Maximising Kidney Preservation in Transplantation Results of the European MP-Trial Rutger J Ploeg  MD PhD FRCS Nuffield De...
The Easy Way or Best Method ?
European Machine Preservation Trial MP vs. CS in Kidney Transplantation in collaboration with Eurotransplant MP-trial incl...
Rutger J Ploeg - Coordinating PI Cyril Moers - Secretary Hugo Maathuis - RPC Liaison Jaap Homan v/d Heide - Member Ernst v...
Methods – Donor Inclusion Regions
Endpoints <ul><li>Primary endpoint:  DGF  (dial. req. in 1st wk post-Tx) </li></ul><ul><li>Secondary endpoints </li></ul><...
Methods – Donor Inclusions <ul><li>All deceased donors  ≥16 yrs </li></ul><ul><ul><li>DBD and DCD (cat. III & IV, only in ...
Team of  “ Perfusionists ”
Results – Demographics Variable MP arm median  (range) CS arm median  (range) p-value DONOR N = 336 Donor age (yrs) 51  (1...
Results – Primary Endpoint N = 672 recipients total 2-sided McNemar test Moers et  al. NEJM 2009 Variable MP arm CS arm p-...
Results – Logistic Regression (DGF) N = 672 recipients total * p  ≤ 0.05 Moers et  al. NEJM 2009 Variable OR  (95% CI) p-v...
Results – Logistic Regression (DGF) N = 672 recipients total * p  ≤ 0.05 Moers et  al. NEJM 2009 Variable OR  (95% CI) p-v...
Serum Creatinine @ day 1 - 14 AUC MP < AUC CS; p  = 0.001 Moers et  al. NEJM 2009
Results – One Year Graft Survival MP and no DGF CS and no DGF MP and DGF CS and DGF p=0.04 (logrank test) 12% Moers et  al...
Summary <ul><li>MP reduced risk DGF with an OR of 0.62 vs. CS </li></ul><ul><li>MP reduced the duration of DGF </li></ul><...
<ul><li>To find a DGF reduction of 20% in DCD ktx </li></ul><ul><li>Based on a presumed 70% DGF rate </li></ul><ul><li>Wit...
Results: Logistic regression (DGF) Jochmans et  al. Ann Surg 2010 Variable Odds Ratio (95% CI) p-value MP vs. CS Cold Isch...
ECD RCT: MP vs. CS 1 y Graft Survival (N= 182) Treckmann et  al. Transplant Int 2011
The European Multicenter Trial on Kidney Preservation on behalf of the Machine Preservation Trial Scientific Steering Comm...
Association between RR and DGF at different time points Jochmans et  al. AJT 2011 30 min P=0.056 10 min P=0.042 1 h P=0.17...
“ Best ”  threshold value / discriminative capacity @ end of MP = 0.28  <ul><li>if RR @end ≥ 0.28, 40% chance kidney suffe...
Machine Preservation Trial MP vs. CS in Kidney Transplantation in collaboration with Eurotransplant The European Multicent...
Results  – DGF p < 0.0005 p < 0.0005
Results  – Donor Type   p < 0.0005 p = 0.001
Machine Preservation Trial MP vs. CS in Kidney Transplantation in collaboration with Eurotransplant The European Multicent...
Economic Evaluation  –  ICER Costs MP – Costs CS Effect MP – Effect CS MP better but more expensive MP better and less exp...
<ul><li>Unit Costs </li></ul><ul><li>Hemodialysis per day* € 465 </li></ul><ul><li>Peritoneal dialysis per day € 109 </li>...
Average costs in 1st year post-Tx   MP   CS Dialysis post-Tx  (HD/CAPD) € 2,773 € 4,354 Organ preservation   € 842   € 167...
Economic Evaluation – Markov Model p = … p = … p = … p = … p = … p = …
<ul><li>Results of long term model </li></ul><ul><li>N=336 recipients per arm, 672 total </li></ul><ul><li>Simulation up t...
