Marilena Fotino

Intravenous immunoglobulin and thymoglobulin facilitate kidney transplantation in complement-dependent cytotoxicity B-cell and flow cytometry T- or B-cell crossmatch-positive patients.

Background. The aim of this study was to investigate the effect of Thymoglobulin and intravenous immunoglobulin (IVIG) therapy on the clinical outcome of a putatively high-risk group of kidney transplant recipients who have positive B-cell complement-dependent cytotoxicity (CDC) along with positive T- or B-cell flow cytometry (FC) crossmatch results. Methods. We prospectively studied the effects of IVIG and Thymoglobulin induction treatment in B-cell CDC, and T- or B-cell FC crossmatch-positive kidney transplant recipients (seven women and one man; mean age, 43±12 years). Results. Mean peak panel-reactive antibody (PRA) was 47±32. Three patients had donor-specific antibody by flow PRA (two anti-DR4 and one anti-A2). Each recipient received induction treatment with IVIG 100 mg/kg for 3 days and Thymoglobulin 1.5 mg/kg for 5 days after transplantation. No acute cellular rejections occurred during a median follow-up of 15 months (range, 12–17 months). Only one acute humoral rejection occurred 8 days after transplantation, which responded to plasmapheresis, IVIG, and rituximab. One allograft was lost because of polyoma nephritis. Patient survival was 100% and allograft survival was 88%. Conclusion. Our results indicate that IVIG and Thymoglobulin induction treatment may facilitate kidney transplantation in B-cell CDC and T- or B-cell FC crossmatch-positive patients.

Excellent outcome with a calcium channel blocker-supplemented immunosuppressive regimen in cadaveric renal transplantation. A potential strategy to avoid antibody induction protocols.

Many transplant centers routinely utilize monoclonal antibody or polyclonal antibody based induction protocols in recipients of cadaver renal allografts. Given the potential complications associated with antibody-based immunosuppression regimens (e.g., CMV disease), we tested the hypothesis that a combination of a calcium antagonist and a triple drug protocol (cyclosporine + prednisone + azathioprine) would be an effective substitute for antibody-based induction protocols in ensuring excellent patient and graft survival rates. Our postulate was tested in a prospective study of 52 consecutive recipients of cadaver renal allografts (44 first, 5 second, and 3 third grafts) utilizing nifedipine as the first line calcium antagonist. Nifedipine was selected over verapamil or diltiazem due to its lack of interference with the metabolism of CsA. Some of the significant outcomes of our prospective trial were (A) a cumulative patient survival rate of 98.1% for the 52 recipients at 18 months posttransplantation; (B) a cumulative allograft survival rate of 92.1% for the 52 consecutive cadaver renal allografts at 18 months; (C) a cumulative allograft survival rate of 100% at 18 months for the 24 of 52 renal allografts without delayed graft function following transplantation; and (D) a cumulative allograft survival rate of 86% at 18 months for the 28 of 52 renal allografts with delayed graft function. Of the 4 of 52 who lost their grafts, 2 grafts were removed following discontinuation of immunosuppressive therapy while the remaining 2 had primary nonfunction; and (E) the lack of a requirement for monoclonal or polyclonal antibodies for the treatment of acute rejection episodes in this patient population.

MINIMAL SENSITIZATION AND EXCELLENT RENAL ALLOGRAFT OUTCOME FOLLOWING DONOR-SPECIFIC BLOOD TRANSFUSION WITH A SHORT COURSE OF CYCLOSPORINE

A new protocol of donor-specific blood transfusion under cyclosporine coverage was developed and examined for immunologic consequences and clinical efficacy in recipients of one- or zero-HLA-haplotype-matched renal allografts

Induction of immune alterations and successful renal transplantation with a simplified method of donor-specific blood transfusion.

We developed a new and simplified donor-specific blood transfusion (DSBT) protocol for prospective kidney transplant recipients from one-haplotype-mismatched related donors. Prospective kidney donors gave 450 ml of blood in a quad-pack unit, and the blood was stored in a blood bank. Twenty-five patients were transfused with 100 ml of the respective donors whole blood at 1, 8, and 15 days after its storage. After DSBT, only three (12%) developed donor-specific lymphocytotoxic antibodies. Following DSBT, donor-specific mixed lymphocyte culture (MLC) was significantly suppressed, without any accelerated (secondary-type) response in early MLC. In addition, sera obtained after DSBT also suppressed donor-specific MLC significantly. Sixteen recipients subsequently received a kidney transplant from the donor, and all had functioning grafts at three months, but one lost the graft thereafter (graft survival rate: 94% at 12 months). This study indicates that (1) 100 ml of stored whole-blood DSBT three times at weekly intervals is a practical, less immunizing, and effective approach to enhance graft survival in recipients of a one-haplotype-mismatched graft; and (2) immune consequences of DSBT include induction of donor-specific cellular and humoral adaptive responses that might be conducive to successful graft outcome.

