A. Donner

Brent

Butkus

D. Gjertson

J. Fung

Katznelson

M. Eliasziw

P. Terasaki

R. Shapiro

Starzl

T.E. Starzl

Takemoto

Thompson

V. Scantlebury

English

PubMed

Scantlebury, V

Gjertson, D

Eliasziw, M

Terasaki, P

Fung, J

Shapiro, R

Donner, A

Starzl, TE

Name not available

The influence of HLA and CREG matching in African-American primary cadaver kidney recipients - UNOS 1991-1995

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Influence of HLA and CREG matching in African-American primary cadaver kidney recipients: UNOS 1991–1995

D-Scholarship@Pitt

.. Influence of HLA and CREG Matching in African-American Primary Cadaver Kidney Recipients: UNOS 1991-1995 V. Scantlebury, D. Gjertson, M. Eliasziw. P. Terasaki. J. Fung, R. Shapiro, A. Donner. and T.E. Starzl THERE have heen on I\' limited investIgations on the influence of HLA match on organ transplant outcome in African-AmericansKlK~ To ohtain this information, a multivariate analysis was performed of 31.291 cases of primarv cadaver kidney transplantation reported to the UNOS Scientific Registry between 1991 and 1995 .. ' The collection included 8111 African-Americans. for whom follow-up was to January I. 1997. The study involved a triple university collaboration involving experts in clinical transplantation. histocompatibilirv. and biostatistical meth-odology. HLA MATCHING The Pittsburgh experience was excluded from the UNOS analysis and reported separatc1y.l hecause tacrolimus was routinely given during the period of case accrual. Neverthe-less, 3.2% of the UNOS patients at other centers were treated with tacrolimus: 2.5% of the 8111 African-Ameri-cans and 3.4% of the 23.180 .. all others." In the total collection of 31.291 cases. I-year graft survival with a zero mismatch was 89%. This fell by 3% to 86% with a single mismatch at either the A. B, or DR locus. Within the full range of one to six mismatches. 4% more were lost. As reported in detail elsewhere,3 the small graft survival differences were statistically significant. But how significant were these survival differences clini-cally? Part of the answer came from the distribution profile (Tahle 1). Only 174 (or 2.1 %) of the 8111 African-Ameri-cans received a zero-mismatched kidnev. compared to 9.90/r in the 23.180 "all-other" population. At the other end of the matching scale. an additional 55R African-Americans (or 0.9%) received a six antigen (full-house) mismatch. Thus. Table 1. Distribution of HLA Mismatches HL4. African-Americans mismatches All Others 174 (2.1%) 0 2286 (9.9%) 206 (2.5%) 1 1128 (4.9%) 783 (9.7%) 2 3225 (13.9%) 2037 (25.1%) 3 6034 (26.0%) 2665 (32.9%) 4 5877 (25.3%) 1688 (20.8%) 5 3509 (15.1%) Subtotal 9 1.2% Subtotal 85.3% 558 (6.9%\ 6 1211(48%) 1997 by ElseVier Science Inc. 655 Avenue of the Americas. New York. NY 10010 Transplantation Proceeamgs. 29. 3733-3736 (1997\ 91.2";' of the African-American recipients werc in the one to five mismatch spectrum. which also bracketed more than 85<;,( of the "all other" cases (Table I). The graft survival in African-Americans at the I-year posttransplant milestone was not markedly lower than that of the "all other" population at any of the HLA mismatch levels. More relevant to the primary objective of our study. the degree of HLA mismatch had very linle effect on I-year African-American outcome. One-year allograft survival from the top to bottom of the one to live HLA mismatch range varied by less than 2'7r (Table 2). The lack of a stepwise effect also was evident in the one to five mismatch range of the "all other" population. where the I-year survival