Biomarkers of immunosuppressant organ toxicity after transplantation: status, concepts and misconceptions

Christians, Uwe; Klawitter, Jost; Klawitter, Jelena; Brunner, Nina; Schmitz, Volker

doi:10.1517/17425255.2011.544249

Cited by 33 publications

(18 citation statements)

References 164 publications

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“…While, as aforementioned, chronic allograft dysfunction is the primary cause of renal allograft loss after the first year, cardiovascular complications remain the foremost cause of death of kidney transplant patients [1]. Although the heightened risk of cardiovascular disease in transplant recipients is the result of multiple factors, immunosuppressant side effects on endothelial function are principal contributors [25].…”

Section: Discussionmentioning

confidence: 99%

“…Kidney transplantation is the preeminent treatment for patients with terminal kidney failure, both in terms of survival advantage and quality of life [1,2]. Although short-term allograft survival has significantly improved over the years, long-term graft survival past 5 y has remained largely unchanged [3,4].…”

Section: Introductionmentioning

confidence: 99%

“…Nevertheless, the lack of sensitivity and specificity of serum creatinine and the risk of damaging the allograft during a biopsy have underlined the need for more sensitive and specific noninvasive diagnostic tools capable of monitoring and predicting kidney dysfunction in a clinical setting. While chronic allograft dysfunction is the primary cause of renal allograft loss after the first year, cardiovascular complications remain the foremost cause of death [1]. The increased prevalence of cardiovascular disease in transplant recipients is the result of multiple factors, and homocysteinemia was found in approximately 60% of renal transplant patients [7].…”

Section: Introductionmentioning

confidence: 99%

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Development and validation of an LC-MS/MS assay for the quantification of the trans-methylation pathway intermediates S-adenosylmethionine and S-adenosylhomocysteine in human plasma

Klepacki

Brunner

Schmitz

et al. 2013

Clinica Chimica Acta

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Background Although increased levels of S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH) have been implicated as markers for renal and vascular dysfunction, until now there have been no studies investigating their association with clinical post-transplant events such as organ rejection and immunosuppressant nephrotoxicity. Methods A newly developed and validated liquid chromatography–tandem mass spectrometry (LC–MS/MS) assay for the quantification of SAM and SAH in human EDTA plasma was used for a clinical proof-of-concept pilot study. Retrospective analysis was performed using samples from a longitudinal clinical study following de novo kidney transplant patients for the first year (n = 16). Results The ranges of reliable response were 8 to 1024 nmol/l for SAM and 16 to 1024 nmol/l for SAH. The inter-day accuracies were 96.7–103.9% and 97.9–99.3% for SAM and SAH, respectively. Inter-day imprecisions were 8.1–9.1% and 8.4–9.8%. The total assay run time was 5 min. SAM and SAH concentrations were significantly elevated in renal transplant patients preceding documented acute rejection and nephrotoxicity events when compared to healthy controls (n = 8) as well as transplant patients void of allograft dysfunction (n = 8). Conclusion The LC-MS/MS assay will provide the basis for further large-scale clinical studies to explore these thiol metabolites as molecular markers for the management of renal transplant patients.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Development and validation of an LC-MS/MS assay for the quantification of the trans-methylation pathway intermediates S-adenosylmethionine and S-adenosylhomocysteine in human plasma

Klepacki

Brunner

Schmitz

et al. 2013

Clinica Chimica Acta

Self Cite

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“…193,194 Therapeutic drug monitoring of trough levels is performed; however, trough levels only provide an indirect measure of immunosuppression. Overimmunosuppression is often late to be identified, generally after the diagnosis of related adverse effects.…”

Section: Strategies For Prevention Of Underimmunosuppressionmentioning

confidence: 99%

“…[193][194][195] Infections occur more commonly during the first year of transplant, when immunosuppression levels are highest ( Figure 9). 193,195 On the other hand, malignancies (other than posttransplant lymphoproliferative disease [PTLD]) tend to occur after the first year of transplantation, presumably due to cumulative immunosuppression.…”

