High Panel Reactive Antibody Research Articles

Time dependency of factors affecting renal allograft survival.

The function of renal transplants can deteriorate at any time posttransplant, but the risks and mechanisms may differ at different times posttransplant. Survival of 522 consecutive cadaveric renal transplant recipients followed for at least 6 mo were analyzed, with patient death censored. The overall risk factors in univariate analysis were acute rejection requiring antibody therapy (AR), delayed graft function, elevated serum creatinine at 6 mo, high panel-reactive antibodies, and donor age > or =55 yr, with borderline effects of recipient age and female gender. These risks were studied in each of three intervals posttransplantation: < or =6 mo, 6 mo to 5 yr, and >5 yr. Of the 135 graft failures, 53 occurred < or =6 mo, 61 between 6 mo and 5 yr, and 21 beyond 5 yr. By multivariate analysis. the risks for graft failure in interval < or =6 mo were AR (hazard ratio (HR) = 4.86, P < 0.001); delayed graft function (HR = 1.47, P = 0.06): and high panel-reactive antibodies (HR = 2.04, P = 0.0(3). Between 6 mo and 5 yr, the risks for graft loss were AR (HR = 2.87, P < 0.001) and serum creatinine at 6 mo > or =150 micromol/L (HR = 3.69, P < 0.001). Beyond 5 yr the risk factors were donor age > or =55 yr (HR = 5.87, P = 0.002), with a borderline effect of kidneys from female donors (HR = 2.28, P = 0.07). HLA-A, -B, and -DR matching and presensitization had most of their effect through early AR and impaired function. The results indicate that risks for graft loss are time-dependent: early losses correlate with injury and rejection, but late events correlate with donor age and possibly workload.

Increased immunosuppressive vulnerability in elderly renal transplant recipients.

The results of renal transplantation have improved steadily over the last 10 years. This improvement is in large part attributable to improvements in immunosuppressive pharmacotherapy. Several phase III clinical trials have demonstrated decreased acute rejection rates with relatively little, if any, increase in infectious complications in a broad cross-section of patients (1‐12). It is possible, however, that in certain subpopulations of patients, such as elderly renal transplant recipients, the risk/benefit ratio of acute rejection versus infection may be different from that of the general renal transplant population. If this were the case, the appropriate immunosuppressive regimen for that population should be reconsidered. Renal transplantation is a relatively safe option for renal replacement therapy in elderly patients with end-stage renal disease (ESRD). In 1976, Tersigni et al. (13) reported a series of nine ESRD patients above the age of 60 years successfully treated with renal transplantation. Shortly thereafter, Wedel et al. (14) published a series of 41 geriatric renal transplant recipients, and pointed out that the risk to these patients was not graft loss from rejection but, rather, death with a functioning graft. This author also reported that there was an increased risk for serious infectious complications in the older age group. With the advent of cyclosporine and more selective immunosuppression, the results of renal transplantation improved in high-risk groups, such as elderly patients. In 1989, Pirsch et al (15) concluded that cadaveric renal transplantation with cyclosporine immunosuppression was safe and an effective therapeutic modality in elderly ESRD patients. Subsequent studies have reinforced that concept (16) but have also reinforced the idea that elderly patients have a degree of immune incompetence (17) and require less aggressive immunosuppressive therapy (17). That theory was supported by the continuing observation of lower rejection rates (17, 18) and lower incidence of chronic rejection (18, 19), but higher risk of infections (19, 20) noted in elderly transplant recipients. Reinforcement of the practice of transplantation in elderly patients came from a study that showed significantly greater survival probability in ESRD patients over the age of 60 who received transplants as opposed to matched patients who remained on dialysis (9). Recent data demonstrate a very similar 5-year graft (54 ‐74%) and patient survival (52‐74%), confirming the improvement made but also the concept that most patients in this high-risk group die with functioning grafts (19). In this study, posttransplant morbidity was attributed primarily to infectious complications and an increased prevalence of malignancy (19). We demonstrated previously, in a single-center study, that intensification of immunosuppressive therapy in elderly transplant recipients increased infectious complications without decreasing the incidence of acute rejection or improvement in graft survival (21). Given the above data, it is possible that the vulnerability to immunosuppression of older renal transplant patients may be very different from that of younger patients. To test this hypothesis, we analyzed a large group of renal transplant recipients with regard to their balance of acute rejection versus death due to infection.

