Kidney donor age of 50 years or above is a risk factor for calcineurin inhibitor-induced nephrotoxicity.

INTRODUCTION: Calcineurin inhibitor (CNI)-induced nephrotoxicity (CNI-T) is a post-transplantation complication that leads to graft dysfunction. Older-donor kidney grafts may be susceptible to chronic CNI exposure because of long-term arteriolar damage. The primary aim of this study was to examine the CNI-T incidence and time-course changes in the graft function according to donor age. METHODS: We included 334 kidney transplant recipients. CNI-T was defined by Banff arteriolar hyaline thickening scores of ≥2 based on allograft protocol biopsy. Depending on donor age, participants were divided into the D > 70 (≥70 years), D60 (60-69 years), D50 (50-59 years), and D < 49: (≤49 years) groups. We investigated the extent to which CNI-T affected the transplanted kidney function. Patients who did not develop CNI-T during the study period were included in the non-CNI-T group; the remaining were grouped into the CNI-T group. RESULTS: The CNI-T incidence was higher in donors aged >50 years. Compared to D < 49, the CNI-T risk was 1.86 times higher in D50 and 2.9 times higher in D > 70. Furthermore, the CNI-T group exhibited a significantly lower graft function 10 years after transplantation. CONCLUSION: CNI-T incidence increases in donors aged ≥50 years and affects renal function after 10 years.

Longitudinal mortality risks and kidney functional outcomes in Japanese living kidney donors.

OBJECTIVES: Previous studies suggested that living kidney donors do not have a higher risk of death or kidney failure than the general population. However, living kidney donor risk is controversial. Furthermore, only a few studies have evaluated long-term kidney function after kidney donation. METHODS: This study evaluated Japanese kidney donor' long-term outcomes, including mortality and kidney function. From 1965 to 2015, 230 donors (76 males, 154 females, and a median age of 54) were enrolled in this study. The median observation period was 11.0 (range, 0.3-41.0) years. RESULTS: In total, 215 donors were still alive, and 15 had died. Causes of death included malignancies, cardiovascular disease, pneumonia, suicide, gastrointestinal bleeding, and kidney failure. Actual donor survival rates at 10, 20, and 30 years were 95.3%, 90.7%, and 80.9%, respectively. These values were comparable to age- and gender-matched expected survival. Long-term kidney function after donation was evaluated in 211 donors with serum creatinine data. Two donors developed kidney failure 24 and 26 years post-donation, respectively. The percentage of donors whose estimated glomerular filtration rate (eGFR) remained ≥45 mL/min/1.73 m2 at 10, 20, and 30 years after donation were 84.2%, 73.0%, and 63.9%, respectively. Survival rates of donors with eGFR <45 mL/min/1.73 m2 were comparable to those in persons with eGFR >45 mL/min/1.73 m2. CONCLUSION: Our findings revealed that kidney donors did not have a higher long-term risk of death than the general population. Although some donors showed decreased kidney function after donation, kidney function did not impact their survival.

Mechanism and treatment for chronic antibody-mediated rejection in kidney transplant recipients.

Chronic antibody-mediated rejection of kidney transplantation is a major cause of late-stage graft loss. Donor-specific antibodies are the main cause of antibody-mediated rejection; in particular, de novo donor-specific antibodies are a risk factor for chronic active antibody-mediated rejection. The level of de novo donor-specific antibodies tends to increase with time throughout long-term graft survival. Donor-specific antibodies induce humoral rejection through complement activation, which results in tissue injury and coagulation. Additionally, complement activation promotes the migration of inflammatory cells through the innate immune response, causing endothelial injury. This inflammatory response may cause persistent glomerulitis and peritubular capillaritis, leading to fixed pathological lesions that impair graft function. No treatment has been established for chronic antibody-mediated rejection, a condition in which antibody-mediated rejection becomes irreversible. Thus, antibody-mediated rejection must be detected and treated while it is still reversible. In this review, we discuss the development of de novo donor-specific antibodies and the mechanisms leading to chronic antibody-mediated rejection and summarize the current treatment options and the latest biomarkers for detecting chronic antibody-mediated rejection at an earlier stage.

