Marchioro, TL

Starzl, TE

Waddell, WR

English

D-Scholarship@Pitt

blood group matchiw cnt pairs, who have nJ tification of t,heir o h  comparison of cel.taip lonor in contrast to a do not necessarily eg le other, and they arc .tisties in permitting a derstood or understood lay be on the basis of otal length of ischemia ;ion crises, and activity laver kidneys hare 11 contrast, over 50% of odialyses. cadavers have a total of kidneys from living lavers never functioned m related donors never rer kidneys have less luently. Recipients of leas frequently. recipients of cadaver following transplanta- on twice that seen in mths 50% of recipients ctivity, and this again other donor group. Denly, J. B,; Dammin, G. ntation 3: 684. 8 ; Walter, C. W.; Brooke, J.; If-ilmn, R. E. 1963. : -1: i . , i  Grants .\>I 06283, A l l  06344, HE 07735, A11 07772, A1 04152, FR 00051 and r k  ('''fi!' irom the rnited States Public Health Senice, and by s grant from the Medical H' 5rPh Council of Great Britain. , , ,.? , ... \TLC'X Vol. 5. So. 4, Part  2 of 2 parts ,,",; I,\. Tile Williams 6 Wilkins CO. Printed i n  L ' .S . I .  . < . :  H ~ > . A L  TRANSPLANTATION AT THE UNIVERSITY OF COLORADO1 . I . ~ ~ ~ ~ ~ I . \ s  L. ARCHIORO, PAUL I. TERASAKI, DAVID E. HUTCHISON, I- .~~\ .HESCE BRETTSCHXEIDER, G. JAMES CERILLI, CARL G .  GROTH, AND THOMAS E. STARZL l . , ,  , ,..c;c!, of Colorodo School of fiiedicit~c ailtl L!ni~versity of Colijor?zia a1 Los Angeles i ! * I  ' I  ' I  i I . , ' ,  i SUhlhl.\RY I-rc,ln >larch 1%2 to -4pril 1966, 118 patients were treated a i th  renal ~ ~ ~ ; , ~ ~ ] ~ l ; ~ n t a t i o n ,  3 with kidneys from identical twins, 9 aith cadaveric i,o1310gl.nfts, and 108 with homografts from volunteer donors. Sixty-two of the patients are still alive after nine months to almost five years. Tllc only completely satisfactory group was that of the identical twin rt.cil\ients. The results after homotransplantation hare not materially improved ,luring tllis time despite the a c ~ ~ u i i t i o n  f increased experience, adjust- I I ~ ,  llts of timing and dosage of azathioprine and prednisone, and attempts idt,ntify biologically suitable donors in advance of operation by tissue :!.ping. It. is suggested that an impasse has been reached, beyond which further reduction in mortality and morbidity will depend primarily upon tltc rti'ectire application of new immunosuppressi,ire techniques. ~.:~.ri.:!~:r techniques for donor selection with the hope of thereby reducing r, t h i  need for these drugs. i ! - .  In this report, we will suggest that an impasse has been reached, imposed la!' the inherent limitations of the agents used t o  control rejection. A survey 011: own esperience has shown that the acquisition of increased experience, I ' I  - :i.. 1:-.-~itution of variations in therapy, and even the application of antigen , !  1 - &! l'ir.2 nlrthods for donol. selection have not eliminated or even significantly 5 hdut-id the nlorbidity and mortality after transplantation. The cases can iw. di~iclcd into four groups. , i I; I '. , ! 111 +te of the increasing acceptance during the last five years of renal t.o!:iu:r;insplontat.ion as a legitimate clinical undertaking, those responsible it*: r!.. rare of such patients have been keenly aware of the imperfections of ti.. ri:ir:~peutic techniques employed during this time. Investigators in - :.t 7 : : :  rrnters including our own have tried to  vary systematically the timing x . 1 :  Co-:igc of the two most important immunosuppressive agents, azathio- isr::.; ::::11 prednisone. Furthermore, efforts have been made to apply antigen- ! 