Combination of pathological, biochemical and behavioral evaluations for peripheral neurotoxicity assessment in isoniazid-treated rats.

In drug development, assessment of non-clinical peripheral neurotoxicity is important to ensure human safety. Clarifying the pathological features and mechanisms of toxicity enables the management of safety risks in humans by estimating the degree of risk and proposing monitoring strategies. Published guidelines for peripheral neurotoxicity assessment do not provide detailed information on which endpoints should be monitored preferentially and how the results should be integrated and discussed. To identify an optimal assessment method for the characterization of peripheral neurotoxicity, we conducted pathological, biochemical (biomaterials contributing to mechanistic considerations and biomarkers), and behavioral evaluations of isoniazid-treated rats. We found a discrepancy between the days on which marked pathological changes were noted and those on which biochemical and behavioral changes were noted, suggesting the importance of combining these evaluations. Although pathological evaluation is essential for pathological characterization, the results of biochemical and behavioral assessments at the same time points as the pathological evaluation are also important for discussion. In this study, since the measurement of serum neurofilament light chain could detect changes earlier than pathological examination, it could be useful as a biomarker for peripheral neurotoxicity. Moreover, examination of semi-thin specimens and choline acetyltransferase immunostaining were useful for characterizing morphological neurotoxicity, and image analysis of semi-thin specimens enabled us to objectively show the pathological features.

Identification and characterization of dystrophin-locus-derived testis-specific protein: A testis-specific gene within the intronic region of the rat dystrophin gene.

The mammalian X chromosome exhibits enrichment in genes associated with germ cell development. Previously, we generated a rat model of Becker muscular dystrophy (BMD) characterized by an in-frame mutation in the dystrophin gene, situated on the X chromosome and responsible for encoding a protein crucial for muscle integrity. Male BMD rats are infertile owing to the absence of normal spermatids in the epididymis. Within the seminiferous tubules of BMD rats, elongated spermatids displayed abnormal morphology. To elucidate the cause of infertility, we identified a putative gene containing an open reading frame situated in the intronic region between exons 6 and 7 of the dystrophin gene, specifically deleted in male BMD rats. This identified gene, along with its encoded protein, exhibited specific detection within the testes, exclusively localized in round to elongated spermatids during spermiogenesis. Consequently, we designated the encoded protein as dystrophin-locus-derived testis-specific protein (DTSP). Given the absence of DTSP in the testes of BMD rats, we hypothesized that the loss of DTSP contributes to the infertility observed in male BMD rats.

Raillietina cesticillus infection causes reduced egg production in chickens in a windowless poultry house.

In a windowless poultry house raising layer chickens in Kanagawa prefecture, Japan, a slight increase in the mortality of chickens and a decrease in egg production were observed. Necropsy revealed numerous tapeworms and proglottids in chicken intestines. Histopathologically, gut-associated lymphoid tissues were observed in the lamina propria of the jejunum; however, no significant changes were observed in the other organs. Numerous hide beetles, Dermestes maculatus DeGeer, intermediate hosts of Raillietina cesticillus, were observed in the poultry house. Following a decline in beetle numbers, egg production increased and chicken mortality decreased. The life cycle of a tapeworm was easily established in a closed space, such as a windowless house, which led to severe infections.

Diversity of mutations in the dystrophin gene and details of muscular lesions in porcine dystrophinopathies.

During meat inspections in pigs, dystrophinopathies are among the muscle lesions targeted for disposal. In this study, the authors examined the lesions and the distribution of dystrophin expression in 25 pigs with dystrophinopathy. In addition, complementary deoxyribonucleic acid (cDNA) sequencing and western blotting were performed in 6 of the 25 cases, all of which were characterized by degeneration, necrosis, and fat replacement of muscle fibers. Comparing the results of immunohistochemistry with anti-dystrophin antibodies that recognized at different sites in the protein, the authors noted that the loss of dystrophin expression was most pronounced in the C-terminus-recognizing antibody (19/25 cases). The authors detected 5 missense mutations and 3 types of shortened transcripts generated by the skipping of exons in the cDNA, which were associated with the pathogenesis. One missense mutation had been reported previously, whereas the remaining mutations identified had not been previously documented in pigs. In the cases with shortened transcripts, normal-sized transcripts were detected together with the defective transcripts, suggesting that these mutations were caused by splicing abnormalities. In addition, they were in-frame mutations, all of which have similar pathogeneses of Becker muscular dystrophy in humans. These cases were 6 months of age and exhibited macroscopic discoloration, fatty replacement, and muscle degeneration, suggesting that the effect of these mutations on skeletal muscle was significant.