Incidence of post-transplant hepatitis B virus reactivation with the use of kidneys from donors with resolved hepatitis B virus infection.

Donors with resolved hepatitis B virus (HBV) infection may be a solution for the organ shortage for kidney transplantation (KT). The purpose of this study was to clarify the current state of HBV markers after KT from donors with resolved HBV infection to HBV naïve recipients and the rate of HBV reactivation in recipients with resolved HBV infection. Furthermore, we investigated HBV covalently closed circular DNA (cccDNA) in transplanted organs from donors with resolved HBV infection and the capability of HBV replication in kidney cell lines. We retrospectively analysed the HBV status of 340 consecutive donors and recipients who underwent KT in a single centre. We prospectively measured cccDNA by real-time polymerase chain reaction in kidney biopsy specimens of 32 donors with resolved HBV infection. HBV reactivation was found in three recipients with resolved HBV infection (4.8%, 3/63) after KT. We analysed 45 cases of transplantation from donors with resolved HBV infection to HBV-naive recipients. One case (2.2%, 1/45) became seropositive for hepatitis B core antibody (anti-HBc) and in another case (2.2%, 1/45), HBV-DNA was detected qualitatively in an HBV naive recipient with a donor with resolved HBV infection. In the latter case, cccDNA was measured in the donor kidney during KT. HBV replication was observed in kidney cell lines with HBV plasmid transfection. In conclusion, the risk of reactivation in anti-HBc-positive donors is relatively low. However, post-transplant HBV monitoring should be conducted in all at-risk cases.

Vesicoureteral reflux treatment following kidney transplantation potentially prevents graft function deterioration and allows long-term graft survival.

OBJECTIVES: The impact of vesicoureteral reflux post-kidney transplantation on graft survival remains unclear, and guidelines on appropriate vesicoureteral reflux management post-kidney transplantation are lacking. For this reason, we conducted a retrospective study on the impact of vesicoureteral reflux and its treatment on graft survival. METHODS: We evaluated 347 consecutive kidney transplantation recipients, who also underwent a ureteroneocystostomy, between 1996 and 2012. RESULTS: Vesicoureteral reflux was diagnosed in 55 cases (15.9%), with a median post-kidney transplantation duration of 50 months (range 0-172 months). Among these, 22 were monitored, 17 underwent transurethral collagen injections, and 16 received a ureteroneocystostomy. The 10-year graft survival rate was significantly lower in recipients with vesicoureteral reflux (68.9%) than in those without vesicoureteral reflux (84.4%) (P = 0.0165). Moreover, among the vesicoureteral reflux recipients, the 10-year graft survival rate was significantly higher in those whose vesicoureteral reflux was cured (80.1%) than in those whose vesicoureteral reflux persisted (53.6%) (P = 0.0062). Multivariate analysis showed that vesicoureteral reflux was significantly associated with both overall and death-censored graft loss (odds ratio 3.737 and 3.685; P = 0.0015 and P = 0.0052, respectively). Lastly, the incidence of interstitial fibrosis and tubular atrophy was higher in recipients with vesicoureteral reflux than in those without vesicoureteral reflux (P = 0.0009). CONCLUSIONS: Post-kidney transplantation vesicoureteral reflux has a negative impact on long-term graft survival, and that treatment prevents graft deterioration. From the perspective of maintaining long-term graft function in kidney recipients, vesicoureteral reflux may be one of the most important complications to be addressed.

Increased urinary exosomal SYT17 levels in chronic active antibody-mediated rejection after kidney transplantation via the IL-6 amplifier.

