Overcoming post-transplant graft failure and adenovirus infection in a patient with FLT3-TKD-mutated mixed-phenotype acute leukemia: A case report.

Mixed-phenotype acute leukemia (MPAL) with FLT3-TKD mutations is a rare and challenging subtype of leukemia. Effective management strategies are crucial for improving patient outcomes. A 31-year-old man with FLT3-TKD-mutated MPAL achieved hematological remission through the JALSG ALL202-O protocol and gilteritinib, followed by cord blood transplantation (CBT). Post-transplant complications included adenovirus-induced hemorrhagic cystitis, managed with bladder irrigation and ribavirin, and engraftment failure, necessitating a second CBT on Day 35. Subsequent adenoviral conjunctivitis resolved with vidarabine. The patient achieved neutrophil engraftment by Day 76 and was discharged on Day 173 without relapse. This case highlights the importance of vigilant supportive care and tailored therapy in managing MPAL with FLT3 mutations, especially in the context of post-transplant complications.

A predictive model for HIV-related lymphoma.

OBJECTIVES: To address the paucity of HIV-related lymphoma (HRL)-specific prognostic scores for the Japanese population by analyzing domestic cases of HRL and constructing a predictive model. DESIGN: A single-center retrospective study coupled with a review of case reports of HRL. METHODS: We reviewed all patients with HRL treated at our hospital between 2007 and 2023 and conducted a comprehensive search for case reports of HRL from Japan using public databases. A multivariate analysis for overall survival (OS) was performed using clinical parameters, leading to the formulation of the HIV-Japanese Prognostic Index (HIV-JPI). RESULTS: A total of 19 patients with HRL were identified in our institution, whereas the literature review yielded 44 cases. In the HIV-JPI, a weighted score of 1 was assigned to the following factors: age at least 45 years, HIV-RNA at least 8.0×10 4  copies/ml, Epstein-Barr virus-encoded small RNA positivity, and Ann Arbor classification stage IV. The overall score ranged from 0 to 4. We defined the low-risk group as scores ranging from 0 to 2 and the high-risk group as scores ranging from 3 to 4. The 3-year OS probability of the high-risk group [30.8%; 95% confidence interval (CI): 9.5-55.4%) was significantly poorer than that of the low-risk group (76.8%; 95% CI: 52.8-89.7%; P  < 0.01). CONCLUSION: This retrospective analysis established pivotal prognostic factors for HRL in Japanese patients. The HIV-JPI, derived exclusively from Japanese patients, highlights the potential for stratified treatments and emphasizes the need for broader studies to further refine this clinical prediction model.

Pioneering cord blood transplantation in relapsed/refractory HIV-related lymphoma: a case study with concurrent intramuscular antiretroviral therapy.

A 44-year-old HIV-positive man diagnosed with diffuse large B-cell lymphoma in 2021 achieved complete remission with six cycles of R-CHOP therapy but had a relapse in November 2022. ESHAP therapy failed to induce remission, leading to complete remission with four cycles of Pola-BR therapy. Post-failure of autologous stem cell harvest, cord blood transplantation (CBT) was performed in June 2023. Notably, this case used recently approved intramuscular antiretroviral therapy (ART) with cabotegravir and rilpivirine, addressing gastrointestinal complications during CBT. This innovative use of intramuscular ART in the treatment of malignancy represents a first in the field, offering a pioneering approach to HIV-related lymphoma.

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.

BK Polyomavirus-Associated Urothelial Carcinoma of the Bladder with a Background of BK Polyomavirus Nephropathy in a Kidney Transplant Recipient.

