Metabolomic Profiling of Mice with Tacrolimus-Induced Nephrotoxicity: Carnitine Deficiency in Renal Tissue.

Tacrolimus (TAC)-induced chronic nephrotoxicity (TAC nephrotoxicity) has a detrimental effect on long-term kidney graft survival. However, the pathogenesis of TAC nephrotoxicity remains largely unknown. We explored it by focusing on metabolic changes in renal tissues. In this study, mice were separated into TAC and control groups (n = 5/group). TAC was administered to the TAC group (1 mg/kg/d for 28 days) subcutaneously. The control group was similarly treated with normal saline. Renal tissue metabolomes were evaluated. Renal fibrosis was observed only in the TAC group. Metabolomic analysis showed that carnitine and related metabolites were substantially lower in the TAC group than in the control group, presumably due to impaired biosynthesis and reabsorption. Low carnitine levels impair antioxidation in renal tissues and ß-oxidation in mitochondria, which may lead to renal tissue damage. This metabolomic analysis revealed that carnitine deficiency in renal tissue appears to explain TAC nephrotoxicity.

Computed Tomography Renal Volumetry Better Predicts Postoperative Donor Renal Function in Live Kidney Donor Transplantation than Renal Scintigraphy: A Comparative Study.

INTRODUCTION AND OBJECTIVES: Both computed tomography (CT) and renal scintigraphy (RS) have been used to assess vascular anatomy, renal status, and split renal function (SRF). In this study, we used a recently developed software that facilitates renal volumetric evaluations to compare RS and automated CT volumetry for assessing residual renal function and, thus, estimating postoperative renal function after donor nephrectomy. METHODS: Fifty-one cases of donor nephrectomy were analyzed. Residual renal function was estimated based on RS and CT volumetry. The correlation between the postoperative estimated glomerular filtration rate (eGFR) and expected SRF, measured using RS and three types of CT volumetry data (ellipsoid, thin-slice, and 5-mm slice data), was determined. RESULTS: The correlation coefficient between actual eGFR and expected SRF was significantly associated at each time point and modality (p < 0.0001). At any time point, the difference in correlation coefficient between RS and 5-mm volumetry was significant (p value: 0.003-0.018), whereas the differences in correlation coefficients between RS and the triaxial volume calculation, and the triaxial volume calculation and 5-mm volumetry, were generally statistically insignificant. CONCLUSIONS: Expected SRF was estimated more accurately by CT volumetric calculations (especially 5-mm slice-based volumetry) than RS.

Orthotopic kidney transplantation from a living renal donor after interventional therapy for bilateral arteriosclerosis obliterans of the iliac arteries: A case report and literature review.

Introduction: Orthotopic kidney transplantation is an option when heterotopic kidney transplantation into the iliac fossa is inappropriate. We report a case of orthotopic kidney transplantation following stenting of both external iliac arteries to treat arteriosclerosis obliterans. Case presentation: A 56-year-old woman on hemodialysis for end-stage kidney disease underwent living-donor kidney transplantation. Desensitization therapy was administered because of her history of sensitization by pregnancy. Stents had been placed previously in both external iliac arteries. The left kidney was removed via an oblique lumbar incision. The two graft arteries were conjoined and anastomosed to the native renal artery end-to-end. The urinary tract was reconstructed by uretero-ureterostomy with ureteral stent placement. Renal function improved promptly after surgery. Conclusion: Preoperative imaging of vascular anatomy is important for successful orthotopic kidney transplantation in patients who have previously undergone stenting of both external iliac arteries for arteriosclerosis obliterans.

Immunological risk and complement genetic evaluations in early onset de novo thrombotic microangiopathy after living donor kidney transplantation: A Japanese multicenter registry.

BACKGROUND: Thrombotic microangiopathy (TMA) after kidney transplantation (KTx), particularly early onset de novo (dn) TMA, requires immediate interventions to prevent irreversible organ damage. This multicenter study was performed to investigate the allogeneic clinical factors and complement genetic background of dnTMA after KTx. METHODS: Perioperative dnTMA after KTx within 1 week after KTx were diagnosed based on pathological or/and hematological criteria at each center, and their immunological backgrounds were researched. Twelve aHUS-related gene variants were examined in dnTMA cases. RESULTS: Seventeen recipients (15 donors) were enrolled, and all dnTMA cases were onset within 72-h of KTx, and 16 of 17 cases were ABO incompatible. The implementation rate of pre-transplant plasmaphereses therapies were low, including cases with high titers of anti-A/anti-B antibodies. Examination of aHUS-related gene variants revealed some deletions and variants with minor allele frequency (MAF) in Japan or East Asian genome databases in genes encoding alternative pathways and complement regulatory factors. These variants was positive in 8 cases, 6 of which were positive in both recipient and donor, but only in one graft loss case. CONCLUSIONS: Although some immunological risks were found for dnTMA after KTx, only a few cases developed into TMA. The characteristic variations revealed in the present study may be novel candidates related to dnTMA in Japanese or Asian patients, but not pathogenic variants of aHUS. Future studies on genetic and antigenic factors are needed to identify factors contributing to dnTMA after KTx.