Chronic active antibody-mediated rejection (CAAMR) is a particular problem in kidney transplantation (KTx), and ~25% of grafts are lost by CAAMR. Further, the pathogenesis remains unclear, and there is no effective cure or marker. We previously found that a hyper NFκB-activating mechanism in non-immune cells, called the IL-6 amplifier, is induced by the co-activation of NFκB and STAT3, and that this activation can develop various chronic inflammatory diseases. Here, we show that synaptotagmin-17 (SYT17) is increased in an exosomal fraction of the urine from CAAMR patients, and that this increase is associated with activation of the IL-6 amplifier. Immunohistochemistry showed that SYT17 protein expression was increased in renal tubule cells of the CAAMR group. While SYT17 protein was not detectable in whole-urine samples by western blotting, urinary exosomal SYT17 levels were significantly elevated in the CAAMR group compared to three other histology groups (normal, interstitial fibrosis and tubular atrophy, and calcineurin inhibitors toxicity) after KTx. On the other hand, current clinical laboratory data could not differentiate the CAAMR group from these groups. These data suggest that urinary exosomal SYT17 is a potential diagnostic marker for CAAMR.

GalT-KO pig lungs are highly susceptible to acute vascular rejection in baboons, which may be mitigated by transgenic expression of hCD47 on porcine blood vessels.

BACKGROUND: Despite recent progress in survival times of xenografts in non-human primates, there are no reports of survival beyond 5 days of histologically well-aerated porcine lung grafts in baboons. Here, we report our initial results of pig-to-baboon xeno-lung transplantation (XLTx). METHODS: Eleven baboons received genetically modified porcine left lungs from either GalT-KO alone (n = 3), GalT-KO/humanCD47(hCD47)/hCD55 (n = 3), GalT-KO/hD47/hCD46 (n = 4), or GalT-KO/hCD39/hCD46/hCD55/TBM/EPCR (n = 1) swine. The first 2 XLTx procedures were performed under a non-survival protocol that allowed a 72-hour follow-up of the recipients with general anesthesia, while the remaining 9 underwent a survival protocol with the intention of weaning from ventilation. RESULTS: Lung graft survivals in the 2 non-survival animals were 48 and >72 hours, while survivals in the other 9 were 25 and 28 hours, at 5, 5, 6, 7, >7, 9, and 10 days. One baboon with graft survival >7 days, whose entire lung graft remained well aerated, was euthanized on POD 7 due to malfunction of femoral catheters. hCD47 expression of donor lungs was detected in both alveoli and vessels only in the 3 grafts surviving >7, 9, and 10 days. All other grafts lacked hCD47 expression in endothelial cells and were completely rejected with diffuse hemorrhagic changes and antibody/complement deposition detected in association with early graft loss. CONCLUSIONS: To our knowledge, this is the first evidence of histologically viable porcine lung grafts beyond 7 days in baboons. Our results indicate that GalT-KO pig lungs are highly susceptible to acute humoral rejection and that this may be mitigated by transgenic expression of hCD47.

Upregulation of CD80 on glomerular podocytes plays an important role in development of proteinuria following pig-to-baboon xeno-renal transplantation - an experimental study.

We have previously reported that co-transplantation of the kidney with vascularized donor thymus from α-1,3-galactosyltransferase gene knockout pigs with an anti-CD154 with rituximab-based regimen led to improved xenograft survival in baboons with donor-specific unresponsiveness. However, nephrotic syndrome emerged as a complication in which the glomeruli showed mild mesangial expansion with similarities to minimal change disease (MCD) in humans. Since MCD is associated with CD80 expression in glomeruli and elevated urinary excretion, we evaluated a potential role for CD80 in xenograft nephropathy. Study 1 confirmed high urinary CD80 excretion in nephrotic animals with renal xenografts showing CD80 expression in glomeruli. In Study 2, baboons receiving xenografts received CTLA4-Ig once a week from the second postoperative week or no CTLA4-Ig. The non-CTLA4-Ig group developed severe proteinuria with modest mesangial expansion with high urinary excretion of CD80 and documented CD80 expression in glomerular podocytes. All of the recipients in non-CTLA4-Ig groups had to be euthanized before POD 60. In contrast, CTLA4-Ig group showed a marked reduction in proteinuria and survived significantly longer, up to 193 days. These results demonstrate that anti-CD80 targeted therapy represents a promising strategy for reduction of proteinuria following renal xeno-transplantation with improved survival.

