Optimization of Calcineurin Inhibitor Treatment after Solid Organ Transplantation

On December 23, 1954, Ronald Herrick donated a kidney to his identical twin brother Richard who was dying of renal failure. The kidney transplant produced urine immediately and in February 1955, Richard Herrick was discharged from hospital. He survived for another nine years (at which time his kidney allograft failed from recurrent glomerulonephritis), married the nurse who attended him, became father of two children and returned to work as a radio and television engineer. His brother Ronald lived on for more than 50 years after donating his kidney.1-3 In the years following this first successful human kidney transplantation, several more kidney transplants were performed between identical twins. Most of these patients had a return of normal kidney function and survived for a considerable period of time.4 However, it was clear from previous experience that if kidney transplantation was to be extended successfully to genetically non-identical individuals, suppressing the recipient’s immune system was necessary in order to prevent acute rejection. Early after World War II, a small number of human kidney transplantations had been performed in Europe and the United States. The recipients had received no immunosuppression except for a few cases in which short courses of ACTH or cortisone had been given. Although some of these kidney allografts did function for a limited period of time -most likely as a result of profound uremia5- most of the transplanted kidneys were acutely rejected or destroyed as a result of thrombosis or infection, and none of the recipients survived for a long period of time

Personalized immunosuppression in elderly renal transplant recipients

The number of elderly people has increased considerably over the last decades, due to a rising life expectancy and ageing populations. As a result, an increased number of elderly with end-stage-renal-disease are diagnosed, for which the preferred treatment is renal transplantation. Over the past years the awareness of the elderly as a specific patient population has grown, which increases the importance of research in this group.Elderly patients often receive kidneys from elderly donors while younger donor kidneys are preferentially reserved for younger recipients. Although the rate of acute rejection after transplantation is lower in the elderly, these rejections may lead to graft loss more frequently, as kidneys from elderly donors have marginal reserve capacity. To prevent acute rejection, immunosuppressive therapy is needed. On the other hand, elderly patients have a higher risk to die from infectious complications, and thus less immunosuppression would be preferable.Immunosuppressive treatm

Clinical validation of Anyplex? II HPV HR Detection according to the guidelines for HPV test requirements for cervical cancer screening.

BACKGROUND: Anyplex? II HPV HR Detection (Seegene, Seoul, Korea) is a multiplex real-time PCR using tagging oligonucleotide cleavage and extension (TOCE) technology for simultaneous detection and genotyping of 14 high-risk (HR) HPV types, including HPV16 and HPV18. OBJECTIVES: To evaluate whether the clinical performance and reproducibility of Anyplex? II HPV HR Detection meet the international consensus guidelines for HPV test requirements for cervical cancer screening [1]. STUDY DESIGN: The clinical performance of Anyplex? II HPV HR Detection for detecting cervical intraepithelial neoplasia grade 2 or worse (CIN2+) was determined relative to that of the reference assay, i.e., HR HPV GP5+/6+-PCR-EIA, by analysis of a total of 879 cervical liquid based cytology (LBC) specimens from a screening population, of which 60 were from women with CIN2+. The intra-laboratory reproducibility and inter-laboratory agreement were determined on 509 LBC samples, of which 172 were positive by the reference assay. RESULTS: Anyplex? II HPV HR Detection showed a clinical sensitivity for CIN2+ of 98.3% (59/60; 95% CI: 89.1-99.8) and a clinical specificity for CIN2+ of 93.6% (764/816; 95% CI: 89.8-96.1). The clinical sensitivity and specificity were non-inferior to those of HR HPV GP5+/6+-PCR-EIA (non-inferiority score test: P=0.005 and P=0.023, respectively). Both intra-laboratory reproducibility (96.8%; 95% CI: 95.3-98.1; kappa value of 0.93) and inter-laboratory agreement (96.0%; 95% CI: 94.3-97.4; kappa value of 0.91) were high. CONCLUSIONS: Anyplex? II HPV HR Detection performs clinically non-inferior to HR HPV GP5+/6+-PCR-EIA. Anyplex? II HPV HR Detection complies with international consensus validation metrics for HPV DNA tests for cervical cancer screening [1]

Down-regulation of surface CD28 under belatacept treatment: An escape mechanism for antigen-reactive T-cells

Background The co-stimulatory inhibitor of the CD28-CD80/86-pathway, belatacept, allows calcineurininhibitor-free immunosuppression in kidney transplantation. However, aggressive T-cell mediated allogeneic responses have been observed in belatacept-treated patients, which could be explained by effector-memory T-cells that lack membrane expression of CD28, i.e. CD28-negative (CD28NULL) T-cells. CD28-positive (CD28POS) T-cells that down regulate their surface CD28 after allogeneic stimulation could also pose a threat against the renal graft. The aim of this study was to investigate this potential escape mechanism for CD28POS T-cells under belatacept treatment. Materials & Methods PBMCs, isolated T-cell memory subsets and isolated CD28POS T-cells were obtained from end-stage renal disease (ESRD) patients and co-cultured with allo-antigen in the presence of belatacept to mimic allogeneic reactions in kidney-transplant patients under belatacept treatment. As a control, IgG was used in the absence of belatacept. Results Despite high in vitro belatacept concentrations, a residual T-cell growth of ±30% was observed compared to the IgG control after allogeneic stimulation. Of the alloreactive Tcells, the majority expressed an effector-memory phenotype. This predominance for effector-memory T-cells within the proliferated cells was even larger when a higher dose of belatacept was added. Contrary to isolated naïve and central-memory T cells, isolated effectormemory T cells could not be inhibited by belatacept in differentiation or allogeneic IFNγ production. The proportion of CD28-positive T cells was lower within the proliferated T cell population, but was still substantial. A fair number of the isolated initially CD28POS T-cells differentiated into CD28NULL T-cells, which made them not targetable by belatacept. These induced CD28NULL T-cells were not anergic as they produced high amounts of IFNγ upon allogeneic stimulat

Should we abandon therapeutic drug monitoring of tacrolimus in whole blood and move to intracellular concentration measurements?

