|
1
|
Duarte S, Fassler AM, Willman M, Lewis D, Warren C, Angeli-Pahim I, Shah R, Vrakas G, El Hinnawi A, De Faria W, Beduschi T, Battula N, Zarrinpar A. Soluble DNA Concentration in the Perfusate is a Predictor of Posttransplant Renal Function in Hypothermic Machine Perfused Kidney Allografts. Transplant Direct 2025; 11:e1768. [PMID: 40124244 PMCID: PMC11927653 DOI: 10.1097/txd.0000000000001768] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2024] [Accepted: 12/19/2024] [Indexed: 03/25/2025] Open
Abstract
Background Hypothermic machine perfusion (HMP) has greatly improved kidney allograft preservation. However, tissue damage still occurs during HMP, affecting posttransplant graft function. Therefore, better methods are needed to continuously assess organ quality and to predict posttransplant graft function and survival. We propose that soluble DNA (sDNA) concentration in HMP perfusate can be used as a noninvasive biomarker for this purpose. Methods Perfusate samples of kidney grafts placed on HMP were collected 5 min after the initiation of HMP and again at the conclusion of HMP. sDNA of nuclear origin from the perfusate was quantified by real-time polymerase chain reaction and correlated with HMP parameters and posttransplant clinical outcomes. Results Kidney grafts from 52 deceased donors placed on HMP were studied. Perfusate sDNA concentration was significantly higher in transplanted kidneys with delayed graft function. Higher concentrations of perfusate sDNA at 5 min and at HMP conclusion were also correlated with lower graft function in the initial posttransplant period, as measured by postoperative day 2, 3, and 4 creatinine reduction ratios. Standard pump parameters such as renal vascular resistance and renal vascular flow were poor indicators of early posttransplant graft function. Conclusions sDNA concentration in HMP perfusate of kidney grafts can indicate the quality of kidney graft preservation and predict posttransplant renal function. This biomarker should be explored further to improve renal organ assessment and transplantation outcomes.
Collapse
Affiliation(s)
- Sergio Duarte
- Division of Transplantation and Hepatobiliary Surgery, Department of Surgery, University of Florida College of Medicine, Gainesville, FL
| | - Anne-Marie Fassler
- Division of Transplantation and Hepatobiliary Surgery, Department of Surgery, University of Florida College of Medicine, Gainesville, FL
| | - Matthew Willman
- Division of Transplantation and Hepatobiliary Surgery, Department of Surgery, University of Florida College of Medicine, Gainesville, FL
| | - Duncan Lewis
- Division of Transplantation and Hepatobiliary Surgery, Department of Surgery, University of Florida College of Medicine, Gainesville, FL
| | - Curtis Warren
- Division of Transplantation and Hepatobiliary Surgery, Department of Surgery, University of Florida College of Medicine, Gainesville, FL
| | - Isabella Angeli-Pahim
- Division of Transplantation and Hepatobiliary Surgery, Department of Surgery, University of Florida College of Medicine, Gainesville, FL
| | - Rushi Shah
- Division of Transplantation and Hepatobiliary Surgery, Department of Surgery, University of Florida College of Medicine, Gainesville, FL
| | - Georgios Vrakas
- Division of Transplantation and Hepatobiliary Surgery, Department of Surgery, University of Florida College of Medicine, Gainesville, FL
| | - Ashraf El Hinnawi
- Division of Transplantation and Hepatobiliary Surgery, Department of Surgery, University of Florida College of Medicine, Gainesville, FL
| | - Werviston De Faria
- Division of Transplantation and Hepatobiliary Surgery, Department of Surgery, University of Florida College of Medicine, Gainesville, FL
| | - Thiago Beduschi
- Division of Transplantation and Hepatobiliary Surgery, Department of Surgery, University of Florida College of Medicine, Gainesville, FL
| | - Narendra Battula
- Division of Transplant Surgery, Department of Surgery, Oklahoma University College of Medicine, Oklahoma City, OK
| | - Ali Zarrinpar
- Division of Transplantation and Hepatobiliary Surgery, Department of Surgery, University of Florida College of Medicine, Gainesville, FL
| |
Collapse
|
|
2
|
Baryła M, Skrzycki M, Danielewicz R, Kosieradzki M, Struga M. Protein biomarkers in assessing kidney quality before transplantation‑current status and future perspectives (Review). Int J Mol Med 2024; 54:107. [PMID: 39370783 PMCID: PMC11448562 DOI: 10.3892/ijmm.2024.5431] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2024] [Accepted: 07/31/2024] [Indexed: 10/08/2024] Open
Abstract
To meet the demand for kidney transplants (KTx), organs are frequently retrieved not only from standard criteria donors (SCD; a donor who is aged <50 years and suffered brain death from any number of causes, such as traumatic injuries or a stroke) but also from expanded criteria donors (any donor aged >60 years or donors aged >50 years with two of the following: A history of high blood pressure, a creatinine serum level ≥1.5 mg/dl or death resulting from a stroke). This comes at the cost of a higher risk of primary non‑function (the permanent hyperkalemia, hyperuremia and fluid overload that result in the need for continuous dialysis after KTx), delayed graft function (the need for dialysis session at least once during the first week after KTx), earlier graft loss and urinary complications (vesico‑ureteral reflux, obstruction of the vesico‑ureteral anastomosis, urine leakage). At present, there are no commercially available diagnostic tools for assessing kidney quality prior to KTx. Currently available predictive models based on clinical data, such as the Kidney Donor Profile Index, are insufficient. One promising option is the application of perfusion solutions for protein biomarkers of kidney quality and predictors of short‑ and long‑term outcomes. However, to date, protein markers that can be detected with ELISA, western blotting and cytotoxic assays have not been identified to be a beneficial predictors of kidney quality. These include lactate dehydrogenases, glutathione S‑transferases, fatty acid binding proteins, extracellular histones, IL‑18, neutrophil gelatinase‑associated lipocalin, MMPs and kidney injury molecule‑1. However, novel methods, including liquid chromatography‑mass spectrometry (LC‑MS) and microarrays, allow the analysis of all renal proteins suspended/dissolved in the acellular preservation solution used for kidney storage before KTx (including hypothermic machine perfusion as one of kidney storage methods) e.g. Belzer University of Wisconsin. Recent proteomic studies utilizing LC‑MS have identified complement pathway elements (C3, C1QB, C4BPA, C1S, C1R and C1RL), desmoplakin, blood coagulation pathway elements and immunoglobulin heavy variable 2‑26 to be novel predictors of kidney quality before transplantation. This was because they were found to correlate with estimated glomerular filtration rate at 3 and 12 months after kidney transplantation. However, further proteomic studies focusing on distinct markers obtained from hypothermic and normothermic machine perfusion are needed to confirm their predictive value and to improve kidney storage methods. Therefore, the present literature review from PubMed, Scopus, Embase and Web of Science was performed with the aims of summarizing the current knowledge on the most frequently studied single protein biomarkers. In addition, novel analytical methods and insights into organ injury during preservation were documented, where future directions in assessing organ quality before kidney transplantation were also discussed.
Collapse
Affiliation(s)
- Maksymilian Baryła
- Chair and Department of Biochemistry, Medical University of Warsaw, 02-097 Warsaw, Poland
- Department of General and Transplant Surgery, Infant Jesus Hospital, Medical University of Warsaw, 02-006 Warsaw, Poland
| | - Michał Skrzycki
- Chair and Department of Biochemistry, Medical University of Warsaw, 02-097 Warsaw, Poland
| | - Roman Danielewicz
- Department of General and Transplant Surgery, Infant Jesus Hospital, Medical University of Warsaw, 02-006 Warsaw, Poland
| | - Maciej Kosieradzki
- Department of General and Transplant Surgery, Infant Jesus Hospital, Medical University of Warsaw, 02-006 Warsaw, Poland
| | - Marta Struga
- Department of General and Transplant Surgery, Infant Jesus Hospital, Medical University of Warsaw, 02-006 Warsaw, Poland
| |
Collapse
|
|
3
|
Van Der Hoek JL, Krommendijk ME, Manohar S, Arens J, Groot Jebbink E. Ex-Vivo Human-Sized Organ Machine Perfusion: A Systematic Review on the Added Value of Medical Imaging for Organ Condition Assessment. Transpl Int 2024; 37:12827. [PMID: 39296469 PMCID: PMC11408214 DOI: 10.3389/ti.2024.12827] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2024] [Accepted: 08/06/2024] [Indexed: 09/21/2024]
Abstract
Machine perfused ex-vivo organs offer an excellent experimental platform, e.g., for studying organ physiology and for conducting pre-clinical trials for drug delivery. One main challenge in machine perfusion is the accurate assessment of organ condition. Assessment is often performed using viability markers, i.e., lactate concentrations and blood gas analysis. Nonetheless, existing markers for condition assessment can be inconclusive, and novel assessment methods remain of interest. Over the last decades, several imaging modalities have given unique insights into the assessment of organ condition. A systematic review was conducted according to accepted guidelines to evaluate these medical imaging methods, focussed on literature that use machine perfused human-sized organs, that determine organ condition with medical imaging. A total of 18 out of 1,465 studies were included that reported organ condition results in perfused hearts, kidneys, and livers, using both conventional viability markers and medical imaging. Laser speckle imaging, ultrasound, computed tomography, and magnetic resonance imaging were used to identify local ischemic regions and quantify intra-organ perfusion. A detailed investigation of metabolic activity was achieved using 31P magnetic resonance imaging and near-infrared spectroscopy. The current review shows that medical imaging is a powerful tool to assess organ condition.