The value of long-term protocol biopsies after kidney transplantation.

Protocol biopsies for the detection and treatment of subclinical rejection in the early period after kidney transplantation are useful for preventing allograft dysfunction. However, little has been reported on the relationship between subclinical rejection and long-term protocol biopsies. In this review, we examine the potential benefits associated with long-term allograft biopsies focusing on the issue of immunological and non-immunological factors. Early detection and treatment of subclinical rejection improves outcome. However, the benefit of long-term allograft biopsies is largely unproved, and the strategy is yet to be widely implemented. The procurement of long-term protocol biopsies for the sole purpose of detecting subclinical rejection may be unwarranted. On the other hand, the early detection of IgA nephropathy using long-term protocol biopsy may improve graft survival. In addition, assessment of long-term protocol biopsies is useful not only for detection of calcineurin inhibitor nephrotoxicity, but also for follow-up after withdrawal of calcineurin inhibitor regimens. Also, identifying normal histology on a protocol biopsy may inform us about the safety of reducing overall immunosuppression. Thus, the potential benefit of long-term protocol biopsy may be of clinical significance for the detection of graft dysfunction as a result of non-immune factors, such as recurrence of glomerulonephritis and calcineurin inhibitor nephrotoxicity, rather than subclinical rejection.

Change in Tacrolimus Concentration Measured in Whole Blood Correlates With Changes in Red Blood Cell Parameters After Red Blood Cell Transfusion in Kidney Transplant Recipients.

BACKGROUND: Tacrolimus (TAC) is a narrow therapeutic range drug that requires therapeutic drug monitoring. TAC concentration is measured using whole blood owing to its high red blood cell (RBC) transfer rate of 95%. The distribution and whole-blood TAC concentration may be affected by the transfusion of red cell concentrates (RCCs); however, this has not been studied in kidney transplant recipients (KTR). Therefore, we investigated the relationship between changes in whole-blood TAC concentration and RBC parameters before and after RCC transfusion in KTR. METHODS: Fifteen KTR who received TAC and RCC transfusions were enrolled. The change rates of RBC parameters (RBC count, hemoglobin [Hgb], hematocrit [Hct]), and TAC concentration/dose before and after transfusion were calculated. The correlation between each RBC parameter and the TAC rate was evaluated. RESULTS: The TAC concentration and rate increased after RCC transfusion. Moreover, the TAC rate showed a significant and strong correlation with RBC count, Hgb, and Hct, with RBC count showing the highest correlation coefficient (r = 0.811, 0.766, and 0.764, respectively; p < .01). Serum creatinine and potassium levels remained stable, suggesting the absence of typical adverse effects associated with TAC, such as acute kidney injury or hyperkalemia. CONCLUSION: Changes in whole-blood TAC concentration and RBC parameters were correlated, and whole-blood TAC concentration increased after RCC transfusion. Therefore, the TAC dose should be adjusted accordingly.

Sequential analysis of donor-specific antibodies and pathological findings in acute antibody-mediated rejection in a rat renal transplantation model.

Alloantibodies contribute significantly to renal transplant rejection by activation of complement and various cytokines with a variety of effector cells, and are a major cause of allograft loss. Although there is clinical evidence of antibody- and complement-mediated injury in renal transplantation, the mechanism of antibody-mediated rejection remains largely unknown. In order to understand the sequential production of antibodies and complement components, we presensitized recipient rats by skin transplantation. Anti-donor-specific IgG levels reached a maximum 2 weeks following presensitization after which the rats underwent renal transplantation from the same donor strain. We then evaluated sequential pathological findings based on the Banff classification and several factors related to graft rejection. In this presensitized model, peritubular capillaries were already dilated and stained for C4d. Neutrophil and mononuclear cell infiltration in these capillaries was detected beginning 2 h after transplantation. Donor-specific antibody IgG levels decreased rapidly and anti-IgG antibody stained glomerular and peritubular capillaries in the grafts beginning 2 h after transplantation. Additionally, several cytokines and complement components showed marked changes in the presensitized group. Thus, in the donor-specific presensitized recipient, alloantibodies and complement were activated immediately after transplant. C4d deposition in peritubular capillaries appears to be a key factor for the diagnosis of antibody-associated rejection.

