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Twice daily TAC (BID TAC) and prolonged released once daily dose tacrolimus (OD TAC) have different pharmacokinetic (PK) profiles in kidney transplant (KT) recipients. Precise dose adjustment recommendations when converting from BID TAC to OD TAC remain inconclusive. A single center, PK study was conducted in stable KT recipients taking constant doses of TAC, mycophenolic acid, and prednisolone. The area under the concentration-time curve (AUC) 0-24 and C trough were measured before and 4 weeks after 1:1 conversion from BID TAC to OD TAC without subsequent dose adjustment. A 90% confidence interval (CI) of geometric mean ratio (GMR) of OD TAC/BID TAC within the range of 0.9-1.11 was utilized to indicate equivalence of the narrow therapeutic index drugs. The roles of CYP3A5 genotypic polymorphism on PK parameters were also assessed. There were 20 patients with median time since transplantation of 18 months. The mean of CKD-EPI eGFR was 60.7 ± 16.43 mL/min/1.73 m 2 . The median total daily TAC dose of 0.058 mg/kg/day. The geometric means (%CV) of AUC 0-24 of OD and BID TAC were 205.16 (36.4%) and 210.3 (32.5%) ng/mL × h, respectively, with a GMR of 0.98 (90%CI 0.91-1.04). The geometric means (%CV) of C trough of OD TAC and BID TAC were 5.43 (33.1%) and 6.09 (34.6%) ng/mL, respectively. The GMR of C trough was 0.89 (90%CI 0.82-0.98), which was below 0.9. The newly calculated target C trough level of OD TAC was 4.8-6.2 ng/mL. The best abbreviated AUC 0-24 was AUC = 0.97(C0) + 5.79(C6) + 18.97(C12) - 4.26. The GMR AUC 0-24 was within the range of 0.9-1.11 irrespective of CYP3A5 genotypic polymorphism while the GMR of C trough was below 0.9 only in the CYP3A5 expressor patients. The 1:1 conversion from BID TAC to OD TAC without subsequent dose adjustment provided similar AUC 0-24 regardless of CYP3A5 genotypic polymorphism. However, the C trough was lower in the CYP3A5 expressor group. Therefore, it is not necessary to routinely increase the OD TAC dose after conversion.Trial registration: Thai Clinical Trials Registry (TCTR20210715002)., (© 2022. The Author(s).)

Kidney transplantation recipients (KTR) with coronavirus disease 2019 (COVID-19) are at higher risk of death than general population. However, mortality risk factors in KTR are still not clearly identified. Our objective was to systematically analyze published evidence for risk factors associated with mortality in COVID-19 KTR. Electronic databases were searched for eligible studies on 1 August 2021. All prospective and retrospective studies of COVID-19 in KTR were considered eligible without language restriction. Since data in case reports and series could potentially be subsets of larger studies, only studies with ≥ 50 patients were included. Random-effects model meta-analysis was used to calculate weighted mean difference (WMD) and pooled odds ratio (OR) of factors associated with mortality. From a total 1,137 articles retrieved, 13 were included in the systematic review and meta-analysis comprising 4,440 KTR. Compared with survivors, non-survivors were significantly older (WMD 10.5 years, 95% CI 9.3-11.8). KTR of deceased donor were at higher risk of death (OR 1.73, 95% CI 1.10-2.74). Comorbidities including diabetes mellitus, cardiovascular disease, and active cancer significantly increased mortality risk. KTR with dyspnea (OR 5.68, 95% CI 2.11-15.33) and pneumonia (OR 10.64, 95% CI 3.37-33.55) at presentation were at higher mortality risk, while diarrhea decreased the risk (OR 0.61, 95% CI 0.47-0.78). Acute kidney injury was associated with mortality (OR 3.24, 95% CI 1.36-7.70). Inflammatory markers were significantly higher in the non-survivors, including C-reactive protein, procalcitonin, and interleukine-6. A number of COVID-19 mortality risk factors were identified from KTR patient characteristics, presenting symptoms, and laboratory investigations. KTR with these risk factors should receive more intensive monitoring and early therapeutic interventions to optimize health outcomes., (© 2021. The Author(s).)