Microchimerism in sensitized renal patients.

Patients exposed to allogeneic human tissue sometimes produce anti-HLA antibody for many years in the absence of further obvious antigen exposure. To investigate the mechanism of sustained sensitization, we identified females awaiting renal transplantation with high panel-reactive antibody but no exposure to allogeneic tissue for at least 1 month. We analyzed peripheral blood microchimerism using nested polymerase chain reaction amplification specific for the SRY region of the Y chromosome. Microchimerism was detected in 3 of 10 patients but in none of 8 normal female subjects. In two cases, the amplified DNA polymerase chain reaction product was sequenced and was confirmed to be identical to the SRY gene. The estimated level of chimerism as compared with serial dilutions of DNA from male peripheral blood leukocytes was about 1/50000. These results do not establish causality but support the possibility that antigens from microchimeric donor cells may sustain the HLA antibody response in certain patients.

Dacluzimab is Comparable to Antithymocyte Globulin (ATG) Induction in Preventing Acute Rejection (AR) Episodes in High Risk Renal Transplant Recipients

577 Dacluzimab has been shown to significantly reduce the incidence of AR in primary cadaveric renal transplants as compared to placebo [cyclosporine (CSA) and prednisone, or CSA, prednisone and azathioprine]. Its role in high risk renal transplant recipients has not been evaluated. Prior to the availability of Dacluzimab, we used ATG induction in these patients. Methods: In this pilot study we used variable doses of Dacluzimab (1-5 doses depending upon the status of graft function) in conjunction with CSA or FK 506, mycophenolate mofetil (MMF) and prednisone in 17 high risk renal transplant recipients. The indications for Dacluzimab induction included primary graft dysfunction in 5, post- transplant graft dysfunction in 4, prolonged cold ischemia time (>24 hours) in 4, and retransplants with high panel reactive antibodies (PRA) in 4. One patient had a combined liver kidney transplant. The number of AR episodes, need for OKT3 treatment, patient and graft survival and serum creatinines at 3 months were compared to 16 retrospective controls who received ATG induction along with CSA or FK 506, MMF and prednisone. The indications for ATG included primary graft dysfunction in 13 and post-transplant graft dysfunction in 3. Results: Both groups were comparable for age, sex, race, HLA mismatches, PRA, primary versus retransplants, cadaver versus living related transplants, number of patients receiving CSA or FK 506, dialysis and duration of dialysis. One patient died in each group (pseudomonas sepsis in the Dacluzimab group and myocardial infarction in the ATG group). The remaining patients are alive with functioning grafts. One patient in ATG group developed cytomegalovirus (CMV) infection. Three patients (17.6%) had AR in the Dacluzimab group. Of these, one had acute vascular rejection on day 3 after transplant and required treatment with OKT3. Four patients (25%) had AR in ATG group. None required treatment with OKT3. The number of Dacluzimab doses ranged from 1-5 (1.8 ± 1.3). The number of ATG doses ranged from 2-14 (8.9 ± 3.5). The length of stay in the hospital was longer in Dacluzimab group 12.6 ± 8.1 versus 8.4 ± 2.8. The difference was due to pseudomonas sepsis, pulmonary hemorrhage, and liver transplant related complications in three patients respectively. Serum creatinines at 3 months were comparable (1.9 ± 1.4 in Dacluzimab group versus 1.7 ± 1.7 in ATG group). The long term data is not yet available. Conclusions: 1) In this pilot study we show that Dacluzimab induction is comparable to ATG in high risk renal transplant recipients in preventing AR. 2) Patient and graft survival, incidence of CMV infections and serum creatinine at 3 months are comparable in both groups. 3) Since the cost of ATG per dose is equivalent to Dacluzimab dose, it is cost effective to use Dacluzimab (2 doses versus 9 doses of ATG). 4) Dacluzimab is also more convenient to administer avoiding a central line essential for ATG. These results need to be validated in a larger multicenter trial.

