Booth, AS

Groth, CG

Halgrimson, CG

Penn, I

Putnam, CW

Starzl, TE

English

PubMed

Booth Jr, AS

Name not available

Renal transplantation under cyclophosphamide

D-Scholarship@Pitt

Renal Transplantation Under Cyclophosphamide By Thomas E. Starzl, Charles W. Putnam, Charles G. Halgrimson, Carl G. Groth, Arthur S. Booth, Jr., and Israel Penn BEGINNING 15 mo ago, at the Univer-sity of Colorado, the alkylating agent, cyclophosphamide (Cytoxan), has been given an extensive clinical trial in the treat-ment of whole organ recipients both early and late after transplantation. This com-munication will deal only with those cases of renal homotransplantation in which cyclophosphamide was used from the out-set. The late substitution of cyclophospha-mide for azathioprine has been thoroughly described elsewhere. l THERAPEUTIC PROTOCOLS Cyclophosphamide was given as part of a triple drug program that also included prednisone and horse ALG. When related donors were available, all three agents were started several days in advance of opera-tion (Fig. 1) but for cadaveric cases (Fig. 2) treatment was started on the day of operation. The ALG was confined to the first 2-4 mo postoperatively. Prednisone was adjusted as needed to control rejection (Fig. 1-3). The donor-recipient combina-tions were not selected on the basis of a good HL-A match, and in most instances this kind of typing information was not even taken into consideration. The precise details of treatment during the early postoperative period have been From the Department of Surgery, University of Colorado School of Medicine and the Veterans Administration Hospital, Denver, Colo. Supported by research grants from the Veterans Administration, by Grants RR-00051 and RR-00069 from the General Clinical Research Centers program of the Division of Research Resources, National Institutes of Health, and by USPHS Grants AI-I0176-01, AI-AM-08898, AM-07772, and HE-09110. published l but it would be good to review some significant points. First, the cyclo-phosphamide was used in almost exactly the same way as has been customary with azathioprine, designing doses on a day-to-day basis according to the white counts, and with a conscious effort to avoid leuko-penia. Second, the correct doses on a mil-ligram per kilogram body weight basis were somewhat smaller than would have been anticipated had azathioprine rather than cyclophosphamide been used. Third, attention was paid to the possibility of specific toxicity of cyclophosphamide, in-cluding alopecia, anorexia, and hemorrhagic cystitis. At the doses used, alopecia was the only complication noted frequently, at about a 4% incidence. Finally, a change was, as a rule, eventu-ally made from cyclophosphamide to main-tenance therapy with azathioprine (Fig. 3). At the earliest, this transition was at about 1 mo posttransplantation and at the latest after more than 1 yr. Lately, the switch has been carried out arbitrarily after 2 mo or before this time if doses of cyclophos-phamide of at least 0.5 mg/kg have not been tolerated without producing leuko-penia. The rationale for the successive use of these two cytotoxic agents lies in the dissimilarity of their properties (Fig. 4). Cyclophosphamide is an alkylating agent said to exert its effect at the premitotic (or G2) phase of the cell cycle of immuno-cytes. In contrast, azathioprine is a purine analog that is an inhibitor of DNA syn-thesis. The objective has been to eliminate more effectively the clone of sensitized and replicating cells responding to the homo-graft antigens. The consecutive use of drugs in order to achieve "longitudinal" syner-gism in contrast to the "horizontal" syner-Transplantation Proceedings, Vol. IV, No.4 (December). 1972 461 462 URINE OUTPUT (ml/doy) wec (mm3) CYCLOPHOSPHAMIDE Img/doy) PREDNISONE l""l/doy) 150 REJECTION CRISIS 200 180 160 140 120 BUN 100 Img"') 80 60 40 20 P 80 60 CC. 40 (mi/minJ 20 0 20 1.5 URINE PROTEIN 1.0 Igmlday) 0 40 39 TEMP. 38 I·C) REJECTION CRISIS STARZL ET AL. WEIGHT 49- 51 Kg 14 YEAR OLD 9 37 ALG OMM~~~~~~==~~~==+-____ ~S~~ ____ ~ ______ ~ __ ~ -5 ? 20 • 40 60 -5 0 20 40 60 t t TRANSPLANT DISCHARGE TRANSPLANT DISCHARGE TIME IN DAYS Fig. 1. The first 60 days after the transplantation of a kidney from a mother to her 14-yr old daughter. The rejection crisis after 1 wk was the most severe observed in the intra-familial cyclophosphamide series, with the exception of two hyperacute rejections. How-ever, it was reversed easily and completely. Note that leukopenia was never produced by the daily doses of cyclophosphamide that were usually between 0.5 to 1 mg/kg/day. Arrow, 625 mg methyl prednisolone intravenously. (By permission of Surg. Gynec. Obstet. 