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In preconditioning highly sensitized kidney transplant candidates, renal allograft outcomes have been better when the serum titer for class I anti-HLA donor-specific antibody (DSA) is low in the recipient at the time of transplantation. However, the ideal level to which the titer should be lowered is still controversial. We report a primary living related kidney transplant in a 34-year-old highly sensitized woman (pretransplant panel-reactive antibody=70%) with end-stage renal disease secondary to chronic glomerulonephritis. We sought to desensitize by lowering the DSA titer specifically to 1:4 pretransplant. A standard complement-dependent cytotoxicity cross-match with her donor (sister) was repeatedly negative, although she was positive for class I antibody against her mismatched HLA antigen (A*2402) at a titer up to 1:16 by the single-antigen flowbead assay. The target DSA titer of 1:4 before transplant was achieved by 12 sessions of plasmapheresis (PP) over 7 weeks, plus two intravenous immune globulin infusions (IVIG) (500 mg/kg/infusion). The patient outcome was excellent. Neither IVIG nor PP was needed posttransplant. The serum creatinine ranged between 0.5 mg/dL and 1.2 mg/dL, and no rejection episode was documented at 28 weeks posttransplant. Therefore, we encourage the use of IVIG and PP to lower the DSA titer to at least 1:4 before kidney transplantation in highly sensitized patients. Large prospective trials are needed to establish a consensus for pretransplant risk assignment and to evaluate the need for desensitization.

A multiscreen serum analysis program has been developed that permits a determination of antibody specificity for the vast majority of highly sensitized patients awaiting transplantation. This program is based on a 2 x 2 table analysis of correlations between serum reactivity with an HLA-typed cell panel and incorporates two modifications. One implements the concept of public HLA determinants based on the serologic crossreactivity among class I HLA antigens. The other modification derives from the premise that most highly sensitized patients maintain the same PRA and antibody profiles over many months and even years. Monthly screening results for patients with persistent PRA values can therefore be combined for analysis. For 132 of 150 highly sensitized patients with greater than 50% PRA, this multiscreen serum analysis program yielded information about antibody specificity toward public and private class I HLA determinants. The vast majority of patients (108 of 112) with PRA values between 50 and 89% showed antibody specificity generally toward one, two, or three public markers and/or the more common private HLA-A,B antigens. For 24 of 38 patients with greater than 90% PRA, it was possible to define one or few HLA-specific antibodies. The primary objective of the multiscreen program was to develop an algorithm about computer-predicted acceptable and unacceptable donor HLA-A,B antigens for patients with preformed antibodies. A retrospective analysis of kidney transplants into 89 highly sensitized patients has demonstrated that allografts with unacceptable HLA-A,B mismatches had significantly lower actuarial survival rates than those with acceptable mismatches (P = 0.01). This was shown for both groups of 32 primary transplants (44% vs. 67% after 1 year) and 60 retransplants (50% vs. 68%). Also, serum creatinine levels were significantly higher in patients with unacceptable class I mismatches (3.0 vs. 8.4 mg% [P = 0.007] after 2 weeks; 3.9 vs. 9.1 mg% [P = 0.014] after 4 weeks). Histopathologic analysis of allograft tissue specimens from 47 transplant recipients revealed a significantly higher incidence of humoral rejection (P = 0.02), but not cellular rejection, in the unacceptable mismatch group. These results suggest that the multiscreen program can establish which donor HLA-A,B mismatches must be avoided in kidney transplantation for most highly sensitized patients. For 18 of 150 high PRA renal dialysis patients, the multiscreen program could not define HLA-specific antibody. Most patients had greater than 90% PRA, and many of their sera appeared to contain IgM type nonspecific lymphocytotoxins that could be inactivated by dithioerythreitol (DTE).(ABSTRACT TRUNCATED AT 400 WORDS)