Collapse
Affiliation(s)
- Jan L. Van Der Hoek
- Multi-Modality Medical Imaging Group, TechMed Centre, University of Twente, Enschede, Netherlands
| | - Marleen E. Krommendijk
- Multi-Modality Medical Imaging Group, TechMed Centre, University of Twente, Enschede, Netherlands
| | - Srirang Manohar
- Multi-Modality Medical Imaging Group, TechMed Centre, University of Twente, Enschede, Netherlands
| | - Jutta Arens
- Engineering Organ Support Technologies Group, Department of Biomechanical Engineering, University of Twente, Enschede, Netherlands
| | - Erik Groot Jebbink
- Multi-Modality Medical Imaging Group, TechMed Centre, University of Twente, Enschede, Netherlands
| |
Collapse
|
|
4
|
Avramidou E, Srinivasan D, Todorov D, Tsoulfas G, Papalois V. Diagnostic and Prognostic Value of Machine Perfusion Biomarkers in Kidney Graft Evaluation. Transplant Proc 2024; 56:1308-1318. [PMID: 39069459 DOI: 10.1016/j.transproceed.2024.05.032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2024] [Accepted: 05/24/2024] [Indexed: 07/30/2024]
Abstract
BACKGROUND With the rising prevalence of end-stage kidney disease, the use of expanded criteria donor allografts, seen as essential for meeting organ demand, still proves challenging due to their higher risk of graft loss, delayed function, and rejection. Machine perfusion, a technique in preserving allografts, offers improved allograft outcomes compared to static cold storage while allowing for the noninvasive measurement of kidney injury biomarkers in the perfusate solution. This offers an objective method to assess graft function at various preservation stages. MATERIALS AND METHODS We conducted a narrative review of the databases PubMed and Scopus, including studies written in the English language and published after 2010. RESULTS In this narrative review, we identified biomarkers, like 4-hydroxyproline, taurine, and glutathione transferase, as predictive markers of delayed graft function. Additionally, biomarkers, like extracellular histone h3, vascular cell adhesion protein, and matrix metalloprotease protein, have shown correlation with decreased graft function, although their predictive ability remains inconclusive. DISCUSSION The review outlines various suggestions for potential areas of research focus to enhance future expanded criteria donor allograft utilization. However, limitations exist, including the absence of a singular reliable biomarker and the challenges of validating biomarker effectiveness across diverse outcomes.
Collapse
Affiliation(s)
- Eleni Avramidou
- Department of Transplantation Surgery, Center for Research and Innovation in Solid Organ Transplantation, Aristotle University School of Medicine, Thessaloniki, Greece.
| | - Divya Srinivasan
- Department of Medicine, Imperial College London, London, United Kingdom
| | - Dominik Todorov
- Department of Medicine, Imperial College London, London, United Kingdom
| | - Georgios Tsoulfas
- Department of Transplantation Surgery, Center for Research and Innovation in Solid Organ Transplantation, Aristotle University School of Medicine, Thessaloniki, Greece
| | - Vassilios Papalois
- Imperial College Renal and Transplant Centre, Hammersmith Hospital, Imperial College Healthcare NHS Trust, London, United Kingdom
| |
Collapse
|
|
5
|
López-Abad A, Piana A, Prudhomme T, Bañuelos Marco B, Dönmez MI, Pecoraro A, Boissier R, Campi R, Breda A, Territo A. Biomarkers in kidney transplantation: Where do we stand? Actas Urol Esp 2024; 48:407-409. [PMID: 38185319 DOI: 10.1016/j.acuroe.2024.01.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2023] [Accepted: 10/20/2023] [Indexed: 01/09/2024]
Affiliation(s)
- A López-Abad
- Servicio de Urología, Hospital Universitario Virgen de la Arrixaca, Murcia, Spain
| | - A Piana
- Servicio de Urología, Hospital San Luigi, Universidad de Turín, Turín, Italy
| | - T Prudhomme
- Servicio de Urología, Trasplante Renal y Andrología, Hospital Universitario de Rangueil, Toulouse, France
| | - B Bañuelos Marco
- Servicio de Urología, Sección de Trasplante Renal y Urología Reconstructiva, Hospital Universitario Clínico San Carlos, Madrid, France
| | - M I Dönmez
- Departamento de Urología, Facultad de Medicina, Universidad de Estambul, Estambul, Turkey
| | - A Pecoraro
- Unidad de Cirugía Robótica Urológica y Trasplante Renal, Universidad de Florencia, Hospital de Careggi, Florencia, Italy
| | - R Boissier
- Servicio de Urología y Trasplante Renal, Hospital Universitario de La Conception, Marsella, France
| | - R Campi
- Unidad de Cirugía Robótica Urológica y Trasplante Renal, Universidad de Florencia, Hospital de Careggi, Florencia, Italy
| | - A Breda
- Servicio de Urología, Fundació Puigvert, Universidad Autónoma de Barcelona, Barcelona, Spain
| | - A Territo
- Servicio de Urología, Fundació Puigvert, Universidad Autónoma de Barcelona, Barcelona, Spain.
| |
Collapse
|
|
6
|
Raynaud M, Al-Awadhi S, Louis K, Zhang H, Su X, Goutaudier V, Wang J, Demir Z, Wei Y, Truchot A, Bouquegneau A, Del Bello A, Bailly É, Lombardi Y, Maanaoui M, Giarraputo A, Naser S, Divard G, Aubert O, Murad MH, Wang C, Liu L, Bestard O, Naesens M, Friedewald JJ, Lefaucheur C, Riella L, Collins G, Ioannidis JP, Loupy A. Prognostic Biomarkers in Kidney Transplantation: A Systematic Review and Critical Appraisal. J Am Soc Nephrol 2024; 35:177-188. [PMID: 38053242 PMCID: PMC10843205 DOI: 10.1681/asn.0000000000000260] [Citation(s) in RCA: 11] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2023] [Accepted: 10/08/2023] [Indexed: 12/07/2023] Open
Abstract
SIGNIFICANCE STATEMENT Why are there so few biomarkers accepted by health authorities and implemented in clinical practice, despite the high and growing number of biomaker studies in medical research ? In this meta-epidemiological study, including 804 studies that were critically appraised by expert reviewers, the authors have identified all prognostic kidney transplant biomarkers and showed overall suboptimal study designs, methods, results, interpretation, reproducible research standards, and transparency. The authors also demonstrated for the first time that the limited number of studies challenged the added value of their candidate biomarkers against standard-of-care routine patient monitoring parameters. Most biomarker studies tended to be single-center, retrospective studies with a small number of patients and clinical events. Less than 5% of the studies performed an external validation. The authors also showed the poor transparency reporting and identified a data beautification phenomenon. These findings suggest that there is much wasted research effort in transplant biomarker medical research and highlight the need to produce more rigorous studies so that more biomarkers may be validated and successfully implemented in clinical practice. BACKGROUND Despite the increasing number of biomarker studies published in the transplant literature over the past 20 years, demonstrations of their clinical benefit and their implementation in routine clinical practice are lacking. We hypothesized that suboptimal design, data, methodology, and reporting might contribute to this phenomenon. METHODS We formed a consortium of experts in systematic reviews, nephrologists, methodologists, and epidemiologists. A systematic literature search was performed in PubMed, Embase, Scopus, Web of Science, and Cochrane Library between January 1, 2005, and November 12, 2022 (PROSPERO ID: CRD42020154747). All English language, original studies investigating the association between a biomarker and kidney allograft outcome were included. The final set of publications was assessed by expert reviewers. After data collection, two independent reviewers randomly evaluated the inconsistencies for 30% of the references for each reviewer. If more than 5% of inconsistencies were observed for one given reviewer, a re-evaluation was conducted for all the references of the reviewer. The biomarkers were categorized according to their type and the biological milieu from which they were measured. The study characteristics related to the design, methods, results, and their interpretation were assessed, as well as reproducible research practices and transparency indicators. RESULTS A total of 7372 publications were screened and 804 studies met the inclusion criteria. A total of 1143 biomarkers were assessed among the included studies from blood ( n =821, 71.8%), intragraft ( n =169, 14.8%), or urine ( n =81, 7.1%) compartments. The number of studies significantly increased, with a median, yearly number of 31.5 studies (interquartile range [IQR], 23.8-35.5) between 2005 and 2012 and 57.5 (IQR, 53.3-59.8) between 2013 and 2022 ( P < 0.001). A total of 655 studies (81.5%) were retrospective, while 595 (74.0%) used data from a single center. The median number of patients included was 232 (IQR, 96-629) with a median follow-up post-transplant of 4.8 years (IQR, 3.0-6.2). Only 4.7% of studies were externally validated. A total of 346 studies (43.0%) did not adjust their biomarker for key prognostic factors, while only 3.1% of studies adjusted the biomarker for standard-of-care patient monitoring factors. Data sharing, code sharing, and registration occurred in 8.8%, 1.1%, and 4.6% of studies, respectively. A total of 158 studies (20.0%) emphasized the clinical relevance of the biomarker, despite the reported nonsignificant association of the biomarker with the outcome measure. A total of 288 studies assessed rejection as an outcome. We showed that these rejection studies shared the same characteristics as other studies. CONCLUSIONS Biomarker studies in kidney transplantation lack validation, rigorous design and methodology, accurate interpretation, and transparency. Higher standards are needed in biomarker research to prove the clinical utility and support clinical use.
