J. M. Tabernero

Randomized, international study of cyclosporine microemulsion absorption profiling in renal transplantation with basiliximab immunoprophylaxis

Increasing information suggests that absorption profiling may be superior to trough level monitoring for optimal concentration control of cyclosporine microemulsion (NeoralTM) therapy, and that CsA exposure early post‐transplant may correlate significantly with reduced risk of acute graft rejection.

Efficacy and safety of tacrolimus compared with ciclosporin A in renal transplantation: three-year observational results.

BACKGROUND The European tacrolimus versus ciclosporin A microemulsion (CsA-ME) renal transplantation study showed that tacrolimus was significantly more effective in preventing acute rejection and had a superior cardiovascular risk profile at 6 months. METHODS The endpoints of this investigator-initiated, observational, 36-month follow-up were acute rejection incidence rates, rates of patient and graft survival and renal function. An additional analysis was performed using the combined endpoints BPAR, graft loss and patient death. Data available from the original ITT population (557 patients; 286 tacrolimus and 271 CsA-ME) were analysed. RESULTS A total of 231 tacrolimus and 217 CsA-ME patients participated. At 36 months, Kaplan-Meier-estimated BPAR-free survival rates were 78.8% in the tacrolimus group and 60.6% in the CsA-ME group, graft survival rates were 88.0% and 86.9% and patient survival rates were 96.6% and 96.7%, respectively. The estimated combined endpoint-free survival rate was 71.4% with tacrolimus and 55.4% with CsA-ME (P <or= 0.001, chi-square test). Significantly more CsA-ME patients crossed over to tacrolimus during the 3-year follow-up: 21.2% versus 2.6%, P <or= 0.0001, chi-square test. Most patients in the tacrolimus arm discontinued steroids and received monotherapy and fewer tacrolimus patients remained on a triple regimen. Mean serum creatinine concentration was 145.4 +/- 90.9 micromol/L with tacrolimus and 149.0 +/- 92.1 micromol/L with CsA-ME. Significantly more CsA-ME patients had a classified cholesterol value >6 mmol/L (26.3% versus 12.6%, P <or= 0.0003, chi-square test). CONCLUSIONS Patients treated with tacrolimus had significantly higher combined endpoint-free survival rates and lower acute rejection rates with less immunosuppressive medication at 36 months.

Changes in coagulation and fibrinolysis in the postoperative period immediately after kidney transplantation in patients receiving OKT3 or cyclosporine A as induction therapy.

Different immunosuppressive agents, in particular OKT3, have been implicated as causative factors in the risk for renal thrombosis in the period immediately after kidney transplantation. Also, in different types of vascular surgery, a state similar to hypercoagulation has been reported. To assess the extent to which OKT3, cyclosporine A (CsA), and surgery itself affect coagulation and fibrinolysis, a study was conducted of 20 patients divided into two groups: group A, 10 patients received OKT3 (first dose during the induction of anesthesia); and group B, 10 patients received CsA (first dose at least 2 hours before transplantation). Basal determinations and determinations at 2, 4, and 24 hours after the induction of anesthesia were made. No differences were found between the groups with respect to the clinical and usual coagulation parameters. The following were studied in both groups: (1) markers of coagulation activity (prekallikrein [PKK] levels and formation of thrombin-antithrombin complexes [TATc]), (2) inhibitors and suppressors of hemostasis (antithrombin III [AT-III] and protein C [PC] activity), (3) markers of fibrinolysis activation (levels of plasminogen [PLG] and of alpha2-antiplasmin [alpha2-APL]), and (4) markers of endothelial damage (tissue plasminogen activator [TPA] and thrombomodulin [TMD]). In both groups, an important formation of TATc was observed early, together with a decrease in PKK levels and consumption of both AT-III and PC, which reached their lowest levels at 24 hours. This points to an activation of coagulation through the intrinsic route and a secondary consumption of hemostasis inhibitors, both possibly caused by surgery. A consumption of PLG and alpha2-APL was also observed, reflecting stimulation of the fibrinolytic system and a physiological response to the activation of coagulation. A greater release of endothelial TPA was only observed in the patients receiving OKT3 (P < 0.0001), possibly signaling endothelial activation. It is concluded that surgical stress could be the major factor triggering the alterations seen in hemostasis and their possible consequences.

The influence of uremia on the accessibility of phosphomycin into interstitial tissue fluid

SummaryThe entry and persistence of phosphomycin in interstitial tissue fluid (ITF) were studied in 9 patients with normal renal function and 8 patients with varying degrees of renal impairment, all of whom received a single i.v. dose of 30 mg/kg. ITF was obtained from skin blisters produced by suction. The antibiotic followed a two-compartment open kinetic model. In patients with normal renal function, phosphomycin is incorporated rapidly into the ITF reaching a level of 60.4 µg/ml 60 min after administration. There was no statistically significant difference between the elimination rates from serum and ITF. The serum half-life of the slow disposition phase was 1.75 h in patients with normal renal function. There was a linear correlation between the elimination half-life of phosphomycin in serum and ITF in subjects with differing degrees of renal impairment.

Pharmacokinetics of cefoxitin during haemofiltration

SummaryThe pharmacokinetics of cefoxitin was studied in patients with renal impairment during haemofiltration and in the intervening periods after administration of 30 and 15 mg/kg of the drug, respectively. Different pharmacokinetic patterns were established during haemofiltration and in the interim period, with average elimination half-lives of 11.85±4.3 and 3.41±0.6 h, respectively. The average fraction of the cefoxitin dose eliminated in haemofiltration was 0.62±0.11, more than that established in haemodialysis. In patients with terminal renal impairment undergoing haemofiltration every 48 h, a dose of 15 or 30 mg/kg is recommended at the start and at the end of each haemofiltration session.