Renal transplant recipients are at increased risk for the development of a malignant neoplasm. Polyomavirus-associated urothelial carcinoma is a rare tumor that occurs in renal transplant recipients, with approximately 41 cases reported since 2002. It accounts for 27-31% of all post-transplant urothelial carcinomas and develops at an average of 8.5 years after transplantation. Histologically, it shows high-grade urothelial carcinoma (95.1%) with a high frequency of glandular differentiation and micropapillary structures (58.5%) and positive immunohistochemistry for polyomavirus large T antigen, p53 (92.9%), and p16 (100%). We encountered a case of BK polyomavirus (BKPyV)-associated urothelial carcinoma of the bladder diagnosed 54 months after kidney transplantation. Histologically, it was a high-grade urothelial carcinoma with micropapillary features, and immunohistochemically, it was diffusely positive for polyomavirus large T antigen, p16, and p53. BKPyV DNA and mRNA for BKPyV large T antigen have been identified in tissues using real-time polymerase chain reaction. The same sequence of the BKPyV VP1 genome hypervariable region was detected in both transplanted kidney tissue with polyomavirus nephropathy and urothelial carcinoma tissue, suggesting that polyomavirus-associated urothelial carcinoma developed in a background of persistent polyomavirus nephropathy. This case showed typical histological features and was detected and treated at an earlier stage than has been reported. It is important to keep in mind that polyomavirus-associated urothelial carcinoma can develop early after transplantation and might be associated with polyomavirus nephropathy. Because of its rapidly progressive nature, careful follow-up with urine cytology and cystoscopy is necessary. We report this case with a literature review.

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.

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.

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.

Banff Human Organ Transplant Transcripts Correlate with Renal Allograft Pathology and Outcome: Importance of Capillaritis and Subpathologic Rejection.

BACKGROUND: To seek insights into the pathogenesis of chronic active antibody-mediated rejection (CAMR), we performed mRNA analysis and correlated transcripts with pathologic component scores and graft outcomes. METHODS: We utilized the NanoString nCounter platform and the Banff Human Organ Transplant gene panel to quantify transcripts on 326 archived renal allograft biopsy samples. This system allowed correlation of transcripts with Banff pathology scores from the same tissue block and correlation with long-term outcomes. RESULTS: The only pathology score that correlated with AMR pathways in CAMR was peritubular capillaritis (ptc). C4d, cg, g, v, i, t, or ci scores did not correlate. DSA-negative CAMR had lower AMR pathway scores than DSA-positive CAMR. Transcript analysis in non-CAMR biopsies yielded evidence of increased risk of later CAMR. Among 108 patients without histologic CAMR, 23 developed overt biopsy-documented CAMR within 5 years and as a group had higher AMR pathway scores (P=3.4 × 10-5). Random forest analysis correlated 3-year graft loss with elevated damage, innate immunity, and macrophage pathway scores in CAMR and TCMR. Graft failure in CAMR was associated with TCMR transcripts but not with AMR transcripts, and graft failure in TCMR was associated with AMR transcripts but not with TCMR transcripts. CONCLUSIONS: Peritubular capillary inflammation and DSA are the primary drivers of AMR transcript elevation. Transcripts revealed subpathological evidence of AMR, which often preceded histologic CAMR and subpathological evidence of TCMR that predicted graft loss in CAMR.

Successful immunomodulation in kidney transplant recipients with cytokine release syndrome after coronavirus disease.

Introduction: Patients with coronavirus disease, especially solid organ transplant recipients, are more susceptible to developing cytokine release syndrome than those with other viral infections. However, currently, treatment methods for such patients have not been established. Here, we describe two cases of successful immunomodulation in Japanese kidney transplant recipients with cytokine release syndrome following coronavirus disease. Case presentation: Two patients who had been receiving long-term immunosuppressant therapy developed coronavirus disease-associated pneumonia caused by cytokine release syndrome, following immunosuppressant dosage reduction. However, they recovered immediately after administration of tocilizumab with or without dexamethasone. Conclusion: The immunosuppressant dosage should be reduced to restore host immunity; however, immunomodulation should be considered in cases of suspected cytokine release syndrome.

Plant debris are hotbeds for pathogenic bacteria on recreational sandy beaches.

On recreational sandy beaches, there are guidelines for the management of bacterial pollution in coastal waters regarding untreated sewage, urban wastewater, and industrial wastewater. However, terrestrial plant debris on coastal beaches can be abundant especially after floods and whilst it has rarely been considered a concern, the bacterial population associated with this type of pollution from the viewpoint of public health has not been adequately assessed. In this study, microbes associated with plant debris drifting onto Kizaki Beach in Japan were monitored for 8 months throughout the rainy season, summer, typhoon season, and winter. Here we show that faecal-indicator bacteria in the plant debris and sand under the debris were significantly higher than the number of faecal bacteria in the sand after a 2015 typhoon. When we focused on specific pathogenic bacteria, Brevundimonas vesicularis and Pseudomonas alcaligenes were commonly detected only in the plant debris and sand under the debris during the survey period. The prompt removal of plant debris would therefore help create safer beaches.