133:981, 1971. gism of simultaneously administered agents has become common in cancer chemo-therapy. RESULTS Follow-ups of 3-15 mo are now avail-able. Thirty-nine recipients of related kid-neys (Table 1) have survived at the rate of 90%; kidney survival has been 32 of 39 (82%). All the living patients now have adequate function of their consanguineous transplants. In recipients of nonrelated kidneys, sur-vival is 28 of 36 (78%). These 36 patients were given 40 kidneys (Table 2) and the kidney survival is 73%. It is necessary in evaluating these results to appreciate that 17 of the recipients were entered into the series by virtue of their retransplantation for the second to fifth times. Kidney sur-vival was only 10 of 17 (59%) in these notoriously bad risk patients with their high incidence of presensitization and other complications (Table 2). Moreover, six of the deaths were in this group. In contrast, there was a 10% patient mortality (two deaths in recipients undergoing cadaveric transplantation for the first time) and a CYCLOPHOSPHAMIDE Fig. 2. The uncomplicated early course of a 20-yr-old re-cipient of a cadaveric kidney. Therapy with cyclophospha-mide, prednisone, and ALG was instituted on the day of operation. (By permission of Lancet 2:70, 1971). BLOOD UREA NITROGEN (mg/lOOml) BUN (mg/lOOml) Ccr (ml/min) 100 RENAL TRANSPLANT 80 60 40 20 0++-----------------120 100 80 60 40 20 0++-----------------. wec 30.000 (per mm3) 20.000 lo.oog r~---K-::::::::::::KK::~::::::::::::::::::=~ CYCLOPHOSPHAMIDE ~gg (mg/day) 100 5gtt ____ ~~~~==~ 50 PREDNISONE 100 (mg/day) 150 ALG RENAL TRANSPLANTATION 100 ... 200 DAILY EVERY TWICE WEEKLY o 10 20 30 40 50 60 70 80 TIME IN DAYS LD 324 14 y.O. ~ 463 80 60 40 20 Wt. 36- 42 Kg. l+---~---------------------------WHITE BLOOD CELL COUNT (mm3) 50,000 40,000 30,000 20,000 10,000 CvCilmelpmeAMfab~ 0+--+-------------OR AZATHIOPRINE Digg (mg/day) 0 PREDNISONE 50 (mg/day) HORSE ALG 100 -10 o 10 20 TIME 30 40 IN DAYS 50 60 Fig. 3. The first 2 mo posttransplantation of a 14-yr-old recipient of a paternal homo-graft. Her initial immunosuppressive therapy was with cyclophosphamide, prednisone, and horse ALG. The daily doses of cyclophosphamide were always greater than 1.3 mg/kg/ day and were given for the first 33 days postoperatively. The switch to azathioprine was then made because of a progressive decline in the white blood cell count. The recipient has never had a rejection episode and her renal funotion continues to be normal 5 mo posttransplantation. 464 STARZL ET AL. AZATHWlPR][NlE CYClLOlPHO§lPHAM][])}E ~ "S" ~ "Gi" (Interphase) present kidney survival of 19 of 23 (83%). SUMMARY In these studies, cyclophosphamide has been shown to be a good enough immuno-suppressive agent to replace azathioprine during the early postoperative period and Table 1. Cyclophosphamide: Related Cases' Recipients Kidneys Follow-ups of 3-15 Mo Ori'linal No. 39 39 Remaining No. 35 32 Per Cent 90 82 *22 Siblings, 14 parents, 1 aunt, 1 cousin, and 1 grandmother. Fig. 4. The different sites of action during the cell cycle of the cytotoxic drugs, azathio-prnie, and cyclophosphamide. Rapidly replicating lymphoid cells are presumably prefer-entially susceptible to destruc-tion by either agent. Table 2. Cyclophosphamide: 40 Cadaveric Kidneys in 36 Recipients Follow-ups of 3-15 Months Primary grafts* Repeat graftst Total *2 Deaths t6 Deaths No. 23 17 40 Functioning 19 (83%) 10 (59%) 29 (73%) for as long as 1 yr with satisfactory results. Eventually, cyclophosphamide was replaced by azathioprine in most cases. The conse-cutive use of these chemically and pharma-cologically dissimilar drugs may have advantages in terms of longitudinal syner-gism. REFERENCES 1. 5tarz!, T. E., Putnam, C. W., HaIgrimson, C. G., and Porter, K. A.: Surg. Gynecol. Obstet. C. G., Schroter, G. T., Martineau, G., Launois, B., 133 ;981, 1971. Corman, J. L., Penn, 1., Booth, A. 5., Jr., Groth, 

Renal transplantation under cyclophosphamide.

http://d-scholarship.pitt.edu/3670/1/31735062108893.pdf

Renal transplantation under cyclophosphamide.

Abstract

Similar works

Full text

Available Versions

Name not available

D-Scholarship@Pitt

Name not available