Long-term clinicopathological impact of calcineurin inhibitor cessation without specific cytoreductive induction in kidney transplantation.

Calcineurin inhibitors (CNIs) have considerably improved renal allograft survival. However, their chronic use has various adverse effects, including hypertension, hyperlipidemia, and nephrotoxicity. We conducted a retrospective study of kidney transplant recipients using a CNI withdrawal protocol. Eleven of 13 patients who had stable graft function on triple-drug therapy including a cyclosporine (CsA) were enrolled in this study. The dose of CsA was reduced by 20% every two wks until complete withdrawal. The mean period between the baseline and last biopsies was 97 (range: 21-123) months. No patient had an acute rejection episode during follow-up. Progression of interstitial fibrosis and tubular atrophy was seen in five and six cases, respectively. Arteriolar hyalinosis improved in three cases, but worsened in four. No patient lost his graft during the study. The mean serum creatinine level was 1.30 ± 0.26 mg/dL at baseline and stable for 10 yr after elimination (1.26 ± 0.11 mg/dL). At the end of the study, four of the eleven patients had reduced their antihypertensive drugs, and one patient had stopped hyperlipidemia treatment. CNI withdrawal can be implemented safely in stable renal transplant recipients and might lead to improved patient outcomes. Additional specific evidence of CNI nephrotoxicity should be elucidated.

Tonsillectomy ameliorates histological damage of recurrent immunoglobulin A nephropathy after kidney transplantation.

AIM: Recurrence of immunoglobulin A (IgA) nephropathy (IgAN) after renal transplantation is important as a cause of graft failure under improving rejection control. However, no specific therapy for recurrent IgAN is currently available. In this study, we evaluated the histological efficacy of tonsillectomy for allograft IgAN. METHODS: Fifteen kidney recipients (male 9, female 6, mean age 40.9 ± 9.3 years), who received a diagnosis of IgA nephropathy by allograft biopsy, were enrolled in this study. Tonsillectomy was performed 44.1 ± 27.1 months after the kidney transplantation. All patients underwent a repeat graft biopsy at 23.8 ± 15.8 months after tonsillectomy. RESULTS: Six patients had microhematuria before tonsillectomy. At 12 months after treatment, the microhematuria disappeared in five of these patients and one patient had mild hematuria. Three patients had severe proteinuria (more than 1.0 g/gCr) before tonsillectomy and improved after treatment. On histological analysis, four patients had acute lesions including cellular or fibrocellular crescents. The acute lesions disappeared after these treatments in all patients. Eleven patients had chronic lesions including global sclerosis, segmental sclerosis and fibrous crescents. The chronic lesion was ameliorated in six patients, unchanged in three and deteriorated in two patients. CONCLUSIONS: Tonsillectomy improves not only clinical findings but also ameliorates histological damage caused by recurrent IgAN after kidney transplantation. Tonsillectomy is a novel and effective treatment for recurrent IgAN.

Exacerbation of Intimal Fibrosis and Endarteritis in a Kidney Transplant Recipient with Chronic Active Antibody-Mediated Rejection and COVID-19: A Case Report.

