Xenotransplantation is emerging as one of several potential solutions for addressing organ donor shortages, with significant progress bringing it closer to clinical application. However, challenges remain, particularly concerning complement system dysregulation caused by species differences, as well as xenoantigens and coagulopathy. Complement regulatory proteins expressed on endothelial cells of donor xenografts are less compatible with complement components in recipients. These difficulties contribute to hyperacute rejection, characterized by antibody-mediated complement activation that destroys the graft within 24 h. Moreover, because molecules are incompatible across different species, ischemia-reperfusion injury or infection can easily elicit complement activity via all three pathways, resulting in xenograft loss via complement-mediated vascular injury. Complement activity also stimulate innate and adaptive immune cells. To address this issue, genetic modifications in donor pigs and the development of novel medicines have been tested in preclinical models with promising results. Pigs modified to express human complement-regulating molecules such as CD46, CD55, and CD59 have shown longer kidney xenograft survivals over years in preclinical models with nonhuman primates, paving the way for clinical trials. Anti-complement component agents such as C1 esterase and C5 inhibitors have also been shown to increase xenograft survivals. This review examines the role of the complement system in kidney xenotransplantation, emphasizing new research and clinical trial advancements.
{"title":"Mechanism and regulation of the complement activity in kidney xenotransplantation","authors":"Takayuki Hirose , Kiyohiko Hotta , Ryo Otsuka , Ken-Ichiro Seino","doi":"10.1016/j.trre.2025.100931","DOIUrl":"10.1016/j.trre.2025.100931","url":null,"abstract":"<div><div>Xenotransplantation is emerging as one of several potential solutions for addressing organ donor shortages, with significant progress bringing it closer to clinical application. However, challenges remain, particularly concerning complement system dysregulation caused by species differences, as well as xenoantigens and coagulopathy. Complement regulatory proteins expressed on endothelial cells of donor xenografts are less compatible with complement components in recipients. These difficulties contribute to hyperacute rejection, characterized by antibody-mediated complement activation that destroys the graft within 24 h. Moreover, because molecules are incompatible across different species, ischemia-reperfusion injury or infection can easily elicit complement activity via all three pathways, resulting in xenograft loss via complement-mediated vascular injury. Complement activity also stimulate innate and adaptive immune cells. To address this issue, genetic modifications in donor pigs and the development of novel medicines have been tested in preclinical models with promising results. Pigs modified to express human complement-regulating molecules such as CD46, CD55, and CD59 have shown longer kidney xenograft survivals over years in preclinical models with nonhuman primates, paving the way for clinical trials. Anti-complement component agents such as C1 esterase and C5 inhibitors have also been shown to increase xenograft survivals. This review examines the role of the complement system in kidney xenotransplantation, emphasizing new research and clinical trial advancements.</div></div>","PeriodicalId":48973,"journal":{"name":"Transplantation Reviews","volume":"39 3","pages":"Article 100931"},"PeriodicalIF":3.6,"publicationDate":"2025-04-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143829632","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-04-08DOI: 10.1016/j.trre.2025.100930
Tanguy Lafont , Subhankar Mukhopadhyay , Sohani N. Dassanayake , Maria Hernández-Fuentes , Paramit Chowdhury , Theodoros Kassimatis
Acute rejection (AR) and interstitial fibrosis/tubular atrophy (IFTA) are significant complications of kidney transplantation that have a negative impact on renal graft lifespan. Kidney transplant monitoring is currently performed with the use of on nonspecific biomarkers (serum creatinine and proteinuria) which have significant limitations and detect AR and IFTA only after significant damage to the kidney has been done. Moreover, many transplant patients are found to have histological evidence of rejection despite a stable creatinine (subclinical rejection – SCR). The “gold standard” diagnostic test for AR and IFTA is the transplant biopsy that also comes with limitations and can have major complications; therefore, it is not an ideal test for routine graft monitoring. The use of novel non-invasive (blood and urine) and invasive (graft biopsy) biomarkers, partly driven by advances in omics technologies, can lead to earlier and more accurate detection of AR/SCR and IFTA and to improved graft monitoring. The identification of the immunological pathways of AR/IFTA may also enable the design of tailormade treatments. This minireview provides a state-of-the-art update on current evidence and limitations from key studies on non-invasive and invasive biomarkers of AR/SCR and IFTA and gives a perspective on their potential future implementation and the underlying challenges.