Collapse
Affiliation(s)
- Marc Raynaud
- INSERM, PARCC, Paris Institute for Transplantation and Organ Regeneration, Université de Paris Cité, Paris, France
| | - Solaf Al-Awadhi
- INSERM, PARCC, Paris Institute for Transplantation and Organ Regeneration, Université de Paris Cité, Paris, France
| | - Kevin Louis
- INSERM, PARCC, Paris Institute for Transplantation and Organ Regeneration, Université de Paris Cité, Paris, France
| | - Huanxi Zhang
- The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Xiaojun Su
- The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Valentin Goutaudier
- INSERM, PARCC, Paris Institute for Transplantation and Organ Regeneration, Université de Paris Cité, Paris, France
| | - Jiali Wang
- The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Zeynep Demir
- INSERM, PARCC, Paris Institute for Transplantation and Organ Regeneration, Université de Paris Cité, Paris, France
| | - Yongcheng Wei
- The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Agathe Truchot
- INSERM, PARCC, Paris Institute for Transplantation and Organ Regeneration, Université de Paris Cité, Paris, France
| | - Antoine Bouquegneau
- Department of Nephrology-Dialysis-Transplantation, University Hospital of Liège, Liège, Belgium
| | - Arnaud Del Bello
- Department of Nephrology and Organ Transplantation, INSERM, CHU Rangueil & Purpan, Université Paul Sabatier, Toulouse, France
| | - Élodie Bailly
- INSERM, PARCC, Paris Institute for Transplantation and Organ Regeneration, Université de Paris Cité, Paris, France
- Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Yannis Lombardi
- Kidney Transplant Department, Tenon Hospital, Assistance Publique – Hôpitaux de Paris, Paris, France
| | - Mehdi Maanaoui
- Nephrology Department, CHU Lille, Lille University, Lille, France
- INSERM U1190, Translational Research for Diabetes, Lille, France
| | - Alessia Giarraputo
- INSERM, PARCC, Paris Institute for Transplantation and Organ Regeneration, Université de Paris Cité, Paris, France
- Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padua, Padua, Italy
| | - Sofia Naser
- INSERM, PARCC, Paris Institute for Transplantation and Organ Regeneration, Université de Paris Cité, Paris, France
| | - Gillian Divard
- INSERM, PARCC, Paris Institute for Transplantation and Organ Regeneration, Université de Paris Cité, Paris, France
| | - Olivier Aubert
- INSERM, PARCC, Paris Institute for Transplantation and Organ Regeneration, Université de Paris Cité, Paris, France
| | | | - Changxi Wang
- The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Longshan Liu
- The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Oriol Bestard
- Nephrology Department, Hospital de Vall d'Hebron, Barcelona, Spain
| | - Maarten Naesens
- Department of Microbiology, Immunology and Transplantation, Nephrology and Renal Transplantation Research Group, KU Leuven, Leuven, Belgium
| | - John J. Friedewald
- Division of Transplantation, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
| | - Carmen Lefaucheur
- Kidney Transplant Department, Saint-Louis Hospital, Assistance Publique - Hôpitaux de Paris, Paris, France
| | - Leonardo Riella
- Renal Division, Schuster Family Transplantation Research Center, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
| | - Gary Collins
- Center for Statistics in Medicine, NDORMS, Botnar Research Center, University of Oxford, Oxford, United Kingdom
| | - John P.A. Ioannidis
- Departments of Medicine, of Epidemiology and Population Health, of Biomedical Data Science, and of Statistics and Meta-Research Innovation Center at Stanford (METRICS), Stanford University, Stanford, California
| | - Alexandre Loupy
- INSERM, PARCC, Paris Institute for Transplantation and Organ Regeneration, Université de Paris Cité, Paris, France
| |
Collapse
|
|
7
|
Phillips B, Asgari E, Berry M, Callaghan C, Cerisuelo MC, Johnson P, Karydis N, Nasralla D, Nutu A, Oniscu G, Perera T, Sinha S, Sutherland A, Van Dellen D, Watson C, White S, O'Neill S. British Transplantation Society guidelines on abdominal organ transplantation from deceased donors after circulatory death. Transplant Rev (Orlando) 2024; 38:100801. [PMID: 37840003 DOI: 10.1016/j.trre.2023.100801] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2023] [Accepted: 10/07/2023] [Indexed: 10/17/2023]
Abstract
The British Transplantation Society (BTS) 'Guideline on transplantation from deceased donors after circulatory death' has recently been updated and this manuscript summarises the relevant recommendations in abdominal organ transplantation from Donation after Circulatory Death (DCD) donors, encompassing the chapters on liver, kidney, pancreas and islet cell transplantation.
Collapse
Affiliation(s)
- Benedict Phillips
- Specialty Registrar in Transplant Surgery, Guy's Hospital, London, United Kingdom
| | - Ellie Asgari
- Consultant Nephrologist, Guy's Hospital, London, United Kingdom
| | - Miriam Berry
- Consultant Nephrologist, Queen Elizabeth Hospital, Birmingham, United Kingdom
| | - Chris Callaghan
- Consultant Transplant Surgeon, Guy's Hospital, London, United Kingdom
| | | | - Paul Johnson
- Consultant Paediatric Surgeon, John Radcliffe Hospital, Oxford, United Kingdom
| | - Nikolaos Karydis
- Consultant Transplant Surgeon, Guy's Hospital, London, United Kingdom
| | - David Nasralla
- Consultant Transplant Surgeon, Royal Free Hospital, London, United Kingdom
| | - Anisa Nutu
- Transplant Fellow, Queen Elizabeth Hospital, Birmingham, United Kingdom
| | - Gabi Oniscu
- Consultant Transplant Surgeon, Royal Infirmary, Edinburgh, United Kingdom
| | - Thamara Perera
- Consultant Transplant Surgeon, Queen Elizabeth Hospital, Birmingham, United Kingdom
| | - Sanjay Sinha
- Consultant Transplant Surgeon, Churchill Hospital, Oxford, United Kingdom
| | - Andrew Sutherland
- Consultant Transplant Surgeon, Royal Infirmary, Edinburgh, United Kingdom
| | - David Van Dellen
- Consultant Transplant Surgeon, Manchester Royal Infirmary, Manchester, United Kingdom
| | - Chris Watson
- Consultant Transplanxt Surgeon, Addenbrooke's Hospital, Cambridge, United Kingdom
| | - Steve White
- Consultant Transplant Surgeon, Freeman Hospital, Newcastle, United Kingdom
| | - Stephen O'Neill
- Consultant Transplant Surgeon, Belfast City Hospital, Belfast, United Kingdom.
