scholarly journals Exome Sequencing and Prediction of Long-Term Kidney Allograft Function

2015 ◽  
Author(s):  
Laurent Mesnard ◽  
Thangamani Muthukumar ◽  
Maren Burbach ◽  
Carol Li ◽  
Huimin Shang ◽  
...  
Keyword(s):  
Amino Acid ◽  
Exome Sequencing ◽  
Amino Acid Level ◽  
Graft Function ◽  
Kidney Graft ◽  
Donor Age ◽  
Post Transplantation ◽  
Kidney Allograft ◽  
Allograft Function

Current strategies to improve graft outcome following kidney transplantation consider information at the HLA loci. Here, we used exome sequencing of DNA from ABO compatible kidney graft recipients and their living donors to determine recipient and donor mismatches at the amino acid level over entire exomes. We estimated the number of amino acid mismatches in transmembrane proteins, more likely to be seen as foreign by the recipient's immune system, and designated this tally as the allogenomics mismatch score (AMS). The AMS can be measured prior to transplantation with DNA for potential donor and recipient pairs. We examined the degree of relationship between the AMS and post-transplantation kidney allograft function by linear regression. In a discovery cohort, we found a significant inverse correlation between the AMS and kidney graft function at 36 months post-transplantation (n=10 recipient/donor pairs; 20 exomes) (r2>=0.57, P<0.05). The predictive ability of the AMS persists when the score is restricted to regions outside of the HLA loci. This relationship was validated using an independent cohort of 24 recipient donor pairs (n=48 exomes) (r2>=0.39, P<0.005). In an additional cohort of living and mostly intra-familial recipient/donor pairs (n=19, 38 exomes), we validated the association after controlling for donor age at time of transplantation. Finally, a model that controls for donor age, HLA mismatches and time post-transplantation yields a consistent AMS effect across these three independent cohorts (P<0.05). Taken together, these results show that the AMS is a strong predictor of long-term graft function in kidney transplant recipients.

scholarly journals Exome sequencing and prediction of long-term kidney allograft function

2015 ◽  
Author(s):  
Laurent Mesnard ◽  
Thangamani Muthukumar ◽  
Maren Burbach ◽  
Carol Li ◽  
Huimin Shang ◽  
...  
Keyword(s):  
Amino Acid ◽  
Exome Sequencing ◽  
Amino Acid Level ◽  
Graft Function ◽  
Kidney Graft ◽  
Donor Age ◽  
Post Transplantation ◽  
Kidney Allograft ◽  
Allograft Function

Current strategies to improve graft outcome following kidney transplantation consider information at the HLA loci. Here, we used exome sequencing of DNA from ABO compatible kidney graft recipients and their living donors to determine recipient and donor mismatches at the amino acid level over entire exomes. We estimated the number of amino acid mismatches in transmembrane proteins, more likely to be seen as foreign by the recipient’s immune system, and designated this tally as the allogenomics mismatch score (AMS). The AMS can be measured prior to transplantation with DNA for potential donor and recipient pairs. We examined the degree of relationship between the AMS and post-transplantation kidney allograft function by linear regression. In a discovery cohort, we found a significant inverse correlation between the AMS and kidney graft function at 36 months post-transplantation (n=10 recipient/donor pairs; 20 exomes) (r2>=0.57, P<0.05). The predictive ability of the AMS persists when the score is restricted to regions outside of the HLA loci. This relationship was validated using an independent cohort of 24 recipient donor pairs (n=48 exomes) (r2>=0.39, P<0.005). In an additional cohort of living and mostly intra-familial recipient/donor pairs (n=19, 38 exomes), we validated the association after controlling for donor age at time of transplantation. Finally, a model that controls for donor age, HLA mismatches and time post-transplantation yields a consistent AMS effect across these three independent cohorts (P<0.05). Taken together, these results show that the AMS is a strong predictor of long-term graft function in kidney transplant recipients.

scholarly journals Exome sequencing and prediction of long-term kidney allograft function

