Comparison of disease activity between tacrolimus and mycophenolate mofetil in lupus nephritis: a randomized controlled trial.

We conducted a prospective multicenter, opened-label, parallel, randomized, controlled trial to compare tacrolimus (TAC) and mycophenolate mofetil (MMF) for induction and maintenance therapy in lupus nephritis (LN). Adult patients with biopsy-proven LN International Society of Nephrology/Renal Pathology Society classes III-V and active nephritis were to receive prednisolone (0.7-1.0 mg/kg/day for four weeks of run-in period and tapered) and randomly assigned to receive TAC (0.1 mg/kg/day) or MMF (1.5-2 g/day) as induction therapy for six months. All patients who had remission received azathioprine (AZA) 1-2 mg/kg/day as standard treatment in the maintenance phase. The primary outcome was Systemic Lupus Erythematosus Disease Activity Index-2000 (SLEDAI-2K) at six and 12 months, and the secondary outcomes included renal SLEDAI, non-renal SLEDAI, modified SLEDAI-2K, immunity SLEDAI, and disease activity remission. Eighty-four patients were randomized. One patient who was randomized to the TAC group withdrew from the study immediately after randomization. Therefore, 42 patients received MMF and 41 patients received TAC. Disease activity remission rate and time to disease activity remission were similar in both groups. Twelve patients (28.57%) in the MMF group and 10 patients (24.39%) in the TAC group achieved disease activity remission. For disease activity scores, both regimens significantly improved SLEDAI-2K during induction and maintenance therapy. Overall, SLEDAI-2K score in the MMF group decreased more compared with the TAC group. In the MMF group, mean SLEDAI-2K decreased from 11.6 ± 4.8 to 6.3 ± 3.9 after induction therapy and to 5.4 ± 4.4 after maintenance therapy. In the TAC group, mean SLEDAI-2K decreased from 9.0 ± 3.7 to 6.3 ± 5.1 after induction therapy and to 7.1 ± 5.4 after maintenance therapy. Renal SLEDAI and modified SLEDAI-2K showed a similar pattern with SLEDAI-2K. In non-renal SLEDAI and immunity SLEDAI, both regimens also resulted in decreased disease activity scores during the first two months. After that the scores were slightly increased. In the MMF group, the scores were still lower than baseline but in the TAC group were not. In conclusion, disease activity remission rate was similar in the MMF and TAC groups. For disease activity score as measured by SLEDAI-2K, TAC was comparable with MMF during induction but MMF was more effective on disease activity of active LN classes III and IV at 12 months, especially in the renal system.

Early Conversion From Calcineurin Inhibitor- to Everolimus-Based Therapy Following Kidney Transplantation: Results of the Randomized ELEVATE Trial.

In a 24-month, multicenter, open-label, randomized trial, 715 de novo kidney transplant recipients were randomized at 10-14 weeks to convert to everolimus (n = 359) or remain on standard calcineurin inhibitor (CNI) therapy (n = 356; 231 tacrolimus; 125 cyclosporine), all with mycophenolic acid and steroids. The primary endpoint, change in estimated glomerular filtration rate (eGFR) from randomization to month 12, was similar for everolimus versus CNI: mean (standard error) 0.3(1.5) mL/min/1.732 versus -1.5(1.5) mL/min/1.732 (p = 0.116). Biopsy-proven acute rejection (BPAR) at month 12 was more frequent under everolimus versus CNI overall (9.7% vs. 4.8%, p = 0.014) and versus tacrolimus-treated patients (2.6%, p < 0.001) but similar to cyclosporine-treated patients (8.8%, p = 0.755). Reporting on de novo donor-specific antibodies (DSA) was limited but suggested more frequent anti-HLA Class I DSA under everolimus. Change in left ventricular mass index was similar. Discontinuation due to adverse events was more frequent with everolimus (23.6%) versus CNI (8.4%). In conclusion, conversion to everolimus at 10-14 weeks posttransplant was associated with renal function similar to that with standard therapy overall. Rates of BPAR were low in all groups, but lower with tacrolimus than everolimus.

Elevated expressions of myeloid-related proteins-8 and -14 are danger biomarkers for lupus nephritis.