did not vary by as much as 3% (Table 2). By 3 years. graft survival in African-Americans had become inferior to the "all others" (Table 2). However, because survival declined by approximately 10% at every level of HLA compatibility. including zero mismatches. the difference in 3-year graft survival from one to five mis-matches was only 2.4%. with a survival crossover of four From The Thomas E. Starzl Transplantation Institute and the Children's Hospital of Pittsburgh, University of Pittsburgh Med-ical Center, PittSburgh, Pennsylvania; the Department of Epide-miology and Biostatistics, University of Western OntariO, On-tario, Canada, and the UCLA Tissue Typing Laboratory, UCLA School of Medicine, Los Angeles. California. Aided by Project Grant No. OK 29961 from the National Institutes of Health, Bethesda, Maryland. Address reprint requests to Thomas E. Starzl, MD. PhD, The Thomas E. Starzl Transplantation Institute. 3601 Fifth Avenue. 4C Falk Clinic. Pittsburgh. PA 15213. Table 2. % Graft Survival at 1 and 3 Years African-Americans N = 8111 87.1 (73.4) 84.6 (68.7) 84.3 (68.2) 83.9 (67.5) 83.0 (65.9) 83.3 (663\ Subtotal 91.2% 81.5 (63.2\ HL4. All Others mismatches N = 23180 0 1 2 3 4 5 6 89.2 (82.3) 86.9 (78.7) 86.4 (77.9) 86.2 (77.6) 84.5 (75.0) 84.0 (74.3) Subtotal 85.3% 83.0 (72.9) 0041 -1345/97/$1 7.00 PII S0041 -1345(97)01091-9 3733 3734 Fig 1. Graft survival and calcu-lations of hazard ratios (relative risk) over the first 3 post-trans-plant years. based on number of HLA mismatches. The reference was provided by zero mismatch cases. HL = half life. ~ > > ::l en ;<: <.:1 C (l) ~ (l) Cl.. '2 co a: D '" .... I African Americans (n=B.111) 100, ~K ~ 90 80 ~ ,. I ~ ~I~DIKKK- I ! MM N pE1FpEP1~;;;;:?~ i 70 i ~c 0 174 87 73 8 ~ I 60 ~ 1 206 85 69 7 [ = 2 783 84 68 6 J • 3 2037 84 68 6 1 50 J ~ ~ 2665 83 66 6 1688 83 66 6 } 1" 6 558 82 63 5 r 0 0 2 3 Years Posttransplantation H 2 .., I f~e 17;] r::1 q [J ~ 1Q 121 }l 0 2 3 4 5 6 Number of HLA Mismatches SCANTLEBURY. GJERTSON. ELlASZIW ET AL ra > > ~ en ra ~ <.:1 C (l) u ~ (l) Cl.. o iii a: '2 '" N co I All Others (n=23.1BO) 100 ': \ 90 ~ ~" t'" '1-:-- ;:,,c ---. BO ~i-D~D"""K . }--"D"~ .. 70 MM N Sil1Si31HL 0 2286 89 82 17 60 1 1128 87 79 14 50 ~ 2 3225 86 78 14 • 3 6034 86 78 13 ., 4 5877 84 75 12 ) 5 3509 84 74 11 1 • 6 1121 83 73 11 0 I 0 2 3 Years Posttransplantatlon ; ~ ~ j~ :7l n n n r n o II, I 1121 M M H IISI H o 2 3 4 5 6 Number of HLA Mismatches and five HLA mismatched tiers. The pattern of results in the "all other" recipient population (Table 2) was essen-tially the same. although there was a small effect from the fifth to the sixth mismatch. At all levels of HLA mismatch. however, the principal and relative separation of curves had already occurred by the end of the first year (Table 2). Although the percentages were slightly different in the 23.180 "all other" cases, the overall picture was much the same. An HLA-associated survival divergence between 1 and 3 years within the African-American population was obvious only with the stepdown from zero to the first mismatch, African-American (n=8, 111) o -ro a: "'0 .... ro .N C'O Fig 2. Relative risks of graft fail- I ure in African-Americans based on cumulative HLA mismatches. uSing one HLA mismatch popu-lation for the reference (hazard ratio = 1.0). The HR for cyclo-SDOrine was calculated with ta-crolimus as reference. The HR for African-American status was calculated uSing "all others" as reference (1.0). 