2015 ◽  
Author(s):  
Laurent Mesnard ◽  
Thangamani Muthukumar ◽  
Maren Burbach ◽  
Carol Li ◽  
Huimin Shang ◽  
...  
Keyword(s):  
Amino Acid ◽  
Exome Sequencing ◽  
Amino Acid Level ◽  
Graft Function ◽  
Kidney Graft ◽  
Donor Age ◽  
Post Transplantation ◽  
Kidney Allograft ◽  
Allograft Function

Current strategies to improve graft outcome following kidney transplantation consider information at the HLA loci. Here, we used exome sequencing of DNA from ABO compatible kidney graft recipients and their living donors to determine recipient and donor mismatches at the amino acid level over entire exomes. We estimated the number of amino acid mismatches in transmembrane proteins, more likely to be seen as foreign by the recipient’s immune system, and designated this tally as the allogenomics mismatch score (AMS). The AMS can be measured prior to transplantation with DNA for potential donor and recipient pairs. We examined the degree of relationship between the AMS and post-transplantation kidney allograft function by linear regression. In a discovery cohort, we found a significant inverse correlation between the AMS and kidney graft function at 36 months post-transplantation (n=10 recipient/donor pairs; 20 exomes) (r2>=0.57, P<0.05). The predictive ability of the AMS persists when the score is restricted to regions outside of the HLA loci. This relationship was validated using an independent cohort of 24 recipient donor pairs (n=48 exomes) (r2>=0.39, P<0.005). In an additional cohort of living and mostly intra-familial recipient/donor pairs (n=19, 38 exomes), we validated the association after controlling for donor age at time of transplantation. Finally, a model that controls for donor age, HLA mismatches and time post-transplantation yields a consistent AMS effect across these three independent cohorts (P<0.05). Taken together, these results show that the AMS is a strong predictor of long-term graft function in kidney transplant recipients.

scholarly journals Exome sequencing, histoincompatibility and long-term kidney allograft function

2015 ◽  
Author(s):  
Laurent Mesnard ◽  
Thangamani Muthukumar ◽  
Maren Burbach ◽  
Carol Li ◽  
Huimin Shang ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Graft Failure ◽  
Graft Function ◽  
Inverse Correlation ◽  
Kidney Graft ◽  
Post Transplantation ◽  
Post Transplant ◽  
Allograft Function ◽  
Kidney Recipient

BACKGROUND: Kidney transplantation is the treatment of choice for most patients with end-stage renal disease and existing data suggest that post transplant graft function is a predictor of kidney graft failure. METHODS: Exome sequencing of DNA from kidney graft recipients and their donors was used to determine recipient and donor mismatches at the amino acid level. The number of mismatches that are more likely to induce an immune response in the recipient was computationally estimated and designated the allogenomics mismatch score. The relationship between the allogenomics score and post transplant kidney allograft function was examined using linear regression. RESULTS: A significant inverse correlation between the allogenomics mismatch score and kidney graft function at 36 months post transplantation was observed in a discovery cohort of kidney recipient-donor pairs (r2>=0.57, P<0.05, the score vs. level of serum creatinine or estimated glomerular filtration rate). This relationship was confirmed in an independent validation cohort of kidney recipient-donor pairs. We observed that the strength of the correlation increased with time post-transplantation. This inverse correlation remained after excluding HLA loci from the calculation of the score. Exome sequencing yielded allogenomics scores with stronger correlations with graft function than simulations of genotyping assays which measure common polymorphisms only. CONCLUSIONS: The allogenomics mismatch score, derived by exome sequencing of recipient-donor pairs, facilitates quantification of histoincompatibility between the organ donor and recipient impacting long-term post transplant graft function. The allogenomics mismatch score, by serving as a prognostic biomarker, may help identify patients at risk for graft failure.

