Kidney and Liver Tissue Tacrolimus Concentrations in Adult Transplant Recipients—The Influence of the Whole Blood and Tissue Concentrations on Efficiency of Treatment during Immunosuppressive Therapy

Tacrolimus (TAC) has a narrow therapeutic index and highly variable pharmacokinetic characteristics. Close monitoring of the TAC concentrations is required in order to avoid the risk of acute rejection or adverse drug reaction. The results in some studies indicate that inter-tissue TAC concentrations can be a better predictor with regards to acute rejection episode than TAC concentration in whole blood. Therefore, the aim of the study was to assess the correlation between dosage, blood, hepatic and kidney tissue concentration of TAC measured by a validated liquid chromatography tandem mass spectrometry (LC-MS/MS) and clinical outcomes in a larger cohort of 100 liver and renal adult transplant recipients. Dried biopsies were weighed, mechanically homogenized and then the samples were treated with a mixture of zinc sulfate—acetonitrile to perform protein precipitation. After centrifugation, the extraction with tert-butyl methyl ether was performed. The analytical range was proven for TAC tissue concentrations of 10–400 pg/mg. The accuracy and precision fell within the acceptance criteria for intraday as well as interday assay. There was no correlation between dosage, blood (C0) and tissue TAC concentrations. TAC concentrations determined in liver and kidney biopsies ranged from 8.5 pg/mg up to 160.0 pg/mg and from 7.1 pg/mg up to 215.7 pg/mg, respectively. To the best of our knowledge, this is the first LC-MS/MS method for kidney and liver tissue TAC monitoring using Tac13C,D2 as the internal standard, which permits measuring tissue TAC concentrations as low as 10 pg/mg.

The Assessment of HLA Sensitization Effect on Graft Function and Survival in Renal Transplant Recipients

Objective: Anti-human leukocyte antibodies (HLA) play an important role in graft survival, particularly in kidney transplantation. Preformed anti-HLA antibodies, especially donor specific antibodies can cause acute and chronic rejections. In this study, it was aimed to assess the effects of anti-HLA antibodies in kidney patients before transplant on graft function, failure, and patient survival. Methods: PRA (Panel Reactive Antibody) levels were monitored using bead based methods such as Luminex and flow cytometry. Post-transplant estimated glomerular filtration ratios (eGFR) among first, third, and fifth year patient survivals and graft failures were statistically analyzed. Results: In this study, it was observed that related transplants had low levels of PRAs, and their eGFRs were at normal reference range. The patients without acute rejection episode (ARE) had higher eGFR values than those with ARE. When five year-graft survival terms were evaluated, it was found that 65.6±9.8% and 86.5±3.2% graft survival terms were detected in anti-HLA Class I/II positive and negative patients, whereas 74.8±6.4% and 84.3 ±2.6% graft survival terms were observed in ARE positive and negative patients, respectively. eGFR value is a predictor of graft failure and patient survival. Our Cox regression analyses (HR=0.843, p=0.00) also supported this information. Conclusion: The study concluded that although the correlation between PRA positivity and graft survival were not significant, the shortest graft survival was observed in PRA positive patients in the whole cohort and ARE positive patients. The importance and requirement of pre- and post-transplant PRA tests continue.

Usefulness of Kidney Donor Profile Index (KDPI) to predict graft survival in a South Brazilian Cohort

Introduction: Kidney Donor Profile Index (KDPI) has been incorporated in the United States to improve the kidney transplant allocation system. Objectives: To evaluate deceased kidney donors’ profile using KDPI and compare to the previous United Network for Organ Sharing (UNOS) definition of expanded criteria donors (ECD) and assess the KDPI applicability to predict five-year graft survival and renal function in our sample. Methods: Retrospective cohort of 589 kidney transplants from deceased donors performed from January 2009 to May 2013 with follow-up until May 2018. Results: In 589 kidney transplants, 36.6% of donors were classified as ECD and 28.8% had KDPI ≥ 85%. Mean KDPI was 63.1 (95%CI: 60.8-65.3). There was an overlap of standard and ECD in KDPI between 60 and 95 and a significantly lower death-censored graft survival in KDPI ≥ 85% (78.6%); KDPI 0-20: 89.8%, KDPI 21-59: 91.6%, and KDPI 60-84: 83.0%; p = 0.006. The AUC-ROC was 0.577 (95%CI: 0.514-0.641; p = 0.027). Renal function at 5 years was significantly lower according to the incremental KDPI (p < 0.002). KDPI (HR 1.011; 95%CI 1.001-1.020; p = 0.008), donor-specific antibodies (HR 2.77; 95%CI 1.69-4.54; p < 0.001), acute rejection episode (HR 1.73; 95%CI 1.04-2.86; p = 0.034) were independent and significant risk factors for death-censored graft loss at 5 years. Conclusion: In our study, 36.6% were classified as ECD and 28.8% had KDPI ≥ 85%. KDPI score showed a moderate power to predict graft survival at 5 years. Renal function was significantly lower in patients with higher KDPI.