Cor triatriatum sinister with dextrocardia in association with ostium secundum atrial septal defect, subpulmonary ventricular septal defect and bicuspid pulmonary valve in a pig.

Necropsy of a 52-day-old Camborough pig revealed numerous cardiac malformations. The positional relationship of the atria, ventricles and great vessels was a mirror image type (I, L and L): inverted arrangement of the atria, with a left-sided right atrium and right-sided left atrium (situs inversus); inverted arrangement of the ventricles, with a left-sided morphological right ventricle and right-sided morphological left ventricle (L-loop); and aortic valve to the front left relative to the pulmonary valve (L-malposed). The major malformations included an ostium secundum atrial septal defect, cor triatriatum sinister (CTS), a subpulmonary ventricular septal defect and a bicuspid pulmonary valve. Histological examination revealed myocyte hypertrophy, focal myocardial necrosis and calcification in the left morphological right ventricle of the heart. To the best of our knowledge, this is the first report of CTS in pigs. Although the individual malformations found in the present case are not unique, an unusual combination of these cardiac malformations has not been described in animals.

Chronological transition of necropsy cases of animals in Tokyo, Japan.

There is no nationwide necropsy database of animals in Japan, and most of the records are available from the postwar period. To clarify the chronological transition of animal necropsy cases in Tokyo, Japan, the records accumulated in The University of Tokyo from 1902 were investigated. Of necropsy records on paper or electronic from 1902 to 2021 kept at the Laboratory of Veterinary Pathology, The University of Tokyo, totally 3,137 cases including 572 in 1903-1914 (the Meiji-Taisho period), 1,258 in 1956-1969 (the Showa period) and 1,307 in 2006-2020 (the Heisei-Reiwa period), respectively, were examined for species, breed, age and pathological diagnosis. Dogs (44.6%) and horses (34.8%) in the Meiji-Taisho period, dogs (62.9%) and cats (17.3%) in the Showa period, and dogs (46.0%), cats (26.1%) and exotic animals (20.5%) in the Heisei-Reiwa period were the most necropsied animal species. With the passage of time, the number of animal species increased, and the breeds of dogs and cats came to be more various. The median ages of death were 2 years, 3 years and 10 years old in dogs in the Meiji-Taisho, Showa and Heisei-Reiwa periods, respectively, and 2 years and 10 years old in cats in the Showa and Heisei-Reiwa periods, respectively. Viral, bacterial and parasitic infections were decreased, and inversely tumor cases increased due to the prolonged lifespan.

First Isolation and Identification of Homologous Recombination Events of Porcine Adenovirus from Wild Boar.

Porcine adenoviruses (PAdVs) are distributed in pig populations and classified into five immunologically distinct serotypes (PAdV-1 to 5). In this study, a PAdV was isolated from a fecal sample of wild boar for the first time. Whole-genome analysis revealed that this strain (Ino5) has sequence homology (approximately > 93%) throughout the genome with the PAdV-5 strain HNF-70 that was isolated from a pig in Japan in 1987, except for the hexon, E3 612R, and fiber coding regions. Two possible recombination breakpoints were detected in the hexon and E3 612R regions, which were found to have reduced GC content. Structural prediction analysis showed that a part of the hexon protein corresponding to the tower region of Ino5 had structural differences when compared with HNF-70, suggesting antigenic heterogeneity between these strains. PAdVs were detected in 1.77% (2/113) and 12% (12/100) of the fecal samples from wild boars and pigs collected in Japan by PCR, respectively. Phylogenetic analyses of the hexon and fiber genes revealed that some samples showed different grouping in the hexon and fiber genes, suggesting that these viruses have recombination events. These findings suggest that the PAdV-5 has evolved with homologous recombination events in the same manner as human adenoviruses among not only pig populations, but also wild boars in Japan.

Pharmacokinetic/pharmacodynamic modeling of roxadustat's effect on LDL cholesterol in patients in Japan with dialysis-dependent chronic kidney disease and anemia.

