BACKGROUND:The effect of massive immunoglobulin G (IgG) elevation on highly protein-bound tacrolimus (TAC) after high-dose intravenous immunoglobulin (IVIG) therapy remains uncharacterized. Misinterpreting IVIG-induced whole-blood TAC elevation as increased unbound fraction risks underdosing and rejection in donor-specific antibody-positive kidney transplant recipients. The aim of this study was to investigate the interaction between IVIG-induced IgG elevation and TAC during preoperative desensitization. METHODS:This retrospective study compared TAC trough levels (C0), area under the concentration-time curve from 0 to 24 hours (AUC0-24), TAC C0/dose (C0/D), TAC AUC0-24/dose (AUC0-24/D), and serum IgG levels predesensitization and postdesensitization among 3 groups: IVIG [high-dose IVIG plus plasmapheresis (PP), n = 12], PP only (n = 7), and control (n = 68). RESULTS:Following IVIG, median whole blood TAC C0 rose from 6.5 to 9.3 ng/mL and AUC0-24 from 238.2 to 325.8 ng·hours/mL. Accordingly, serum IgG levels increased from 968 (898-1396) to 2647 (2349-2927) mg/dL. A linear mixed model confirmed that an increase in serum IgG levels was independently associated with an elevated TAC AUC0-24/D. This apparent TAC AUC0-24/D increase peaked at 1.3-fold and persisted for 2 weeks; however, no clinical evidence of TAC toxicity (eg, hyperkalemia) was observed, suggesting an unlikely rise in the unbound concentration. CONCLUSIONS:IVIG induced an apparent elevation in whole-blood TAC concentrations, mediated by elevated serum IgG levels. Because this elevation theoretically may not reflect an increase in the unbound fraction, empirical dose reductions based solely on whole-blood levels risk compromising immunosuppression. A vigilant therapeutic drug monitoring strategy is essential to account for the protein-binding interaction and potentially optimize immunosuppression in high-risk patients.

OBJECTIVES:Preemptive kidney transplantation (PEKT) is known to have better outcomes than kidney transplantation (KT) after dialysis therapy. However, the effect of pretransplant dialysis duration (PTDD) on KT outcomes under good hemodialysis control remains unclear. We investigated the association between PTDD and KT outcomes in a Japanese cohort with favorable dialysis management. METHODS:Among three institutions, 805 patients who underwent a living donor KT between 2001 and 2021 were enrolled in this study. Those who underwent more than one KT, multiple organ transplantations in addition to KT, or transplantations at < 20 years of age were excluded. Calcineurin inhibitors, mycophenolate mofetil, and steroids were the primary maintenance immunosuppressors. RESULTS:The allograft survival rates of the non-PEKT group were significantly lower than those of the PEKT group (hazard ratio [HR] 1.67, 95% confidence interval [CI] 1.04-2.70). Univariate analysis showed that ≥ 2 years of PTDD demonstrated the highest HR for allograft loss when PTDD was separated by year (95% CI 1.11-2.55). Multivariate analysis showed that ≥ 2 years of PTDD (HR 2.61 [95% CI 1.58-4.38]), being a male recipient (HR 2.35 [95% CI 1.30-4.53]), and having diabetic nephropathy (HR 2.94 [95% CI 1.71-4.98]) were suggested to be risk factors for allograft loss. Additionally, < 2 years of PTDD resulted in significantly higher allograft survival rates; the 10-year allograft survival rates of recipients with ≥ 2 years and < 2 years of PTDD were 82.0% and 91.8%, respectively. CONCLUSIONS:Allograft survival remained unaffected when KT is performed after a short-term dialysis introduction.

The efficacy and safety of maribavir, an oral benzimidazole nucleoside that inhibits viral kinase UL97, were evaluated in hematopoietic stem cell transplant (HSCT) or solid organ transplant (SOT) recipients with cytomegalovirus (CMV) infection. This phase III, multicenter, open-label, single-arm, interventional study (ClinicalTrials.gov: NCT05137717; Japan Registry of Clinical Trials: jRCT2021210056) investigated oral maribavir 400 mg twice daily for 8 weeks. Japanese HSCT/SOT recipients aged ≥ 16 years with symptomatic or asymptomatic CMV infection (including those resistant/refractory to ganciclovir, valganciclovir, or foscarnet) and without central nervous system CMV tissue-invasive disease or CMV retinitis were enrolled. Primary endpoints were confirmed CMV viremia clearance at week 8 for efficacy and treatment-emergent adverse events (TEAEs) for safety. Among 61 patients enrolled across 22 sites, 41 patients (median age 56.0 years; 36/41 [87.8