Rethinking chronic allograft nephropathy: the concept of accelerated senescence.

Rethinking chronic allograft nephropathy: the concept of accelerated senescence.

HLA antibodies present in the sera of sensitized patients awaiting renal transplant are also reactive to swine leukocyte antigens.

To determine whether preformed HLA alloantibodies present in the sera of patients awaiting kidney transplantation will be detrimental to a potential porcine xenograft, we tested their cross-reactivity to swine leukocyte antigens (SLA). Sera obtained from patients with varying levels of HLA sensitization (high panel-reactive antibodies > 70%, n= 7; moderate panel-reactive antibodies 30-40%, n=2) were analyzed. Pooled normal human AB sera and sera from nonsensitized patients (n=3) served as negative control. IgG was purified by protein-G chromatography, and xenoreactive natural antibodies (XNA) were depleted by passing the IgG through a series of melibiose and thyroglobulin-agarose columns. The elimination of XNA from HLA IgG preparations was confirmed by GS-IB4 lectin blocking assay and by an ELISA. IgG isolated from normal AB serum and three nonsensitized patients, which was depleted of XNA (HLA-IgG), did not react to human or porcine lymphocytes (peripheral blood mononuclear cells; PBMC) either by flow cytometry or by complement-dependent microcytotoxicity assays. However, HLA-IgG isolated from nine sensitized patients were reactive to a panel of porcine peripheral blood lymphocytes (n=6) by flow cytometry (>50 mean channel shift) and in complement-dependent microcytotoxicity assays in addition to their reactivity to human PBMC. The binding of HLA-IgG to porcine PBMC was significantly reduced by preabsorption with pooled human platelet concentrate. Further, the HLA IgG showed recognition of 45-kDa affinity-purified SLA class I on Western blots. This study demonstrates that HLA antibodies present in the sera of sensitized individuals can cross-react with SLA. Thus, xenotransplantation of porcine organs into HLA-sensitized patients has the potential to be rejected by humoral mechanisms. Testing to avoid such cross-reactive antibodies should be considered.

Positive panel reactive antibody titers in patients bridged to transplantation with a mechanical assist device: risk factors and treatment.

Patients who are bridged-to-transplantation with mechanical support have a high incidence of pretransplant sensitization defined by panel reactive antibody (PRA) titers greater than 10. Risk factors for positive PRA in patients with assist devices were investigated. From 1993 to 1997, 17 patients underwent implant surgery with CardioWest C-70 total artificial hearts (TAHs; CardioWest Technologies, Inc., Tucson, AZ), and 13 with Novacor left ventricular assist systems (LVASs; Baxter Healthcare, Novacor Division, Oakland, CA) for bridge-to-transplantation at this institution. Two patients died during implantation of the assist devices. Of the remaining 28 patients, four (14%) were women (3 with TAHs and 1 with an LVAS). All four women (100%) had a positive PRA, whereas only two of the 24 men (8%) had positive PRA (p < 0.0001). The transfusion histories of these patients were reviewed. Using chi-squared analysis (alpha = 0.05), the PRA levels were independent of transfusion of packed red blood cells and fresh frozen plasma. There was an association, however, between platelet transfusions and PRA levels. The times on device awaiting cardiac transplantation were also compared between the PRA positive and PRA negative groups. The average time to transplantation for PRA positive patients was 116 days, whereas the average waiting time for the PRA negative patients was 55 days (p = 0.05). Based on these data, a female patient with consistently positive PRA (93%) after TAH implantation underwent a transplant on post implant day 25 despite a positive lymphocytotoxic crossmatch with the donor. She was treated with plasmapheresis during cardiopulmonary bypass at the time of transplantation, and with four further treatments post transplant. As of this writing, she is alive and well on our standard triple immunotherapy. Therefore, women who are bridged-to-transplantation with assist devices are at risk for positive PRA. It is recommended that patients who are bridged-to-transplantation with assist devices and have high PRA levels be treated with perioperative plasmapheresis. With this aggressive approach, it may no longer be necessary to keep patients on mechanical support for prolonged periods, but possible to perform transplants as soon as suitable donors become available.