| |
Collapse
|
|
8
|
van de Leemkolk FEM, Lo Faro ML, Shaheed S, Mulvey JF, Huurman VAL, Alwayn IPJ, Putter H, Jochmans I, Lindeman JHN, Ploeg RJ. The role of flavin mononucleotide (FMN) as a potentially clinically relevant biomarker to predict the quality of kidney grafts during hypothermic (oxygenated) machine perfusion. PLoS One 2023; 18:e0287713. [PMID: 37352336 PMCID: PMC10289320 DOI: 10.1371/journal.pone.0287713] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Accepted: 05/21/2023] [Indexed: 06/25/2023] Open
Abstract
Hypothermic machine perfusion (HMP) provides preservation superior to cold storage and may allow for organ assessment prior to transplantation. Since flavin mononucleotide (FMN) in perfusate has been proposed as a biomarker of organ quality during HMP of donor livers, the aim of this study was to validate FMN as a biomarker for organ quality in the context of HMP preserved kidneys. Perfusate samples (n = 422) from the paired randomised controlled COPE-COMPARE-trial, comparing HMP with oxygenation (HMPO2) versus standard HMP in kidneys, were used. Fluorescence intensity (FI) was assessed using fluorescence spectroscopy (excitation 450nm; emission 500-600nm) and validated by fluorospectrophotometer and targeted liquid chromatography mass spectrometry (LC-MS/MS). Fluorescence intensity (FI)(ex450;em500-600) increased over time during machine perfusion in both groups (p<0.0001). This increase was similar for both groups (p = 0.83). No correlation, however, was found between FI(ex450;em500-600) and post-transplant outcomes, including day 5 or 7 serum creatinine (p = 0.11; p = 0.16), immediate graft function (p = 0.91), creatinine clearance and biopsy-proven rejection at one year (p = 0.14; p = 0.59). LC-MS/MS validation experiments of samples detected FMN in only one perfusate sample, whilst the majority of samples with the highest fluorescence (n = 37/38, 97.4%) remained negative. In the context of clinical kidney HMP, fluorescence spectroscopy unfortunately appears to be not specific and probably unsuitable for FMN. This study shows that FMN does not classify as a clinically relevant predictive biomarker of kidney graft function after transplantation.
Collapse
Affiliation(s)
- Fenna E. M. van de Leemkolk
- Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands
- LUMC Transplant Center, Leiden University Medical Center, Leiden, The Netherlands
- Nuffield Department of Surgical Sciences, University of Oxford, Oxford, United Kingdom
| | - M. Letizia Lo Faro
- Nuffield Department of Surgical Sciences, University of Oxford, Oxford, United Kingdom
- NIHR Oxford Biomedical Research Centre, Oxford University Hospitals Trust, Oxford, United Kingdom
| | - Sadr Shaheed
- Nuffield Department of Surgical Sciences, University of Oxford, Oxford, United Kingdom
- NIHR Oxford Biomedical Research Centre, Oxford University Hospitals Trust, Oxford, United Kingdom
| | - John F. Mulvey
- Nuffield Department of Surgical Sciences, University of Oxford, Oxford, United Kingdom
| | - Volkert A. L. Huurman
- Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands
- LUMC Transplant Center, Leiden University Medical Center, Leiden, The Netherlands
| | - Ian P. J. Alwayn
- Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands
- LUMC Transplant Center, Leiden University Medical Center, Leiden, The Netherlands
| | - Hein Putter
- LUMC Transplant Center, Leiden University Medical Center, Leiden, The Netherlands
- Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, The Netherlands
| | - Ina Jochmans
- Department of Abdominal Transplant Surgery, University Hospitals Leuven, Leuven, Belgium
- Transplantation Research Group, Lab of Abdominal Transplantation, Department of Microbiology, Immunology, and Transplantation, KU Leuven, Belgium
| | - Jan H. N. Lindeman
- Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands
- LUMC Transplant Center, Leiden University Medical Center, Leiden, The Netherlands
| | - Rutger J. Ploeg
- LUMC Transplant Center, Leiden University Medical Center, Leiden, The Netherlands
- Nuffield Department of Surgical Sciences, University of Oxford, Oxford, United Kingdom
- NIHR Oxford Biomedical Research Centre, Oxford University Hospitals Trust, Oxford, United Kingdom
| | | |
Collapse
|
|
9
|
Meertens P, Mellati A, Dumbill R, Lo Faro ML, Rozenberg K, Mulvey J, Fliri H, Ploeg R, Hunter J. CC-4066 therapy delivered to kidneys during cold storage and assessed with normothermic reperfusion is feasible and safe. FRONTIERS IN TRANSPLANTATION 2023; 2:1166661. [PMID: 39055309 PMCID: PMC11270626 DOI: 10.3389/frtra.2023.1166661] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Accepted: 04/21/2023] [Indexed: 07/27/2024]
Abstract
Introduction Currently there is an urgent need to translate interventions that may be beneficial to marginal donor kidneys prior to transplant, to improve their quality from bench to bedside. This project investigated the effects of CC-4066, a potent dual inhibitor of cyclophilin proteins A and D, treatment during static cold storage (SCS) in a porcine model of renal ischemia-reperfusion injury (IRI) using Normothermic Reperfusion (NR). Materials and methods Porcine kidneys and autologous blood were retrieved in pairs from a local abattoir (n = 7). One kidney from each pair was randomly allocated to treatment and one allocated to control and flushed with preservation solution containing CC-4066 or vehicle. After 7 h of SCS kidneys underwent 3 h Normothermic Reperfusion (NR) with autologous whole blood while perfusion characteristics and samples were collected. Results Perfusion and metabolic parameters showed similar trends and no statistical differences were observed between the groups. IL-6 showed a significant increase over time but no significant difference between groups (p-value 0.009 and 0.14 respectively, two-way ANOVA). Oxygen consumption and lactate levels were similar between groups but there was increased vacuolation on histology in the control group. Conclusions The addition of CC-4066 during SCS of kidneys is safe and feasible and has no adverse or detrimental effects on perfusion during assessment on NR. There was no difference in cytokine levels although there was a trend towards less vacuolation on histology in the treatment group.
Collapse
Affiliation(s)
- Pommelien Meertens
- Nuffield Department of Surgical Sciences, University of Oxford, Oxford, United Kingdoms
- Leiden University Medical Centre, Leiden University, Leiden, Netherlands
| | - Azita Mellati
- Nuffield Department of Surgical Sciences, University of Oxford, Oxford, United Kingdoms
| | - Richard Dumbill
- Nuffield Department of Surgical Sciences, University of Oxford, Oxford, United Kingdoms
- Oxford University Hospital National Health Service (NHS) Foundation Trust, Oxford, United Kingdom
| | - M. Letizia Lo Faro
- Nuffield Department of Surgical Sciences, University of Oxford, Oxford, United Kingdoms
| | - Kaithlyn Rozenberg
- Nuffield Department of Surgical Sciences, University of Oxford, Oxford, United Kingdoms
| | - John Mulvey
- Nuffield Department of Surgical Sciences, University of Oxford, Oxford, United Kingdoms
| | - Hans Fliri
- Cypralis Ltd., Cambridge, United Kingdom
| | - Rutger Ploeg
- Nuffield Department of Surgical Sciences, University of Oxford, Oxford, United Kingdoms
- Leiden University Medical Centre, Leiden University, Leiden, Netherlands
- Oxford University Hospital National Health Service (NHS) Foundation Trust, Oxford, United Kingdom
| | - James Hunter
- Nuffield Department of Surgical Sciences, University of Oxford, Oxford, United Kingdoms
- University Hospitals of Coventry and Warwickshire National Health Service (NHS) Trust, Coventry, United Kingdom
| |
Collapse
|
|
10
|
Liu RX, Koyawala N, Thiessen-Philbrook HR, Doshi MD, Reese PP, Hall IE, Mohan S, Parikh CR. Untargeted metabolomics of perfusate and their association with hypothermic machine perfusion and allograft failure. Kidney Int 2023; 103:762-771. [PMID: 36549364 DOI: 10.1016/j.kint.2022.11.020] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Revised: 10/28/2022] [Accepted: 11/14/2022] [Indexed: 12/24/2022]
Abstract
Although hypothermic machine perfusion (HMP) is associated with improved kidney graft viability and function, the underlying biological mechanisms are unknown. Untargeted metabolomic profiling may identify potential metabolites and pathways that can help assess allograft viability and contribute to organ preservation. Therefore, in this multicenter study, we measured all detectable metabolites in perfusate collected at the beginning and end of deceased-donor kidney perfusion and evaluated their associations with graft failure. In our cohort of 190 kidney transplants, 33 (17%) had death-censored graft failure over a median follow-up of 5.0 years (IQR 3.0-6.1 years). We identified 553 known metabolites in perfusate and characterized their experimental and biological consistency through duplicate samples and unsupervised clustering. After perfusion-time adjustment and false discovery correction, six metabolites in post-HMP perfusate were significantly associated with death-censored graft failure, including alpha-ketoglutarate, 3-carboxy-4-methyl-5-propyl-2-furanpropanoate, 1-carboxyethylphenylalanine, and three glycerol-phosphatidylcholines. All six metabolites were associated with an increased risk of graft failure (Hazard Ratio per median absolute deviation range 1.04-1.45). Four of six metabolites also demonstrated significant interaction with donation after cardiac death with notably greater risk in the donation after cardiac death group (Hazard Ratios up to 1.69). Discarded kidneys did not have significantly different levels of any death-censored graft failure-associated metabolites. On interrogation of pathway analysis, production of reactive oxygen species and increased metabolism of fatty acids were upregulated in kidneys that subsequently developed death-censored graft failure. Thus, further understanding the role of these metabolites may inform the HMP process and help improve the objective evaluation of allograft offers, thereby reducing the discard of potentially viable organs.
