prescribed doses. Standard dose adjustment alone may be insufficient. Renal function stage warrants closer integration into gabapentinoid selection in patients with CKD, with pregabalin a candidate alternative where cardiovascular risk permits.