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Abstract Background Osteoporosis is a serious complication for both patients undergoing maintenance hemodialysis (MHD) and kidney transplant (KTx) recipients. Denosumab (Dmab) is a highly efficacious drug used to treat osteoporosis. However, like bisphosphonates, Dmab has the rare complication of atypical femur fracture (AFF). Here, we report two cases of AFF in a patient on MHD and a KTx recipient during treatment with Dmab. Case presentation Case 1 was a 78-year-old female patient undergoing MHD diagnosed with an AFF in April 2023. In 2018, she started hemodialysis necessitated by glomerulonephritis caused by parvovirus B19. She had been receiving intravenous alendronate for osteoporosis since 2005, then changed to subcutaneous Dmab in 2020. She underwent an intramedullary nail osteosynthesis for her AFF and is doing well on teriparatide. Case 2 was a 67-year-old female KTx recipient diagnosed with an AFF in June 2023. She had been on oral minodronate since 2014 but was switched to subcutaneous Dmab in 2020 owing to repeated fractures. She is doing well on romosozumab after intramedullary nail osteosynthesis. Conclusions We report two cases of AFF treated with Dmab. Case 1 was a patient undergoing MHD and case 2 was a KTx recipient. AFFs are relatively rare and, to our knowledge, have not been reported in patients undergoing MHD or KTx recipients. Dmab-associated AFFs are likely to increase in the future as the population ages, and adequate attention should be paid to patients undergoing MHD and KTx recipients.

Abstract Patients on haemodialysis (HD) have high mortality risk, and prognostic values of the major cardiovascular biomarkers cardiac troponin I (cTnI), N-terminal pro-brain natriuretic peptide (NT-proBNP), and adiponectin should be ascertained over longer follow-up periods using higher-sensitivity assays, which we undertook. In 221 HD patients, levels of high-sensitivity (hs)-cTnI, NT-proBNP, and adiponectin, were measured using high-sensitivity assays, and their associations with all-cause mortality (ACM) and cardiovascular mortality (CVM) were prospectively investigated for 7 years. Higher hs-cTnI and NT-proBNP levels were significant risk factors for ACM and CVM in the Kaplan–Meier analysis. Multivariate Cox proportional hazards analyses in a model including hs-cTnI and NT-proBNP identified log hs-cTnI, but not log NT-proBNP, as an independent risk factor for ACM (HR 2.12, P

Abstract Background With the widespread use of the vaccine and the predominance of the Omicron strain, the number of patients presenting with typical coronavirus-infection disease 2019 (COVID-19) pneumonia on computed tomography (CT) has decreased dramatically. This has also been true for hemodialysis patients. Case report A 72-year-old female maintenance hemodialysis patient with hypogammaglobulinemia was diagnosed with COVID-19 based on a nasopharyngeal swab severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) polymerase chain reaction (PCR) test. She had previously received five doses of COVID-19 BNT162b2 vaccine. Initially, the patient had only a slight fever, mild sore throat and sputum, and molnupiravir 1600 mg/day was administered for 5 days. No high fever was observed during that period. On day 11 after diagnosis, bloody sputum was observed, and by day 13 the cough had worsened and her CRP level had increased to 13.10 mg/dL. Chest CT performed on the same day showed multiple subpleural ground-glass-like shadows typical of COVID-19 pneumonia predominantly in the right lung. She was immediately admitted to the hospital, where her temperature rose to 38.4 °C. Intravenous remdesivir 100 mg/day was administered for 5 days. This resolved her fever and the bloody sputum disappeared. She was discharged from the hospital without sequelae on the 21st day after diagnosis. Conclusion We experienced a case of typical COVID-19 pneumonia in a patient on maintenance hemodialysis who had received five doses of COVID-19 BNT162b2 vaccine. There was a flare-up of symptoms after administration of molnupiravir, suggesting that a hypogammaglobulinemia complication was involved. This highlights the need for attention to its potential transition to severe disease when patients with hypogammaglobulinemia or other highly immunocompromised conditions are affected by COVID-19.