The high grade match kidney sharing algorithm of the South-Eastern Organ Procurement Foundation (SEOPF): altering recipient demographics through improved matching.

Studies of kidneys shared through the South-Eastern Organ Procurement Foundation (SEOPF) have shown that regional organ procurement (ROP) trays can predict negative crossmatch in highly sensitized patients when the HLA match is of a high grade. In an attempt to offer more well-matched kidneys to highly sensitized patients, SEOPF organized the High Grade Match (HGM) Program. This United Network for Organ Sharing (UNOS)-approved allocation variance requires mandatory sharing of all kidneys by participating centers after UNOS mandatory sharing requirements have been met. The HGM levels of sharing are: (1) 0 A,B mismatch (MM); panel-reactive antibody (PRA) > or = 40%; negative ROP crossmatch; (2) 0 B,DR MM with > or = 40% PRA; negative ROP crossmatch; (3) 0 B,DR MM with PRA < 40%. Non-HGM cadaveric transplants at the same participating centers--locally or distally procured--serve as the control group. During the first 18 months of this program, the 23 participating centers shared 124 kidneys of the 1592 that were available. Well-matched kidneys (two mismatches or less) accounted for 91.1% in the HGM group, but only 19% of the controls (P<0.0001). Highly sensitized patients (PRA > or = 40%) represented 13.8% of the HGM group, but only 3.3% of the non-HGM group (P<.0001). With HGM kidneys, there was a shift in recipient demographics. Patients with blood group O, female patients, older patients, and retransplanted patients all accounted for significantly larger percentages of the HGM group compared with the non-HGM control group. The racial composition of the recipients of high-grade matches was, however, no different than that of the control recipients at the same centers. The HGM Program resulted in longer ischemia times, but graft survival was not affected. The 1-year actuarial graft survival rate (Kaplan-Meier) for HGM kidneys was not different from the control cadaveric graft survival rate. By sharing kidneys based on improved HLA matches with consideration for high PRA, the HGM Program offered more transplant opportunities to women, blood group O recipients, retransplants, and older patients.

A positive crossmatch in liver transplantation--no effect or inappropriate analysis? A prospective study.

Controversy over the relationship of preformed lymphocytotoxic antibodies and liver graft outcome remains. Because graft loss associated with preformed lymphocytotoxic antibodies probably occurs early after transplant, analysis of long-term survival is of questionable value. We therefore prospectively analyzed the effect on short- and long-term graft survival of the presence of lymphocytotoxic alloantibody in 207 primary adult liver allograft recipients. Pretransplant serum was tested for donor-specific lymphocytotoxic antibodies and panel-reactive antibodies (PRA) using donor splenic lymphocytes and lymphocytes obtained for routine tissue typing. A positive crossmatch was detected in 24 recipients (11.5%): T-cell positive in 11 recipients and B-cell positive in 13 recipients. PRA were detected in 68 of 179 recipients tested (37.4%). High T-cell PRA (>55%) was detected in 17 recipients, and high B-cell PRA was detected in 20 recipients. Low PRA (<15%) against T cells was detected in 19 recipients and against B cells in 24 recipients. Graft failures occurred in 5 of 24 (21%) crossmatch-positive recipients and in 7 of 172 (4%) crossmatch-negative recipients. Graft survival was significantly lower in crossmatch-positive recipients at 1 month after transplant (chi-square=10.3, P=0.00133) but not at 3 months or 1 year. Causes of early graft loss were associated with immunological mechanisms, whereas later losses were due to nonimmunological mechanisms. Early graft loss may be increased in those recipients who are crossmatch positive. However, the logistical problems and consequences associated with allocation probably outweigh the benefits of prospective crossmatching.

Determination of HLA-A,B residue mismatch acceptability for kidneys transplanted into highly sensitized patients: a report of a collaborative study conducted during the 12th International Histocompatibility Workshop.

