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Validation of genetic variants associated with early acute rejection in kidney allograft transplantation.

ABSTRACT: Numerous reports have identified genetic variants associated with kidney transplant outcome, but only a few have been validated in subsequent studies. We analyzed the association of 21 previously reported genetic variants associated with acute rejection (AR), in an effort to validate these associations in our kidney transplant population. All recipients (n = 585) received Ab induction, rapid discontinuation of prednisone, and calcineurin inhibitors with either mycophenolate mofetil or sirolimus. Both univariate analysis and logistic regression were used for determining the association between the genotypes and AR. Univariate analysis detected one significant single-nucleotide polymorphism (p = 0.03), rs1801133, within the methylenetetrahydrofolate reductase (MTHFR) gene associated with AR. Logistic regression analysis identified two variants associated with AR, the 32-bp deletion within chemokine (C-C motif) receptor 5 gene (rs333) and the p.222A/V variant (rs1801133) within the MTHFR gene. Although our analysis utilized a much larger cohort than used in previous reports, we were only able to detect an association with two of these variants. The lack of validation for the other 19 variants may be due to the small effect size, or that, they are not associated with AR. These results stress the need for larger cohorts for both future studies as well as for validation studies.

SUBMITTER: Oetting WS

PROVIDER: S-EPMC3374041 | biostudies-literature | 2012 May-Jun

REPOSITORIES: biostudies-literature

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Validation of genetic variants associated with early acute rejection in kidney allograft transplantation.

Oetting William S WS Zhu Yanni Y Brott Marcia J MJ Matas Arthur J AJ Cordner Gretchen K GK Pan Wei W

Clinical transplantation 20110915 3

Numerous reports have identified genetic variants associated with kidney transplant outcome, but only a few have been validated in subsequent studies. We analyzed the association of 21 previously reported genetic variants associated with acute rejection (AR), in an effort to validate these associations in our kidney transplant population. All recipients (n = 585) received Ab induction, rapid discontinuation of prednisone, and calcineurin inhibitors with either mycophenolate mofetil or sirolimus. ...[more]

PMID: 21919968

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Project description:ObjectiveTo evaluate the clinical and laboratory characteristics in pregnancy that differentiate preeclampsia from acute renal allograft rejection and to investigate the maternal, neonatal, and graft sequelae of these diagnoses.MethodsWe conducted a retrospective case-controlled registry study of data abstracted from Transplant Pregnancy Registry International deliveries between 1968 and 2019. All adult kidney transplant recipients with singleton pregnancies of at least 20 weeks of gestation were included. Acute rejection was biopsy proven and preeclampsia was diagnosed based on contemporary criteria. Variables were compared using χ2, Fisher exact, and Wilcoxon rank sum tests as appropriate. Multivariable linear regression was used to analyze preterm birth. Kaplan-Meier curves with log-rank test and Cox proportional hazards model were used to compare graft loss over time.ResultsThere were 26 pregnant women with biopsy-confirmed acute rejection who were matched by the year they conceived to 78 pregnant women with preeclampsia. Recipients with acute rejection had elevated peripartum serum creatinine levels (73% vs 14%, P<.001), with median intrapartum creatinine of 3.90 compared with 1.15 mg/dL (P<.001). Conversely, only patients with preeclampsia had a significant increase in proteinuria from baseline. Although there were no significant differences in maternal outcomes, graft loss within 2 years postpartum (42% vs 10%) and long-term graft loss (73% vs 35%) were significantly increased in recipients who experienced acute rejection (P<.001 for both). The frequency of delivery before 32 weeks of gestation was 53% with acute rejection and 20% with preeclampsia. After controlling for hypertension and immunosuppressant use, acute rejection was associated with higher frequency of delivery at less than 32 weeks of gestation (adjusted odds ratio 4.04, 95% CI 1.10-15.2).ConclusionIn pregnancy, acute rejection is associated with higher creatinine levels, and preeclampsia is associated with increased proteinuria. Acute rejection in pregnancy carries a risk of prematurity and graft loss beyond that of preeclampsia for kidney transplant recipients.Funding sourceThe Transplant Pregnancy Registry International is supported in part by an educational grant from Veloxis Pharmaceuticals.

Project description:Acute graft rejection is an important clinical problem in renal transplantation and an adverse predictor for long term graft survival. Plasma biomarkers may offer an important option for post-transplant monitoring and permit timely and effective therapeutic intervention to minimize graft damage. This case-control discovery study (n = 32) used isobaric tagging for relative and absolute protein quantification (iTRAQ) technology to quantitate plasma protein relative concentrations in precise cohorts of patients with and without biopsy-confirmed acute rejection (BCAR). Plasma samples were depleted of the 14 most abundant plasma proteins to enhance detection sensitivity. A total of 18 plasma proteins that encompassed processes related to inflammation, complement activation, blood coagulation, and wound repair exhibited significantly different relative concentrations between patient cohorts with and without BCAR (p value <0.05). Twelve proteins with a fold-change >or=1.15 were selected for diagnostic purposes: seven were increased (titin, lipopolysaccharide-binding protein, peptidase inhibitor 16, complement factor D, mannose-binding lectin, protein Z-dependent protease and beta(2)-microglobulin) and five were decreased (kininogen-1, afamin, serine protease inhibitor, phosphatidylcholine-sterol acyltransferase, and sex hormone-binding globulin) in patients with BCAR. The first three principal components of these proteins showed clear separation of cohorts with and without BCAR. Performance improved with the inclusion of sequential proteins, reaching a primary asymptote after the first three (titin, kininogen-1, and lipopolysaccharide-binding protein). Longitudinal monitoring over the first 3 months post-transplant based on ratios of these three proteins showed clear discrimination between the two patient cohorts at time of rejection. The score then declined to baseline following treatment and resolution of the rejection episode and remained comparable between cases and controls throughout the period of quiescent follow-up. Results were validated using ELISA where possible, and initial cross-validation estimated a sensitivity of 80% and specificity of 90% for classification of BCAR based on a four-protein ELISA classifier. This study provides evidence that protein concentrations in plasma may provide a relevant measure for the occurrence of BCAR and offers a potential tool for immunologic monitoring.

Dataset Information

Validation of genetic variants associated with early acute rejection in kidney allograft transplantation.

Publications

Validation of genetic variants associated with early acute rejection in kidney allograft transplantation.

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