Background/Objectives: Lipid metabolism and adiponectin modulate erythropoiesis in vitro and in general population studies and may also affect responsiveness to erythropoietin in patients undergoing haemodialysis (HD). However, little is known about the impact of lipid-associated biomarkers on reticulocyte production and erythropoietin resistance index (ERI) in patients undergoing HD. Therefore, we aimed to investigate their impacts in 167 stable patients undergoing HD. Methods: Pre-dialysis blood samples were collected and analysed for reticulocyte counts and serum lipid profiles by routine analyses and serum carnitine profiles (C0–C18) by LC-MS/MS. ERI was calculated as erythropoietin dose/kg/week normalized for haemoglobin levels. Results: The independent positive determinants of reticulocyte count were log [Triglyceride (TG)] and logC18:1. A large proportion of longer-chain acylcarnitines was positively correlated with reticulocyte counts, possibly resulting from the accumulation of acylcarnitines in mitochondria undergoing fateful exocytosis from reticulocytes. These results indicate a possible association between reticulocyte formation and reduced β-oxidation, which occurs during the peripheral phase of erythroblast enucleation. Total cholesterol (TC) and log [C2/(C16 + C18:1)] as a putative marker of β-oxidation efficiency were negative independent determinants of ERI. Moreover, acyl chain length had a significantly positive impact on the correlation coefficients of individual acylcarnitines with ERI, suggesting that enhanced β-oxidation may be associated with reduced ERI. Finally, adiponectin had no independent association with reticulocyte counts or ERI despite its negative association with HDL-C levels. Conclusions: Enhanced fatty acid β-oxidation and higher TC levels may be associated with lower ERI, whereas higher TG levels and longer acylcarnitines may be related to the latest production of reticulocytes in stable patients undergoing HD.

Abstract In this paper, we propose a technique for removing a specific type of interference from a monaural recording. Nonstationary interferences are generally challenging to eliminate from such recordings. However, if the interference is a known sound like a cell phone ringtone, music from a CD or streaming service, or a radio or TV broadcast, its source signal can be easily obtained. In our method, we define such interference as an acoustic object. Even if the sampling frequencies of the recording and the acoustic object do not match, we compensate for the mismatch and use the maximum likelihood estimation technique with the auxiliary function to remove the interference from the recording. We compare several probabilistic models for representing the object-canceled signal. Experimental evaluations confirm the effectiveness of our proposed method.

Abstract Background Renal transplant recipients with chronic kidney disease often develop post-transplant diabetes mellitus or metabolic syndrome (MetS), which are poor prognostic factors after renal grafts. Although recent studies have reported the protective effects of glucagon-like peptide-1 receptor agonist (GLP-1RA) on the heart and kidneys, few have assessed its effects in renal transplant patients. Moreover, to our knowledge there have been no studies on the effects of oral GLP-1RA (semaglutide) in renal transplantation recipients in Japan. Case presentation Case 1 was a 52-year-old male renal transplant recipient with MetS. Semaglutide was administered orally for 12 months, starting at 3 mg/day and titrating up to 14 mg/day. Over time, his HbA1c level decreased from 5.9 to 5.5% and weight from 100.6 to 96.3 kg. No adverse events were observed. Case 2 was a 62-year-old male renal transplant recipient with MetS. Oral semaglutide was started at 3 mg/day. However, the patient had severe nausea, and the dose was reduced to 1.5 mg/day and then gradually increased to 14 mg/day for 12 months. Over time, triglyceride decreased from 308 to 277 mg/dL and weight decreased from 75.4 to 63.2 kg. Case 3 was a 59-year-old male renal transplant recipient with MetS and fatty liver. Oral semaglutide was started at 3 mg/day and titrated up to 12 mg/day for 12 months. Over time, triglyceride decreased from 205 to 119 mg/dL and weight decreased from 79.1 to 76.4 kg. No adverse events were observed. Conclusions In all three patients, oral semaglutide significantly reduced body weight and improved metabolic parameters. Additional studies are needed to further evaluate the efficacy of oral semaglutide and the incidence of associated adverse events in a large number of renal transplant recipients. Trial registration: UMIN, UMIN000050853. Registered 14 April 2023—Retrospectively registered, https://center6.umin.ac.jp/cgi-bin/ctr/ctr_reg_rec.cgi

