Immunopathological studies of the ruptured human renal allograft.

The immunopathology of five cases of spontaneous allograft rupture has been studied. All kidneys were edematous on exploration and routine histological sections showed interstitial edema and mononuclear cell infiltration characteristic of acute rejection. Immunofluorescence revealed, at most, scattered vascular deposition of IgM and mild mesangial C3 deposition. These findings are compared with findings in normal kidneys and kidneys which had been hyperacutely rejected. The normal kidney showed focal afferent arteriolar and proximal mesangial stalk deposition of C3 without IgM. The kidneys of patients with hyperacute rejection showed brilliant staining for fibrin and IgM in all arterial and arteriolar walls with lesser amounts of C3 and IgG; IgM and C3 were prominent in the glomerulus. These findings suggest that mechanisms other than circulating preformed antibodies are responsible for the pathogenesis of spontaneous allograft rupture.     

The definition of ABO factors in transplantation: relation to other humoral antibody states

The first examples of hyperacute rejection of renal hemografts were seen almost 25 years ago when kidneys were transplanted to ABO incompatible recipients whose plasma contained antigraft isoagglutinins. Hyperacute rejection caused in sensitized recipients by lymphocytotoxic antibodies is similar in that the immune reaction triggers an acute inflammatory reaction that leads to widespread thrombotic occlusion and devascularization of the graft. The events after xenotransplantation between certain species are essentially the same. Potential strategies to avoid the precipitating antigen antibody reaction or to mitigate the resulting effector cascade are described.     

异种肾移植超急性排斥反应时血液流变学的变化

采用猪-犬肾移植建立超急性排斥反应模型，以研究此时的血液流变学变化。分别在移植前、移植肾超急性排斥发生时和排斥肾切除后10～15分钟检测外周血的血液流变学参数变化。结果异种肾移植发生超急性排斥时，血小板聚集显著增高，移植肾切除后血中的血小板数和纤维蛋白原明显下降，血小板聚集也恢复原有水平。提示血小板、纤维蛋白原参与了异种移植超急性排斥反应的发生过程，而血小板聚集可能是诊断异种移植超急性排斥反应一个有价值的指标。     

移植肾自发性破裂的诊治

目的：探讨移植肾自发性破裂的原因及防治措施。方法：回顾分析本院３９２例同种肾移植术后发生移植肾自发性破裂２０例临床资料。结果：发生率为５．１％。１４例保留肾脏功能，其中２例经保守治疗痊愈。６例肾切除者中有４例为急性排斥反应引起。结论：肾破裂的发生与排斥反应、肾缺血性损害、肾静脉引流不畅及尿路梗阻有关。对于出血量少、肾功能好者，可采用保守治疗。预防要从肾脏摘取与灌洗、植肾手术、合理应用免疫抑制剂、及     

Characterization of human CD55 and CD59 transgenic pigs and kidney xenotransplantation in the pig-to-baboon combination

New transgenic pigs expressing combinations of regulators of complement activation and other molecules are needed to resist xenograft hyperacute rejection (HAR) and to further analyze and treat xenograft rejection. Double transgenic pigs for human CD55 (hCD55) and human CD59 (hCD59) using the promoter of the human elongation factor 1 alpha gene were generated, and their kidneys were transplanted into nonimmunosuppressed baboons. hCD55 and hCD59 were mainly expressed by the endothelial cells, and these cells showed increased resistance to complement-mediated lysis. Baboons receiving kidneys from hCD55hCD59 pigs survived for 5 and 6 days, and displayed alterations in coagulation. Thrombocytopenia and platelet microthrombi were present within the kidneys. Nontransgenic kidneys showed HAR in less than 2 days. Kidneys from pigs expressing hCD55hCD59 displayed protection against HAR in the absence of immunosuppression. Rejection was associated with coagulopathy leukocyte infiltration and a rebound of anti-alpha Gal antibodies.     

Hyperacute rejection of the transplanted mouse heart

Mouse hearts transplanted heterotopically to MHC-disparate recipients can be hyperacutely rejected (HAR) after a single or 3 sequential donor type skin grafts, or a single intradermal injection of lymphoid cells. In the combinations tested, not all hearts are HAR; most of them are rejected in accelerated fashion. Our results with transplanted rat hearts are similar, even in a genetic combination for which HAR of all hearts has been reported. However, in rats, HAR tends to occur more rapidly and to be associated with more-intense vascular changes. Transfer of serum from mice or rats sensitized by 3 sequential skin grafts likewise resulted in occasional hyperacute but never accelerated rejection. Transfer of lymph node cells from mice sensitized with a single skin graft always resulted in accelerated but never in hyperacute rejection; transfer of cells after 3 sequential skin grafts caused neither accelerated nor hyperacute rejection.     

