Association between plasma aldosterone concentration and intraglomerular hemodynamics in primary aldosteronism.

BACKGROUND/AIMS: In primary aldosteronism (PA), aldosterone could affect glomerular hemodynamics by elevating renal vascular resistance and glomerular capillary pressure. However, the relationship between plasma aldosterone concentrations (PAC) and glomerular hemodynamics including efferent arteriolar resistance (Re), afferent arteriolar resistance (Ra) in humans is still unclear. The aim of this study was to investigate the relationships of PAC with intraglomerular hemodynamic parameters in patients with PA. METHODS: An observational study of glomerular hemodynamics was performed using simultaneous measurements of plasma clearance of para-aminohippurate and inulin (Cin; glomerular filtration rate (GFR)) in 17 patients with PA. Kidney function was evaluated by Cin, estimated GFR based on serum creatine (eGFRcre) and serum cystatin C (eGFRcys) and creatine clearance (Ccr). Intraglomerular hemodynamic parameters, including Re, Ra, and intraglomerular hydrostatic pressure (Pglo) were calculated using Gomez's formulae. RESULTS: In the 17 PA cases, PAC was significantly correlated with Cin (rho=0.752, p=0.001) and eGFRcys (rho=0.567, p=0.018), but was not correlated witheGFRcreand Ccr. PAC was also significantly correlated with Pglo, Re, and urinary protein/day (rho=0.775, p=0.0004, rho=0.625, p=0.009, and rho=0.625, p=0.007, respectively). Multivariable regression analysis showed that PAC was significantly associated with Cin and Re. In comparing aldosterone producing adenoma (APA) and non-APA cases, Cin was significantly elevated in APA (p=0.037), whereas eGFRcre, eGFRcys, and Ccr were not. Re tended to be higher in APA (p=0.064). CONCLUSIONS: These results suggest high aldosterone cause glomerular hyperfiltration by constricting Re. Cin, but not eGFRcre and Ccr, may be useful for evaluating kidney function in PA.

Seasonal variations for newly prescribed urate-lowering drugs for asymptomatic hyperuricemia and gout in Japan.

Background: Urate-lowering drugs (ULDs) have been approved for treatment of asymptomatic hyperuricemia and gout in Japan. Although serum urate levels and rates of gout onset are known to have seasonal variations, no survey results regarding the seasonality of ULD prescriptions for asymptomatic hyperuricemia and gout have been reported. Methods: A large-scale database of medical claims in Japan filed between January 2019 and December 2022 was accessed. In addition to total size of the recorded population for each month examined, the numbers of patients every month with newly prescribed ULDs for asymptomatic hyperuricemia and gout were noted, based on the International Classification of Diseases, 10th Revision, codes E79.0 and M10. Results: The results identified 201,008 patients with newly prescribed ULDs (median age 49.0 years, male 95.6%). Of those, 64.0% were prescribed ULDs for asymptomatic hyperuricemia and 36.0% for gout. The proportion of new ULD prescriptions was seasonal, with that significantly (p < 0.001) higher in summer (June-August) [risk ratio (RR) 1.322, 95% CI 1.218 to 1.436] and autumn (September-November) (RR 1.227, 95% CI 1.129-1.335) than in winter (December-February), whereas the proportion in spring (March-May) was not significantly different from winter. There was no significant difference after stratification by drug type (uric acid production inhibitor/uricosuric agent) or size of the medical institution, nor subgrouping by age or sex (p for interaction = 0.739, 0.727, 0.886, and 0.978, respectively). On the other hand, the proportions of new ULD prescriptions for asymptomatic hyperuricemia were significantly lower and for gout significantly higher in spring than winter, while those were similar in summer and autumn for both groups (p for interaction<0.001). Conclusion: The present findings indicate that new prescriptions for ULDs to treat asymptomatic hyperuricemia or gout in Japan show seasonal differences, with higher rates noted in summer and autumn as compared to winter.

Dysuricemia.

