Over the past few years, discoveries of chemical modifications in a variety of RNA species, which expand the functional repertoire of simple RNA molecules, have revolutionized our understanding of RNA biology and established a new research field known as epitranscriptomics. To date, about 150 species of RNA modifications have been identified in RNA molecules of organisms from all domains of life. RNA modifications are indispensable for fundamental biology, and dysregulation of RNA modification has been implicated in various human diseases, either rare or common. Furthermore, chemical modifications of mRNA have emerged as crucial regulators of gene expression. In particular, N6-methyladenosine (m⁶A), which is the most abundant modification in messenger RNA (mRNA), regulates gene expression by controlling alternative splicing, stability, processing, and translation, and therefore has been implicated in multiple biological functions including immune responses and tumorigenesis. Modified nucleosides cannot be further degraded and are excreted in urine after circulation in blood, and some of them have been identified as potential biomarkers of certain diseases. We previously reported that m⁶A acts as a ligand for the human adenosine A3 receptor, for which it has greater affinity than unmodified adenosine. m⁶A is dynamically released in response to cytotoxic stimuli and facilitates inflammation both in vitro and in vivo. In this study, we collected urine samples before and after the application of vaccines against COVID-19, and measured multiple nucleoside derivatives by LC-MS. We found that m⁶A and m⁵C (5-methylcytidine) significantly increase and m¹acp³Y (1-methyl-3-(3-amino-3-carboxypropyl) pseudouridine) significantly decreases 24 ± 12 h after receiving the COVID-19 vaccine. On the contrary, unmodified nucleosides or major metabolites of nucleic acids (uric acids, hypoxanthine, and xanthine) show no change. Our results indicate that metabolism of RNA modification dynamically changes after COVID-19 vaccination.

We reported that serum uric acid levels in postmenopausal women and men no longer differ significantly, but uric acid excretion is significantly higher in women. To clarify the background of this sex difference, we added further analysis to the data. Twenty-three men aged 50 years or older (male group, mean age: 67 ± 10 years) and 26 postmenopausal women (female group, mean age: 73 ± 9 years) were included in the analysis. Serum uric acid levels were 5.2 ± 1.0 mg/dL in the male group and 4.9 ± 1.2 mg/dL in the female group (p = 0.361). The urinary UA/Cr ratio was 0.48 ± 0.12 in the male group and 0.67 ± 0.20 in the female group (p < 0.001). The urinary pH was 5.7 ± 0.7 in the male group and 6.0 ± 1.1 in the female group (p = 0.252). In the male group, the only correlation finding was between the urinary UA/Cr ratio and salt intake (r=0.641, p<0.001). In the female group, the urinary UA/Cr ratio showed a strong positive correlation with salt intake (r=0.673, p<0.001), potassium excretion (r=0.580, p<0.003), and urinary pH (r=0.552, p<0.003). These results suggest that sex differences in urinary uric acid excretion in relation to potassium excretion and urinary pH remain after menopause.

Background: Accumulating evidences has suggested that hyperuricemia is associated with aggravation of chronic kidney disease (CKD). Treatment guidelines propose, the administration of a uric acid production inhibitor to achieve serum uric acid level below 6 mg /dL in CKD patients with hyperuricemia; however, the success rate is not satisfactory.

Case Series: Herein, we outlined our experience of the treatment of six patients with advanced CKD with the newly launched uric acid-lowering agent dotinurad, which inhibits the reabsorption of uric acid in the proximal tubule by blocking urate transporter 1 (URAT1). Dotinuradwas administered at a low dose of 0.5 mg per day for 24 weeks. The serum uric acid levels improved significantly in all patients (7.58 ± 0.47 mg / dL to 6.10 ± 0.29 mg / dL after 4 weeks, 6.16 ± 1.02 mg / dL after 12 weeks and 6.12 ± 1.08 mg / dL after 24 weeks). Further, the uric acid clearance / creatinine clearance ratio increased from 5.0 ± 1.8 % to 7.3 ± 2.6 % after 4 weeks. Urinary pH was significantly increased, achieving “alkalization” after 4 weeks (5.8 ± 0.9 to 6.6 ± 0.9). Renal function deterioration and new-onset gout attacks did not appear.

Conclusion: A small dose of dotinurad administered for 24 weeks improved CKD symptoms in all patients, resulting in an increase in uric acid excretion into the urine. Interestingly, the urine became alkalized, indicating that this agent may also inhibit the production of urinary stones.

Background: Nocturnal hypertension is chiefly based on an excessive salt-intake, and diuretics which promote urinary excretion of sodium are known to decrease blood pressure (BP) at night. It was reported that diuretics tended to cause hyperuricemia, and correcting the uric acid (UA) level led to hypotension. The incidence of hyperuricemia, changes in BP and BP variability due to UA-lowering therapy, and differences depending on the type of drugs were examined in hypertensive patients receiving diuretics.

Methods: The frequency of hyperuricemia in hypertensive patients was studied with or without diuretics. For 78 patients taking diuretics among hyperuricemia-combined hypertensive subjects, serum UA (SUA), home morning BP (HMBP), and 24-hour ambulatory BP monitoring (ABPM) were measured before and 24 weeks after the administration of benzbromarone or febuxostat and assessed retrospectively. Coefficient of variation (CV) calculated from HMBP was employed as an indicator of the daily fluctuation in BP. Analyzing circadian rhythms via ABPM data, dippers and non-dippers regarding night-time BP were defined as 10-20% and below 10% decline from daytime BP, respectively.

Results: For refractory hypertension, the complication rate of hyperuricemia was 87.2% in recipients of diuretics, being clearly higher than 43.3% in non-diuretic users. When SUA ≦ 6.0 mg/dL was achieved by UA-decreasing treatment, average HMBP and 24-hour BP were both reduced and CV was decreased significantly. After achievement of the target SUA, the average BPs for day and night were lower as compared with pre-treatment values in either case, while the step-down degree at night was smaller. In terms of drug-specific effects, benzbromarone and febuxostat given to the subjects elicited equivalent decreases in diurnal BP, whereas only the latter reduced night-time BP significantly. Moreover, the degree of decrease in the non-dipper/dipper ratio in the febuxostat group was greater even without achieving the desired SUA.

Conclusion: In patients with diuretic-resistant hypertension, improved BP control and a reduction in daily BP variation can be expected with UA-reducing medication. Additionally, diurnal hypertension could arise from hyperuricemia, whereas it was suggested that nocturnal hypertension could be evoked by XO activation rather than an increase in SUA.