P1695OUTCOMES OF KIDNEY TRANSPLANTATION IN RECIPIENTS WITH MENTAL RETARDATION

Background and Aims Mental retardation in patients with chronic kidney disease is a relative contraindication for kidney transplantation. Currently, in the literature there are limited outcome data in renal transplant recipients with mental retardation and approaches to decision of transplantation changes in different centers. The aim of this study is to evaluate the results of kidney transplantation recipients with mental retardation in our center. Method In this study, we examined retrospectively 8 kidney transplant recipients with mental retardation in Renal Transplantation Unit of Ankara University School of Medicine between 2006-2018 years. Results The cause of mental retardation in these patients were; genetic syndromes in three patients, meningoencephalitis in one patient, prematurity in one patient, and chromosomal abnormality in one patient. In two patients, the cause of mental retardation is unknown. All patients had good social support for drug compliance and follow-up. The causes of end-stage renal failure were; cystic kidney disease in three patients, hypertensive nephropathy in one patient and vesicoureteral reflux in one patient. In three patients, the etiology of kidney disease is unknown. At the time of pretransplantation period evaluation, six candidates were receiving hemodialysis and two candidates were receiving peritoneal dialysis respectively. Mean dialysis duration before transplantation was 50.7±22.8 months (min 4-max 180). Cadaveric kidney transplantation was performed in three of eight patients (deceased donor kidney allocated to patient with medical urgency in the event of potential imminent loss of dialysis access in one patient and in normal conditions in two patients) and living kidney transplantation was performed in five patients. The mean follow-up period after transplantation was 54.1±48.0 months. Three patients had early posttransplant complications; including urinary tract infection in three patients, deep vein trombosis in one patient and cardiopulmoner arrest with septic shock secondary to femoral graft infection and parailiac abscess in one patient (Table). No patients underwent graft biopsy and no patients experienced acute rejection episode. At the end of the follow-up time, graft and patient survival were 100%. Conclusion Mental retardation is not a contraindication for kidney transplantation in candidates without the history of noncompliance with proper social support.

Comparison of machine perfusion versus cold storage in kidney transplant recipients from expanded criteria donors: a cohort-based study

Background Most studies comparing the efficacy of hypothermic machine perfusion (HMP) versus static cold storage (SCS) are based on short-term outcomes. We aimed to better evaluate the mid-term impact of HMP in patients receiving expanded criteria donor (ECD) kidneys. Methods The analyses were based on the French Données Informatisées et VAlidées en Transplantation (DIVAT) observational cohort. Patients aged ≥45 years transplanted for the first or second times from an ECD donor since 2010 were studied. Our study reported the graft and/or patient survivals and the incidence of acute rejection episode. The Cox models and the Kaplan–Meier estimators, weighted on the propensity score, were used to study the times-to-events. Results Among the 2019 included patients, 1073 were in the SCS group versus 946 in the HMP group. The mean life expectancy with functioning graft was 5.7 years [95% confidence interval (CI) 5.4–6.1] for the HMP cohort followed-up for 8 years post-transplantation versus 6.0 years (95% CI 5.7–6.2) for the SCS group. These mid-term results were comparable in the patients receiving grafts from donors aged ≥70 years and in the transplantations with cold ischaemia time ≥18 h. Conclusions Our study challenges the utility of using HMP to improve mid-term patient and graft survival. Nevertheless, the improvement of the short-term outcomes is indisputable. It is necessary to continue technological innovations to obtain long-term results.

The Cytochrome P450 3A5 Non-Expressor Kidney Allograft as a Risk Factor for Calcineurin Inhibitor Nephrotoxicity

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.

Basiliximab as Induction in Kidney Transplantation: Are There any Real-Life Advantages?

