Tubular transporters and clearance of adefovir.

Adefovir is transported by the organic anion transporter (OAT1) and the multidrug resistant protein (MRP2, 4 and 5). We studied adefovir clearance in rat after inhibition of transporters by probenecid and in mutant transport-deficient (TR-) rats, in which MRP2 is lacking. After treatment by probenecid or placebo, pharmacokinetics of adefovir 10mg/kg was studied via population nonlinear mixed effect modeling. The fraction of drug excreted in the urine was low. Renal clearance of adefovir was significantly lower (P < 0.05) in probenecid TR- rats (0.03+/-0.02l/h) than in normal control (0.09+/-0.05l/h), in normal probenecid (0.10+/-0.07l/h) and in TR- control rats (0.13+/-0.07l/h). In vivo in rats MRP2 mutation alone did not affect adefovir clearance suggesting that MRP2 does not play a critical role in the secretion of adefovir. Additional pharmacological inhibition of transporters decreased renal clearance, which may reflect inhibition of compensating transport mechanisms activated when MRP2 is lacking.

Changing electrolyte and acido-basic profile in HIV-infected patients in the HAART era.

BACKGROUND: HIV-infected patients may develop a variety of underreported metabolic abnormalities that may be classified into HIVAN, specific HIV abnormalities, coincidental renal disorders and anti-retroviral-treatment-induced side effects. METHODS: Our descriptive cross-sectional study evaluates the prevalence of electrolyte and acid base disorders in HIV patients in the HAART era in a tertiary care teaching hospital. All consecutive HIV-infected patients (n = 1,232) presenting at our Department of Infectious Disease over 3 months were included. MEASUREMENTS: All available biochemical data obtained at admission or on the day of the visit were analyzed. We identified risk factors for electrolyte and acid base disorders with univariate regression analysis and multivariate stepwise regression analysis. Variables tested for significance included age, sex, absolute CD4 and CD8 counts, hepatitis B and C antibodies, and use and type of anti-retroviral medication. RESULTS: Most frequent and clinically relevant abnormalities were hyperuricemia in 41.3%, hypophosphatemia in 17.2% and low bicarbonate level in 13.6% of HIV-tested patients. Plasma magnesium was out of the normal range in 38.9% and blood glucose in 25.3% of the tested patients. When CD4 count was below 200/mm3, 9.2% of tested patients experienced low serum calcium (vs. 0.5% if CD4 count >200/mm3, p < 0.002), 11.4% increased creatinine plasma level (vs. 2.3% if CD4 count >200/mm3, p < 0.0001) and 24.5% low serum bicarbonate (vs. 13.7% if CD4 count >200/mm3, p < 0.0001). Protease inhibitor treatment was a significant risk factor of hyperuricemia (p < 0.003). Non-nucleoside reverse transcriptase inhibitor therapy was significantly associated with less hyperuricemia (OR = 0.6, 95% CI 0.38-0.96) and with hypophosphatemia (OR = 2.0, 95% CI 1.1-3.4). CONCLUSIONS: The profile of biochemical abnormalities in HIV-infected patients has changed, hyperuricemia and hypophosphatemia being the most prevalent. Causes are poorly understood. Interpretation of drug-induced side effects in the HIV patient is only meaningful if performed versus a control group of patients.

[Tubular transporters OAT1 and MRP2 and clearance of adefovir]. / Effet de l'inhibition des transporteurs OAT1 et MRP2 sur la clairance de l'adéfovir.

Adefovir is transported by the organic anion transporter (OAT1) and the multidrug resistant protein (MRP2, 4 and 5). We studied adefovir clearance in rat after inhibition of transporters by probenecid and in TR- rats, in which MRP2 is lacking. After treatment by probenecid or placebo, pharmacokinetics of adefovir 10 mg/kg was studied via population modeling (NONMEM). The fraction of drug excreted in the urine was low. Renal clearance of adefovir was significantly lower (P < 0.05) in probenecid TR- rats (0.03 +/- 0.02 l/hour) than in normal control (0.09 +/- 0.05 l/hour), in normal probenecid (0.10 +/- 0.07 l/hour) and in TR- control rats (0.13 +/- 0.07 l/hour). In vivo in rats MRP2 mutation alone did not affect adefovir clearance suggesting that MRP2 does not play a critical role in the secretion of adefovir. Additional pharmacological inhibition of transporters decreased renal clearance, which may reflect inhibition of compensating transport mechanisms activated when MRP2 is lacking.

Blood oxidative stress status in patients with macrophagic myofasciitis.

The study aimed at determining the presence of an oxidative stress in patients with macrophagic myofasciitis (MMF), a new inflammatory myopathy with suspected toxic etiology related to aluminium hydroxide-containing vaccines. A total of 30 MMF patients (nine males, 21 females; aged 42+/-14 years), whose diagnosis was confirmed by deltoid biopsy, have been included and compared to 38 sex- and age-matched healthy control subjects (10 males, 28 females; aged 43+/-8 years). The blood oxidative stress status has been evaluated by assaying six parameters: plasma lipid peroxidation products (thiobarbituric acid-reactive substances: TBARS) and antioxidant defense systems: plasma vitamin E and glutathione peroxidase (GSH-Px) activity, erythrocyte GSH-Px and Cu,Zn-superoxide dismutase (SOD) activities. Plasma selenium was also determined as a trace element essential to the activity of GSH-Px. Statistical significance was evaluated by the Mann-Whitney test. Plasma GSH-Px activity, selenium and vitamin E concentration were significantly lower in MMF group than in controls (P=0.004, P=0.003 and P=0.009, respectively), with a positive correlation in MMF patients between plasma GSH-Px activity and selenium concentration (rho=0.0001). The other parameters of oxidative stress did not significantly differ between both groups. A macrophage activation could occur in MMF, consequently to chronic stimulation by aluminium-containing vaccines, and could participate to the lower values of selenium and vitamin E observed in comparison with controls. Nevertheless, since no deficiency in these elements has been observed, no supplementation is to be considered.

