Effectiveness of a Second Course of OKT3 Monoclonal Anti-T Cell Antibody for Treatment of Renal Allograft Rejection

KIDNEY TRANSPLANTATION AND RENOVASCULAR HYPERTENSION

of the radionuclide renogram in the differential diagnosis of renovascular hypertension.

Editorial Comment: Captopril renog:raphy is based on the fact that angiotensin II-induced vasoconstriction causes hypertension and decreased regional blood flow in patients with renovascular hypertension. Therefore, administration of the angiotensin converting enzyme inhibitor captopril causes a further reduction of regional blood flow to the kidney with the renal artery stenosis as blood pressure decreases and increased regional blood flow to the opposite kidney as a result of angiotensin II blockade. These differential effects on regional blood flow provide a better differential renal renogram. Although physiologically sound, the variability of scanning technique limits usefulness and more studies are needed before this test is substituted for those used currently. E. Darracott Vaughan, Jr., M.D.

KIDNEY TRANSPLANTATION AND RENOV ASCULAR HYPERTENSION Cadaveric Renal Transplantation in the Cyclosporine and OKT 3 Eras

R. J. STRATTA, A. M. D'ALESSANDRO, R. M. HOFFMANN, H. W. SOLLINGER, M. KALAYOGLU, D. F. LORENTZEN, J. D. PrnscH AND F. 0. BELZER, Department of Surgery, University of Wisconsin-Madison, Madison, Wisconsin Surgery, 104: 606-615, 1988 With advances in clinical immunosuppression, results in organ transplantation continue to improve. During a 52-month period, 507 cadaver renal transplants were performed, including 435 primary and 72 nonprimary transplants. All patients were managed with quadruple immunosuppression (prednisone, azathioprine, sequential MALG and cyclosporine). Our experience is divided into pre-OKT 3 (n = 228) and OKT 3 (n = 279) eras. All kidneys were harvested locally and preserved with pulsatile machine perfusion. The mean duration of preservation was 30.1 hours, with an organ utilization rate of 98.1%. The preservation-related dialysis rate was 13.6%, and primary nonfunction occurred in 8 kidneys (1.6% ). Actuarial patient survival in primary and secondary transplant recipients was 90% at 3 years. Overall primary graft survival was 81.6% and nonprimary graft survival, 6Ll %. However, the current OKTs era is characterized by improved patient survival (98% vs 90%, p = 0.001) and primary graft survival (91 % vs 80%, p = 0.002) at 1 year when compared with the previous era. Forty-nine patients have received OKT 3 therapy, with 31 grafts (63.3%) successfully rescued. Cadaveric renal transplantation with machine preservation, quadruple therapy, and OKT 3 rescue is associated with excellent early graft function, reduced acute rejection, and improved patient and allograft survival, even in high-risk recipients.

Editorial Comment: This large single-center study highlights contemporary results of cadaver renal transplantation, and emphasizes recent advances that have led to improved patient and allograft outcome. Foremost among the latter have been the development of more potent and safe immunosuppressive regimens incorporating newer agents, such as cyclosporine and the mono-

