The place of baseline biopsy histology
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Presentation at the Société Francophone Nephrology Dialysis Transplantation on October 12th in Nice, France
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The place of baseline biopsy histology
- 1. La biopsie du rein de donneur décédé permet une évaluation prédictive Maarten Naesens, MD PhD University Hospitals Leuven, Belgium
- 2. Who is involved in decisions of kidney graft allocation? Does your center perform implantation biopsies of kidney grafts? Who uses baseline biopsies for decisions on allocation?
- 4. Gaber L et al. Transplantation 1995
- 5. “In the US, biopsies are currently obtained in 50% of all deceased donor kidneys procured for transplantation and in nearly 85% of extended criteria donor (ECD) kidneys.” “About 40% of deceased donor kidneys and 45% ECD kidneys were discarded in 2012”. “In 37% of discarded kidneys, the decision to discard was based on histology reports.” Kasiske et al C J Am Soc Nephrol 2014 Wang et al Am J Transplant 2015 Performing day-0 biopsies for graft allocation leads to discard of organs
- 6. “Last year, 4,720 people died while waiting for kidney transplants in the United States. And yet, as in each of the last five years, more than 2,600 kidneys were recovered from deceased donors and then discarded without being transplanted.”
- 8. How?
- 9. Naesens M. Transplantation 2016
- 10. Naesens M. Transplantation 2016
- 11. Naesens M. Transplantation 2016
- 12. Naesens M. Transplantation 2016
- 13. The timing of the day-0 biopsy is relevant for its interpretation Naesens M. Transplantation 2016
- 14. The timing of the day-0 biopsy is relevant for its interpretation Use Procurement Pre-implantation Post-reperfusion Number of studies Limited Most studied Very limited Allocation ✔ ✗ ✗ Routine use Routine in US Not used in EU Sometimes in EU Not used Molecular evaluation Agonal phase Warm ischemia Cold ischemia preservation Full spectrum of IRI + early allo- immunity Risks ? No serious complications? Safe?
- 15. The timing of the day-0 biopsy is relevant for its interpretation Use Procurement Pre-implantation Post-reperfusion Number of studies Limited Most studied Very limited Allocation ✔ ✗ ✗ Routine use Routine in US Not used in EU Sometimes in EU Not used Molecular evaluation Agonal phase Warm ischemia Cold ischemia preservation Full spectrum of IRI + early allo- immunity Risks ? No serious complications? Safe?
- 16. The timing of the day-0 biopsy is relevant for its interpretation Use Procurement Pre-implantation Post-reperfusion Number of studies Limited Most studied Very limited Allocation ✔ ✗ ✗ Routine use Routine in US Not used in EU Sometimes in EU Not used Molecular evaluation Agonal phase Warm ischemia Cold ischemia preservation Full spectrum of IRI + early allo- immunity Risks ? No serious complications? Safe?
- 17. Frozen vs. paraffin-embedded tissue? Faster (allowing allocation) Standard stains complicated Less contrast Subtle lesions can be missed Artifacts (e.g. interstitial widening) Slower Less suitable for allocation Standard stains Good contrast Less artifacts
- 18. Experience and reproducibility Azancot et al Kidney Int 2013
- 19. Experience and reproducibility Azancot et al Kidney Int 2013
- 20. What?
- 21. Individual histological lesions in day 0 biopsies are scored according to Banff for post-transplant biopsies Arteriosclerosis Interstitial fibrosis+atrophy Arteriolar hyalinosis Glomerulosclerosis
- 22. Computerized morphometry has been suggested to overcome problems of reproducibility of semiquantitative Banff scores Munivenkatappa et al Am J Transplant 2008
- 23. Individual histological lesions in day 0 biopsies are scored according to Banff for post-transplant biopsies Chronic histological lesions are collinear Chronic histological lesions have cumulative impact
- 24. “CIV score”: ci + cv “Donor chronic damage score”: ci + cv + gs “MAPI score”: ah + periglomerular fibrosis + arterial wall-to-lumen ratio + scar + gs
- 25. “CIV score”: ci + cv “Donor chronic damage score”: ci + cv + gs “MAPI score”: ah + periglomerular fibrosis + arterial wall-to-lumen ratio + scar + gs
- 26. “CIV score”: ci + cv “Donor chronic damage score”: ci + cv + gs “MAPI score”: ah + periglomerular fibrosis + arterial wall-to-lumen ratio + scar + gs
- 27. “MAPI score” “Leuven Donor Risk Score”“Paris Composite Score” Munivenkatappa et al Am J Transplant 2008 Anglicheau et al Am J Transplant 2008 De Vusser et al J Am Soc Nephrol 2014 All validated composite scores associate with graft failure
- 28. Why?