{"title":"Advances in biomarkers of acute allograft rejection and interstitial fibrosis/tubular atrophy in kidney transplantation; future perspective and challenges in clinical implementation","authors":"Tanguy Lafont , Subhankar Mukhopadhyay , Sohani N. Dassanayake , Maria Hernández-Fuentes , Paramit Chowdhury , Theodoros Kassimatis","doi":"10.1016/j.trre.2025.100930","DOIUrl":"10.1016/j.trre.2025.100930","url":null,"abstract":"<div><div>Acute rejection (AR) and interstitial fibrosis/tubular atrophy (IFTA) are significant complications of kidney transplantation that have a negative impact on renal graft lifespan. Kidney transplant monitoring is currently performed with the use of on nonspecific biomarkers (serum creatinine and proteinuria) which have significant limitations and detect AR and IFTA only after significant damage to the kidney has been done. Moreover, many transplant patients are found to have histological evidence of rejection despite a stable creatinine (subclinical rejection – SCR). The “gold standard” diagnostic test for AR and IFTA is the transplant biopsy that also comes with limitations and can have major complications; therefore, it is not an ideal test for routine graft monitoring. The use of novel non-invasive (blood and urine) and invasive (graft biopsy) biomarkers, partly driven by advances in omics technologies, can lead to earlier and more accurate detection of AR/SCR and IFTA and to improved graft monitoring. The identification of the immunological pathways of AR/IFTA may also enable the design of tailormade treatments. This minireview provides a state-of-the-art update on current evidence and limitations from key studies on non-invasive and invasive biomarkers of AR/SCR and IFTA and gives a perspective on their potential future implementation and the underlying challenges.</div></div>","PeriodicalId":48973,"journal":{"name":"Transplantation Reviews","volume":"39 3","pages":"Article 100930"},"PeriodicalIF":3.6,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143808654","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-04-03DOI: 10.1016/j.trre.2025.100919
Esther Mancebo , Fritz Diekmann , Eduard Palou , Carlos Vilches , Marta Crespo , Auxiliadora Mazuecos , José L. Caro , Josep M. Cruzado , David San Segundo , Manuel Muro , Jesús Ontañón , Antonia Álvarez , Oriol Bestard , Constantino Fernández , M. Francisca González , Antonio Nieto , Rocío Vega , Estela Paz-Artal , Elisabeth Coll , Amado Andrés , Beatriz Domínguez-Gil
Highly sensitized patients awaiting kidney transplantation face substantial challenges due to the presence of potential donor-specific anti-HLA antibodies (DSA). These antibodies increase the risk of antibody-mediated rejection (ABMR), but also complicate their access to HLA compatible transplantation. Although advancements in allocation priority programs, such as the Spanish Program for the Access of Highly Sensitized Patients to Kidney Transplantation (PATHI), have introduced virtual crossmatching (v-XM) to streamline compatibility assessments, patients with >99,5 % virtual panel reactive antibodies (vPRA) often remain on waiting lists for extended periods with minimal chances of receiving a transplant.
This article summarizes Spanish guidelines for a harmonized and comprehensive framework for the management of highly sensitized patients. These guidelines focus on strategies to facilitate transplantation in the presence of DSA, including a stepwise approach to delist HLA antigens, prioritizing those recognized as “less deleterious” antibodies, to expand transplant options while minimizing immunological risks. Conventional desensitization techniques are discussed, alongside the innovative use of imlifidase to enable transplants in particularly complex cases. Post-transplant monitoring protocols are also exposed, with a focus on early detection of antibody rebound and effective management of ABMR.
Ultimately, this resource offers clinicians a structured framework to navigate the intricate challenges of kidney transplantation in high-risk populations, aiming to enhance access to life-saving procedures and improve patient outcomes.
{"title":"Spanish guidelines for kidney transplantation in highly sensitized patients with donor-specific anti-HLA antibodies","authors":"Esther Mancebo , Fritz Diekmann , Eduard Palou , Carlos Vilches , Marta Crespo , Auxiliadora Mazuecos , José L. Caro , Josep M. Cruzado , David San Segundo , Manuel Muro , Jesús Ontañón , Antonia Álvarez , Oriol Bestard , Constantino Fernández , M. Francisca González , Antonio Nieto , Rocío Vega , Estela Paz-Artal , Elisabeth Coll , Amado Andrés , Beatriz Domínguez-Gil","doi":"10.1016/j.trre.2025.100919","DOIUrl":"10.1016/j.trre.2025.100919","url":null,"abstract":"<div><div>Highly sensitized patients awaiting kidney transplantation face substantial challenges due to the presence of potential donor-specific anti-HLA antibodies (DSA). These antibodies increase the risk of antibody-mediated rejection (ABMR), but also complicate their access to HLA compatible transplantation. Although advancements in allocation priority programs, such as the Spanish Program for the Access of Highly Sensitized Patients to Kidney Transplantation (PATHI), have introduced virtual crossmatching (v-XM) to streamline compatibility assessments, patients with >99,5 % virtual panel reactive antibodies (vPRA) often remain on waiting lists for extended periods with minimal chances of receiving a transplant.</div><div>This article summarizes Spanish guidelines for a harmonized and comprehensive framework for the management of highly sensitized patients. These guidelines focus on strategies to facilitate transplantation in the presence of DSA, including a stepwise approach to delist HLA antigens, prioritizing those recognized as “less deleterious” antibodies, to expand transplant options while minimizing immunological risks. Conventional desensitization techniques are discussed, alongside the innovative use of imlifidase to enable transplants in particularly complex cases. Post-transplant monitoring protocols are also exposed, with a focus on early detection of antibody rebound and effective management of ABMR.</div><div>Ultimately, this resource offers clinicians a structured framework to navigate the intricate challenges of kidney transplantation in high-risk populations, aiming to enhance access to life-saving procedures and improve patient outcomes.</div></div>","PeriodicalId":48973,"journal":{"name":"Transplantation Reviews","volume":"39 3","pages":"Article 100919"},"PeriodicalIF":3.6,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143808653","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-03-28DOI: 10.1016/j.trre.2025.100918
Haichen Yan , Yitian Fang , Jacqueline van de Wetering , Hendrikus J.A.N. Kimenai , Ron W.F. de Bruin , Robert C. Minnee
Background
The shortage of donor grafts for kidney transplantation remains a critical challenge. En bloc kidney transplantation (EBKT) using small deceased pediatric donors has the potential to expand the donor pool. This review aimed to investigate the outcomes of pediatric-donor EBKT in adults compared with standard single kidney transplantation (SKT).
