Tissue Typing,Antilymphocyte Globulin,and Prophylactic Graft Irradiation in Cadaver Kidney Transplantation

In a series of 27 recipients of cadaver kidney grafts, 26 were at the time of writing alive, 3 to 25 months after transplantation, and 25 patients were alive with functioning first grafts. The one-year patient survival in 18 patients was 94% and the one-year graft survival was 89%. There was no beneficial correlation between tissue matching and the frequency of major early rejection episodes or graft function 12 or more months after transplantation. Antilymphocyte globulin administration was associated with a lower incidence of early rejection episodes, but this was not statistically significant. A combination of prophylactic graft irradiation and antilymphocyte globulin administration for at least the first two weeks was associated with a significantly reduced frequency of major early rejection episodes and appreciably better graft function at 12 months. This effect could not be ascribed to better tissue matching.     

Superiority of B locus matching over other HLA matching in renal graft survival.

Graft survival after 348 consecutive first cadaver-donor renal transplants was significantly improved by HLA matching when recipients who had received pretransplant blood transfusions were matched with their kidney donor for two HLA-B locus antigens. No other type of HLA matching significantly improved graft survival in transfused recipients nor did any type of HLA matching in non-transfused recipients. Matching for one HLA-DR antigen had no benefit in transfused recipients. Only two patients received kidneys matched for both DR antigens and only two of those in whom DR matching had been performed had not been transfused. These results indicate that pretransplant blood transfusion and selection of graft recipients predominantly on the basis of HLA-B matching has significantly reduced the renal graft rejection rate in Newcastle upon Tyne over two years. Thus, HLA-B antigen matching should be adopted as the main criterion for kidney sharing between transplant centres.     

Allogeneic transplantation of the radial side of the hand in the rhesus monkey: I. Technical aspects.

Since allogeneic transplantation of extremities can only be considered if uneventful long-term survival and functional recovery can be achieved, a series of 12 transplantations of the radial side of the hand were performed in rhesus monkeys so that these factors could be assessed. The transplant incorporated the first ray of the hand in conjunction with the radial forearm flap. Graft survival times varied from 21 to 179 days. Ten of 12 transplants showed rejection. In 2 of the 10, rejection could be reversed. Immunosuppressive therapy consisted of cyclosporin A, prednisone, monoclonal antibodies, and preoperative third-party blood transfusions. Monitoring of the microcirculation of the allograft could not provide a predictive value for transplant rejection. The first clinical signs of sensory and motor function recovery were detected after an average of 42 and 44 days, respectively. Indefinite uneventful allograft survival could not be established. Major complications such as sepsis, shock, and lymphoma development leading to death were encountered. The model, however, is technically feasible, and the results for functional recovery under immunosuppression are promising.     

High versus "low" dose corticosteroids in recipients of cadaveric kidneys: prospective controlled trial.

Corticosteroids have the major role in the immunosuppressive treatment of patients who have received renal transplants. Despite their extensive use there is still debate about the appropriate dose that will prevent rejection of the renal allograft with the least morbidity. From March 1979 to November 1981 a randomised controlled trial of high (33 patients) v low oral dose (34 patients) of prednisolone along with azathioprine was conducted in recipients of first cadaveric transplants who had received a blood transfusion within six months of transplantation. The main difference in outcome between the two groups was a high incidence of some infections in the high dose group. Patient mortality, graft survival, transplant function, and number of rejection episodes were indistinguishable in the two groups, but rejection episodes tended to occur later in the high dose group. These findings suggest that the use of lower doses of corticosteroids soon after cadaveric renal transplantation does not jeopardise graft survival and results in lower patient morbidity.     

Canadian clinical trial of antilymphocyte globulin in human cadaver renal transplantation.