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don.al antibody OKT3. AH patients in the study were managed with a quadruple-drug immunosuppressive protocol involving azathioprine, prednisone, an initial course of prophylactic antilymphoblast globuJin and delayed administration of cyclosporine, The advantages of this approach include effective early immmwsuppression, avoidance of cydosporine nephrotoxicity during allograft recovery from ischemic injury and minimization of side effects by use of multiple agents at lower doses. The proved benefits of quadruple therapy have led to its adoption by many transplant centers in the United States. In this study immunological patient selection was on the basis of ABO blood type compatibility and a negative current T-cell lymphocytotoxic crossmatch. Prospective HLA antigen matching was not used and this policy did not adversely affect graft outcome. With current immunosuppressive techniques, HLA matching no longer is an important determinant of primary cadaver transplant success. All study patients received at least 5 blood transfusions preoperatively. However, the beneficial effect of this policy currently is unresolved. The development of OKT3 has provided a new and effective approach to the treatment of rejection episodes after transplantation. This drug may be used as primary antirejection therapy or as rescue therapy for rejection episodes that do not respond to conventional treatment with high dose steroids and/or antilymphocyte globulin. In this study the use of OKT3 for rescue therapy led to improved I-year patient survival (98 versus 90 per cent) and primary g:raft survival (91 versus 80 per cent) rates. The authors i.llustrate the dramatic improvement in cadaver kidney transplant success that has been achieved through advances in basic immunology and clinical transplantation. Similar results currently are being attained at most major transplant centers. Attention is being directed to methods of improving graft outcome in clinical subgroups with an increased risk of immunological graft loss, such as highly sensitized patients and retransplant candidates. Andrew C. Novick, M.D. Effectiveness of a Second Course of OKT3 l\fonodonal Anti-T Cell Antibody for Treatment of Renal Allograft Rejection

D. J. NORMAN, C. F. SHIELD, HI, KR HENELL, J. KIMBALL, J. M. BARRY, W. M. BENNETT AND M. LEONE, Departments of Medicine, Surgery and Pediatrics, The Oregon Health Sciences University, Portland, Oregon and St. Francis Medical Center, Wichita, Kansas Transplantation, 46: 523-529, 1988 A second course of OKT3 monoclonal anti-T cell antibody was given to 21 recipients of kidney transplants. Rejections reversed in 43% of patients in whom 95% of rejections had reversed with their initial OKT3 course. Reversal was highly dependent upon the timing of rejection, anti-OKT3 antibody production, and T cell CD3 modulation. Rejections treated greater than 90 days after transplantation were resistant to OKT3 reversal. High-titer anti-OKT3 antibodies prevented OKT3 reversal of rejection, and effective CD3 (the cell surface target of OKT3) modulation was necessary for successful OKT3

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KIDNEY TRANSPLANTATION AND RENOVASCULAR HYPERTENSION

reversal of rejection. Reexposure to OKT3 further stimulated anti-OKT3 antibody production and broadened the specificity of the antibodies produced. OKT3 can effectively and safely be used a second time for treatment of early T cell-mediated renal allograft rejections if high-titer anti-OKT3 antibodies have not been made.

Editorial Comment: The monoclonal antibody OKT3 has emerged as an important part of the therapeutic armamentarium for primary or resistant rejection episodes after transplantation. Notwithstanding the immunological efficacy of OKT3, approximately 50 per cent of the patients who receive this drug make human lgG anti-OKT3 antibodies. This has led to concern that second treatments with OKT3 may be less effective or may elicit severe immune complex mediated symptoms. In this important study the authors have defined the safety and efficacy of a second course of OKT3 antirejection therapy in 21 renal allograft recipients. All patients had previously received a course of OKT3 for treatment of an earlier rejection episode. Serum antiOKT3 antibody levels were monitored after courses 1 and 2 of therapy. Peripheral blood T-cell monitoring also was done to measure the desired effect of OKT3 in reducing the level of T-cells bearing the CD3 cell surface target. OKT3-induced symptoms were the same for most patients during treatment 2 compared to treatment 1, even for those with persistent anti-OKT3 antibodies. The initial dose often elicited a febrile reaction and, occasionally, erythema and itching. There were no instances of anaphylaxis or serum sickness. The immunological efficacy of second OKT3 treatment in reversing rejection episodes was diminished. Second treatments were effective in only 43 per cent of the rejections, whereas first treatments had been effective in 95 per cent of the rejections. Treatment 2 rejection reversal was most likely to be achieved for rejections occurring less than 90 days after transplantation, in patients with no antiOKT3 antibody development and in patients in whom immunological monitoring demonstrated effective Tcell CD3 modulation. The presence of anti-OKT3 antibodies led to inactivation of injected OKT3 to prevent the desired immunological and clinical effect. The specificity of the antibody response changed after a second OKT3 treatment from mostly idiotypic to idiotypic and allotypic. This broader antibody response may limit the efficacy of additional monoclonal antibody therapy if this is needed for subsequent rejection. The authors demonstrate that OKT3 can be used safely for a second treatment course in patients with recurrent renal allograft rejection, albeit with a diminished immunological efficacy. This is important information for clinicians involved in the care of transplant patients. Andrew C. Novick, M.D. Early Function as the Principal Correlate of Graft Survival. A Multivariate Analysis of 200 Cadaveric Renal Transplants Treated With a Protocol Incorporating Antilymphocyte Globulin and Cyclosporine P. F. HALLORAN, M. A. APRILE, V. FAREWELL, D. LUDWIN, E. K. SMITH, S. Y. TSAI, R. A. BEAR, E. H. COLE, S. S. FENTON AND D. C. CATTRAN, Toronto General Hospital,

