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Changing Paradigms in the Management of Rejection in Kidney Transplantation: Evolving From Protocol-Based Care to the Era of P4 Medicine.

ABSTRACT: PURPOSE OF REVIEW:P4 medicine denotes an evolving field of medicine encompassing predictive, preventive, personalized, and participatory medicine. Using the example of kidney allograft rejection because of donor-recipient incompatibility in human leukocyte antigens, this review outlines P4 medicine's relevance to the various stages of the kidney transplant cycle. SOURCES OF INFORMATION:A search for English articles was conducted in Medline via OvidSP (up to August 18, 2016) using a combination of subject headings (MeSH) and free text in titles, abstracts, and author keywords for the concepts kidney transplantation and P4 medicine. The electronic database search was expanded further on particular subject headings. FINDINGS:Available histocompatibility methods exemplify current applications of the predictive and preventive domains of P4 medicine in kidney transplant recipients' care. Pharmacogenomics are discussed as means to facilitate personalized immunosuppression regimens and promotion of active patient participation as a means to improve adherence. LIMITATIONS:For simplicity, this review focuses on rejection. P4 medicine, however, should more broadly address health concerns in kidney transplant recipients, including competing outcomes such as infections, malignancies, and cardiovascular disease. This review highlights how biomarkers to evaluate these competing outcomes warrant validation and standardization prior to their incorporation into clinical practice. IMPLICATIONS:Consideration of all 4 domains of the P4 medicine framework when caring for and/or studying kidney transplant recipients has the potential of increasing therapeutic efficiency, minimizing adverse effects, decreasing health care costs, and maximizing wellness. Technologies to gauge immune competency, immunosuppression requirements, and early/reversible immune-mediated injuries are required to optimize kidney transplant care.

SUBMITTER: Maier M

PROVIDER: S-EPMC5308536 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Changing Paradigms in the Management of Rejection in Kidney Transplantation: Evolving From Protocol-Based Care to the Era of P4 Medicine.

Maier Mirela M Takano Tomoko T Sapir-Pichhadze Ruth R

Canadian journal of kidney health and disease 20170123

<h4>Purpose of review</h4>P4 medicine denotes an evolving field of medicine encompassing predictive, preventive, personalized, and participatory medicine. Using the example of kidney allograft rejection because of donor-recipient incompatibility in human leukocyte antigens, this review outlines P4 medicine's relevance to the various stages of the kidney transplant cycle.<h4>Sources of information</h4>A search for English articles was conducted in Medline via OvidSP (up to August 18, 2016) using ...[more]

PMID: 28270929

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Project description:ImportanceAcute rejection is one of the most frequent complications in facial transplantation, with potentially severe consequences for the recipient if overlooked. Clinical signs, such as erythema or edema, are helpful to diagnose acute rejection in the early follow-up stage; however, it is not well known whether these clinical signs remain reliable markers of acute rejection beyond the second posttransplant year.ObjectiveTo determine the diagnostic value of clinical signs of acute rejection after facial transplantation over time.Design, setting, and participantsA retrospective, single-center cohort study was conducted of patients who underwent facial transplantation at Brigham and Women's Hospital between April 2009 and October 2014, with up to an 8-year follow-up. Medical records were reviewed until September 30, 2017. The medical records from 104 encounters with 7 patients who underwent partial or full facial transplantation were analyzed for symptoms of rejection, immunosuppressive therapy, and histopathologic findings.Main outcomes and measuresThe occurrence of 5 clinical signs of acute rejection were evaluated: erythema, edema, exanthema, suture line erythema, and mucosal lesions. Odds ratios (ORs) were calculated to determine the statistically significant association of these signs with the histopathologic diagnosis of rejection. In addition, tacrolimus blood levels, as a surrogate marker of immunosuppressive therapy, were evaluated.ResultsOf the 7 patients included in the study, 5 were men. The mean follow-up was 66 months (range, 35-101). Of 104 clinical encounters, 46 encounters (44.2%) represented rejection episodes and 58 encounters (55.8%) represented no-rejection episodes. Beyond 2 years posttransplantation, only erythema (OR, 6.53; 95% CI, 1.84-20.11; P = .004) and exanthema (OR, ∞; 95% CI, 2.2-∞; P = .004) were demonstrated to be reliable clinical signs of acute rejection in facial transplantation. There was also a statistically significant association of subtherapeutic tacrolimus levels with late rejection episodes (OR, 3.79; 95% CI, 1.25-12.88; P = .03). In addition, the occurrence of subclinical rejection was more frequent during later follow-up times (7 [24.1%] late rejections vs 1 [5.9%] early rejection). Five of 8 subclinical rejections (62.5%) were associated with subtherapeutic tacrolimus levels.Conclusions and relevanceClinical signs of acute rejection in facial transplantation appear to be of limited diagnostic value, particularly after the second postoperative year. Until alternative biomarkers for rejection are identified, protocol skin biopsies will remain necessary for guiding assessments of allograft rejection.Level of evidence3.

Project description:Background and objectivesDefinition of individual risk profile is the first step to implement strategies to keep the delicate balance between under- and overimmunosuppression after kidney transplantation.Design, setting, participants, & measurementsWe used data from the Efficacy Limiting Toxicity Elimination Symphony Study (1190 patients between 2002 and 2004) to model risk of rejection and infection in the first year after kidney transplantation. External validation was performed in a study population from the Fixed-Dose Concentration-Controlled Trial (630 patients between 2003 and 2006).ResultsDespite different temporal dynamics, rejections and severe infections had similar overall incidences in the first year after transplantation (23.4% and 25.5%, respectively), and infections were the principal cause of death (43.2% of all deaths). Recipient older age, deceased donor, higher number of HLA mismatches, and high risk for cytomegalovirus disease were associated with infection; deceased donor, higher number of HLA mismatches, and immunosuppressive therapy including cyclosporin A (compared with tacrolimus), with rejection. These factors were integrated into a two-dimensional risk stratification model, which defined four risk groups: low risk for infection and rejection (30.8%), isolated risk for rejection (36.1%), isolated risk for infection (7.0%), and high risk for infection and rejection (26.1%). In internal validation, this model significantly discriminated the subgroups in terms of composite end point (low risk for infection/rejection, 24.4%; isolated risk for rejection and isolated risk for infection, 31.3%; high risk for infection/rejection, 54.4%; P<0.001), rejection episodes (isolated risk for infection and low risk for infection/rejection, 13.0%; isolated risk for rejection and high risk for infection/rejection, 24.2%; P=0.001), and infection episodes (low risk for infection/rejection and isolated risk for rejection, 12.0%; isolated risk for infection and high risk for infection/rejection, 37.6%; P<0.001). External validation confirmed the applicability of the model to an independent cohort.ConclusionsWe propose a two-dimensional risk stratification model able to disentangle the individual risk for rejection and infection in the first year after kidney transplantation. This concept can be applied to implement a personalized immunosuppressive and antimicrobial treatment approach.

Dataset Information

Changing Paradigms in the Management of Rejection in Kidney Transplantation: Evolving From Protocol-Based Care to the Era of P4 Medicine.

Publications

Changing Paradigms in the Management of Rejection in Kidney Transplantation: Evolving From Protocol-Based Care to the Era of P4 Medicine.

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