During the 12th International Histocompatibility Workshop, a collaborative study between 35 laboratories was conducted on a group of highly allosensitized patients who had received a kidney transplant from 1981 to 1995. The major goal of the study was to assess how serum screening against a large cell panel could determine donor HLA mismatch acceptability in relation to graft outcome. Twenty laboratories participated in an extensive screening of 92 high panel-reactive antibody (PRA) sera from patients at 29 transplant centers worldwide; each patient had received a kidney allograft from an HLA-A,B mismatched unrelated donor. Screening was done by complement-dependent lymphocytotoxicity and antihuman globulin augmentation techniques using a common protocol and shared standardized reagents. After an extensive quality-control assessment, we selected data from 14 participants who had screened the sera against a combined panel of 535 HLA-typed cells. With the 2x2 table-based Multiscreen computer program, we could readily determine for virtually every patient the significant correlations between serum reactivity and the presence of panel cell markers, including private and public HLA-A,B epitopes and amino acid residues assigned from published sequencing data. Donor mismatch acceptability was assessed at the amino acid residue level. In the complement-dependent lymphocytotoxicity (n=49; PRA=84.1+/-12.1%) and antihuman globulin (n=60; PRA=92.5+/-5.8%) groups, the 3-month graft survivals were 28% and 30% lower for unacceptable residue mismatches. These studies underscore the importance of a comprehensive serum screening analysis in the selection of appropriately mismatched donors for highly sensitized transplant patients.

Utility of xenografts: Lack of correlation between PRA and natural antibodies to swine

Abstract: Among the patients that might potentially benefit from the availability of xenografts are those in kidney failure who demonstrate high levels of antibody reactivity to panels of typing lymphocytes. Such individuals with high PRA (panel reactive antibody) are unlikely to receive a renal allograft because they are highly sensitized to the vast majority of potential donors. In addition, all humans have demonstrable levels of natural antibodies reactive to distantly related species such as the pig. If there were a correlation between PRA and levels of natural antibodies, then such patients would also be at greater risk for hyperacute rejection of xenografts. We have therefore examined, in a blinded fashion, the porcine lymphocyte reactivity of sera from PRA positive donors. Subsets of the 105 sera tested were grouped by PRA level and analyzed for levels of natural antibodies detectable by a complement‐dependent cytotoxicity assay on porcine lymphocytes. There was no significant difference in the range of titers of natural antibodies between subsets. Thus, there was no demonstrable correlation between levels of PRA and levels of natural antibodies to porcine lymphocytes.In addition, we studied the sera of 11 highly sensitized patients who received renal allografts and conventional triple drug immunosuppression in order to determine whether immunosuppression to maintain a vascularized allograft had an effect on PRA and/or xenoreactivity. Mean post‐operative PRA was significantly lower than mean pre‐operative PRA, while there was no significant difference in xenoreactivity. Thus, pre‐transplant immunosuppression may permit an increased opportunity to identify compatible human donors for highly sensitized recipients and will not help or hinder the pre‐transplant conditioning of a candidate for I xenotransplantation.

Hyperacute Rejection Following Lung Transplantation

Although hyperacute rejection has been clinically and pathologically fully described in recipients of other solid organ transplants, to our knowledge, there have been no previous fully documented cases in recipients of lung transplants. This case of clinical hyperacute rejection is corroborated by a positive, donor-antigen-specific IgG-mediated lymphocytotoxic crossmatch (LXM), and demonstrated histopathologic, immunofluorescent, and electron microscopic features consistent with hyperacute rejection as described in other organs. Features of diffuse alveolar damage, neutrophilic infiltrates, and endothelial and epithelial damage with IgG-fluorescent staining within alveolar spaces and septae were demonstrated. The management of hyperacute rejection and its outcome are reviewed. Historically a pretransplant crossmatch is not considered a routine part of lung transplantation. The outcome of this patient suggests that LXM should be performed routinely prior to lung transplant in all patients with high panel-reactive antibodies, and should be performed whenever circumstances permit.