Long-Term Outcome of ABO-Incompatible Kidney Transplantation in Patients Treated With Low-Dose Rituximab Regimen.

BACKGROUND: Introduction of rituximab in the desensitization protocols for ABO-incompatible (ABOI) kidney transplantation (KTX) has afforded excellent results. However, the acceptability of minimal dosage of rituximab in these protocols remains to be defined. METHODS: Sixty-three patients who underwent ABOI KTX were included in this study. The desensitization protocol consisted of plasmapheresis, tacrolimus, mycophenolate mofetil, methylprednisolone, intravenous immunoglobulin, basiliximab, and low-dose rituximab (100 mg/body). We evaluated the efficacy, safety, and long-term outcome of this protocol (group R, n = 39) and compared them with those of patients who underwent splenectomy (group S, n = 24). RESULTS: Graft and patient survival at 10 years after KTX were comparable between the groups (94.4% [group R] vs 95.4% [group S] and 94.6% [group R] vs 95.8% [group S], respectively). The incidence of acute antibody-mediated rejection (AAMR) was similar in the 2 groups (10.2% vs 12.5%). There were no significant differences in the incidence of chronic active antibody-mediated rejection. Of the patients, 7 developed AAMR and 3 of these patients (1 in group R and 2 in group S) lost their grafts. There were no significant differences in the incidence of chronic active antibody-mediated rejection. The incidence of postoperative cytomegalovirus infection in group R was significantly lower than that in group S. Furthermore, the incidence of postoperative late-onset neutropenia was low in group R. CONCLUSIONS: A low-dose rituximab regimen for ABOI KTX is acceptable for preventing AAMR with a low incidence of delayed adverse events.

A study of the translational temperature dependence of the reaction rate constant between CH3CN and Ne+ at low temperatures.

We have measured the translational temperature dependence of the reaction rate constant for CH3CN + Ne+ → products at low temperatures. A cold Ne+ ensemble was embedded in Ca+ Coulomb crystals by a sympathetic laser cooling technique, while cold acetonitrile (CH3CN) molecules were produced by two types of Stark velocity filters to widely change the translational temperatures. The measured reaction rate constant gradually increases with the decrease in the translational temperature of the velocity-selected CH3CN molecules from 60 K down to 2 K, and thereby, a steep increase was observed at temperatures lower than 5 K. A comparison between experimental rate constants and the ion-dipole capture rate constants by the Perturbed Rotational State (PRS) theory was performed. The PRS capture rate constant reproduces well the reaction rate constant at a few kelvin but not for temperatures higher than 5 K. The result indicates that the reaction probability is small compared to typical ion-polar molecule reactions at temperatures above 5 K.

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.

Orosomucoid 1 is involved in the development of chronic allograft rejection after kidney transplantation.

Chronic allograft rejection is the most common cause of long-term allograft failure. One reason is that current diagnostics and therapeutics for chronic allograft rejection are very limited. We here show that enhanced NFκB signaling in kidney grafts contributes to chronic active antibody-mediated rejection (CAAMR), which is a major pathology of chronic kidney allograft rejections. Moreover, we found that urinary orosomucoid 1 (ORM1) is a candidate marker molecule and therapeutic target for CAAMR. Indeed, urinary ORM1 concentration was significantly higher in kidney transplant recipients pathologically diagnosed with CAAMR than in kidney transplant recipients with normal histology, calcineurin inhibitor toxicity, or interstitial fibrosis and tubular atrophy. Additionally, we found that kidney biopsy samples with CAAMR expressed more ORM1 and had higher NFκB and STAT3 activation in tubular cells than samples from non-CAAMR samples. Consistently, ORM1 production was induced after cytokine-mediated NFκB and STAT3 activation in primary kidney tubular cells. The loss- and gain-of-function of ORM1 suppressed and promoted NFκB activation, respectively. Finally, ORM1-enhanced NFκB-mediated inflammation development in vivo. These results suggest that an enhanced NFκB-dependent pathway following NFκB and STAT3 activation in the grafts is involved in the development of chronic allograft rejection after kidney transplantation and that ORM1 is a non-invasive candidate biomarker and possible therapeutic target for chronic kidney allograft rejection.