A predictive test for the efficacy of intravenous immunoglobulin in the inhibition of alloantibodies

Preformed recipient HLA-specific antibodies can cause hyperacute rejection of a transplanted kidney if they are directed against mismatched donor HLA antigens. To avoid hyperacute rejection it is essential that recipient antibodies be identified during patient workup for transplantation and HLA antigens to which a patient is sensitized then be avoided when selecting a kidney donor for them. Absence of donor-specific reactivity is then confirmed by a pretransplantation crossmatch test.     

The role of natural IgM in the hyperacute rejection of discordant heart xenografts.

The mechanism of xenograft hyperacute rejection in discordant species combinations remains controversial. The purpose of this work was to study the role of natural antibodies in the hyperacute rejection of guinea pig hearts transplanted into rats, a highly discordant combination. This study was conducted in vitro, ex vivo, and in vivo. The endothelial cells of the graft being the first targets damaged in the process of hyperacute rejection, the binding of rat natural antibodies to guinea pig endothelial cells was studied by immunofluorescence. The study was carried out in vitro on guinea pig endothelial cells in culture, and ex vivo on isolated guinea pig hearts perfused with either rat serum or immunoglobulins or immunoglobulin fragments bearing the antigen-binding site. In vitro and ex vivo, rat natural IgM were found to bind specifically to guinea pig endothelial cells, since IgM fragments bearing the antigen-binding site (Fab mu and Fab' mu) could be detected on these cells. IgM fragments were able to inhibit the fixation of native IgM molecules. In contrast, rat IgG only bound to endothelial cells through Fc portions. Thus rat natural IgM might play a role in hyperacute rejection by binding to the graft endothelial cells and triggering the complement cascade activation. In order to test the role of natural IgM in vivo, isolated guinea pig hearts were first perfused with rat Fab' mu, which inhibit the binding of IgM and are unable to activate the complement cascade. These hearts were then transplanted into Lewis rats. The rejection time of Fab' mu-perfused guinea pig hearts was prolonged compared with hearts perfused with buffer or IgG F(ab')2. Therefore, in the guinea pig to rat combination, preventing the binding of the recipient's natural IgM to the graft endothelium delays the hyperacute rejection. In addition, natural IgM are likely to play a greater role than natural IgG.     

Renal transplantation across the ABO barrier using A2 kidneys.

BACKGROUND: The waiting list for cadaveric kidney transplantation has continued to grow, and with the relative scarcity of cadaver donors, the median waiting time for patients in the United States increased to 824 days in 1994. The median waiting times for patients with blood groups B or O were 1329 and 1007 days, respectively. Allocation of blood group A2 kidneys (20% of group A) to blood group O and B patients expands their potential donor pool and shortens their waiting time for a kidney transplantation. METHODS: Between May 1991 and June 1998, we transplanted 15 A2 kidneys into 6 blood group O and 9 blood group B patients. Anti-A isoagglutinins were measured before transplantation, and patients with anti-A1 titers > or = 1:8 underwent plasmapheresis (PP). RESULTS: One patient with high titer anti-A antibodies, who did not receive PP, lost her allograft because of hyperacute rejection. Allograft function was excellent in the remaining 14 patients, with a mean serum creatinine level of 1.7 (+/-0.89) mg/dl at 1 month and 1.3 (+/-0.34) mg/dl at 1 year. The actuarial 1-year graft survival rate was 93.3+/-6.4% and the patient survival rate was 100%. CONCLUSION: We conclude that the allocation of blood group A2 kidneys for blood group O and B recipients is a practical way to expand the donor pool for these transplant candidates. PP may be important for reducing the levels of anti-A1 and anti-A2 antibodies and for reducing the risk of hyperacute rejection. Splenectomy seems to be unnecessary.     

Cell-mediated hyperacute rejection. VI. Prolonged survival of heterotopic mouse heart transplants

The survival of heterotopically transplanted mouse hearts was enhanced in recipients who were sensitized intraperitoneally to give rise to cell-mediated hyperacute rejection, a T-cell-mediated response characterized by very rapid sensitization and rejection of allogeneic skin grafts.     