Donor Age Amplifies the Detrimental Effects of Cold Ischemia Time on Long-Term Kidney Allograft Survival Independently of the Occurrence of Delayed Graft Function or Early Acute Rejection

2020 ◽  
Vol 18 (4) ◽  
pp. 436-443
Author(s):  
Pedro Rincon Cintra da Cruz ◽  
Aderivaldo Cabral Dias Filho ◽  
Viviane Brandão Bandeira Mello Santana ◽  
Rubia Bethania Biela Boaretto ◽  
Cassio Luis Zanettini Riccetto
Keyword(s):  
Acute Rejection ◽  
Graft Function ◽  
Delayed Graft Function ◽  
Cold Ischemia Time ◽  
Donor Age ◽  
Allograft Survival ◽  
Cold Ischemia ◽  
Kidney Allograft ◽  
Ischemia Time

scholarly journals Effect of the Interrelation between CYP3A5 Genotype, Concentration/Dose Ratio and Intrapatient Variability of Tacrolimus on Kidney Graft Function: Monte Carlo Simulation Approach

Pharmaceutics ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 1970
Author(s):  
Nikola Stefanović ◽  
Radmila Veličković-Radovanović ◽  
Katarina Danković ◽  
Ivan Pavlović ◽  
Aleksandra Catić-Đorđević ◽  
...  
Keyword(s):  
Monte Carlo ◽  
Graft Function ◽  
Kidney Graft ◽  
Dose Ratio ◽  
Post Transplantation ◽  
Cyp3a5 Genotype ◽  
Lower Egfr ◽  
Mc Simulation ◽  
D Values

Background: Tacrolimus (Tac) is characterized by large between- and within-patient (IPV) variability in pharmacokinetics and exposure. Aim: This study aimed to assess and validate the effect of Tac IPV and trough concentration-to-dose ratio (C0/D) over 6–12 months on reduced estimated glomerular filtration rate (eGFR) values in the late period after kidney transplantation (Tx), applying Monte Carlo (MC) simulation. Methods: The previously published linear regression was the basis for MC simulation, performed to determine how variations in significant predictors affect the distribution of eGFR from 13 to 36 months post-transplantation. The input C0/D values were derived from CYP3A5 genotype subgroups. Results: Patients characterized by high Tac IPV and low mean C0/D over 6–12 months could have been at greater risk of lower eGFR values in a three-year period following Tx compared to the other patient groups. This effect was more pronounced in patients with a lower eGFR at the 6th month and a history of acute rejection. The proven contribution of CYP3A5 expresser genotype to low C0/D values may suggest its indirect effect on long-term graft function. Conclusion: The findings indicate that simultaneous assessment of Tac IPV, C0/D, and CYP3A5 genotype may identify patients at risk of deterioration of graft function in the long-term post-transplantation period.

scholarly journals Over Ten-Year Kidney Graft Survival Determinants

2012 ◽  
Vol 2012 ◽  
pp. 1-5 ◽  
Author(s):  
Anabela Malho Guedes ◽  
Jorge Malheiro ◽  
Isabel Fonseca ◽  
La Salete Martins ◽  
Sofia Pedroso ◽  
...  
Keyword(s):  
Graft Survival ◽  
Graft Failure ◽  
Graft Function ◽  
Kidney Graft ◽  
Donor Age ◽  
Patient Death ◽  
Chi Square ◽  
Predictive Variables ◽  
Chi Square Test

Kidney graft survival has been mainly evaluated using an up to 10-year threshold. Instead, in this study our aim was to evaluate predictive variables that impact long-term kidney graft survival (≥10 years). We enrolled 892 patients in our analysis: 638 patients with functioning graft at 10 years PT and 254 patients with graft failure at 10 years PT (considering patient death with a functioning graft <10 years PT as graft failure). Between groups comparisons were done using Mann-Whitney and chi-square test. To determine independent predictive variables for long-term graft survival a multivariate-adjusted logistic regression was performed. Significant predictors of long term graft survival were lower 12-month PT creatinine (, ), lower donor age (, ), shorter time on dialysis (, ), recipient positive CMV IgG (, ), absence of AR episodes (, ), 0 to 1 (versus 2) HLA-B mismatch (, ), and recipients male gender (, ). Our results show that an early KT, younger donor age, and an optimal first year graft function are of paramount importance for long-term graft survival. Measures that address these issues (careful donor selection, preemptive KT, and effective immunosuppressive protocols) are still warranted.