Gout results from elevated serum urate (SU) levels, or hyperuricemia, and is a globally widespread and increasingly burdensome disease. Recent studies have illuminated the pathophysiology of gout/hyperuricemia and its epidemiology, diagnosis, treatment, and complications. The genetic involvement of urate transporters and enzymes is also proven. URAT1, a molecular therapeutic target for gout/hyperuricemia, was initially derived from research into hereditary renal hypouricemia (RHUC). RHUC is often accompanied by complications such as exercise-induced acute kidney injury, which indicates the key physiological role of uric acid. Several studies have also revealed its physiological role as both an anti-oxidant and a pro-oxidant, acting as both a scavenger and a generator of reactive oxygen species (ROSs). These discoveries have prompted research interest in SU and xanthine oxidoreductase (XOR), an enzyme that produces both urate and ROSs, as status or progression biomarkers of chronic kidney disease and cardiovascular disease. The notion of "the lower, the better" is therefore incorrect; a better understanding of uric acid handling and metabolism/transport comes from an awareness that excessively high and low levels both cause problems. We summarize here the current body of evidence, demonstrate that uric acid is much more than a metabolic waste product, and finally propose the novel disease concept of "dysuricemia" on the path toward "normouricemia", or optimal SU level, to take advantage of the dual roles of uric acid. Our proposal should help to interpret the spectrum from hypouricemia to hyperuricemia/gout as a single disease category.

Exploring the Multifaceted Nexus of Uric Acid and Health: A Review of Recent Studies on Diverse Diseases.

The prevalence of patients with hyperuricemia or gout is increasing worldwide. Hyperuricemia and gout are primarily attributed to genetic factors, along with lifestyle factors like consuming a purine-rich diet, alcohol and/or fructose intake, and physical activity. While numerous studies have reported various comorbidities linked to hyperuricemia or gout, the range of these associations is extensive. This review article focuses on the relationship between uric acid and thirteen specific domains: transporters, genetic factors, diet, lifestyle, gout, diabetes mellitus, metabolic syndrome, atherosclerosis, hypertension, kidney diseases, cardiovascular diseases, neurological diseases, and malignancies. The present article provides a comprehensive review of recent developments in these areas, compiled by experts from the Young Committee of the Japanese Society of Gout and Uric and Nucleic Acids. The consolidated summary serves to enhance the global comprehension of uric acid-related matters.

Association of plasma xanthine oxidoreductase activity with vascular endothelial function independent of serum uric acid level: MedCity21 health examination registry.

Background: Xanthine oxidoreductase (XOR) inhibitor administration, known to reduce uric acid and reactive oxygen species (ROS) production, also improves vascular endothelial function (VEF). This cross-sectional study examined our hypothesis that XOR contributes to impaired VEF through ROS but not uric acid production. Methods: In 395 subjects (196 males, 199 females) without urate-lowering agent administration who underwent a health examination, plasma XOR activity was determined using our highly sensitive assay based on [13C2,15N2] xanthine and liquid chromatography/triple quadrupole mass spectrometry. For VEF evaluation, flow-mediated dilatation (FMD) in the brachial artery was determined by ultrasound, with physical and laboratory measurements also obtained. Results: The median values for plasma XOR activity, serum uric acid, and FMD were 26.6 pmol/h/mL, 5.4 mg/dL, and 6.2%, respectively. Simple regression analysis showed weak correlations of both log plasma XOR activity and serum uric acid level with FMD (r = -0.213, p < 0.001 and r = -0.139, p = 0.006, respectively). However, multivariable linear regression analyses revealed that log plasma XOR activity but not serum uric acid level remained associated with FMD (ß = -0.116, p = 0.037 and ß = 0.041, p = 0.549, respectively) after adjustments for various clinical parameters, with no remarkable inconsistencies for the association observed in subgroups divided based on sex or uric acid level. Finally, a series of mediation analyses showed that serum uric acid level did not meet the criteria for mediator of the association of plasma XOR activity with FMD (p = 0.538). Conclusions: These findings suggest the possibility that XOR contributes to the pathophysiology of impaired VEF through ROS but not uric acid production.

Serum Fibroblast Growth Factor 23 Levels are Associated with Vascular Smooth Muscle Dysfunction in Type 2 Diabetes.