AIMS: The objective of this analysis was to develop and evaluate a pharmacokinetic/pharmacodynamic (PK/PD) model of the effect of roxadustat on low-density lipoprotein cholesterol (LDL-C) in Japanese patients with anemia of dialysis-dependent chronic kidney disease while considering the impact of covariates on model parameters. METHODS: A total of 2330 LDL-C measurements from 275 patients in 3 clinical studies were analyzed using a nonlinear-mixed effects modeling approach in NONMEM software. RESULTS: The PK/PD relationship between roxadustat exposure and LDL-C was well described by a kinetic-pharmacodynamic model with a physiological indirect response model as the PD component. Co-administered statin usage, sevelamer usage, type of dialysis (hemodialysis or peritoneal dialysis), and sex were selected as covariates for LDLbaseline. Weight was selected as a covariate for ID50. Imax and ID50 were estimated as 0.661 and 1.51 mg/h, respectively. CONCLUSION: Roxadustat can decrease LDL-C independent of statins and sevelamer. Further study of the ability of roxadustat to lower LDL-C and any potential effects on outcomes is needed.

Genetic diversity, reassortment, and recombination of mammalian orthoreoviruses from Japanese porcine fecal samples.

Mammalian orthoreoviruses (MRVs) are non-enveloped double-stranded RNA viruses with a broad host range. MRVs are prevalent worldwide, and in Japan, they have been isolated from various hosts, including humans, dogs, cats, wild boars, and pigs, and they have also been found in sewage. However, Japanese porcine MRVs have not been genetically characterized. While investigating porcine enteric viruses including MRV, five MRVs were isolated from the feces of Japanese pigs using MA104 cell culture. Genetic analysis of the S1 gene revealed that the Japanese porcine MRV isolates could be classified as MRV-2 and MRV-3. Whole genome analysis showed that Japanese porcine MRVs exhibited genetic diversity, although they shared sequence similarity with porcine MRV sequences in the DDBJ/EMBL/GenBank database. Several potential intragenetic reassortment events were detected among MRV strains from pigs, sewage, and humans in Japan, suggesting zoonotic transmission. Furthermore, homologous recombination events were identified in the M1 and S1 genes of Japanese porcine MRV. These findings imply that different strains of Japanese porcine MRV share a porcine MRV genomic backbone and have evolved through intragenetic reassortment and homologous recombination events.

Macroglossia in a pig diagnosed as Becker muscular dystrophy due to dystrophin pseudoexon insertion derived from intron 26.

We report a case of Becker muscular dystrophy in a 6-month-old, mixed-breed, castrated male pig detected with macroglossia at a meat inspection center. The pig presented a severely enlarged tongue extending outside its mouth. The tongue was firm and pale with discolored muscles. Histologically, there was severe fibrosis, fatty replacement, and myofiber necrosis, degeneration, and regeneration. Immunofluorescence showed focal and severely weak labeling for dystrophin at the sarcolemma of myocytes in the tongue. Analysis of dystrophin mRNA showed a 62 base pair insertion between exons 26 and 27. The insertion was derived from intron 26. Based on these findings, we diagnosed the case as Becker muscular dystrophy-the first known muscular dystrophy case induced by pseudoexon insertion in animals.

Detection and genetic analysis of a novel atypical porcine pestivirus from piglets with congenital tremor in Japan.

Atypical porcine pestivirus (APPV), which has been confirmed to be associated with congenital tremor (CT) in pigs, is a newly discovered porcine virus that has been found in the Americas, Europe and Asia; however, no report of APPV in Japan has been published. We identified an APPV in the central nervous system of Japanese piglets with CT and firstly determined and analysed the complete genome sequence. Phylogenetic analysis using the complete genome nucleotide sequence of the Japanese APPV, named Anna/2020, and those of APPVs from the NCBI database showed that APPVs were divided into three genotypes (genotypes 1 to 3), and that Anna/2020 clustered with the genotype 3 APPV strains, but distantly branched from these strains. Pairwise complete coding region nucleotide sequence comparisons revealed that there was 94.0%- 99.7% sequence identity among the genotype 3 strains, while Anna/2020 showed 87.0%-89.3% identity to those genotype 3 strains, suggesting that Anna/2020 represents a novel APPV lineage within genotype 3. Retrospective examinations using RT-PCR revealed one genotype 1 and two novel genotype 3 APPVs from pigs without CT, and that novel genotype 3 APPVs have been prevalent in Japan since at least 2007.