Section: Strategies For Prevention Of Underimmunosuppressionmentioning

confidence: 99%

Practical Recommendations for Long-term Management of Modifiable Risks in Kidney and Liver Transplant Recipients

et al. 2017

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Short-term patient and graft outcomes continue to improve after kidney and liver transplantation, with 1-year survival rates over 80%; however, improving longer-term outcomes remains a challenge. Improving the function of grafts and health of recipients would not only enhance quality and length of life, but would also reduce the need for retransplantation, and thus increase the number of organs available for transplant. The clinical transplant community needs to identify and manage those patient modifiable factors, to decrease the risk of graft failure, and improve longer-term outcomes. COMMIT was formed in 2015 and is composed of 20 leading kidney and liver transplant specialists from 9 countries across Europe. The group's remit is to provide expert guidance for the long-term management of kidney and liver transplant patients, with the aim of improving outcomes by minimizing modifiable risks associated with poor graft and patient survival posttransplant. The objective of this supplement is to provide specific, practical recommendations, through the discussion of current evidence and best practice, for the management of modifiable risks in those kidney and liver transplant patients who have survived the first postoperative year. In addition, the provision of a checklist increases the clinical utility and accessibility of these recommendations, by offering a systematic and efficient way to implement screening and monitoring of modifiable risks in the clinical setting. 12 Department of Gastroenterology and Hepatology, Erasmus MC, University Hospital Rotterdam, the Netherlands. 13 Department of Gastroenterology and Hepatology, University Hospitals KU Leuven, Belgium.14 Abdominal Transplant Surgery, Microbiology and Immunology Department, University Hospitals KU Leuven, Belgium. 15 Department of Hepatology and Liver Transplantation, Reina Sofía University Hospital, IMIBIC, CIBERehd, Spain. www.transplantjournal.com S1 S olid organ transplantation has evolved from an experimental procedure to an established treatment option for many types of end-stage organ failure. Both patient and graft outcomes are continuing to improve, and 1-year patient and graft survival currently exceed 80%.1,2 However, survival rates gradually decline over the long term. In kidney transplant, 5-and 10-year graft survival rates in Europe are 77% and 56%, and for liver transplant, 64% and 54% (Figures 1 and 2). 3,4 Although most European countries have seen an increase in both living and deceased donation, transplantation is not available to all who would benefit from the procedure, and there is considerable morbidity and mortality for those listed for transplant.6 Therefore, maximizing long-term graft survival and reducing the need for retransplantation is paramount, not only in improving outcomes for the recipients but also for those awaiting a graft. The improvement in outcomes is predominantly due to reduction in (Transplantation. 2017;101:S1-S41). The authors were approached by Astellas to discuss the practical implementation o...

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Regulatory T cells in solid organ transplantation

et al. 2020

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The induction of graft tolerance remains the holy grail of transplantation. This is important as chronic allograft dysfunction and the side effects of immunosuppression regimens place a major burden on the lives of transplant patients and their healthcare systems. This has mandated the need to understand the immunobiology of graft rejection and identify novel therapeutics. Regulatory T (Treg) cells play an important role in modulating pro‐inflammatory microenvironments and maintaining tissue homeostasis. However, there are fundamental unanswered questions regarding Treg cell immunobiology. These cells are a heterogeneous entity with functionally diverse roles. Moreover, the adoption of novel deeper immunophenotyping and genomic sequencing technologies has identified this phenotype and function to be more complex than expected. Hence, a comprehensive understanding of Treg cell heterogeneity is needed to safely and effectively exploit their therapeutic potential. From a clinical perspective, the recent decade has seen different clinical teams commence and complete first‐in‐man clinical trials utilising Treg cells as an adoptive cellular therapy. In this review, we discuss these trials from a translational perspective with an important focus on safety. Finally, we identify crucial knowledge gaps for future study.

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Biomarkers of immunosuppressant organ toxicity after transplantation: status, concepts and misconceptions

Cited by 33 publications

References 164 publications

Development and validation of an LC-MS/MS assay for the quantification of the trans-methylation pathway intermediates S-adenosylmethionine and S-adenosylhomocysteine in human plasma

Development and validation of an LC-MS/MS assay for the quantification of the trans-methylation pathway intermediates S-adenosylmethionine and S-adenosylhomocysteine in human plasma

Practical Recommendations for Long-term Management of Modifiable Risks in Kidney and Liver Transplant Recipients

Regulatory T cells in solid organ transplantation

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