Renal outcome after ciclosporin-induced nephrotoxicity.

BACKGROUND: Renal outcome after ciclosporin (CsA) is not clear in most studies involving patients with many renal comorbid conditions. We first report on renal function recovery after CsA in previously healthy kidney patients. METHODS: Uveitis patients, enroled in a unique single centre cohort follow-up study initiated in 1987, were prospectively evaluated for plasma creatinine and glomerular filtration rate (GFR) before, during (>2 years) and after (>6 months) CsA therapy. We hypothesized that CsA alters renal function progressively over time according to two additive exponential components (irreversible and reversible) and used a mixed linear model with exponential speed parameters maximizing the likelihood. RESULTS: Twenty-seven patients treated for 60+/-34 months (CsA 5.1+/-2.5 mg/kg/day) were followed up for 56+/-42 months after CsA withdrawal. Baseline creatinine was 0.92+/-0.15 mg/dl. The reversible effect of CsA was quantified as a 0.11+/-0.07 mg/dl increase in creatinine/100 mg CsA/day (P<0.001) and a 6.0+/-3.7 ml/min/1.73 m(2) decrease in GFR/100 mg CsA/day (P<0.0001). The irreversible effect was quantified as a 0.03+/-0.05 mg/dl increase in creatinine/100 g cumulative CsA received (P<0.007) and a decrease of 3.3+/-3.9 ml/min/1.73 m(2) GFR/100 g CsA. CONCLUSIONS: Although significant decrease in GFR is induced by low-dose CsA therapy in previously healthy kidney patients, renal function recovery is possible after CsA withdrawal and best predicted by CsA daily dosage. Irreversible loss in GFR is correlated to cumulated CsA exposure. The lowest CsA dosage and shortest exposure time effect as well as unlimited renal monitoring are required in order to provide the best long-term renal outcome.

Ionic dialysance vs urea clearance in the absence of cardiopulmonary recirculation.

BACKGROUND: Several studies have shown a slight discrepancy between ionic dialysance (D) and dialyser urea clearance (UK), even in the absence of access recirculation. As it has been suggested that this discrepancy could be due to the cardiopulmonary recirculation, we studied the relationship between these two parameters in a particular dialysis setting without cardiopulmonary recirculation. METHODS: Paired measurement of urea clearance and ionic dialysance were performed in five patients without arterio-venous access who were dialysed via an internal jugular vein twin catheter. Fifty paired measurements were used for statistical analysis. Vascular access recirculation was assessed by an ultrasound dilution technique. The measured value of ionic dialysance was corrected (D(0)) for the effect of vascular access recirculation and was compared with instant urea clearance calculated from the dialysate side. RESULTS: The difference between the paired measurements of D(0) and UK (n=50) was equal to 0.6+/-16.9 ml/min (NS). With a statistical power of 90% and taking into account this standard deviation, this study might have shown a difference of at least 10.9 ml/min. The correlation was highly significant (P<0.0001). The discrepancy of the two parameters varied with dialysis efficiency, with a decreasing D(0):UK ratio for the higher dialysis efficiency. CONCLUSIONS: Compared with our previous results obtained in patients dialysed on arterio-venous access and performed with similar methods, the relationship between D(0) and UK is modified. This difference between D(0) and UK gets lower in patients dialysed on central catheters and this variance is in accordance with that expected when the influence of the cardiopulmonary recirculation on the measurement of ionic dialysance is taken into account. The limits of agreement (+/-2 SD) between D(0) and UK (+/-34 ml/min, Bland-Altman analysis) were higher than expected and raised questions about the accuracy of the measurement of each parameter via a central venous catheter.

Long-term renal effects of low-dose cyclosporine in uveitis-treated patients: follow-up study.

Cyclosporine (CsA), a widely used immunosuppressive drug, is an effective treatment of sight-threatening posterior idiopathic uveitis. CsA's main side effect is nephrotoxicity. The aim of this single-center prospective cohort study (conducted in a tertiary care teaching hospital in Paris, France) was to assess the long-term renal tolerance of a low-dose CsA treatment in patients with previously healthy kidneys on clinical, biologic, and pathologic criteria. Forty-one patients treated with 4.3 +/- 1.6 mg/kg body wt per day CsA for 44.9 +/- 3.6 mo were included. Mean follow-up was 55.4 +/- 0.2 mo. BP, CsA trough level, and renal function were prospectively monitored together with blood urea, creatinine clearance, GFR, and effective renal plasma flow. Eleven patients underwent serial kidney biopsies before and after 2 yr of a 4 +/- 0.9 mg/kg daily CsA treatment. Sustained low-dose CsA treatment induced a significant increase in plasma creatinine (P < 0.0001), a significant decrease in creatinine clearance (P < 0.0001), and isotopic GFR (P < 0.0001) over time. The highest dose induced more severe alterations in any of the renal parameters than the lowest dose. Prevalence of hypertension was particularly high. Histopathologic data showed significant interstitial fibrosis (P < 0.003) and tubular atrophy (P < 0.003) after 2 yr. Low-dose long-term CsA treatment induces significant renal impairment and a high incidence of hypertension. Our study suggests that lowering daily dosage may prevent CsA-induced nephrotoxicity if a daily dose of < or =3 mg/kg is used. Whether once established it is reversible is still prospective, although the occurrence of interstitial fibrosis in the kidney would argue against reversibility.