Gerhard Opelz

Deliberate donor-specific blood transfusions prior to living related renal transplantation. A new approach.

In order to select MLC incompatible one-haplotype related donor-recipient pairs that would achieve better graft survival and in an effort to alter the recipient immune response, 45 patients received three fresh blood transfusions from their prospective kidney donors. Recipient sensitization was evaluated by cross-match testing weekly sera obtained during and after the blood transfusions against donor T- and B-lymphocytes at 5 C (cold) and 37 C (warm). Thirteen (29%) of the 45 potential related recipients developed a positive warm T-cell cross-match or a persistent warm B-cell cross-match to their blood donor and related transplantation was not performed. Thirty-two (71%) patients had an appropriate negative cross-match to their blood donor. Thirty of these patients subsequently received kidneys from their blood donor. Ninety-seven per cent of the kidneys are functioning from one to 25 months with a single graft failure due to a patient discontinuing immunosuppressive medication. In addition to the excellent graft survival there was an unusually low incidence of rejection episodes in the recipients of kidneys from their blood donor so that the posttransplant course paralleled that of HLA-identical siblings. This approach may have future application with two-haplotype mismatched donor-recipient pairs, both related and unrelated.

POOR KIDNEY-TRANSPLANT SURVIVAL IN RECIPIENTS WITH FROZEN-BLOOD TRANSFUSIONS OR NO TRANSFUSIONS

Abstract The one-year cadaver-kidney survival-rate in 93 recipients who had not been exposed to transfused white blood-cells prior to transplantation was 28±6%, which was significantly lower than the 53±4% survival-rate of 197 cadaver transplants in patients who were known to have been transfused (p

INDUCTION OF HIGH KIDNEY GRAFT SURVIVAL RATE BY MULTIPLE TRANSFUSION

In 33 centres that adopted a policy of liberal preoperative blood transfusion 174 recipients of cadaver donor transplants were followed up. Those who received no pretransplant transfusions had a 23% 1-year graft survival rate whereas those who had greater than 10 transfusions had an 87% survival rate (p less than 0.000001). 3% of those transfused acquired highly reactive cytotoxic antibodies and greater than 70% had no antibodies, so transfusions do not exert their beneficial effect by excluding strong immune responders. Since transplant survival rates improved with the number of transfusions, they probably produce their beneficial effect by inducing a state of unresponsiveness. Multiple transfusion seems a simple and effective way of improving kidney transplant survival rates. Moreover, the immunosuppressive effect is specific in that it does not alter the immune response to infectious agents.

IDENTIFICATION OF UNRESPONSIVE KIDNEY-TRANSPLANT RECIPIENTS

Abstract Non-presensitised kidney-transplant recipients, defined by the absence of lymphocytotoxic antibodies in their serum before transplantation, were divided according to the length of time they were free of cytotoxins. Recipients of cadaver kidneys who had not developed cytotoxic antibodies during haemodialysis treatment of more than one year before transplantation subsequently had a high kidney-transplant survival-rate at one year of 85% in contrast to a 50% survival-rate for recipients who did not develop cytotoxins during a haemodialysis period of less than one year. The statistical significance of the difference between these two groups, comprising 48 and 214 patients, respectively, was (P

SUPPRESSION OF LYMPHOCYTE TRANSFORMATION BY ASPIRIN

Abstract Aspirin in physiological dose ranges (10-40 mg. per 100 ml. plasma) has been shown to inhibit the incorporation of 3 H-thymidine in the lymphocyte transformation reaction in response to phytohaemagglutinin (P.H.A.) and allogeneic human lymphocytes. The inhibition was not due to the toxicity of the drug, for the lymphocytes responded well after washing out the aspirin. Later stages in D.N.A. synthesis appear to be involved, since aspirin was effective even 3 days after initial stimulation with P.H.A. Sodium salicylate suppressed lymphocyte transformation but salicin did not. Another related compound, o -hydroxyphenylacetic acid, did not affect the P.H.A. response but was definitely suppressive to allogeneic response.