Hepatitis A virus (HAV) is able to cause a spectrum of illnesses ranging from no symptom to fulminant hepatitis which may lead to acute kidney injury. Although hepatitis A vaccine is recommended in non-immune solid organ transplant recipients who live in or travel to endemic areas, the standard 2-dose vaccination regimen demonstrated less favorable immunogenicity among these population. The 3-dose regimen showed higher response rate and immune durability in patients with human immunodeficiency virus. However, this strategy has never been studied in solid organ transplant recipients. A single-center, open-labeled, computer-based randomized controlled trial (RCT) with a 2:1 allocation ratio was conducted from August 2017 to December 2018. The study compared the seroconversion rate after receiving 2- or 3-dose regimen of hepatitis A vaccine at 0, 6 and 0, 1, 6 months, respectively, in non-immune kidney transplant recipients. A total of 401 adult kidney transplant recipients were screened for anti-HAV IgG and 285 subjects had positive results so the seroprevalence was 71.1%. Of 116 seronegative recipients, 93 (80.2%) completed vaccination; 60 and 33 participants completed 2- and 3-dose vaccination, respectively. The baseline characteristics were comparable between both groups. The seroconversion rate at 1 month after vaccination was 51.7% in the standard 2-dose regimen and 48.5% in the 3-dose regimen (p = 0.769). Overall, the seroconversion rate appeared to be associated with high estimated glomerular infiltration rate, high serum albumin, and low intensity immunosuppressive regimen. Seroconversion rate after hepatitis A vaccination in kidney transplant recipients was less favorable than healthy population. Three-dose regimen did not show superior benefit over the standard 2-dose regimen. Other strategies of immunization may increase immunogenicity among kidney transplant recipients.

Competing Interests: The authors declare no funding or conflicts of interest.

Background: Several kidney transplantation (KT) prediction models for patient and graft outcomes have been developed based on Caucasian populations. However, KT in Asian countries differs due to patient characteristics and practices. To date, there has been no equation developed for predicting outcomes among Asian KT recipients., Methods: We developed equations for predicting 5- and 10-year patient survival (PS) and death-censored graft survival (DCGS) based on 6662 patients in the Thai Transplant Registry. The cohort was divided into training and validation data sets. We identified factors significantly associated with outcomes by Cox regression. In the validation data set, we also compared our models with another model based on KT in the United States., Results: Variables included for developing the DCGS and PS models were recipient and donor age, background kidney disease, dialysis vintage, donor hepatitis C virus status, cardiovascular diseases, panel reactive antibody, donor types, donor creatinine, ischemic time, and immunosuppression regimens. The C statistics of our model in the validation data set were 0.69 (0.66-0.71) and 0.64 (0.59-0.68) for DCGS and PS. Our model performed better when compared with a model based on US patients. Compared with tacrolimus, KT recipients aged ≤44 years receiving cyclosporine A had a higher risk of graft loss (adjusted hazard ratio = 1.26; P = 0.046). The risk of death was higher in recipients aged >44 years and taking cyclosporine A (adjusted hazard ratio = 1.44; P = 0.011)., Conclusions: Our prediction model is the first based on an Asian population, can be used immediately after transplantation. The model can be accessed at www.nephrochula.com/ktmodels.