Collapse
Affiliation(s)
- Richard X Liu
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Neel Koyawala
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | | | - Mona D Doshi
- Department of Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Peter P Reese
- Renal-Electrolyte and Hypertension Division, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
| | - Isaac E Hall
- Division of Nephrology and Hypertension, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, Utah, USA
| | - Sumit Mohan
- Department of Medicine, Vagelos College of Physicians and Surgeons, New York, New York, USA; Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, New York, USA
| | - Chirag R Parikh
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
| |
Collapse
|
|
11
|
Sirolli V, Piscitani L, Bonomini M. Biomarker-Development Proteomics in Kidney Transplantation: An Updated Review. Int J Mol Sci 2023; 24:ijms24065287. [PMID: 36982359 PMCID: PMC10049725 DOI: 10.3390/ijms24065287] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2022] [Revised: 02/27/2023] [Accepted: 03/08/2023] [Indexed: 03/12/2023] Open
Abstract
Kidney transplantation (KT) is the optimal therapeutic strategy for patients with end-stage renal disease. The key to post-transplantation management is careful surveillance of allograft function. Kidney injury may occur from several different causes that require different patient management approaches. However, routine clinical monitoring has several limitations and detects alterations only at a later stage of graft damage. Accurate new noninvasive biomarker molecules are clearly needed for continuous monitoring after KT in the hope that early diagnosis of allograft dysfunction will lead to an improvement in the clinical outcome. The advent of “omics sciences”, and in particular of proteomic technologies, has revolutionized medical research. Proteomic technologies allow us to achieve the identification, quantification, and functional characterization of proteins/peptides in biological samples such as urine or blood through supervised or targeted analysis. Many studies have investigated proteomic techniques as potential molecular markers discriminating among or predicting allograft outcomes. Proteomic studies in KT have explored the whole transplant process: donor, organ procurement, preservation, and posttransplant surgery. The current article reviews the most recent findings on proteomic studies in the setting of renal transplantation in order to better understand the effective potential of this new diagnostic approach.
Collapse
Affiliation(s)
- Vittorio Sirolli
- Nephrology and Dialysis Unit, Department of Medicine, G. d’Annunzio University, Chieti-Pescara, SS. Annunziata Hospital, 66013 Chieti, Italy
| | - Luca Piscitani
- Nephrology and Dialysis Unit, Department of Medicine, San Salvatore Hospital, 67100 L’Aquila, Italy
| | - Mario Bonomini
- Nephrology and Dialysis Unit, Department of Medicine, G. d’Annunzio University, Chieti-Pescara, SS. Annunziata Hospital, 66013 Chieti, Italy
- Correspondence:
| |
Collapse
|
|
12
|
Li JH, Xu X, Wang YF, Xie HY, Chen JY, Dong NG, Badiwala M, Xin LM, Ribeiro RVP, Yin H, Zhang H, Zhang JZ, Huo F, Yang JY, Yang HJ, Pan H, Li SG, Qiao YB, Luo J, Li HY, Jia JJ, Yu H, Liang H, Yang SJ, Wang H, Liu ZY, Zhang LC, Hu XY, Wu H, Hu YQ, Tang PF, Ye QF, Zheng SS. Chinese expert consensus on organ protection of transplantation (2022 edition). Hepatobiliary Pancreat Dis Int 2022; 21:516-526. [PMID: 36376226 DOI: 10.1016/j.hbpd.2022.10.010] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Accepted: 10/24/2022] [Indexed: 11/07/2022]
Affiliation(s)
- Jian-Hui Li
- Department of Hepatobiliary and Pancreatic Surgery, Department of Liver Transplantation, Shulan (Hangzhou) Hospital, Zhejiang Shuren University School of Medicine, Hangzhou 310022, China
| | - Xiao Xu
- Department of Hepatobiliary and Pancreatic Surgery, Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou 310000, China
| | - Yan-Feng Wang
- Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, Hubei Key Laboratory of Medical Technology on Transplantation, Wuhan 430062, China
| | - Hai-Yang Xie
- NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou 310003, China
| | - Jing-Yu Chen
- Wuxi Lung Transplantation Center, Wuxi People's Hospital Affiliated with Nanjing Medical University, Wuxi 214023, China
| | - Nian-Guo Dong
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Mitesh Badiwala
- Peter Munk Cardiac Centre, Toronto General Hospital-University Health Network, Toronto, Canada
| | - Li-Ming Xin
- School of Computer Engineering and Science, Shanghai University, Shanghai 200444, China
| | | | - Hao Yin
- Organ Transplant Center, Shanghai Changzheng Hospital, Shanghai 200003, China
| | - Hao Zhang
- Department of Orthopedics, Chinese PLA General Hospital, Beijing 100039, China; National Clinical Research Center for Orthopedics, Sports Medicine & Rehabilitation, Beijing 100039, China
| | - Jian-Zheng Zhang
- Department of Orthopedics, Chinese PLA General Hospital, Beijing 100039, China; National Clinical Research Center for Orthopedics, Sports Medicine & Rehabilitation, Beijing 100039, China
| | - Feng Huo
- Department of Surgery, General Hospital of Guangzhou Military Command of PLA, Guangzhou 510040, China
| | - Jia-Yin Yang
- Department of Liver Surgery, Liver Transplantation Center, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Hong-Ji Yang
- Organ Transplantation Center, Sichuan Provincial People's Hospital and School of Medicine, University of Electronic Science and Technology of China, Chengdu 610072, China
| | - Hui Pan
- Department of Lung Transplantation, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Shao-Guang Li
- Department of Orthopedics, Chinese PLA General Hospital, Beijing 100039, China; National Clinical Research Center for Orthopedics, Sports Medicine & Rehabilitation, Beijing 100039, China
| | - Yin-Biao Qiao
- NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou 310003, China
| | - Jia Luo
- NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou 310003, China
| | - Hao-Yu Li
- NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou 310003, China
| | - Jun-Jun Jia
- Division of Hepatobiliary Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Hao Yu
- Division of Hepatobiliary Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Han Liang
- Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, Hubei Key Laboratory of Medical Technology on Transplantation, Wuhan 430062, China
| | - Si-Jia Yang
- Department of Lung Transplantation, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Hao Wang
- Department of Orthopedics, Chinese PLA General Hospital, Beijing 100039, China; National Clinical Research Center for Orthopedics, Sports Medicine & Rehabilitation, Beijing 100039, China
| | - Zhong-Yang Liu
- Department of Orthopedics, Chinese PLA General Hospital, Beijing 100039, China; National Clinical Research Center for Orthopedics, Sports Medicine & Rehabilitation, Beijing 100039, China
| | - Li-Cheng Zhang
- Department of Orthopedics, Chinese PLA General Hospital, Beijing 100039, China; National Clinical Research Center for Orthopedics, Sports Medicine & Rehabilitation, Beijing 100039, China
| | - Xiao-Yi Hu
- Division of Hepatobiliary Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Hao Wu
- Division of Hepatobiliary Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Yi-Qing Hu
- Division of Hepatobiliary Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Pei-Fu Tang
- Department of Orthopedics, Chinese PLA General Hospital, Beijing 100039, China; National Clinical Research Center for Orthopedics, Sports Medicine & Rehabilitation, Beijing 100039, China
| | - Qi-Fa Ye
- Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, Hubei Key Laboratory of Medical Technology on Transplantation, Wuhan 430062, China
| | - Shu-Sen Zheng
- Department of Hepatobiliary and Pancreatic Surgery, Department of Liver Transplantation, Shulan (Hangzhou) Hospital, Zhejiang Shuren University School of Medicine, Hangzhou 310022, China; NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou 310003, China; Division of Hepatobiliary Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China.
