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An Insight Into the Immunologic Events and Risk Assessment in Renal Transplantation.

ABSTRACT: Organ transplantation has always been considered to be the optimal therapeutic intervention in patients with end-stage organ failure. In the US, approximately 615,000 patients are diagnosed with end-stage renal disease and less than 30% have received a kidney transplant. One of the crucial drawbacks in successful renal transplantation is allograft rejection. Survival rates among transplant recipients have greatly improved due to better understanding of transplant biology and more effective immunosuppressive agents. Post-transplant immune monitoring and optimization of the immunosuppressive therapy using non-invasive biomarkers can effectively predict impending graft rejection and may spare the need for renal biopsy. This article provides an insight into the immunomodulations of renal transplant recipients. It depicts the immune system including several types of kidney rejection and reviews the biomarkers that may serve in near future, as surveillance tools for graft monitoring. Finally, a summary on the main immunosuppressive drugs used in kidney transplant both in the induction and maintenance phases is also covered.

SUBMITTER: Khan A

PROVIDER: S-EPMC4817575 | biostudies-other | 2016 May

REPOSITORIES: biostudies-other

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An Insight Into the Immunologic Events and Risk Assessment in Renal Transplantation.

Khan Asif A Nasr Patricia P El-Charabaty Elie E El-Sayegh Suzanne S

Journal of clinical medicine research 20160320 5

Organ transplantation has always been considered to be the optimal therapeutic intervention in patients with end-stage organ failure. In the US, approximately 615,000 patients are diagnosed with end-stage renal disease and less than 30% have received a kidney transplant. One of the crucial drawbacks in successful renal transplantation is allograft rejection. Survival rates among transplant recipients have greatly improved due to better understanding of transplant biology and more effective immun ...[more]

PMID: 27081421

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Project description:This study includes 1,220 cases with young onset stroke (stroke before age 60 years) who are participants of the larger RACE study. Risk Assessment of Cerebrovascular Events (RACE) is an on-going existing case-control study of stroke now involving over 5000 imaging confirmed cases of stroke and 5000 controls, recruited from seven centers in Pakistan. The study is aimed to investigate the genetic, biomarker and lifestyle determinants of stroke and its subtypes. Cases are eligible for inclusion in the study if they: (i) are aged at least 18 years; (ii) present with a sudden onset of neurological deficit respecting a vascular territory with sustained deficit at 24 hours verified by medical attention within 72 hours after onset (onset is defined by when the patient was last seen normal and not when found with deficit); and (iii) the diagnosis is supported by CT/MRI; and (iv) present with a Modified Rankin Score < 2 prior to the stroke. Findings from patient's history, 12-lead ECG and CT or MRI of the brain. The mandatory procedures for inclusion in this investigation are: (i) clinical verification of cerebrovascular event within 72 hours of onset; (ii) neuroimaging CT (non-contrast) or MRI (MRI is not a mandatory investigation but recorded whenever ordered by the attending physician); and (iii) 12-lead ECG. All other ancillary investigations ordered by the attending physician are recorded as well. The TOAST classification method is used to classify ischemic stroke based on aetiology whereas the Oxfordshire classification is used to classify stroke neuro-anatomically. Control participants for this subset of young onset stroke were individuals enrolled in the Pakistan Risk of Myocardial Infarction Study (PROMIS), a case-control study of acute MI based in Pakistan. RACE capitalizes on the genetic data (including information on GWAS) that has already been collected from the healthy participants enrolled in PROMIS. RACE and PROMIS share similar methodology of recruitment. Participants from both these investigations are derived from similar catchment areas, hence providing an attractive opportunity for RACE to utilize PROMIS controls as common controls for genetic investigations. Controls in PROMIS were recruited following procedures and inclusion criteria as adopted for RACE cases. In order to minimize any potential selection biases, PROMIS controls selected for this stroke substudy were frequency matched to RACE cases based on age and gender and were recruited in the following order of priority: (1) non-blood related or blood related visitors of patients of the out-patient department; (2) non-blood related visitors of stroke patients; (3) patients of the out-patient department presenting with minor complaints (e.g. back pain, minor gastric complaints). Control subjects from the PROMIS study were genotyped at the Wellcome Trust Sanger Institute on the Illumina 660W Quad array. The Center for Non-Communicable Diseases, Pakistan, serves as the coordinating center for both RACE and PROMIS. More information on these research investigations can be found at <a href="http://www.cncdpk.com">www.cncdpk.com.</a> This young onset stroke component to the RACE study was funded through the Gene Environment Association Studies initiative (GENEVA, <a href="https://www.genevastudy.org">www.genevastudy.org</a> as one of three studies designed to assess the genetics of young onset stroke and modification of genetic effects by smoking. GENEVA is part of the trans-NIH Genes, Environment, and Health Initiative (GEI). Genotyping of 1,220 young onset stroke cases was performed at the Johns Hopkins University Center for Inherited Disease Research (CIDR). Data cleaning and harmonization were done at the GEI-funded GENEVA Coordinating Center at the University of Washington. This study is part of the Gene Environment Association Studies initiative (GENEVA, http://www.genevastudy.org) funded by the trans-NIH Genes, Environment, and Health Initiative (GEI). The overarching goal is to identify novel genetic factors that contribute to stroke through large-scale genome-wide association studies of cases and controls recruited within Pakistan. Genotyping was performed at the Johns Hopkins University Center for Inherited Disease Research (CIDR). Data cleaning and harmonization were done at the GEI-funded GENEVA Coordinating Center at the University of Washington.

Project description:BackgroundInducing donor-specific tolerance in renal transplant patients could potentially prevent allograft rejection and calcineurin inhibitor nephrotoxicity. Combined kidney and hematopoietic stem cell transplant from an HLA-matched donor is an exploratory and promising therapy to induce immune tolerance. Investigation of molecular mechanisms involved in the disease is needed to understand the potential process of cell therapy and develop strategies to prevent this immunologic rejection.MethodsWe enrolled nine patients in a clinical study in which cryopreserved donor hematopoietic stem cells were infused on days 2, 4, and 6 after kidney transplantation. One month post-transplant, 4 plasma samples were collected from combined transplants (C?+?Tx), and 8 plasma samples from patients with kidney transplantation alone (Tx). High abundance proteins in plasma were depleted and the two-dimensional liquid chromatography-tandem mass spectrometry coupled with iTRAQ labeling was utilized to identify the protein profiling between the two groups. Clusters of up- and down-regulated protein profiles were submitted to MetaCore for the construction of transcriptional factors and regulation networks.Results and discussionAmong the 179 identified proteins, 65 proteins were found in C?+?Tx with at least a 2-fold change as compared with Tx. A subset of proteins related to the complement and coagulation cascade, including complement C3a,complement C5a, precrusors to fibrinogen alpha and beta chains,was significantly downregulated in C?+?Tx. Meanwhile, Apolipoprotein-A1(ApoA1), ApoC1, ApoA2, ApoE, and ApoB were significantly lower in Tx compared to C?+?Tx. Gene ontology analysis showed that the dominant processes of differentially expressed proteins were associated with the inflammatory response and positive regulation of plasma lipoprotein particle remodeling.ConclusionsThus, our study provides new insight into the molecular events in the hematopoietic stem cell-induced immunologic tolerance.

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An Insight Into the Immunologic Events and Risk Assessment in Renal Transplantation.

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An Insight Into the Immunologic Events and Risk Assessment in Renal Transplantation.

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