A student prepared presentation on kidney preservation methods and current journal reviews.

1. JOURNAL REVIEW
KIDNEY PRESERVATION:
METHODS AND TRENDS
Keith Tsui, Daniel Wong, Kenneth Kwok, Patrick Tsai, Bernard Yung

2. Outline
• History of kidney preservation
• Static Cold Storage (SCS)
• Hypothermic Machine Perfusion (HMP)
• SCS vs HMC
• Conclusion

3. Organ transplantation
• Major advances in latter half of the 20th century
• Only curative treatment for end-stage organ
failure in many cases

4. Deceased Donor Types
• Donation after brain death (DBD)
• Standard criteria donors (SCD)
 Under 50 years old
• Expanded criteria donors (ECD)
 Over 60 years old OR
 Aged 50-59 years old with at least 2 of the following:
• Hypertension
• Cerebrovascular cause of brain death
• Pre-retrieval serum creatinine level > 1.5 mg/dL (132.6umol/L)
• Donation after circulatory death (DCD)
Metzger RA, Delmonico FL, Feng S, et al. Expanded criteria donors for kidney transplantation. Am J Transplant. 2003

5. Kidney transplant
1. Retrieving the organ from donor
2. Preserving the kidney
3. Implantation in the recipient

6. Why organ preservation?
 Preservation buys “time”
 Good organ preservation is a major
determinant of graft outcome after
re-vascularisation
Organ Preservation: Current Concepts and New Strategies for the Next Decade;
Transfus Med Hemother. Apr 2011

7. Methods of Organ Preservation
• Static Cold Storage (SCS)
• Dynamic Preservation
• Hypothermic machine perfusion (HMP)
• Normothermic machine perfusion
• Oxygen persufflation

8. KIDNEY
PRESERVATION
Static Cold Storage

9. Kidney Preservation
Warm
ischaemic time
in donor
Cold
ischaemic time
Warm
ischaemic time
in recipient

10. Static Cold Storage (SCS)
• First used in 1969, with Collins solution
• Mainstay method of preservation for kidneys,
livers, and others
• Tackle problems during cold ischaemic time
preservation possible up to 24 hours or longer
“Preservation Solutions for Static Cold Storage of Kidney Allografts: A Systematic Review
and Meta-Analysis”, American Journal of Transplantation 2012

11. Static Cold Storage (SCS)
•Wash with sterile hypothermic preservation
solution
• Kidney core temperature  0-4oC
• Store in ice water
Image source: St. Louis Public Radio

12. In ischaemic condition…
No Oxygen
Intracellular ATP depletion
Impaired Na/K ATPase
Passive inflow of Na
Water influx
Cell swelling and
damage
Anaerobic respiration
Lactic acid builds up
Activate intracellular enzymes
Lysosomal damage
Na/Ca exchange
Build up of
intracellular Ca
“Kidney Preservation: Review of Present and Future Perspective”, Transplantation Proceedings 2013

13. Principles used in SCS
1. Hypothermia decrease kinetics of metabolic
activities
2. Specific solutions preserve intracellular
environment in the absence of Na+/K+ pumps
3. High osmolarity in solutions reduce cell
swelling
4. Remove free radicals
“Preservation methods for kidney and liver”, Organogenesis 2009

14. Advantages of SCS
• Cheaper
- 1L UW solution:
£116 (~HKD$1500)
- LifePort kidney transporter x1:
£10,700 (~HKD$135,000)
+ other costs
Nice Guideline 2010
• Technically easier

15. Disadvantages of SCS
• No standardised parameters to evaluate:
1. organ viability
2. ischaemic damage
 predictors of post-transplant outcomes

16. KIDNEY
PRESERVATION
The Solutions

17. EC, Eurocollins
UW, University of Wisconsin
HTK, histidine-tryptophan-ketoglutarate;

18. Euro-Collins solution
•Phosphate - as pH buffer
•Glucose - as osmotic agent
Preservation methods for kidney and liver; Organogenesis. 2009

19. EC, Eurocollins
UW, University of Wisconsin
HTK, histidine-tryptophan-ketoglutarate;

20. UW solution
• Cell impermeant agents (lactobionic acid,
raffinose, hydroxyethyl starch)
• prevent the cells from swelling during cold ischemic
storage
• Glutathione and adenosine
• stimulate recovery of normal metabolism upon
reperfusion
Organ Preservation; Annual Review of Medicine; Vol. 46

21. EC, Eurocollins
UW, University of Wisconsin
HTK, histidine-tryptophan-ketoglutarate;

22. Histidine-Tryptophane-Ketoglutarate
(HTK)**
• Histidine – as potent buffer
•Tryptophan – as membrane stabilizer and
anti-oxidant
• Ketoglutarate – improve ATP production
during reperfusion

23. KIDNEY
PRESERVATION
Machine Perfusion

24. Original method of preservation
• Replaced by SCS due to
development of
preservation solutions as a
cheaper alternative
Photo from Kidney Transplant: Principles and Practice

