Background: Tenofovir disoproxil fumarate (TDF) was associated with an increased risk of renal toxicity, resulting in proximal tubular dysfunction, proteinuria, and chronic kidney disease (CKD). However, TDF-related nephrotoxicity has not been studied in the context of end-state renal disease (ESRD). We hypothesized that TDF-induced toxicity mainly affected a subset of susceptible HIV-infected patients that led to faster progression to ESRD. Methods: Data was extracted from 12 clinical cohorts under the North American AIDS Cohort Collaboration for Research and Design study that carried out systematic ESRD validation from January 2000 to December 2009. Piece-wise log-linear mixed effects models were used to compare and contrast estimated glomerular filtration rate (eGFR) trajectories in TDF and other nucleoside reverse transcriptase inhibitor (NRTI) therapy groups. A nested design was employed to identify risk factors associated with increased ESRD risk after TDF exposure. Results: Among the 19,653 patients, over 20% of high-risk individuals received less than two serum creatinine-based assessments of kidney function per year. For TDF users with baseline eGFR≥90, 60-89.9 and 45-59.9 mL/min/1.73m2, the annualized eGFR change decreased at -10.1% (p<-0.001), -9.9% (p<-0.001) and -27.2% (p<-0.001), respectively during the first 6 months after therapy initiation. In contrast, eGFR decreased at a slower rate or stabilized among alternative NRTI initiators during this period at rates of -5.9% (p<0.001), 0.7% (p=0.596) and 9.8% (p=0.027) for the same eGFR categories. For patients with baseline eGFR in ranges of 30-44.9 and <30 mL/min/1.73m2, eGFR change was non-significant at -14.0% (p=0.068) and -9.3% (p=0.617) per year, respectively among TDF initiators, whereas among alternative NRTI users, eGFR declined at -27.7% (p<0.001) and -31.2% (p<0.001) per year. Among TDF-exposed patients, black race was independently associated with 3.4 [95% CI: 1.2-9.6] times higher ESRD risk. Conclusion: Insufficient screening and monitoring of kidney function remains as an issue for clinical care of kidney diseases among HIV-infected patients. TDF-based therapies are associated with higher ESRD risks. TDF-induced toxicity mainly affects a small subset of susceptible individuals. Advisors/Committee Members: Abraham, Alison G (advisor).