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Impairment in Kidney Tubular Function in Patients Receiving Tenofovir Is Associated with Higher Plasma Tenofovir Levels
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Reported by Jules Levin
CROI 2009 Feb 8-12 Montreal
Sonia Rodriguez Novoa*1, P Labarga1, A D'avolio2, P Barreiro1, M Albalater3, C Solera1, M Siccardi2, S Bonora2, G Di Perri2, and V Soriano1
1Hosp Carlos III, Madrid, Spain; 2Univ of Torino, Italy; and 3Fndn Jimenez-Diaz, Madrid, Spain
Background: Tenofovir (TDF) is a nucleotide analogue active against HIV and hepatitis B virus. Although TDF does not seem to affect kidney glomerular function, several studies have found significant impairment in kidney tubular function after prolonged exposure to TNF, as compared with other nucleoside analogs. Possible influence of TDF exposure on kidney tubular function has not been explored so far.
Methods: All consecutive HIV patients receiving TDF for longer than 6 months at a referral HIV clinic in Madrid during year 2008 were identified. Kidney tubular function was assessed in all patients in plasma and 24-hours urine. Altered kidney tubular function was defined when at least 2 of the following abnormalities were present: non-diabetic glucosuria, urine phosphate wasting, hyperaminoaciduria, b2-microglobulinuria, and increased fractional excretion of uric acid. Mid-dose plasma levels of TDF were measured using a validated high-performance liquid chromatography (HPLC) -mass method.
Results: A total of 92 HIV patients, with a median exposure to TDF of 33 months (IQR 10 to 46), were included in the study: 18 patients had altered kidney tubular function, and 74 controls had normal kidney tubular function. Creatinine clearance (24 h) was normal and comparable between groups (94 vs 118 mL/minute, respectively). Both groups were well matched in gender, age, weight, hepatitis C virus (HCV) co-infection, months under TDF, exposure to nephrotoxic drugs, concomitant PI use, and history of hypertension. History of diabetes was more frequent in cases (44%) than controls (22%) (p = 0.05). Plasma levels of TDF were higher in cases than controls (182 [IQR 105 to 220] vs 104 [IQR 75 to 139] ng/mL, respectively; p = 0.001). The best TDF plasma concentration threshold associated with altered kidney tubular function was 160 ng/mL (AUROC 0.75 [95%CI 0.63 to 0.87], p = 0.001) (61% sensitivity and 80% specificity). Multivariate analysis including all relevant variables showed that only TDF plasma levels >160 ng/mL were associated to abnormal kidney tubular function (OR, 4.8 [95%CI 1.5 to 16], p = 0.008).
Conclusions: Plasma levels of TDF are increased in patients experiencing abnormal kidney tubular function on treatment. These results confirm the potential specific toxicity of TDF on the kidney tubular epithelium, as other nucleoside monophosphates (adefovir and cidofovir). Studies assessing the efficacy and safety of lower doses of TDF are warranted, and this information could be helpful for hepatitis B mono-infected patients as well.
Tenofovir and Protease Inhibitor Use Are Associated with an Increased Prevalence of Proximal Renal Tubular Dysfunction
in the Swiss HIV Cohort Study (SHCS)
Christoph A. Fux1, M Opravil2, M Cavassini3, A Calmy4, B Spycher5, M Flepp6, B Hasse2, P Schmid7,
M Stockle8, V Gurtner-De la Fuente9, A Rauch1, H Furrer1 and the Swiss HIV Cohort Study
1 University Clinic for Infectious Diseases and University of Berne; 2 University Hospital Zurich; 3 Centre Universitaire Hospitalier Vaudois, Lausanne; 4 Geneva University Hospital; 8 Institute for Social and Preventive Medicine, University of Bern; 6 Klinik im Park, Zurich; 7 Kantonsspital St Gallen; 8 University Hospital Basel; 9 Ospedale Civico Lugano; Switzerland
Autor Conclusions
Proximal renal tubulopathy was documented in 22% to 50% of cART-treated patients depending on the regimn used.
The prevalence was increased under TDF and PI, especially when combined.
FE_p is most accurate to document proximal tubular dysfunction.
Confirmatory testing is necessary, as pathologica findings only persist in 50-75%.
Background
Tenofovir (TDF)-use has been associated with proximal renal tubulopathy (PRT). Excessive renal phosphate losses are of particular concern, as they may stimulate compensatory bone resorption and result in reduced bone mineral density over time.
Aims
To analyze the prevalence of PRT in general and excessive renal phosphate losses in particular and identify associated risk factors in HIV-positive patients
Patients and Methods
We performed a cross-sectional analysis in 1202 unselected patients treated within the SHCS. Four parameters with the following thresholds for pathology were measured in fasting state:
Logistic regression analyses were performed to identify associated risk factors. 174 patients with pathologic findings and 41 controls were re-tested to examine the reproducibility of our findings. Furthermore, we tried to overcome the lack of a gold standard for PRT with statistical modeling using latent class analysis, multiple imputation and factor analysis.
Results I: Cross-sectional analysis
Rates of PRT and pathological FE_p differed significantly between treatment groups (p=0.006 for PRT, p<0.001 for FE_p), being highest in patients treated with TDF and a PI (Table 1, Figure 1).
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