Search

The calcineurin inhibitors (CNI) cyclosporine A and tacrolimus comprise the basis of immunosuppressive regimes in all solid organ transplantation. However, long-term or high exposure to CNI leads to histological and functional renal damage (CNI-associated nephrotoxicity). In the kidney, proximal tubule cells are the only cells that metabolize CNI and these cells are believed to play a central role in the origin of the toxicity for this class of drugs, although the underlying mechanisms are not clear. Several studies have reported oxidative stress as an important mediator of CNI-associated nephrotoxicity in response to CNI exposure in different available proximal tubule cell models. However, former models often made use of supra-therapeutic levels of tissue drug exposure. In addition, they were not shown to express the relevant enzymes (e.g., CYP3A5) and transporters (e.g., P-glycoprotein) for the metabolism of CNI in human proximal tubule cells. Moreover, the used methods for detecting ROS were potentially prone to false positive results. In this study, we used a novel proximal tubule cell model established from human allograft biopsies that demonstrated functional expression of relevant enzymes and transporters for the disposition of CNI. We exposed these cells to CNI concentrations as found in tissue of stable solid organ transplant recipients with therapeutic blood concentrations. We measured the glutathione redox balance in this cell model by using organelle-targeted variants of roGFP2, a highly sensitive green fluorescent reporter protein that dynamically equilibrates with the glutathione redox couple through the action of endogenous glutaredoxins. Our findings provide evidence that CNI, at concentrations commonly found in allograft biopsies, do not alter the glutathione redox balance in mitochondria, peroxisomes, and the cytosol. However, at supra-therapeutic concentrations, cyclosporine A but not tacrolimus increases the ratio of oxidized/reduced glutathione in the mitochondria, suggestive of imbalances in the redox environment., Competing Interests: The authors have declared that no competing interests exist.

We present a 12-yr-old boy who received a combined liver-pancreas small bowel transplantation at the age of two. The post-operative period was complicated by wound closure problems resulting in a large asymptomatic abdominal wall defect. Further follow-up was uneventful, with the exception of new onset growth failure not explained by extensive routine investigations. An indirect calorimetry was performed. The resting energy expenditure (REE) was significantly increased (126% of predicted), demanding a daily caloric intake of 123 kcal/kg body weight (normal for age: 80 kcal/kg). In the absence of classic reasons for increased REE, a thermal camera revealed increased dermal heat loss at the abdominal wall defect (estimated surplus in energy loss of at least 29 kcal/day: 10.4% of the elevated REE). In addition, we found lower total lung capacity due to impaired abdominal breathing. In the exploration of growth failure in children after (ITx), increased REE must be taken into account. Indirect calorimetry can serve as a valuable diagnostic tool for evaluating individual energy requirements and nutritional support. In this child, exaggerated heat loss through an aberrant abdominal wall could be a potential important contributor to the patient's increased energy requirements., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Since their introduction circa 35 years ago, calcineurin-inhibitors (CNI) have become the cornerstone of immunosuppressive therapy in solid organ transplantation. However, CNI's possess a narrow therapeutic index with potential severe consequences of drug under- or overexposure. This demands a meticulous policy of Therapeutic Drug Monitoring (TDM) to optimize outcome. In clinical practice optimal dosing is difficult to achieve due to important inter- and intraindividual variation in CNI pharmacokinetics. A complex and often interdependent set of factors appears relevant in determining drug exposure. These include recipient characteristics such as age, race, body composition, organ function, and food intake, but also graft-related characteristics such as: size, donor-age, and time after transplantation can be important. Fundamental (in vitro) and clinical studies have pointed out the intrinsic relation between the aforementioned variables and the functional capacity of enzymes and transporters involved in CNI metabolism, primarily located in intestine, liver and kidney. Commonly occurring polymorphisms in genes responsible for CNI metabolism (CYP3A4, CYP3A5, CYP3A7, PXR, POR, ABCB1 (P-gp) and possibly UGT) are able to explain an important part of interindividual variability. In particular, a highly prevalent SNP in CYP3A5 has proven to be an important determinant of CNI dose requirements and drug-dose-interactions. In addition, a discrepancy in genotype between graft and receptor has to be taken into account. Furthermore, common phenomena in solid organ transplantation such as inflammation, ischemia- reperfusion injury, graft function, co-medication, altered food intake and intestinal motility can have a differential effect on the expression enzymes and transporters involved in CNI metabolism. Notwithstanding the built-up knowledge, predicting individual CNI pharmacokinetics and dose requirements on the basis of current clinical and experimental data remains a challenge., (Copyright © 2013 Elsevier B.V. All rights reserved.)