Methods
Relevant databases, including Ovid, Web of Knowledge, Google Scholar, Wiley, and Embase, were searched for eligible studies. Demographic data and transplant outcomes were extracted from the included studies. The primary outcome was graft survival. A random-effects model was used for the meta-analysis.
Results
Thirteen studies were included. The median 1-year graft survival rates were 83.8 % and 89.2 % for EBKT and SKT, respectively (risk ratio [RR], 0.97; 95 % confidence interval [CI], 0.93–1.01). The median 5-year graft survival rates were 78.7 % and 72.7 % for EBKT and SKT, respectively (RR, 1.05; 95 % CI, 0.93–1.19). For donors with a body weight > 10 kg (EBKT >10 kg) and ≤ 10 kg (EBKT ≤10 kg), the median 1-year graft survival rates were 100.0 % and 90.0 %, respectively (RR, 1.08; 95 % CI, 1.05–1.12). Vascular complications were identified as the primary cause of graft loss.
Conclusions
Pediatric-donor EBKT in adults is a safe approach with excellent long-term functional outcomes comparable to those of SKT. EBKT represents an effective option to further utilizing pediatric donor kidneys. Outcomes of EBKT vary based on donor body weight. EBKT ≤10 kg was associated with higher short-term graft failure rates despite long-term performance being comparable to EBKT >10 kg.
{"title":"Effect of donor body weight on en bloc pediatric kidney transplantation in adults: A systematic review and meta-analysis","authors":"Haichen Yan , Yitian Fang , Jacqueline van de Wetering , Hendrikus J.A.N. Kimenai , Ron W.F. de Bruin , Robert C. Minnee","doi":"10.1016/j.trre.2025.100918","DOIUrl":"10.1016/j.trre.2025.100918","url":null,"abstract":"<div><h3>Background</h3><div>The shortage of donor grafts for kidney transplantation remains a critical challenge. En bloc kidney transplantation (EBKT) using small deceased pediatric donors has the potential to expand the donor pool. This review aimed to investigate the outcomes of pediatric-donor EBKT in adults compared with standard single kidney transplantation (SKT).</div></div><div><h3>Methods</h3><div>Relevant databases, including Ovid, Web of Knowledge, Google Scholar, Wiley, and Embase, were searched for eligible studies. Demographic data and transplant outcomes were extracted from the included studies. The primary outcome was graft survival. A random-effects model was used for the meta-analysis.</div></div><div><h3>Results</h3><div>Thirteen studies were included. The median 1-year graft survival rates were 83.8 % and 89.2 % for EBKT and SKT, respectively (risk ratio [RR], 0.97; 95 % confidence interval [CI], 0.93–1.01). The median 5-year graft survival rates were 78.7 % and 72.7 % for EBKT and SKT, respectively (RR, 1.05; 95 % CI, 0.93–1.19). For donors with a body weight > 10 kg (EBKT >10 kg) and ≤ 10 kg (EBKT ≤10 kg), the median 1-year graft survival rates were 100.0 % and 90.0 %, respectively (RR, 1.08; 95 % CI, 1.05–1.12). Vascular complications were identified as the primary cause of graft loss.</div></div><div><h3>Conclusions</h3><div>Pediatric-donor EBKT in adults is a safe approach with excellent long-term functional outcomes comparable to those of SKT. EBKT represents an effective option to further utilizing pediatric donor kidneys. Outcomes of EBKT vary based on donor body weight. EBKT ≤10 kg was associated with higher short-term graft failure rates despite long-term performance being comparable to EBKT >10 kg.</div></div>","PeriodicalId":48973,"journal":{"name":"Transplantation Reviews","volume":"39 3","pages":"Article 100918"},"PeriodicalIF":3.6,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143767753","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-03-21DOI: 10.1016/j.trre.2025.100917
Mohammed Al-Tawil , William Wang , Ashwini Chandiramani , Feras Zaqout , Abdel Hannan Diab , Serge Sicouri , Basel Ramlawi , Assad Haneya
Background
Heart transplantation (HTx) using donors after circulatory death (DCD) has the potential to significantly boost overall transplant rates. This study aims to reconstruct data from individual studies comparing survival between HTx from DCD recipients and donation after brain (DBD) recipients.