Development and nationwide validation of kidney graft injury markers using urinary exosomes and microvesicles (complete English translation of the Japanese version).

BACKGROUND: Non-invasive, prompt, and proper detection tools for kidney graft injuries (KGIs) are awaited to ensure graft longevity. We screened diagnostic biomarkers for KGIs following kidney transplantation using extracellular vesicles (EVs; exosomes and microvesicles) from the urine samples of patients. METHODS: One hundred and twenty-seven kidney recipients at 11 Japanese institutions were enrolled in this study; urine samples were obtained prior to protocol/episode biopsies. EVs were isolated from urine samples, and EV RNA markers were assayed using quantitative reverse transcription polymerase chain reaction. Diagnostic performance of EV RNA markers and diagnostic formulas comprising these markers were evaluated by comparison with the corresponding pathological diagnoses. RESULTS: EV CXCL9, CXCL10, and UMOD were elevated in T-cell-mediated rejection samples compared with other KGI samples, while SPNS2 was elevated in chronic antibody-mediated rejection (cABMR) samples. A diagnostic formula developed through Sparse Logistic Regression analysis using EV RNA markers allowed us to accurately (with an area under the receiver operator characteristic curve [AUC] of 0.875) distinguish cABMR from other KGI samples. EV B4GALT1 and SPNS2 were also elevated in cABMR, and a diagnostic formula using these markers was able to distinguish between cABMR and chronic calcineurin toxicity accurately (AUC 0.886). In interstitial fibrosis and tubular atrophy (IFTA) urine samples and those with high Banff chronicity score sums (BChS), POTEM levels may reflect disease severity, and diagnostic formulas using POTEM detected IFTA (AUC 0.830) and high BChS (AUC 0.850). CONCLUSIONS: KGIs could be diagnosed with urinary EV mRNA analysis with relatively high accuracy.

Retroperitoneoscopic Donor Nephrectomy on the Right Side Provides Equivalent Outcomes and Donor Safety to That on the Left Side.

BACKGROUND: The left kidney is typically selected for laparoscopic donor nephrectomy. In contrast, right kidney donation raises concerns for donor safety, and venous anastomosis may be difficult to achieve due to the short renal vein. We investigated the safety and operative outcomes of right donor nephrectomy compared with those of the left. METHODS: We retrospectively analyzed the clinical records of living donor-kidney transplant donors and evaluated operative outcomes such as operative time, ischemic time, blood loss, and surgical complications in the donor. RESULTS: We identified 79 donors (left:right = 62:17 cases) between May 2020 and March 2023. There were no significant differences between the 2 groups regarding age, sex, body mass index, and number of renal arteries. Although the operative time (left and right: 190 and 225 minutes, excluding waiting time; P = .009) and warm ischemic time (left and right: 143 and 193 seconds, P = .021) were significantly longer on the right side, the total ischemic time (82 and 86 minutes, P = .463) and blood loss (left and right: 35 and 25 mL, P = .159) were comparable between the groups. There were no significant differences between the groups regarding the surgical complications. CONCLUSIONS: Operative outcomes were similar in both donor sides in the retroperitoneoscopic donor nephrectomies. The right side should be considered for donation in this operative procedure.

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.

Single-center survey of incidental imaging findings on computed tomography in patients with psoriasis on biologic therapy.