Abstract Background Hemodialysis patients have chronic kidney disease, are often elderly, and have many complications such as hypertension, type 2 diabetes, cardiac disease, and cerebrovascular disease. Therefore, hemodialysis patients infected with COVID-19 are prone to severe disease. Vaccination is the most promising means of preventing the onset and reducing the severity of COVID-19. However, many reports have found that anti-spike antibody titers after two doses of mRNA vaccine are lower in hemodialysis patients than in healthy controls. For this reason, a third vaccination is recommended for hemodialysis patients. In Japan, there are several reports of a third vaccination, especially for hemodialysis patients. In this study, we also examined the antibody response to COVID-19 vaccine in Japanese hemodialysis patients who received the third dose of the vaccine. Methods Study participants received a third vaccination (257 with BNT162b2 vaccine and 5 with mRNA-1273 vaccine) approximately 7–9 months after the second (BNT162b2 vaccine). Anti-SARS-CoV-2 spike IgG antibody titers were measured (Abbott SARS-CoV-2 IgG II Quan) in 185 hemodialysis patients and 109 healthcare workers approximately 2 weeks after the second vaccination and in 162 hemodialysis patients and 100 healthcare workers approximately 2 weeks after the third. Results Following the second vaccination, 97.6% of the hemodialysis group and 100% of the control group were positive for the anti-spike antibody. The median level of the anti-spike antibody was 2728.7 AU/mL (IQR, 1024.2–7688.2 AU/mL) in the hemodialysis group and 10,500 AU/ml (IQR, 9346.1–2,4500 AU/mL) in the controls. Following the third vaccination, 99.4% of the hemodialysis group (only one person tested negative for the antibody) and 100% of the control group were positive for the anti-spike antibody. The median level of the anti-spike antibody was 20,000 AU/mL (IQR, 7729–37,000 AU/mL) in the hemodialysis group and 21,500 AU/ml (IQR, 14,000–32,250 AU/mL) in the control group. The factors involved in the low response to the BNT152b2 vaccine after the second vaccination included old age, low BMI, low Cr index, low nPCR, low GNRI, low lymphocyte count, steroid administration, and complications related to blood disorders. However, in hemodialysis patients, the response after the third vaccination was excellent, and all factors associated with the suppressed response to these vaccines were no longer significant. Conclusions The humoral response of hemodialysis patients to two doses of mRNA vaccine was weaker than that of healthy controls. However, a third vaccination eliminated that difference.

Abstract Background Hemodialysis patients are more likely to be severely affected if infected by COVID-19. Contributing factors include chronic kidney disease, old age, hypertension, type 2 diabetes, heart disease, and cerebrovascular disease. Therefore, action against COVID-19 for hemodialysis patients is an urgent issue. Vaccines are effective in preventing COVID 19 infection. In hemodialysis patients, however, responses to hepatitis B and influenza vaccines are reportedly weak. The BNT162b2 vaccine has shown an efficacy rate of about 95% in the general population, but as far as we know there are only several reports of efficacy data in hemodialysis patients in Japan. Methods We assessed serum anti-SARS-CoV-2 IgG antibody (Abbott SARS-CoV-2 IgG II Quan) in 185 hemodialysis patients and 109 health care workers. The exclusion criterion was positivity for SARS-CoV-2 IgG antibody before vaccination. Adverse reactions to BNT162b2 vaccine were evaluated through interviews. Results Following vaccination, 97.6% of the hemodialysis group and 100% of the control group were positive for the anti-spike antibody. The median level of anti-spike antibody was 2,728.7 AU/mL (IQR, 1,024.2–7,688.2 AU/mL) in the hemodialysis group and 10,500 AU/ml (IQR, 9,346.1–2,4500 AU/mL) in the health care workers group. The factors involved in the low response to the BNT152b2 vaccine included old age, low BMI, low Cr index, low nPCR, low GNRI, low lymphocyte count, steroid administration, and complications related to blood disorders. Conclusions Humoral responses to BNT162b2 vaccine in hemodialysis patients are weaker than in a healthy control sample. Booster vaccination is necessary for hemodialysis patients, especially those showing a weak or non-response to the two-dose BNT162b2 vaccine. Trial registration UMIN, UMIN000047032. Registered 28 February 2022, https://center6.umin.ac.jp/cgi-bin/ctr/ctr_reg_rec.cgi.

