Evaluation of Kidney Function in HIV-Infected Patients Receiving an Antiretroviral Regimen Containing One or Two Inhibitors of the Tubular Secretion of Creatinine

JL Casado; M Monsalvo; P Vizcarra; M Fontecha; S Serrano-Villar; S Moreno

Disclosures

HIV Medicine. 2019;20(10):648-656. 

In This Article

Abstract and Introduction

Abstract

Objectives: The aim of this study was to determine the evolution of renal function in patients receiving one or two inhibitors, according to different baseline factors. Some antiretroviral drugs such as rilpivirine (RPV), dolutegravir (DTG), or cobicistat (COBI), interact with the tubular secretion of creatinine, but there are no data about their impact in renal function evaluation in patients with renal disease or when these drugs are used concomitantly.

Methods: A prospective cohort study was carried out in HIV-infected patients who switched to a dual regimen including DTG, RPV or darunavir/COBI, separately or in combination. The primary endpoint was the evolution of the serum creatinine-based estimated glomerular filtration rate (eGFR-scr). A control group not receiving any transporter inhibitor was included.

Results: A total of 288 patients on different dual regimens were included (DTG + RPV, 92; DTG + darunavir/COBI, 23; DTG, 26; COBI, 19; control group, 128). In patients receiving two transporter inhibitors, eGFR-scr decreased by a mean of −8.4 mL/min/1.73 m2, similar to that observed with the separate use of DTG or COBI (mean of both groups, −8.6 mL/min/1.73 m2), while eGFR-scr improved in the control group. Similar evolution of proteinuria and tubular dysfunction was observed in all the groups, and there were no significant changes in the cystatin C-based eGFR. Mean eGFR-scr change inversely correlated with baseline eGFR-scr value (r = −0.39; P < 0.01), with a lower eGFR-scr decrease in patients with chronic kidney disease.

Conclusions: Similar eGFR-scr decreases were observed in patients using different antiretroviral drugs inhibiting the tubular transport of creatinine, separately or in combination, with no alterations in proteinuria or cystatin C-based eGFR. The lack of additional changes when the drugs were used in combination, and the lower impact in cases of previous chronic kidney disease, suggest that there are compensatory mechanisms for creatinine secretion.

Introduction

Renal involvement has become an important issue in HIV-infected patients. Multiple cohort studies have found a decreased estimated glomerular filtration rate (eGFR) and an increased incidence of chronic kidney disease (CKD) in this population, related to traditional risk factors and the effects of various antiretroviral drugs,[1] and therefore kidney function monitoring is mandatory.

In clinical practice, the preferred method to assess overall kidney function is the measurement of serum creatinine concentration, which allows us to estimate the eGFR, usually by using the Chronic Kidney Disease Epidemiology Collaboration (CKD-epi) equation.[2] However, in subjects with normal renal function, active tubular renal secretion accounts for 10–40% of creatinine clearance. Specifically, creatinine has been shown to be a substrate for the basolaterally expressed organic cation transporter 2/solute carrier family 22 member 2 (OCT2/SLC22A2) and the apically expressed multidrug and toxin extrusion (MATE) transporters.[3]

Regarding antiretroviral drugs, interactions with the tubular transport of creatinine have mainly been identified with rilpivirine (RPV), dolutegravir (DTG), and the pharmacoenhancer cobicistat (COBI). While RPV and DTG mainly inhibit the renal transporter OCT2, COBI predominantly inhibits MATE1. As a result, this interaction can cause mild-to-moderate increases in serum creatinine concentrations and moderate reductions in serum creatinine-based eGFR (eGFR-scr).[3–5]

This creatinine increase can give cause for concern, especially when the patient is receiving combinations that include other nephrotoxic HIV drugs such as tenofovir disoproxil fumarate (TDF).[3,6] To safely use these combinations, clinicians must correctly interpret changes in serum creatinine upon initiation or switch of therapy. However, there are no data in the clinical setting on the evolution of renal function, in terms of eGFR-scr, in different subgroups, such as those with CKD or previous renal toxicity on TDF, or in the case of the simultaneous use of two of these transport inhibitors.

We therefore conducted a prospective analysis to determine the evolution of renal function, including eGFR-scr, serum cystatin C and various urinary parameters, in patients receiving one inhibitor or a combination of two inhibitors of the renal transporters OCT2 and/or MATE1, according to different baseline factors, with inclusion of a control group of patients switching to a dual regimen not including DTG, RPV or COBI.

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