Influence of CYP3A polymorphisms on tacrolimus pharmacokinetics in kidney transplant recipients.

Tacrolimus is characterized by a highly variable pharmacokinetics (PK) and a small therapeutic window. It is metabolized specifically by the CYP3A isoenzymes. This study aimed to determine, in kidney transplant patients, the influence of different genotypic clusters involving these SNPs CYP3A4*1B, CYP3A4*22, and CYP3A5*3 on Tacrolimus bioavailability during the first (PTP1) and the second (PTP2) posttransplant phase (PT). We included kidney transplant patients who received Tacrolimus and underwent drug monitoring by C0 monitoring. CYP3A4 and CYP3A5 genotyping were performed using PCR-RFLP. We classified the patients into four groups: Slow, Intermediate, rapid, and ultra-rapid metabolizers. We included 80 patients. The Tacrolimus dose-normalized C0 (C0/D ratio) was significantly decreased in intermediate, rapid, and ultra-rapid comparing with slow metabolisers. During PTP1 only CYP3A5*3 and CYP3A4*22 polymorphisms correlate significantly with C0/D ratio. Regardless of the PT phase and during the late one, only the CYP3A4 polymorphisms correlate significantly with the C0/D ratio. We identified that these SNPs are all associated independently with Tacrolimus exposure in different PT phases. Moreover, we are the first to define a genotypic cluster including the three CYP3A SNPs.

Risk Classification for Respiratory Viral Infections in Adult Solid Organ Transplantation Recipients.

INTRODUCTION: Molecular testing such as nasopharyngeal viral polymerase chain reaction (PCR) (NVP) is available now in most hospitals and widely used to identify respiratory viral infections (RVIs) in solid organ transplantation (SOT) recipients. MATERIALS AND METHODS: A retrospective multicenter study at 8 hospitals from March 1, 2016, to April 30, 2019. We included all adult SOT recipients who were admitted to the hospitals and had their first NVP post transplantation. RESULTS: A total of 102 adult SOT recipients were enrolled. NVP test was positive in 33 (32.4%) SOT recipients and negative in 69 (67.6%). Median age was more than 60 years old with female predominance in both groups. The majority of patients who had positive NVP were hospitalized either in fall or winter seasons (91%). RVI symptoms were documented in about 73% of the positive NVP group. Rhinovirus was the most common identified virus (48.4%). On logistic regression analysis, clinical presentation in fall or winter seasons, presenting with upper respiratory infection (URI) symptoms and taking prednisone ≥10 mg/d were significantly associated with positive NVP. This model classified patients into 3 categories of risk for RVIs-low (none of the variables), 0%; intermediate (1 variable), 6.5%; and high (≥2 variables), 55.4% with P < .001 for all predictors. CONCLUSION: SOT recipients who are taking prednisone (≥10 mg) and have URI symptoms in fall or winter seasons are more likely to have RVIs.

The Differential Influence of Cold Ischemia Time on Outcome After Liver Transplantation for Different Indications-Who Is at Risk? A Collaborative Transplant Study Report.

Introduction: Despite increasing awareness of the negative impact of cold ischemia time (CIT) in liver transplantation, its precise influence in different subgroups of liver transplant recipients has not been analyzed in detail. This study aimed to identify liver transplant recipients with an unfavorable outcome due to prolonged cold ischemia. Methods: 40,288 adult liver transplantations, performed between 1998 and 2017 and reported to the Collaborative Transplant Study were analyzed. Results: Prolonged CIT significantly reduced graft and patient survival only during the first post-transplant year. On average, each hour added to the cold ischemia was associated with a 3.4% increase in the risk of graft loss (hazard ratio (HR) 1.034, P < 0.001). The impact of CIT was strongest in patients with hepatitis C-related (HCV) cirrhosis with a 24% higher risk of graft loss already at 8-9 h (HR 1.24, 95% CI 1.05-1.47, P = 0.011) and 64% higher risk at ≥14 h (HR 1.64, 95% CI 1.30-2.09, P < 0.001). In contrast, patients with hepatocellular cancer (HCC) and alcoholic cirrhosis tolerated longer ischemia times up to <10 and <12 h, respectively, without significant impact on graft survival (P = 0.47 and 0.42). In HCC patients with model of end-stage liver disease scores (MELD) <20, graft survival was not significantly impaired in the cases of CIT up to 13 h. Conclusion: The negative influence of CIT on liver transplant outcome depends on the underlying disease, patients with HCV-related cirrhosis being at the highest risk of graft loss due to prolonged cold ischemia. Grafts with longer cold preservation times should preferentially be allocated to recipients with alcoholic cirrhosis and HCC patients with MELD <20, in whom the effect of cold ischemia is less pronounced.