Abstract Aims Portopulmonary hypertension (PoPH) is a subtype of pulmonary arterial hypertension related to portal hypertension. The definitive diagnosis of PoPH is made by invasive right heart catheterization. Alternatively, pulmonary arterial hypertension may be recognized noninvasively from the tricuspid regurgitant pressure gradient (TRPG), measured by echocardiography. In this study, we aimed to establish a simple algorithm to identify chronic liver disease patients with a high TRPG value in order to narrow down the candidates to receive echocardiography. Methods and Results TRPG was measured by echocardiography in 152 patients with chronic liver disease. Factors predictive of TRPG >30 mmHg were investigated. There were 28 (18%) cases with TRPG >30 mmHg. Independent factors associated with a high TRPG were the presence of shortness of breath, high serum brain natriuretic peptide (BNP), and low serum albumin. Child–Pugh class or the presence of ascites, varices, or encephalopathy was not associated with TRPG. There was a correlation between the serum BNP and TRPG, and the optimal cutoff value of BNP by the Youden index was 122 pg/mL, and by 100% sensitivity was 50 pg/mL. A combination of these factors identified patients with a high probability of TRPG >30 mmHg (n = 12, positive predictive value [PPV] of 83%), no probability (n = 80, PPV 0%), and intermediate probability (n = 60, PPV 25–34%). This algorithm has reduced the number of patients needing echocardiography by 53%. Conclusions A simple algorithm using the presence of shortness of breath, serum BNP, and albumin levels can narrow down the candidates to receive echocardiography.

Abstract Background For the optimal management of patients with both allograft kidneys and native kidney diseases, the recognition of the histological features associated with older age is important. This is because most pathological findings are non-specific. Central fibrous areas (CFAs) have recently been proposed to be age-related. However, the components of CFAs and whether CFAs are observed in various kidney diseases remain undetermined. This cross-sectional study was undertaken to clarify the histological features, epidemiology, and clinicopathological features of CFAs. Methods One hundred and one consecutive kidney needle biopsy specimens were retrospectively collected from seven facilities in the Hokuriku region and diagnosed at the Kanazawa University Hospital in 2015. First, the components of CFAs were analyzed using normal histostaining, immunostaining, and electron microscopy. Second, the patients were divided into two groups (CFA [+] or CFA [−]) according to the presence of CFA in the obtained samples. Clinical and histological features were compared between the two groups, and factors associated with CFA formation were determined using univariate and multivariate analyses. The number of CFAs per specimen was counted in the CFA (+) group. Third, the presence of myofibroblasts in CFA was examined by immunostaining. Results CFAs were observed in 56 of 101 patients (55.4%) with various kidney diseases. CFAs consist of fibrillar collagens (collagen I and III) in addition to non-fibrillar collagens (collagen IV and VI), as confirmed by electron microscopy. Clinically, the CFA (+) group was older and had a significantly higher prevalence of hypertension and hyperlipidemia than the CFA (−) group. Histologically, elastofibrosis of the interlobular artery, arteriolar hyalinosis, and membranous nephropathy were significantly more evident in the CFA (+) group than in the CFA (−) group. Multivariate analysis revealed that older age was the sole factor associated with CFA formation. Finally, 27 of 58 (46.6%) CFA-containing glomeruli in 26 cases included alpha-smooth muscle actin-positive cells in or adjacent to the CFA. Conclusions CFAs consist of fibrous collagens in addition to matrix collagens. CFA formation is associated with older age and was observed in various kidney diseases.