AIM: Increased level of serum fibroblast growth factor 23 (FGF23) is a hallmark of abnormal phosphate metabolism in patients with chronic kidney disease (CKD) and is recently shown to be associated with the risk of cardiovascular disease even in those without CKD. This study investigated the association between serum FGF23 levels and vascular function in patients with type 2 diabetes. METHODS: This was a cross-sectional study involving 283 Japanese patients with type 2 diabetes. Flow-mediated dilatation (FMD) and nitroglycerin-mediated dilatation (NMD) of the brachial artery were measured via ultrasonography to evaluate vascular endothelial and smooth muscle functions, respectively. Serum intact FGF23 levels were determined via a sandwich enzyme-linked immunosorbent assay. RESULTS: The median values of FMD, NMD, and serum FGF23 were 6.0%, 14.0%, and 27.3 pg/mL, respectively. The serum FGF23 levels were inversely associated with NMD but not with FMD, and the association was independent of atherosclerotic risk factors, estimated glomerular filtration rate (eGFR), and serum phosphate levels. Furthermore, the relationship between serum FGF23 levels and NMD was modified by kidney function, which was pronounced in subjects with normal kidney function (eGFR ≥ 60 mL/min/1.73 m2). CONCLUSION: Serum FGF23 levels are independently and inversely associated with NMD in patients with type 2 diabetes, particularly in those with normal kidney function. Our results indicate that FGF23 is involved in vascular smooth muscle dysfunction and that increased serum levels of FGF23 may serve as a novel biomarker for vascular smooth muscle dysfunction in patients with type 2 diabetes.

Inflammation Related to Association of Low Uric Acid and Progression to Severe Disease in Patients Hospitalized for Non-Severe Coronavirus Disease 2019.

Uric acid has antioxidant properties. To examine whether a low uric acid level is associated with severe coronavirus disease 2019 (COVID-19) progression via inflammation, alveolar damage, and/or coagulation abnormality, a retrospective observational study of 488 patients with non-severe COVID-19 and serum uric acid level ≤7 mg/dL at admission was conducted. Serum C-reactive protein (CRP), serum Krebs von den Lungen 6 (KL-6), and plasma D-dimer levels were also measured as markers of inflammation, alveolar damage, and coagulation abnormality, respectively. Median values for uric acid, CRP, KL-6, and D-dimer at admission were 4.4 mg/dL, 3.33 mg/dL, 252.0 U/mL, and 0.8 µg/mL, respectively. Among the total cohort, 95 (19.5%) progressed to severe COVID-19 with a median (interquartile range) time of 7 (4-14) days. Multivariable Cox proportional hazards regression analysis showed that low uric acid level was associated with a higher rate of severe COVID-19 progression. However, uric acid level was inversely associated with CRP level, and the association between the level of uric acid and severe COVID-19 progression was significantly different with and without CRP level inclusion. In contrast, no such association was found for KL-6 or D-dimer level. Low uric acid may contribute to severe COVID-19 progression via increased inflammation in subjects without hyperuricemia.

Improvement in the mobility of a patient with fibroblast growth factor 23-related hypophosphatemic osteomalacia and decompensated liver cirrhosis in response to burosumab: a case report.

Acquired fibroblast growth factor (FGF) 23-related hypophosphatemic osteomalacia is characterized clinically by muscle weakness, bone pain, and fractures. Its biochemical features include hypophosphatemia, caused by renal phosphate wasting, and inappropriately normal or low 1,25-dihydroxy-vitamin D levels. Recently, burosumab, a fully human monoclonal antibody targeting FGF23, was approved for the treatment of FGF23-related hypophosphatemic rickets and osteomalacia. We report the case of a 75-year-old Japanese woman with decompensated liver cirrhosis and hepatic encephalopathy, caused by primary biliary cholangitis, who complained of back pain and limited mobility resulting from multiple vertebral fractures. She was not receiving iron infusion therapy and denied alcohol consumption. The patient exhibited hypophosphatemia with a low tubular maximum reabsorption of phosphate per unit glomerular filtration rate (TmP/GFR) and a high circulating concentration of FGF23. Conventional therapy with alfacalcidol and oral phosphate slightly improved her serum phosphate concentration and back pain, but she experienced a hip fracture, causing her to become wheelchair-dependent. Burosumab was initiated 8 weeks after the hip fracture, which increased her serum phosphate concentration and TmP/GFR. Her mobility gradually improved, such that she could walk without a cane after 16 weeks of treatment. Her lumbar bone mineral density increased after 48 weeks. Hepatic encephalopathy developed once before the initiation of treatment and twice after the initiation of the therapy, but her liver function was preserved. This is the first study to report the efficacy and safety of burosumab treatment for FGF23-related hypophosphatemic osteomalacia with decompensated liver cirrhosis.

