Transplant Kidneys Sooner Discard Kidneys Less Francis L. Delmonico, M.D., F.A.C.S. Professor of Surgery, Harvard Medical School Director, Renal Transplantation Massachusetts General Hospital Medical Director, Medical Director, New England Organ Bank

For the year 2000: 15 % of donors > 60 years of age Discarded: 45%

New England Organ Bank Year /285 discarded 20/ /279 discarded 21/ /289 discarded 20/45 _____________ 101/853 61/129 11% 47% 11% 47%

Discard Rates after Recovery of Cadaveric Kidneys SRTR analyses of data supplied by OPTN contractor through November 30, 2000

Recover organs from marginal donor OPO incentives OPO disincentives legal and ethical extensive clinical testing responsibility fewer organs recovered more organs discarded more organs discarded meet HCFA difficult to place performance cost per organ increased standards organ acquisition fee increased disappointing to staff disappointing to staff disappointing to families disappointing to families

HCFA Performance Standards HCFA Performance Standards Analysis of performance over 24 month period divided by two to yield average "annual" results Donors / million population Kidneys recovered / million population Kidneys transplanted / million population Extrarenal organs recovered / million population Extrarenal organs transplanted / million pop. OPO must achieve > 75% of the national mean for at least three of the five standards

Transplant organs from marginal donor Center incentives Center disincentives increase number delayed graft function of transplants increased rejection longer hospital stay of transplants increased rejection longer hospital stay assure financial worse long-term outcome stability recipient informed consent assure financial worse long-term outcome stability recipient informed consent worse center-specific results worse center-specific results attract managed managed care disapproval care providers criticism of public press

Terasaki, et al N Engl J Med 1995 Effect of DGF

Id Sib 1-haplo Sib Unrelated Cadaver Percent Survival Years Post transplant 2,129 3,140 2,071 34, nT1/2 Relationship Graft Survival Rates for LRD and LURD grafts Cecka, M. UNOS

The New England Journal of Medicine -- August 10, Vol. 343, No. 6 Nondirected Donation of Kidneys from Living Donors Arthur J. Matas, M.D., Catherine A. Garvey, R.N., Cheryl L. Jacobs, L.I.C.S.W., M.S.W. Jeffrey P. Kahn, Ph.D., M.P.H. As of March 31, 2000, 98 persons had contacted us for information on nondirected donation. 18 of these persons have been evaluated, and 20 are being evaluated or are about to be evaluated; the other 60 persons have not pursued donation. Of the 18 persons who have been evaluated, 6 have been accepted as donors (the transplantation has been performed in 4 cases and scheduled in 2), the evaluation of 1 person is being reviewed, and 11 persons have not been accepted as donors because of medical or psychosocial factors. The donors for our first four nondirected transplantations have remained anonymous. We elected to admit each donor under an alias. With the use of organs from living related donors, both the donor and the recipient are usually admitted on the day of surgery. For our nondirected donations, the donors and recipients (each accompanied by family members) were admitted to different parts of the hospital to maintain anonymity. The operations in the donors and the recipients were performed simultaneously with the use of standard open techniques. The transplanted kidneys functioned immediately. Neither the donors nor the recipients had complications.

High Survival Rates of Kidney Transplants from Spousal and Living Unrelated Donors Paul I. Terasaki, J. Michael Cecka, David W. Gjertson, Steven Takemoto N Engl J Med 1995; 333: Conclusion: Spouses are an important source of living-donor kidney grafts because, despite poor HLA matching, the graft-survival rate is similar to that of parental-donor kidneys. This high rate of survival attributed to fact kidneys were uniformly healthy.

Brain dead LURD Cytokine storm none CIT 20 hrs < 1 hour INJURY INJURY DGF 25% < 1%

Cold Ischemia Time (hrs) Percent DGF The Effect of Cold Ischemia Time on DGF CeckaUNOS ,032 18,915 9,924 1,

1999 UNOS 3m 1 yr 96 – 97 3yr 5 yr

CIT may not affect outcome but it may affect rate of discard especially of the marginal donor kidney because well known to affect DGF centers have compelling reasons to avoid DGF to avoid DGF

Cold Ischemia Time (hrs) Percent DGF Cold Ischemia Time and Donor Age Donor age (yrs) CeckaUNOS

CIT by Age, Mismatch, Sharing, DGF No DGF DGF From Dolly Tyan : Crystal City Conference March 28, 2001

>60 Donor Age Percent >18hr CIT Cold Ischemia Time and Donor Age Cecka

Exhibit 5 From Held and Merion: Crystal City Conference March 28, 2001

Years Post transplant Percent Graft Survival (Log) > Effect of Donor Age on Graft Survival Age Cecka, M. UNOS

>65 Donor Age Turndown Rate (%) Turndown Rate for Donor Quality Cecka

Loc55+Loc55+ Loc55+Loc55+ coldischemiatime Sharing of kidneys by age Kidney Cold Ischemia by Age, Mismatch, Sharing From Dolly Tyan: Crystal City Conference March 28, 2001

Current system of HLA matching as a basis of allocation priority affects preservation time to determine HLA to identify national match or necessity of payback to make contact with candidate to determine candidate acceptable to transport kidney 12 hours to transplant kidney

Why impose the duration of cold ischemia upon the cadaver kidney? To achieve 0 mm HLA matching and the required payback which has all of the ischemia and none of the HLA match

% 3 Year Survival 3 Year Kidney Graft Survival by Sharing, Age, Mismatch < 55 years of age 55 + From Dolly Tyan : Crystal City Conference March 28, 2001 (1) (7) (10) (65) (99) (data NS)

Survival Benefit from Marginal Kidneys Days since transplantation (Equal time from wait-listing) Relative Risk (RR) of Death Ojo et al. J Am Soc Nephrol 2001; 12: 589.