Background: Patients on dialysis are at risk of hepatitis B virus (HBV) infection, and antibodies against the hepatitis B surface antigen (anti-HBs) ≥ 10 IU/L are required. However, a high percentages of HBV vaccine nonresponders have been reported. We aimed to determine the optimal HBV vaccination protocol., Materials and Methods: Kidney transplant waitlisted patients were followed for 12 months and categorized into two groups. Group A included patients with sustained anti-HBs ≥ 10 IU/L who did not require vaccination. Group B consisted of patients with anti-HBs < 10 IU/L who were treated with a course of 4 double-dose HBV vaccinations. Without seroconversion after the first course, a second course was initiated. A third course, coadministered with the tetanus-diphtheria (Td) vaccine, was performed upon failure of the second course., Results: A total of 266 patients were included, 140 were categorized into group A and 126 into group B. Higher serum phosphorus, hemoglobin, and antibodies against the hepatitis core antigen (anti-HBc) were associated with sustaining anti-HBs ≥ 10 IU/L without vaccination. Diabetes mellitus (DM) was associated with the need for vaccination. For group B, 107 patients required 1 course of vaccination, 15 patients required 2 courses, and 4 patients required the third course with Td vaccine coadministration. Long dialysis vintage and low hemoglobin level were associated with seroconversion failure after the first course., Conclusion: Serum phosphorus, hemoglobin, DM, anti-HBc, and dialysis vintage were associated with the anti-HBs seroresponsiveness and sustainability. Our 3-course of 4 double-dose HBV vaccines regimen (with Td vaccine in the final course) conferred immunity to all patients.

Background The effects of mycophenolic acid exposure in the early period after transplantation on clinical outcomes have been reported; however, mycophenolic acid exposure in the early period after transplantation in Asian kidney transplant recipients who receive 1.5 g/d mycophenolate mofetil has never been investigated. Objective To determine mycophenolic acid exposure on day 3 post-transplantation in kidney transplant recipiens who receive 1.5 g/d mycophenolate mofetil. The effects of the reduced renal function on mycophenolic acid area under the concentration-time curve (AUC) and the achievement of the target AUC on the incidence of biopsy proven acute rejection during the first month post-transplantation were also evaluated. Setting A university hospital Method Blood samples and 24-h urine were collected on day 3 post-transplantation. Main outcome measures The mycophenolic acid AUC was calculated by linear trapezoidal rule and compared with the target of 45 mg*h/L. Results Of 42 Thai kidney transplant recipiens, the mean mycophenolic acid AUC of 45.1 mg*h/L (SD 14.7) was comparable to the AUC target (P = 0.962). Significant differences of the mycophenolic acid AUC were observed between patients with urine output of < 2400 mL and those with urine output ≥ 2400 mL (35.3 ± 6.6 and 47.4 ± 15.2, respectively; P = 0.002), and between patients with 24-h measured CrCl < 25 mL/min and those with CrCl ≥ 25 mL/min (38.0 (29.0, 42.2) and 49.2 ± 14.0, respectively; P = 0.017). Proportions of overall biopsy proven acute rejection among patients with mycophenolic acid AUC of < 45 and ≥ 45 mg*h/L were comparable (20.0% and 23.5%, respectively; P = 1.000). Conclusions After the starting dosage of 1.5 g/d mycophenolate mofetil, the mean mycophenolic acid AUC on day 3 post-kidney transplantation is comparable with the target of 45 mg*h/L. Severely reduced renal function significantly influences mycophenolic acid exposure.

Background: Delayed graft function (DGF) could worsen early and long-term outcomes of kidney transplantation (KT). DGF is caused by several pre-transplantation and perioperative factors in both donors and recipients. At present, there are no biomarkers or tests during the immediate post-KT period that can accurately predict the development of DGF., Materials and Methods: This prospective study was conducted in deceased donor KT (DDKT) at King Chulalongkorn Memorial Hospital, Thailand. All recipients underwent furosemide stress test (FST) by receiving a single dose of intravenous furosemide, 1.5 mg/kg at 3 h after allograft reperfusion. We determined the correlations between DGF (requiring dialysis within the first week after transplantation) and the values of urine volume recorded hourly after FST until 6 h, the parameters of postoperative dynamic tests, including resistive index (RI) of renal arteries and effective renal plasma flow (ERPF), and urine neutrophil gelatinase-associated lipocalin (NGAL)., Results: Of the 59 total DDKT recipients enrolled, 24 developed DGF. The FST is a more accurate biomarker than urine NGAL, RI of renal arteries, and ERPF in the prediction of DGF. The 4-h urine volume less than 350 mL (FST non-responsive) was the best cut-off value in predicting DGF with 87.5% sensitivity, 82.9% specificity, and 82.5% accuracy. Multiple logistic regression analyses showed an odds ratio of 0.993 (0.986-0.999, p = 0.035) for the 4-h urine volume to predict DGF., Conclusions: The FST is a simple and accurate biomarker for predicting DGF in early post-KT period. Close monitoring and well prepared dialysis are suggested in patients with urine volume < 350 mL after 4 h of FST. The FST non-responsive patients could be the target for further DGF preventive intervention. ClinicalTrials.gov identifier: NCT03071536., (© 2019 S. Karger AG, Basel.)