scholarly journals Exome Sequencing and Prediction of Long-Term Kidney Allograft Function

2016 ◽  
Vol 12 (9) ◽  
pp. e1005088 ◽  
Author(s):  
Laurent Mesnard ◽  
Thangamani Muthukumar ◽  
Maren Burbach ◽  
Carol Li ◽  
Huimin Shang ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Kidney Allograft ◽  
Allograft Function

Kidney Function Decline Prediction and Risk Factor Analysis After Kidney Transplantation: Machine Learning and Network Analysis on Nationwide Cohort Data (Preprint)

2021 ◽  
Author(s):  
Moongi Simon Hong ◽  
Yu Ho Lee ◽  
Jin Min Kong ◽  
Oh Jung Kwon ◽  
Cheol Woong Jung ◽  
...  
Keyword(s):  
Kidney Transplantation ◽  
Renal Allograft ◽  
Statistical Significance ◽  
Graft Function ◽  
Donor Age ◽  
Post Transplantation ◽  
Development Data ◽  
One Year ◽  
The One

BACKGROUND Early identification of graft loss risk and timely therapeutic intervention are crucial for preventing late renal allograft failure and improving long-term graft function. The one-year estimated glomerular filtration rate (eGFR) is the best predictor of long-term graft function in kidney transplant recipients; there is an increased risk of late graft failure in recipients with low one-year eGFR. OBJECTIVE To create a sparse model capable of predicting the one-year renal allograft dysfunction and to build a factor network suggesting risk control targets. METHODS Development data were constructed using the Korean Organ Transplant Registry (KOTRY), a national cohort data of 4317 recipients who underwent kidney transplantation between 2014 and 2019. The XGBoost algorithm was trained to predict the model outcome with 112 features, and the relevant factors were selected. The statistical significance of factors was calculated using multiple logistic regression for the development data. A factor correlation network was drawn and simplified by excluding spurious connections with LASSO (least absolute shrinkage and selection operator) regularization with EBIC (extended bayesian information criterium) model selection. The model outcome was one-year eGFR < 45 mL/min/1.73 m2, and model performance was measured using AUC, sensitivity, and specificity. A SHAP value plot was used to determine the feature importance of the model. The clinical importance of the model outcome was assessed using long-term graft survival and rejection-free survival. The factor network was built using inter-factor partial correlations and the statistical significance of each factor. RESULTS The model achieved an AUC of 0.82, a sensitivity of 0.8, and a specificity of 0.8 using seven pre- or peri-transplantation factors. Three pre-transplantation factors (donor age, recipient age, recipient-donor height difference) and four peri-transplantation factors (low eGFR at discharge, high eGFR at discharge, serum creatinine at discharge, post-transplantation stay) were chosen by the model. Model prediction was significantly associated with a five-year survival of graft and rejection-free survival (P = .02 and P = .007). Post-transplantation stay and discharge eGFR ≥ 88.0 were the most prominent risk and preventive nodes on the network, respectively. Donor age and discharge eGFR < 59.8 had a high impact on model prediction and could be effective risk control targets for their multiple connections to other risk nodes. CONCLUSIONS One-year renal allograft dysfunction could be predicted early after transplantation. The long-term outcomes of kidney transplantation might be improved by preemptive measures on donor age, kidney function at discharge, and post-transplantation stay. INTERNATIONAL REGISTERED REPORT RR2-doi: 10.1097/TXD.0000000000000678

Fibrous Intimal Thickening at Implantation Adversely Affects Long-Term Kidney Allograft Function

2009 ◽  
Vol 87 (1) ◽  
pp. 72-78 ◽  
Author(s):  
Annemie T. Woestenburg ◽  
Gert A. Verpooten ◽  
Dirk K. Ysebaert ◽  
Eric A. Van Marck ◽  
Dierik Verbeelen ◽  
...  
Keyword(s):  
Intimal Thickening ◽  
Kidney Allograft ◽  
Allograft Function
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