Population pharmacokinetics of roxadustat in Japanese dialysis-dependent chronic kidney disease patients with anaemia.

AIMS: Our objective was to develop a population pharmacokinetic (PK) model to describe roxadustat plasma concentrations in Japanese dialysis-dependent chronic kidney disease (DD-CKD) patients with renal anaemia and to identify the covariate factors that affect exposure of roxadustat. METHODS: In total, 367 patients (male, 256; female, 111) contributing 1285 concentration values from 4 clinical studies were analysed using a nonlinear mixed-effects modelling approach. Candidate covariates included clinical characteristics hypothesized to affect roxadustat clearance and bioavailability, such as demographics, hepatic parameters and concomitant drugs. RESULTS: The roxadustat PK data in Japanese DD-CKD patients with renal anaemia were well described by a 2-compartment disposition model with first-order absorption and interindividual variability on clearance, central volume of distribution and absorption rate constant. Age was identified as a significant covariate on clearance. PK profiles of haemodialysis and peritoneal dialysis patients were comparable. Eighty-two percent of patients were administered at least 1 phosphate binder (PB). The effect of PBs on roxadustat concentration was modelled as a decrease in bioavailability. Staggered administration of PBs reduced the effect on roxadustat bioavailability. The clinical impact of all covariates on roxadustat PK was mild and manageable as the roxadustat dose was titrated based on haemoglobin level and administered starting from a low dose. CONCLUSION: Roxadustat PK in Japanese DD-CKD patients were successfully described by a population PK model. The identified key covariates included coadministration of PBs on the roxadustat bioavailability and age on clearance of roxadustat.

Pathological and Immunohistochemical Findings of Disseminated Histiocytic Sarcoma in a Sugar Glider (Petaurus breviceps).

A 6-year-old intact female sugar glider (Petaurus breviceps) had a swelling at the pouch region and died 8 days after presentation. At necropsy, the urinary bladder and abdominal lymph nodes were enlarged and a mass was located in the pericloacal region. Tumour infiltration was also observed in the medial iliac lymph nodes, liver, spleen, small intestine, uterus and left ovary. Histopathologically, the tumours were composed of pleomorphic histiocytes that had round or bizarre nuclei and abundant pale eosinophilic cytoplasm. Immunohistochemically, tumour cells were positive for ionized calcium-binding adaptor molecule 1 and human leukocyte antigen and negative for CD3, B lymphocyte antigen 36 and cytokeratin. Histopathological and immunohistochemical examinations confirmed a diagnosis of disseminated histiocytic sarcoma. This neoplasm has not been previously reported in a sugar glider.

Loss of p16/Ink4a drives high frequency of rhabdomyosarcoma in a rat model of Duchenne muscular dystrophy.

Rhabdomyosarcoma (RMS) is an aggressive type of soft tissue sarcoma, and pleomorphic RMS is a rare subtype of RMS found in adult. p16 is a tumor suppressor which inhibits cell cycle. In human RMS, p16 gene is frequently deleted, but p16-null mice do not develop RMS. We reported that genetic ablation of p16 by the crossbreeding of p16 knock-out rats (p16-KO rats) improved the dystrophic phenotype of a rat model of Duchenne muscular dystrophy (Dmd-KO rats). However, p16/Dmd double knock-out rats (dKO rats) unexpectedly developed sarcoma. In the present study, we raised p16-KO, Dmd-KO, and dKO rats until 11 months of age. Twelve out of 22 dKO rats developed pleomorphic RMS after 9 months of age, while none of p16-KO rats and Dmd-KO rats developed tumor. The neoplasms were connected to skeletal muscle tissue with indistinct borders and characterized by diffuse proliferation of pleomorphic cells which had eosinophilic cytoplasm and atypical nuclei with anisokaryosis. For almost all cases, the tumor cells immunohistochemically expressed myogenic markers including desmin, MyoD, and myogenin. The single cell cloning from tumor primary cells gained 20 individual Pax7-negative MyoD-positive RMS cell clones. Our results demonstrated that double knock-out of p16 and dystrophin in rats leads to the development of pleomorphic RMS, providing an animal model that may be useful to study the developmental mechanism of pleomorphic RMS.

Age-Dependent Echocardiographic and Pathologic Findings in a Rat Model with Duchenne Muscular Dystrophy Generated by CRISPR/Cas9 Genome Editing.