Despite tacrolimus (TAC) drug-level monitoring, TAC-induced chronic renal allograft fibrosis remains an important problem. This study investigated the potential of urinary neutrophil gelatinase-associated lipocalin (uNGAL) as a chronic renal allograft fibrosis biomarker in a two-phase study (proof of concept and cohort). In the proof of concept stage of the study, increased TAC-doses at 3 days after dose adjustment compared with the baseline were associated with elevated uNGAL (+ΔuNGAL) and urinary interleukin 18 (IL-18), but normal serum creatinine (SCr), despite the therapeutic trough levels of TAC. In the cohort study, the patients with elevated uNGAL post-recruitment in comparison with the baseline (+ΔuNGAL) was associated with the more severe renal allograft fibrosis from renal pathology of the protocol biopsy at 12 months post kidney transplantation (post-KT). A cut-off value of uNGAL ≥ 125.2 ng/mL during a 3, 6, 9 and 12 months post-KT was associated with a higher fibrosis score, with an area under the receiver operating characteristics curve of 0.80 (95% confidence interval [CI] 0.72 to 0.88, p < 0.0001) and a hazard ratio (HR) of 2.54 (95% CI 1.45 to 9.33; p < 0.001). We conclude that uNGAL is a sensitive biomarker of TAC induced subtle renal injury and TAC-induced chronic renal allograft fibrosis. We propose that uNGAL measurements, in addition to trough levels of TAC, should be used to predict TAC-induced chronic renal allograft fibrosis in the recipients of KT., Competing Interests: The authors have declared that no competing interests exist.

BACKGROUND Calcineurin inhibitors (CNI) are the mainstay immunosuppressive drugs for kidney transplantation. Although they provide excellent allograft and patient outcomes, adverse effects are frequently encountered. Calcineurin inhibitor-induced pain syndrome (CIPS) is a rare adverse effect of CNI. Previous case reports with CIPS diagnosis involved incapacitating pain in the lower extremities. CASE REPORT In this article, we report the first case of CIPS with severe back pain as the presenting symptom, which was correlated with a high tacrolimus trough concentration due to a drug interaction with clotrimazole troche. Magnetic resonance imaging (MRI) of the spine showed bone marrow edema, which is consistent with previous case reports. The patient's symptoms resolved within 3 weeks of the onset of pain. Treatments were symptomatic care and lowering the tacrolimus trough concentration. Pain was improved significantly with pregabalin but not with nifedipine. CONCLUSIONS We reviewed the literature of kidney transplant cohorts with CIPS to ascertain prevalence, pain characteristics, and treatment outcomes. Apart from our case, all patients experienced lower extremities pain and were pain-free during the follow-up period, without any residual abnormalities. CIPS is a benign but adverse effect of CNI. Counselling patients about the disease's natural history and supportive care remain the best treatment.

