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Serological characterization of antibodies eluted from chronically rejected human renal allografts.

Serum samples collected pre- and post-transplant nephrectomy were screened for alloreactive lymphocytotoxins. Three patients demonstrated circulating anti-B cell antibodies with markedly increased cytotoxicity titers after nephrectomy, suggesting that there was active binding of antibodies within the renal allograft. Two of the postnephrectomy serum samples after absorptions with platelets and B cells reacted by immunofluorescence with cultured primary kidney cells but not against B or T cells from the same donor. To clarify further the role of such alloreactive antibodies, eluates were prepared from 14 rejected renal allografts and were analyzed for reactivity to cultured primary kidney cells against different leukocyte targets and endothelial cells. Reactivity toward B cells and kidney cells was demonstrated with 80% of the eluates. Absorption experiments of the positive eluates demonstrated multiple types of alloreactive antibodies. In addition to anti-DR activity, eluates had antibodies reactive to kidney cell antigens, monocytes, macrophages, endothelial cells, and polymorphonuclear leukocytes. The demonstration of multispecific alloantibodies in eluates of rejected kidneys is consistent with an important role(s) in maintenance and/or rejection of the kidney allograft.

Effects of blood transfusion on cadaver renal transplantation: The southeastern organ procurement foundation prospective study (1977 to 1979)

The dominant beneficial effect of blood transfusions on cadaver renal allograft survival is now well established, although the mechanism of this phenomenon is unexplained. We evaluated data from a multicenter prospective series of 1,101 primary cadaver renal transplants done in the Southeastern Organ Procurement Foundation over a 30-month period. Data on pretransplant blood transfusions were obtained prospectively for transfusions given during the study period and retrospectively for blood transfusions given prior to the study. The administration of pretransplant blood transfusions was not randomized. The transfusion effect accounted for a 20% improved 1-year graft survival rate when the effect of antilymphocyte sera (ALS) and histocompatibility matching were factored out. The type of blood product was important. In patients who received only one type of blood product pretransplant, packed red blood cells (PRBC), washed red blood cells (WRBC), and mixed varieties of blood products (MRBC) were more effective than frozen red cells (FRBC) in achieving improved graft survival. The timing of pretransplant transfusions was important. PRBC, WRBC, and MRBC given 10 to 365 days pretransplant were highly effective while blood products administered at the time of renal transplantation and up to 10 days or over 1 year prior to transplant were less effective. ALS accounted for an average of 15% improved graft survival, but was most effective in the presence of previous transfusions and/or a high HLA match (0 or 1 HLA-A or B antigens mismatched). High HLA match accounted for a 9% improvement in graft survival in the transfused or ALS-treated recipient groups. Our study suggests that blood transfusions are the dominant beneficial factor in primary cadaver renal transplants, and that ALS and high HLA matching provide additional benefit. The best graft survival rates occurred with a combination of transfusions, ALS treatment, and high HLA match; the worst occurred with nontransfused recipients who did not receive ALS and had low HLA match. We showed no graft effects relative to age, HBsAg antigenemia, sex, parity, blood group, or preformed cytotoxic antibody status. It is now clear from reports of over 100 transplant centers that blood transfusions before cadaver renal transplantation exert a beneficial transfusion effect (TE) on graft survival. The practical implications of this finding are still being critically assessed, since the accuracy of the report data is inherently subject to recording errors, and various factors influencing the success of renal transplantation are easily confounded with TE. Few randomized prospective studies have been done on a large enough scale for interpretation, and much of the transfusion history of renal transplant recipients is necessarily retrospective (1). Furthermore, there is caution in accepting a liberal transfusion policy since preformed antileukocyte antibodies may make it difficult or impossible to obtain a cadaver kidney for presensitized patients. Also, hyperacute rejections may occasionally occur even when antibodies cannot be detected by the usual tests. Finally, the risk of hepatitis transmission is as high as 10%, a substantial danger (2). How efficacious is blood transfusion for cadaver renal transplantation, and how can we separate its effects from those of ALS, HLA matching, and other treatment variables? Is the TE synergistic with or antagonistic against other graft-enhancing therapeutic options? In order to assess these questions, the data from a prospective study of the Southeastern Organ Procurement Foundation were critically analyzed. This preliminary report covers 1,101 primary cadaver renal allografts. It confirms the dominant effects of transfusion on cadaver renal grafts and further clarifies the therapeutic value of ALS and HLA matching.