Kidney transplants in cyclosporine-treated Sprague-Dawley rats

Previous studies by others have shown that transplanted rat kidneys have abnormally low clearances of paraaminohippuric acid, inulin, and creatinine, due to rejection and/or to warm-ischemia-induced injury. In the present studies, randomly bred Sprague-Dawley rats were used as donors and recipients. The left kidneys of recipients were removed, and the right kidneys were left intact. Donor kidneys were flushed with an ice-cold hypertonic solution (150 mM NaCl, 200 mM mannitol, pH 6.4), and the kidneys were kept cold during surgery. Renal function was assessed 1 week later. The left transplanted kidneys in untreated recipients exhibited morphologic evidence of rejection, and the clearances of PAH and inulin were approximately 50% of those of the right native kidneys. CsA-treated rats did not reject the transplants, and the PAH and inulin clearances of the left transplanted kidneys were identical to those of the right native kidneys. Untreated and CsA-treated rats with both native kidneys intact served as controls. The amount of CsA given during the 7-day period produced no measurable change in renal function. This is the first demonstration of virtually normal hemodynamics in transplanted rat kidneys when randomly bred animals are used as donors and recipients. Moreover, the results indicate that if both rejection and warm ischemia are avoided, the presence of a functioning native kidney does not have a detrimental effect on the function of a transplanted kidney.     

Immune injury from organ preservation. A potential cause of hyperacute rejection in human cadaver kidney transplantation.

Two pairs of plasma-perfused human cadaver kidneys were rejected in a hyperacute manner by recipients who had not previously received a transplant. Crossmatches between recipient sera and donor lymphocytes were negative in all cases. A fifth kidney was plasma-perfused but not transplanted because the perfusate was shown to be cytotoxic to donor lymphocytes. IgM and complement, but not IgG, were demonstrated in these kidneys by immunofluorescent microscopy and confirmed by further immunological studies. The IgM was broadly reactive against multiple HL-A specificities and was present in 11 percent of sera from normal, healthy male donors. It appears from our studies that cytotoxic IgM may be present in homologous plasma and cause immune injury to the kidney during ex vivo pulsatile preservation. This may be responsible for some cases of otherwise unexplained accelerated allograft rejection.     

Successful renal allografts in recipients with crossmatch-positive, dithioerythritol-treated negative sera. Race, transplant history, and HLA-DR1 phenotype

Graft survival was examined in 15 renal allograft recipients from a group of 20 patients with IgM autolymphocytotoxic antibody that could be removed in a crossmatch assay using a reducing agent, dithioerythritol (DTE). The significant differences in this group of 20 patients compared with end-stage renal disease (ESRD) patients lacking autolymphocytotoxic antibodies included an increased frequency of black patients (P = 0.002), a lack of previous transplants (P = 0.003), and an increased frequency of the HLA-DR1 phenotype (P = 0.0001). Sex and the number of transfusions did not appear significant, whereas the cause of ESRD was primarily systemic lupus erythematosus. Fifteen of the 20 patients were transplanted against a positive donor crossmatch. Eleven were recipients of cadaveric kidneys, nine of which are still functioning for periods ranging from 0.5 to 40 months. Two fo the cadaveric recipients died with functional grafts. Four received living-related donor transplants, one of which was lost to acute rejection one month posttransplant, while the remaining three have survived 1.5, 9, and 21 months, respectively. Fourteen patients had immediate allograft function with no hyperacute rejection and only one case of acute tubular necrosis (ATN) was found. In summary, a negative crossmatch using DTE-treated, autologous reactive recipient sera may identify a group of patients who can be transplanted with minimal concern for hyperacute rejection or ATN. In addition to cause of ESRD, race, transplant history, and HLA-DR phenotype may further define this group of transplant candidates having IgM autolymphocytotoxic antibody. Extrapolation of these conclusions to transplant candidates lacking autolymphocytotoxic antibodies is not warranted.     

Allograft rupture after kidney transplantation

Spontaneous rupture of the parenchyma of the transplanted kidney occurs in 0.8 to 9.6 per cent of transplantations. Mortality is reported to be up to 9 per cent.Every rupture requires surgical intervention. In most cases graftectomy has to be performed. The cause of the rupture is an immunological destruction of the graft, the histological finding being a massive rejection of an interstitial type.In a set of 51 transplantations of cadaver kidneys rupture occurred in 4 patients (7.8 per cent). It was necessary to carry out a graftectomy in all cases immediately or later on.     