Myeloid-related proteins, MRP-8 and -14, which have been identified as molecules that mediate the danger signaling in innate immune response, are also known as the DAMPs (damage associated molecular pattern molecules). The proteins were found in infiltrating macrophages and neutrophils at inflammatory sites. Their expression was correlated with severe forms of glomerulonephritis. Therefore, this study examined whether or not MRP-8 and -14 can be used as biomarkers for identifying severely active lupus nephritis (LN). Total blood leukocyte samples and renal biopsy tissues from a prospective cohort of LN patients were used to determine mRNA and protein expression levels of MRP-8 and -14. The mRNA levels of MRP-8 and -14 in total blood leukocytes were significantly higher in active LN patients than quiescent LN patients and healthy controls. Moreover, the mRNA levels of MRP-8 and -14 in the total blood leukocytes and kidney tissues were significantly correlated with therapeutic response and the mRNA expression levels in the kidney were associated with an early loss of the kidney function. MRP-8 and -14 can be used as non-invasive prognostic biomarkers in patients with LN.

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.

The outcomes of kidney transplantation in hepatitis B surface antigen (HBsAg)-negative recipients receiving graft from HBsAg-positive donors: a retrospective, propensity score-matched study.

The outcomes of kidney transplantation (KT) from hepatitis B surface antigen-positive [HBsAg(+)] donors to HBsAg(-) recipients remain inconclusive, possibly due to substantial differences in methodological and statistical models, number of patients, follow-up duration, hepatitis B virus (HBV) prophylactic regimens and hepatitis B surface antibody (anti-HBs) levels. The present retrospective, longitudinal study (clinicaltrial.gov NCT02044588) using propensity score matching technique was conducted to compare outcomes of KT between HBsAg(-) recipients with anti-HBs titer above 100 mIU/mL undergoing KT from HBsAg(+) donors (n = 43) and HBsAg(-) donors (n = 86). During the median follow-up duration of 58.2 months (range 16.7-158.3 months), there were no significant differences in graft and patient survivals. No HBV-infective markers, including HBsAg, hepatitis B core antibody, hepatitis B extracellular antigen and HBV DNA quantitative test were detected in HBsAg(+) donor group. Renal pathology outcomes revealed comparable incidences of kidney allograft rejection while there were no incidences of HBV-associated glomerulonephritis and viral antigen staining. Recipients undergoing KT from HBsAg(+) donors with no HBV prophylaxis (n = 20) provided comparable outcomes with those treated with lamivudine alone (n = 21) or lamivudine in combination with HBV immunoglobulin (n = 2). In conclusion, KT without HBV prophylaxis from HBsAg(+) donors without hepatitis B viremia to HBsAg(-) recipients with anti-HBs titer above 100 mIU/mL provides excellent graft and patient survivals without evidence of HBV transmission.

Therapeutic drug monitoring of mycophenolate mofetil for the treatment of severely active lupus nephritis.

BACKGROUND: Plasma mycophenolic acid (MPA) concentrations may predict therapeutic response in active lupus nephritis (LN). We determined the efficacy and safety of a concentration-controlled MPA regime in the treatment of severely active LN. METHODS: In this prospective study, 19 biopsy-proven class III/IV LN patients were treated with mycophenolate mofetil (MMF) for 48 weeks. The MMF dosage was based on maximal plasma MPA concentration at 1-hour post dose (MPA-C1). All patients had plasma MPA-C1 levels monitored weekly until achieving the targeted level of >13 mg/L. A low-dose steroid protocol was started at 0.5 mg/kg/day and rapidly tapered to 5 mg/day. Therapeutic response was evaluated at week 24 and week 48. MPA area-under-the curve (MPA-AUC0-12h) was measured at week 12 to verify the optimum dosage. RESULTS: No death or end-stage kidney disease occurred in this study. Seventeen patients (89%) responded to therapy at week 24 with four (21%) patients having complete response. There was no renal relapse at week 48 and four more patients had converted from partial response to complete response. Seventy eight percent of patients achieved the recommended MPA-AUC0-12h level. No association between plasma MPA concentrations and adverse reactions or infections was found. CONCLUSIONS: MPA-C1 may be a practical monitoring of MPA levels in patients with LN. It is convenient to monitor and may facilitate an optimum estimate of MPA exposure.

Association of CD247 with systemic lupus erythematosus in Asian populations.

