Kidney Disease in HIV: Moving beyond HIV-Associated Nephropathy

Abstract

In developed countries, remarkable advances in antiretroviral therapy have transformed HIV infection into a chronic condition. As a result, HIV-associated nephropathy, the classic HIV-driven kidney lesion among individuals of African descent, has largely disappeared in these regions. However, HIV-positive blacks continue to have much higher rates of ESRD than HIV-positive whites, which could be attributed to the APOL1 renal risk variants. Additionally, HIV-positive individuals face adverse consequences beyond HIV itself, including traditional risk factors for CKD and nephrotoxic effects of antiretroviral therapy. Concerns for nephrotoxicity also extend to HIV-negative individuals using tenofovir disoproxil fumarate-based pre-exposure prophylaxis for the prevention of HIV infection. Therefore, CKD remains an important comorbid condition in the HIV-positive population and an emerging concern among HIV-negative persons receiving pre-exposure prophylaxis. With the improved longevity of HIV-positive individuals, a kidney transplant has become a viable option for many who have progressed to ESRD. Herein, we review the growing knowledge regarding the APOL1 renal risk variants in the context of HIV infection, antiretroviral therapy-related nephrotoxicity, and developments in kidney transplantation among HIV-positive individuals.

Keywords: Apolipoprotein L1; HIV nephropathy; chronic kidney disease.

Figure 1.

Several antiretroviral drugs and pharmacoenhancers affect renal tubular secretion of creatinine (Cr). Cr transport through tubular cells is mediated on the basolateral side by organic cation transporter 2 (OCT-2) and OCT-3 and possibly organic anion transporter 2 (OAT-2) and OAT-3. On the apical side, Cr is secreted via multidrug and toxin extrusion transporter-1 (MATE-1). Dolutegravir and rilpivirine inhibit OCT2 and thus, impair Cr entry into the tubular cell. Conversely, ritonavir and cobicistat inhibit MATE-1 and inhibit Cr efflux into urine.

Figure 2.

Proximal tubular cells handle the renal excretion of tenofovir (TFV), the active metabolite of TDF and TAF. (A) TDF is rapidly metabolized to TFV, within the plasma. TFV influx into the proximal tubular cell at the basolateral membrane occurs via human organic anion transporter 1 (OAT-1) and to a lesser degree, OAT-3; TFV efflux into urine at the apical membrane is mediated by multidrug resistance–associated protein type 4 (MRP-4) and possibly, MRP-2. Accumulation of TFV within proximal tubular cells leads to mitochondrial injury and tissue hypoxia. (B) TAF is stable within plasma and largely metabolized to TFV within target cells, resulting in lower plasma TFV levels and less likelihood of tubular injury. TAF itself is not a substrate for OAT-1 or OAT-3.