Population pharmacokinetics of tacrolimus in Thai kidney transplant patients: comparison with similar data from other populations.

WHAT IS KNOWN AND OBJECTIVE: Tacrolimus, the most widely used calcineurin inhibitor in kidney transplantation, has a narrow therapeutic window with high interindividual variability in its pharmacokinetics. Clinically feasible models that combine important factors may help guide individual tacrolimus dosage adjustment in kidney transplant patients. The purpose of this study was to develop a population pharmacokinetic model and investigate the influence of clinical factors on the pharmacokinetics of tacrolimus in adult Thai kidney transplant patients from routine data monitoring. METHODS: A total of 1183 whole blood concentrations from 96 patients were characterized using nonlinear mixed-effects modelling. Clinical factors tested for influence on pharmacokinetic parameters were weight, haemoglobin, duration of tacrolimus therapy, prednisolone dose, serum albumin and estimated glomerular filtration rate. RESULTS AND DISCUSSION: A one-compartment model with first-order absorption best described the data. The population estimate of tacrolimus apparent clearance (CL/F) and apparent volume of distribution (V/F) in the final population model was 21·5 L/h (95% CI; 18·38, 24·34) and 333 L (95% CI; 222·66, 484·35), respectively. CL/F increased with decreasing haemoglobin levels and decreased with increasing duration of tacrolimus therapy (both P < 0·001). The population pharmacokinetic equation that predicted CL/F of tacrolimus was CL/F = 21·5 × exp((-0·05 () (HB) ( - 11·8)))  × (DOT/125)(-0·06) , where CL/F was tacrolimus apparent oral clearance (L/h), HB was haemoglobin levels (g/dL), and DOT was duration of tacrolimus therapy (days). No covariates significantly influenced V/F. WHAT IS NEW AND CONCLUSION: The first population pharmacokinetic model of tacrolimus in Thai adult kidney transplant patients was developed and validated. Haemoglobin and duration of tacrolimus therapy could partly explain the interindividual variability in the apparent clearance of tacrolimus. This manuscript also provides a summary review of previously reported population pharmacokinetic models of twice daily tacrolimus in adult kidney transplant recipients.

Treatment of simultaneous acute antibody-mediated rejection and acute cellular rejection with alemtuzumab in kidney transplantation: a case report.

This is a case report of a living related donor kidney transplantation using basiliximab induction and maintenance immunosuppression with cyclosporine, mycophenolate sodium, and steroid. On the second posttransplant day, the patient developed acute antibody-mediated rejection, which was treated with plasmapheresis and intravenous immunoglobulin (IVIG). Five days later, the graft had still not responded to the treatment. Another biopsy revealed additional acute cellular rejection (Banff IIA). As alemtuzumab can rapidly deplete T and B lymphocytes, monocytes, and natural killer cells, the patient was treated with alemtuzumab (30 mg subcutaneously) together with methylprednisolone (500 mg) and two more plasmaphereses. The kidney graft responded within 48 hours, producing more than 4 L of urine per day. The total lymphocyte decreased from 530/microL to 50/microL remaining in the 50 to 220/microL range. The patient received valgancyclovir and cotrimoxazole as infection prophylaxis. The kidney graft responded well to the rescue treatment and the patient was discharged with a serum creatinine of 1.1 mg/mL and has been uneventfully followed in the outpatient clinic for 8 months. Today, with the potent, effective, and selective immunosuppressive regimens, the rate and severity of acute cellular rejection in kidney transplantation has decreased in most centers. However, the rate of acute antibody-mediated rejection has increased to levels greater than those of acute cellular rejection in many centers. Acute antibody-mediated rejection is more difficult and expensive to treat successfully. The treatment of acute antibody-mediated rejection included plasmapheresis and IVIG. Herein we have reported a case of kidney transplantation simultaneously developing acute antibody-mediated and acute cellular rejection; the patient was successfully treated with alemtuzumab.

A novel simple hemoglobin dilution technique to measure hemodialysis vascular access flow.

Measurement of the vascular access flow rate (Q(a)) is a widely accepted method for surveillance and predicting access failure. Among current practical methods, the ultrasound dilution technique is standard, but this requires a costly device available in few hemodialysis (HD) centers. Here, we devised a simple hemoglobin dilution technique to accurately measure Q(a) without the need for any special machines. Before HD, values of Q(a) were determined in each of 30 patients by hemoglobin dilution and then, in the same session, by ultrasound dilution. There was a significant correlation between the two techniques using automated hemoglobin and hematocrit or centrifuge-measured hematocrit levels to calculate HD fluid-derived Q(a) values. Our study shows that the HD dilution technique, using no special device, is economical, highly accurate, and easy to perform, and can be used as an alternative to standard ultrasound dilution for vascular access surveillance.