OBJECTIVE: Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease with complex genetic inheritance. CD247 (CD3Z, TCRZ) plays a vital role in antigen recognition and signal transduction in antigen-specific immune responses, and is known to be involved in SLE pathogenesis. Weak disease association was reported for genetic variants in this gene in Caucasian studies for SLE, Crohn's disease and systemic sclerosis, but its role as a genetic risk factor was never firmly established. METHODS: In this study, using a collection of 612 SLE patients and 2193 controls of Chinese ethnicity living in Hong Kong in a genome-wide study, single nucleotide polymorphisms (SNPs) in and around CD247 were identified as being associated with SLE. The two most significant SNPs in this locus were selected for further replication using TaqMan genotyping assay in 3339 Asian patients from Hong Kong, Mainland China, and Thailand, as well as 4737 ethnically and geographically matched controls. RESULTS: The association of CD247 with SLE in Asian populations was confirmed (rs704853: odds ratio [OR] = 0. 81, p = 2.47 × 10(-7); rs858543: OR = 1.10, p = 0.0048). Patient-only analysis suggested that rs704853 is also linked to oral ulcers, hematologic disorders and anti-double-stranded DNA (dsDNA) antibody production. CONCLUSION: A significant association between variants in CD247 and SLE was demonstrated in Asian populations. Understanding the involvement of CD247 in SLE may shed new light on disease mechanisms and development of new treatment paradigms.

The association of single nucleotide polymorphism within vascular endothelial growth factor gene with systemic lupus erythematosus and lupus nephritis.

There were no statistically significant difference in allele and genotype frequency of the polymorphisms within the vascular endothelial growth factor (VEGF) gene (-460 and +405) between 193 systemic lupus erythematosus patients and 234 healthy controls. However, the +405 GG was significantly associated with lupus nephritis (LN) patients with low VEGF mRNA expression and LN with end-stage renal disease.

Major lupus organ involvement: severe lupus nephritis.

Lupus nephritis is a common and severe complication of systemic lupus erythematosus. A number of patients have nephritis as a presenting feature that, in its severe form, can shortly lead to end-stage renal disease and/or death. Renal flare usually occurs a few years after the first episode and is remarkably predominant in the Asian population. Frequent monitoring for renal flare enhances early recognition and timely treatment. The mainstay therapy continues to be the prolonged use of cytotoxic/immunosuppressive drugs that have a number of undesirable effects, particularly ovarian failure and development of opportunistic infections. This review will focus on the pathogenesis and the unique genetic factors found in Asian patients with lupus nephritis. Here, we propose an appropriate management scheme for the treatment of lupus nephritis in Asian patients.

Population differences in SLE susceptibility genes: STAT4 and BLK, but not PXK, are associated with systemic lupus erythematosus in Hong Kong Chinese.

In this study, we compared the association of several newly discovered susceptibility genes for systemic lupus erythematosus (SLE) between populations of European origin and two Asian populations. Using 910 SLE patients and 1440 healthy controls from Chinese living in Hong Kong, and 278 SLE patients and 383 controls in Thailand, we studied association of STAT4, BLK and PXK with the disease. Our data confirmed association of STAT4 (rs7574865, odds ratio (OR) =1.71, P=3.55 x 10(-23)) and BLK (rs13277113, OR=0.77, P=1.34 x 10(-5)) with SLE. It was showed that rs7574865 of STAT4 is also linked to hematologic disorders and potentially some other subphenotypes of the disease. More than one genetic variant in STAT4 were found to be associated with the disease independently in our populations (rs7601754, OR=0.59, P=1.39 x 10(-9), and P=0.00034 when controlling the effect of rs7574865). With the same set of samples, however, our study did not detect any significant disease association for PXK, a risk factor for populations of European origin (rs6445975, joint P=0.36, OR=1.06, 95% confidence interval: 0.93-1.21). Our study indicates that some of the susceptibility genes for this disease may be population specific.

Expression profile of HIN200 in leukocytes and renal biopsy of SLE patients by real-time RT-PCR.