833 TRASSPLASTATIOS I 'of. 6, KO. 4, Pa7, IDEXTICAL TKINS TRAKSPLASTS All three patients had glomerulonephritis. They were 27, 20, and 54 yea old when their operations n-ere performed 58, 42, and 9 mont,hs ago. Each no. has normal renal function although the patient with the lo~igest follow-u has had persistent n~icroecopic he~iiaturia for almost five years. A biopsy i. the second case after two years was normal. FIRST LII'IXG DONOR SERIES These 64 patients were operated upon from 34 to 50 lnol~tlis ago. F o ~ t y - ~ i )  received kidneys from family menlbers (20 parents, 23 siblings, and 3 aunts uncles, or cousins) ; the other 18 donors were nonrelated. No other egon was made to match donor-recipient pairs than, with a few exceptions, to ensure against ABO blood group incompatibilities. The first 45 patients were treated solely with azathioprine until rejection developed, a t  which time prednirone was added. The last 19 received b0t.h drugs from the beginning. Actinomycin C and local homograft irradiation were used irregularly. Thirty-two of the patients are still alive. The sur~iva l  of the recipients of related kidneys is 29 of 46 (63%). In  contrast, only three of the 18 patients in the nonrelated group (16.7%) remain alive (Fig. l ) ,  one by virtue of a second graft after 2% years. The change in the timing of prednisone admjnistrat.ion in the second part of the series did not result in an  increase in the total amount. of this drug which nas given. By using large quantities of steroids fro111 the beginning, the incidence of seyere early rejections was reduced, making i t  possible to attenuate dosage a t  a more rapid rate. The consequent balancing effect is shown in Figure 2 in which the average dose per day for the first 105 days was found to be almost identical for the recipients of related homografts in both the earlier and later groups who lived this long; analysis of the nonrelated cases revealed the same thing. During the acquisition of the series, there was a trend to conservatism in LIVING DONOR SERIES I lo - ,  ------------- i FIGURE I. Survival in the first series of 64 patients treated with homografts from living donors. -411 patienb are alive beyond the points indicated by the vertical arrows. Follow-up is thus 34 to 50 months. \ - -- -  )S 1-01. 5, h'o. 4, poll, SPLASTS ley were 27, 20, and 54 Yeah . and 9 1~011th~ ago. Each now t with the longest follow, "P most  five years. A biopsy to 50 months ago. Forty-*& ~ts ,  23 siblings, and 3 aunt., nonrelated. No other effort h a few exceptions, to  ensm irst 45 patients were treated I ,  a t  ahirh time prednisooe the beginning. Actinomycio irly. umivai of the recipients of 11y three of the 18 patients Fig. 1): one by virtue of tration in the second part total amount of this dmg roids from the beginning, ed, making i t  possible to ~quent  balancing effect ia lay for the first 105 day8 of related homografts in analysis of the nonrelated trend to conservatism in :h homosaits from Iiving vertical mows. Follow-up LIVING DONOR SERIES 105 ONS I 101 DAYS AZATHlWRlNE W I C  lmgm/kg/dayl F ~ ( ~ c R E  ?. Analysis oi doses of immunosuppression in the two fractions of the first and ,,, tl,,. *cond xriee oi l~on~otrans~~l:~ntations from living related donors. Tllc division of the fir-1 group \vap on rhe basis of differences in the administration of steroids; the first pa- 1,.-111; ( a r rrceivrti Prrdnisone for t he specific indication of rejection and the later patients t 1,) rcvr~\.ed this drug propl~ylactically from the time of operation. The data are from the tir-1 105 postopernti~e days; patients who failed to live this long were esrluded. The influ- ~11t.c  oi tliese changes on the white cell counts and creatinine clearance is shown. illr use of azathioprine t Fig. 2) which reflected growing apprehension about ~ h c  acute bone marrow depression which was then a common complication. .In expected corollary change was an increase in the white cell counts (Fig. ? I .  