Freeman W Chabala ^1* Edward D Siew ² William C Wester ³ Alana T Brennan ⁴ Masauso M Phiri ⁵ Sepiso K Masenga ^6* Aliyu H Muktar ³

• ¹ Levy Mwanawasa Medical University, Lusaka, Zambia
• ² Vanderbilt O’Brien Center for Kidney Disease, Nashville, United States
• ³ Vanderbilt Institute for Global Health, Vanderbilt University Medical Center, Nashville, Tennessee, United States
• ⁴ Department of Global Health, School of Public Health, Boston University, Boston, Massachusetts, United States
• ⁵ University of Zambia, Lusaka, Zambia
• ⁶ Mulungushi University, Kabwe, Zambia

Antiretroviral therapy (ART) increases the life expectancy of persons living with HIV (PLWH), but not without potentially serious adverse effects. Tenofovir disoproxil fumarate (TDF) can cause nephrotoxicity, manifesting as acute kidney injury that may persist after treatment discontinuation. Kidney injury biomarkers like kidney injury molecule-1 (KIM-1), retinol-binding protein-4 (RBP-4), interleukin-18 (IL-18), and neutrophil gelatinaseassociated lipocalin (NGAL) can aid early diagnosis and prognosticate TDF-associated nephrotoxicity. This study aimed at determining whether the change from baseline in urine KIM-1 (δKIM-1) and NGAL(δNGAL) following two weeks of TDF use could predict subclinical TDF-associated nephrotoxicity before overt manifestation as acute kidney disease in three months.A prospective cohort study of 205 PLWH was conducted at the Adult Center for Infectious Disease Research (AIDC) in Lusaka, Zambia. ART naïve PLWH initiating TDF with intact kidney function (estimated glomerular filtration rate (eGFR)> 60 mL/min/1.73m 2 ) were followed from initiation, at two weeks, and approximately 3 months to determine the incidence of TDF-associated nephrotoxicity. We measured urine KIM-1 and NGAL at baseline and at two weeks of treatment to determine if it predicted subclinical nephrotoxicity. The presence of TDF-associated nephrotoxicity was defined according to the established acute kidney disease and disorders criteria (AKD) as having either 1) one or more episodes of eGFR< 60ml/ min/1.73m 2 within three months, 2) a reduction in eGFR by greater than 35% (from baseline) within three months, and/or 3) an increase in serum creatinine by more than 50% (from baseline) within three months.The incidence of TDF-associated nephrotoxicity was 22%. Baseline eGFR, creatinine, age, female sex, and BMI predicted the risk of overt TDF-associated nephrotoxicity. The median baseline KIM-1-to-creatinine and NGAL-1-to-creatinine ratios among participants who developed and those who did not develop overt TDF-associated nephrotoxicity were not significantly different. However, every 1 pg/mg increase in the δKIM-1 was associated with a 41% higher risk of TDF-associated nephrotoxicity but no association was observed with δNGAL.The incidence of TDF-associated nephrotoxicity was high. Change in KIM-1 within 2 weeks of TDF can predict subclinical TDF-associated nephrotoxicity before overt manifestation as acute kidney disease while δNGAL within the same period did not predict subclinical TDF-associated nephrotoxicity.