Aim: Donor-specific antibody (DSA) is a widely-used biomarker for antibody-mediated rejection (ABMR) but correctly indicates only 30-40% of patients with ABMR. Additional biomarkers of ABMR in kidney transplant recipients are needed., Methods: All 68 kidney transplanted-recipients enrolled in this study were negative for graft rejection as determined by surveillance-biopsy ELISA at day 7 post-transplantation. Allograft biopsy was then performed at 6 months post-transplantation for subclinical-ABMR detection. Recipients were stratified by pre-transplant DSA and BAFF at day 7 into four groups., Results: During the study period, 13.2% of the recipients demonstrated subclinical-ABMR at 6 months, without patient with clinical ABMR presentations. Overall mean BAFF at day 7 was 393 pg/mL (95% CI = 316-471 pg/mL). The optimal cut-off value for low vs. high BAFF level was 573 pg/mL, with sensitivity and specificity at 77.8% and 88.1%, respectively. Fifty percent of recipients with high BAFF at day 7 (14 patients) and only 3.7% of patients with low BAFF demonstrated ABMR (P < 0.05). Indeed, ABMR was more common in patients high BAFF level (hazard ratio = 7.30; 95% CI = 3.77-14.15). The prevalence of ABMR among negative pre-transplant DSA/low BAFF, positive DSA/low BAFF, negative DSA/high BAFF, and positive DSA/ high BAFF recipients were 4.4, 0, 37.5 and 66.7%, respectively (P < 0.05)., Conclusions: Post-transplant ABMR can be predicted by perioperative serum BAFF level. Together with DSA testing, BAFF provides additional predictive value for ABMR., (© 2016 Asian Pacific Society of Nephrology.)

Background: Tacrolimus is mainly metabolized by cytochrome P450 3A5 (CYP3A5), which is expressed in the liver. However, CYP3A5 is also expressed in the kidney tissue and may contribute to local tacrolimus clearance in the kidney allograft. We aimed to evaluate the association between the allograft CYP3A5 genotype and transplant outcomes., Methods: We conducted a retrospective cohort study at the King Chulalongkorn Memorial Hospital, Thailand, comparing 2 groups of donor and recipient CYP3A5 genotypes, the expressor (*1/*1 and *1/*3) and the non-expressor (*3/*3). The primary outcomes were allograft complications including calcineurin inhibitor (CNI) nephrotoxicity and acute rejection episode., Results: Of the 50 enrolled patients, 21 donors were expressors and 29 donors were the non-expressors. Tacrolimus trough concentrations were similar between the 2 genotypes. The incidence of CNI nephrotoxicity was higher in recipients with non-expressor donor genotype compared with the expressor donor genotype (72.4 vs. 33.3%, p = 0.006). CNI nephrotoxicity incidence was not different when recipient's genotypes were compared. Multivariate analysis from Cox-regression showed a hazard ratio of 3.18 (p = 0.026) for CNI nephrotoxicity in the non-expressor compared with the expressor donor. The recipient CYP3A5 genotypes did not significantly contribute to CNI nephrotoxicity. Kaplan-Meier analysis demonstrated the lowest CNI nephrotoxicity-free survival in recipients with the expressor genotype who received allograft from the non-expressor donors (p = 0.005)., Conclusion: In conclusion, our results suggest that donor CYP3A5 non-expressor genotype (*3/*3) is a risk for CNI nephrotoxicity., (© 2018 S. Karger AG, Basel.)

Aim: Recurrent IgA nephropathy (IgAN) is a common recurrent glomerular disease after kidney transplantation. Recurrent IgAN, in particular, with crescent formation or endocapillary proliferation might result in kidney allograft loss. However, the current treatment options of recurrent IgAN are conflicting., Methods: We have reported three kidney-transplanted recipients with biopsy-proven recurrent IgAN treated with four consecutive months of rituximab at the dose of 375 mg/1.73m 2 without corticosteroids., Results: At median follow-up 20 months following rituximab administration, all three recipients demonstrated decrease in proteinuria severity, slow disease progression with a well-tolerated condition. This therapeutic effect is most probably mediated by the B cell depletion., Conclusion: Our three case reports suggest that the disease severity of recurrent IgAN with endocapillary proliferation regardless of crescent formation can be minimized by the four doses of monthly rituximab regimen., (© 2016 Asian Pacific Society of Nephrology.)