1. Hyperacute rejections occurred in 0.6% of 19,415 first cadaver donor grafts and 1.9% of 4,326 regrafts. When grouped into those without preformed cytotoxins, 0.5% first grafts and 1.3% of regrafts had hyperacute rejection. Among patients with cytotoxins 1.3% of first grafts and 2.6% of regrafts had hyperacute rejections. 2. A total of 923 first cadaver donor transplants and 238 multiple transplants were crossmatched by 6 variations of microcytotoxicity tests: standard, long 4-hour incubation, B lymphocytes at 4 degrees C and 37 degrees C and T lymphocytes at 4 degrees C and 37 degrees C. All crossmatching was done in one laboratory. 3. For first cadaver donor transplants, 178 patients with long positive crossmatches and 56 patients with T warm positive crossmatches had a significantly lower survival rate than crossmatch negative patients. Those with short positive (weak), B warm, B cold, and T cold positive crossmatches had the same graft survival as crossmatch negative patients. 4. In regrafted patients from cadaver donors those with a short and T warm positive crossmatches had lower graft survival than crossmatch negative patients. 5. Preformed T warm cytotoxins were associated with lower graft survival in first grafts and B warm cytotoxins were associated with lower graft survival in regrafts. 6. Eight patients with T warm positive crossmatches were successfully transplanted (function at 3 months) after they were shown to have IgM antibodies removable by 2-ME treatment. 7. A total of 136 patients were tested by FCXM at the time of transplant on a retrospective basis. Although all patients were crossmatch negative by the T warm tests, 24 were FCXM positive.(ABSTRACT TRUNCATED AT 250 WORDS)

Over 200 cadaver donor transplants were crossmatched against T and B lymphocytes at 5 and 37 C. Of 54 positive B cell crossmatches, one-half had cold antibodies and one-half had warm antibodies. The 1-year transplant survival was 58% for B-cold-positive crossmatches and 42% for B-warm-positive crossmatches. The B-warm-positive crossmatches, when subdivided into those with strong HLA-DR antibodies showed a 27% 1-year transplant survival rate. We conclude that B cell-positive crossmatches with HLA-DR antibodies are deleterious and that those with cold anti-IgM antibodies may enhance graft survival.

1. Positive FCXM reactions were associated with sensitization in transplants with negative cytotoxic crossmatches. Recipients of regrafts, females, particularly those with previous pregnancies, and recipients with historical cytotoxic antibody reactivity were more likely to have FCXM detectable antibodies. 2. Primary nonfunction grafts were associated with a positive FCXM, but predominantly in those transplants involving female, older, or nontrauma donors. Nearly 40% of the FCXM positive transplants of these organs did not function during the first month posttransplant 3. Low 3-month graft survival rates were associated with a positive FCXM reaction, but once again this was seen with female, older, and nontrauma donor transplants. In addition, approximately 40% of FCXM positive transplants involving older or nontrauma donors that did survive had poor graft function at 3 months.

Prospective pretreatment with deliberate DST has afforded MLC reactive related donor-recipient pairs enhanced opportunity for successful transplantation. The sensitization rate in patients receiving DST prior to primary transplantation was 30%, but this sensitization has been generally specific and narrow-those patients developing a positive DSXM do not appear to be jeopardized regarding later cadaver transplantation. Graft survival rates in 86 recipients of kidneys from their blood donors are 95% (1-year) and 93% (2-year). This graft survival rate appears to outweigh the minimal risk of possible unfavorable sensitization. Potentially unsuccessful transplants in immunologically disparate related donor-recipient pairs can be avoided, and the transplants actually performed have enhanced prospects of success.

1. Overall, positive FCXM reactions were associated with graft losses in regrafts but not in primary transplants. 2. In transplants involving older female or CVA donors, a positive FCXM appeared to be deleterious in both first transplants and regrafts. If the donor were a younger male and not a CVA victim, only FCXM positive regrafts had low graft survival rates. 3. We presented a 3-color technique allowing the differentiation of antibody reactions against T cells, B cells, and monocytes. Another method allows the simultaneous evaluation of both IgG and IgM reactions against T cells. Using these kinds of methods may make better identification of antibodies that may be harmful to a transplant allograft possible.

We reviewed 77 potential cadaveric allograft recipients who had undergone prospective HLA-A and B locus and HLA-DR antigen identification. Matching was accomplished, giving first priority to HLA-DR compatibility and relying on HLA-A and B antigen matching only in situations of total HLA-DR incompatibility. Complete HLA-DR identification occurred in 56 per cent of all patients. There were 15 patients (19.5 per cent) who received a 2/2 HLA-DR perfect match, with 86.7 plus or minus 8.8 per cent 1-year actuarial graft survival, and 41 (53 per cent) who received a 1/2 HLA-DR match, with 58.2 plus or minus 7.8 per cent 1-year actual allograft survival. Finally, 21 patients (27 per cent) received a 0/2 HLA-DR match, with 64.9 plus or minus 10.7 per cent actual survival. These results and their mirrored mismatching results showed statistically significant allograft success in only the HLA-DR 2/2 matches. Matching for HLA 2 DR donors proved a statistically significant success over the other HLA-DR allograft matches and the older controversial matching system based on HLA-A and B locus antigens. The restricted gene polymorphism of the HLA-DR systems allows for a relatively high percentage of perfect HLA-DR matches.