1.5 1.0 0.5 o +-- 91.2% of all cases ---+-o 2 3 4 5 6 : eya AA Number of HLA Mismatches vs. vs. Tac Other < HLA AND CREG MATCHING IN CADAVER TRANSPLANT;:: o ro a::: "D .... ro 1.5 ~ 0,5 I o All Others (n=23.180) +-- X5.3 ('0 i.lfall cusCD~---K Ar--- - - - - - - - - - - - - - r-- -..-- _ ..-- ~ ~ :;. f- I " 1+ il-" I -I • I -:-t I-o 2 3 4 5 6 I l,·" Number of liLA Mismatchc, Fig 3. Relative risks of graft failure in "al\ other" than African-American recipients based on cumulative HLA mismatches using one HLA mismatch population as the reference (1,0), The reference hazard ratio for cyclosporine was provided by tacroli-mus, In Figure I. the hazard ratio (or relative risk) over the first 3 years with various degrees of mismatch in African-Americans (left) or in all others (right). was calculated using the zero HLA mismatch as the reference standard of 1.0, The principal adverse effect came with the first mis-match. which for the African-Americans increased the relative risk of graft loss within 3 years to a modest 1.2. However. the relative risk only increased further to 1.3 from one to five mismatches. For the "all other"" population (Fig 1. right), the relative risk between one and five mismatches rose from 1.2 to 1.5. It has been known for more than 25 vears that the absence of an HLA incompatibility (zero ~ismatch or six antigen mismatch) confers a graft survival advantage:'" The practical question is what is the effect of various levels of mismatch, Consequently. the relative risk of cumulative mismatches was recalculated using the one HLA mismatch as the reference standard of 1,0, The relative risk for both African-American and the "'all other"" patients with a zero mismatch was then 0,83 (Figs 2 and 3). The relative risk in the spectrum of one to five mismatches that encompassed 9 I. 2 (;{, of all African-American recipients increased onl\ from 1.0 to 1.08 (Fig 2), This was less than the condition pe'r se of being African-American versus "all other"" (relative HLA mismatches 0 1 2 3 4 5 6 Table 3, CREG Matched Cases (31.291) CREG Match/Mismatch 2460/2460 471/1334 416/4008 206/8071 57/8542 0/5197 0/1679 100% 35,3% 10.4% 2.6% 0.7% 00/0 0% For one to tlve HLA mlsmatcnes. CREG mJ1Cn vleld if.' 1150) 'v\,'as 3.6("'. 3735 n:-,f, fK-D~ tlsln~ "":111 others" d.S the rderence uf 1.01. and it \\<lS \cs'> thall the risk oj trcatlll!! \Iith nl"iosporillc (1.311 rather than with tacroitmus (1.(1) (Fig 2), In the ""all other" population Eci~:;FK the rciativc risk fl)Sl' unl\' lrom the relen:nce of 1.(1 provided hv the Slll!.!1e HL\ lllism;ltch to 1.2; with live mismatches. :·\s with ',-\iric;llI-:\mericans. thiS increasc in risk oj graft loss over a 3-year period was less than what incurred with choice of cyclospo-rine-hased immunoslIppression (I.-L') verSlIS tacrolimus ( I.()), CREG MATCHING Because it has been suggested that matching of cross reactive antigen groups (the so-called CREGs or public determinants) can be more discriminatinl!,',,7 we examined the eflcct of the CREG match in the 31.2y I UNOS cases, The computer program of Takemoto et ai" was used to convert the conventional HL\ phenotypes to CREGs, We began with a distrihution study (Table 3). Because CREG matching is directlv derived from HLA phenotypes. the 2460 zero HLA mismatched UNOS cases were by definition also CREG matched (a IOWI{ yield), eoweve~K with the succession from one to four HLA mismatches. the CREG match yield fell to 35'/C. 10<:;'.2,50. and less than I % in the respective tiers. There were no CREG matches in the five and six HLA mismatched categories (Table 3), The overall yield of CREG matches from the one to five HLA population in which 90<;( of the UNOS recipients fell was only 3.6':0. qhe~e CREG-matched