Psoriasis is an immune-mediated chronic inflammatory disease that predominantly affects the skin and joints. Systemic therapies are required for patients with moderate-to-severe psoriasis, and biologics can provide significant symptomatic improvement. Computed tomography (CT) analysis is recommended before and after biologic therapy to exclude the possibility of comorbid infections and malignancies; incidental findings are often detected in asymptomatic patients. In this study, we analyzed the common incidental findings on CT in 227 patients with psoriasis on biologic therapy and 219 living-kidney transplant donors at our hospital. Incidental findings on CT were observed in 176 (77.5%) patients with psoriasis. The most common were fatty liver (82 patients, 36.1%), urolithiasis (54 patients, 23.8%), pulmonary lesions (47 patients, 20.7%), gallstones or postoperative gallstones (38 patients, 16.7%), liver cysts (36 patients, 15.9%), renal cysts (33 patients, 14.5%), and colonic diverticulum (22 patients, 9.7%), which were observed in 38 (17.4%), eight (3.7%), 68 (31.1%), 12 (5.5%), 58 (26.5%), 88 (40.2%), and 10 (4.6%) donors, respectively. The prevalence of fatty liver, urolithiasis, gallstones, and postoperative gallstones was significantly higher in patients with psoriasis. Multivariate logistic regression showed that psoriasis was a risk factor for fatty liver disease, urolithiasis, and gallstones. Currently, incidental findings on CT in patients with psoriasis have not been well studied. The results of this survey will lead to increased awareness of the incidental findings on CT as a complication of psoriasis.

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.

Complete response to pembrolizumab for metastatic urothelial carcinoma in the renal pelvis of allograft kidney.

Introduction: We present a case of urothelial carcinoma in a renal allograft successfully treated with pembrolizumab. Case presentation: A 39-year-old woman presented with nausea and anorexia 9 years after a renal transplantation. Positron emission tomography revealed a neoplasm of the renal pelvis of the allograft and multiple lymph nodes with peritoneal metastasis. A diagnosis of a non-muscle-invasive bladder tumor with peritoneal dissemination and jejunal metastasis of urothelial carcinoma was made. After five cycles of gemcitabine and carboplatin, the tumor progressed and pembrolizumab was administered. One week after the first dose, the allograft was rejected, necessitating arterial embolization. After the second cycle, the patient developed Stevens-Johnson syndrome. After discontinuing pembrolizumab, positron emission tomography revealed no increased tumor activity. A complete response was achieved for 21 months without additional treatment. Conclusion: Pembrolizumab was effective in treating urothelial carcinoma of the renal allograft; however, allograft rejection and loss should be considered.

CASE REPORT: Serial Cases of False-Positive Flow-Cytometry T Cell Crossmatch Associated With Anti-Blood Type Antibodies in Patients Undergoing ABO-Incompatible Kidney Transplantation.

Background: A positive flow-cytometry T cell crossmatch (FTXM) has important prognostic implications, even when the complement-dependent cytotoxicity crossmatch is negative. Recent studies have shown that ABO incompatibility is associated with positive FTXM, but the underlying mechanism remains poorly understood. Cases: In five ABO blood type O recipients of kidneys from wives with type B, FTXM was positive but complement-dependent cytotoxicity crossmatch was negative. Application of a solid-phase technique (LABScreen) revealed no case with antibodies to donor-specific human leukocyte antigen. After removal of type B antibodies from patient sera, FTXM was negative for all five patients. In one tested case, the eluate prepared from the donor's T lymphocyte agglutinated only type B red blood cells, implying the existence of blood type B substances on donor T lymphocytes. Discussion: False-positive FTXM reflects blood type B substrates bound to T lymphocytes. Repeat FTXM after incubation with donor-type red blood cells (to adsorb anti-ABO antibodies) was negative. This phenomenon explains the discrepancy between FTXM and solid-phase bead assays. Demonstration of type B substances on donor T lymphocytes is necessary before absolute test validity is confirmed. Conclusion: False-positive FTXM may be associated with type B antibodies bound to T lymphocytes when a blood type O recipient receives tissue from a type B donor. This phenomenon explains the false-positive FTXM observed in the setting of ABO-incompatible kidney transplantation.

Novel high-quality and reality biomaterial as a kidney surgery simulation model.

Surgical training using live animals such as pigs is one of the best ways of achieving skilled techniques and fostering confidence in preclinical medical students and surgeon trainees. However, due to animal welfare ethics, laboratory animals' usage for training should be kept to a minimum. We have developed a novel kidney organ model utilizing a simple procedure in which the kidney is first refluxed with N-vinyl-2-pyrrolidone (NVP) solution for 1 hour in its bath, followed by permeation for 23 hours, with a subsequent freshwater refluxed for 48 hours in the washing step. Surgical simulation of the prepared kidney model (NVP-fixed kidney) was compared with three types of other basic known simulation models (fresh kidney, freeze-thaw kidney, and FA-fixed kidney) by various evaluations. We found the NVP-fixed kidney to mimicked fresh kidney function the most, pertaining to the hardness, and strength of the renal parenchyma. Moreover, the NVP-fixed kidney demonstrated successful blood-like fluids perfusion and electrocautery. Further, we confirmed that surgical training could be performed under conditions closer to actual clinical practice. Our findings suggest that our model does not only contribute to improving surgical skills but also inspires the utilization of otherwise, discarded inedible livestock organs as models for surgical training.

