The Comparison between Vadadustat and Daprodustat Regarding Dose, Cost, and Safety of Treatment for Renal Anemia in Non-dialysis Patients with Chronic Kidney Diseases.

Objective We retrospectively compared the dose, cost, and safety of vadadustat and daprodustat for the treatment of renal anemia in patients with chronic kidney diseases who were not undergoing dialysis. Methods The primary outcome of this study was the change in dose and cost from the initiation of vadadustat and daprodustat treatment. The secondary outcome was the drug safety. Patients We treated 30 patients each with the hypoxia-inducible factor prolyl-hydroxylase inhibitors (HIF-PHIs) daprodustat and vadadustat. The hemoglobin (Hb) concentration was targeted at 11-13 g/dL, and transferrin saturation was maintained at ≥20%, as per the 2018 Japanese guidelines for the diagnosis and treatment of chronic kidney disease. Results Hb levels increased from 10.7 to 11.5 g/dL after the first month of daprodustat administration, whereas those for vadadustat patients remained relatively stable, going from 10.7 to 10.6 g/dL. After six months, the Hb level reached 12.1 g/dL and 11.3 g/dL for daprodustat and vadadustat, respectively. The dosage of vadadustat was significantly increased by 46% and 70% after 3 and 12 months, respectively, compared with the initial doses, whereas that of daprodustat did not change substantially. The average cost of vadadustat also increased in the first 3 months and remained over 500 yen/day after 3 months, while that of daprodustat showed little change from the initial cost of 360 yen/day. Conclusion These results suggest that heterogeneity exists in the drug potency and dosage required for treatment between daprodustat and vadadustat. Serious adverse events (death, cardiovascular disease, end stage renal disease (ESRD), and malignancy) occurred in more than 20% of participants with both HIF-PHIs. Further studies are required to confirm the safety of HIF-PHIs.

Spatiotemporally quantitative in vivo imaging of mitochondrial fatty acid ß-oxidation at cellular-level resolution in mice.

Mitochondrial fatty acid ß-oxidation (FAO) plays a key role in energy homeostasis. Several FAO evaluation methods are currently available, but they are not necessarily suitable for capturing the dynamics of FAO in vivo at a cellular-level spatial resolution and seconds-level time resolution. FAOBlue is a coumarin-based probe that undergoes ß-oxidation to produce a fluorescent substrate, 7-hydroxycoumarin-3-(N-(2-hydroxyethyl))-carboxamide (7-HC). After confirming that 7-HC could be specifically detected using multiphoton microscopy at excitation/emission wavelength = 820/415-485 nm, wild-type C57BL/6 mice were randomly divided into control, pemafibrate, fasting (24 or 72 h), and etomoxir groups. These mice received a single intravenous injection of FAOBlue. FAO activities in the liver of these mice were visualized using multiphoton microscopy at 4.2 s/frame. These approaches could visualize the difference in FAO activities between periportal and pericentral hepatocytes in the control, pemafibrate, and fasting groups. FAO velocity, which was expressed by the maximum slope of the fluorescence intensity curve, was accelerated in the pemafibrate and 72-h fasting groups both in the periportal and the pericentral hepatocytes in comparison with the control group. Our approach revealed differences in the FAO activation mode by the two stimuli, i.e., pemafibrate and fasting, with pemafibrate accelerating the time of first detection of FAO-derived fluorescence. No increase in the fluorescence was observed in etomoxir-pretreated mice, confirming that FAOBlue specifically detected FAO in vivo. Thus, FAOBlue is useful for visualizing in vivo liver FAO dynamics at the single-cell-level spatial resolution and seconds-level time resolution.NEW & NOTEWORTHY Fatty acid ß-oxidation (FAO) plays a key role in energy homeostasis. Here, the authors established a strategy for visualizing FAO activity in vivo at the cellular-level spatial resolution and seconds-level time resolution in mice. Quantitative analysis revealed spatiotemporal heterogeneity in hepatic FAO dynamics. Our method is widely applicable because it is simple and uses a multiphoton microscope to observe the FAOBlue-injected mice.