Reduced Risk of Progression from Non-Severe to Severe COVID-19 in Hospitalized Dialysis Patients by Full COVID-19 Vaccination.

Coronavirus disease 2019 (COVID-19) vaccination reduces the risk of progression to severe COVID-19 in the general population. To examine that preventive effect in dialysis patients, the association of vaccination status with severe COVID-19 progression was investigated in this retrospective observational study conducted from December 2020 to May 2022 of 100 such patients hospitalized for non-severe COVID-19 at Inoue Hospital (Suita, Japan). Fifty-seven were fully vaccinated, defined as receiving a COVID-19 vaccine second dose at least 14 days prior to the onset of COVID-19, while 43 were not. Among all patients, 13 (13.0%) progressed to severe COVID-19 with a median (interquartile range) time of 6 (2.5-9.5) days, while 87 (87.0%) were discharged after 11 (8-16) days. Kaplan-Meier analysis showed that fully vaccinated patients had a significantly lower rate of progression to severe COVID-19 (p = 0.001, log-rank test). Cox proportional hazard analysis also indicated that full COVID-19 vaccination was significantly associated with reduced instances of progression to severe COVID-19 (hazard ratio 0.104, 95% confidence interval 0.022 to 0.483; p = 0.004) after balancing patient background characteristics using an inverse probability of treatment weight method. These results suggest that full vaccination status contributes to reducing the risk of progression from non-severe to severe COVID-19 in dialysis patients.

Possible role of insulin resistance in activation of plasma xanthine oxidoreductase in health check-up examinees.

We previously found an association of insulin resistance (IR) with plasma xanthine oxidoreductase (XOR) activity in a cross-sectional study. However, whether IR induces increased XOR activity has not been elucidated. This retrospective longitudinal observational study included 347 participants (173 males, 174 females) who underwent annual health examinations and were medication naïve. Homeostasis model assessment of IR (HOMA-IR) index, and physical and laboratory measurements were determined at the baseline. At baseline and 12-month follow-up examinations, plasma XOR activity was determined using our novel assay based on [13C2,15N2] xanthine and liquid chromatography/triple quadrupole mass spectrometry. Subjects with IR, defined as HOMA-IR index ≥ 1.7 (n = 92), exhibited significantly (p < 0.001) higher plasma XOR activity levels than those without IR (n = 255), with an increase in that activity seen in 180 (51.9%) after 12 months. Multivariable linear and logistic regression analyses showed that IR, but not BMI or waist circumference, at baseline was significantly associated with plasma XOR activity (ß = 0.094, p = 0.033) and increased plasma XOR activity over the 12-month period (odds ratio, 1.986; 95% confidence interval, 1.048-3.761; p = 0.035), after adjustments for various clinical parameters, including plasma XOR activity at baseline. These results suggest that IR induces increased plasma XOR activity in a manner independent of adiposity.

Glycated hemoglobin level on admission associated with progression to severe disease in hospitalized patients with non-severe coronavirus disease 2019.

AIMS/INTRODUCTION: Poor glycemic control is known to be associated with severe infection development. This retrospective observational study examined whether glycemic control before coronavirus disease 2019 (COVID-19) onset contributes to progression from non-severe to severe COVID-19. MATERIALS AND METHODS: Glycated hemoglobin (HbA1c) was measured on hospital admission in 415 patients with non-severe COVID-19. The outcome was determined from time of hospital admission to severe progression, based on clinical practice guidelines for COVID-19 in Japan. RESULTS: The median value for HbA1c on admission was 6.1%, with diabetes present in 138 patients (33.3%). Among the total cohort, 93 (22.4%) progressed to severe COVID-19 with a median (interquartile range) time of 4 days (3-7 days), whereas 322 (77.6%) were discharged after 13 days (10-17 days). A multivariable Cox proportional hazards regression model showed that HbA1c level on admission was independently associated with progression to severe COVID-19 (hazard ratio for 1% increase 1.237, 95% confidence interval 1.037-1.475; P = 0.018), with findings consistent among several sensitivity analyses. In subgroup analyses, such an association was significant in patients with diabetes, as well as older age, current smoking habit, lower estimated glomerular filtration rate, higher C-reactive protein level, moderate II COVID-19, dyslipidemia and chronic respiratory disease, with no remarkable inconsistency among the subgroups. Finally, higher HbA1c level (≥7%) was more strongly associated with severe COVID-19 progression than diabetes. CONCLUSIONS: The results suggest that poor glycemic control before COVID-19 onset contributes to progression from non-severe to severe COVID-19, even in patients with severe COVID-19 risk factors regardless of the presence of diabetes.