3 Year Graft Survival – DGF vs. no DGF
<ul><li>Machine perfusion </li></ul><ul><ul><li>improves short term outcome </li></ul></ul><ul><ul><li>improves long term ...
Thanks to all perfusionists and participating centers ! Austria Landeskrankenhaus Graz Universitätsklinik für Chirurgie In...
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Rutger Ploeg - The Netherlands - Tuesday 29 - Use of Perfusion Machines or Cold Storage

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  • Any difference between IF versus DGf versus PNF? PNF curve not on top of DGf curve as we would have expected! Cave only 6 PNF cases!!! ( 1 PNF Case cata not downloaded) Remember that for this Trial; we have only used kidneys which had already been accepted for transplantation based on donor characteristics, no matter what preservation method. This might be different for more extended criteria kidneys for which evolution on MP might be taken into account during the decision making proces. 2 reported cases to safety commitee: have been tranbsplanted : 1 PNF, 1 ??? Contralateral also perfused and OK: have been excluded from trial !!!
  • The incremental cost-effectiveness was expressed as the ratio of the difference in costs of both treatments over the difference in effects of both treatments, in this case the difference in graft survival after 1 year
  • This slide shows the most important unit costs used. Costs of hemodialysis were based on data from the NECOSAD study as reported by Merkus and De Wit. For peritoneal dialysis tariffs were used. Costs of complications were based on expert opinions regarding procedures performed. In case of DGF costs of a renogram, a renal ultrasound and a renal biopsy were added. In case of primary non-function, costs of graft removal were also included. For costs of hospital admission, Dutch standard prices were used.
  • Here you see the effects of imputation of costs of dialysis. Of the 23 subjects with PNF, 15 had missing data regarding dialysis. These caused average costs of 792 Euro in the MP arm and 1839 Euro in the CS arm. Of the subjects with graft failure other than PNF, 16 had missing data, leading to costs of approximately 100 Euro for MP and 1500 for CS. After addition of actual and imputed costs of dialysis, there is a big difference of about 1800 Euro in favour of MP. As a result, addition of the other unchanged cost items of preservation and graft failure management (ultrasound, biopsy etc) leaves a cost difference of 1250 Euro in favour of MP. Due to the fact that data regarding readmission were missing in a number of cases, the overall total cannot be calculated for all cases. For this reason, the last three numbers in both columns do not add up. The readmissions appeared to be missing especially in cases with PNF, causing the cost difference to diminish. However, the result is still a cost difference of almost 500 Euro.
  • Here you see the effects of imputation of costs of dialysis. Of the 23 subjects with PNF, 15 had missing data regarding dialysis. These caused average costs of 792 Euro in the MP arm and 1839 Euro in the CS arm. Of the subjects with graft failure other than PNF, 16 had missing data, leading to costs of approximately 100 Euro for MP and 1500 for CS. After addition of actual and imputed costs of dialysis, there is a big difference of about 1800 Euro in favour of MP. As a result, addition of the other unchanged cost items of preservation and graft failure management (ultrasound, biopsy etc) leaves a cost difference of 1250 Euro in favour of MP. Due to the fact that data regarding readmission were missing in a number of cases, the overall total cannot be calculated for all cases. For this reason, the last three numbers in both columns do not add up. The readmissions appeared to be missing especially in cases with PNF, causing the cost difference to diminish. However, the result is still a cost difference of almost 500 Euro.
  • Rutger Ploeg - The Netherlands - Tuesday 29 - Use of Perfusion Machines or Cold Storage

    1. 1. Maximising Kidney Preservation in Transplantation Results of the European MP-Trial Rutger J Ploeg MD PhD FRCS Nuffield Department of Surgical Sciences University of Oxford, UK
    2. 2. The Easy Way or Best Method ?
