BACKGROUND: The primary limitation to kidney transplantation is organ shortage. Recent progress in gene editing and immunosuppressive regimens has made xenotransplantation with porcine organs a possibility. However, evidence in pig-to-human xenotransplantation remains scarce, and antibody-mediated rejection (AMR) is a major obstacle to clinical applications of xenotransplantation. METHODS: We conducted a kidney xenotransplantation in a brain-dead human recipient using a porcine kidney with five gene edits (5GE) on March 25, 2024 at Xijing Hospital, China. Clinical-grade immunosuppressive regimens were employed, and the observation period lasted 22 days. We collected and analyzed the xenograft function, ultrasound findings, sequential protocol biopsies, and immune surveillance of the recipient during the observation. RESULTS: The combination of 5GE in the porcine kidney and clinical-grade immunosuppressive regimens prevented hyperacute rejection. The xenograft kidney underwent delayed graft function in the first week, but urine output increased later and the single xenograft kidney maintained electrolyte and pH homeostasis from postoperative day (POD) 12 to 19. We observed AMR at 24 h post-transplantation, due to the presence of pre-existing anti-porcine antibodies and cytotoxicity before transplantation; this AMR persisted throughout the observation period. Plasma exchange and intravenous immunoglobulin treatment mitigated the AMR. We observed activation of latent porcine cytomegalovirus toward the end of the study, which might have contributed to coagulation disorder in the recipient. CONCLUSIONS 5GE and clinical-grade immunosuppressive regimens were sufficient to prevent hyperacute rejection during pig-to-human kidney xenotransplantation. Pre-existing anti-porcine antibodies predisposed the xenograft to AMR. Plasma exchange and intravenous immunoglobulin were safe and effective in the treatment of AMR after kidney xenotransplantation.
Transplantation, Heterologous/methods* ; Kidney Transplantation/methods* ; Heterografts/pathology* ; Immunoglobulins, Intravenous/administration & dosage* ; Graft Survival/immunology* ; Humans ; Animals ; Sus scrofa ; Graft Rejection/prevention & control* ; Kidney/pathology* ; Gene Editing ; Species Specificity ; Immunosuppression Therapy/methods* ; Plasma Exchange ; Brain Death ; Biopsy ; Male ; Aged

BackgroundImmunosuppressive agents are still inefficient in preventing biopsy-proven acute rejection (BPAR) after expanded criteria donor (ECD) kidney transplantation. The aim of this study was to investigate the relationships between early immunosuppressive exposure and the development of BPAR.

MethodsWe performed a retrospective study of 58 recipients of ECD kidney transplantation treated with enteric-coated-mycophenolate sodium, tacrolimus (Tac), and prednisone. The levels of mycophenolic acid-area under the curve (MPA-AUC) and Tac Cwere measured at the 1 week and the 1 month posttransplant, respectively. The correlation was assessed by multivariate logistic regression.

ResultsThe occurrence rates of BPAR and antibody-mediated rejection were 24.1% and 10.3%, respectively. A low level of MPA-AUC at the 1 week posttransplant was found in BPAR recipients (38.42 ± 8.37 vs. 50.64 ± 13.22, P < 0.01). In addition, the incidence of BPAR was significantly high (P < 0.05) when the MPA-AUClevel was <30 mg·h·L at the 1 week (15.0% vs. 44.4%) or the Tac Cwas <4 ng/ml at the 1 month posttransplant (33.3% vs. 21.6%). Multivariable logistic regression analysis showed that the MPA-AUC at the 1 week (OR: 0.842, 95% CI: 0.784-0.903) and the Tac Cat the 1 month (OR: 0.904, 95% CI: 0.822-0.986) had significant inverse correlation with BPAR (P < 0.05).

ConclusionsLow-level exposure of MPA and Tac Cin the early weeks posttransplant reflects an increased acute rejection risk, which suggested that MPA-AUC <30 mg·h·L and Tac C <4 ng/ml should be avoided in the first few weeks after transplantation.