Background: Limited sampling strategies (LSS) have been proposed for predicting total exposure of tacrolimus, a widely used immunosuppressant in transplantation. This study aims to validate the equation developed by Wong et al for estimation of the tacrolimus area-under-the-concentration-over-12-hour-curve (AUC0-12) and to assess the effects of hemoglobin and duration of tacrolimus therapy on predictive performance of the equation in adult kidney transplant recipients., Methods: Seven time point blood concentration profiles were collected from 31 stable kidney transplant recipients who received oral tacrolimus twice daily. The chemiluminescent microparticle immunoassay method was used to determine the tacrolimus concentration. Measured AUC0-12 (AUCm) was calculated by the linear trapezoidal rule. Predicted AUC0-12 (AUCp) was calculated using the equation that used tacrolimus concentrations measured at 2 hours (C2) and 4 hours (C4) after dose: 16.2 + 2.4(C2) + 5.9(C4). Predictive performance of the equation was determined by calculating bias and precision. Agreement between AUCp and AUCm was assessed. The effects of hemoglobin and duration of tacrolimus therapy on bias and precision were also evaluated., Results: The median (interquartile range) of AUCm was 133.00 (98.25, 185.70) ng·h·mL. The AUCp well correlated with the AUCm (r = 0.962, P < 0.001). The equation had a mean percentage prediction error of -2.22% (95% CI, -5.14 to 0.71), mean absolute percentage prediction error of 6.67% (95% CI, 4.92-8.42), and root mean squared error (%CV) of 14.08 (10.29%) ng·h·mL. A Bland-Altman plot showed good agreement between AUCp and AUCm with a mean bias of -5.43 ng·h·mL (95% CI, -10.28 to -0.59). The hemoglobin level and duration of tacrolimus therapy did not influence the predictive performance of the equation., Conclusions: The equation had low bias and high precision in predicting the AUC0-12 of tacrolimus. The equation is a simple and reliable tool for estimating tacrolimus exposure.

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., (Copyright © 2015 Elsevier Inc. All rights reserved.)

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., (Copyright © 2015 Elsevier Inc. All rights reserved.)

