The HIV protease inhibitor darunavir prevents kidney injury via HIV-independent mechanisms

Abstract

HIV-associated nephropathy (HIVAN) is a rapidly progressive kidney disease that is caused by HIV infection of renal epithelial cells with subsequent expression of viral genes, including vpr. Antiretroviral therapy ameliorates HIVAN without eradicating HIV from the kidneys and the mechanism by which it protects kidneys is poorly understood. Since HIV protease inhibitors have “off target” cellular effects, we studied whether darunavir, the most commonly prescribed protease inhibitor, protects kidneys from HIV-induced injury via mechanisms independent of HIV protease and viral replication. Renal epithelial cells were transduced with lentiviruses encoding HIV (lacking protease and reverse transcriptase), Vpr, or vector control. Darunavir attenuated HIV and Vpr-induced activation of Stat3, Src, Erk, and cytokines, which are critical for HIVAN pathogenesis. We then studied HIV-transgenic mice, which develop HIVAN in the absence of HIV protease or reverse transcriptase. Mice were treated with darunavir, zidovudine, darunavir + zidovudine, or control. Darunavir and darunavir + zidovudine reduced albuminuria and histologic kidney injury and normalized expression of dysregulated proteins. RNA-seq analyses demonstrated that darunavir suppressed HIV-induced upregulation of immune response genes in human kidney cells. These data demonstrate that darunavir protects against HIV-induced renal injury via mechanisms that are independent of inhibition of HIV protease.

Acute kidney injury caused by darunavir in a patient with COVID-19: A Case Report

“…[9] Moreover, Gao X et al demonstrated that darunavir has a protective effect against HIV-induced renal injury by reducing albuminuria and kidney injury and suppressing HIV-induced upregulation of immune response genes in human kidney cells. [10] Based on a cross-sectional study published by de Lastours et al in 2013, 4 out of 51 HIV patients who received a DRV-based regimen developed high levels of DVR crystals in urine, and the author concluded that DVR potential renal toxicity should be considered. [11] Risk factors that can increase the risk of developing AKI in patients on ART therapy include diabetes mellitus, hypertension, nephrotoxic drug intake, preexisting kidney disease, older age, elevated baseline creatinine level, female gender and African American ethnicity.…”

Fármacos Antimicrobianos E Antivirais Com Potencial Uso Terapêutico Para a Covid-19

“…O Darunavir é um inibidor de protease de segunda geração aprovado para o tratamento inicial de pacientes com HIV, bem como para aqueles que possuam a doença há mais tempo e que resistem a outros inibidores de proteases (41). O Darunavir deve ser administrado com alimentação para aumentar a sua absorção e é biotransformado intensamente pelas CIP3A4 (42).…”

Transient dynamics of the renal disease epidemic among HIV-infected individuals

“…However, when ART is employed along with the close monitoring of kidney function, it has been shown to effectively manage HIV-associated kidney disease. Importantly, studies have shown that effective treatment with ART decreases the morbidity and mortality in patients with HIV-associated kidney diseases and also the progression to ESKD [9,17,20], though the exact mechanisms by which ART ameliorates kidney disease are not yet clear [10], .…”