25. Resurgence of interest
• Changes in donor pool
• US
• ECDs increased 36% between 1999 and 2005
• 22% of kidneys transplanted in 2009
• DCD accounted for 13% of donors
United States Organ Transplantation OPTN & SRTR Annual Data Report 2010
• UK
• DCD kidneys in UK increased from 3% to 32% between
2000 and 2009
Summers DM, Johnson RJ, Allen J, et al. Analysis of factors that affect outcome after transplantation
of kidneys donated after cardiac death in the UK: a cohort study. Lancet 2010

26. Machine Perfusion
• Solutions
• Eurocollins solution, UW solution, HTK solution,
hyperosmolar citrate solution, Celsior solution, Institute
Georges Lopez-1 solution
• Hypothermic perfusion
• Waters MOX DCM-100
• UP-100
• LifePort Kidney Transporter
• Kidney assist
• Normothermic perfusion
• POPS system

27. Basic design of a perfusion machine
Waters MOX DCM-100

28. Hypothermic perfusion
machine
Normothermic perfusion
machine

30. Cost effective?
•LifePort Kidney transporter
• Cost savings = $86 750 per life-year
gained
• Cost utility ratio was minus $496 223 per
quality-adjusted life-year (QALY) gained
Cost-Effectiveness of Hypothermic Machine Preservation Versus Static Cold Storage in
Renal Transplantation; H Groen; American journal of transplantation 2012

31. Not inferior or even better?
• No difference in primary non-function, acute
rejection, long-term renal function or patient
survival
Systematic review and meta-analysis of hypothermic machine
perfusion versus static cold storage of kidney allografts on
transplant outcomes; J. M. O’Callaghan; Transplantation 2012
• Decreased rates of DGF
To Pump or Not to Pump: A Comparison of Machine
Perfusion vs Cold Storage for Deceased Donor Kidney
Transplantation; Robert M Cannon; J Am Coll Surg 2013

32. Static Cold Storage
vs
Hypothermic Machine Perfusion

33. Study end points
• Delayed graft function (DGF)
• Requirement for dialysis during the first week after
transplantation
• Primary Non-Function (PNF)
• Permanent lack of function of allograft from the time of
transplantation
• Graft survival/ failure
• Censored at the time of death

34. SCS vs HMP
• International randomized controlled trial with 336 donors

35. Results
• Delayed graft function
• significantly reduced risk of DGF (adjusted odds ratio,
0.57, p=0.01)
• Primary Non-Function
• More than 2 times higher in SCS but not significant
(4.8% vs 2.1%, p=0.08)
• Graft survival/ failure
• Three-year allograft survival superior in MP group (91%
vs 87%, hazard ratio, 0.60 p=0.04)

36. ECD Subgroup analysis
• Expanded criteria donors (94 out of 336) had a
significant three-year graft survival (86% vs 76%;
adjusted hazard ratio, 0.38; p=0.01)
• Another RCT with 91 ECDs had similar results:
• significantly reduced the risk of DGF (29.7% vs 22%,
OR 0.460, P = 0.047).
• incidence of nonfunction in the CS group (12%) was
four times higher than in the MP group (3%) (P = 0.04).
• One-year graft survival was significantly higher in
machine perfused kidneys (92.3% vs. 80.2%, P = 0.02).
Treckmann J, Moers C, Smits J, et al. Machine perfusion versus cold storage for
preservation of kidneys from expanded criteria donors after brain death. Transpl Int

37. Donation after Circulatory Death (DCD)
• Donors not declared brain death
• Ethical concerns
“Hypothermic machine perfusion was associated with a reduced risk of
DGF and better early graft function up to 1 month after transplantation.
Routine preservation of DCD kidneys by hypothermic machine
perfusion is therefore advisable.”

38. Future of HMP
• Renal resistance indexes to evaluate marginal
organs
Jochmans I, Moers C, Smits J, et al. The prognostic value of renal resistance during
hypothermic machine perfusion of deceased donor kidneys. Am J Transplant 2011
• Biomarkers to predict delayed graft function
Moers C, Varnav OC, van Heurn E, et al. The value of machine perfusion perfusate
biomarkers for predicting kidney transplant outcome. Transplantation 2010
• Other methods: normothermic perfusion, oxygen
persufflation
Matsuno N, Konno O, Mejit A, et al. Application of machine perfusion preservation as a
viability test for marginal kidney graft. Transplantation 2006

39. Take Home Messages
• Only possible improvement in SCS is new solutions
• HMP is the way to go?
• Rapidly advancing field
• Possible additional benefit of HMP in the future
• Not inferior to SCS
• Significant advantage for ECD
• Look out for other developing methods
• HMP in other organs?

40. Special Thanks
Supervisor: Dr. G Leung
Acknowledgement: Dr. MK Yiu

41. UW VS HTK

42. Which one better?
Primary end point = Delayed Graft
Function (DGF)

43. Which one better?
Lynch RJ, et al. AJT 2008; 8:567-73

44. Post-transplant kidney graft survival
Living Donor: HTK n=475
UW n=475
Deceased donor: HTK n=317
UW n=317
Lynch RJ, et al. AJT 2008; 8:567-73

45. Lynch RJ, et al. AJT 2008; 8:567-73