- 29. Prediction of delayed graft function (DGF) Prediction of graft function Prediction of graft failure Kidney discard Dual kidney transplantation - Few studies - No robust associations - Several studies - Most show association with eGFR - Glomerulosclerosis?? Arteriosclerosis?? - Large registry studies: no association - Several single-center studies: association - Glomerulosclerosis?? IF/TA??
- 30. Transplanted, 81% Discarded, 19% Based on biopsy, 34% Not based on biopsy, 66% From Tanriover et al Am J Transplant 2014 (UNOS) Recovered kidneys
- 31. 1 - S p e c ific ity S e n s itiv ity% Id e n tity % R O C c u rv e : S c o re 2 (5 y e a r s u rv iv a l) G s + 3 IF T A + A g e 1 - S p e c ific ity Sensitivity 0 2 0 4 0 6 0 8 0 1 0 0 0 2 0 4 0 6 0 8 0 1 0 0 S e n s itiv ity% Id e n tity % p < 0 .0 0 0 1 A U C = 0 .8 1 G S + 3 IF T A + A g e T im e p o stT X g ra ft su rv iv a l ce n so re d fo r d e a th Percentsurvival 0 5 0 1 0 0 s c o re < 6 0 s c o re > 6 0 1 2 3 4 5 p < 0 ,0 0 0 1 "N u m b e r o f p a tie n ts a t ris k " 0 1 2 3 5 y e a r > 6 0 2 9 4 2 8 1 2 7 7 2 2 9 2 0 2 < 6 0 6 1 5 7 5 3 3 2 1 3 1 - S p e c ific ity 1 - S p e c ific ity R O C c u rv e : S c o re 2 (5 y e a r s u rv iv a l) G s + 3 IF T A + A g e 1 - S p e c ific ity Sensitivity 0 2 0 4 0 6 0 8 0 1 0 0 0 2 0 4 0 6 0 8 0 1 0 0 S e n s itiv ity% Id e n tity % p = 0 .0 0 2 A U C = 0 .6 7 R O C c u rv e : S c o re 2 (5 y e a r s u rv iv a l) G s + 3 IF T A + A g e 1 - S p e c ific ity Sensitivity 0 2 0 4 0 6 0 8 0 1 0 0 0 2 0 4 0 6 0 8 0 1 0 0 S e n s itiv ity% Id e n tity % p < 0 .0 0 0 1 A U C = 0 .8 1 Test cohort Validation cohort De Vusser et al J Am Soc Nephrol 2013 Donor risk scores associate with graft failure but are insufficient to guide kidney discard Worse than remaining in dialysis??
- 32. ? Kidney discard Kidney transplantation
- 33. Remuzzi et al New Engl J Med 2006 Day 0 histology has been used for decisions on dual kidney transplantation, leading to better outcome
- 34. Gandolfini et al Am J Transplant 2014 Two single transplantations = - Two patients with worse prognosis One dual transplantation= - One patient with good prognosis - Another patient still in dialysis Worse than remaining in dialysis?? Dual transplantation programs represent a fundamental choice!
- 35. De Vusser et al J Am Soc Nephrol 2013 The Pirani score (and also all other scores) associates significantly with graft outcome, but remains a poor predictor
- 36. Prediction of delayed graft function Prediction of graft function Prediction of graft failure Kidney discard Dual kidney transplantation Baseline for comparison with post-transplant histology Research on ischemia- reperfusion injury, machine perfusion, aging etc.
- 37. Nankivell et al. Transplantation 2004 “Delta analyses” could become very valuable for clinical research in transplantation, starting from day 0 Naesens et al. J Am Soc Nephrol 2009
- 39. Telomere length Presence of severe arteriosclerosis 5 y protocol biopsy DeltaCalenderage-Biologicalage CV 0-1 CV 2-3 -4 -2 0 2 4 p = 0.001 0 20 40 60 80 0.5 1.0 1.5 Donor Calender age (Median 47) IntrarenalTelomerelength(T/S) 5yProtocolBiopsy(Median0.94) CV =2-3 CV = 0-1 1 2 3 4 (13%) (26%) (43%) (28%)
- 40. Genome-wide DNA methylation changes upon aging
- 41. Genome-wide DNA methylation changes upon aging
- 43. Who uses baseline biopsies for decisions on allocation? Who will continue to use baseline biopsies for decisions on allocation?
