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Background: The outcomes after kidney transplantation (KT), including access, wait time, and other issues around the globe, have been studied. However, issues do vary from one country to another., Methods: We obtained data from several countries from North America, South America, Europe, Asia, and Australia, including the number of patients awaiting KT from 2015, transplant rate per million population (pmp), proportion of living donor and deceased donor (LD/DD) KT, and posttransplant survival. We also sought opinions on key difficulties faced by each of these countries with respect to KT and long-term survival., Results: Variation in access to KT across the globe was noted. Countries with the highest rates of KT pmp included the United States (79%) and Spain (71%). A higher proportion of LD transplants was noted in Japan (93%), India (85%), Singapore (63%), and South Korea (63%). A higher proportion of DD KTs was noted in Spain (90%), Brazil (90%), France (85%), Italy (85%), Finland (85%), Australia-New Zealand (80%), and the United States (77%). The 5-y graft survival for LD was highest in South Korea (95%), Singapore (94%), Italy (93%), Finland (93%), and Japan (93%), whereas for DD, it was South Korea (93%), Italy (88%), Japan (86%), and Singapore (86%). The common issues surrounding KTs are access and a limited number of LDs and DDs. Key issues identified for long-term survival were increasing age of donors and recipients, higher recipient comorbidity, and posttransplant events, such as alloimmune injury to the kidney, infection, cancer, and suboptimal adherence to therapy., Conclusions: A unified approach is necessary to improve issues surrounding KT as the demand continues to increase., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: The requirement for a prospective crossmatch limits some organ allocation to local areas. The delay necessitated by the crossmatch restricts the distance across which offers can be made without unduly increasing the ischemia time. A collaborative study involving 14 transplant centers was undertaken by the Organ Procurement and Transplantation Network/United Network for Organ Sharing (OPTN/UNOS) Histocompatibility Committee to evaluate the accuracy with which the detection of unacceptable human leukocyte antigen (HLA) antigens by most advanced solid phase immunoassays can predict crossmatch results. In addition, using actual patients' unacceptable HLA antigens, the number of compatible donors that would have been available from the OPTN deceased kidney donors during 2002 to 2004 were investigated., Methods: Panel reactive antibodies were performed by conventional or solid phase assays, and crossmatches were performed by cytotoxicity or flow cytometry. Analyses were stratified for T and B cell and by method of identifying unacceptable HLA antigens and crossmatch techniques., Results: Combination of solid phase immunoassays and flow cytometry crossmatches resulted in a higher prediction rates of positive T cell (86.1%-93.5%) and B-cell crossmatches (91%-97.8%). Prediction of negative crossmatches based on different combination of panel reactive antibodies and crossmatch techniques varied from 14.3% to 57.1%. Furthermore, numerous potential compatible donors were identified for each patient, regardless of their ethnicity, in the OPTN database, when predicted incompatible ones were excluded., Conclusions: The above results showed that with the advent of solid phase immunoassays, HLA antibodies can now be accurately detected resulting in prediction of crossmatch outcome. This should facilitate organ allocation and prevents shipment of organs to distant incompatible recipients.

Background: In a pilot trial we evaluated the toxicity and efficacy of sirolimus (rapamycin) as second-line therapy for the treatment of acute graft-versus-host disease (GVHD) in 21 patients (1-46 years of age) after allogeneic hematopoietic stem cell transplantation (HSCT)., Methods: All patients were treated with methylprednisolone at 2 mg/kg/day, but failed to respond satisfactorily. Sirolimus was started 19-78 (median 37) days after HSCT when 10 patients had grade III and 11 had grade IV GVHD. The first four patients received a loading dose (15 mg/m2) of oral sirolimus on day 1 followed by 5 mg/m2/day for 13 days. The next 17 patients received either 5 (n=7) or 4 (n=10) mg/m2/day for 14 days without a loading dose. Eleven patients completed the 14-day sirolimus course. Five patients were treated for 9-13 days, two for 6 days, and three for 1-3 days., Results: Sirolimus was discontinued early in 10 patients because of lack of improvement in GVHD (n=5), myelosuppression (n=2), seizure (n=2), and attending physician preference (n=1). The most common and significant adverse events were thrombocytopenia (n=7) and neutropenia (n=4). Other side effects included increased blood triglycerides (n=8) and cholesterol (n=3). Five patients had evidence of a hemolytic uremic syndrome concurrently with or after sirolimus treatment. Eighteen of the 21 patients received 6 or more doses of sirolimus and 12 responded, 5 with complete and 7 with partial responses. Six of the 12 responders (28% of all patients enrolled) and 1 nonresponder are currently alive at 400-907 days after HSCT, 3 with chronic GVHD. Fourteen of the 21 patients (66%) died 40-263 days after transplant., Conclusion: These data suggest that sirolimus has activity in the treatment of steroid-refractory acute GVHD. However, there was considerable toxicity and further dose optimization studies seem warranted.

