Long-term treatment with tenofovir: prevalence of kidney tubular dysfunction and its association with tenofovir plasma concentration

Background: Monitoring of side effects of long-term HIV treatment has become increasingly important. Tenofovir disoproxil fumarate (TDF), a first-line treatment option, is associated with kidney tubular dysfunction (KTD). Our objective was to further investigate the prevalence and risk factors of KTD, in particular its association with TDF plasma concentration in HIV-infected patients treated with TDF for at least one year. Methods: An observational cross-sectional single-centre study was conducted. KTD was defined as the presence of at least two of the following criteria: urinary alpha 1-microglobulin/creatinine ratio > 15 mg/10 mmol; fractional excretion (FE) of phosphate >20% in the presence of hypophosphataemia; FE of uric acid >10% in the presence of hypouricaemia and glucosuria. Multivariate logistic regression was used to study which variable was associated with KTD. Results: A total of 161 HIV patients were included. Abnormalities in tubular function were observed in 101 patients (62.7%), while 17 patients (10.6%) fulfilled the definition of KTD. Urinary a1-microglobulin/creatinine ratio was the most sensitive parameter to detect KTD. Multivariate logistic regression showed TDF plasma concentration to be the only variable associated with KTD. Post hoc analysis showed a stronger association between the product of TDF plasma concentration and TDF exposure and KTD. Conclusions: Parameters of KTD are frequently observed in patients on long-term TDF-containing combination antiretroviral therapy. KTD is associated with higher TDF plasma concentrations. A stronger association between the product of TDF plasma concentration and TDF exposure and KTD could suggest cumulative toxicity. A causative role for elevated TDF plasma concentration in development of KTD cannot be demonstrated in this cross-sectional analysis. Longitudinal research is needed to investigate the development and clinical relevance of KTD.