| |
Collapse
|
|
13
|
Gonzalez-Viedma A, Van Dyck R, De Beule J, Ghesquière B, Jochmans I. Unraveling metabolism during kidney perfusion using tracer studies, a systematic review. Artif Organs 2022; 46:2118-2134. [PMID: 35848397 DOI: 10.1111/aor.14355] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Revised: 06/02/2022] [Accepted: 07/03/2022] [Indexed: 12/09/2022]
Abstract
BACKGROUND Understanding kidney metabolism during perfusion is vital to further develop the technology as a preservation, viability assessment, and resuscitation platform. We reviewed the evidence on the use of labeled metabolites (tracers) to understand "on-pump" kidney behavior. METHODS PubMed, Embase, Web of Science, and Cochrane databases were systematically searched for studies evaluating metabolism of (non)radioactively labeled endogenous compounds during kidney perfusion. RESULTS Of 5899 articles, 30 were included. All were animal studies [rat (70%), dog (13%), pig (10%), rabbit (7%)] perfusing but not transplanting kidneys. Perfusion took place at hypothermic (4-12°C) (20%), normothermic (35-40°C) (77%), or undefined temperatures (3%). Hypothermic perfusion used albumin or a clinical kidney preservation solution, mostly in the presence of oxygen. Normothermic perfusion was mostly performed with oxygenated crystalloids often containing glucose and amino acids with unclear partial oxygen tensions. Active metabolism of carbohydrate, amino acid, lipids, and large molecules was shown in hypothermic and normothermic perfusion. Production of macromolecules, such as prostaglandin, thromboxane, and vitamin D, takes place during normothermic perfusion. No experiments compared differences in metabolic activity between hypothermic and normothermic perfusion. One conference abstract showed increased anaerobic metabolism in kidneys donated after circulatory death by adding labeled glucose to hypothermically perfused human kidneys. CONCLUSIONS Tracer studies during kidney perfusion contribute to unraveling kidney metabolic behavior in pre-clinical models. Whether findings are truly translational needs further investigation in large animal models of human kidneys. Furthermore, it is essential to better understand how ischemia changes this metabolic behavior.
Collapse
Affiliation(s)
- Arantxa Gonzalez-Viedma
- Department of Microbiology, Immunology, and Transplantation, Transplantation Research Group, Lab of Abdominal Transplantation, KU Leuven, Leuven, Belgium
| | - Robbe Van Dyck
- Department of Microbiology, Immunology, and Transplantation, Transplantation Research Group, Lab of Abdominal Transplantation, KU Leuven, Leuven, Belgium
| | - Julie De Beule
- Department of Microbiology, Immunology, and Transplantation, Transplantation Research Group, Lab of Abdominal Transplantation, KU Leuven, Leuven, Belgium
| | - Bart Ghesquière
- Metabolomics Expertise Center, Center for Cancer Biology, VIB Center for Cancer Biology, Leuven, Belgium.,Metabolomics Expertise Center, Department of Oncology, KU Leuven, Leuven, Belgium
| | - Ina Jochmans
- Department of Microbiology, Immunology, and Transplantation, Transplantation Research Group, Lab of Abdominal Transplantation, KU Leuven, Leuven, Belgium.,Department of Abdominal Transplant Surgery, University Hospitals Leuven, Leuven, Belgium
| |
Collapse
|
|
14
|
Perfusate Metabolomics Content and Expression of Tubular Transporters During Human Kidney Graft Preservation by Hypothermic Machine Perfusion. Transplantation 2022; 106:1831-1843. [PMID: 35442245 DOI: 10.1097/tp.0000000000004129] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
BACKGROUND Ischemia-related injury during the preimplantation period impacts kidney graft outcome. Evaluating these lesions by a noninvasive approach before transplantation could help us to understand graft injury mechanisms and identify potential biomarkers predictive of graft outcomes. This study aims to determine the metabolomic content of graft perfusion fluids and its dependence on preservation time and to explore whether tubular transporters are possibly involved in metabolomics variations. METHODS Kidneys were stored on hypothermic perfusion machines. We evaluated the metabolomic profiles of perfusion fluids (n = 35) using liquid chromatography coupled with tandem mass spectrometry and studied the transcriptional expression of tubular transporters on preimplantation biopsies (n = 26), both collected at the end of graft perfusion. We used univariate and multivariate analyses to assess the impact of perfusion time on these parameters and their relationship with graft outcome. RESULTS Seventy-two metabolites were found in preservation fluids at the end of perfusion, of which 40% were already present in the native conservation solution. We observed an increase of 23 metabolites with a longer perfusion time and a decrease of 8. The predictive model for time-dependent variation of metabolomics content showed good performance (R2 = 76%, Q2 = 54%, accuracy = 41%, and permutation test significant). Perfusion time did not affect the mRNA expression of transporters. We found no correlation between metabolomics and transporters expression. Neither the metabolomics content nor transporter expression was predictive of graft outcome. CONCLUSIONS Our results call for further studies, focusing on both intra- and extratissue metabolome, to investigate whether transporter alterations can explain the variations observed in the preimplantation period.
Collapse
|
|
15
|
Verstraeten L, Jochmans I. Sense and Sensibilities of Organ Perfusion as a Kidney and Liver Viability Assessment Platform. Transpl Int 2022; 35:10312. [PMID: 35356401 PMCID: PMC8958413 DOI: 10.3389/ti.2022.10312] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Accepted: 01/26/2022] [Indexed: 12/13/2022]
Abstract
Predicting organ viability before transplantation remains one of the most challenging and ambitious objectives in transplant surgery. Waitlist mortality is high while transplantable organs are discarded. Currently, around 20% of deceased donor kidneys and livers are discarded because of “poor organ quality”, Decisions to discard are still mainly a subjective judgement since there are only limited reliable tools predictive of outcome available. Organ perfusion technology has been posed as a platform for pre-transplant organ viability assessment. Markers of graft injury and function as well as perfusion parameters have been investigated as possible viability markers during ex-situ hypothermic and normothermic perfusion. We provide an overview of the available evidence for the use of kidney and liver perfusion as a tool to predict posttransplant outcomes. Although evidence shows post-transplant outcomes can be predicted by both injury markers and perfusion parameters during hypothermic kidney perfusion, the predictive accuracy is too low to warrant clinical decision making based upon these parameters alone. In liver, further evidence on the usefulness of hypothermic perfusion as a predictive tool is needed. Normothermic perfusion, during which the organ remains fully metabolically active, seems a more promising platform for true viability assessment. Although we do not yet fully understand “on-pump” organ behaviour at normothermia, initial data in kidney and liver are promising. Besides the need for well-designed (registry) studies to advance the field, the catch-22 of selection bias in clinical studies needs addressing.
Collapse
Affiliation(s)
- Laurence Verstraeten
- Lab of Abdominal Transplantation, Transplantation Research Group, Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium
| | - Ina Jochmans
- Lab of Abdominal Transplantation, Transplantation Research Group, Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium
- Department of Abdominal Transplantation, University Hospitals Leuven, Leuven, Belgium
- *Correspondence: Ina Jochmans,
| |
Collapse
|
|
16
|
Weissenbacher A, Stone JP, Lo Faro ML, Hunter JP, Ploeg RJ, Coussios CC, Fildes JE, Friend PJ. Hemodynamics and Metabolic Parameters in Normothermic Kidney Preservation Are Linked With Donor Factors, Perfusate Cells, and Cytokines. Front Med (Lausanne) 2022; 8:801098. [PMID: 35083252 PMCID: PMC8784871 DOI: 10.3389/fmed.2021.801098] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2021] [Accepted: 12/08/2021] [Indexed: 12/29/2022] Open
Abstract
Kidney transplantation is the best renal-replacement option for most patients with end-stage renal disease. Normothermic machine preservation (NMP) of the kidney has been studied extensively during the last two decades and implemented in clinical trials. Biomarker research led to success in identifying molecules with diagnostic, predictive and therapeutic properties in chronic kidney disease. However, perfusate biomarkers and potential predictive mechanisms in NMP have not been identified yet. Twelve discarded human kidneys (n = 7 DBD, n = 5 DCD) underwent NMP for up to 24 h. Eight were perfused applying urine recirculation (URC), four with replacement of urine (UR) using Ringer's lactate. The aim of our study was to investigate biomarkers (NGAL, KIM-1, and L-FABP), cells and cytokines in the perfusate in context with donor characteristics, perfusate hemodynamics and metabolic parameters. Cold ischemia time did not correlate with any of the markers. Perfusates of DBD kidneys had a significantly lower number of leukocytes after 6 h of NMP compared to DCD. Arterial flow, pH, NGAL and L-FABP correlated with donor creatinine and eGFR. Arterial flow was higher in kidneys with lower perfusate lactate. Perfusate TNF-α was higher in kidneys with lower arterial flow. The cytokines IL-1β and GM-CSF decreased during 6 h of NMP. Kidneys with more urine output had lower perfusate KIM-1 levels. Median and 6-h values of lactate, arterial flow, pH, NGAL, KIM-1, and L-FABP correlated with each other indicating a 6-h period being applicable for kidney viability assessment. The study results demonstrate a comparable cytokine and cell profile in perfusates with URC and UR. In conclusion, clinically available perfusate and hemodynamic parameters correlate well with donor characteristics and measured biomarkers in a discarded human NMP model.