Expanded Criteria Donor Kidneys With Kidney Donor Profile Index ≤ 85%: Are We Doing Enough to Counsel Our Patients?

BACKGROUND: Kidneys at higher risk for allograft failure are defined by the Kidney Donor Profile Index (KDPI) > 85% in the current kidney allocation system (KAS), replacing the historical concept of expanded criteria donor (ECD) kidneys in the previous KAS. Discrepancies exist in the classification of "high-risk kidneys" between the 2 KAS. In the current KAS, only recipients of KDPI > 85% kidneys are counseled about the high risk of allograft failure and are required to sign a consent. In this study, we evaluated the outcomes and allocation of kidneys with discordant classification. METHODS: Using the Scientific Registry of Transplant Recipients, kidneys transplanted between 01/2002 and 09/2016 were classified according to the old (standard criteria donor [SCD]/ECD) and current (KDPI) KAS. We then grouped them as concordant (KDPI ≤ 85% + SCD or KDPI > 85% + ECD) and discordant (KDPI ≤ 85% + ECD or KDPI > 85% + SCD) kidneys. RESULTS: Approximately 11% of transplanted kidneys were discordant in classification. Among kidneys with KDPI ≤ 85%, ECD status conferred a 64% (95% CI: 56%-73%) higher risk of allograft failure compared to SCD status. However, SCD/ECD status was not associated with differential outcomes in KDPI > 85% kidneys. These ECD kidneys have KDPIs > 50% and have been transplanted across all estimated post-transplant survival (EPTS) deciles. CONCLUSION: Adequate counseling about the risk and benefit of accepting ECD kidneys with KDPI ≤ 85% versus waiting on dialysis should be explored with the patients, especially those with lower EPTS.

The Revised International Staging System Compared to the Classical International Staging System Better Discriminates Risk Groups among Transplant-Ineligible Multiple Myeloma Patients.

BACKGROUND: The Revised International Staging System (R-ISS) has recently been introduced as a comprehensive prognostic score for multiple myeloma (MM). Validation of the R-ISS in patients treated outside of clinical trials is the focus of current investigations. The aim of this study was to test the prognostic role of the R-ISS in MM patients ineligible for autologous stem cell transplantation. PATIENTS AND METHODS: A total of 102 newly diagnosed MM patients were analyzed. All patients were initially treated with thalidomide-based combinations. RESULTS: An overall response rate was achieved in 77.4% patients. Both the International Staging System (ISS) and the R-ISS influenced the event-free survival and the overall survival (OS). However, the ISS was unable to discriminate patients in stages ISS1 and ISS2 regarding OS. On the contrary, the R-ISS clearly differentiated risk categories regarding OS and provided an improved discriminative power of 6.3% compared to the ISS. Furthermore, among the parameters that were significant in univariate analysis (presence of renal impairment, anemia, platelet count < 130 × 109/l, and R-ISS), the multivariate model pointed to the R-ISS (p = 0.001) as the most important parameter influencing OS. CONCLUSION: The R-ISS represents a useful tool for risk stratification of transplant-ineligible MM patients and should be considered as a prognostic index in daily clinical practice.

Soluble ST2 does not change cardiovascular risk prediction compared to cardiac troponin T in kidney transplant candidates.