Nutritional Status Association With Sarcopenia in Patients Undergoing Maintenance Hemodialysis Assessed by Nutritional Risk Index.

Background: Malnutrition and sarcopenia are frequently observed in patients undergoing maintenance hemodialysis (MHD). To elucidate whether malnutrition is associated with sarcopenia in those cases, the relationship of nutritional status with sarcopenia was investigated. Methods: Nutritional status was assessed using a nutritional risk index (NRI) developed for patients undergoing MHD. This retrospective cross-sectional study included 315 MHD patients (199 males, 116 females), who were divided into low-risk (score 0-7) and medium-/high-risk (score 8-13) groups. Sarcopenia and severe sarcopenia, along with low muscle mass, low muscle strength, and low physical performance were defined using the Asian Working Group for Sarcopenia 2019 criteria. Results: The median NRI score was 5.0, while the prevalence of medium-/high-risk cases among the patients was 31.1%. Additionally, the rates of those with low muscle mass, low muscle strength, and low physical performance were 55.9, 60.6, and 31.4%, respectively, while those of sarcopenia and severe sarcopenia were 44.1 and 20.0%, respectively. Multivariable logistic regression analyses revealed a significant (P < 0.001) association of NRI score with sarcopenia [odds ratio (OR) 1.255, 95% confidence interval (CI) 1.143-1.377] and severe sarcopenia (OR 1.257, 95% CI 1.122-1.407), as well as low muscle mass (OR 1.260, 95% CI 1.157-1.374), low muscle strength (OR 1.310, 95% CI 1.178-1.457), and low physical performance (OR 1.216, 95% CI 1.104-1.339). Furthermore, medium-/high-risk status showed a significant (P < 0.05) association with sarcopenia (OR 2.960, 95% CI 1.623-5.401) and severe sarcopenia (OR 2.241, 95% CI 1.151-4.362), as well as low muscle mass (OR 2.141, 95% CI 1.219-3.760), low muscle strength (OR 7.665, 95% CI 3.438-17.091), and low physical performance (OR 2.570, 95% CI 1.401-4.716). Conclusions: These results suggest that malnutrition contributes to sarcopenia/severe sarcopenia in MHD patients by reducing muscle mass and strength, and physical performance.

Parathyroid Hormone Regulates Circulating Levels of Sclerostin and FGF23 in a Primary Hyperparathyroidism Model.

Parathyroid hormone (PTH) increases fibroblast growth factor 23 (FGF23), mediated both by protein kinase A (PKA) and Wnt signaling, and decreases expression of sclerostin, a Wnt antagonist derived from osteocytes. Patients with primary hyperparathyroidism (PHPT) have lower serum sclerostin levels than healthy controls, consistent with the idea of SOST downregulation by PTH. Nevertheless, the relationship between FGF23 and sclerostin in PHPT is still unclear. We examined this issue in a mouse model of PHPT. PHPT mice had increased FGF23 and decreased sclerostin expression in calvaria and in their serum concentrations compared with wild-type (WT) mice. In UMR106 osteoblasts, PTH increased Fgf23 expression and decreased Sost expression, as well as forskolin, a PKA agonist, whereas inhibition of PKA reversed the changes in Fgf23 and Sost expression, stimulated by PTH. Sclerostin treatment had no effect on Fgf23 expression, but when it was added together with PTH, it statistically significantly abrogated the increase in Fgf23 expression. By contrast, there was no statistically significant correlation between serum FGF23 and sclerostin, whereas PTH was positively and negatively correlated with serum FGF23 and sclerostin, respectively. These results indicate that the high level of PTH in PHPT mice leads to increased FGF23 and decreased sclerostin expression in serum and calvaria. A decrease of sclerostin may further augment FGF23 in vitro; however, there was no statistically significant association between circulating FGF23 and sclerostin. It is suggested that the pathogenesis of increased FGF23 expression in PHPT mice may be modified by not only sclerostin, but also other regulatory factors modulated by PTH.