Background: Basiliximab is an interleukin-2 receptor antagonist used as induction therapy in kidney transplantation and is believed to reduce acute rejection episode (ARE). Our aims were to compare the impact of basiliximab induction therapy with no induction therapy on incidence of ARE, time requirement for serum creatinine (S.Cr) to normalize after transplantation, initial post-transplant hospital stay, infection in immediate post-transplant period, chronic allograft injury and graft survival at 1 and 3 years.Methods: We retrospectively reviewed the medical records of patients who had undergone living related donor kidney transplantation in a tertiary care hospital of a developing country between July 2004 and June 2014. We selected patients who received calcineurin inhibitors, mycophenolate and prednisolone to classify as no induction therapy (n=50; group 1, receiving prednisolone, mycophenolate and cyclosporine as maintenance therapy) and induction therapy with basiliximab (n=61; group 2, receiving prednisolone, mycophenolate and tacrolimus as maintenance therapy).Results: Among the 111 study subjects, only two had experienced ARE (one from each group, p=0.889). Patients who received basiliximab had a shorter mean hospital stay (11.4±3.3 versus 13.7±5.0 days, p=0.005) and shorter mean duration for normalization of S.Cr (4.7±2.3 versus 7.3±5.6 days, p=0.002) after transplantation. There was no significant difference in incidence of infection in immediate post-transplant period (p=0.134). One year graft survival rate was better in those who received basiliximab (98.2% versus 89.4%, p=0.010) but there was no significant difference at 3 years (79% versus 74%, p=0.549). Overall incidence of chronic allograft injury was less with basiliximab (11.5% versus 36%, p=0.002) induction.Conclusions: Induction therapy with basiliximab was associated with shorter mean hospital stay, early renal function recovery, better 1 year graft survival and less overall incidence of chronic allograft injury. We have encountered minimum ARE to comment on benefit of basiliximab on ARE.Birdem Med J 2017; 7(2): 90-94

Serum Cystatin C in Patients with Delayed Graft Function

SummaryDespite recent studies showing that serum Cystatin C (CysC) is a better marker for glomerular filtration rate (GFR) than the ubiquitously used creatinine, the clinical utility of these findings remains to be evaluated. This marker is very sensitive for allograft function after renal transplantation. The concentration of CysC was compared with that of the creatinine. Decreased renal function was followed in 64 transplanted patients. Serum CysC significantly correlated with creatinine in healthy controls (r = 0.625, p < 0.0001), whereas in the transplanted patients the mean serum creatinine and CysC concentrations were: 81 ± 13 mmol/L and 0.90 ± 0.22 mg/L, respectively. Serum CysC and creatinine significantly correlated throughout the post transplantation period (r = 0.686, p < 0.001), but we confirmed differences between kinetics of these parameters. In the first four days after transplantation the CysC concentration was normalized faster than the creatinine concentration. Development of acute rejection episode (between 5 and 7 days) showed high sensitivity and specificity of the changes of CysC compared with those of creatinine.

Longitudinal Analysis of Whole Blood Transcriptomes to Explore Molecular Signatures Associated with Acute Renal Allograft Rejection

In this study, we explored a time course of peripheral whole blood transcriptomes from kidney transplantation patients who either experienced an acute rejection episode or did not in order to better delineate the immunological and biological processes measureable in blood leukocytes that are associated with acute renal allograft rejection. Using microarrays, we generated gene expression data from 24 acute rejectors and 24 nonrejectors. We filtered the data to obtain the most unambiguous and robustly expressing probe sets and selected a subset of patients with the clearest phenotype. We then performed a data-driven exploratory analysis using data reduction and differential gene expression analysis tools in order to reveal gene expression signatures associated with acute allograft rejection. Using a template-matching algorithm, we then expanded our analysis to include time course data, identifying genes whose expression is modulated leading up to acute rejection. We have identified molecular phenotypes associated with acute renal allograft rejection, including a significantly upregulated signature of neutrophil activation and accumulation following transplant surgery that is common to both acute rejectors and nonrejectors. Our analysis shows that this expression signature appears to stabilize over time in nonrejectors but persists in patients who go on to reject the transplanted organ. In addition, we describe an expression signature characteristic of lymphocyte activity and proliferation. This lymphocyte signature is significantly downregulated in both acute rejectors and nonrejectors following surgery; however, patients who go on to reject the organ show a persistent downregulation of this signature relative to the neutrophil signature.