A multicentre, randomized clinical trial of antilymphocyte globulin (ALG) was conducted among patients who had undergone cadaver kidney transplantation; follow-up was continued for a minimum of 1 year. Of the 179 patients 92 were given conventional treatment only, while 87 were given in addition ALG (from a standardized, highly immunosuppressive, common pool of equine ALG), 20 mg/kg-d intravenously for 10 days after transplantation. The ALG-treated group had better accumulated graft survival, fewer nephrectomies, better graft function, less than half the number of acute rejection episodes and less prednisone use. There was a beneficial drug (ALG)-related effect in both the graft and the host during the first 3 months after transplantation.     

Relationship between chimerism and tolerance in a kidney transplantation model

The persistence of donor leukocytes in recipients of organ allografts has been associated with long-term graft acceptance. However, it remains unclear whether this peripheral donor cell microchimerism plays an active role in graft acceptance or is simply a consequence of the maintenance of sufficient immunosuppression to avoid rejection. A model of kidney transplantation between swine leukocyte Ag (SLA)-matched miniature swine, in which tolerance can be established with or without immunosuppressive treatment, has been used to study the correlation between donor leukocyte chimerism and kidney graft acceptance. SLA-identical kidney transplants were performed from animals positive for an allelic pig leukocyte Ag to animals negative for this marker. SLA-identical kidney transplant recipients given a 12-day course of cyclosporine (CyA) (n = 3) became tolerant, showing stable serum creatinine levels (1-2 mg/dl) after cessation of CyA treatment. Donor cell chimerism (0.2-0.7%) was present by FACS in all three animals with peak levels detected at 3 wk. Two control animals receiving SLA-identical kidney grafts without CyA also showed stable serum creatinine levels and became tolerant. However, in neither of these animals could donor leukocytes be detected in the peripheral blood beyond 1 wk following transplantation. In one additional control animal, ureteral obstruction occurred at day 10, and was associated with additional peripheral chimerism, presumably related to inflammation rather than to immune status. These results indicate that the persistence of donor cell chimerism is not a requirement for the maintenance of tolerance to organ allografts in this model.     

Vascular knee allograft transplantation in a rabbit model

Using a rabbit model in which vascularized knee autograft transplantation was successful, vascularized knee allograft transplants survived an average of 9 days, as determined by serial bone scan. The longest surviving allograft was one of 3 months. Immunosuppression and irradiation did not significantly increase survival. Both vascularized and nonvascularized allografts elicited a second-set skin graft response but no histologic evidence of rejection. This suggests that joint allografts are clearly immunogenic but do not undergo the same destructive rejection process with a clear end point seen with soft-tissue grafts. Donor vessels did show a classic rejection picture with severe intimal damage presumably predisposing to vessel thrombosis and graft loss. Vascular rejection, therefore, limited joint allograft survival. Immediate vascularization of the allograft with subsequent limited survival does not enhance host revascularization and creeping substitution at 1, 3, or 6 months. These findings do not suggest clinical applicability for vascularized joint allograft transplantation at this time. Future experimental studies should employ genetically defined models.     

Use of allograft biopsies to assess thymopoiesis after thymus transplantation

Thymus allograft biopsies were performed in athymic infants with complete DiGeorge anomaly after thymus transplantation to assess whether the thymus allograft tissue was able to support thymopoiesis. Forty-four consecutive infants were treated with postnatal cultured thymus allografts. Thirty biopsies and six autopsies evaluating the allograft site were obtained in 33 infants, 23 of whom survive. The allograft was examined by immunohistochemistry for evidence of thymopoiesis. Grafted thymus tissue was found in 25 of 30 biopsies, 23 of which showed thymopoiesis. All 19 survivors with thymopoiesis on biopsy developed naive T cells and T cell function. Autopsies were done in six subjects, three of whom had biopsies. All autopsy samples contained thymus tissue including one for which the biopsy had not contained graft. Of the six autopsies, one had evidence of thymopoiesis. Epithelium without thymopoiesis was seen in two of 25 biopsies in which thymus tissue was detected and in five of six autopsies. Graft rejection was seen in one autopsy. Biopsies were important for showing the following: 1) the damaging effect of pulse steroids on thymopoiesis; 2) the need for adequate immunosuppression of atypical subjects; and 3) the presence of thymopoiesis in the presence of ongoing immunosuppression. In addition, the biopsy could rule out graft rejection in the atypical subjects who had oligoclonal T cells that could cause rejection. In summary, combining biopsy and autopsy data, allogeneic thymus tissues showed thymopoiesis in 24 of 29 (86%) evaluable transplants. The results of these biopsies led to improved care of these complex patients.     