Adult ; Female ; Graft Rejection ; immunology ; prevention & control ; Humans ; Immunosuppressive Agents ; chemistry ; therapeutic use ; Kidney Transplantation ; adverse effects ; methods ; Male ; Middle Aged ; Mycophenolic Acid ; chemistry ; therapeutic use ; Retrospective Studies ; Tacrolimus ; chemistry ; therapeutic use ; Time Factors

BACKGROUND: Angiotensin II type 1 receptor (AT1R) is responsible for cardiovascular effects mediated by angiotensin II. This study aimed to investigate the impact of antibodies directed against AT1R (anti-AT1R) in renal allograft rejection. METHODS: We evaluated 53 patients who had biopsy-proven rejection including antibody-mediated rejection (AMR) (N=22), T-cell-mediated rejection (TCMR) (N=29), and mixed AMR and TCMR (N=2). Donor specific HLA antibodies (DSA) and anti-AT1Rs were simultaneously determined. RESULTS: Anti-AT1Rs were detected in 9.4% (5/53) of rejection patients (one with acute AMR, two with chronic active AMR, one with acute TCMR, and one with mixed acute AMR & TCMR). HLA antibodies and DSA were detected in 75.5% (40/53) and 49.1% (26/53) of patients, respectively. There was no significant difference in transplant characteristics between anti-AT1R(+) and anti-AT1R(-) patients except for the association of HLA class-I DSA(+) and anti-AT1R(+). Four of five anti-AT1R(+) patients had DSA and were also found to have AMR. A single anti-AT1R(+)/DSA(-) patient developed acute TCMR. Detection rates of DSA, HLA antibodies, or anti-AT1R were not different between AMR and TCMR. However, DSA(+)/anti-AT1R(+) was more frequently found in AMR than in TCMR (P=0.036). Patients with anti-AT1R showed a greater tendency to develop high-grade rejection as Banff IIA/IIB or AMR. CONCLUSIONS: The presence of anti-AT1R was significantly associated with HLA class-I DSA in renal allograft rejection patients. Both anti-AT1R and DSA positivity was associated with AMR in patients with renal allograft rejection.
Adult ; Antibodies/blood ; Female ; Graft Rejection/*etiology ; HLA Antigens/immunology ; Humans ; Kidney/pathology ; Kidney Transplantation/*adverse effects ; Male ; Middle Aged ; Receptor, Angiotensin, Type 1/*immunology ; Tissue Donors ; Transplantation, Homologous

No abstract available.
Adult ; Female ; Graft Rejection/immunology/*prevention & control ; Graft Survival ; *Hematopoietic Stem Cell Transplantation ; Humans ; *Immune Tolerance ; Immunosuppressive Agents/therapeutic use ; Kidney Failure, Chronic/diagnosis/*surgery ; *Kidney Transplantation ; Living Donors ; Siblings ; Time Factors ; *Transplantation Chimera ; Treatment Outcome

BACKGROUND/AIMS: Patients who undergo repeat kidney transplantations (KTs) are considered at high risk for experiencing immunologic and non-immunologic complications. In this study, we investigated the clinical outcomes, including medical and surgical complications, of patients who underwent a third KT at our center. METHODS: Between March 1969 and December 2012, a total of 2,110 KTs were performed at the Seoul St. Mary's Hospital. Of them, we examined 11 patients who underwent a third KT, and investigated the allograft outcomes and complication rates. RESULTS: The mean follow-up duration after KT was 72.4 ± 78.3 months. The mean age at KT was 38.2 ± 8.0 years, and seven patients (63.6%) were males. Nine patients (81.8%) underwent living-donor KT. A cross-match test yielded positive results in four of the nine patients, and all underwent pretransplant desensitization therapy. After KT, three patients (27.2%) showed delayed graft function. Acute rejection developed in four patients (36.4%), and surgical complications that required surgical correction occurred in three patients. Allograft failure developed due to acute rejection (n = 3) or chronic rejection (n = 1) in four patients. Allograft survival rates at 1, 5, and 10 years were 81.8%, 42.9%, and 42.9%, respectively; however, the allograft survival rate at 5 years was > 80% in patients who underwent KT only after results of the panel reactive antibody test became available. CONCLUSIONS: Thus, a third KT procedure may be acceptable, although aggressive pretransplant immune monitoring and patient selection may be required to reduce the risks of acute rejection and surgical complications.
Acute Disease ; Adult ; Allografts ; Chronic Disease ; Delayed Graft Function/diagnosis/*etiology/therapy ; Female ; Graft Rejection/diagnosis/*immunology/therapy ; Graft Survival ; *Histocompatibility ; Humans ; Immunosuppressive Agents/therapeutic use ; Kidney Transplantation/*adverse effects ; Male ; Middle Aged ; Patient Selection ; Reoperation ; Republic of Korea ; Risk Assessment ; Risk Factors ; Time Factors ; Treatment Outcome