Methods
MEDLINE, Embase, Scopus, were searched up to August 2024. We included studies that reported a Kaplan-Meier summary of survival comparing DCD and DBD HTx. Digitization of the Kaplan-Meier curves and reconstruction of individual patient data followed by survival analysis that was conducted using R software.
Results
Six studies including a total of 3240 patients (2242 DBD and 998 DCD) were included in the final analysis. There was no significant difference in the overall survival rates between DCD and DBD patients (Hazard Ratio (HR): 1.01, 95 % CI [0.81–1.25], P = 0.91). However, the proportional hazard assumption was violated, deeming such results inconclusive. Time-varying flexible parametric model revealed a significantly declining survival in DCD recipients 3 years after surgery. Landmark analyses further suggest this declining trend in the DCD group at the two-year landmark (HR: 1.67, p = 0.021) and the four-year mark (HR: 2.78, p = 0.002). However, data beyond 6 years is limited. Evidence comparing direct procurement and normothermic regional perfusion is scarce, with no significant survival differences observed.
Conclusion
This meta-analysis shows that, despite similar early survival outcomes, DCD heart transplants showed a trend towards a lower long-term survival, with the difference becoming evident around three years post-transplantation. These findings highlight the need for enhanced monitoring and optimized post-transplant care in DCD recipients. Further studies with strict and long-term follow-up are warranted to confirm these results.
{"title":"Survival after heart transplants from circulatory-dead versus brain-dead donors: Meta-analysis of reconstructed time-to-event data","authors":"Mohammed Al-Tawil , William Wang , Ashwini Chandiramani , Feras Zaqout , Abdel Hannan Diab , Serge Sicouri , Basel Ramlawi , Assad Haneya","doi":"10.1016/j.trre.2025.100917","DOIUrl":"10.1016/j.trre.2025.100917","url":null,"abstract":"<div><h3>Background</h3><div>Heart transplantation (HTx) using donors after circulatory death (DCD) has the potential to significantly boost overall transplant rates. This study aims to reconstruct data from individual studies comparing survival between HTx from DCD recipients and donation after brain (DBD) recipients.</div></div><div><h3>Methods</h3><div>MEDLINE, Embase, Scopus, were searched up to August 2024. We included studies that reported a Kaplan-Meier summary of survival comparing DCD and DBD HTx. Digitization of the Kaplan-Meier curves and reconstruction of individual patient data followed by survival analysis that was conducted using R software.</div></div><div><h3>Results</h3><div>Six studies including a total of 3240 patients (2242 DBD and 998 DCD) were included in the final analysis. There was no significant difference in the overall survival rates between DCD and DBD patients (Hazard Ratio (HR): 1.01, 95 % CI [0.81–1.25], <em>P</em> = 0.91). However, the proportional hazard assumption was violated, deeming such results inconclusive. Time-varying flexible parametric model revealed a significantly declining survival in DCD recipients 3 years after surgery. Landmark analyses further suggest this declining trend in the DCD group at the two-year landmark (HR: 1.67, <em>p</em> = 0.021) and the four-year mark (HR: 2.78, <em>p</em> = 0.002). However, data beyond 6 years is limited. Evidence comparing direct procurement and normothermic regional perfusion is scarce, with no significant survival differences observed.</div></div><div><h3>Conclusion</h3><div>This meta-analysis shows that, despite similar early survival outcomes, DCD heart transplants showed a trend towards a lower long-term survival, with the difference becoming evident around three years post-transplantation. These findings highlight the need for enhanced monitoring and optimized post-transplant care in DCD recipients. Further studies with strict and long-term follow-up are warranted to confirm these results.</div></div>","PeriodicalId":48973,"journal":{"name":"Transplantation Reviews","volume":"39 2","pages":"Article 100917"},"PeriodicalIF":3.6,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143680503","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-03-20DOI: 10.1016/j.trre.2025.100915
Quirino Lai , Roberta Angelico , Nicola Guglielmo , Duilio Pagano , Paulo N. Martins , Davide Ghinolfi
Background & aims
Liver transplantation (LT) is the gold standard for end-stage liver disease, but ischemic cholangiopathy (IC) remains a significant complication. Ex-situ normothermic machine perfusion (ESNMP) has emerged as a potential strategy to mitigate ischemic injury. However, the effect of ESNMP on reducing post-LT IC remains controversial. This study aimed to perform an updated meta-analysis to evaluate the impact of ESNMP on IC incidence.