Kidney Transplantation: Improvement in Patient and Graft Survival

Patient and graft survival were reviewed in a series of 249 kidney transplants done from 1963 to March 1973. Patient survival was calculated by the life table method for the periods 1963-1970, and 1970-1973, since in 1970 a formal Kidney Center was established and mortality rates changed. Graft survival was analyzed in terms of donor source, HL-A matching and immune responsiveness to HL-A antigens. Three-year predicted mortality for cadaver kidney recipients was 62% between 1963 and 1969 (42 patients) and 8% between 1970 anid 1973 (67 patients). Similar predicted mortality for related living donors was 30% between 1963 and 1969 (52 patients) and 14% between 1970 and 1973 (85 patients). Mortality has continued to decrease and there has been only one death in the last 87 consecutive transplants, including 57 consecutive cadaver transplants. Oneyear predicted kidney survival for the 10-year period is 44% for cadaveric, 60% for non HL-A identical related living and 90% for HL-A identical sibling donors. In the cadaver group, those sharing 2 or more HL-A antigens had the same kidney survival as the non HL-A identical related living donor grafts. Since cadaver graft recipients are on dialysis for a longer period of time, immune responsiveness can be detected by their response to blood transfusions, whereas this determination could not be made in our related living donor group. Non-responsive cadaver kidney recipients had 80% one year kidney survival. We conclude that transplant mortality can be reduced to less than 10% by the Center approach to treatment of renal disease, dialysis does not adversely affect future transplantation, and excellent (80%) kidney survival can be expected in properly selected cadaver graft recipients.

Enhanced kidney graft survival with retroplacental source γ-globulin: results of a 5-year prospective study at a single center

We examined the possibility that retroplacental source γ-globulin (RPGG), with its content of anti-HLA antibodies, would improve cadaver kidney graft survival rates. In a 5-year controlled prospective study of 208 transplants, we found that the addition of RPGG to a standard immunosuppressive drug regimen (azathioprine and prednisone) resulted in significant improvement of the cumulative survival rate (CSR) of first and second grafts. At 2 years, the overall CSR of first grafts increased from a control value of 37% ± 6 to 52% ± 6 (P = 0.037). Among second graft recipients, the CSR increased from a value of 19% ± 8 to 50% ± 10 (P = 0.014). This improvement in graft survival was seen as early as 3 months after surgery and was sustained through 3 years without added recipient morbidity or mortality. When recipient populations were stratified for various factors, those groupings remonstrative of an intact or active humoral immune response capacity were found to have the highest survival rates in the study; 2-year graft CSRs of 70% ± 6 and 65% ± 10 were found in recipients with preformed antibody resulting from blood transfusions (P = 0.003) and cytomegalovirus infectivity (P = 0.0006), respectively. These findings indicate that the improved graft survival seen in this study may have resulted from a recipients immunological response to challenge with RPGG.

ADVERSE PRESENSITIZATION TO RENAL TRANSPLANTS: Detection by Utilization of a D Locus Antigen-Defined Lymphoblastoid Cell Panel as Targets in Antibody-Dependent Cell-Mediated Cytotoxicity Assays

Sera obtained before transplantation from 52 consecutive renal allograft recipients were tested for antibody-dependent cell-mediated cytotoxicity (ADCC) and for complement-dependent cytotoxic antibodies (CDC). A D locus antigen-defined lymphoblastoid cell panel (B lymphoblastoid cell panel) was used as targets for the ADCC, and a peripheral blood lymphocyte (PBL) panel from 40 donors was used as targets for the CDC. Of the 343 ADCC assays, 118 of 168 performed with pretransplant sera from 24 recipients with early graft loss were positive, whereas only 81 of 175 performed with pretransplant sera from 25 recipients with a successful graft outcome were positive (P less than 0.001). A significantly greater degree of presensitization to the B lymphoblastoid cell panel was found in the group that lost their grafts as compared to the group with successful grafts (69% versus 49%, P less than 0.001). Sera from all six recipients with hyperacute rejection were positive in the ADCC before and after absorption with pooled platelets. In contrast, pretransplant CDC results were not predictive of ultimate graft outcome. Utilizing any level of cytotoxicity against the PBL panel as an index of adverse presensitization, no significant correlation between pretransplant CDC results and graft outcome was observed. These results suggest a prognostic role for ADCC using a B lymphoblastoid cell panel as targets to screen and identify high-risk potential graft recipients.

Positive crossmatches against mandatorily shared kidneys.

&NA; From October 1987 through February 1990 approximately 8.5% (29/341) of all donor kidneys shipped under the UNOS Mandatory Sharing Policy were denied to 27 intended recipients due to a positive final crossmatch [XM(+)]. The intended recipients included 18.5% hispanics and 7.4% blacks compared to 2.4% and 1.6%, respectively, for XM(-) recipients (1–3). Further, more were highly sensitized with 81% having a current PRA >10% and 56% with a peak PRA >80% compared to 65% and 14%, respectively, for XM(-) recipients. More importantly, 19/27 (70%) of the recipient candidates may have had irrelevant positive XMs. The XM(+) patients were classified into five categories defined by: I) autoantibodies; II) transfusions in the 2 weeks prior to the availability of the donor; III) the XM technique; IV) highly sensitized regraft candidates with current and peak PRAs >85% and V) antibody to unreported MHC antigens. Of these, 70% may have been denied a transplant due to IgM autoantibodies or the use of XM techniques lacking extensive evaluation. The authors propose that all XM(+) mandatorily-shared kidneys be examined for IgM autoantibody and that kidneys not be denied to potential recipients due to IgM autoantibody. In addition, to minimize exclusions based on positive B-cell XMs, it is proposed that man-datorily-shared kidneys be shared on the basis of the DR subtypes, insofar as is currently practical.