Xanthine Oxidoreductase Inhibitor Use Associated With Reduced Risk of Sarcopenia and Severe Sarcopenia in Patients Undergoing Hemodialysis.

BACKGROUND: Xanthine oxidoreductase (XOR) inhibition reduces reactive oxygen species (ROS) production and enhances adenosine triphosphate (ATP) synthesis. We investigated the protective effects of XOR inhibitor treatment on sarcopenia, frequently observed in patients undergoing hemodialysis (HD), in which increased ROS and ATP shortage are known to be involved. METHODS: This retrospective cross-sectional study included 296 HD patient (203 males, 93 females). Muscle mass, physical performance, and muscle strength were assessed using dual-energy X-ray absorptiometry, five-time chair stand testing, and handgrip strength, respectively. The Asian Working Group for Sarcopenia 2019 criteria were used to define low muscle mass, low physical performance, and low muscle strength, as well as sarcopenia and severe sarcopenia. RESULTS: Sarcopenia and severe sarcopenia prevalence rates were 42.2 and 20.9%, respectively. XOR inhibitor users (n = 119) showed a significantly (p < 0.05) lower prevalence of sarcopenia and severe sarcopenia, as well as reduced muscle mass, physical performance, and muscle strength than non-users (n = 177). Multivariate logistic regression analyses also revealed XOR inhibitor use to be significantly associated with low muscle mass [odds ratio (OR), 0.384; 95% confidence interval (CI), 0.183-0.806; p = 0.011] and low physical performance (OR, 0.286; 95% CI, 0.142-0.578; p < 0.001), while significance with low muscle strength was borderline. Furthermore, XOR inhibitor use was significantly associated with sarcopenia (OR, 0.462; 95% CI, 0.226-0.947; p = 0.035) and severe sarcopenia (OR, 0.236; 95% CI, 0.091-0.614; p = 0.003). CONCLUSIONS: XOR inhibitor use was significantly associated with reduced risk of sarcopenia/severe sarcopenia in HD patients, suggesting that XOR inhibitor treatment has protective effects on sarcopenia in HD patients.

Role of adiponectin in the relationship between visceral adiposity and fibroblast growth factor 23 in non-diabetic men with normal kidney function.

Fibroblast growth factor 23 (FGF23) is a key regulator of phosphate metabolism. Circulating FGF23 levels are associated with obesity, metabolic syndrome, and cardiovascular disease in the general population, but the underlying mechanism remains unclear. Therefore, we aimed to determine the associations between serum FGF23 levels and visceral adiposity as well as serum adiponectin levels in 189 adults without diabetes and with normal kidney function who were selected from the MedCity21 health examination registry. The exclusion criteria included diabetes mellitus or impaired kidney function (estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m2). Levels of serum FGF23 and total adiponectin, and visceral fat area (VFA) on computed tomography images were measured. Serum FGF23 levels were higher and VFA was greater, whereas serum adiponectin levels were lower in men than in women. Serum FGF23 levels positively correlated with VFA in men; they remained marginally significant after adjusting for age, eGFR, and serum levels of calcium, phosphate, intact parathyroid hormone, and 1,25-dihydroxyvitamin D. Importantly, when serum adiponectin levels were included as a covariate, serum adiponectin levels comprised an independent determinant of serum FGF23 levels in men, whereas VFA did not. In conclusion, lower serum adiponectin, rather than a greater VFA, was associated with higher serum FGF23 levels in non-diabetic men with normal kidney function. These findings suggest that adiponectin plays a role in the relationship between visceral adiposity and FGF23 in men.

Bexarotene-induced central hypothyroidism assessed by TRH stimulation test in cutaneous T-cell lymphoma patients.