Comparison of middle-molecule clearance between convective control double high-flux hemodiafiltration and on-line hemodiafiltration.

Hemodiafiltration (HDF) is now a well-recognized treatment modality for end-stage renal disease (ESRD) patients. It provides superior characteristics over conventional hemodialysis in many respects. On-line HDF, however, which has been mainly used in clinical practice, requires a special machine. Interestingly, the recently innovated convective-control double high-flux hemodiafiltration (CC-DHF) machine can provide HDF treatment with an adjustable convection rate by using the conventional volume-controlled dialysate flow hemodialysis machine in a modified way. The present study was conducted to compare the efficacy of CC-DHF compared to on-line HDF in terms of middle and small solute clearances in 12 stable, chronic hemodialysis patients who underwent hemodialysis three times a week for at least 6 months. The results showed that the beta 2-microglobulin (beta 2M) removal represented by the beta 2M clearance in CC-DHF was comparable to that in on-line HDF (112.4+/-17.0 vs. 119.4+/-15.5 ml/min respectively, NS). Also, the beta 2M reduction ratio in the CC-DHF group did not differ from the on-line HDF group (85.5+/-4.2% vs. 86.1+/-6.7%, NS). With regard to small solute clearances, the values of single-pool Kt/V and phosphate clearance did not differ between CC-DHF and on-line HDF groups. In conclusion, CC-DHF provides removal of beta 2M and small molecule uremic toxins that is comparable to on-line HDF. An on-line HDF machine may not be available in all hemodialysis centers, whereas CC-DHF can be easily set up, with proper precautions regarding the fluid quality. Therefore, CC-DHF can provide the benefits of convective therapy to patients in situations where use of an on-line HDF machine is limited.

Dialytic performance evaluation of Rexeed: a new polysulfone-based dialyzer with improved flow distributions.

New dialyzers are designed to optimize the convective and diffusive components of solute transport. Asahi Kasei Medical Co.,Ltd.has developed a new high flux dialyzer series called Rexeed with improved flow distributions. We evaluated the in vivo dialytic performance of two dialyzers of the Rexeed series: Rexeed-18A and Rexeed-25A (1.8 m2 and 2.5 m2 ). We calculated the clearance for urea,creatinine,phosphate and b2-microglobulin both in high flux dialysis (HFD)and in 15 liter postidiluitional on-line hemodiafiltration (HDF)mode. With n = 3 patients in high flux HD at blood flow 450, 400, 350 and 250 ml/min we found remarkably high clearance for urea (347 +/- 4%, 305 +/- 0%, 288 +/- 5%, 230 +/- 3%, for Rexeed-18A and 361 +/- 3%, 329 +/- 0%, 313 +/- 1%, 234 +/- 3%for Rexeed-25A),creatinine (282 +/- 10%, 234 +/- 0%, 221 +/- 8%, 174 +/- 8%, for Rexeed-18A and 276 +/- 6%, 245 +/- 0%, 226 +/- 9%, 172 +/- 13% for Rexeed-25A),phosphate (347 +/- 0%, 316 +/- 0%, 275 +/- 4%, 202 +/- 16%, for Rexeed-18A and 364 +/- 3%, 365 +/- 0%,286 +/- 3%, 224 +/- 2% for Rexeed-25A)and b2-microglobulin (133 +/- 21%, 124 +/- 0%,118 +/- 12%, 98 +/- 11%, for Rexeed-18A and 159 +/- 8%, 169 +/- 0%,157 +/- 8%, 129 +/- 7% for Rexeed-25A) With n = 2 patients in HDF at blood flow 300 ml/min we found remarkably high clearance for urea (268 +/- 2%, for Rexeed-18A and 283 +/- 2% for Rexeed-25A),creatinine (183 +/- 6%for Rexeed-18A and 205 +/- 9% for Rexeed-25A),phosphate (245 +/- 3%, for Rexeed-18A and 270 +/- 2% for Rexeed-25A)and b2-microglobulin (166 +/- 12%, for Rexeed-18A and 192 +/- 4% for Rexeed-25A). Our preliminary evaluation describes the characteristics and the performances of a new polysulfone-based hemodialyzer series called Rexeed. Several innovative features have been implemented by the manufacturer. These constructive approaches seem to have produced a positive effect on the dialyzer performance at the bedside.