    3. 3. European Machine Preservation Trial MP vs. CS in Kidney Transplantation in collaboration with Eurotransplant MP-trial included 3 separate RCTs: Overall Study, DCD Study, ECD Study
    4. 4. Rutger J Ploeg - Coordinating PI Cyril Moers - Secretary Hugo Maathuis - RPC Liaison Jaap Homan v/d Heide - Member Ernst van Heurn - Member Andreas Paul - Principal Investigator Jürgen Treckmann - Member Jacques Pirenne - Principal Investigator Frank van Gelder - Member Jean-Paul Squifflet - Member Scientific Steering Committee Eurotransplant Arie Oosterlee - Director Axel Rahmel - Medical Director Jacqueline Smits - Statistician Margitta van Kasterop - Data Manager Deutsche Stiftung Organtransplantation Günter Kirste - Chairman Ulrike Wirges - Director NRW Central Trial Assistance David Kravitz - CEO Luanne Rodgers - Director Marketing & Sales Peter de Muylder - Director Perfusion Services Trial Sponsor Groningen, The Netherlands Henri Leuvenink - Coordinator Essen, NRW - Germany Bogdan Napieralski - Coordinator Leuven, Belgium Frank van Gelder - Coordinator Regional Perfusion Centres Tasks & Coordination
    5. 5. Methods – Donor Inclusion Regions
    6. 6. Endpoints <ul><li>Primary endpoint: DGF (dial. req. in 1st wk post-Tx) </li></ul><ul><li>Secondary endpoints </li></ul><ul><ul><li>functional DGF ( f -DGF) </li></ul></ul><ul><ul><li>PNF </li></ul></ul><ul><ul><li>serum creatinine & clearance after Tx </li></ul></ul><ul><ul><li>duration of DGF & hospital stay </li></ul></ul><ul><ul><li>acute rejection </li></ul></ul><ul><ul><li>patient and graft survival @ 1, 3, 6, 12 months </li></ul></ul>
    7. 7. Methods – Donor Inclusions <ul><li>All deceased donors ≥16 yrs </li></ul><ul><ul><li>DBD and DCD (cat. III & IV, only in NL and B) </li></ul></ul><ul><li>Strictly paired design </li></ul><ul><ul><li>one kidney randomized to MP, contralateral kidney CS </li></ul></ul><ul><ul><li>randomization by Eurotransplant </li></ul></ul><ul><ul><li>mandatory both kidneys transplanted </li></ul></ul><ul><ul><li>mandatory Tx into 2 different recipients </li></ul></ul><ul><ul><li>pair excluded if combined organ Tx </li></ul></ul>APPROVED
    8. 8. Team of “ Perfusionists ”
    9. 9. Results – Demographics Variable MP arm median (range) CS arm median (range) p-value DONOR N = 336 Donor age (yrs) 51 (16-81) - Donor type (DBD / DCD) 294 / 42 - RECIPIENT N = 336 N = 336 Age (yrs) 53 (11-79) 52 (2-79) 0.2 Pre-Tx dialysis duration (yrs) 4.5 (0.15-18) 4.4 (0.19-24) 0.6 Previous transplants 23% 21% 0.3 PRA (0-5% / 6-84% / >84%) 297 / 35 / 4 304 / 29 / 3 0.7 TRANSPLANT N = 336 N = 336 HLA mismatches (% of 0 MM) 16% 15% 0.9 Cold Ischemic Time (hrs) 15.0 (3.5-26.3) 15.0 (2.5-29.7) 0.3
    10. 10. Results – Primary Endpoint N = 672 recipients total 2-sided McNemar test Moers et al. NEJM 2009 Variable MP arm CS arm p-value DGF 20.8% (70 / 336) 26.5% (89 / 336) 0.046