The prevention of cytomegalovirus (CMV) infection after kidney transplantation (KTx) is important. Letermovir (LTV), a drug used for CMV prophylaxis, has various drug–drug interactions. Repaglinide (RPG), an antidiabetic drug administered after KTx, is a substrate for CYP2C8, which may interact with LTV. We report the first case of a KTx recipient with prolonged severe hypoglycemia due to the enhanced effects of RPG caused by CYP2C8 inhibition by LTV. The patient was a woman in her 60s who underwent living-donor KTx. RPG (0.5 mg three times a day immediately before each meal) was started on day 27 post KTx. Although renal function did not improve sufficiently owing to the development of acute tubular necrosis and thrombotic microangiopathy, the patient was weaned off hemodialysis and discharged on day 36 post KTx (creatinine, 3.57 mg/dL; estimated glomerular filtration rate, 10.8 mL/min/1.73 m2). On the day of discharge (day 0), 480 mg LTV was administered once daily for CMV prophylaxis. The patient was brought to the emergency room because she lost consciousness at home at approximately 4 p.m. on day 2. The blood glucose level (BGL) at the time of transport was 33 mg/dL, indicating severe hypoglycemia. Therefore, RPG was discontinued immediately before lunch on day 2, and 40 mL 50

BACKGROUND:Polyomavirus nephropathy (PyVN) is a significant complication following kidney transplantation, characterized by tubulointerstitial inflammation that mimics T-cell-mediated rejection (TCMR). The Banff Human Organ Transplant (B-HOT) panel, a transcriptomic analysis tool comprising 770 genes, has been developed to facilitate the diagnosis of allograft rejection. However, its utility in distinguishing PyVN from TCMR remains unclear. OBJECTIVE:This study aimed to evaluate the biochemical characteristics of PyVN and TCMR using the B-HOT panel, investigate changes after PyVN treatment, and assess the panel's diagnostic utility. METHODS:Formalin-fixed paraffin-embedded tissue samples from 11 PyVN patients were analyzed both at diagnosis and follow-up using the B-HOT panel. Public datasets were compared to identify differentially expressed genes and activated pathways. Prognostic factors were explored based on viral clearance and renal function outcomes. RESULTS:BK VP1 gene expression was significantly elevated in PyVN cases, aiding diagnosis. While tissue homeostasis pathways were upregulated in PyVN compared to TCMR in the original data, no specific pathways were identified in public datasets. Successful viral clearance correlated with enhanced T-cell checkpoint signaling at diagnosis, suggesting its role in immune-mediated viral elimination. CONCLUSION:The B-HOT panel provides limited utility for diagnosing PyVN beyond viral gene quantification. However, T-cell checkpoint signaling may serve as a prognostic marker for viral clearance and renal function preservation in PyVN cases. Further studies are needed to refine molecular diagnostics for PyVN and improve transplant outcomes.

INTRODUCTION:High-dose intravenous immunoglobulin (H-IVIg) has been used as a desensitization therapy for donor-specific anti-HLA antibody (DSA)-positive kidney transplant recipients in Japan since 2019. This study reports the clinical and pathological outcomes of patients who received H-IVIg at Sapporo City General Hospital. METHODS:This study included 7 patients who underwent kidney transplantation at our hospital and received H-IVIg as pretransplant desensitization therapy. At our institution, H-IVIg is indicated for patients with a history of sensitization, such as prior blood transfusion, pregnancy, or organ transplantation, and who tested positive in a flow cytometry crossmatch (FCXM) before transplantation. The recipients (mean age: 55.2 ± 11 years) included one male and six females. The donors (mean age: 62.8 ± 8.8 years) included five males and two females. All were living donor transplants, with four cases involving spousal donation. We assessed the immunological status before and after desensitization and retrospectively analyzed kidney function, anti-donor antibody status, and pathological findings. RESULTS:Before desensitization, 6 patients were FCXM-T positive, and all were FCXM-B positive. After desensitization, 3 patients converted to FCXM-T negative; however, all remained FCXM-B positive. The Luminex single antigen test was positive in 4 patients before desensitization; one converted to negative, while one initially negative patient became positive. Consequently, 4 patients remained DSA positive at transplantation. Three patients experienced acute rejection within 1 month: one had antibody-mediated rejection (ABMR), and two had T-cell-mediated rejection. All patients responded to antirejection therapy, preserving their graft function. At 36 months of follow-up, all the patients survived with functional grafts. Pathological findings revealed early rejection in 3 patients, who later developed chronic ABMR. The remaining 4 patients did not experience rejection episodes. CONCLUSION:The H-IVIg regimen facilitates kidney transplantation in immunologically high-risk recipients. However, the risk of early postoperative rejection and the potential development of chronic ABMR necessitate careful posttransplant monitoring.