Duchenne muscular dystrophy (DMD) is X-linked recessive myopathy caused by mutations in the dystrophin gene. Although conventional treatments have improved their prognosis, inevitable progressive cardiomyopathy is still the leading cause of death in patients with DMD. To explore novel therapeutic options, a suitable animal model with heart involvement has been warranted.We have generated a rat model with an out-of-frame mutation in the dystrophin gene using CRISPR/Cas9 genome editing (DMD rats). The aim of this study was to evaluate their cardiac functions and pathologies to provide baseline data for future experiments developing treatment options for DMD.In comparison with age-matched wild rats, 6-month-old DMD rats showed no significant differences by echocardiographic evaluations. However, 10-month-old DMD rats showed significant deterioration in left ventricular (LV) fractional shortening (P = 0.024), and in tissue Doppler peak systolic velocity (Sa) at the LV lateral wall (P = 0.041) as well as at the right ventricular (RV) free-wall (P = 0.004). These functional findings were consistent with the fibrotic distributions by histological analysis.Although the cardiac phenotype was milder than anticipated, DMD rats showed similar distributions and progression of heart involvement to those of patients with DMD. This animal may be a useful model with which to develop effective drugs and to understand the underlying mechanisms of progressive heart failure in patients with DMD.

Cardiac lesions in Duchenne muscular dystrophy model rats with out-of-frame Dmd gene mutation mediated by CRISPR/Cas9 system.

Duchenne muscular dystrophy (DMD) is a progressive muscular disorder caused by X-chromosomal DMD gene mutations. Recently, a new CRISPR/Cas9-mediated DMD rat model (cDMDR) was established and is expected to show cardiac lesions similar to those in humans. We therefore investigated the pathological and pathophysiological features of the cardiac lesions and their progression in cDMDR. For our cDMDR, Dmd-mutated rats (W-Dmd em1Kykn ) were obtained. Dmd heterozygous-deficient females and wild-type (WT) males were mated, and male offspring including WT as controls were used. (1) Hearts were collected at 3, 5, and 10 months of age, and HE- and Masson's trichrome-stained specimens were observed. (2) Electrocardiogram (ECG) recordings were made and analyzed at 3, 5, and 8 months of age. (3) Echocardiography was performed at 9 months of age. In cDMDR rats, (1) degeneration/necrosis of cardiomyocytes and myocardial fibrosis prominent in the right ventricular wall and the outer layer of the left ventricular wall were observed. Fibrosis became more prominent with aging. (2) Lower P wave amplitudes and greater R wave amplitudes were detected. PR intervals tended to be shorter. QT intervals were longer at 3 months but tended to be shorter at 8 months. Sinus irregularity and premature ventricular contraction were observed at 8 months. (3) Echocardiography indicated myocardial sclerosis and a tendency of systolic dysfunction. Pathological and pathophysiological changes occurred in cDMDR rat hearts and progressed with aging, which is, to some extent, similar to what occurs in humans. Thus, cDMDR could be a valuable model for studying cardiology of human DMD.

Cellular senescence-mediated exacerbation of Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) is a progressive disease characterised by chronic muscle degeneration and inflammation. Our previously established DMD model rats (DMD rats) have a more severe disease phenotype than the broadly used mouse model. We aimed to investigate the role of senescence in DMD using DMD rats and patients. Senescence was induced in satellite cells and mesenchymal progenitor cells, owing to the increased expression of CDKN2A, p16- and p19-encoding gene. Genetic ablation of p16 in DMD rats dramatically restored body weight and muscle strength. Histological analysis showed a reduction of fibrotic and adipose tissues invading skeletal muscle, with increased muscle regeneration. Senolytic drug ABT263 prevented loss of body weight and muscle strength, and increased muscle regeneration in rats even at 8 months-the late stage of DMD. Moreover, senescence markers were highly expressed in the skeletal muscle of DMD patients. In situ hybridization of CDKN2A confirmed the expression of it in satellite cells and mesenchymal progenitor cells in patients with DMD. Collectively, these data provide new insights into the integral role of senescence in DMD progression.

Pathological evaluation of rats carrying in-frame mutations in the dystrophin gene: a new model of Becker muscular dystrophy.