Abstract Background Sodium-glucose cotransporter 2 (SGLT2) inhibitors have been shown to exert cardiorenal protective effects in diabetic patients and are widely used clinically. In addition, an increasing number of reports now suggest these drugs may even be beneficial in non-diabetic patients. However, SGLT2 inhibitors are rarely prescribed for kidney transplant recipients due to the risk of renal graft damage and urogenital infections. Case presentation We report the cases of 5 renal transplant recipients with chronic kidney disease G3a-4 and metabolic syndrome who were administered the SGLT2 inhibitor empagliflozin, which yielded beneficial results in 4 cases. With the exception of one patient with an initial estimated glomerular filtration rate (eGFR) of less than 30 ml/min/1.73 m2, administration of empagliflozin elicited beneficial metabolic effects. There were no significant reductions in eGFR before or after empagliflozin administration, and no dehydration or urogenital infections were observed during the treatment course. Conclusion Empagliflozin showed some positive effects in 4 cases with better renal function than CKD stage 4. Further studies will be required to clarify the efficacy and safety of SGLT2 inhibitors in a larger group of patients with similar medical conditions.

Background: Catheter ablation is a standard therapy for frequent premature ventricular complex (PVCs). Predicting their origin from a 12-lead electrocardiogram (ECG) is crucial but it requires specialized knowledge and experience. Objective: The objective of the present study was to develop and evaluate machine learning algorithms that predicted PVC origins from an ECG. Methods: We developed the algorithms utilizing a support vector machine (SVM) and a convolutional neural network (CNN). The training, validating, and testing data consisted of 116 PVCs from 111 patients who underwent catheter ablation. The ECG signals were labeled with the PVC origin, which was confirmed using a 3-dimensional electroanatomical mapping system. We classified the origins into 4 groups: right or left, outflow tract, or other sites. We trained and evaluated the model performance. The testing datasets were also evaluated by board-certified electrophysiologists and an existing classification algorithm. We also developed binary classification models that predicted whether the origin was on the right or left side of the heart. Results: The weighted accuracies of the 4-class classification were as follows: SVM 0.85, CNN 0.80, electrophysiologists 0.73, and existing algorithm 0.86. The precision, recall, and F1 in the machine learning models marked better than physicians and comparable to the existing algorithm. The SVM model scored among the best accuracy in the binary classification (the accuracies were 0.94, 0.87, 0.79, and 0.90, respectively). Conclusion: Artificial intelligence–enabled algorithms that predict the origin of PVCs achieved superior accuracy compared to the electrophysiologists and comparable accuracy to the existing algorithm.

Abstract Background Renal transplant recipients with chronic kidney disease (CKD) often develop abnormal glucose metabolism. Although recent studies have reported the protective effects of sodium-glucose transport protein 2 (SGLT2) inhibitors on the heart and kidneys, few have assessed their effect in renal transplant patients. Moreover, to our knowledge, there have been no studies on the effects of SGLT2 inhibitors in renal transplant recipients in Japan. Case presentation Case 1 was a 67-year-old male renal transplant recipient with post-transplant diabetes mellitus. He was administered empagliflozin 10 mg once a day for 9 months. Over time, his HbA1c levels decreased from 6.8 to 6.0%. Case 2 was a 56-year-old male renal transplant recipient with fatty liver disease. He was administered empagliflozin 10 mg once a day for 9 months. His ALT, γ-GTP, and LDL-cholesterol levels all decreased. In both patients, body weight and the urine albumin to creatinine ratio (UACR) decreased after empagliflozin administration, but there were no changes in the estimated glomerular filtration rate. No adverse events occurred in either case. Conclusions Administration of empagliflozin had favorable outcomes in two patients with stage G3b CKD and abnormal glucose metabolism after renal transplantation. Further studies will be required to clarify the efficacy and safety of SGLT2 inhibitors in a larger population of patients with similar medical conditions.