HIN200 is a human IFN-inducible gene and homologous to murine IFI202 gene, which was identified as a candidate gene for SLE susceptibility in lupus mouse model. We determined these gene expressions in leukocytes from 20 SLE patients and 10 healthy controls and in renal biopsies from 29 SLE patients and 15 kidney donors using sensitive real-time reverse transcriptase-polymerase chain reaction (RT-PCR). The expressions of MNDA, IFIX, IFI16 and AIM2 genes significantly increased in leukocytes but not in kidney biopsies from SLE patients as compared to the control individuals, with P = 0.0003, P = 0.0056, P = 0.0002 and P < 0.0001, respectively. We also assessed the expression profiles of IFIX and IFI16 isoforms using semi-quantitative RT-PCR. We found up-regulation of B isoform (short product) of IFI16 in SLE patients. In addition, the expression levels were analyzed in correlation with disease activity and clinical characteristics. Interestingly, higher expression of MNDA was observed in patients who were positive for anti-dsDNA antibodies than in patients who were negative (P = 0.0276). In conclusion, it is suggested that the HIN200 genes have a role in SLE pathogenesis. Our study also observed a possible important role of a specific short isoform of IFI16 as well as a link between MNDA and anti-dsDNA antibody production.

Association of the CTG (-2578/-460/+405) haplotype within the vascular endothelial growth factor gene with early-onset psoriasis.

Polymorphism of vascular endothelial growth factor (VEGF) influences the VEGF production and is subjected to genetic susceptibility of many diseases including psoriasis. Three single nucleotide polymorphisms (SNPs) within the promoter and exon 1 region [-2578(C/A), -460(C/T) and +405(C/G)] were analyzed in 154 patients with chronic plaque psoriasis and in 234 ethnically matched healthy controls from Thailand. The CTG (-2578/-460/+405) haplotype frequency was higher in patients with early-onset psoriasis (44.12%) compared with healthy controls (33.33%) (odds ratio = 1.54, 95% confidence interval = 1.08-2.18, P = 0.016, corrected P value: P(c) = 0.048). The results suggest that the CTG haplotype can be used as a genetic marker for psoriasis especially the early-onset group of Thais.

Genetic association of interferon-alpha subtypes 1, 2 and 5 in systemic lupus erythematosus.

In this study, the association between the systemic lupus erythematosus (SLE) susceptibility and the new candidate genes, IFNA1, IFNA2 and IFNA5 genes, major interferon-alpha subtypes, in responses to viral infection was investigated. Allele and genotype frequencies of each marker were compared between 150 SLE patients and 150 healthy control subjects. This study indicated that the A/A genotype of IFNA5 (-2529) and the G/G genotype of IFNA1 (-1823) were associated with the protection of SLE disease in a recessive model [P(c) = 0.03, P = 0.01, odds ratio (OR) = 0.4, 95% confidence interval (CI) = 0.2-0.8 and P(c) = 0.09, P = 0.03, OR = 0.5, 95% CI = 0.2-0.9, respectively). Multifactor dimensionality reduction analysis showed a marginal interaction between IFNA5 (-2529) and IFNA1 (-1823) gene, with a cross-validation consistency of 10 of 10 and a prediction error of 46% (permutation P-value = 0.05). This is the first report of positive association of IFNA gene in SLE, especially the role of specific subtypes IFNA1 and IFNA5.

De novo sirolimus-based regimen in Thai renal transplant recipients.

BACKGROUND: Calcineurin inhibitor (CNI) toxicity is a common cause of chronic allograft nephropathy. Although de novo sirolimus (SRL) with CNI minimization may provide better graft function, studies in Asian recipients are lacking. AIM: We sought to determine the 1-year outcomes of renal transplant patients who received a de novo SRL-based regimen with CNI minimization. PATIENTS AND METHODS: A single-center, prospective study of de novo SRL-based, reduced-dose cyclosporine regimen was performed from 2004 to 2007. The control group was a historical cohort of a cyclosporine-based regimen (cyclosporine, prednisolone, and mycophenolate mofetil). The 1-year outcome parameters included renal function, rate of acute rejection, biopsy-proven CNI toxicity, graft and patient survivals. RESULTS: The SRL-based regimen achieved 100% 1-year graft and patient survivals. The renal function was comparable between the SRL-based and CNI-based regimens (serum creatinine 1.32 +/- 0.45 and 1.45 +/- 0.43 mg/dL; P = .27). The rate of biopsy-proven acute rejection was comparable (9.5% and 13%; P = .68). The SRL-based regimen had a higher rate of biopsy-proven CNI toxicity (28.5% and 9.7%; P = .03). CONCLUSIONS: De novo SRL-based regimen with CNI minimization provides excellent transplant outcomes. The strategy to minimize or withdraw CNIs may achieve excellent graft function. A prospective study targeting lower CNI trough levels in Asian transplant recipients is required.