Current status of renal transplantation.

The success rate of renal transplantation has improved considerably during the past decade, with substantial improvements in both graft and patient survival. The quality of graft function, however, and not graft survival alone is increasingly determining the standards by which transplantation outcome is being judged. As the demand for kidney transplants continues to rise and transplants are being offered to an ever-increasing number of patients, organs are being sought from new supply pools and efforts are being made to use current resources more efficiently. Improvements in clinical management have allowed short-term complications such as infection and rejection to be better prevented or better diagnosed and treated. Fundamental advances in the understanding of the immunologic processes underlying both allograft rejection and acceptance and the introduction of new immunosuppressive agents have allowed a better use of drug therapy and have moved the goal of acquired transplant tolerance closer to attainment. With improved initial transplant success rates, the long-term transplantation outcome is becoming more important. The role of tissue matching in preventing chronic rejection is becoming more appreciated, and the long-term risks of malignancy, arteriosclerosis, and chronic rejection are being better recognized and managed.     

Use of EQUORAL in de novo renal transplant recipients

This paper presents our experience to date with using a cyclosporine formulation Equoral (IVAX Pharmaceuticals) together with mycophenolate mofetil plus a steroid immunosuppressive regimen in the treatment of de novo renal transplant recipients. Ten cadaveric donor renal transplant recipients of mean age 51.6 years (range 37-66) were followed up over 6 months for the development of rejection attacks and side effects. All patients received prednisolone, mycophenolate mofetil (1 g/day during the first 5 days posttransplant and then 20 mg/kg/day) plus cyclosporine (3 mg/kg/day). Biopsy proven acute rejection episodes were observed in 2 out of 10 patients (20%). Six months patient as well as renal graft survival rate was 100%. The development of graft function was immediate after transplantation. The mean serum creatinine levels were gradually decreased. Over the 6-month posttransplant period, the function of the graft was satisfactory and stable. The majority of observed adverse events were those commonly reported with the use of cyclosporine and they resolved with a reduction in cyclosporine dose. Equoral treatment demonstrated an acceptable safety profile with maintenance of adequate renal function without incidence of malignancy/lymphoproliferative disease or serious infections. In conclusion, Equoral plus mycophenolate mofetil immunosuppression seems effective and safe on terms acute rejection rates, patient and renal graft survival rates and side profiles.     