Xvel.age renal iunction, illustrated in terms of creatinine clearance was .lightly better in the second group of patients n-ho were treated from the I~c.:inlii~i_r with prednisone (Fig. 2) but the difference was not statistically si:~~ificant. Studies of these original cases provided hope tha t  future results could be improved using white cell antigen matching in donor selection. Thirty-seven of tlie original 64 patients who survived for a t  least one year were typed by Tcrn*nki along with their respective donors. I t  was found that the best rli~~ical results tentled to I)e in those cases with a high degree of donor- rc.ripient compatibility of lymphocyte antigens. Furthermore, there was a very firm correlation between the completeness of this matching and the r~llnlity of preservation in the homograft biopsies studied at about two years 121. SECOSD LIVING DOSOR SERIES These 42 p a t i w e  received homografts 9 to 27 months ago from volunteers "110 were chosen insofar as possible on the basis of the best available TIIASSPLASTATIOS RELATED - 1 9  z 0 ; .4 -  0 a a .3-  LL . 2 -  . I  - TIME IN MONTHS F I C ~ R E  3. Survi\.al in the first year follolvinp homotmnsl~lantation in the second living donor wries. The patients included have been follo\r-ed from 12 to 27 months. One of the nonreluted group subsequently died after 17 months. antigen inatch. In 25 cases, there were related donors (15 parents, 9 siblinga, 1 uncle). Because the selectivity within mosb families was limited, the quality of matching was only slightly (and not significantly) better thm could have been achieved with random intrafan~ilial pairing; the donor pool for the 17 nonrelated cases was a large one allowing much greater discrimina- tion (91. Imlnunosuppression was similar to that in the previous series except - that prednisone was usually started in relatively snlall doses on the day of operation and later increased if iequired for control of rejection. Twenty-five of the patients are still alive. I i  of 25 (68%) in the related and 8 of 17 (47%) in the unrelated groups. The statistics for the first 36 cases, all operated upon 12 months or longer ago are shown for the first year in Figure 3. The s u m i ~ a l  after one year was slightly worse in the related cases (63.1%) than in the original series, but it was better (53%) in the The previously described tendency to use smaller doses of azathioprine, which had already been noted during the treatment of the original series, of patients, continued (Fig. 2) into the last group.; Now, however, the penalty became the need to use higher maintenance doses of prednisone; the data shown are from the related cases, but analysis of 'the nonrelated trans- plantations revealed exactly the same'thing. In spite of this adjustment the. duntation in the second liviag I 12 to 27 months. One of ,rs (15 parents, 9 sibline nmilies was limited, th iignificantly) better thm I pairipg; the donor pmt much greater discrimina- the previous series except nall doses on the day of rejection. 25 i68%) in the related tatistics for the first 36 are shown for the first htly worse in the related as better (53%) in the ~en t ly  died of hepatitis distinguished the second 'actor in unsuccessfully imon fungal, protozoan, ~aracter of the autopsy doses oi azathioprine, : of the original series p. KO\\*, however. the oses of prednisone; the f the nonrclated trans- of this adjustment the , , , : , 9 ~  .\I,\JICHIOILO ET AL. 8:j.i ,,,:,l,l,j,lc ]c~aranrcs during t11c first. 105 days was distinctly poorel* t p  < 0.05,) , , 1 f i r  series (Fig. 21. The incidence of acute f:~ilul.e from drug ,,,,,,.ity lI:Ic] thus been greatly reduced but a t  the expense of lcss adequate ,,.,it protection, a delayed lllortality which is apt to bc a t  least as t . l ! l l d l ' - .  : ,,,, :;. :,. i l l  rile original series since several of the patients still living are not -. :,,:!.,. ,,.,.11. :II,,I ill1 u~~qucstionshly incrcasrd long-term nlorbidity. , ~ l ~ l l l ~ j ~ s ~  of scven of thesc hol~logrnfts were obtained a t  al~prosin~atcly two ?;01,p \vcrc normal tilid only two \yere free of more or less serious .tr,,l.tur:~l a1)normalities. C-ADAVERIC SERIES - r ~ , ~ ~ . ~  l.cripicnts, ~)~.ovitlcd wit11 cadaveric homogl.afts in 1963. died within 4 39 cl:~y.s: with unrelicvcd uremia. In the last 10 to 14 molitl~a, six lnore .:I!.:::.:. :,ttc.mpt+ 1vel.e m:rdc; :ill of the kidneys functiolled following delays ,,i 10 llliilutcs to 23 days after revascularization. Four of these recipients died ~,irl.!. 3 8. 