This report updates the results of marrow transplantation at the Fred Hutchinson Cancer Research Center for patients with severe aplastic anemia whose donors were HLA-nonidentical relatives. Between 1970 and 1993, 40 patients received transplants for severe aplastic anemia from related donors other than HLA genotypically matched siblings. Nine patients (group 1) were conditioned with cyclophosphamide (Cy) at 50 mg/kg for 4 doses and received marrow from phenotypically HLA-matched relatives. With the exception of one accidental death, all patients are alive and disease free 3-18 years after transplantation. Thirty-one patients received marrow from HLA-mismatched relatives who differed by one or more loci. Fifteen of these patients (group 2) received Cy at 50 mg/kg for 4 doses without total body irradiation (TBI) and none survived. Because of failure to sustain engraftment in 9 of 14 evaluable patients in group 2, the regimen for HLA-mismatched patients was changed in 1984 to include Cy at 60 mg/kg for 2 doses and TBI was added at 1200 cGy to increase immunosuppression (group 3). Sixteen patients in group 3 received marrow grafts after failure to respond to immunosuppressive therapy. Eight of the 16 patients in group 3 remain alive without disease between 1.5 and 11.3 years after transplantation. In conclusion, transplants from phenotypically HLA-identical related donors can be carried after Cy alone and results are comparable to those observed with genotypically HLA-identical siblings. Transplants from related donors mismatched for one or more HLA loci require a more intensive conditioning regimen, for example, one containing TBI, to achieve sustained engraftment.

This study evaluated the acute toxicity of trimetrexate (TMTX) used in combination with cyclosporine (CsA) for prevention of acute graft-versus-host disease (GVHD) in patients undergoing allogeneic marrow transplantation from HLA-mismatched, related donors. TMTX has a mechanism of action similar to that of methotrexate (MTX); however, unlike MTX, TMTX is not primarily dependent on renal excretion. Patients were conditioned for transplant with cyclophosphamide, anti-thymocyte globulin, and total body irradiation. TMTX, 10 mg/m2 i.v., was administered on days 1, 3, 6, 11, 18, 25, 32, and 39 after transplant. CsA, 1.5 mg/kg i.v., was administered every 12 hr beginning on day-1. Eleven patients with hematologic malignancies or aplastic anemia (median age = 34 yr) received TMTX. Toxicity assessed included nausea, vomiting, fever, rash, time to myeloid and platelet engraftment, mucositis, and hepatic and renal dysfunction. Toxicity of TMTX was not different from that observed with MTX in a similar patient population. One patient died on day 16 before engraftment. The other 10 patients all engrafted and all developed acute GVHD at a median time of 11 days after transplant. The major manifestation of acute GVHD was in the skin, and all but one patient responded to primary therapy with corticosteroids. Seven patients have survived a median of 447 days after transplant. No significant toxicity from TMTX was observed. Further trials are warranted to define the role of TMTX in marrow transplantation.