[A suspicious case of coagulation disorder caused by vitamin K deficiency associated with fasting and antibiotics].

Coagulation disorders due to some antibiotics containing N-methyl-thiotetrazole group and vitamin K (VK) deficiency by microbial substitution in the intestinal flora can occur. We report a case of coagulation disorder under fasting with conventional antibiotics which are not containing N-methyl-thiotetrazole. A 91-year-old man was hospitalized for diagnosis of acute exacerbation of chronic heart failure because of bronchitis. He received treatment of fasting, fluid replacement, antibiotics, and a diuretic. On the 3rd day, left frontal lobe bleeding occurred. We performed conservative treatment with central venous nutrition not containing VK. Administration of antibiotics was completed after 14 days. On the 28th day, catheter-related bloodstream infection developed. Vancomycin and cefazolin were administered. The prothrombin time-international standard ratio (PT-INR) on the 1st day of administration was 1.2; however, it gradually increased to 7.4 on the 7th day of administration. Menatetrenone and fresh frozen plasma were administered as symptomatic treatment. Vancomycin was discontinued because a blood culture was positive for methicillin- susceptible coagulase negative Staphylococcus (CNS). After the 8th day of administration, the PT-INR improved to 1.1, but it increased to 1.9 on the 14th day. VK deficiency due to the antimicrobial drug was predicted. Therefore, VK and fresh frozen plasma were re-administered to improve the PT-INR. The PT-INR returned to normal after administration of cefazolin was terminated. Antimicrobial administration in the long term under the fasting condition can suppress endogenous production of VK by changing intestinal bacteria. And it has been reported that cefazolin which containing Methyl-thiadiazole thiol inhibits VK metabolic cycle and causes coagulation disorder. These reasons seems to a coagulation disorder. Therefore, physicians should monitor the coagulation system in this situation.

A 2-mm Cutoff Value Is Reasonable and Feasible for Vascular Reconstruction in a Kidney Allograft With Multiple Arteries.

BACKGROUND: Multiple renal arteries are found in approximately 20% of living donor kidneys. We have been using an accessory artery cutoff diameter of 2 mm on preoperative computed tomography angiography to determine whether to sacrifice or reconstruct the artery. In this study, we assessed the validity and feasibility of this cutoff value. METHODS: Living related kidney recipients from 2005 to 2013 were enrolled in this retrospective study. The diameter of the accessory artery and adverse events were evaluated. The lost parenchymal volume (%) due to vascular obstruction or branch ligation was calculated by computed tomography volumetry. RESULTS: Among 128 kidney transplants, 30 donor kidneys had multiple arteries. Accessory arteries were reconstructed in 18 cases and intentionally ligated in 12 cases (mean diameter of accessory arteries, 3.10 [SD, 0.75] mm and 1.81 [SD, 0.28] mm, respectively). The mean estimated glomerular filtration rate at 1 or 12 months after transplant was not significantly different between the groups. Among reconstructed cases, 14 cases (77.8%) had good patency in the reconstructed arteries whereas the other 4 had vascular complications. The percentage of lost parenchymal volume due to ligation or occlusion of the reconstructed artery (calculated in 16 cases) was predictable with the following formula: lost volume (%) = 9.09 × diameter (mm) - 10.5 (P= .03, rs= 0.533 by Spearman rank correlation coefficient). This formula indicated that ligation of a 2-mm accessory artery leads to 7.68% loss of the renal parenchyma. CONCLUSIONS: Reconstruction using a cutoff diameter of 2 mm is worth attempting in terms of the success rate and graft function. Sacrifice of a 2-mm accessory artery leads to parenchymal loss of <8%.