Collapse
Affiliation(s)
- Annemarie Weissenbacher
- Oxford Transplant Centre, Nuffield Department of Surgical Sciences, University of Oxford, Oxford, United Kingdom.,Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, Innsbruck, Austria
| | - John P Stone
- The ex-vivo Lab, Division of Cell Matrix Biology and Regenerative Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester Academic Health Science Centre, Manchester, United Kingdom.,The ex-vivo Research Centre Community Interest Company (CIC), Macclesfield, United Kingdom
| | - Maria Letizia Lo Faro
- Oxford Transplant Centre, Nuffield Department of Surgical Sciences, University of Oxford, Oxford, United Kingdom
| | - James P Hunter
- Oxford Transplant Centre, Nuffield Department of Surgical Sciences, University of Oxford, Oxford, United Kingdom
| | - Rutger J Ploeg
- Oxford Transplant Centre, Nuffield Department of Surgical Sciences, University of Oxford, Oxford, United Kingdom
| | | | - James E Fildes
- The ex-vivo Lab, Division of Cell Matrix Biology and Regenerative Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester Academic Health Science Centre, Manchester, United Kingdom.,The ex-vivo Research Centre Community Interest Company (CIC), Macclesfield, United Kingdom
| | - Peter J Friend
- Oxford Transplant Centre, Nuffield Department of Surgical Sciences, University of Oxford, Oxford, United Kingdom
| |
Collapse
|
|
17
|
Bouari S, Rijkse E, Hosgood SA, Minnee RC. Ex situ machine perfusion in kidney transplantation. Artif Organs 2021; 46:173-176. [PMID: 34888895 DOI: 10.1111/aor.14134] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Revised: 11/16/2021] [Accepted: 12/01/2021] [Indexed: 11/26/2022]
Affiliation(s)
- Sarah Bouari
- Division of HPB and Transplant Surgery, Department of Surgery, Erasmus MC Transplant Institute, Rotterdam, The Netherlands
| | - Elsaline Rijkse
- Division of HPB and Transplant Surgery, Department of Surgery, Erasmus MC Transplant Institute, Rotterdam, The Netherlands
| | - Sarah A Hosgood
- Department of Surgery, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK
| | - Robert C Minnee
- Division of HPB and Transplant Surgery, Department of Surgery, Erasmus MC Transplant Institute, Rotterdam, The Netherlands
| |
Collapse
|
|
18
|
Abstract
Hypothermic and normothermic machine perfusion in kidney transplantation are purported to exert a beneficial effect on post-transplant outcomes compared to the traditionally used method of static cold storage. Kidney perfusion techniques provide a window for organ reconditioning and quality assessment. However, how best to deliver these preservation methods or improve organ quality has not yet been conclusively defined. This review summarises the promising advances in machine perfusion science in recent years, which have the potential to further improve early graft function and prolong graft survival.
Collapse
|
|
19
|
Tatsis V, Dounousi E, Mitsis M. Hypothermic Machine Perfusion of Kidney Transplant: A Mini-Review. Transplant Proc 2021; 53:2793-2796. [PMID: 34696905 DOI: 10.1016/j.transproceed.2021.09.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
Most kidney grafts are marginal and from deceased donors, which yield worse clinical outcomes. Hypothermic machine perfusion has created a paradigm shift in kidney preservation. This mini-review summarizes the main points of hypothermic machine perfusion of kidney transplants that should be known by any physician and surgeon involved with kidney transplantation. Specifically, this review explains a proposed mechanism of action of hypothermic machine perfusion of kidney transplants. This review also describes the clinical effectiveness of hypothermic machine perfusion and explains how to evaluate and predict graft functionality according to machine parameters and perfusate biomarkers. Finally, treatment options and the most recent studies on oxygenated hypothermic machine perfusion are mentioned.
Collapse
Affiliation(s)
| | - Evangelia Dounousi
- Department of Nephrology, University Hospital of Ioannina, Ioannina, Greece
| | | |
Collapse
|
|
20
|
Darius T, Nath J, Mourad M. Simply Adding Oxygen during Hypothermic Machine Perfusion to Combat the Negative Effects of Ischemia-Reperfusion Injury: Fundamentals and Current Evidence for Kidneys. Biomedicines 2021; 9:993. [PMID: 34440197 PMCID: PMC8394874 DOI: 10.3390/biomedicines9080993] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Revised: 08/04/2021] [Accepted: 08/06/2021] [Indexed: 12/11/2022] Open
Abstract
The use of high-risk renal grafts for transplantation requires optimization of pretransplant preservation and assessment strategies to improve clinical outcomes as well as to decrease organ discard rate. With oxygenation proposed as a resuscitative measure during hypothermic machine preservation, this review provides a critical overview of the fundamentals of active oxygenation during hypothermic machine perfusion, as well as the current preclinical and clinical evidence and suggests different strategies for clinical implementation.
Collapse
Affiliation(s)
- Tom Darius
- Surgery and Abdominal Transplant Unit, University Clinics Saint Luc, Université Catholique de Louvain, 1200 Brussels, Belgium;
- Pole de Chirurgie Expérimentale et Transplantation, Université Catholique de Louvain, 1200 Brussels, Belgium
| | - Jay Nath
- Department of Renal Transplantation, Southmead Hospital Bristol, Bristol BS10 5NB, UK;
| | - Michel Mourad
- Surgery and Abdominal Transplant Unit, University Clinics Saint Luc, Université Catholique de Louvain, 1200 Brussels, Belgium;
- Pole de Chirurgie Expérimentale et Transplantation, Université Catholique de Louvain, 1200 Brussels, Belgium
| |
Collapse
|
|
21
|
Assessing Kidney Graft Viability and Its Cells Metabolism during Machine Perfusion. Int J Mol Sci 2021; 22:ijms22031121. [PMID: 33498732 PMCID: PMC7865666 DOI: 10.3390/ijms22031121] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Revised: 01/13/2021] [Accepted: 01/21/2021] [Indexed: 12/16/2022] Open
Abstract
Kidney transplantation is the golden treatment for end-stage renal disease. Static cold storage is currently considered the standard method of preservation, but dynamic techniques, such as machine perfusion (MP), have been shown to improve graft function, especially in kidneys donated by extended criteria donors and donation after circulatory death. With poor organ quality being a major reason for kidneys not being transplanted, an accurate, objective and reliable quality assessment during preservation could add value and support to clinicians’ decisions. MPs are emerging technologies with the potential to assess kidney graft viability and quality, both in the hypothermic and normothermic scenarios. The aim of this review is to summarize current tools for graft viability assessment using MP prior to implantation in relation to the ischemic damage.
Collapse
|
|
22
|
Becker F, Pascher A, Brockmann JG. [Machine perfusion for conditioning liver and kidneys before transplantation]. Chirurg 2020; 91:913-917. [PMID: 32613274 DOI: 10.1007/s00104-020-01227-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
Machine perfusion will become established as the standard of care for solid organ transplantation in the near future. Ongoing studies are investigating the appropriate perfusion algorithms for each specific organ. Although it is neither proven which perfusion principle nor type of device is superior, it has already been sufficiently shown that the increasing number of marginal organs that are currently transplanted in Germany would benefit from machine perfusion for conditioning before transplantation. The addition of hypothermic and normothermic perfusion sequences opens up the possibility of conditioning of previously damaged organs as well as viability testing. Overall, machine perfusion increases the safety for the recipient and can counteract the increasingly more difficult scenario of working hour restrictions because solid organ transplantations in the future will be plannable and carried out during the day.