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., (© Copyright 2014 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Background: Hyperlipidemia occurs in up to 50% of kidney transplant (KT) recipients who take everolimus (EVL). As a result of this, statins are the most commonly prescribed lipid-lowering drugs among these patients. However, we are concerned whether there are any drug interactions between EVL and statins, because both of these drugs use the same pharmacokinetics pathway. Therefore, we assessed the effects of concomitant use of EVL and atorvastatin., Methods: In this randomized, open-label, crossover study, 20 KT patients were assigned (1:1) to receive EVL with or without 20 mg atorvastatin for 1 month. One-month washout period was used before crossover. Plasma EVL concentrations were measured by homogeneous particle-enhanced turbidimetric immunoassay. Twelve-hour area under the time-concentration curve (AUC0-12) of EVL was calculated with the use of whole-blood EVL concentrations from 10 different time points (0, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, and 12 hours)., Results: The mean (SD) AUC0-12 for EVL and EVL plus atorvastatin was 155.9 (41.6) ng·h/mL and 151.3 (51.4) ng·h/mL, respectively (P > .05; paired t test). No difference of EVL Cmax or Tmax was found after atorvastatin coadministration. Even though the EVL AUC0-12 levels were not affected by atorvastatin coadministration in one-half of the subjects, for the rest of the patients, there were unpredictable changes in the EVL AUC0-12 levels. This may be due to the high intrapatient variability of EVL drug concentration (coefficient of variation ranges from 9.8% to 34.1%)., Conclusions: Coadministration of atorvastatin with EVL in KT recipients did not affect the pharmacokinetics of EVL., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: The re-expressed Modification of Diet in the Renal Disease (MDRD) equation and the Chronic Kidney Disease Epidemiology (CKD-EPI) equation were developed to estimate glomerular filtration rate in non-transplant chronic kidney disease (CKD) patients. The Nankivell equation was created to estimate GFR in transplant recipients. However, none of these formulas have been validated in Asian renal transplant patients. Several recently published studies have highlighted the need to adapt estimated glomerular filtration rate (eGFR) equations to the race of their patients. Although the eGFR equation for Thai CKD has been derived, it has not been validated for transplant recipients. Our study aimed validating the Nankivell equation, re-expressed MDRD equation, CKD-EPI, re-expressed MDRD equation with Thai racial factor correction, as well as the Thai eGFR equation in Thai renal transplant recipients., Methods: A total of 97 adult Thai renal transplant recipients were studied. The 99mTc-DTPA plasma clearance was used as a reference GFR. The serum creatinine was determined by IDMS reference enzymatic methods (CrEnz)., Results: The mean reference GFR and CrEnz were 67.86 ± 20.72 ml/min/1.73 m2 and 1.23 ± 0.59 mg/dl. The bias estimated by Bland-Altman analysis can be expressed as -12.11 ± 15.87 ml/ min/1.73 m2 for the Nankivell equation, 2.72 ± 13.90 ml/min/1.73 m2 for the re-expressed IDMS-traceable MDRD equation, -2.59 ± 14.16 ml/min/1.73 m2 for the CKD-EPI equation, -7.05 ± 17.34 ml/min/1.73 m2 for the Thai re-expressed MDRD with Thai racial factor, and -8.62 ± 16.00 ml/min/1.73 m2 for the Thai eGFR equation. The CKD-EPI equation provided the best accuracy and precision in terms of Pearson correlation coefficient, mean difference, error, and accuracy within 10%, 20%, and 30%., Conclusions: The equations derived mainly from Caucasian and/or non-transplant status can be applied to Thai transplantation recipients with some bias. The CKD-EPI had the least bias compared with other eGFR equations.

Background: Endothelial progenitor cells (EPC) involved in endothelial repair and maintenance are restored following renal transplantation. There are scarce data regarding EPC in Asian kidney allograft patients., Aim: We determined the EPC numbers in Thai renal allograft patients to compare with various other parameters., Patients and Methods: The EPC numbers which were verified as CD 133+/VEGFR-2 cells in peripheral blood of 38 renal transplant recipients were measured by flow cytometry, and by a cell culture assay using acetylated low-density lipoprotein and Ulex europaeus agglutinin-1 immunofluorescence. Renal function calculated as estimated glomerular filtration rate (eGFR) was obtained by the abbreviated Modification of Diet in Renal Disease (MDRD) formula., Results: Renal allograft patients had lower EPC numbers than normal controls (P < .05). The EPC numbers showed a significant correlation with renal allograft function (P < .05). Recipients with stable eGFR at 12 months of follow-up displayed significantly greater EPC numbers at baseline compared with those subjects who experienced a decline in eGFR (P < .05). Recipients using angiotensin receptor blockers had greater EPC numbers at baseline and better 12-month renal allograft function (P < .05)., Conclusion: EPC numbers may influence the fate of renal allograft function. Enhancing EPC numbers may be a new strategy to improve long term renal allograft function.

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.

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.