BACKGROUND/AIMS: BK virus-associated nephropathy (BKVAN) is an important cause of allograft dysfunction in kidney transplant recipients. It has an unfavorable clinical course, and no definite treatment guidelines have yet been established. Here, we report our center's experience with biopsy-proven BKVAN and investigate factors associated with its progression. METHODS: From January 2004 to April 2013, 25 patients with BKVAN were diagnosed by biopsy at Seoul St. Mary's Hospital. Of the 25 patients, 10 were deceaseddonor transplant recipients and 15 were living-donor transplant recipients. Three of the patients underwent retransplantation. The primary immunosuppressant used was tacrolimus in 17 patients and cyclosporine in eight patients. RESULTS: BKVAN was observed at a mean duration of 22.8 ± 29.1 months after transplantation. The mean serum creatinine level at biopsy was 2.2 ± 0.7 mg/dL. BKVAN occurred with acute rejection in eight patients (28%). Immunosuppression modification was performed in 21 patients (84%). Additionally, leflunomide and intravenous immunoglobulin were administered to 13 patients (52%) and two (8%), respectively. Allograft loss occurred in five patients (27.8%) during the follow- up period at 0.7, 17.1, 21.8, 39.8, and 41.5 months after the BKVAN diagnosis. Advanced stages of BKVAN, increased creatinine levels, and accompanying acute rejection at the time of BKVAN diagnosis increased the risk of allograft failure. CONCLUSIONS: The clinical outcomes in patients with biopsy-proven BKVAN were unfavorable in the present study, especially in patients with advanced-stage BKVAN, poor renal function, and acute allograft rejection.
Adult ; Allografts ; Antiviral Agents/therapeutic use ; BK Virus/*pathogenicity ; Biomarkers/blood ; Biopsy ; Creatinine/blood ; Disease Progression ; Female ; Graft Rejection/diagnosis/drug therapy/immunology/*virology ; Graft Survival ; Humans ; Immunocompromised Host ; Immunosuppressive Agents/adverse effects ; Kaplan-Meier Estimate ; Kidney Transplantation/*adverse effects ; Male ; Middle Aged ; Opportunistic Infections/diagnosis/drug therapy/immunology/*virology ; Polyomavirus Infections/diagnosis/drug therapy/immunology/*virology ; Republic of Korea ; Retrospective Studies ; Risk Factors ; Time Factors ; Treatment Outcome ; Tumor Virus Infections/diagnosis/drug therapy/immunology/*virology

PURPOSE: To evaluate tumor-specific immunity and define the mechanisms involved in the cryoimmunologic response, we compared the tumor control efficacy and immunologic responses of cryoablation with those of surgical excision in a tumor rechallenge model. MATERIALS AND METHODS: Sixty BALB/c mice with RENCA tumors that were generated in the left flank area underwent cryoablation or radical excision. The mice successfully treated were rechallenged with RENCA or an undifferentiated colon carcinoma cell line, CT26, in the contralateral right flank area. The recurrence rate after tumor rechallenge in each group was then observed. To assess the immunologic response of each treatment modality, fluorescent-activated cell sorting (FACS) analysis and a cytotoxicity assay using 51Cr release were performed. RESULTS: After reinoculation of the RENCA cells, the rate of tumor growth was significantly higher in the surgical excision group than in the cryoablation group (94.4% vs. 11.1%, p=0.001). In the cryoablation group, the tumor growth rate was significantly increased after rechallenge of CT26 cells compared with RENCA (94.1% vs. 11.1%, p=0.001). The cryoablation group showed an elevated CD3, CD4, CD8 T, and natural killer cell count in the FACS analysis and also showed significantly increased cytotoxicity in the 51Cr release assay compared with the excision group. CONCLUSIONS: These results showed that cryoablation, compared to surgical resection, was more effective in preventing tumor growth after rechallenge with RENCA cells and that this response was tumor-specific, because the CT26 cells did not have the same effect.
Animals ; CD4-Positive T-Lymphocytes/immunology ; CD8-Positive T-Lymphocytes/immunology ; Carcinoma, Renal Cell/*immunology/pathology/*surgery ; Cell Death ; Cryosurgery/*methods ; Cytotoxicity, Immunologic ; Disease Models, Animal ; Kidney Neoplasms/*immunology/pathology/*surgery ; Lymphocyte Count ; Lymphocytes, Tumor-Infiltrating/immunology ; Mice, Inbred BALB C ; Neoplasm Recurrence, Local/immunology ; Neoplasm Transplantation