Kidney Transplantation from Pediatric Donors in a Single Chinese Center

To report clinical outcomes of kidney transplantation from pediatric brain and cardiac death donors (DBCD) in a single Chinese center and to investigate its feasibility to expand organ donor pool. 18 recipients, transplanted between August 2011 and October 2013 in the First Affiliated Hospital of Zhengzhou University, receive a single graft from DBCD donors age ranged from 1.5 to 13 years old. Renal function expressed as serum creatinine, blood urea nitrogen as well as eGFR values at 1, 2 weeks as well as 1-, 3-, 6-, and 12-months post-transplantation was evaluated. Graft size was also monitored at the same time by ultrasonography. In addition, delayed graft function, acute rejection, surgical complication as well as patient and graft survival were also assessed. The primary causes of DBCD donors included six cases of severe brain trauma and three cases of cerebral hemorrhage. The mean age of DBCD donors was (7.2 ± 3.4) years (range 1.5–13). The mean weight of DBCD donors was (29.8 ± 15.3) kilogram (range 13–67). The mean height of DBCD donors was (118.3 ± 27.8) centimeter (range 70–173). ECMO was applied to DBCD donors to avoid warm ischemia time and the applicating time was (79.8 ± 44.5) (range 32–180) minutes.There were seven males and 11 females recipients. Among which, 16 recipients were pediatrics and two recipients were adults. The mean age of the recipients was (14.6 ± 9.7) years (range 4–47). The mean weight of recipients was (31.9 ± 12.4) kilogram (range 11–54). The mean height of recipients was (138.0 ± 23.7) centimeter (range 84–172). Renal function recovered to normal within the first-week post-operation except one recipient which occurred acute rejection. Two cases of renal artery stenosis were found 2-week and 3-month post-transplantation, respectively. They subsequently underwent ballon angioplasty and followed up for 8 and 12 months, respectively, and no recurrence was found. One recipient developed ureteral leak. Five weeks later, the ureter leak healed after adequate drainage and prolongation of indwelling catheter. Graft size significantly and continuously increased during the first year, especially in the first 3-month post-transplantation. All the 18 recipients are alive at the last follow-up. Among which, 16 recipients are followed up for 12 months and 1-year recipient/graft survival rate is 100 %. The use of single kidney graft from pediatric DBCD could yield good short-term results.     

Organ transplantations: from basic research to clinical applications. A personal odyssey

This article is a summary of the impact on contemporary medicine of organ and tissue transplantation. The article describes how, via trial and error, and beginning from basic research, the results of organ transplantation have steadily increased as has the number of organs that can be transplanted. Currently, the short-term results of most organ transplants, with the notable exception of the pancreas and the lung, are close to perfect; very few organs are lost any longer due to acute rejection. There is, however, little information on long-term results using the current modalities of immunosuppression, particularly on the effect of chronic rejection on late graft survival.     

The Association Between Glycemic Control and Clinical Outcomes after Kidney Transplantation

ObjectiveTo analyze the relationship between glycemic control after renal transplantation and subsequent graft function and complications.MethodsWe conducted a retrospective chart review of 202 consecutive patients undergoing kidney transplantation to analyze the association between perioperative and chronic glycemic control and clinical outcomes of rejection, infection, and hospital readmission during the first year after kidney transplantation.ResultsMean in-hospital blood glucose (BG) was 157 ± 34.5 mg/dL. Mean hemoglobin A1c (HbA1c) during the first 12 months posttransplantation was 6.84 ± 1.46%. Fiftyfour patients (27%) were treated for acute or chronic rejection, 88 (44%) for infection, and 149 (74%) patients were readmitted at least once within the first year after transplantation. There were no significant differences in the risks for rejection, infection, or readmission across the 5 mean initial inpatient BG or subsequent HbA1c quintiles. In addition, there was no significant relationship between the percentage of BG measurements that fell in the “tight control” range of 80 to 110 mg/dL for each patient and any of the outcomes.ConclusionWe did not find an association between glycemic control (perioperative or chronic) and the outcomes of graft rejection, infection, or hospital readmission in the first 12 months after renal transplantation. Our results suggest that “near normal” glycemic targets are not necessary for managing hyperglycemia after renal transplantation. (Endocr Pract. 2014;20:894-900)     

Carbon monoxide generated by heme oxygenase-1 suppresses the rejection of mouse-to-rat cardiac transplants