Creatinine reduction ratio on postoperative day 2 predicts long-term outcomes after living donor kidney transplantation.

OBJECTIVES: To evaluate the relationship between the creatinine reduction ratio between postoperative days 1 and 2 and post-transplantation clinical outcomes after living donor kidney transplantation. METHODS: Clinical data of patients who underwent living donor kidney transplantation at Jichi Medical University Hospital, Tochigi, Japan, between 2006 and 2019 were retrieved. The creatinine reduction ratio between postoperative days 1 and 2 was calculated based on the formula: (Cre1 - Cre2) × 100/Cre1; patients were then classified into either the slow graft function (creatinine reduction ratio between postoperative days 1 and 2 ≤30%) or immediate graft function (creatinine reduction ratio between postoperative days 1 and 2 >30%) group. We carried out the log-rank test and multivariate Cox proportional hazards regression analyses to assess graft survival and rejection-free survival, and the unpaired t-test and multivariate linear regression to assess post-transplantation estimated glomerular filtration rates. Multivariate analyses used age, sex, dialysis duration, ABO compatibility, donor-specific antibody positivity and medically complex living donors as explanatory variables. RESULTS: Of the 272 patients, 30 and 242 were in the slow graft function and immediate graft function groups, respectively. Multivariate Cox proportional hazards regression analyses showed a significantly higher incidence of overall and death-censored graft loss in the slow graft function group than the immediate graft function group. The frequency of rejection after 1 week post-transplantation did not differ within the groups. Post-transplantation estimated glomerular filtration rates tended to decline earlier in the slow graft function group than in the immediate graft function group; however, the difference was not statistically significant. CONCLUSIONS: The creatinine reduction ratio between postoperative days 1 and 2 could potentially predict long-term outcomes after living donor kidney transplantation. Using the creatinine reduction ratio between postoperative days 1 and 2 and other conventional indicators might allow accurate risk classification and appropriate therapeutic interventions.

Recurrent lupus nephritis in renal allograft triggered by pregnancy.

Herein we report the case of a 37-year-old woman with recurrence of lupus nephritis (LN) in a renal allograft during pregnancy. She had developed end-stage renal disease due to LN and was put on hemodialysis at the age of 26 years. She underwent kidney transplantation at the age 28 years. Maintenance immunosuppressants included methylprednisolone, tacrolimus, and mycophenolate mofetil, which were changed to azathioprine when she desired pregnancy. The renal allograft function remained stable and seemingly disease-free until proteinuria and functional decline occurred during the pregnancy (age: 34 years). The baby was delivered by performing a cesarean section at 33 weeks of gestation. Renal allograft biopsy revealed crescent formation. Light microscopy revealed tuft necrosis and endocapillary proliferation. Immunofluorescence microscopy revealed the deposition of immunoglobulin G and C1q. A recurrence of LN (ISN/RPS class IV-G [A/C]) was diagnosed, and the patient was treated with pulse steroid therapy and azathioprine was replaced with mycophenolate mofetil. This treatment improved acute or active lesions of LN and temporarily benefited the renal allograft function. Unfortunately, there were irreversible chronic changes and a gradual decline in the renal allograft function.

[TREATMENT OF BLADDER UROTHELIAL CARCINOMA WITH LUNG METASTASIS AFTER RENAL TRANSPLANTATION].

We report a case of bladder cancer in a 54-year-old woman who underwent renal transplantation for chronic renal failure. Six years after the transplantation, she was diagnosed with muscle-invasive bladder cancer with multiple lung metastases. She received gemcitabine/cisplatin therapy for Stage IV bladder cancer, and the dose of the immunosuppressants was reduced to prevent adverse effects. Since lung metastatic lesions disappeared after four courses of chemotherapy and no new lesions were found, we performed radical cystectomy and right nephroureterectomy with ileal conduit construction. Although she was followed closely without therapy, multiple lung metastases appeared 6 months after the radical cystectomy. Gemcitabine/carboplatin therapy was administered, and the lung metastasis improved slightly until the end of the 4th course, but aggressive growth was observed after the 5th course. She switched to palliative treatment without requesting additional treatment and died of cancer 1 year and 9 months after total cystectomy.There is no evidence-based treatment strategy for advanced bladder cancer after kidney transplantation. It is necessary to recognize that the patient had renal dysfunction and was in an immunosuppressed state. Thus, it is crucial to select appropriate drug and surgical treatments for each patient.