- 44. La biopsie du rein de donneur décédé permet une évaluation prédictive Maarten Naesens, MD PhD University Hospitals Leuven, Belgium
- 45. La biopsie du rein de donneur décédé ne permet pas une évaluation prédictive pour le moment Maarten Naesens, MD PhD University Hospitals Leuven, Belgium
Editor's Notes
- This title was given to me by the organizers of this congress. I did not choose it myself, and I have to say that the title seems to give me somewhat limited freedom of speech and free thinking. In this presentation, I will discuss with you what I really think about this statement.
- I admire those of you that are here without being involved in this clinical problem. To sit here, in beautiful Nice, with a presentation that does not affect you. Either the rest of the program this morning is uninteresting, or it must be raining outside. Of course, Hopital Necker uses this. I suppose they do everything that is possible, including this. But the fact that so few of you actually use biopsies for decision-making on kidney allocation, is very different than current practice in the US.
- It all started with this publicaiton by the Memphis, Tenesse, US group 22 years ago.
- Very different from the title I was given for this presentation
- We will evaluate the How What Why Of baseline biopsy evaluation
- You could ask, as nephrologist, is it relevant to know how the surgeons perform the biopsy? In fact, despite the fact that it is ALWAYS important to know and control what surgeons are doing, it is especially relevant also in this case. Surgeons like to use knifes, and most often, this is how they perform the day-0 biopsy.
- Few studies on concorddance. We have shown that frozen is OK, provided that the biopsy is read by a very experienced pathologist, given the subtlety of lesions and artifacts
- To partly overcome issues of reproducibility and experience, the Banff working group on implantation biopsy histology recently suggested that digital slides are equivalent to glass slides for evaluation of zero-time kidney graft biopsies.25 Further analysis is necessary, but it may be unnecessary to have a trained on-call pathologist at every transplant center. A more centralized and more practical organization could be feasible in the future.
- We will evaluate the How What Why Of baseline biopsy evaluation
- Munivenkatappa;
- Only the coloured ones were statistically modeled and sometimes independently validated.
- All validated composite scores associate with graft failure
- We will evaluate the How What Why Of baseline biopsy evaluation
- Unclear which lesions predict outcome: not robust at all. We cannot just use this!!
- Much lower in EU and Australia. Not clear what the contribution of histology to this is: At first sight, based on these data, one could suggest that performing procurement biopsies is the cause of high rates of kidney discard in the United States. However, these associations do not prove any causality, and caution is warranted. Ambiguous kidneys will be biopsied more often, and will more often show "bad" histology, whatever this might be. Therefore, it is not clearwhat is the relative contribution of procurement biopsies in high rates of kidney discard, as (financial) risk aversion is also inherent to the US allocation system, partly associated with the use of graft and patient survival rates as center benchmark for reimbursement.
- Kaplan Meier illustrates that the “ideal” cut-off leads to identification of a group with worse outcome, but still quite acceptable long-term graft survival. We did not discard these kidneys, and should not have discarded these basd on the “bad” histology… In addition, whether the 5-year graft survival statistic reflects clinical benefit (improved patient survival, quality of life, and so on), in comparison with longer waiting time in dialysis if high score kidneys would have been discarded, was not evaluated in this study. Much more data are necessary, and a large-scale multicenter prospective study should be set up, to provide insight in which clinical/histological/biochemical parameters are necessary or sufficient for decisions on kidney acceptance or discard.89 In the meantime, clinicians should remain very reluctant to use simple histological prejudices for this purpose.
- In discussing the prediction of kidney transplant outcome by baseline histology and the potential for kidney discard, you should not compare the outcome of bad histology with the outcome of good histology. You should compare discarding a kidney, thus remaining in dialysis, with being transplanted with a bad kidney. Such studies do not exist! And while we have no data, we should therefore be very reluctant to discard kidneys based on
- Kidneys with a score equal or above 4 were transplanted bilaterally, whereas kidneys with lower scores were transplanted as single grafts.
- And we lack the data at the moment!! So no real scientific underpinning of dual kidney transplantation practice!
- The Pirani score associates significantly with graft outcome, but remains a poor predictor
- Becoming more important with increasing donor age and donor comorbidities. Perhaps less important clinically, because of sampling error. Leuven: 20% of baseline biopsies already IFTA. Very important to know this, otherwise we could think that at 3 months, 40% have de novo IFTA, which is clearly not the case. Also for intervention studies, e.g. to halt fibrosis processes in transplantation, it will be extremely important to have the baseline value.
- Start with short questionaire: Who of you is involved in decisions on transplant acceptance or discard? Who of you performs baseline biopsies? Who uses these baseline biopsies to make clinical decisions?
- At least not at this moment, perhaps the molecules will change this in the future