Mouse-to-rat cardiac transplants survive long term after transient complement depletion by cobra venom factor and T cell immunosuppression by cyclosporin A. Expression of heme oxygenase-1 (HO-1) by the graft vasculature is critical to achieve graft survival. In the present study, we asked whether this protective effect was attributable to the generation of one of the catabolic products of HO-1, carbon monoxide (CO). Our present data suggests that this is the case. Under the same immunosuppressive regimen that allows mouse-to-rat cardiac transplants to survive long term (i.e., cobra venom factor plus cyclosporin A), inhibition of HO-1 activity by tin protoporphyrin, caused graft rejection in 3--7 days. Rejection was associated with widespread platelet sequestration, thrombosis of coronary arterioles, myocardial infarction, and apoptosis of endothelial cells as well as cardiac myocytes. Under inhibition of HO-1 activity by tin protoporphyrin, exogenous CO suppressed graft rejection and restored long-term graft survival. This effect of CO was associated with inhibition of platelet aggregation, thrombosis, myocardial infarction, and apoptosis. We also found that expression of HO-1 by endothelial cells in vitro inhibits platelet aggregation and protects endothelial cells from apoptosis. Both these actions of HO-1 are mediated through the generation of CO. These data suggests that HO-1 suppresses the rejection of mouse-to-rat cardiac transplants through a mechanism that involves the generation of CO. Presumably CO suppresses graft rejection by inhibiting platelet aggregation that facilitates vascular thrombosis and myocardial infarction. Additional mechanisms by which CO overcomes graft rejection may involve its ability to suppress endothelial cell apoptosis.     

Posttransplant administration of donor leukocytes induces long-term acceptance of kidney or liver transplants by an activation-associated immune mechanism

Donor leukocytes play a dual role in rejection and acceptance of transplanted organs. They provide the major stimulus for rejection, and their removal from the transplanted organ prolongs its survival. Paradoxically, administration of donor leukocytes also prolongs allograft survival provided that they are administered 1 wk or more before transplantation. Here we show that administration of donor leukocytes immediately after transplantation induced long-term acceptance of completely MHC-mismatched rat kidney or liver transplants. The majority of long-term recipients of kidney transplants were tolerant of donor-strain skin grafts. Acceptance was associated with early activation of recipient T cells in the spleen, demonstrated by a rapid increase in IL-2 and IFN-gamma at that site followed by an early diffuse infiltrate of activated T cells and apoptosis within the tolerant grafts. In contrast, IL-2 and IFN-gamma mRNA were not increased in the spleens of rejecting animals, and the diffuse infiltrate of activated T cells appeared later but resulted in rapid graft destruction. These results define a mechanism of allograft acceptance induced by donor leukocytes that is associated with activation-induced cell death of recipient T cells. They demonstrate for the first time that posttransplant administration of donor leukocytes leads to organ allograft tolerance across a complete MHC class I plus class II barrier, a finding with direct clinical application.     

Potential immunologic effects of statins in cancer following transplantation

3-hydroxy-3-methyglutaryl CoA reductase inhibitors (statins) are frequently used following organ transplantation and have well reported pleiotropic effects, including immunomodulation, which may be of benefit in preventing graft rejection. However, the immunomodulatory effects of statins on cell transformation and malignancy, combined with the immunologic processes and administration of immunosuppression are almost completely unknown. The administration of immunosuppression is well recognised as the main cause of cancer following transplantation, so the addition of an immunomodulatory agent should be associated with an increased incidence of cancer, as immune surveillance and response may be suppressed, allowing cellular transformation and proliferation combined with lack of recognition to occur. This hypothetical review attempts to delineate the mode of action of statins in terms of pro/anti-carcinogenic mechanisms, while considering graft rejection and the presence of immunosuppression.     

Long-term survival after cadaveric renal transplantation.

In a series of 404 consecutive first cadaver kidney transplants performed since 1967 the actuarial five- and 10-year survival of patients were 61% and 47% respectively and of grafts 46% and 36%. In more than four-fifths of the patients surviving these intervals the original cadaveric grafts were functioning at these times, and most of the remainder were sustained by subsequent grafts. Although graft survival has remained static since 1967, patient survival improved. Results for 43 consecutive second cadaver transplants were similar after five years to those of first grafts. These results promote the acceptability of cadaveric transplantation as a long-term treatment for chronic renal failure.     