Dystrophin, encoded by the DMD gene on the X chromosome, stabilizes the sarcolemma by linking the actin cytoskeleton with the dystrophin-glycoprotein complex (DGC). In-frame mutations in DMD cause a milder form of X-linked muscular dystrophy, called Becker muscular dystrophy (BMD), characterized by the reduced expression of truncated dystrophin. So far, no animal model with in-frame mutations in Dmd has been established. As a result, the effect of in-frame mutations on the dystrophin expression profile and disease progression of BMD remains unclear. In this study, we established a novel rat model carrying in-frame Dmd gene mutations (IF rats) and evaluated the pathology. We found that IF rats exhibited reduced expression of truncated dystrophin in a proteasome-independent manner. This abnormal dystrophin expression caused dystrophic changes in muscle tissues but did not lead to functional deficiency. We also found that the expression of additional dystrophin named dpX, which forms the DGC in the sarcolemma, was associated with the appearance of truncated dystrophin. In conclusion, the outcomes of this study contribute to the further understanding of BMD pathology and help elucidate the efficiency of dystrophin recovery treatments in Duchenne muscular dystrophy, a more severe form of X-linked muscular dystrophy.

Long-Term Observation of the Progression From Nodal Marginal Zone Lymphoma to Diffuse Large B-Cell Lymphoma in a Dog.

A 4-year and 10-month old female Pembroke Welsh Corgi presented with an enlarged right popliteal lymph node, and a histopathological diagnosis of nodal marginal zone lymphoma (nMZL) was made. After resection of the lymph node, follow-up observation was continued without chemotherapy. At 22 months after initial presentation, the dog developed enlargement of peripheral lymph nodes, and the histopathological diagnosis was late-stage nMZL. Multidrug chemotherapy induced clinical complete remission, but the tumor relapsed with enlargement of peripheral and abdominal lymph nodes 42 months after initial presentation. Second-round multidrug chemotherapy induced complete clinical remission again; however, the tumor relapsed with lymphadenopathy 47 months after initial presentation. The dog died 59 months after initial presentation, and postmortem examination revealed generalized lymphadenopathy; the histopathological diagnosis was diffuse large B-cell lymphoma (DLBCL). Polymerase chain reaction for antigen receptor gene rearrangements revealed that the nMZL and DLBCL samples were derived from the same B-lymphocyte clone.

Oral roxadustat three times weekly in ESA-naïve and ESA-converted patients with anemia of chronic kidney disease on hemodialysis: Results from two phase 3 studies.

Roxadustat is a hypoxia-inducible factor prolyl hydroxylase inhibitor approved in China for anemia of dialysis-dependent chronic kidney disease (CKD). Japanese hemodialysis patients with anemia of CKD previously naïve to, or converted from, erythropoiesis-stimulating agents (ESAs) were enrolled in two open-label, noncomparative studies of titrated oral roxadustat administered three times weekly. ESA-naïve patients (n = 75) were randomized to roxadustat (initial dose, 50 or 70 mg) for 24 weeks; ESA-converted patients (n = 164) were assigned to roxadustat (initial dose, 70 or 100 mg based on prior ESA dose) for 52 weeks. Efficacy outcomes included average hemoglobin (Hb, weeks 18-24 or 46-52), change of Hb from baseline to weeks 18 to 24 (ΔHb18-24 ) or weeks 46 to 52 (ΔHb46-52 ), and maintenance rate (proportion of patients who achieved average Hb of 10.0-12.0 g/dL for weeks 18-24 or weeks 46-52). Treatment-emergent adverse events (TEAEs) were monitored. Mean (SD) Hb was 10.93 (0.79) g/dL (weeks 18-24) (ESA-Naïve Study), and 10.93 (0.69; weeks 18-24) g/dL and 11.11 (0.67; weeks 46-52) g/dL (ESA-Converted Study). Mean (SD) ΔHb18-24 was 2.26 (1.02) g/dL (ESA-Naïve Study) and -0.03 (0.90) g/dL (ESA-Converted Study); mean (SD) ΔHb46-52 was 0.12 (0.83) g/dL (ESA-Converted Study). The overall maintenance rate was 73.0% (54/74) (ESA-Naïve Study) (weeks 18-24), and 79.1% (129/163; weeks 18-24) and 71.2% (116/163; weeks 46-52) (ESA-Converted Study). Nasopharyngitis was the most common TEAE. Two deaths, considered unrelated to roxadustat, occurred in the ESA-Converted Study. Roxadustat effectively corrected and maintained Hb, regardless of previous ESA treatment, in Japanese anemic CKD patients on hemodialysis.