Hepatic phosphate uptake and subsequent nerve-mediated phosphaturia are crucial for phosphate homeostasis following portal vein passage of phosphate in rats.

Fibroblast growth factor 23, parathyroid hormone, and 1,25-dihydroxyvitamin D are critical in phosphate homeostasis. Despite these factors' importance, regulators of phosphaturia in the acute postprandial phase remain largely unknown. This study investigated the mechanism of acute phosphate regulation in the postprandial phase in rats. Duodenal administration of radiolabeled phosphate (32P) showed that 32P levels in the inferior vena cava (IVC) blood were lower than those in the portal vein (PV) blood. Serum phosphate concentration transiently increased 5 min after phosphate solution administration through IVC, while it was maintained after the administration through PV. Phosphate administration through both IVC and PV resulted in increased fractional excretion of phosphate (FEPi) at 10 min without elevation of the known circulating factors, but urinary phosphate excretion during the period was 8% of the dose. Experiments using 32P or partial hepatectomy showed that the liver was one of the phosphate reservoirs. The elevation of FEPi and suppression of sodium-phosphate cotransporter 2a in the kidney at 10 min was attenuated in rats with SCH23390, hepatic denervation, or renal denervation, thus indicating that the liver communicated with the kidney via the nervous system to promote phosphaturia. These results revealed previously unknown mechanisms for serum phosphate maintenance.

Effect of Pemafibrate on Serum Creatinine in Patients with Chronic Kidney Disease.

Introduction: Fibrates are recommended not to be used for the treatment of hypertriglyceridemia in patients with chronic kidney disease (CKD) based on clinical practice guidelines. The major reason for the negative suggestion is the elevation of serum creatinine and rhabdomyolysis by fibrates. This may cause clinical inertia for the treatment of hypertriglyceridemia using fibrate in patients with CKD, who are associated with an increasing risk of cardiovascular disease. Methods: We retrospectively studied the change of serum creatinine via the treatment of pemafibrate. Results: A total of 39 patients with CKD were treated with 0.2 mg of pemafibrate. Serum triglyceride was decreased in 23 fibrate-naïve patients from 380 [308, 455] mg/dL to 180 [152, 215] mg/dL via treatment with pemafibrate (p = 0.00003). Serum creatinine and eGFR were not changed from 1.22 ± 0.29 mg/dL to 1.21 ± 0.28 mg/dL (p = 0.70) and from 45.7 ± 10.9 mL/min/1.73 m2 to 46.2 ± 12.0 mL/min/1.73 m2 (p = 0.67) via treatment with pemafibrate, respectively. In 16 patients, with a change of treatment from fenofibrate or bezafibrate to pemafibrate, serum creatinine was significantly decreased from 1.32 ± 0.36 mg/dL to 1.17 ± 0.24 mg/dL (p = 0.003). eGFR was significantly increased from 45.2 ± 9.9 mL/min/1.73 m2 to 50.1 ± 8.6 mL/min/1.73 m2 (p = 0.001). Conclusions: These results suggest that treatment with pemafibrate does not affect the serum creatinine level and is suitable for use in patients with CKD for the treatment of hypertriglyceridemia.

[A Case of Pararectal Epidermoid Cyst Removed by Sacral Approach].

A 30-year-old woman was admittedto the hospital because of fecal occult bloodpositivity . Endoscopic colonoscopy indicated pressure on the right side of the rectum from the wall. Abdominal contrast CT and pelvic MRI revealed a cystic lesion with a maximum diameter of 5 cm on the pre-coccyx andthe right side of rectum. There was no continuity between the tumor andthe uterus/ovary. We diagnoseda pararectal tumor andremovedit via a sacral approach. The cyst was diagnosed as an epidermoid cyst. She was discharged on the 5th postoperative day. We could resect the tumor completely, because we chose an appropriate approach, considering the position, developmental direction, and size of the tumor.