The use of cryopreserved arteries as arterial vascular prostheses]

The aim of the study is investigation of possibility to bypass small and medium-size arteries with cryopreserved artery allografts, storing 7-10 days at -196 degrees C under the protection of 15% dimethylsulfoxide. In experiments on 40 rabbits were placed a region of the left renal artery by cryopreserved bioprosthesis. Graft patency was 80% after observation up to 6 months. By angiography it was 8 cases of graft thrombosis (all during the 1st week after implantation) and 5 cases of moderate graft dilation (in 4 of them it was accompanied with stenosis of distal anastomosis). In 20 dogs we replaced a region of the femoral artery by cryostoring bioprosthesis. It was only one case of graft thrombosis which occurred on month 2 after the implantation during 1-year follow-up. After 3 months in 3 cases there developed 3 cases of diffuse narrowing of graft lumen without decreasing of blood flow through the prosthesis. Later, the graft lumen did not change. Histological investigations have revealed a viability of cryopreserved vessels, its almost complete de-endothelialization at 3 days and total re-endothelialization 2 weeks after implantation. During the first 2 weeks there were morphological events of graft rejection, which disappeared after 3 months.     

Total body irradiation of donors can alter the course of tolerance and induce acute rejection in a spontaneous tolerance rat liver transplantation model

Liver transplantation is an established therapy for end-stage liver diseases. Graft rejection occurs unless the recipient receives immunosuppression after transplantation. This study aimed to explore the mechanism of acute rejection of liver allografts in rats pre-treated with total body irradiation to eliminate passenger lymphocytes and to define the role of CD4⁺CD25⁺ regulatory T cells in the induction of immunotolerance in the recipient. Male Lewis rats were used as donors and male DA rats were recipients. Rats were randomly assigned to the following four groups: control group, homogeneity liver transplantation group, idio-immunotolerance group and acute rejection group. After transplantation, the survival time of each group, serum alanine aminotransferase, total bilirubin levels, number of Foxp3⁺CD4⁺CD25⁺ regulatory T cells, expression of glucocorticoid-induced tumor necrosis factor receptor on T cell subgroups, histopathology of the hepatic graft and spleen cytotoxic T lymphocyte lytic activity were measured. In the acute rejection group, where donors were preconditioned with total body irradiation before liver transplantation, all recipients died between day 17 and day 21. On day 14, serum alanine aminotransferase increased significantly to (459.2±76.9) U L^?1, total bilirubin increased to (124.1±33.7) ??mol L^?1 (P<0.05) and the ratio of Foxp3⁺CD4⁺CD25⁺ regulatory T cells decreased significantly to 1.50%±0.50% (P<0.05) compared with the other groups. Analysis of the T cell subpopulations in the acute rejection group varied from the other groups. Histological analysis showed typical changes of acute rejection in the acute rejection group only. Preconditioning of the donors with total body irradiation eliminated passenger lymphocytes of the liver graft, and thus affected the course of tolerance and induced acute rejection after liver transplantation.     

Prolongation of canine pancreas allograft survival with cyclosporin A: preliminary report.

Studies were conducted on dogs to test the efficacy of cyclosporin A (CyA) in prolonging normoglycaemia and graft survival after whole-organ pancreas allograft transplantation. Five dogs subjected to pancreatectomy alone served as controls. Withholding immunosuppression after transplantation (five animals) resulted in the same median duration of survival as occurred in the controls (13 days). Azathioprine and steroids (seven animals) produced median durations of normoglycaemia and survival of 9 and 23 days respectively. Animals given CyA 18 mg/kg/day (five) and 25 mg/kg/day (10), however, showed median durations of normoglycaemia of 18 and 55 days (p less than 0.05 and p less than 0.02) respectively and median survival times of 36 and 85 days (NS and p less than 0.02). If CyA proved effective in controlling rejection of pancreas allografts in man it would offer unstable diabetics in renal failure a more hopeful outlook than conventional immunosuppression.