Kidney transplant recipients are immunocompromised hosts at risk for comorbidity and mortality due to infection. Currently, there are no established guidelines for the management of immunosuppressed transplant recipients with coronavirus disease 2019 (COVID-19). The impact of COVID-19 and its therapeutic management on chronic active antibody-mediated rejection (CAAMR) are still unclear. Here, we report a case of CAAMR exacerbation with endarteritis and intimal fibrosis after COVID-19. A 41-year-old female kidney transplant recipient with CAAMR was admitted to a local hospital with moderately severe COVID-19. Her doses of tacrolimus and mycophenolate mofetil were reduced, and she was administered methylprednisolone pulse and antiviral drugs. This resulted in a good clinical course and she was discharged in 15 days. During and after hospitalization, the immunosuppressants were gradually returned to the baseline levels. However, about 1.5 months after discharge, the serum creatinine level became elevated. An indication kidney biopsy showed CAAMR with intimal fibrosis and endarteritis in all interlobular arteries. An increase of immunosuppressant led to a decrease of the serum creatinine level. Factors contributing to CAAMR with intimal fibrosis and endarteritis may include (1) insufficient immunosuppression due to changes in the levels of immunosuppressive; (2) overlap with endothelial cell injury caused by COVID-19, and (3) an immune-activated state associated with COVID-19. COVID-19 is a life-threatening disease that can result in unexpected changes in immunological status. Possible allograft rejection should be carefully managed in such patients.

Use of Mixed Lymphocyte Reaction Assay to Evaluate Immune Tolerance before Kidney Transplantation with an Immunosuppression-Free Protocol following Hematopoietic Stem Cell Transplantation from the Same Donor.

Several cases of kidney transplantation after hematopoietic stem cell transplantation (HSCT) from the same donor for end-stage renal disease have been reported. In those cases, immunosuppressive drugs were discontinued since immune tolerance was supposed to be induced. Theoretically, the recipient's immune system recognizes the kidney allograft as its own tissue with the same human leukocyte antigen (HLA) profile, and the kidney allograft will not be rejected, even without the use of immunosuppressive agents. However, almost all recipients receive immunosuppressants in the early stages after kidney transplantation owing to concerns of acute rejection. Here, we report a successful case of post-HSCT kidney transplantation without the use of immunosuppressive drugs, in which a mixed lymphocyte reaction (MLR) assay was used to evaluate immune tolerance before kidney transplantation. The patient was a 25-year-old woman. Five years prior, she developed acute myeloid leukemia and underwent HLA-half-matched peripheral blood stem cell transplantation. Thereafter, she was in remission of the acute myeloid leukemia, but 1 year later, she developed renal graft-versus-host disease. Subsequently, the patient's renal function gradually deteriorated to end-stage renal failure, and she underwent kidney transplantation with the previous stem cell donor: her mother. HLA typing of donor and recipient showed a complete chimerism in the peripheral blood. The pretransplantation complement-dependent cytotoxic crossmatch and flow cytometric T-cell crossmatch results were both negative, and HLA antibody measurements were all negative. The MLR assay revealed no T-lymphocyte reaction to the donor; therefore, immunosuppressants were not used. Two years after transplantation, the patient's serum creatinine concentration was around 0.8 mg/dL (down from 4 mg/dL before transplantation). No abnormalities were observed in a renal biopsy performed after 3 months. Our study, along with others, indicates that immune tolerance to a donor develops in post-HSCT kidney transplantation from the same donor.

Comparison of Humoral Response in Kidney Transplant Recipients and Donors and Healthy Volunteers Following Second Dose of SARS-CoV-2 mRNA Vaccine.

PURPOSE: To investigate the kinetics and durability of anti-spike glycoprotein (S) immunoglobulin G (IgG) after the second dose of mRNA-based SARS-CoV-2 vaccine in kidney transplant recipients (recipients) compared with those in kidney donors (donors) and healthy volunteers (HVs) and identify factors negatively associated with SARS-CoV-2 vaccine effectiveness in recipients. METHODS: We enrolled 378 recipients with no history of COVID-19 and no anti-S-IgG before the first vaccine and who received a second mRNA-based vaccine dose. Antibodies were detected using an immunoassay more than 4 weeks after the second vaccine dose. Anti-S-IgG <0.8, ≥0.8 to 15, and ≥15 U/mL were considered negative, weak positive, and strongly positive, respectively, whereas anti-nucleocapsid protein IgG was negative. Anti-S-IgG titer was determined in 990 HVs and 102 donors. RESULTS: Anti-S-IgG titers were 154, 2475, and 1181 U/mL in the recipient, HV, and donor groups, respectively, with values significantly lower in recipients. The anti-S-IgG-positivity rate of recipients gradually increased following the second vaccination, suggesting that recipients had a delayed response compared with the HV and donor groups, who had a 100% positivity rate at an earlier time point. Anti-S-IgG titers decreased in donors and HVs, whereas they remained stable in recipients, although at a significantly lower level. Independent negative factors associated with anti-S-IgG titers in recipients were age >60 years and lymphocytopenia (odds ratio: 2.35 and 2.44, respectively). CONCLUSIONS: Kidney transplant recipients demonstrate delayed and attenuated responses, with lower SARS-CoV-2 antibody titers after the second dose of the mRNA-based COVID-19 vaccine.