Methods
A systematic review and meta-analysis were conducted following PRISMA guidelines. The literature search included studies from 2015 to 2025 comparing LT outcomes using ESNMP vs. static cold storage (SCS). The primary outcome was the incidence of IC. Risk of bias was assessed using the ROBINS-E tool. Statistical analysis, including random-effects meta-analysis, sensitivity analysis, and meta-regression, was performed to evaluate heterogeneity, potential confounders, and the impact of follow-up duration.
Results
Seventeen studies, including 76,045 patients (4843 ESNMP; 71,202 SCS), were analyzed. No statistically significant difference in IC incidence was found between ESNMP and SCS (1.3 % vs. 0.6 %; RR = 0.68, 95 %CI = 0.41–1.13; P = 0.14). Sensitivity analysis excluding one outlier study revealed a reduction in IC risk with ESNMP (RR = 0.62, 95 %CI = 0.38–1.01; P = 0.054).
Two sub-analyses of studies with ≥12 months of follow-up (RR = 0.51, 95 %CI = 0.26–0.99; P = 0.049) and DCDs (RR = 0.33, 95 %CI = 0.16–0.67; P = 0.002) showed risk reduction. The meta-regression revealed that the back-to-base perfusion approach was associated with the occurrence of IC, with an OR of 1.03 (95 %CI = 1.00–1.07, P = 0.035).
Conclusions
a correlation between ESNMP use and IC reduced risk appears to exist, especially with longer follow-up periods and DCDs, though more high-quality studies are needed to confirm this finding.
{"title":"Ex-situ normothermic machine perfusion prevents ischemic cholangiopathy after liver transplantation: A meta-regression analysis","authors":"Quirino Lai , Roberta Angelico , Nicola Guglielmo , Duilio Pagano , Paulo N. Martins , Davide Ghinolfi","doi":"10.1016/j.trre.2025.100915","DOIUrl":"10.1016/j.trre.2025.100915","url":null,"abstract":"<div><h3>Background & aims</h3><div>Liver transplantation (LT) is the gold standard for end-stage liver disease, but ischemic cholangiopathy (IC) remains a significant complication. Ex-situ normothermic machine perfusion (ESNMP) has emerged as a potential strategy to mitigate ischemic injury. However, the effect of ESNMP on reducing post-LT IC remains controversial. This study aimed to perform an updated meta-analysis to evaluate the impact of ESNMP on IC incidence.</div></div><div><h3>Methods</h3><div>A systematic review and meta-analysis were conducted following PRISMA guidelines. The literature search included studies from 2015 to 2025 comparing LT outcomes using ESNMP vs. static cold storage (SCS). The primary outcome was the incidence of IC. Risk of bias was assessed using the ROBINS-E tool. Statistical analysis, including random-effects meta-analysis, sensitivity analysis, and meta-regression, was performed to evaluate heterogeneity, potential confounders, and the impact of follow-up duration.</div></div><div><h3>Results</h3><div>Seventeen studies, including 76,045 patients (4843 ESNMP; 71,202 SCS), were analyzed. No statistically significant difference in IC incidence was found between ESNMP and SCS (1.3 % vs. 0.6 %; RR = 0.68, 95 %CI = 0.41–1.13; <em>P</em> = 0.14). Sensitivity analysis excluding one outlier study revealed a reduction in IC risk with ESNMP (RR = 0.62, 95 %CI = 0.38–1.01; <em>P</em> = 0.054).</div><div>Two sub-analyses of studies with ≥12 months of follow-up (RR = 0.51, 95 %CI = 0.26–0.99; <em>P</em> = 0.049) and DCDs (RR = 0.33, 95 %CI = 0.16–0.67; <em>P</em> = 0.002) showed risk reduction. The meta-regression revealed that the back-to-base perfusion approach was associated with the occurrence of IC, with an OR of 1.03 (95 %CI = 1.00–1.07, <em>P</em> = 0.035).</div></div><div><h3>Conclusions</h3><div>a correlation between ESNMP use and IC reduced risk appears to exist, especially with longer follow-up periods and DCDs, though more high-quality studies are needed to confirm this finding.</div></div>","PeriodicalId":48973,"journal":{"name":"Transplantation Reviews","volume":"39 2","pages":"Article 100915"},"PeriodicalIF":3.6,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143725882","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-03-20DOI: 10.1016/j.trre.2025.100916
Shujun Liu, Lixing Wang, Shan Liu, Yinlong Zhao
Background
Endomyocardial biopsy is widely acknowledged as the gold standard for detecting rejection following heart transplantation. However, the operation itself carries a risk of myocardial tissue damage and associated complications during and after surgery. Given the limitations of existing diagnostic approaches, non-invasive biomarkers are crucial.