Relationship of B cell alloantibodies to renal allograft survival.

SUMMARY To define the relationship of donor-specific B lymphocyte alloantibodies to renal allograft survival, longitudinal serum samples obtained pre- and post-transplantation were examined for antibodies cytotoxic to donor B lymphocytes. Ten of 17 renal allograft recipients had antibodies to donor B lymphocytes but not T lymphocytes either pre- and/or post-transplantation. Three patients underwent successful transplants despite preformed B cell antibodies; however, seven who developed B cell antibodies only after transplantation are either undergoing chronic rejection (4) or have had severe rejection crisis (3). Seven patients with no B cell antibodies have functioning grafts. In all cases, B cell antibodies were detected before biochemical and clinical evidence of rejection. Similar findings were noted when sera of 38 renal transplant recipients were examined for B cell antibodies cytotoxic to an unrelated panel of B lymphocytes. These results demonstrate that the development of B cell alloantibodies after transplantation is often associated with rejection and that successful renal transplantation can be performed across a positive B cell crossmatch.

METHOD OF PRESERVATION IS NOT A DETERMINANT OF GRAFT OUTCOME IN KIDNEYS TRANSPLANTED BY SOUTHEASTERN ORGAN PROCUREMENT FOUNDATION INSTITUTIONS

We report the observation that the major sources of variation in cadaver renal allograft survival rates are not related to the technique of donor organ preservation but are related solely to other factors including pretransplant blood transfusion of the recipient, antilymphocyte serum (ALS) treatment of the recipient, and high HLA match. In contrast to prior studies which used univariate methods to analyze similar data, our analysis shows that it is imperative that comparisons of different methods of cadaver preservation must include adjustments for the effects of pretransplant blood transfusions, antilymphocyte serum, and HLA match.

THE IMPORTANCE OF THE LEWIS SYSTEM IN CADAVER RENAL TRANSPLANTATION

Previous reports have suggested that Lewis (Le) antigens may exert a significant effect on cadaver renal allograft (CRA) survival, especially in black recipients in whom there is a higher frequency of Le-negative phenotypes. We review our experience with this problem in 70 donor-recipient pairs of CRA who underwent prospective Le typing and received conventional immunosuppression between 1980 and 1983 Recipient typing alone yielded the following graft survival ((IS) and patient survival (PS) at 2 years by life table analysis: (a+,b;-_) (n = 12) 51% GS, 937c PS; (a-,b+) (n = 44) 57% GS, 88% PS; and (a-,b;-) (n = 14) 51% GS, 93% PS(P-ns for GS, PS). Recipient racial characteristics did not effect ultimate graft survival, as whites and blacks had similar two-year GS in all phenotypic groups. When Le matching was considered, no significant differences in one-year graft survivals could be ascertained between Le-matched and Le-mismatched donor-recipient pairs, and this effect persisted despite stratification for race and HLA-A.B and DR histoincompatibilities In light of these results, we do not recommend using Lewis compatibility as a criterion for donor selection in cadaver renal allografting, as this substantially increases the difficulty in finding suitable matches, especially in the (a-,b-) recipient group

Potentiating effect of HLA matching and blood transfusion on renal allograft survival.

An analysis of HLA (A and B) recipient-donor matching on the outcome of 105 cadaver kidney transplants performed at the Medical College of Virginia transplant center revealed that there is a significant, overall difference (P = 0.03) between recipients receiving kidneys mismatched at two or less HLA loci versus recipients mismatched at three or more loci, the fewer mismatch category showing a better graft survival. The effect of blood transfusion prior to transplantation was studied and found to improve the outlook, especially in the best matched groups. The number of transfusions does show a significant effect (P = 0.04) in the subgroup of patients with two or less mismatches, but for patients with three or more mismatches, the number of transfusions does not seem to matter (P = 0.83). However, in this study even the allografts mismatched at three or more loci had a 1-year graft survival of greater than 65%, indicating that factors other than HLA or blood transfusion play significant roles in the graft outcome. Although the findings are based on a somewhat small number of patients, the statistical significance suggests a potentiating effect of HLA matching and blood transfusion on renal allograft survival.