A Case of Kidney Transplantation from a Deceased Donor with Acute Kidney Injury due to Rhabdomyolysis.

Acute kidney injury (AKI) due to rhabdomyolysis occurs because of renal ischemia or acute tubular necrosis due to the deposition of myoglobin casts in the renal tubules. Donors with AKI due to rhabdomyolysis are not contraindication for transplantation. However, the dark red kidney raises concerns about renal hypofunction or primary nonfunction after transplantation. We report the case of a 34-year-old man with a 15-year history of hemodialysis for chronic renal failure due to congenital anomalies of the kidney and urinary tract. The patient received a renal allograft from a young woman who suffered cardiac death. The serum creatinine (sCre) level of the donor at the time of transport was 0.6 mg/dL, and renal ultrasonography revealed no abnormalities in renal morphology or blood flow. Her serum creatinine kinase level increased to 57,000 IU/L 58 h after femoral artery cannulation and sCre level worsened to 1.4 mg/dL, suggesting AKI due to rhabdomyolysis. However, since the urine output of the donor was maintained, the sCre elevation was thought to be nonproblematic. The allograft had a dark red appearance at the time of procurement. The perfusion of the isolated kidney was good, but the dark red color did not improve. A 0-h biopsy showed flattening of the renal tubular epithelium and absence of the brush border and myoglobin casts in 30% of the renal tubules. Rhabdomyolysis-related tubular damage was diagnosed. Hemodialysis was discontinued on postoperative day 14. Twenty-four days after the operation, the transplanted kidney function progressed favorably (sCre 1.18 mg/dL), and the patient was discharged. Protocol biopsy 1 month after transplantation showed disappearance of myoglobin casts and improvement in renal tubular epithelial damage. The patient's sCre level was approximately 1.0 mg/dL 24 months after transplantation, and he is doing well without complications.

Analysis of T-cell alloantigen response via a direct pathway in kidney transplant recipients with donor-specific antibodies.

Donor-specific antibodies (DSAs) are the main cause of graft loss over time. The direct pathway of alloantigen recognition is important in the pathogenesis of acute rejection. Recent studies have suggested that the direct pathway also contributes to the pathogenesis of chronic injury. Nevertheless, there are no reports on T-cell alloantigen response via the direct pathway in kidney recipients with DSAs. We analyzed the T-cell alloantigen response via the direct pathway in kidney recipients with DSAs (DSA+) or without DSAs (DSA-). A mixed lymphocyte reaction assay was implemented to assess the direct pathway response. DSA+ patients showed significantly higher CD8+ and CD4+ T cell responses to donor cells than DSA- patients. Furthermore, proliferating CD4+ T cells showed a marked increase in Th1 and Th17 responses in DSA+ patients than in DSA- patients. In a comparison between anti-donor and third-party responses, the anti-donor CD8+ and CD4+ T cell response was significantly lower than the anti-third-party response. In contrast, the donor-specific hyporesponsiveness was absent in DSA+ patients. Our study demonstrated that DSA+ recipients have a greater potential for developing immune responses against the donor tissues via the direct alloantigen recognition pathway. These data contribute to an understanding of DSAs pathogenicity during kidney transplantation.