A prevalence of posttransplantation cancers compared with cancers in people with human immunodeficiency virus/acquired immunodeficiency syndrome after highly active antiretroviral therapy.

BACKGROUND: Organ transplant recipients and human immunodeficiency virus & acquired Immunodeficiency Syndrome (HIV/AIDS) patients have immune deficiencies that are possible mechanisms to develop malignancy. The type of cancers associated with these 2 conditions might elucidate this premise. AIM: Our aim was to compare prevalence and type of cancers between kidney transplant recipients and patients with HIV/AIDS. PATIENTS AND METHODS: We retrospectively reviewed 344 patients who underwent kidney transplantation from 1973 to 2007 compared them with 863 subjects with HIV/AIDS at the HIV-Netherlands/Australia/Thailand Research Collaboration (HIV-NAT) from 1997 to 2007. AIDS-defining cancers were excluded from the analysis. We compared the relative tumor risk with the age- and gender- matched general population of metropolitan Bangkok. RESULTS: The overall cancer risk for kidney transplant recipients (standardized incidence ratio [SIR] = 4.21) was comparable with HIV-infected patients (SIR = 3.88). Uroepithelial cancer was the most prevalent type in kidney transplant recipients, whereas cervical cancer was the most common malignancy in HIV-infected patients. The risks of developing hepatoma and non-Hodgkin's lymphoma were comparable between the groups. CONCLUSION: Kidney transplant recipients and HIV-infected patients show increased overall risks of certain types of cancers.

A Simple Novel Technique to Estimate Tacrolimus Dosages During the Early Post Kidney Transplantation Period.

BACKGROUND: Tacrolimus pharmacokinetics prediction by CYP3A5 genotyping is not available in many Asian resource-limited settings. Therefore, an alternative technique is needed to estimate the dose of tacrolimus perioperatively. The 12-hour level after the first dose (C12-0) is an alternative technique for estimating the dose of tacrolimus. This simple and inexpensive calculation technique can be used by any transplantation center. METHODS: A prospective study on a cohort of 57 incident post-kidney transplant recipients was conducted. The whole-blood tacrolimus trough level (C12-0) was measured at 12 hours after the first dose (0.1 mg/kg) of orally administered tacrolimus during transplantation. Concomitant medications with CYP3A5 inhibitors/inducers were not allowed. Genotyping for CYP3A5 expression was carried out by reverse transcription polymerase chain reaction. The dosages and trough levels of tacrolimus at postoperative day 7 and postoperative months 1 to 3 were measured and analyzed for the dose requirements for therapeutic levels (mg/kg/d). RESULTS: The doses of tacrolimus were widely diverse, ranging from 0.049 to 0.260 mg/kg/d and 0.031 to 0.298 mg/kg/d at day 7 and months 1 to 3, respectively. There were 9, 28, and 20 patients (15.8%, 49.1%, and 35.1%) with CYP3A5 *1/*1, *1/*3, and *3/*3, respectively. The CYP3A5 genotypes were significantly correlated with the target tacrolimus dose at day 7 (r(2) = 0.307) and the stable dose at months 1 to 3 (r(2) = 0.337). The C12-0 level also was significantly correlated with the dose of tacrolimus at day 7 (r(2) = 0.546) and the stable dose at months 1 to 3 (r(2) = 0.406). CONCLUSIONS: There were strong correlations between the C12-0 level and the tacrolimus doses during the perioperative period at day 7 and the stable period at 1 to 3 months. Countries with limited resources for genotype testing can use the C12-0 level as an alternative to estimate the tacrolimus dose.

Risk Factors of Cytomegalovirus Disease in Kidney Transplant Recipients: A Single-Center Study in Thailand.