SUCCESSFUL RENAL ALLOGRAFTS ACROSS A POSITIVE CROSS-MATCH FOR DONOR B-LYMPHOCYTE ALLOANTIGENS

Seven patients received a renal allograft with negative standard and T-lymphocyte microlymphocytotoxicity cross-matches, but a positive B-lymphocyte cross-match using donor lymphocytes. In spite of this presensitisation, none underwent hyperacute rejection and all are functioning from one and a half to six months after transplantation. This procedure may help in the detection of false-positive cross-matches and possibly in detection of enhancing antibodies against a specific donor.

Intact humoral and cell-mediated immunity in chronic marijuana smoking

The immune system of 12 healthy chronic marijuana-smoking adults was evaluated while they smoked marijuana daily for 64 consecutive days under controlled hospitalized conditions. Studies included enumeration of B and T cell subpopulations, lymphocyte proliferative responses to PHA and to allogeneic cells, and serum immunoglobulin levels. Percent B cells, initially low in 2 patients, became normal. Baseline total B cells, determined either by surface immunoglobulins (338 cells/mm3 +/- 60 SEM) or complement receptors (162 cells/mms +/- 27) were significantly (p less than 0.05) less than control but increased to normal (485 +/- 97 and 239 +/- 47) over time. Percent T cells, initially low (less than 40%) in 4 patients, became normal. Baseline T cells (951 cells/mm3 +/- 70 SEM), significantly lower than controls (2,010 +/- 210, p less than 0.05), increased to normal by day 63 (1,875 +/- 281). In vitro lymphocyte response to graded doses of PHA and to allogeneic cells was normal initially and did not change over time. Serum IgG (1,064 +/- 33), IgA (166 +/- 13), and IgM (96 +/- 6) were normal. Serum IgE levels increased in 4 subjects without evidence of allergy. Short-term chronic marijuana use does not have a substantial adverse effect on B or T cells of young healthy adults.

Clinical kidney transplants

Abstract From the first 15 years of clinical kidney transplantation, the principal single “truth” to emerge is that the HLA chromosome is the major factor influencing outcome of transplantation and that there is a marked difference between matching for two HLA chromosomes (HLA-identical sibs), one HLA chromosome (parental donors), and zero HLA chromosomes (cadaver donor transplants). Aside from the use of imuran and prednisone, which were introduced in 1962, there have been no new major factors and therefore the outcome of transplantation has not changed for the last 15 years, despite massive efforts to improve immunosuppression and histocompatibility matching methods. However, now with the retrospective identification of transfusion as being a major factor, it is expected that a major change in the outcome of transplantation will occur in the coming years. Together with the new emerging ability to account for multiple factors using computers and new developments in immunosuppression and HLA-DR matching, higher transplant survival rates in the immediate future are almost assured.

EVALUATION OF BELZER AND COLLINS KIDNEY-PRESERVATION METHODS

Abstract Information pooled from sixty-nine transplant centres on 686 human kidneys preserved by simple hypothermia with Collins solution or by the Belzer perfusion machine was collected. First-graft survival data were supplied for 146 kidneys preserved by the Collins method and 401 kidneys preserved on the Belzer machine. One-year-survival rates were: Collins 58% and Belzer 48%. Warm-ischaemia time greater than thirty minutes produced a greater proportion of failures at one-month post-transplant by both preservation methods. One-year graft-survival rates for cytotoxicity-negative patients were Collins solution 71% and Belzer machine 50%. Immediate function was also obtained at a higher rate with Collins (66%) than with the Belzer machine kidneys (45%). The results were subject to technical and learning problems at the different centres; nevertheless, they show that high survival-rates can be obtained by the pooled efforts of many centres with the use of a simple preservation solution employing hypothermia alone.

Lymphocyte Antigenicity Loss with Retention of Responsiveness

During culturing at 22�C for more than 4 days, human peripheral blood lymphocytes lose their ability to stimulate allogeneic lymphocytes in mixed lymphocyte cultures. The cells retain their ability to respond to allogeneic lymphocytes or phytohemagglutinin for up to 10 days of culturing. The findings are relevant to reports on successful transplantation of cultured skin.