    11. 11. Results – Logistic Regression (DGF) N = 672 recipients total * p ≤ 0.05 Moers et al. NEJM 2009 Variable OR (95% CI) p-value MP vs. CS* 0.62 (0.42 - 0.92) 0.02 Most recent PRA (%) 1.00 (0.99 - 1.02) 0.53 Recipient age (yr) 1.01 (0.99 - 1.03) 0.19 Donor age (yr)* 1.02 (1.00 - 1.05) 0.04 ECD vs. SCD 1.04 (0.55 – 1.97) 0.91 Cold ischemic time (hrs)* 1.07 (1.03 - 1.12) 0.002 Duration of pre-Tx dial. (yr)* 1.08 (1.01 - 1.16) 0.04 Nr. of HLA mismatches 1.12 (0.96 - 1.30) 0.16 Re-Tx vs. 1st Tx* 2.08 (1.46 - 2.95) <0.001 DCD vs. DBD* 9.68 (5.44 - 17.2) <0.001
    12. 12. Results – Logistic Regression (DGF) N = 672 recipients total * p ≤ 0.05 Moers et al. NEJM 2009 Variable OR (95% CI) p-value MP vs. CS* 0.62 (0.42 - 0.92) 0.02 Most recent PRA (%) 1.00 (0.99 - 1.02) 0.53 Recipient age (yr) 1.01 (0.99 - 1.03) 0.19 Donor age (yr)* 1.02 (1.00 - 1.05) 0.04 ECD vs. SCD 1.04 (0.55 – 1.97) 0.91 Cold ischemic time (hrs)* 1.07 (1.03 - 1.12) 0.002 Duration of pre-Tx dial. (yr)* 1.08 (1.01 - 1.16) 0.04 Nr. of HLA mismatches 1.12 (0.96 - 1.30) 0.16 Re-Tx vs. 1st Tx* 2.08 (1.46 - 2.95) <0.001 DCD vs. DBD* 9.68 (5.44 - 17.2) <0.001
    13. 13. Serum Creatinine @ day 1 - 14 AUC MP < AUC CS; p = 0.001 Moers et al. NEJM 2009
    14. 14. Results – One Year Graft Survival MP and no DGF CS and no DGF MP and DGF CS and DGF p=0.04 (logrank test) 12% Moers et al. NEJM 2009
    15. 15. Summary <ul><li>MP reduced risk DGF with an OR of 0.62 vs. CS </li></ul><ul><li>MP reduced the duration of DGF </li></ul><ul><li>One year graft survival was better after MP vs. CS </li></ul><ul><li>MP protected against graft loss with a HR of 0.39 </li></ul><ul><li>DGF had a negative effect on patient survival, but only in the CS group </li></ul><ul><li>In recipients with DGF, 1 y GS was 12% better if kidney was machine perfused </li></ul>
    16. 16. <ul><li>To find a DGF reduction of 20% in DCD ktx </li></ul><ul><li>Based on a presumed 70% DGF rate </li></ul><ul><li>With a power of 0.8 and alfa of 0.05 </li></ul><ul><li>160 kidney tx to be included in the study </li></ul>DCD RCT: MP vs CS Design & Results of Primary Endpoint (DGF) N = 164 enrolled in RCT Jochmans et al. Ann Surg 2010 Variable MP arm CS arm p-value DGF 54% 70% 0.02
    17. 17. Results: Logistic regression (DGF) Jochmans et al. Ann Surg 2010 Variable Odds Ratio (95% CI) p-value MP vs. CS Cold Ischemia Time HLA mismatch Recent PRA Recipient age Donor age Re-/ first tx Length pre-tx dialysis 0.476 (0.239 - 0.949) 1.118 (1.028- 1.215) 1.073 (0.761- 1.514) 1.032 (0.992- 1.074) 1.031 (1.000- 1.062 ) 1.025 (0.997- 1.055) 1.051 (0.497- 2.225) 1.085 (0.927-1.271) 0.035 0.009 0.688 0.123 0.048 0.083 0.897 0.310
    18. 18. ECD RCT: MP vs. CS 1 y Graft Survival (N= 182) Treckmann et al. Transplant Int 2011
    19. 19. The European Multicenter Trial on Kidney Preservation on behalf of the Machine Preservation Trial Scientific Steering Committee RENAL RESISTANCE DURING MACHINE PERFUSION IS A RISK FACTOR FOR DELAYED GRAFT FUNCTION AND POORER GRAFT SURVIVAL Jochmans et al. AJT 2011
    20. 20. Association between RR and DGF at different time points Jochmans et al. AJT 2011 30 min P=0.056 10 min P=0.042 1 h P=0.175 4 h P=0.025 END P=0.021 2 h P=0. 021 Perfusion time (hrs) End-MP