Influence of anti-HLA antibodies and positive T-lymphocytotoxic crossmatch on survival and graft rejection in human liver transplantation

Background/Aims: The role of crossmatching in liver transplantation is controversial. The aim of this study was to investigate retrospectively the effect of sensitization and IgG lymphocytotoxic crossmatching on liver transplantation. Methods/Results: Over 5 years, 20 of 243 (8.2%) first liver transplants were performed with a positive crossmatch and their outcome was compared with the remaining 223 performed with a negative crossmatch. Women had a higher incidence of positive crossmatch than men ( p<0.001). Significant differences in mean panel reactive antibody of 2.7% and 43.3% were found in negative and positive crossmatch patients, respectively ( p<0.001). Severe early rejection resulting in graft loss occurred in eight of 20 positive crossmatch patients, and only one of 223 negative crossmatch patients ( p<0.001). Five of the remaining positive crossmatch patients suffered several acute rejection episodes some months after liver transplantation. Two of 20 in the positive crossmatch group developed chronic rejection (10%) compared with ten of 223 negatives (4.4%) (N.S). Nine of 16 positive crossmatch female recipients suffered graft loss and seven died, representing 1-year graft and patient survival of 56% and 43%, respectively. Fifteen of 68 negative crossmatch female recipients presented graft loss and 12 died, accounting for 1-year patient and graft survival of 82% and 78% ( p<0.005), respectively. Five patients (20%) displayed positive crossmatch at the time of retransplantation, compared with 24 (10%) who were negative (N.S). Conclusion: Our experience confirms the adverse impact of a positive crossmatch in liver transplantation, particularly in female recipients. Candidates with high panel reactive antibody are more likely to display a positive crossmatch, and therefore to develop early severe rejection and graft failure.

Adverse impact of high panel-reactive antibody (PRA) and positive cytotoxic crossmatch in liver transplantation.

Of 91 liver transplants (LTX) performed from October 1988 to December 1992, 13 (14.2%) of the patients received a liver from a lymphocytotoxic-positive crossmatch (CM) donor. Severe early rejection resulting in graft floss occurred in seven positive CM patients. Three of the remaining positive CM patients suffered several rejection episodes leading to chronic rejection and FK 506 was required as rescue treatment. A significant difference in mean panel-reactive antibody (PRA) of 8.6% and 56.9% was found in negative and positive CM patients, respectively (P = 0.012). A higher mean PRA (67.7%) was found in positive CM patients with rejection compared with positive CM patients without rejection (PRA 38%). Overall graft and patient survival were 31.9% and 35% in positive CM patients compared with 57.0% and 61.9% in negative CM patients. These differences were statistically significant (P = 0.023). In our experience the risk of developing severe acute rejection with graft failure and chronic rejection is related to PRA > 60% and positive CM. We recommend that in patients with PRA > 60%, the result of CM should be awaited before proceeding to LTX.

Retrospective evaluation of flow cytometry as a platelet crossmatching procedure.

We performed a retrospective analysis of flow cytometry as a platelet crossmatching procedure. Sera from 17 alloimmunized refractory patients were tested against 32 donor platelets, which had been stored as platelet-rich plasma for up to 36 months. Overall, 14/32 (44%) crossmatches were positive. The mean 1 h posttransfusion corrected count increments (CCIs) were 9,195 and 2,269 for a negative and a positive crossmatch, respectively. The predictive value of a positive crossmatch was 86%, whereas the predictive value of a negative crossmatch was 56%. When samples with low background fluorescence or with high panel-reactive antibody (PRA) levels were evaluated separately, the accuracy of the crossmatch improved from 69% to 80%. When compared to the platelet adhesion immunofluorescence test (PAIFT) and the standard and antiglobulin-enhanced lymphocytotoxicity tests for the detection of HLA antibodies, flow cytometry appeared to be more sensitive. We conclude that flow cytometry is a useful technique for platelet crossmatching, particularly for alloimmunized patients for whom HLA compatible platelets may not be readily available.

Effect of panel reactive antibody on live related donor kidney transplantation: Indian experience

Serum samples from 95 recipients, transplanted with kidneys from live related donors, were tested for the presence of panel reactive antibodies (PRA) in pre- and post-transplant serum samples by the extended microdroplet lymphocytotoxicity test. The immunoglobulin class of antibodies was tested by treatment of serum with dithiothreitol. A significant correlation was found between the high PRA found in the 75 pretransplant sera tested and the subsequent rejection episodes. In addition, the level of pretransplant PRA activity was associated with graft survival in that patients with low PRA had significantly superior graft survival than shose with high PRA. Furthermore, the present data show that patients with historical high PRA, but current low PRA, had graft survival similar to that in recipients who had moderate PRA in their current sera. High PRA patients had more often a positive crossmatch than patients with low PRA. The PRA level was also associated with prolonged waiting period. Immunoglobulin class of antibodies was related to graft acceptance in that the presence of IgM antibodies was not detrimental to transplantation. The results in the present study suggest that PRA of <10% is negligible, while more attention should be paid to patients with PRA > 10%.