Treatment with the monoclonal antibody OKT3 specific for the CD3 complex associated with the T cell antigen receptor can reverse acute rejection of human renal allografts. However, efficacy of anti-CD3 antibodies for treatment of patients with acute graft-versus-host disease after marrow transplantation has not been established. The dose-limiting side effects resulting from T cell activation induced by some anti-CD3 antibodies in vivo have discouraged their use for this application. We now report a phase I-II study of GVHD treatment with the anti-CD3 antibody BC3, a monoclonal murine IgG2b that, unlike OKT3, does not activate T cells. Fourteen patients were treated with BC3 after progression of acute GVHD despite treatment with cyclosporine and corticosteroids, and three patients received BC3 as primary treatment for GVHD. BC3 was administered at a dose of 0.1 or 0.2 mg/kg/day for seven or eight days. Five patients achieved complete resolution of GVHD, eight patients had partial improvement, two patients had no change, and two patients had progression of GVHD on therapy. Responses were sustained in 8 of 13 patients. Mild chills, fever, hypertension, and chest discomfort occurred in various combinations following 6 of 17 (35%) initial infusions of BC3 and following 4 of 99 (4%) subsequent infusions. In each instance it was possible to continue BC3 therapy without adjusting the dose or treatment schedule. In each patient treated, the absolute count of peripheral blood lymphocytes decreased transiently but returned to baseline within 22 hr after the first infusion. Circulating T cells had surface CD3 molecules saturated by the infused antibody in all but one patient. Four patients survived longer than one year after treatment with antibody BC3, and 13 patients died of infection or organ failure. Administration of the nonmitogenic anti-CD3 antibody BC3 was associated with improvement in the clinical manifestations of GVHD with minimal acute toxicity. Efficacy of antibody treatment did not depend on depletion of circulating T cells. Therefore, antibody BC3 may be achieving therapeutic immunosuppression by modulating T cell function. Controlled studies in patients treated earlier in the course of GVHD should determine whether antibody BC3 can improve survival.

We studied a variety of soft-tissue and composite-tissue allografts (CTA) in a histoincompatible rat model to determine the outcome and the nature of the immunologic responses to these tissues using continuous low-dose cyclosporine (CsA) therapy. Brown-Norway (RT1n) rats served as donors of soft tissue and CTA to Lewis (RT1l) rat recipients given low-dose CsA immunosuppressive therapy by gavage. Nine groups were studied. Three control groups were not treated with CsA: group 1, skin grafts alone; group 2, skin flaps alone; and group 3, skin grafts and delayed vessel allotransplants. Six groups were treated with CsA: group 4, skin grafts alone; group 5, skin flaps alone; group 6, skin grafts and delayed vessel allotransplants; group 7, aortas alone; group 8, muscle flaps alone; and group 9, bone grafts alone. Isografts were performed in all groups as technical controls. The appearance posttransplant of donor-directed cytotoxic antibodies was determined in recipient serum using a complement-mediated cytotoxicity assay and was compared to control and pretransplant sera. In the absence of CsA therapy, recipients in groups 1, 2, and 3 rejected their allografts early (8.5-9.4 days) and developed profound antidonor cytotoxic antibody activity posttransplant by day 7. Groups 4, 5, 6, 7, and 9 had prolonged graft survival in the presence of low-dose CsA, despite the presence of antidonor antibody activity. By contrast, group 8 (muscle flaps) were all uniformly rejected in the presence of profound recipient cytotoxic antidonor antibody activity. These results suggest that long-term soft-tissue and CTA survival can be achieved in histoincompatible rat recipients using continuous low-dose CsA immunosuppressive therapy despite the presence of cytotoxic antidonor antibodies.

Whole saliva samples and lip biopsies were collected from 12 allogeneic bone marrow transplant recipients who developed extensive chronic graft-versus-host disease (GVHD) and from 10 healthy allogeneic and syngeneic recipients without GVHD. Six of ten biopsies from patients with chronic GVHD had lichenoid stomatitis or sialadenitis, or both, with sialodochitis. Seven of nine biopsies from patients free of chronic GVHD were entirely normal, and two had either mild glandular or mucosal changes. Salivary gland involvement in chronic GVHD was associated with decreased or absent levels of salivary IgA and inorganic phosphate, decreased salivary flow rates, and increased concentrations of salivary sodium, albumin, and IgG. The most striking abnormalities were found in patients with histologic evidence of sialadenitis. In contrast, marrow transplant recipients without chronic GVHD had normal salivary immunoglobulin and electrolyte levels. Secretory IgA deficiency may contribute to the frequent sinobronchial infections observed in patients with chronic GVHD.