Objective
This study assessed the diagnostic utility of donor-derived cell-free DNA (dd-cfDNA) in detecting AR in heart transplant recipients.
Methods
A systematic literature search was conducted across PubMed, Embase, Cochrane Library, and Web of Science from inception to August 1, 2024, to identify studies evaluating the diagnostic performance of dd-cfDNA for AR in heart transplant recipients. Retrieved studies were screened using EndNote X9. Meta-analysis was performed using Meta-Disc software version 1.4 and STATA/SE 14.0.
Results
Ten studies were included in the meta-analysis. The pooled sensitivity, specificity, and area under the receiver operating characteristic curve with 95 % confidence intervals (CIs) were 65 % (95 % CI, 61–68 %), 79 % (95 % CI, 78–80 %), and 0.83, respectively.
Conclusions
This meta-analysis indicates that plasma dd-cfDNA may serve as a promising non-invasive biomarker for the diagnosis of acute rejection in heart transplant recipients. However, further research is warranted to investigate factors influencing diagnostic performance and optimize clinical utility.
{"title":"Donor–derived cell–free dna as a diagnostic biomarker for acute rejection in heart transplantation: A systematic review and meta–analysis","authors":"Shujun Liu, Lixing Wang, Shan Liu, Yinlong Zhao","doi":"10.1016/j.trre.2025.100916","DOIUrl":"10.1016/j.trre.2025.100916","url":null,"abstract":"<div><h3>Background</h3><div>Endomyocardial biopsy is widely acknowledged as the gold standard for detecting rejection following heart transplantation. However, the operation itself carries a risk of myocardial tissue damage and associated complications during and after surgery. Given the limitations of existing diagnostic approaches, non-invasive biomarkers are crucial.</div></div><div><h3>Objective</h3><div>This study assessed the diagnostic utility of donor-derived cell-free DNA (dd-cfDNA) in detecting AR in heart transplant recipients.</div></div><div><h3>Methods</h3><div>A systematic literature search was conducted across PubMed, Embase, Cochrane Library, and Web of Science from inception to August 1, 2024, to identify studies evaluating the diagnostic performance of dd-cfDNA for AR in heart transplant recipients. Retrieved studies were screened using EndNote X9. Meta-analysis was performed using Meta-Disc software version 1.4 and STATA/SE 14.0.</div></div><div><h3>Results</h3><div>Ten studies were included in the meta-analysis. The pooled sensitivity, specificity, and area under the receiver operating characteristic curve with 95 % confidence intervals (CIs) were 65 % (95 % CI, 61–68 %), 79 % (95 % CI, 78–80 %), and 0.83, respectively.</div></div><div><h3>Conclusions</h3><div>This meta-analysis indicates that plasma dd-cfDNA may serve as a promising non-invasive biomarker for the diagnosis of acute rejection in heart transplant recipients. However, further research is warranted to investigate factors influencing diagnostic performance and optimize clinical utility.</div></div>","PeriodicalId":48973,"journal":{"name":"Transplantation Reviews","volume":"39 2","pages":"Article 100916"},"PeriodicalIF":3.6,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143680588","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-03-09DOI: 10.1016/j.trre.2025.100914
Cavizshajan Skanthan , Emily Nguyen , Lakindu Somaweera , Madhumitha Rabindranath , Ani Orchanian-Cheff , Alexandra Viau-Trudel , Myriam Khalili , Olusegun Famure , S. Joseph Kim
Immunosuppressive drugs are used in the management of transplant patients to prevent organ rejection. However, immunosuppression can be associated with adverse effects such as infections and cancers. This study aimed to characterize the measures of cumulative immunosuppressive drug exposure (CIDE) used in the literature and their associated outcomes in transplant patients. A literature search was conducted in Ovid MEDLINE, Ovid EMBASE, Cochrane CENTRAL, and Cochrane Database of Systematic Reviews using search terms related to maintenance immunosuppressants and CIDE. Study risk of bias was assessed using the Quality in Prognostic Studies tool. Thirty-one articles were included in this qualitative synthesis. Sixteen articles (52 %) calculated the total dose of immunosuppression over the treatment period, while eight (26 %) used area-under-the-curve of trough level concentrations to quantify CIDE. Five (16 %) articles investigated time-weighted metrics of calcineurin inhibitors and four (13 %) used other metrics that could not be categorized into the previous groups. Most studies investigated CIDE with calcineurin inhibitors and used additive dosing methods. This approach was also popular with corticosteroids and multi-drug exposures. The variety of metrics used in the literature reveals a lack of standardization in the evaluation of CIDE and long-term outcomes. Future studies should validate these metrics for clinical application, especially pertaining to infectious outcomes.