BACKGROUND: Solubility of Tumorigenicity 2 (sST2) is a novel biomarker that better stratifies risk of cardiovascular events (CVE) compared to cardiac troponin T(cTnT) in heart failure. We assessed the association of sST2 with the composite outcome of CVE and/or mortality compared to cTnT in kidney transplant candidates. METHODS: 200 kidney transplant candidates between 2010 and 2013 were included. Elevated sST2 was defined as ≥30ng/ml, cTnT≥0.01 ng/ml. RESULTS: Median age 53 (interquartile range (IQR) 42-61) years, 59.7% male and 82.0% white. 33.5% had history of CVE, 42.5% left ventricular hypertrophy (LVH) and 15.6% positive cardiac stress test. Elevated sST2 correlated with male gender, history of prior-transplants, CVE, positive stress test, LVH, elevated cTnT, anemia, hyperphosphatemia, increased CRP and non-transplanted status. Male gender, history of CVE and LVH were independent determinants of sST2. During 28 months (IQR 25.3-30), 7.5% died, 13.0% developed CVE and 19.0% developed the composite outcome. Elevated sST2 was associated with the composite outcome (hazard ratio = 1.76, CI 1.06-2.73, p = 0.029) on univariate analysis but not after adjusting for age, diabetes and cTnT (p = 0.068). sST2 did not change the risk prediction model for composite outcome after including age, diabetes, prior history of CVE and elevated cTnT. CONCLUSIONS: Increased sST2 level is significantly associated with variables associated with CVE in kidney transplant candidates. sST2 was associated with increased risk of the composite outcome of CVE and/or death but not independent of cTnT. Larger studies are needed to confirm these findings and determine whether sST2 has added value in CV risk stratification in this cohort of patients.

Scandiatransplant acceptable mismatch program (STAMP) a bridge to transplanting highly immunized patients.

BACKGROUND: Highly immunized patients are a challenge for organ transplantation programs. One way of increasing the likelihood of transplantation in this group of patients is to expand the possible donations by defining acceptable HLA mismatches. In the Scandiatransplant Acceptable Mismatch Program (STAMP), a de-centralized approach has been implemented in 2009. AIMS: The program has been improved during the years from utilizing HLA-A, -B, -DR matching only to include typing of all deceased donors for HLA-A, -B, -C, -DRB1 and -DQB1. The calculation of a transplantability score (TS) has been introduced in order to take both HLA and AB0 into consideration resulting in a more realistic picture of the transplantability chance. MATERIALS AND METHODS: Patients were selected for eligibility and results of immunisation status were prepared in each of the 9 tissue typing laboratories, while access to the program is finally governed by a common steering group of immunologists and clinicians. RESULTS: In the period from March 2009 until February 2015, 96 patients were transplanted within this program. The mean recipient age was 49 years and 57% were females, 30% of the patients were first transplants and of these 93% were females. The majority of the patients had 2-5 HLA-A, -B. -DR mismatches. The allograft survival at 60 months was 79.1%. Applying the TS to the cohort confirmed that patients with a low TS score had longer waiting times. CONCLUSION: The program has matured during the years and now proves to be a valid approach for transplanting highly immunized patients.

Updated status of deceased-donor liver graft allocation for high-urgency adult patients in a Korean high-volume liver transplantation center.

BACKGROUND: The number of deceased organ donors in Korea has been gradually increased to reach 8 per million population. This study intended to analyze the updated status of urgent deceased-donor liver transplantation in a Korean high-volume liver transplantation center. METHODS: A retrospective study was performed with a 4-year study period from 2010 to 2013. RESULTS: During the study period, 328 adult patients were enrolled at the Asan Medical Center for urgent orthotopic liver transplantation (OLT) with Korean Network for Organ Sharing status 1 in 56 (17.1%) and status 2A in 272 (82.9%). Of them, 201 (61.3%) were allocated for OLT and 195 (58.2%) actually underwent OLT after exclusion of 6 cases of spontaneous withdrawal. In KONOS status 1, liver grafts were initially allocated to 33 (58.9%), but 6 were withdrawn owing to clinical improvement, so 27 (48.2%) actually underwent OLT. In status 2A, 168 (61.8%) underwent OLT within 2 weeks of priority waiting period. According to ABO blood groups in recipients, the allocation probability was 68% (68 of 100) in group A, 60.6% (60 of 99) in group B, 64.1% (25 of 39) in group AB, and 53.3% (48 of 90) in group O. Mean waiting period for OLT was 5.7 ± 2.1 days. CONCLUSIONS: Deceased donor incidence of ∼8 per million population contributed to meeting ∼60% of the demand for urgent deceased-donor liver transplantation in a Korean transplantation center, so further increasing deceased organ donor numbers is necessary to improve the current status of organ shortage.