Bexarotene-induced central hypothyroidism (CH), for which levothyroxine (LT4) replacement is recommended, has been shown to be caused by pituitary but not hypothalamic disorder experimentally, though the underlying mechanism in humans remains unclear. Here, the pathophysiology of bexarotene-induced CH was examined using a TRH stimulation test in cutaneous T-cell lymphoma (CTCL) patients. In this retrospective longitudinal observational study, serum TSH and free T4 (F-T4) levels were measured in 10 euthyroid patients with CTCL during 24 weeks of bexarotene treatment. TRH stimulation testing was performed following CH diagnosis, with LT4 replacement dosage adjusted to maintain F-T4 at the pre-treatment level. After one week of bexarotene administration, all 10 patients developed CH, based on combined findings of low or low-normal F-T4 with low or normal TSH levels. TSH peak response after a stimulation test at one week was reached at 30 minutes. However, that was <4 µIU/mL in all patients, indicating a blunted though not exaggerated and delayed TSH response. In eight who continued bexarotene for 24 weeks, median LT4 replacement dosage was 125 (range, 75-150) µg/day. TSH level at 30 as well as 15, 60, 90, and 120 minutes after TRH stimulation was significantly correlated with LT4 replacement dosage (ρ = -0.913, p = 0.002), whereas TSH and F-T4 basal levels at one week were not. These results suggest that pituitary hypothyroidism is responsible for bexarotene-induced CH, while TSH levels after TRH stimulation precisely reflect residual pituitary-thyroid function in patients receiving bexarotene.

Plasma Xanthine Oxidoreductase Activity Associated with Glycemic Control in Patients with Pre-Dialysis Chronic Kidney Disease.

INTRODUCTION: Xanthine oxidoreductase (XOR) activity plays an important role as a pivotal source of reactive oxygen species, which is associated with cardiovascular disease (CVD) events. Patients with CKD have increased risk of CVD events. In the present study, factors associated with plasma XOR activity in pre-dialysis CKD patients were investigated. METHODS: In this cross-sectional study, plasma XOR activity in 118 pre-dialysis CKD patients (age 68 [57-75] years; 64 males, 26 with diabetes mellitus [DM]) was determined using a newly established highly sensitive assay based on (13C2,15N2) xanthine and liquid chromatography/triple quadrupole mass spectrometry. RESULTS: Plasma glucose, hemoglobin A1c, and estimated glomerular filtration (eGFR) were significantly and positively correlated with plasma logarithmically transformed XOR (ln-XOR) activity. In multiple regression analyses, eGFR and hemoglobin A1c or plasma glucose were significantly, independently, and positively associated with plasma ln-XOR activity after adjusting for several confounders. Plasma XOR activity was significantly higher in CKD patients with (n = 26) than in those without (n = 92) DM (62.7 [32.3-122] vs. 25.7 [13.4-45.8] pmol/h/mL, p < 0.001). A total of 38 patients were taking uric acid-lowering drugs. Multiple regression analysis of CKD patients not administered uric acid-lowering drugs (n = 80) showed no significant association between eGFR and plasma ln-XOR activity. In contrast, association between glycemic control and plasma ln-XOR activity was significant even in CKD patients without uric acid-lowering drug treatment. CONCLUSIONS: These results indicate the importance of glycemic control in CKD patients in regard to decreased XOR, possibly leading to a decrease in CVD events.

Uric acid shown to contribute to increased oxidative stress level independent of xanthine oxidoreductase activity in MedCity21 health examination registry.

Uric acid has both antioxidant and pro-oxidant properties in vitro by scavenging and production of reactive oxygen species (ROS). This cross-sectional study examined whether uric acid possesses effects on oxidative stress under physiological conditions independent of xanthine oxidoreductase (XOR), which is involved in uric acid and ROS production. Serum uric acid level was measured, while plasma XOR activity was determined using our high-sensitive assay in 192 participants (91 males, 101 females) who underwent health examinations and were not taking an antihyperuricemic agent. For antioxidant potential and oxidative stress level, biological antioxidant potential (BAP) and derivative of reactive oxygen metabolites (d-ROMs) in serum, respectively, were measured. Median uric acid level and plasma XOR activity were 5.6 mg/dL and 26.1 pmol/h/mL, respectively, and BAP and d-ROMs levels were 2112.8 µmol/L and 305.5 Carr U, respectively. Multivariable regression analyses revealed no significant association of serum uric acid level with BAP level, whereas serum uric acid level showed a significant association with d-ROMs level independent of plasma XOR activity (p = 0.045), which was prominent in females (p = 0.036; p for interaction = 0.148). Uric acid might contribute to increased oxidative stress independent of XOR activity by increasing ROS production, without affecting ROS scavenging, especially in females.