{"title":"Assessing cumulative exposure to maintenance immunosuppressive drugs: Metrics, outcomes, and implications for transplant patients","authors":"Cavizshajan Skanthan , Emily Nguyen , Lakindu Somaweera , Madhumitha Rabindranath , Ani Orchanian-Cheff , Alexandra Viau-Trudel , Myriam Khalili , Olusegun Famure , S. Joseph Kim","doi":"10.1016/j.trre.2025.100914","DOIUrl":"10.1016/j.trre.2025.100914","url":null,"abstract":"<div><div>Immunosuppressive drugs are used in the management of transplant patients to prevent organ rejection. However, immunosuppression can be associated with adverse effects such as infections and cancers. This study aimed to characterize the measures of cumulative immunosuppressive drug exposure (CIDE) used in the literature and their associated outcomes in transplant patients. A literature search was conducted in Ovid MEDLINE, Ovid EMBASE, Cochrane CENTRAL, and Cochrane Database of Systematic Reviews using search terms related to maintenance immunosuppressants and CIDE. Study risk of bias was assessed using the Quality in Prognostic Studies tool. Thirty-one articles were included in this qualitative synthesis. Sixteen articles (52 %) calculated the total dose of immunosuppression over the treatment period, while eight (26 %) used area-under-the-curve of trough level concentrations to quantify CIDE. Five (16 %) articles investigated time-weighted metrics of calcineurin inhibitors and four (13 %) used other metrics that could not be categorized into the previous groups. Most studies investigated CIDE with calcineurin inhibitors and used additive dosing methods. This approach was also popular with corticosteroids and multi-drug exposures. The variety of metrics used in the literature reveals a lack of standardization in the evaluation of CIDE and long-term outcomes. Future studies should validate these metrics for clinical application, especially pertaining to infectious outcomes.</div></div>","PeriodicalId":48973,"journal":{"name":"Transplantation Reviews","volume":"39 2","pages":"Article 100914"},"PeriodicalIF":3.6,"publicationDate":"2025-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143610460","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-03-02DOI: 10.1016/j.trre.2025.100913
Quentin Perrier , Johan Noble , Sandrine Lablanche
Beta-cell replacement therapies, including islet and pancreas transplantation, offer promising results in term of glycemic control for patients with type 1 diabetes experiencing high glycemic variability and severe hypoglycemia. However, long-term insulin independence remains challenging due to progressive graft function decline. Immunosuppressive regimens, especially calcineurin inhibitors such as tacrolimus, are known to be diabetogenic, contributing to the paradox of impaired beta-cell function in a diabetes treatment setting. Recent studies have focused on CTLA4-Ig (e.g., belatacept) as a potential alternative to calcineurin inhibitors, showing promising results in preclinical and clinical models. This review summarizes key advancements and remaining challenges in CTLA4 applications for beta-cell replacement. First, genetic engineering approaches aiming for CTLA4 expression in islets demonstrated initial success in delaying rejection but remain hindered by immune escape and limited integration efficacy. Coating techniques and exogenous CTLA4-Ig administration offer simpler, albeit transient, immunosuppressive effects, which, combined with encapsulation technologies, can improve graft survival. In non-human primate models, islet transplantation with immunosuppressant regimen using CTLA4-Ig combined with agents such as sirolimus or anti-CD154 has shown extended insulin independence, though full immune tolerance remains elusive. A limited number of human studies using belatacept for beta-cell replacement indicate reduced HbA1c levels and avoidance of severe hypoglycemia, yet consistent absence of rejection remains unachieved. Future research on BCR with CTLA4-Ig should explore graft survival in human islets transplantation and refine immunosuppressive protocols to leverage CTLA4-Ig potential in improving long-term graft function, thus enhancing the sustainability of CTLA4-Ig in clinical beta-cell replacement approach.