Expected Lifetime (years) Expected Lifetime According to Donor Characteristics SRTR 2001

The Crystal City kidney work group proposal: Allocate older donor kidneys > 60 years of age Allocate older donor kidneys > 60 years of age to a pre-informed group of patients to a pre-informed group of patients based upon waiting time only. based upon waiting time only. Identify the recipients before organ procurement. Identify the recipients before organ procurement. Develop a standard UNOS policy Develop a standard UNOS policy whereby a local OPO could adopt whereby a local OPO could adopt the preferential allocation of 60 year old kidneys the preferential allocation of 60 year old kidneys upon UNOS notification of local OPO approval. upon UNOS notification of local OPO approval. Allocation would occur at the level of the OPO Allocation would occur at the level of the OPO except for the identification of a except for the identification of a 6 antigen matched recipient nationally. 6 antigen matched recipient nationally.

The Crystal City kidney work group goals: Increase utilization of older donor kidneysIncrease utilization of older donor kidneys by increasing procurement rates and decreasing discard rates; Improve patient outcomes Improve patient outcomes by decreasing cold ischemia times and delayed graft function; thus Decrease hospitalizationDecrease hospitalization (length of stay) and costs.

Not all DGF is the same; data do not reveal adverse affect upon outcome at the CIT of 24 hours; benefit of CIT of 4 hours; Why impose the duration of cold ischemia upon the cadaver kidney?

Factors by Cecka that increase DGF: CIT > 24 hours PRA > 50 % Donor > 50 years of age Dialysis > 3 years

HLA Mismatches Percent of Kidneys Zero MM (23.5 hr) Contralateral (19.9 hr) Other MM (21.7 hr) 100 HLA Matching and Cold Ischemia in 4,000 Kidney Pairs UNOS

URREA HLA Matching: Number of HLA mismatches Cumulative Frequency Percent Mismatch

URREA PRA: Cumulative Frequency Percent Cumulative Frequency PercentPRA Unknown ________

Degree of HLA Match Points are assigned based on # of mm between transplant candidate’s antigens and donor’s antigens. 7 points if there are no B or DR mm; 5 points if there is one B or DR mm; and 2 points if there is a total of 2 mismatches at the B and DR loci.

Obstacles to CIT of < hours for cadaver donor recipient: Identifying recipient by HLA typing and T- cell crossmatching; Communication of organ center with tissue typing lab and transplant center; Acceptance of kidney by transplant center: finding the recipient and evaluating to be medically suitable ; scheduling and performing the transplant.

Hypothesis: If the unrelated living donor kidney without the benefit of HLA matching can achieve such a successful outcome usually with < 1 hour CIT and <1% DGF the cadaver donor kidney with < 4 hours CIT, reduced rate of DGF, and improved regimen of immunosuppression, would achieve a much improved outcome for a majority of recipients.

UNOS Region 1 kidney transplants transplants 1063 transplants Kidneys allocated by Region 1 plan54.1% by special criteria5.4% 0 mismatch Reg 13.1% not used in Region19.7% discarded 14.7% sent out of Region5.2% exported mandatory share17.7% 100%

Id Sib 1-haplo Sib Unrelated Cadaver Percent Survival Years Post transplant 2,129 3,140 2,071 34, nT1/2 Relationship Graft Survival Rates for LRD and LURD grafts Cecka, M. UNOS

Kusaka, M.; Pratschke, J.; Wilhelm, M.; ….Hancock, W.; Tilney, N. Activation of inflammatory mediators in rat renal isografts by donor brain death. Transplantation 69: , 2000 Brain death triggers nonspecific inflammatory events. In this study,changes in kidney isografts from BD donors compared to normal anesthetized, ventilated controls. numbers of infiltrating polymorphonuclear leukocytes peaked at 24 hr in parallel with intragraft induction of P- and E-selectin, complement, and proinflammatory chemokines and cytokines. At 5 days, isografts from BD donors infiltrated by host leukocyte populations assoc with up- regulation of products. In contrast, those from control donors remained relatively normal. Accelerated rejection of renal allografts from brain dead donors. Annals of Surgery 232: , 2000

HLA Mismatches Percent Shorter Longer 0123 Years Posttransplant Percent Graft Survival ShorterLonger 3,1093, nT1/ CIT CIT HLA Matching and Graft Survival in Recipients of Paired Cadaver Kidneys with Longer or Shorter CIT Cecka, Clinical Transplants 1999 (p. 13)