Objective: Absorption profiling of cyclosporine is a current concept of drug monitoring. A single blood concentration measurement 2 hours after cyclosporine administration (C2) has been shown to be a good predictor of drug exposure and clinical outcome. The recommendation states that achieving the recommended target level of 1700 +/- 340 ng/ml within 3-5 days after renal transplantation is associated with a lower rate of acute rejection and nephrotoxicity. The high variation of pharmacokinetic profile and short limited time during early post-transplantation period make it hard to adjust the cyclosporine dose that can reach that target level on time. The present study was designed to be a method to predict the optimal pre-transplant CsA dose., Material and Method: Eleven living-related kidney transplant recipients were recruited to receive cyclosporine and were monitored for C2 concentration during the 2 weeks before operation by the designed method. The pre-transplant empirical dose of 3.5 mg/kg/dose every 12 hours were assigned to all patients. The first predicted dose was estimated by using C2 concentration of 1,700 ng/mL. The first predicted dose was prescribed to the patients. The second predicted dose was estimated by using C2 concentration of the first predicted dose. All patients received the average of the first and the second predicted doses of cyclosporine within 12-24 hrs before transplantation and until the 3rd day after transplantation., Results: Nine out of 11 patients (81.81%) reached the target C2 level on the 3rd day after transplantation without any serious side effect and complications. The most common side effect was nausea and a flushing sensation that usually abated with a later dose after transplantation., Conclusion: The early postoperative optimal cyclosporine dose can be effectively predicted by pre-transplant C2 measurement as conducted in the present study.

Objectives: To determine the prevalence and risk factors of osteoporosis after renal transplantation in Thai patients., Material and Method: A single-center cross-sectional study of bone mineral density was conducted in 102 Thai renal allograft recipients. Correlations were made between the clinical parameters and the occurrences of osteoporosis., Results: The prevalence of osteoporosis was 24.5%, 9.8% and 26.4% at lumbar vertebrae, hip region, and any sites, respectively. Binary logistic regression analysis revealed that cumulative dosage of steroids was significantly correlated with osteoporosis of the lumbar spine (p = 0.023, adjusted OR = 1.005), while body mass index (p = 0.005, adjusted OR = 0.738) and age (p = 0.052, adjusted OR = 1.077) were correlated with osteoporosis of the hip region., Conclusion: Osteoporosis is common in Thai renal allograft recipients, particularly of the lumbar vertebrae. Cumulative dosage of steroids is the most important risk factor of low BMD of the lumbar vertebrae.

Profiling of absorption of cyclosporine (CsA) microemulsion is a concept in therapeutic drug monitoring (TDM) designed to optimize the clinical benefits of the drug in transplant recipients. A single blood concentration at 2 h (C(2)) after CsA microemulsion administration in kidney transplant recipients accurately predicts graft outcome. An international guidelines has recommended the target C(2) over time-course post-transplantation. We determined whether this recommendation is appropriate for our patients who are Asian ethnic. The clinical data of these C(2) monitoring kidney transplant recipients were compared with the historical cohort of microemulsion CsA trough (C(0)) level monitoring during the first 24-month post-transplantation. The inclusion and exclusion criteria were applied for both C(2) and C(0) cohorts. The mean target C(2) concentrations at 1, 3, 6, and 12-month post-transplantation were achieved in the C(2) cohort as the international guildlines. At 3-month post-transplantation, patients who had C(2) concentrations over 1500 ng/mL had higher serum creatinine as compared with those who had C(2) levels <1300 ng/mL (2.23 +/- 0.8 vs. 1.44 +/- 0.38 mg/dL: p = 0.01). Also, at 6-month post-transplantation, patients who had C(2) concentrations over 1300 ng/mL had higher serum creatinine (1.96 +/- 0.29 vs. 1.37 +/- 0.34 mg/dL: p < 0.01) as compared with those who had C(2) levels <1100 ng/mL. There was no statistical difference of acute rejection episodes between the two cohorts. The international consensus for C(2) concentraion may be too high for Asian ethnic kidney transplant recipients. The data from this study indicated lower than recommended C(2) concentraion as an appropriate C(2) target concentraion.

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.

Tuberculosis of a transplanted kidney is a rare and serious complication. Search for renal tuberculosis as the cause of deterioration of graft function is mandatory in a renal transplant recipient with tuberculosis of other organs e.g. pulmonary tuberculosis in this patient. Renal histopathology is required for the diagnosis. Treatment with anti-tuberculosis drugs can improve renal function. Drug interactions should be considered when rifampicin is administered with cyclosporin A.