Collapse
Affiliation(s)
- F Becker
- Klinik für Allgemein‑, Viszeral- und Transplantationschirurgie, Universitätsklinikum Münster, Albert-Schweitzer-Campus 1, Gebäude W1, 48149, Münster, Deutschland
| | - A Pascher
- Klinik für Allgemein‑, Viszeral- und Transplantationschirurgie, Universitätsklinikum Münster, Albert-Schweitzer-Campus 1, Gebäude W1, 48149, Münster, Deutschland
| | - J G Brockmann
- Klinik für Allgemein‑, Viszeral- und Transplantationschirurgie, Universitätsklinikum Münster, Albert-Schweitzer-Campus 1, Gebäude W1, 48149, Münster, Deutschland.
| |
Collapse
|
|
23
|
Perfusate Analysis During Dual Hypothermic Oxygenated Machine Perfusion of Liver Grafts: Correlations With Donor Factors and Early Outcomes. Transplantation 2020; 104:1929-1942. [PMID: 32769628 DOI: 10.1097/tp.0000000000003398] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Liver graft viability assessment has long been considered a limit of hypothermic oxygenated machine perfusion (HOPE). Aim of this study was assessing correlations of easily available perfusate parameters (PP) (aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, glucose, lactate, and pH) with graft features and outcome. METHODS In the period October 2018-February 2020, perfusate samples were obtained every 30 minutes during 50 dual-HOPE (D-HOPE) procedures. Correlations of PP with graft factors, 90-day graft loss, early allograft dysfunction (EAD), L-GrAFT score, acute kidney injury, and comprehensive complication index were analyzed using Pearson coefficient, receiver-operating characteristics analysis and by univariable and multivariable regression. RESULTS Median D-HOPE time was 122 minutes. All parameters were normalized to liver weight. Only macrovesicular steatosis (MaS) significantly impacted PP levels and slope. Grafts with ≥30% MaS exhibited significantly different PP values and slope. Graft loss and EAD rate were 2% (n = 1) and 26% (n = 13). All PP except lactate correlated with EAD, 90-minute alanine aminotransferase showing the highest area under the receiver-operating characteristics curve (0.84). However, at multivariable analysis, the only factor independently associated with EAD was MaS (odds ratio, 5.44; confidence interval, 1.05-28.21; P = 0.04). Ninety minutes lactate dehydrogenase had the strongest correlation with L-GrAFT (R = 0.70; P < 0.001). PP correlated poorly with comprehensive complication index and grades 2-3 acute kidney injury rate. CONCLUSIONS PP were predictive of graft function after transplant, but their association with graft survival and clinical outcomes requires further evaluation. MaS influenced levels of PP and was the only independent predictor of EAD.
Collapse
|
|
24
|
Abstract
Because of the high demand of organs, the usage of marginal grafts has increased. These marginal organs have a higher risk of developing ischemia-reperfusion injury, which can lead to posttransplant complications. Ex situ machine perfusion (MP), compared with the traditional static cold storage, may better protect these organs from ischemia-reperfusion injury. In addition, MP can also act as a platform for dynamic administration of pharmacological agents or gene therapy to further improve transplant outcomes. Numerous therapeutic agents have been studied under both hypothermic (1-8°C) and normothermic settings. Here, we review all the therapeutics used during MP in different organ systems (lung, liver, kidney, heart). The major categories of therapeutic agents include vasodilators, mesenchymal stem cells, antiinflammatory agents, antiinfection agents, siRNA, and defatting agents. Numerous animal and clinical studies have examined MP therapeutic agents, some of which have even led to the successful reconditioning of discarded grafts. More clinical studies, especially randomized controlled trials, will need to be conducted in the future to solidify these promising results and to define the role of MP therapeutic agents in solid organ transplantation.
Collapse
|
|
25
|
Urinary Biomarkers for Diagnosis and Prediction of Acute Kidney Allograft Rejection: A Systematic Review. Int J Mol Sci 2020; 21:ijms21186889. [PMID: 32961825 PMCID: PMC7555436 DOI: 10.3390/ijms21186889] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2020] [Revised: 09/16/2020] [Accepted: 09/18/2020] [Indexed: 01/10/2023] Open
Abstract
Noninvasive tools for diagnosis or prediction of acute kidney allograft rejection have been extensively investigated in recent years. Biochemical and molecular analyses of blood and urine provide a liquid biopsy that could offer new possibilities for rejection prevention, monitoring, and therefore, treatment. Nevertheless, these tools are not yet available for routine use in clinical practice. In this systematic review, MEDLINE was searched for articles assessing urinary biomarkers for diagnosis or prediction of kidney allograft acute rejection published in the last five years (from 1 January 2015 to 31 May 2020). This review follows the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines. Articles providing targeted or unbiased urine sample analysis for the diagnosis or prediction of both acute cellular and antibody-mediated kidney allograft rejection were included, analyzed, and graded for methodological quality with a particular focus on study design and diagnostic test accuracy measures. Urinary C-X-C motif chemokine ligands were the most promising and frequently studied biomarkers. The combination of precise diagnostic reference in training sets with accurate validation in real-life cohorts provided the most relevant results and exciting groundwork for future studies.
Collapse
|
|
26
|
Swanson KJ, Aziz F, Garg N, Mohamed M, Mandelbrot D, Djamali A, Parajuli S. Role of novel biomarkers in kidney transplantation. World J Transplant 2020; 10:230-255. [PMID: 32995319 PMCID: PMC7504189 DOI: 10.5500/wjt.v10.i9.230] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2020] [Revised: 07/21/2020] [Accepted: 08/26/2020] [Indexed: 02/05/2023] Open
Abstract
Clinical application of biomarkers is an integral component of transplant care. Clinicians and scientists alike are in search of better biomarkers than the current serologic (serum creatinine, donor-specific antibodies), urine-derived (urinalysis, urine protein), and histologic ones we now use. The science behind recent biomarker discovery spans across multiple molecular biologic disciplines, including transcriptomics, proteomics, and metabolomics. Innovative methodology and integration of basic and clinical approaches have allowed researchers to unearth molecular phenomena preceding clinical disease. Biomarkers can be classified in several ways. In this review, we have classified them via their origin and outcome: Primarily immunologic, i.e., representative of immune regulation and dysfunction and non-immunologic, pertaining to delayed graft function, cardiovascular events/mortality, infection, malignancy, post-transplant diabetes, graft, and patient survival. Novel biomarker uses to guide the diagnosis and management of transplant-related outcomes is a promising area of research. However, the use of biomarkers to predict outcomes after kidney transplantation is not well studied. In this review, we summarize the recent studies illustrating biomarker use and transplant outcomes.
Collapse
Affiliation(s)
- Kurtis J Swanson
- Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, United States
| | - Fahad Aziz
- Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, United States
| | - Neetika Garg
- Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, United States
| | - Maha Mohamed
- Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, United States
| | - Didier Mandelbrot
- Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, United States
| | - Arjang Djamali
- Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, United States
- Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, United States
| | - Sandesh Parajuli
- Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, United States
| |
Collapse
|
|
27
|
Kidney Perfusion as an Organ Quality Assessment Tool-Are We Counting Our Chickens Before They Have Hatched? J Clin Med 2020; 9:jcm9030879. [PMID: 32210197 PMCID: PMC7141526 DOI: 10.3390/jcm9030879] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2020] [Revised: 03/16/2020] [Accepted: 03/19/2020] [Indexed: 02/07/2023] Open
Abstract
The final decision to accept an organ for transplantation remains a subjective one. With “poor organ quality” commonly cited as a major reason for kidney discard, accurate, objective, and reliable quality assessment is essential. In an era of increasingly higher-risk deceased donor kidneys, the catch is to accept those where the risk–benefit scale will tip in the right direction. Currently available assessment tools, such as risk-scores predicting outcome and zero-time biopsy, perform unsatisfactory, and assessment options during static cold storage are limited. Kidney perfusion technologies are finding their way into clinical practice, and they bring a new opportunity to assess kidney graft viability and quality, both in hypothermic and normothermic conditions. We give an overview of the current understanding of kidney viability assessment during ex situ kidney perfusion. A pragmatic framework to approach viability assessment is proposed as an interplay of three different compartments: the nephron, the vascular compartment, and the immune compartment. Although many interesting ways to assess kidney injury and function during perfusion have been proposed, none have reached the stage where they can reliably predict posttransplant outcome. Larger well-designed studies and validation cohorts are needed to provide better guidance.
Collapse
|