    21. 21. “ Best ” threshold value / discriminative capacity @ end of MP = 0.28 <ul><li>if RR @end ≥ 0.28, 40% chance kidney suffers DGF </li></ul><ul><li>if RR @end < 0.28, 81% chance kidney will function immediately </li></ul>DGF IF RR @ end≥0.28 12 True Positive 18 False Positive Positive Predictive Value TP/TP+FP (40%) RR @ end<0.28 58 False Negative 248 True Negative Negative Predictive Value TN/TN+FN (81%) Sensitivity TP/TP+FN 17% Specificity TN/FP+TN 93%
    22. 22. Machine Preservation Trial MP vs. CS in Kidney Transplantation in collaboration with Eurotransplant The European Multicenter Trial on Kidney Preservation The Value of Machine Perfusion Perfusate Biomarkers GST and H-FABP for Predicting Outcome after Kidney Transplantation
    23. 23. Results – DGF p < 0.0005 p < 0.0005
    24. 24. Results – Donor Type p < 0.0005 p = 0.001
    25. 25. Machine Preservation Trial MP vs. CS in Kidney Transplantation in collaboration with Eurotransplant The European Multicenter Trial on Kidney Preservation Cost Effectiveness of Hypothermic Machine Perfusion versus Static Cold Storage Rutger J. Ploeg, MD PhD on behalf of the Machine Preservation Trial Scientific Steering Committee
    26. 26. Economic Evaluation – ICER Costs MP – Costs CS Effect MP – Effect CS MP better but more expensive MP better and less expensive CS better and less expensive CS better but more expensive + + - -
    27. 27. <ul><li>Unit Costs </li></ul><ul><li>Hemodialysis per day* € 465 </li></ul><ul><li>Peritoneal dialysis per day € 109 </li></ul><ul><li>Renogram € 218 </li></ul><ul><li>Renal ultrasound € 62 </li></ul><ul><li>Renal biopsy (excl. pathology) € 280 </li></ul><ul><li>Graft removal (nephrectomy) € 1,464 </li></ul><ul><li>Hospital admission per day € 505 </li></ul><ul><li>*Merkus et al., NDT 1999, De Wit et al., HealthPolicy 1998 </li></ul>Economic Evaluation – Methods
    28. 28. Average costs in 1st year post-Tx MP CS Dialysis post-Tx (HD/CAPD) € 2,773 € 4,354 Organ preservation € 842 € 167 Early dysfunction (DGF/PNF) € 147 € 218 Hospital readmission € 2,062 € 2,264 Total costs per recipient € 5,824 € 7,003 Total costs N=336 / arm € 1,956,864 € 2,353,008 Savings due to MP in 1st year: € 396,144 Economic Evaluation – Results
    29. 29. Economic Evaluation – Markov Model p = … p = … p = … p = … p = … p = …
    30. 30. <ul><li>Results of long term model </li></ul><ul><li>N=336 recipients per arm, 672 total </li></ul><ul><li>Simulation up to 20 years post-Tx </li></ul><ul><li> MP CS MP – CS </li></ul><ul><li>Total costs € 66,620,514 € 69,399,362 – € 2,778,848 </li></ul><ul><li>Total life years 3,238 3,135 103 </li></ul><ul><li>Total QALYs 2,335 2,293 42 </li></ul><ul><li>Functional grafts 71 56 15 </li></ul>Economic Evaluation – Results
    31. 31. 3 Year Graft Survival – DGF vs. no DGF
    32. 32. <ul><li>Machine perfusion </li></ul><ul><ul><li>improves short term outcome </li></ul></ul><ul><ul><li>improves long term outcome </li></ul></ul><ul><ul><li>reduces short and long term costs </li></ul></ul><ul><li>MP is cost effective versus CS </li></ul>Economic Evaluation – Conclusion