Acute myocarditis is a rare but serious complication associated with mRNA-based coronavirus disease 2019 (COVID-19) vaccination. In this article, four COVID-19 mRNA vaccination induced myocarditis cases managed at our tertiary Medical Center have been discussed. Three patients had typical myocarditis. One patient suffered from atrioventricular block and heart failure, which required more intensive treatment, but eventually improved. Additionally, a review of cardiac magnetic resonance imaging (MRI) features related to the diagnosis of myocarditis showed that COVID-19 mRNA vaccine-associated myocarditis tend to have more late-gadolinium enhancement (LGE) accumulation in the inferior lateral wall direction. According to a report by the U.S. Centers for Disease Control and Prevention (CDC), the diagnosis of COVID-19 mRNA vaccine-associated myocarditis is based on clinical symptoms, altered myocardial enzymes, cardiac MRI finding, or histopathology. Cardiac MRI is relatively less invasive than myocardial biopsy and plays an important role in the diagnosis of myocarditis. This review may aid in the diagnosis of COVID-19 mRNA vaccine-associated myocarditis.

BackgroundAlthough long sinus arrest is occasionally observed during atrial fibrillation (AF) catheter ablation when the fibrillation was terminated, its meaning and prognosis have not yet been clearly elucidated. We hypothesized that sinus node recovery time (SNRT) after termination of AF (time from termination of AF to the earliest sinus node activation) could reflect the extent of atrial remodeling, influencing the formation of non-pulmonary vein (non-PV) triggers and post-ablation outcomes.MethodThe participants were 157 consecutive patients with persistent AF (male: 77.1%, age: 63.3±11.2 years) who underwent catheter ablation. We recorded SNRT after terminating AF by radiofrequency delivery or electrical cardioversion during the first ablation and evaluated the relationships between SNRT and atrial tachyarrhythmia recurrence and between SNRT and non-PV triggers after repeat ablation.ResultsForty-five patients (28.7%) experienced recurrence of atrial tachyarrhythmias. Patients with recurrence had longer SNRTs (1738 ms vs. 1394 ms, p = 0.012). In the multivariate logistic regression analysis, only SNRT ≥2128ms was a significant independent predictor of clinical AF recurrence (hazard ratio 7.48; 95% confidence interval 2.94-19.00; PConclusionsPatients with a prolonged SNRT had a higher prevalence of AF recurrence after the first ablation and higher inducibility of non-PV triggers. Measuring SNRT might be used for the stratification of patients with persistent AF.

Abstract Background Oral anticoagulants, including direct oral anticoagulants (DOACs), are usually required in atrial fibrillation (AF) patients who are at a high risk of thromboembolism (TE), even if they had undergone catheter ablation (CA). Although several studies have reported the safety and efficacy of DOACs around CA in AF patients, there are only limited data regarding the midterm incidence of TE and bleeding complications post‐CA among AF patients treated with warfarin or DOACs. Methods We studied 629 AF patients (mean age: 65.3 ± 10.3 years; 442 men) undergoing CA, to calculate the midterm incidence of TE and bleeding complications associated with warfarin or DOACs. Results In total, 292 patients used warfarin and 337 used DOACs (dabigatran: 90 patients; rivaroxaban: 137; and apixaban: 110). At baseline, the CHA2DS2‐VASc and HAS‐BLED scores were similar between the 2 groups. During a median follow‐up period of 7 months, no TE complications occurred. The warfarin group had a significantly higher bleeding event rate than did the DOACs group (all bleeding complications: 32 [11.0%] vs 15 [4.5%], respectively, P = .002). The rate of all bleeding complications was significantly higher in the warfarin group than in the DOACs group (10.1% vs 3.7%, respectively, at 10 months; P = .024). In Cox proportional hazards modeling, DOAC use was significantly associated with a decreased risk of bleeding (adjusted hazard ratio: 0.497; 95% confidence interval: 0.261‐0.906, P = .022). Conclusions Direct oral anticoagulant use in AF patients undergoing CA may be associated with a similar risk of TE as warfarin but is associated with a lower risk of bleeding.