10, and 12% ~llollths with failing grafts and with selltic coil~plica- ll,,l,. of tlle kind described in the preceding section. An additional patient 11:irl normal function for the first seven months had a late uncontrolled r,.,c.~.rion and is awaiting homograft removal and retransplantation. The f i l l : r I  1):ltient is one year postoperative with normal renal function. DISCUSSIOS 'ri,(. iorcgoing obser\rations make it clear that, if renal homotra~lsplantation I,:,. Ib(.,,olne a standard form of therapy for terminal renal disease, it has :tc.llic.vc*tl this status prematurely. Every active transplantation center has its I~r. i l l i : t l l t  results, but the incidence of failure is high and, what is worse, it -V~.IIIS to have reached an irreducible minimum employing the "standard" im- rr~~~tlo+uppressive ag nts. In  our own institutions, tlie progressively more timid 11-t. oi azathioprine, combined with altered programs of prednisone adminis- tr:triul~. 112s virtually eliminated the early postoperative deaths from acute 11(111t. 111:1rr01v clepres~ion, but a t  the expense of later diminished function and :I IIIC!!~.~ ultimate steroid need in many cases. The eventual mortality has n.l~l::il:cli ~*elat i~ely fixed with each such adjustment in management. I [  i -  cclunlly discouraging to note that the use of prospective antigen 111:11rIiiiig for donor selection did not have more influence upon prognosis. Titi$ was not surprising in the consanguineous transplantations since selec- t l~ i t y  could- not be significantly improved due to the problem of supply. This was not the situation. however, in the nonrelated cases where the one-year 'llr\.i1.:11 was upgraded by only 20%, reaching the still unsatisfactory figure 5 3 5 .  The latter finding emphasizes the futility, with the presently avail- :ll1l(' tllcrapeutic protocols, of envisioning effective and large scale application ofti+ut, typing techniques in cadaver programs. TI11> does not imply either that the tissue typing methods now being ""\'~.lol'(~d are not a direct or indirect measure of histocompatibility factors, Or 'll:it the use of these techniques will play an insignificant role in trans- ~'l:llltatioa practices of the future. Indeed, evidence has been cited earlier TRASFPLASTATIOS to the degree of antigen nonconformity between donors and recipients. fair trial with the treatment programs now widely being used unless trans. plantation is performed only between allnost perfectly matched pairs or, alternatively, that they require for exploitation a setting of far more adequate' immunosuppression. The former approach would limit consideration to au but a very small number of patients who need this kind of therapy. ~ b t  latter development would allow extension rather than restriction of the indications for acceptance into a transplantation program. Investigations new methods of immunosuppression, reported elsewhere in this ~ y m p o s i u ~ ,  provide hope this object i~e can be realized. REFERESCES 1. Hill, R. B. Jr.; Dahrling, B. E. 11; Starzl, T. E.; Rikind, D. 1967. Am. J. hied. 46: a. 2. Porter, K. -1.; Rendall, J. hl.; Stolinski, C.; Termki, P. I.; Marchioro, T. L.; St* T. E. 1966. Ann. New Tork Acad. Sci. 129: 615. 3. Terasaki, P. I.; Porter, K. A.; Marchioro, T. L.; Mickey, hi. R.; Vredevoe, D. L.; Faris, T. D.; Starzl, T. E. 1966. Ann. New Tork Icad. Sci. 129: 500. 

Renal homotransplantation at the University of Colorado Medical Center

Name not available

http://d-scholarship.pitt.edu/3458/1/31735062123868.pdf

Renal homotransplantation at the University of Colorado Medical Center

Abstract

Similar works

Full text

Available Versions

D-Scholarship@Pitt

Name not available

Name not available