Toronto, St. Joseph's Hospital, Hamilton, St. Michael's Hospital, Toronto, and Department of Health Studies, University of Waterloo, Waterloo, Ontario, Canada Transplantation, 46: 223-228, 1988 We examined the factors determining graft survival in 200 consecutive cadaveric renal transplants managed on a quadruple-therapy protocol: Minnesota antilymphoblast globulin, cyclosporine, azathioprine, and low-dose prednisone. Perioperative central venous pressure monitoring and volume expansion were emphasized. To avoid CsA nephrotoxicity in the early posttransplant period, patients were treated with ALG until renal function was established (a mean of 7 days). Therapeutic CsA levels were achieved before ALG was discontinued. Azathioprine was used to supplement CsA in patients with nephrotoxicity or rejection. Twelve-month graft survival was 85% (first transplants 86%, retransplants 79%), with patient survival of 95%. ALG was not associated with excessive clinical cytomegalovirus infections, which occurred in 5% of patients, or with malignancy. When 3 technical failures were excluded, an analysis of numerous factors in the pretransplant and peritransplant period revealed that the strongest correlate of one-year graft survival was early renal function. Grafts with delayed function (DF) had 75% survival, compared with 91% for grafts with good early function (EF). A multivariate analysis confirmed this association: the relative risk of graft loss was increased 2.86 times for DF compared with EF. The mechanism of the deleterious effect of DF was apparently multifactorial: the DF group, by definition, contained all the kidneys that never functioned, but some risk also persisted in kidneys that achieved function. One reason for this may be that DF kidneys that achieved function had higher mean serum creatinine values at 1 month: elevated serum creatinine values at 1 month were strongly associated with increased risk of graft loss regardless of initial function. There was also a higher number of rejection episodes diagnosed in the DF group. These observations suggest that early renal function is a major determinant of graft outcome and should be a target for efforts to further improve renal graft survival.

Editorial Comment: A multivariate analysis was done to determine the importance of various factors affecting graft survival in 200 consecutive cadaver kidney transplants from 3 centers. All but 4 patients were transfused preoperatively and all patients were managed with a quadruple-therapy immunosuppressive regimen involving antilymphocyte globulin, azathioprine, prednisone and cyclosporine. The multivariate analysis revealed that the strongest correlate of 1-year graft survival was early renal function. Delayed function was the only risk factor for graft survival to achieve statistical significance and the effect was independent of other variables. Patients with initial delayed function who subsequently recovered graft function maintained higher serum creatinine levels and had more rejection episodes than those with early renal function. This finding was reflected in a significantly longer initial hospitalization for the latter group (30 + 1. 7 days) compared to the former group (21 + 0.9 days). In the entire series there were 33 failed grafts, of which 21 (64 per cent) were in the delayed function group. The predominant cause of graft loss in the delayed function group was allograft rejection. It long has been recognized that ischemically damaged