{"title":"Transition from preclinical to clinical application of CTLA4-Ig co-stimulation blockage in beta-cell replacement therapy","authors":"Quentin Perrier , Johan Noble , Sandrine Lablanche","doi":"10.1016/j.trre.2025.100913","DOIUrl":"10.1016/j.trre.2025.100913","url":null,"abstract":"<div><div>Beta-cell replacement therapies, including islet and pancreas transplantation, offer promising results in term of glycemic control for patients with type 1 diabetes experiencing high glycemic variability and severe hypoglycemia. However, long-term insulin independence remains challenging due to progressive graft function decline. Immunosuppressive regimens, especially calcineurin inhibitors such as tacrolimus, are known to be diabetogenic, contributing to the paradox of impaired beta-cell function in a diabetes treatment setting. Recent studies have focused on CTLA4-Ig (e.g., belatacept) as a potential alternative to calcineurin inhibitors, showing promising results in preclinical and clinical models. This review summarizes key advancements and remaining challenges in CTLA4 applications for beta-cell replacement. First, genetic engineering approaches aiming for CTLA4 expression in islets demonstrated initial success in delaying rejection but remain hindered by immune escape and limited integration efficacy. Coating techniques and exogenous CTLA4-Ig administration offer simpler, albeit transient, immunosuppressive effects, which, combined with encapsulation technologies, can improve graft survival. In non-human primate models, islet transplantation with immunosuppressant regimen using CTLA4-Ig combined with agents such as sirolimus or anti-CD154 has shown extended insulin independence, though full immune tolerance remains elusive. A limited number of human studies using belatacept for beta-cell replacement indicate reduced HbA1c levels and avoidance of severe hypoglycemia, yet consistent absence of rejection remains unachieved. Future research on BCR with CTLA4-Ig should explore graft survival in human islets transplantation and refine immunosuppressive protocols to leverage CTLA4-Ig potential in improving long-term graft function, thus enhancing the sustainability of CTLA4-Ig in clinical beta-cell replacement approach.</div></div>","PeriodicalId":48973,"journal":{"name":"Transplantation Reviews","volume":"39 2","pages":"Article 100913"},"PeriodicalIF":3.6,"publicationDate":"2025-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143550224","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Everolimus (EVL) is an effective post-transplant immunosuppressant; however, its optimal trough concentration when switching from calcineurin inhibitors (CNIs) remains unknown. The optimal dosing troughs for CNI-to-EVL switching in kidney transplant recipients were investigated. We searched multiple electronic databases (from inception to March 15, 2024) to identify double-blind or open-label randomized controlled trials evaluating groups (all ages, both sexes) that converted from CNIs to EVL and continued CNI treatment in kidney transplant recipients. Treatment responses, defined as changes in estimated glomerular filtration rate (eGFR), mortality, dropouts for any reason, and adverse events, were the outcomes. We performed a random-effects, one-stage dose–effect meta-analysis with restricted cubic splines. Nine studies were included, comprising 1872 participants. Changes in eGFR increased with increasing trough concentrations; however, the evidence was highly uncertain (95 % effective dose: 4.13 ng/mL, odds ratio [OR]: 1.31, 95 % confidence interval [CI]: 0.10–9.50). Mortality was not estimated owing to the low number of events. The evidence for the relationship between EVL trough levels and treatment discontinuation was also highly uncertain (OR: 1.31, 95 % CI: 0.10–9.39). Adverse events increased with a switch to EVL; however, this evidence was also uncertain (OR: 1.31, 95 % CI: 0.10–9.60). This study could not indicate an appropriate optimal EVL trough concentration owing to the high result uncertainty, and the results do not support the routine switch from CNIs to EVL. Further trials are required to explore the CNI-to-EVL switch timing and the effects of increased EVL dosing to establish a more definitive therapeutic strategy.
{"title":"Effect of everolimus administration on renal function in renal transplant recipients: A systematic review and dose–response meta-analysis","authors":"Takehiro Ohyama , Shodai Yoshihiro , Tomoyuki Fujikura , Takamasa Miyauchi , Yuki Kataoka","doi":"10.1016/j.trre.2025.100911","DOIUrl":"10.1016/j.trre.2025.100911","url":null,"abstract":"<div><div>Everolimus (EVL) is an effective post-transplant immunosuppressant; however, its optimal trough concentration when switching from calcineurin inhibitors (CNIs) remains unknown. The optimal dosing troughs for CNI-to-EVL switching in kidney transplant recipients were investigated. We searched multiple electronic databases (from inception to March 15, 2024) to identify double-blind or open-label randomized controlled trials evaluating groups (all ages, both sexes) that converted from CNIs to EVL and continued CNI treatment in kidney transplant recipients. Treatment responses, defined as changes in estimated glomerular filtration rate (eGFR), mortality, dropouts for any reason, and adverse events, were the outcomes. We performed a random-effects, one-stage dose–effect meta-analysis with restricted cubic splines. Nine studies were included, comprising 1872 participants. Changes in eGFR increased with increasing trough concentrations; however, the evidence was highly uncertain (95 % effective dose: 4.13 ng/mL, odds ratio [OR]: 1.31, 95 % confidence interval [CI]: 0.10–9.50). Mortality was not estimated owing to the low number of events. The evidence for the relationship between EVL trough levels and treatment discontinuation was also highly uncertain (OR: 1.31, 95 % CI: 0.10–9.39). Adverse events increased with a switch to EVL; however, this evidence was also uncertain (OR: 1.31, 95 % CI: 0.10–9.60). This study could not indicate an appropriate optimal EVL trough concentration owing to the high result uncertainty, and the results do not support the routine switch from CNIs to EVL. Further trials are required to explore the CNI-to-EVL switch timing and the effects of increased EVL dosing to establish a more definitive therapeutic strategy.</div></div>","PeriodicalId":48973,"journal":{"name":"Transplantation Reviews","volume":"39 2","pages":"Article 100911"},"PeriodicalIF":3.6,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143454604","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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