Encephalopathy caused by lanthanum carbonate.

Lanthanum carbonate is a nonaluminum, noncalcium phosphate-binding agent, which is widely used in patients with end-stage chronic kidney disease. Until now, no significant side-effects have been described for the clinical use of lanthanum carbonate, and there are no available clinical data regarding its tissue stores. Here we report the case of a 59-year-old patient who was admitted with confusional syndrome. The patient received 3750 mg of lanthanum carbonate daily. Examinations were carried out, and the etiology of the encephalopathy of the patient could not be singled out. The lanthanum carbonate levels in serum and cerebrospinal fluid were high, and the syndrome eased after the drug was removed. The results of our study confirm that, in our case, the lanthanum carbonate did cross the blood-brain barrier (BBB). Although lanthanum carbonate seems a safe drug with minimal absorption, this work reveals the problem derived from the increase of serum levels of lanthanum carbonate, and the possibility that it may cross the BBB. Further research is required on the possible pathologies that increase serum levels of lanthanum carbonate, as well as the risks and side-effects derived from its absorption.

Influence of the route of administration on the pharmacokinetics of amikacin.

SummaryThe pharmacokinetics of amikacin was studied in 17 hospitalized patients with normal renal function (creatinine clearance greater than 90 ml/min), after the administration of a single dose of 7.5 mg/kg body weight. In 10 patients the antibiotic was administered intravenously and in the other 7 it was injected intramuscularly. After i. v. administration, the antibiotic followed an open two-compartment kinetic model, and after i. m. administration it followed a single compartment kinetic model. The route of administration did not significantly modify the pharmacokinetic parameters of amikacin. On the basis of the pharmacokinetic parameters thus established, an intravenous infusion for therapeutic use should have an administration rate of 2.5 [mg/kg/h] and a duration of 6 h.

Hypotension, as consequence of the interaction between tacrolimus and mirtazapine, in a patient with renal transplant

The prevalence of psychiatric disorders in dialyzed patients is estimated around 5-20% of the cases. This explains the high use of antidepressant drugs in these patients. We present the case of a 68-year-old woman with a history of renal failure, with chronic hemodialysis and a depressive syndrome in treatment with Mirtazapine. In November 2008, the patient received a renal graft. An immunosuppressant treatment was started with Basiliximab, Tacrolimus, Mycophenolate Mofetil, and corticosteroids. The patient did not present renal immediate renal function. Four days after the transplant, the treatment with Mirtazapine was re-applied, with an asymptomatic hypotension after 2 hours, and without surgical complications. Tacrolimus blood levels were higher than 15 ng/ml. In our opinion, hypotension was a consequence of the interaction Mirtazapine-Tacrolimus in a patient without immediate renal function. This situation has not been described in the literature before, and hypotension could have had negative consequences in the evolution of the graft.

Elimination of Cefroxadine (CGP-9000) from Patients Undergoing Dialysis

SummaryThe pharmacokinetics of cefroxadine was studied in 17 patients with terminal renal impairment, 10 of whom were undergoing 5 h dialysis sessions. The antibiotic was administered as a single oral dose of 500 mg. Cefroxadine followed a single compartment open kinetic model. During the interdialysis period in patients with terminal renal impairment, an average Cmax of 26.59 µg/ml and a tmax of 3.65 h were reached, which are greater than in patients with normal renal function. The serum half-life was reduced from 23.55 h in the interdialysis periods to 3.40 h during the dialysis sessions. The average extraction coefficient was 0.249. It is recommended that a 500 mg dose cefroxadine should be administered at the end of each dialysis session if the interdialysis period is 48 h.

Very low doses of direct intravenous iron in each session as maintenance therapy in hemodialysis patients.

Abstract Background: Intravenous (IV) iron supplementation is widely used in hemodialysis (HD) patients to treat their periodic losses. However, the ideal dose and frequency is unknown. The goal of the study is to see if a 20 mg dose of iron IV at the end of each session of HD as iron maintenance is better than the iron prior therapy. We analyze the erythropoiesis activity (EA) and functional iron (FI) after four weeks of treatment. Methods: In 36 patients, we measure reticulocyte count and content of hemoglobin reticulocyte (CHr) as EA and FI markers, respectively, before and after the treatment. Before the study, 23 patients received another different therapy with IV iron as maintenance therapy. Results: Reticulocyte count: 49.7 ± 23.8 × 103 before and 47.2 ± 17.2 × 103 after the treatment (p= 0.51). The CHr: 34.8 ± 3.7 pg and 34.4 ± 3.5 pg, respectively, (p= 0.35), showing an excellent correlation with the other FI markers (serum iron r = 0.6; p = 0.001; saturation transferrin r = 0.49; p = 0.004); that is not shown with the serum ferritin (r = 0.23; p = 0.192) or the hepcidin levels (r = 0.22; p = 0.251). There was not a correlation between the C-Reactive Protein, reticulocyte count, and CHr. The 13 patients who did not receive the iron prior to the study showed high FI levels, but not an increased of the serum ferritin or the serum hepcidin levels. Conclusions: The administration of a small quantity of iron at the end of every HD session keeps the EA and the FI levels and allows reducing the iron overload administered and/or decreasing the iron stores markers in some patients.