Pediatric heart allocation and transplantation in Eurotransplant.

Pediatric heart allocation in Eurotransplant (ET) has evolved over the past decades to better serve patients and improve utilization. Pediatric heart transplants (HT) account for 6% of the annual transplant volume in ET. Death rates on the pediatric heart transplant waiting list have decreased over the years, from 25% in 1997 to 18% in 2011. Within the first year after listing, 32% of all infants (<12 months), 20% of all children aged 1-10 years, and 15% of all children aged 11-15 years died without having received a heart transplant. Survival after transplantation improved over the years, and in almost a decade, the 1-year survival went from 83% to 89%, and the 3-year rates increased from 81% to 85%. Improved medical management of heart failure patients and the availability of mechanical support for children have significantly improved the prospects for children on the heart transplant waiting list.

Pharmaceutical care in transplant patients in a university hospital: pharmaceutical interventions

A descriptive and prospective study was conducted on the pharmaceutical care in the post-transplant outpatient clinic of Hospital Universitario Walter Cantidio of Universidade Federal do Ceará (HUWC/UFC), in Fortaleza- Ceará in the period of April to October of 2011. The aim of the present study was to describe the pharmaceutical interventions performed in a Pharmaceutical Care service structured in the liver and kidney transplant outpatient clinic of an academic hospital. The Pharmaceutical interventions (PI) were classified according to Sabater et al.(2005), with significance based on Riba et al.(2000) and the Negative Outcomes associated with Medication (NOM) established at the Third Consensus of Granada. Statistical analyses were performed using the Epi Info v.3.5.1 program and hypothesis tests were done with the SigmaPlot v.10.0 program. A chi-squared (X²) test was utilized for statistical analysis of the sample. A total of 97 patients were followed, where 54 problems related to medications were identified and 139 PI performed. The main PI were in education of the patient about treatment (n=111; 80%) (p<0.05), while the significance of all interventions were appropriate, where 83.4% (n=116) of PI performed in the study period were shown to be "significant" (p<0.05). Through pharmaceutical care, the pharmacist is capable of monitoring the pharmacotherapeutic treatment and intervening when necessary, while being part of the multiprofessional team caring for the transplant patient.

Trata-se de um estudo de descritivo e prospectivo, realizado durante o atendimento farmacêutico nos ambulatórios de pós-transplante do Hospital Universitário Walter Cantídio da Universidade Federal do Ceará (HUWC/UFC), em Fortaleza-Ceará no período de abril a outubro de 2011. O presente trabalho objetiva apresentar as intervenções farmacêuticas realizadas em um serviço de Atenção Farmacêutica (ATENFAR) estruturado nos ambulatórios do transplante hepático e renal de um Hospital Universitário. As intervenções farmacêuticas (IF) foram classificadas de acordo com Sabater et al.(2005), a significância baseadas em Riba et al.(2000) e os Resultados Negativos associados a Medicamentos (RNM) fundamentados no Terceiro Consenso de Granada. As análises estatísticas foram realizadas no programa Epi Info v.3.5.1 e os testes de hipótese foram feitos no programa SigmaPlot v.10.0. O teste estatístico utilizado para análise da amostra foi o qui-quadrado (X²). Foram acompanhados 97 pacientes, identificados 54 problemas relacionados aos medicamentos e realizadas 139 intervenções farmacêuticas. As principais IF realizadas foram na educação do paciente sobre o tratamento (n=111; 80%) (p<0,05), já enquanto a significância todas as intervenções foram apropriadas, sendo que 83,4% (n=116) das IF realizadas no período do estudo mostram ser "significantes" (p<0,05). O farmacêutico, através do exercício da ATENFAR, é capaz de monitorar o tratamento farmacoterapêutico e intervir, quando necessário, integrando-se a equipe multiprofissional no cuidado ao paciente transplantado.

¿Cuándo y cómo derivar al receptor? / How and when to refer the recipient?

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