Early Markers of Tubular Dysfunction in Antiretroviral-Experienced HIV-Infected Patients Treated with Tenofovir Versus Abacavir

Abstract

Tenofovir disoproxil fumerate (TDF) is an effective nucleoside reverse transcriptase inhibitor for HIV infection but it is potentially nephrotoxic. A selective mithochondrial toxicity has been hypothesized. To assess early markers of renal toxicity, we evaluated a cohort of antiretroviral (ARV)-experienced HIV patients who had been switched from a thymidinic backbone to either a TDF/emtricitabine regimen (TDF; 73 patients) or an abacavir/lamivudine (ABV) regimen (28 patients). Markers of mitochondrial toxicity (cytochrome c, Cyc) or cytosolic (α-glutathione S transferase, α-GST) together with common indicators of renal damage were assessed at baseline (T0) and after 1 (T1), 3 (T2), 6 (T3), and 12 (T4) months of patient exposure to therapy. Clinical features of both groups were comparable at T0. There was no significant variation in estimated glomerular filtration rate (eGRF), median urine protein excretion, or microalbuminuria and serum phosphate levels in both groups during the study period. There was a significant increase in urinary excretion of phosphate in patients on TDF compared to those on ABV at T3 and T4. Fractional excretion of uric acid was also altered in the two treatment groups; there was no change in the ABV (constantly less than 0.10), but a progressive increase in TDF patients. Serum potassium levels were significantly lower in ABV than in TDF treated patients. Urine concentrations of α-GST showed a nonsignificant variation in both groups, while Cyc excretion was significantly higher at T1 and T3 in TDF-treated compared to ABV-treated patients. In conclusion, TDF may be associated with subclinical mitochondrial damage, inducing at a later stage increased urinary excretion of phosphate and uric acid, as markers of incipient tubular injury.

Association of Higher Plasma Vitamin D Binding Protein and Lower Free Calcitriol Levels with Tenofovir Disoproxil Fumarate Use and Plasma and Intracellular Tenofovir Pharmacokinetics: Cause of a Functional Vitamin D Deficiency?

“…TDF, tenofovir, renal phosphate loss, and FGF23. In the TDF group, we found mild phosphaturia in the absence of significant tubular proteinuria or glycosuria, consistent with other studies showing that TDF-associated increased renal excretion of phosphate occurs in the absence of proteinuria or more generalized renal tubular dysfunction (14,39). Note that the low TRP was not associated with high parathyroid hormone levels.…”

“…There is a complex interplay between bone, endocrine, and renal physiology (Table 1). TDF use is associated with decreased bone mineral density (2)(3)(4)(5)(6), possibly caused by TDF-induced phosphaturia (7)(8)(9)(10)(11)(12)(13)(14) with accompanying hypophosphatemia and osteomalacia (15)(16)(17). The phosphaturic hormone fibroblast growth factor 23 (FGF23) is not altered by TDF use (18,19).…”

The Problem of Renal Function Monitoring in Patients Treated With the Novel Antiretroviral Drugs

“…Finally, the potential toxic effect of some antiretroviral agents, such as indinavir or tenofovir (TDF), is well known with a body of evidence. [4][5][6] Although these drugs may rarely induce clinically evident nephrotoxic renal damage, they more often represent a cofactor in the determinism of CKD.…”

Simulating the development and progression of Chronic Kidney Disease and osteoporosis in people living with HIV

“…These external validations compare data observed in the studies with model predictions obtained simulating the experience of a cohort with the same distribution of risk factors of the patients enrolled in the study; unfortunately, the overlapping among risk factors is not reported in detail in any of such studies, but it had to be inferred from epidemiological data. Furthermore, no study was identified that reported all evaluated outcomes on the same population, so we tested the components of the overall model separately: predicted evolution of EGFR values has been compared (Figure 4) to data reported by Maggi in 2012 [29], while the effect of EGFR declining in a baseline period on risk of ESRD and mortality ( Figure 5) was compared with data observed in [30][31][32][33], which were clinical studies conducted on a non-HIV population. Overall, the models' predictions compare reasonably well with observed data: if EGFR decrease appears to be slightly overestimated, in particular by model 2 (ICONA-cohort based risks), this is offset by an opposite modest underestimation of subsequent hard end-points incidence.…”