BACKGROUND: Cytomegalovirus (CMV) infection significantly causes morbidity in kidney transplant (KT) recipients. This study aims to investigate the incidence, timing, and risk factors of CMV infection in KT recipients. METHODS: This is a single-center retrospective study at a tertiary referral hospital. Patients who underwent KT from January 2012 to September 2014 were included. CMV infection was defined as the presence of CMV measured by polymerase chain reaction. Logistic regression analysis was performed to assess independent risk factors of CMV infection after KT. RESULTS: Of 121 KT patients enrolled, 120 patients had CMV D(+)/R(+) serostatus, and 1 had D-/R(+). CMV infection occurred in 33 (27.2%) of patients with a median follow-up time of 16 (IQR 4-25) months. Of those, 25 had CMV viremia and 8 had CMV disease mainly involving the gastrointestinal system. In total, 86% of CMV cases occurred within 3 months. All recipients received anti-IL-2 receptor antibody (IL-2 RA), low-dose rabbit antithymocyte globulin (rATG; total of 1.5 mg/kg), or standard-dose rATG (1.5 mg/kg/day for 3-5 days) for induction. Of those, the incidences of CMV infection were 19.6%, 50%, and 67%, respectively. Preemptive strategy was used in all but 1 patient in the IL-2 RA and low-dose rATG group, whereas universal prophylaxis was given in 67% of patients in the standard-dose rATG group. Independent risk factors of CMV infection were older recipient age (per 10-year increase, OR 1.5; 95% CI 1.04-2.23), and induction with standard (OR 8.19; 95% CI 2.29-34) and low-dose rATG (OR 3.87; 95% CI 1.06-12.23). CONCLUSIONS: More than 25% of KT recipients developed CMV infection within 6 months after KT. The risk is increased in older recipients and induction with rATG. The level of CMV risk in low-dose rATG is 52% lower than in standard-dose rATG. In a limited-resource setting such as Thailand, deferred or preemptive strategy may be acceptable in patients who received IL-2 RA and low-dose rATG, while prophylactic therapy should be given to patients who received standard-dose rATG.

New concepts in organ transplantation.

Long-term graft survival is the desired outcome of organ transplantation. The surrogate metric elimination of acute rejection episodes is not only inadequate but also deceptive, since this freedom does not promise long-term graft survival. Current clinical immunosuppressive agents have reduced acute rejection, but not prolonged graft survival. New paradigms in organ transplantation focus on adhesion-migration events using a selectin antagonist, an antisense oligonucleotide, and FTY 720; on peptide or allochimeric antigens on cytokine disruption, and on inhibition of costimulatory signals. Due to the array of adverse reactions to the available immunosuppressive drugs, these new approaches aim not only to augment long-term graft survival, but also minimize the associated toxicities.

Monitoring of T-cell subsets in patients treated with anti-CD 25 antibody.

Daclizumab and basiliximab, the antibodies to the interleukin-2 receptor (anti-IL-2R), decrease the incidence of acute rejection in renal transplantation. However, prolonged blockade of IL-2 receptor (IL-2R:CD25) may hamper apoptosis of reactive T-cell clones and thus may obstruct tolerance induction. We determined the effect of varying doses of anti-IL-2R on the number of CD3+CD25+ cells as an index of CD 25 blockade. The number of CD3+CD25+ cells was determined in four groups of induction therapies: no antibody induction; two doses of 50 or 25 mg daclizumab on day 0 and day 14; and two doses of 20 mg basiliximab at day 0 and day 4 (n=10, 24, 10, and 10, respectively). The number of CD3+CD25+ cells were monitored in whole blood before antibody infusion as well as 24 hours thereafter and weekly after transplantation. With two doses of 50 mg daclizumab, two doses of 25 mg daclizumab, and two doses of 20 mg basiliximab, the expression of CD3+CD25+ cells was completely suppressed for 12, 10, and 12 weeks posttransplantation, respectively. The reappearance of CD3+CD25+ cells above the baseline for each induction regimen was: 17 weeks for two doses of 50 mg daclizumab, 11 weeks for two doses of 25 mg daclizumab, and 13 weeks for two doses of 20 mg basiliximab. Monitoring of CD3+CD25+ cells may be utilized to tailor anti-IL-2R administration at a minimal dosage, yet retaining adequate IL-2R blockade for at least 3 months posttransplantation.

Pharmacokinetic studies of cyclosporin in Thai kidney transplantation patients.

Pharmacokinetic studies were performed in 10 Thai patients with kidney transplantation who received microemulsion formulation (Neoral) of cyclosporin A (CsA) twice daily. No agents having pharmacokinetic effect on CsA had been used in these patients. The mean values of 12-h AUC (area under the concentration-blood curve) were 4603.63 +/- 344.61 ng x h/ml. CsA concentrations at 2 hours after dosing had the best value of correlation coefficient with the 12-h AUC. Abbreviated AUC could be calculated by stepwise multiple linear regression analysis and linear trapezoidal rule. The latter is more simple and superior to the former one.