The measurement of whole blood (WB) concentrations has been the primary method for therapeutic drug monitoring of tacrolimus since its introduction in the field of organ transplantation. However, >99% of tacrolimus measured in WB is bound to erythrocytes and plasma proteins, which are the pharmacologically inactive fractions. The pharmacologically active fractions, the free (or unbound) tacrolimus in plasma and the intracellular tacrolimus, make up 1% or less of the WB concentration. The mechanism of action of tacrolimus is to inhibit the enzyme calcineurin within T lymphocytes and, therefore, measuring the intralymphocytic tacrolimus concentration may better reflect its pharmacodynamic effects and better correlate with clinical outcomes. However, studies on intracellular tacrolimus concentrations have shown conflicting results. In this review, we argue that we need to overcome the analytical limitations of current assays for the measurement of intracellular tacrolimus before moving this technique into the clinical setting. The validity and standardization of the cell isolation process before the measurement of the intracellular tacrolimus concentration is as important as the measurement itself but has received little attention in our view. Recent evidence suggests that the addition of an inhibitor of P-glycoprotein, an efflux transporter expressed on lymphocytes, prevents the expulsion of tacrolimus during the cell isolation process. Refining the technique for the intracellular tacrolimus concentration measurement should be the focus followed by clinical evaluation of its association with rejection risk.Personalised Therapeutic

Usage of Tacrolimus and Mycophenolic Acid During Conception, Pregnancy, and Lactation, and Its Implications for Therapeutic Drug Monitoring: A Systematic Critical Review

BACKGROUND: Conception, pregnancy, and lactation following solid organ transplantation require appropriate management. The most frequently used immunosu

Pharmacogenetic aspects of the use of tacrolimus in renal transplantation: Recent developments and ethnic considerations

Introduction: Tacrolimus (Tac) is effective in preventing acute rejection but has considerable toxicity and inter-individual variability in pharmacokinetics and pharmacodynamics. Part of this is explained by polymorphisms in genes encoding Tac-metabolizing enzymes and transporters. A better understanding of Tac pharmacokinetics and pharmacodynamics may help to minimize different outcomes amongst transplant recipients by personalizing immunosuppression.Areas covered: The pharmacogenetic contribution of Tac metabolism will be examined, with a focus on recent discoveries, new developments and ethnic considerations.Expert opinion: The strongest and most consistent association in pharmacogenetics is between the CYP3A5 genotype and Tac dose requirement, with CYP3A5 expressers having a ∼ 40-50% higher dose requirement compared to non-expressers. Two recent randomized-controlled clinical trials using CYP3A5 genotype, however, did not show a decrease in acute rejections nor reduced toxicity. CYP3A4∗22, CYP3A4∗26, and POR∗28 are also associated with Tac dose requirements and may be included to provide the expected improvement of Tac therapy. Studies focusing on the intracellular drug concentrations and on calcineurin inhibitor-induced nephrotoxicity also seem promising. For all studies, however, the ethnic prevalence of genotypes should be taken into account, as this may significantly impact the effect of pre-emptive genotyping

Usage of tacrolimus and mycophenolic acid during conception, pregnancy, and lactation, and its implications for therapeutic drug monitoring: a systematic critical review

Background: Conception, pregnancy, and lactation following solid organ transplantation require appropriate management. The most frequently used immunosuppressive drug combination after solid organ transplantation consists of tacrolimus (Tac) plus mycophenolic acid (MPA). Here, the effects of Tac and MPA on fertility, pregnancy, and lactation are systematically reviewed, and their implications for therapeutic drug monitoring (TDM) are discussed. Methods: A systematic literature search was performed (August 19, 2019) using Ovid MEDLINE, EMBASE, the Cochrane Central Register of controlled trials, Google Scholar, and Web of Science, and 102 studies were included. Another 60 were included from the reference list of the published articles. Results: As MPA is teratogenic, women who are trying to conceive are strongly recommended to switch from MPA to azathioprine. MPA treatment in men during conception seems to have no adverse effect on pregnancy outcomes. Nevertheless, in 2015, the drug label was updated with additional risk minimization measures in a pregnancy prevention program. Data on MPA pharmacokinetics during pregnancy and lactation are limited. Tac treatment during conception, pregnancy, and lactation seems to be safe in terms of the health of the mother, (unborn) child, and allograft. However, Tac may increase the risk of hypertension, preeclampsia, preterm birth, and low birth weight. Infants will ingest very small amounts of Tac via breast milk from mothers treated with Tac. However, no adverse outcomes have been reported in children exposed to Tac during lactation. During pregnancy, changes in Tac pharmacokinetics result in increased unbound to whole-blood Tac concentration ratio. To maintain Tac concentrations within the target range, increased Tac dose and intensified TDM may be required. However, it is unclear if dose adjustments during pregnancy are necessary, considering the higher concentration of (active) unbound Tac. Conclusions: Tac treatment during conception, pregnancy and lactation seems to be relatively safe. Due to pharmacokinetic changes during pregnancy, a higher Tac dose might be indicated to maintain target concentrations. However, more evidence is needed to make recommendations on both Tac dose adjustments and alternative matrices than whole-blood for TDM of Tac during pregnancy. MPA treatment in men during conception seems to have no adverse effect on pregnancy outcomes, whereas MPA use in women during conception and pregnancy is strongly discouraged.Personalised Therapeutic