One hundred thirty-seven patients had gonadal function evaluated 1-11 years after marrow transplantation. All 15 women less than age 26 and three of nine older than age 26 who were treated with 200 mg/kg cyclophosphamide recovered normal gonadotropin levels and menstruation. Five have had five pregnancies resulting in three live births, one spontaneous abortion, and one elective abortion. Three of 38 women who were prepared with 120 mg/kg cyclophosphamide and 920-1200 rad total-body irradiation had normal gonadotropin levels and menstruation. Two had pregnancies resulting in one spontaneous and one elective abortion. Of 31 men prepared with 200 mg/kg cyclophosphamide, 30 had normal luteinizing hormone levels, 20 had normal follicle-stimulating hormone levels, and 10 of 15 had spermatogenesis. Four have fathered five normal children. Thirty-six of 41 men prepared with 120 mg/kg cyclophosphamide and 920-1750 rad total-body irradiation had normal luteinizing hormone levels, ten had normal follicle-stimulating hormone levels, and 2 of 32 studied had spermatogenesis. One has fathered two normal children. It was concluded that cyclophosphamide does not prevent return of normal gonadal function in younger women and in most men. Total-body irradiation prevents return of normal gonadal function in the majority of patients.

Bone marrow transplant recipients undergo ablation of host immune defenses with total-body irradiation or high dose chemotherapy, or both. Over a 5.6-year period, mycobacterial infections were observed in 7 of 682 patients with leukemia who received marrow grafts. Four patients had pulmonary and three extrapulmonary infection. Granulomas were observed in the lungs of three patients, in the liver of one patient, and in the skin of one patient. Cultures revealed Mycobacterium tuberculosis in two patients, Mycobacterium fortuitum in two patients, and Mycobacterium kansasii in one patient. In the six patients treated with antimycobacterial therapy in either the pretransplant or posttransplant period, complete resolution of the infection was achieved. Pretransplant chest radiograph abnormalities suggesting mycobacterial infections should be aggressively evaluated in these immunocompromised hosts. Prophylaxis should be considered in marrow graft recipients with a well-established history of inadequately treated tuberculosis, previous Bacille Calmette-Guerin immunotherapy, known family contacts, recent skin test conversion, or past skin test positivity.

Chronic mucocutaneous candidiasis (CMC) is typically associated with the inability of T lymphocytes to proliferate and produce lymphokines in response to Candida antigen. A 7-year-old girl with CMC developed severe aplastic anemia and, after conditioning with cyclophosphamide, 200 mg/kg, underwent bone marrow transplantation from her HLA-identical sister. Engraftment was prompt and complete. The patient is surviving more than 3 years after transplantation with normal donor-derived hemopoiesis and immune function. Manifestations of CMC have resolved completely and she has not received antifungal therapy for more than 2 years.

Forty-eight patients with hematologic malignancies treated by allogeneic marrow transplantation developed acute graft-versus-host disease (GVHD), grades II-IV, despite prophylaxis with methotrexate. They were treated with a combination of antithymocyte globulin (ATG) and cyclosporine (CsA), with or without the addition of methylprednisolone (MP). Thirty patients had received HLA-identical and 18 HLA-nonidentical transplants. Median onset of GVHD was day 13 (range 8-60) for patients with HLA-nonidentical grafts and day 18 (range 7-48) for patients given HLA-identical grafts (P = 0.01). Forty-five patients could be evaluated for response on day 7 of therapy. Among these, 13 of 27 given ATG/CSP and 6 of 18 given ATG/CSP/MP improved. Among 33 patients evaluable on day 14 of therapy 13 of 19 given ATG/CSP and 5 of 14 given ATG/CSP/MP showed improvement of GVHD. Patients given HLA-nonidentical grafts responded somewhat (although not significantly) less frequently than patients given HLA-identical grafts. Chronic GVHD developed in 16 of 18 evaluable patients given ATG/CSP and in 5 of 6 given ATG/CSP/MP. Viral, bacterial, and fungal infections were the major cause of death in both groups. Interstitial pneumonitis was more frequent among patients given ATG/CSP/MP. Survival beyond 6 months was 67% among patients treated with ATG/CSP and 25% with ATG/CSP/MP. These data indicate that a regimen of ATG/CSP is of value in the treatment of acute GVHD. The addition of MP was not beneficial and resulted in decreased survival--presumably because of excessive immunosuppression and associated complications.