Serum and cell-mediated responses in tolerance and hyperacute rejection of transplanted mouse hearts

MHC-disparate recipients that have been sensitized intradermally or via a skin graft reject transplanted mouse hearts hyperacutely. However, transplant survival is prolonged after intraperitoneal or intravenous sensitization. These opposite in vivo events are not correlated with differences in serum antibody responses, but the correlation of hyperacute rejection with delayed-type hypersensitivity is fairly strong. Prolonged survival of heart transplants is probably related to suppressor cells, and adoptively transferable in MHC-compatible combinations. Intraperitoneal or intravenous sensitization, while prolonging survival of heart transplants, causes hyperacute rejection of skin grafts, indicating the importance of the target; it is probably related to differences in the establishment of a blood supply.     

Nontraumatic rupture of renal allografts.

Eight cases of nontraumatic renal allograft rupture were identified in 237 renal transplants performed at UCLA Medical Center. Careful clinicopathologic studies in these patients suggest three principal underlying causes: major graft vessel occlusion, hyperacute or accelerated rejection, and acute rejection. The clinical and pathologic features of these various categories are compared and contrasted.     

尸体供肾体外循环试验病理形态学观察和受者免疫变化

对１０例高度致敏受者在植肾术前进行尸体供肾体外循环试验，术后加强免疫治疗，成功地避免了无效植肾手术。病理形态学观察试验前后受试肾之病理变化，肾间质、血管、肾小球及肾小管基本正常。受者血中ｌｇＭ、ｌｇＡ、ｌｇＧ监测，体外循环后ｌｇＧ浓度明显降低（Ｐ＜０．０５－０．０１），而ｌｇＭ和ｌｇＡ无明显差异（Ｐ＞０．０５）。     

Gal Knockout and Beyond

Recently, Galalpha1-3Galbeta1-4GlcNAc (Gal) knockout (k/o) pigs have been developed using genetic cloning technologies. This remarkable achievement has generated great enthusiasm in xenotransplantation studies. This review summarizes the current status of nonhuman primate experiments using Gal k/o pig organs. Briefly, when Gal k/o pig organs are transplanted into primates, hyperacute rejection does not occur. Although graft survival has been prolonged up to a few months in some cases, the overall results were not better than those using Gal-positive pig organs with human complement regulatory protein transgenes. Gal k/o pig kidneys rapidly developed rejection which was associated with increased anti-non-Gal antibodies. Although the precise mechanisms of Gal k/o pig organ rejection are not clear, it could result from incomplete deletion of Gal, up-regulation of new antigen (non-Gal antigen) and/or production of non-Gal antibodies. Future work in xenotransplantation should place emphasis on further modification of donors, such as combining human complement regulatory genes with Gal k/o, deleting non-Gal antigens and adding protective/surviving genes or a gene that inhibits coagulation. Induction of donor-specific T- and B-cell tolerance and promotion of accommodation are also warranted.     

Case Report: Suspected Hyperacute Rejection During Living Kidney Transplantation

BackgroundWe report a case of suspected hyperacute rejection during living kidney transplantation.Case reportA 61-year-old man underwent kidney transplantation in November 2019. Before the transplantation, immunologic tests revealed the presence of anti-HLA antibodies but not donor-specific HLA antibodies. The patient was intravenously administered 500 mg of methylprednisolone (MP) and basiliximab before perioperative blood flow reperfusion. After blood flow restoration, the transplanted kidney turned bright red and then blue. Hyperacute rejection was suspected. After the intravenous administration of 500 mg of MP and 30 g of intravenous immunoglobulin, the transplanted kidney gradually changed from blue to bright red. The initial postoperative urine output was good. On the 22nd day after the renal transplantation, the patient was discharged with a serum creatinine level of 2.38 mg/dL, and the function of the transplanted kidney gradually improved.ConclusionsIn this study, non-HLA antibodies may have been a cause of the hyperacute rejection, which was managed with additional perioperative therapies.     

Tolerance across discordant xenogeneic barriers

Abstract: In contrast to islet transplants, which appear to enjoy privileged survival when transplanted across some species barriers, organ xenografts are subject to vigorous immunologic rejection. Part of this rejection is immediate and is caused by the binding of natural antibodies to vascular endothelial cells, followed by activation of complement and coagulation factors, and hyperacute destruction of the graft. Such hyperacute rejection, in a pig-to-monkey kidney model that we are studying, can be avoided by removal of natural antibodies, which we have accomplished by absorption procedures. However, the cellular immune response to xenografts is also stronger than that to allografts. One might therefore expect the amount of nonspecific immunosuppression that would be required to avoid xenograft rejection to be so great that recipients would succumb to infectious complications. For this reason, we have pursued an approach to discordant xenografting involving the induction of tolerance though establishment of mixed lymphohematopoietic chimerism. We summarize here the present status of these experiments.