organs had gone to only 3,2% of the 7937 African-Americans ~ho did n~t get a zero HLA mismatched kidnev (Table 4), The vield rate was onlv 4.3% of the comparable' 20.894 "all othe~s" (Table 4 l, The next question was whether the CREG-matched kidneys were associated with an improved graft survival in the miniscule fraction of the patients in which thev were used. This analysis is heing reported in detail cise~herCK"D Interpretation of the results in the African-American recip-ients was undermined hv inexplicable findings. The 81 CREG-matched patients from the one HLA mismatch tier (Table 4) had a nearl\' 10':( higher graft survival at 3 years than the 174 zero HLA misma;ched-patients (Table I; who hy definition also were CREG matched. Survival should have been essentiallv the same, In addition. CREG mis-matched patients from the pooled two to four HLA incom-Table 4. CREG-Matched Cases in Different HLA Mismatch Tiers HLA Afncan-Amenc3n mIsmatches All Others 174/174 (100go) 0 2286/2286 (100%) 81/206 (39.3%) 1 390/1128 (34,6%) 172/5485 (3.1 % I 2-4 507/15136 (3,3%) 0/2246 (0%) 5,6 0/6034 (0%1 CREG Matcn Yield Other Than 0 HLA Match 253/7937 (3.2%1 897/20894 (43%) " 3736 patlbility tIers actually did better than patlellts who were CREG matched.' In the "all other"' population. no distinctioll could be made between the CREG matched and mismatched pa-tients in any of the one to four HLA defined tiers. all of which had graft survival below the zero HLA mismatch standard. as expected.' DISCUSSION AND CONCLUSIONS Three conclusions are justified about the use of HLA matching as an instrument of organ distribution. First. short of a zero mismatch. allocation of primary cadaver kidneys by graded HLA incompatibility scoring has little effect on overall short- or long-term graft survival. Second, the current allocation policies prejudice the candidacy of Afri-can-Americans and other hard-to-match populations. Third, tacrolimus-based immune suppression influenced outcome more than the cumulative effect of all HLA mismatches beyond the first one. There was no clear evidence that CREG matched pri-mary cadaver kidney allografts survived better than CREG mismatched kidneys (reported elsewhere'). Furthermore. SCANTLEBURY GJERTSON. ELlASZIW ET AL the distribution studv descrihed showcd that CREG match· ing. even if predictIve of outcome. would not correct organ allocation inequities. Theretore. prospective matching trials either arc not justified or must be viewed as Helsinki Declaration Type I (acquisition of human knowledge) experiments. Such experiments must not be done without informed consent. specificd analyses. and conditions of trial stoppage. REFERENCES I. Butkus DE. Meydrcch EF. Rajc SR: New Engl 1 Mcd 327:840. 1992 2. Katznelson S. Gjcrtson OW. Cccka 1M: In Cccka 1M. Ter· asaki PI (eds) Clinical Transplants 1995. Los Angeles. Calif: UCLA Tissue Typing Laboratory: 1994. p 379-394 3. Starzl TE. Eliasziw M. Gjertson D. et al: Transplantation (in press) 4. Starzl TE. Porter KA. Andres G. et al: Ann Surg 172:437. 1970 5. Brent L: In A Historv of Transplantation Immuno!ol,'Y. Lon-don: Academic Press: J 997 P 131 6. Takemoto S. Tcrasaki PI. Gjertson OW. ct al: New Engl J Med 331:760. 1994 7. Thompson 1S. Thacker LR: Clin Transplant 10:586. 1996 d 

Influence of HLA and CREG matching in African-American primary cadaver kidney recipients: UNOS 1991-1995

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Influence of HLA and CREG matching in African-American primary cadaver kidney recipients: UNOS 1991-1995

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