Development of strangulation ileus associated with the ureter of the transplanted kidney 18 years after kidney transplantation.

INTRODUCTION: After kidney transplantation, patients should be treated with caution and monitored for surgical complications. Among the possible surgical complications, strangulation ileus after kidney transplantation is rare. CASE PRESENTATION: A 59-year-old woman who had undergone kidney transplantation at 41 years of age presented to our hospital with lower abdominal pain. She was diagnosed with strangulation ileus and underwent emergency surgery. In the lower right abdomen, the small intestine was compressed by cord-like tissue running from the intraperitoneal space to the retroperitoneal space. We confirmed that the cord-like tissue was the ureter of the transplanted kidney. The necrotic small intestine was resected, and ureter-ureteral anastomosis of the ureter of the transplanted kidney was performed. CONCLUSION: All surgical procedures, including ureteroneocystostomy, require careful attention. The occurrence of some postoperative surgical complications can be prevented by carefully performing the kidney transplantation procedure.

A case report of percutaneous direct injection of N-butyl-2-cyanoacrylate (NBCA) to treat a pancreatic duodenal stump leak after a simultaneous pancreas and kidney transplantation.

BACKGROUND: Simultaneous pancreas and kidney transplantation (SPK) is a treatment option for patients with end-stage renal disease due to type 1 diabetes mellitus. We report a patient with a refractory fistula due to leakage from the duodenal stump of the pancreas graft after an SPK with bladder drainage who was successfully treated with a percutaneous direct injection of N-butyl-2-cyanoacrylate (NBCA). CASE PRESENTATION: A 60-year-old female with a 33-year history of type 1 diabetes mellitus and a 10-year history of renal replacement therapy underwent an SPK in 2015. At the time of transplantation, an abdominal aortic aneurysm with a high risk of rupture was treated by a Y-graft replacement prior to the SPK. Bladder drainage of the pancreas graft was chosen to avoid a vessel graft infection. The patient's postoperative course was uneventful. The patient was discharged on postoperative day 93 with good-functioning pancreas and kidney grafts. One and a half years after the operation, the patient was found to have acute graft pancreatitis and a leak from the duodenal stump of the pancreas graft due to a paralytic neurogenic bladder. The insertion of an indwelling catheter into the bladder and the endoscopic-guided insertion of a catheter into the graft pancreatic duct through the duodenum/bladder anastomosis did not result in the closure of the fistula. Therefore, NBCA was injected at the site of the leak point using CT-guided technique. The fistula was completely closed immediately after the injection, with no recurrences of leaks. CONCLUSIONS: A percutaneous direct injection of NBCA is one of the treatment options to treat intractable fistulas.

Correcting anemia and native vitamin D supplementation in kidney transplant recipients: a multicenter, 2 × 2 factorial, open-label, randomized clinical trial.

Anemia and vitamin D deficiency are associated with allograft failure, and hence, are potential therapeutic targets among kidney transplant recipients (KTRs). We conducted a multicenter, two-by-two factorial, open-label, randomized clinical trial to examine the effects of anemia correction and vitamin D supplementation on 2-year change in eGFR among KTRs (CANDLE-KIT). We enrolled 153 patients with anemia and >1-year history of transplantation across 23 facilities in Japan, and randomly assigned them to either a high or low hemoglobin target (>12.5 vs. <10.5 g/dl) and to either cholecalciferol 1000 IU/day or control. This trial was terminated early based on the planned interim intention-to-treat analyses (α = 0.034). Among 125 patients who completed the study, 2-year decline in eGFR was smaller in the high vs. low hemoglobin group (i.e., -1.6 ± 4.5 vs. -4.0 ± 6.9 ml/min/1.73 m2 ; P = 0.021), but did not differ between the cholecalciferol and control groups. These findings were supported by the fully adjusted mixed effects model evaluating the rate of eGFR decline among all 153 participants. There were no significant between-group differences in all-cause death or the renal composite outcome in either arm. In conclusion, aggressive anemia correction showed a potential to preserve allograft kidney function.