Introduction:We report a case in which enfortumab vedotin (EV) therapy was administered as a third-line treatment for locally advanced bladder cancer (bc), enabling successful radical resection. Case Presentation:This report describes the case of a 69-year-old male patient with locally advanced bc and pelvic lymph node (LN) metastases. After the failure of first-line chemotherapy and second-line immunotherapy, the patient received EV as third-line treatment. EV therapy resulted in significant tumor reduction, enabling successful radical cystectomy and lymph node dissection (LND). The patient remained recurrence-free for 22 months post-surgery. Conclusion:EV therapy suggests that it is a promising avenue for further exploration, potentially redefining the therapeutic landscape of historically challenging cases.

We report a case of testicular cancer after kidney transplantation in a 29-year-old man. Twenty-two years after the surgery, computed tomography (CT) showed a retroperitoneal mass 3 cm in diameter. Positron emission tomography (PET) -CT revealed high FDG uptake in both the right testis and retroperitoneal mass. Regarding serum tumor markers, α fetoprotein (AFP) was slightly elevated to 12.5 ng/ml. He underwent right radical orchiectomy, and pathological examination revealed pure seminoma. After surgery, the serum AFP level remained high (12. 9 ng/ml), and we initially considered this nonseminoma patient to have a good prognosis according to International Germ Cell Consensus Classification. During three cycles of a combination regimen including bleomycin, etoposide, and cisplatin (BEP), we performed adjustment of immunosuppressive therapy, treatment for Cytomegalovirus infection (valganciclovir hydrochloride), and that for other adverse events associated with systemic chemotherapy. The chemotherapy schedule was delayed, and bleomycin (third course, day 15) was skipped due to adverse effects. After 3 cycles of BEP, the retroperitoneal lymph node metastasis shrunk from 3.0 to 1.5 cm in diameter. In contrast to the good radiological response, the serum AFP level gradually increased during the treatment to 102.6 ng/ml. Therefore, we did not consider the AFP elevation to have derived from residual cancer, and decided to perform close follow-up. During the 3-year follow-up, AFP decreased to around 20 ng/ml, and PET-CT did not show any uptake in the retroperitoneal mass or other sites.

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.

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: (<= 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.

All authors declare no conflicts of interest.

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 m 2 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 m 2 were comparable to those in persons with eGFR >45 mL/min/1.73 m 2 . 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.

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.

Purpose. To investigate the kinetics and durability of anti-spike glycoprotein (S) immuno-globulin G (IgG) after the second dose of mRNA-based SARS-CoV-2 vaccine in kidney trans-plant recipients (recipients) compared with those in kidney donors (donors) and healthy volunteers (HVs) and identify factors negatively associated with SARS-CoV-2 vaccine effective-ness 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 deter-mined 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 fac-tors 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.

The development of diabetes mellitus (DM) after living donor kidney transplantation (KT) is a risk factor for worsening transplant kidney function, cardiac disease, and cerebrovascular disease, which may affect prognosis after KT. At our institution, all patients' glucose tolerance is evaluated perioperatively by oral glucose tolerance tests (OGTTs) at pre-KT, and 3, 6, and 12 month (mo.) after KT. We analyzed the insulinogenic index (ISI) and homeostasis model assessment beta cell (HOMA-β) based on the immunoreactive insulin (IRI) levels to determine how glucose tolerance changed after KT in 214 patients who had not been diagnosed with DM before KT. In addition, we analyzed the body mass index (BMI) which may also influence glucose tolerance after KT. The concentration of tacrolimus (TAC) in blood was also measured as the area under the curve (AUC) to examine its effects at each sampling point. The preoperative-OGTTs showed that DM was newly diagnosed in 22 of 214 patients (10.3%) who had not been given a diagnosis of DM by the pre-KT fasting blood sugar (FBS) tests. The glucose tolerance was improved in 15 of 22 DM patients at 12 mo. after KT. ISI and IRI deteriorated only at 3 mo. after KT but improved over time. There was a trend of an inverse correlation between HOMA-β and TAC-AUC. We also found inverse correlations between IRI and an increase in BMI from 3 to 12 mo. after KT. Early corticosteroid withdrawal or the steroid minimization protocol with tacrolimus to maintain a low level of diabetogenic tacrolimus and BMI decrease after KT used by our hospital individualizes lifestyle interventions for each patient might contribute to an improvement in post-KT glucose tolerance.

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.