Renal Transplantation in Patients 65 Years Old or Older

Between January 1982 and August 1989, cadaveric renal transplantation was performed in 22 patients 65 years old or older. Mean recipient age was 68 years (range 65 to 73 years). There were 17 men and 5 women. Additional risk factors included retransplantation (3 patients), high (greater than 30%) panel reactive antibody (4) and diabetes (1). All patients received cyclosporine as part of the immunosuppressive regimen. The 3-year actuarial patient and allograft survival rates were 89% and 71%, respectively. There were 6 graft losses due to chronic rejection (2 patients), renal vein thrombosis (1), myocardial infarction (1), withdrawal of immunosuppression because of sepsis (1) and primary nonfunction (1). Of the 16 patients with a functioning graft 12 currently have a serum creatinine of less than 2.0mg./dl. These results suggest that cadaveric renal transplantation is an acceptable form of treatment for patients older than 65 years with end stage renal disease.

Evaluation of flowcytometric crossmatching in renal allograft recipients.

Forty-four cadaver renal allograft recipients who had flowcytometric cross-match (FCXM) testing and sequential quadruple immunosuppression were studied with respect to the number of rejection episodes and the functional viability of the graft in the first year after transplantation. Fourteen of these patients had antibodies to donor T cells by FCXM. All were negative by conventional crossmatch. Multiple-regression analysis with HLA mismatches, panel-reactive antibody (PRA) percentage, flowcytometric channel shifts and transplant number as independent variables revealed that transplant number and high PRA (> 50%) impacted (p < 0.05) on serum creatinine at 1 month and 1 year, and graft survival at 1 year. In first transplants, a positive FCXM had no impact on 1-year graft survival rates; however, in retransplants, a positive FCXM and/or high PRA had a significant negative impact on 1-year graft survival. This study indicates that the FCXM should be utilized for retransplant patients, and in patients with a high PRA, in an attempt to improve graft survival for these high-risk recipients.

Evaluation of B-cell immunity in patients with pretransplant sensitization.

The influence of presensitization (blood transfusions) on B-cell immunity as reflected in the serum of two groups of candidates for cadaveric donor renal allografts was examined. The first group initially had a high level of panel-reactive antibody (PRA) greater than 72% but experienced a large decrease in PRA (greater than 70%) 6-34 months prior to transplantation. In contrast, the second group maintained a high PRA (100%) for up to 28 months after sensitization and before transplantation. Three blood Three blood samples from each patient, representing a maximum time span of 34 months, were analyzed. Levels of IgG, IgM isohemagglutinins, and antitetanus antibody were used as indicators of B-cell function. There were no significant differences between the individual values of a single patient with regard to each parameter. However, Group II patients had elevated values of total IgG relative to Group I patients. Total serum IgG-subclass levels (IgG1, IgG2, IgG3, IgG4) were measured and the relationship between a specific IgG subclass and the PRA activity was determined. IgG1 values in Group II were higher than those found for Group I. The other IgG subclasses were all within normal levels and were not significantly different between Group I and Group II. When IgG-subclass typing of PRA was performed, IgG1 accounted for most of the activity in both groups and a fall in PRA-specific IgG1 was associated with the reduced PRA observed in Group I. The data indicate that humoral immunity, as reflected by total and specific immunoglobulin levels, is intact in general in the two groups of presensitized renal allograft candidates examined and that any loss of PRA activity reflects a reduction in a specific immune response.

OKT3 therapy as a cause of high panel-reactive antibodies in serum using standard microcytotoxicity techniques.

OKT3 therapy as a cause of high panel-reactive antibodies in serum using standard microcytotoxicity techniques.