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Donor caveolin 1 (CAV1) genetic polymorphism influences graft function after renal transplantation.

ABSTRACT: BACKGROUND:Identification of the culprit genes underlying multifactorial diseases is one of the most important current challenges of molecular genetics. While recent advances in genomics research have accelerated the discovery of susceptibility genes, much remains to be learned about the functions of disease-associated genetic variants. Recently, Moore and co-workers identified, in the donor genome, an association between a common genetic variant (rs4730751) in the gene encoding caveolin-1 (CAV1), a major structural component of caveolae, and long-term allograft survival. METHODS:Four hundred seventy-five renal recipients consecutively transplanted were included in this study. Donor genomic DNA was extracted and used to genotype CAV1 rs4730751 Single Nucleotide Polymorphism. RESULTS:Patients receiving a graft carrying CAV1 rs4730751 AA genotype displayed a significant decrease in estimated glomerular filtration rate and a significant increase in serum creatinine in both univariate and multivariate analyzes. Moreover, patients receiving a graft with CAV1 AA genotype significantly developed more interstitial fibrosis lesions on systematic biopsies performed 3 months post-transplantation. CONCLUSIONS:Genotyping of CAV1 may be relevant to identify patients at risk of adverse renal transplant outcome.

SUBMITTER: Van der Hauwaert C

PROVIDER: S-EPMC4419392 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Donor caveolin 1 (CAV1) genetic polymorphism influences graft function after renal transplantation.

Van der Hauwaert Cynthia C Savary Grégoire G Pinçon Claire C Gnemmi Viviane V Noël Christian C Broly Franck F Labalette Myriam M Perrais Michaël M Pottier Nicolas N Glowacki François F Cauffiez Christelle C

Fibrogenesis & tissue repair 20150505

<h4>Background</h4>Identification of the culprit genes underlying multifactorial diseases is one of the most important current challenges of molecular genetics. While recent advances in genomics research have accelerated the discovery of susceptibility genes, much remains to be learned about the functions of disease-associated genetic variants. Recently, Moore and co-workers identified, in the donor genome, an association between a common genetic variant (rs4730751) in the gene encoding caveolin ...[more]

PMID: 25945124

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Project description:This study evaluated the combined effect of recipient-to-donor weight and sex mismatch after deceased-donor renal transplantation in a German transplant cohort and the evolution of recipient-to-donor weight difference over a 13-year observation period. The association of absolute weight and sex difference with graft failure was explored in an outpatient cohort of deceased-donor transplant recipients who underwent kidney transplantation between 2000 and 2012. Graft failure was defined as repeated need for dialysis or death with a functioning graft. Recipient and donor sex pairings were classified as sex concordant (MDMR/FDFR) or discordant (MDFR/FDMR). These classes were further stratified into four groups according to recipient-to-donor weight mismatch ≥10 kg (recipient > donor) or <10 kg (recipient < donor). Multivariable Cox proportional hazards models were applied to evaluate the time to graft loss adjusting for donor, immunologic, surgical, organizational, and recipient predictors. Sex-concordant transplant pairings <10 kg weight difference served as the reference group. Among 826 transplant recipients, 154 developed graft failure (18.6%). Median graft survival time was 3.9 years; first quartile (0.2-1.2), second quartile (1.2-2.9), third quartile (2.9-5.8), and fourth quartile (5.8-12.4). After multivariable adjustment, the highest relative hazard for graft failure was observed for sex-discordant transplant pairings with a ≥10 kg weight difference between recipient and donor (compared to the reference group MDMR/FDFR with weight difference <10 kg, MDMR/FDFR with weight difference ≥10 kg, hazard ratio 1.86, 95% confidence interval 1.07-3.32-p = 0.029; MDFR/FDMR with weight difference <10 kg, hazard ratio 1.14, 95% confidence interval 0.78-1.68-p = 0.507, and MDFR/FDMR with weight difference ≥10 kg, hazard ratio 2.00, 95% confidence interval 1.15-3.48-p = 0.014). A recipient-to-donor weight mismatch of ≥10 kg was associated with an increased risk of graft loss or recipient death with a functioning graft. Concurrent sex discordance seemed to enhance this effect as indicated by an increase in the hazard ratio. We detected no significant tendency for increasing recipient-to-donor weight differences from 2000 to 2012.

Project description:Several recipient biomarkers are reported to predict graft dysfunction, but these are not useful in decision making for the acceptance or allocation of deceased donor kidneys; thus, it is necessary to develop donor biomarkers predictive of graft dysfunction. To address this issue, we prospectively enrolled 94 deceased donors and their 109 recipients who underwent transplantation between 2010 and 2013 at 4 Korean transplantation centers. We investigated the predictive values of donor urinary neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), and L-type fatty acid binding protein (L-FABP) for reduced graft function (RGF). We also developed a prediction model of RGF using these donor biomarkers. RGF was defined as delayed or slow graft function. Multiple logistic regression analysis was used to generate a prediction model, which was internally validated using a bootstrapping method. Multiple linear regression analysis was used to assess the association of biomarkers with 1-year graft function. Notably, donor urinary NGAL levels were associated with donor AKI (P = 0.014), and donor urinary NGAL and L-FABP were predictive for RGF, with area under the receiver-operating characteristic curves (AUROC) of 0.758 and 0.704 for NGAL and L-FABP, respectively. The best-fit model including donor urinary NGAL, L-FABP, and serum creatinine conveyed a better predictive value for RGF than donor serum creatinine alone (P = 0.02). In addition, we generated a scoring method to predict RGF based on donor urinary NGAL, L-FABP, and serum creatinine levels. Diagnostic performance of the RGF prediction score (AUROC 0.808) was significantly better than that of the DGF calculator (AUROC 0.627) and the kidney donor profile index (AUROC 0.606). Donor urinary L-FABP levels were also predictive of 1-year graft function (P = 0.005). Collectively, these findings suggest donor urinary NGAL and L-FABP to be useful biomarkers for RGF, and support the use of a new scoring system based on donor biomarkers to facilitate decision-making in acceptance and allocation of deceased donor kidneys and contribute to maximal organ utilization.

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Donor caveolin 1 (CAV1) genetic polymorphism influences graft function after renal transplantation.

Publications

Donor caveolin 1 (CAV1) genetic polymorphism influences graft function after renal transplantation.

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