    33. 33. Thanks to all perfusionists and participating centers ! Austria Landeskrankenhaus Graz Universitätsklinik für Chirurgie Innsbruck Allgemeines Krankenhaus der Stadt Linz Allgemeines Krankenhaus Wien Belgium Universitair Ziekenhuis Antwerpen Universitair Ziekenhuis Brussel Hôpital Erasme Bruxelles Cliniques Universitaires St. Luc Bruxelles Universitair Ziekenhuis Gent Universitaire Ziekenhuizen Leuven Centre Hospitalier Universitaire Liège Luxemburg Centre Hospitalier de Luxembourg The Netherlands Academisch Medisch Centrum Amsterdam Universitair Medisch Centrum Groningen Leids Universitair Medisch Centrum Academisch Ziekenhuis Maastricht UMC St. Radboud Nijmegen Erasmus Medisch Centrum Rotterdam Sophia Kinderziekenhuis Rotterdam Universitair Medisch Centrum Utrecht Wilhelmina Kinderziekenhuis Utrecht Slovenia University Medical Center Ljubljana Germany Universitätsklinikum Aachen Zentralklinikum Augsburg Charité Berlin - Campus Benjamin Franklin Universitätsklinikum Charité Berlin Knappschaftskrankenhaus Bochum Universitätsklinik Bonn Zentralkrankenhaus Bremen Universitätsklinikum Carl Gustav Carus Dresden Universitätsklinikum Düsseldorf Universitätskrankenhaus Erlangen-Nürnberg Universitätsklinikum Essen Klinikum der JW Goethe Universität Frankfurt Klinikum der AL Universität Freiburg Universitätsklinikum Halle Universitätskrankenhaus Eppendorf Hamburg Nephrologisches Zentrum Niedersachsen Medizinische Hochschule Hannover Klinikum der Universität Heidelberg Universitätsklinik des Saarlandes Homburg/Saar Medizinische Fakultät/Klinikum Jena Westpfalz-Klinikum Kaiserslautern Universitätsklinikum Schleswig-Holstein Kiel Universitäts Kinderklinik Köln Medizinische Universitätsklinik Köln Städtische Krankenanstalten Köln Universitätskrankenhaus Leipzig Universitätsklinikum Schleswig-Holstein Lübeck Klinikum der Joh. Gutenberg Universität Mainz Klinikum der Stadt Mannheim Klinikum Lahnberge Marburg/Lahn Klinikum Rechts der Isar München Klinikum Grosshadern München Westfälische WU Klinikum Münster Medizinische Fakultät Rostock Katharinenhospital Stuttgart Chirurgische Universitätsklinik Tübingen Universitätskrankenhaus Ulm Klinikum der Bayerischen J-M-U Würzburg Perfusionists Alexandra de Rotte Agnes de Boer Anton Hosman Anton Romeijn Bas Lier Christiaan Roosendaal Edwin Dierselhuis Eva Kingma Elsbeth Witte Gysbert de Vries Hanneke Jansen Hilde Oosterhuis Ibrahim Abou Habaga Joanne Sierink Leo Boneschansker Jan Willem Buikema Janna Munster Judith Wind Lotte van Hessem Laura van Nunspeet Leonie van den Heuvel Lieske Wierenga Merel Lambregts Madeleine Stakelbeek Marije Mellema Marjon Wiegman Melvin Kilsdonk Merel Hellemons Miranda Bijvoet Nienke Luiting Pieter-Jan Vlaar Jeannette Bronkhorst Rinske Grond Robert Jan Sprong Susan Schipperijn Thijs Stege Lam Trang Willemein Jager Wouter Stomp Joost Sprakel Elsbeth de Vries Jenneke Hamminga Nirvana Kornmann Bert Theunis Jonathan Vercruysse Tom Rosseel Melanie Wandelt Daniel Lochmann Britta Ganske Anja Gallinat Ines Thies Janina Siebe Stephanie Lehnick Tobias Schwert Michael Schlusen Michael Drescher Dietmar Reimer Frank Heisterkamp

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