{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T01:15:10Z","timestamp":1778807710573,"version":"3.51.4"},"posted":{"date-parts":[[2026,3,18]]},"group-title":"Nephrology","reference-count":30,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,3,18]],"date-time":"2026-03-18T00:00:00Z","timestamp":1773792000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,5,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>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\u20137 hours to 52\u2013132 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.<\/jats:p>\n                <jats:p>\n                  Among 33,791 adults aged \u226540 years with hypertension initiating gabapentinoids in the Rutgers Clinical Research Data Warehouse (2018\u20132024), gabapentin was associated with substantially elevated dementia risk in patients with CKD (hazard ratio [HR] 7.39; 95% CI, 3.43\u201315.92;\n                  <jats:italic>P<\/jats:italic>\n                  &lt;0.001) versus a near-null association in patients without CKD (HR 1.09; 95% CI, 0.89\u20131.34;\n                  <jats:italic>P<\/jats:italic>\n                  =0.41). The elevated risk in CKD persisted within the low-dose stratum (\u2264300 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\u2013G4: HR 4.54; 95% CI, 1.62\u201312.76) and attenuated in CKD stage 5 (HR 1.57;\n                  <jats:italic>P<\/jats:italic>\n                  =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\u2013pregabalin signal (HR 1.59; 95% CI, 1.35\u20131.88;\n                  <jats:italic>P<\/jats:italic>\n                  &lt;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).\n                <\/jats:p>\n                <jats:p>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.<\/jats:p>\n                <jats:sec>\n                  <jats:title>Key Points<\/jats:title>\n                  <jats:list list-type=\"bullet\">\n                    <jats:list-item>\n                      <jats:p>In an active comparator new-user cohort of 33,791 gabapentinoid initiators, gabapentin was associated with substantially elevated dementia risk in patients with chronic kidney disease (CKD) compared with pregabalin, with the excess risk persisting even within the low-dose stratum (\u2264300 mg) \u2014 a pattern consistent with the interpretation that standard renal dose adjustment alone may not fully offset the cognitive safety risk of gabapentin in CKD.<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>The signal concentrated in non-dialysis CKD (KDIGO stages G3b\u2013G4) and attenuated in CKD stage 5, paralleling expected pharmacokinetic exposure: gabapentin half-life extends 10-to 20-fold in advanced CKD versus approximately 4-fold for pregabalin, while dialysis partially restores clearance.<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>Convergent evidence from external replication in the NIH All of Us Research Program (N=47,079) and FDA FAERS pharmacovigilance data \u2014 including disproportionately higher renal adverse event reporting for gabapentin versus pregabalin (chronic kidney disease reporting odds ratio [ROR] 5.98; renal failure ROR 2.43) \u2014 supported the interpretation of a renal pharmacokinetic cognitive safety vulnerability.<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>These findings suggest that renal function stage warrants closer integration into gabapentinoid selection in older adults with CKD, with pregabalin a candidate alternative where cardiovascular risk permits.<\/jats:p>\n                    <\/jats:list-item>\n                  <\/jats:list>\n                <\/jats:sec>","DOI":"10.64898\/2026.03.15.26348418","type":"posted-content","created":{"date-parts":[[2026,3,18]],"date-time":"2026-03-18T22:45:24Z","timestamp":1773873924000},"source":"Crossref","is-referenced-by-count":0,"title":["Chronic Kidney Disease Amplifies Gabapentin-Associated Dementia Risk in Non-Dialysis Patients: Findings Consistent with a Renal Pharmacokinetic Vulnerability"],"prefix":"10.64898","author":[{"given":"James","family":"Green","sequence":"first","affiliation":[{"name":"Department of Health Informatics, Rutgers School of Health Professions, Newark, New Jersey"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laura D.","family":"Byham-Gray","sequence":"additional","affiliation":[{"name":"Department of Clinical and Preventive Nutrition Sciences, Rutgers School of Health Professions, Newark, New Jersey"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joshua","family":"Kaplan","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Medicine, Rutgers New Jersey Medical School, Newark, New Jersey"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Suril","family":"Gohel","sequence":"additional","affiliation":[{"name":"Department of Health Informatics, Rutgers School of Health Professions, Newark, New Jersey"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Branimir","family":"Ljubic","sequence":"additional","affiliation":[{"name":"Office of Advanced Research Computing (OARC), Rutgers University, Piscataway, New Jersey"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael","family":"Schulewski","sequence":"additional","affiliation":[{"name":"Office of Advanced Research Computing (OARC), Rutgers University, Piscataway, New Jersey"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Barbara","family":"Tafuto","sequence":"additional","affiliation":[{"name":"Department of Health Informatics, Rutgers School of Health Professions, Newark, New Jersey"},{"name":"New Jersey Alliance for Clinical and Translational Science, Rutgers University, New Brunswick, New Jersey"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2026051417501878000_2026.03.15.26348418v2.1","doi-asserted-by":"crossref","first-page":"1816","DOI":"10.7326\/ANNALS-25-01750","article-title":"Trends in dispensed gabapentin prescriptions in the United States, 2010 to 2024","volume":"178","year":"2025","journal-title":"Ann Intern 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