Kidney transplantation is the treatment of choice for end stage renal disease. Successful kidney transplantation improves the quality of life and reduces the mortality risk for most patients, when compared with maintenance dialysis. Recent advances, including immunosuppressants, desensitization treatment for highly sensitized kidney transplant candidates, and better medical care, have resulted in an increase number of transplants with improved outcomes. However, kidney transplant recipients require close follow-up after transplantation since they are on complex immunosuppressive regimens that render them susceptible to infection, malignancy, and cardiovascular disease. The additional obstacles of kidney transplantation include the lack of improvement in long term outcomes, shortage of organs, and multiple co-morbidities due to their underlying chronic kidney disease. To improve the long-term outcome of renal allograft, physicians must be aware in developing newer immunosuppressive regimens, with lower side effects, and reduction of death with functioning graft and chronic allograft dysfunction will be the greatest challenge of all physicians who care for kidney transplant recipients. This review highlights current status of kidney transplantation in Korea, brief transplant immunology, immunologic tests, donor/recipient evaluation, immunosuppressive medications, and complications of kidney transplantation involving rejection, post transplantation infections, malignancy, cardiovascular disease and recurrence of primary disease.
Allergy and Immunology ; Allografts ; Cardiovascular Diseases ; Dialysis ; Humans ; Immunologic Tests ; Immunosuppressive Agents ; Kidney Failure, Chronic ; Kidney Transplantation* ; Kidney* ; Korea ; Mortality ; Quality of Life ; Recurrence ; Renal Insufficiency, Chronic ; Tissue Donors ; Transplantation ; Transplants

Kidney transplantation is the treatment of choice for end stage renal disease. Successful kidney transplantation improves the quality of life and reduces the mortality risk for most patients, when compared with maintenance dialysis. Recent advances, including immunosuppressants, desensitization treatment for highly sensitized kidney transplant candidates, and better medical care, have resulted in an increase number of transplants with improved outcomes. However, kidney transplant recipients require close follow-up after transplantation since they are on complex immunosuppressive regimens that render them susceptible to infection, malignancy, and cardiovascular disease. The additional obstacles of kidney transplantation include the lack of improvement in long term outcomes, shortage of organs, and multiple co-morbidities due to their underlying chronic kidney disease. To improve the long-term outcome of renal allograft, physicians must be aware in developing newer immunosuppressive regimens, with lower side effects, and reduction of death with functioning graft and chronic allograft dysfunction will be the greatest challenge of all physicians who care for kidney transplant recipients. This review highlights current status of kidney transplantation in Korea, brief transplant immunology, immunologic tests, donor/recipient evaluation, immunosuppressive medications, and complications of kidney transplantation involving rejection, post transplantation infections, malignancy, cardiovascular disease and recurrence of primary disease.
Allergy and Immunology ; Allografts ; Cardiovascular Diseases ; Dialysis ; Humans ; Immunologic Tests ; Immunosuppressive Agents ; Kidney Failure, Chronic ; Kidney Transplantation* ; Kidney* ; Korea ; Mortality ; Quality of Life ; Recurrence ; Renal Insufficiency, Chronic ; Tissue Donors ; Transplantation ; Transplants

BACKGROUND/AIMS: Recurrent focal segmental glomerulosclerosis (FSGS) following renal transplantation is relatively common. However, the risk factors and optimal pretransplant treatment preventing recurrence of FSGS remain controversial. METHODS: We retrospectively reviewed 27 adult renal transplant recipients with FSGS over a period of 10 years. We first compared possible risk factors for FSGS recurrence between the recurrence and nonrecurrence groups. Then we evaluated the effect of pretransplant plasmapheresis (PP; n = 4) and PP with rituximab (PP + RTX; n = 5) on recurrence of FSGS after transplantation compared to control patients that were not treated with these modalities. RESULTS: There were seven recurrences in 27 patients (25.9%), but there were no significant differences in possible risk factors for FSGS recurrence between the two groups. Recurrence rates between patients with pretransplant PP or PP + RTX and control patients were not significantly different (22.2% vs. 27.7%, p > 0.05). There was also no significant difference in recurrence between the pretransplant PP and PP + RTX groups (25% vs. 20%, p > 0.05). CONCLUSIONS: Pretransplant PP or PP + RTX do not significantly decrease the recurrence of FSGS in adult renal transplant candidates.
Adult ; Antibodies, Monoclonal, Murine-Derived/*administration & dosage ; Female ; Glomerulosclerosis, Focal Segmental/diagnosis/immunology/*surgery ; Humans ; Immunosuppressive Agents/*administration & dosage ; *Kidney Transplantation/adverse effects ; Male ; Middle Aged ; *Plasmapheresis ; Recurrence ; Retrospective Studies ; Risk Factors ; Treatment Outcome