桑原 政成

Although elevated soluble uric acid (SUA) levels enhance the production of IL-1β in macrophages stimulated with monosodium urate (MSU) crystals, the underlying mechanism remains unelucidated. The aim of this study was to examine the effects of SUA on inflammatory response-related gene expression in lipopolysaccharide-primed and MSU crystal-stimulated macrophages using mouse macrophage-like J774.1 cells. Differential gene expression in SUA-pretreated and untreated group cells was analyzed by RNA sequencing and quantitative reverse transcription-polymerase chain reaction. SUA upregulated the genes related to pro-inflammatory reactions and downregulated those related to anti-inflammatory reactions. SUA also upregulated M1 pro-inflammatory macrophage-related genes and enhanced mRNA expression of CD44 responsible for phagocytosis of MSU crystals. These results suggest that SUA enhances gouty inflammation via promoting the expression of genes related to pro-inflammatory reactions, polarization toward the M1 phenotype, and MSU crystal phagocytosis in macrophages. Enhanced expression of the transcription factor genes Nfkb1 and Stat1 may underlie the SUA-induced M1 polarization and resulting enhancement of inflammasome activation and IL-1β transcription.

BACKGROUND: Dysuricemia, encompassing both hyperuricemia (serum uric acid: SUA > 7 mg/dl) and hypouricemia (SUA ≤ 3 mg/dL), has been linked to cardio-renal risks, but it remains unclear whether consistent or transient dysuricemia contributes to the risk of chronic kidney disease (CKD). PURPOSE: To investigate whether consistent and transient dysuricemia influences annual changes in the estimated glomerular filtration rate (eGFR) in healthy participants. METHODS: We retrospectively analyzed 1142 healthy participants who underwent health checkups with at least four consecutive annual measurements of eGFR and SUA. Participants with consistently hyperuricemia, hypouricemia, or normouricemia (7 mg/dL ≥ SUA > 3 mg/dL) throughout follow-up were categorized as consistent hyperuricemia (n = 36), consistent hypouricemia (n = 8) and normouricemia (n = 759), respectively. Others were classified as transient hyperuricemia (n = 282) and transient hypouricemia (n = 57). Annualized eGFR decline was compared using ANOVA, and incident CKD stage 3 events were evaluated using χ² or Fisher's exact tests. Multivariable analyses were performed to examine the association between baseline SUA and subsequent renal outcomes. RESULTS: Hyperuricemia was positively associated with obesity, liver dysfunction, dyslipidemia, and higher baseline eGFR compared with normouricemia, whereas hypouricemia showed negative associations with obesity and liver dysfunction. Transient hyperuricemia was significantly associated with obesity, liver dysfunction, and dyslipidemia relative to consistent normouricemia, while transient hypouricemia was negatively associated with obesity and liver dysfunction. Transient hyperuricemia exhibited significantly faster annual eGFR decline than normouricemia, while transient hypouricemia showed no significant difference. Baseline SUA ≥ 7 mg/dL was associated with higher baseline eGFR but predicted a significantly faster subsequent eGFR decline. In multivariable linear regression, baseline SUA level was independently associated with eGFR change, whereas baseline SUA status did not independently predict incident CKD stage 3. CONCLUSION: Transient hyperuricemia, rather than transient hypouricemia, is associated with accelerated eGFR decline in healthy individuals. Baseline SUA provides prognostic information regarding renal function trajectory, but does not independently predict CKD stage 3, suggesting that SUA should be interpreted as a clinically useful marker of renal vulnerability rather than a proven causal factor.

<h4>Background</h4>A previous study reported that among patients with complete Kawasaki Disease (KD), those exhibiting all six principal clinical features were more likely to develop coronary artery (CA) sequelae than those exhibiting only five features. We aimed to determine which specific features are associated with CA sequelae.<h4>Methods</h4>This retrospective cohort study analyzed 14,732 patients diagnosed with complete KD across Japan from January 2019 to March 2020. Separate multivariable conditional logistic regression analyses were performed to evaluate relative risk for CA sequelae in patients with all six principal clinical features, compared individually to those lacking each specific feature.<h4>Results</h4>7234 (49.1%) exhibited all six principal clinical features, while 7498 (50.9%) presented with five features. CA sequelae occurred in 2.1% of those with six features versus 1.7% with five. Multivariable conditional logistic regression analysis determined that patients with conjunctival injection were significantly more likely to develop CA sequelae compared with those lacking it (adjusted odds ratio [95% confidence interval], 3.6 [1.3-10.1]).<h4>Conclusions</h4>Among patients with complete KD, the absence of conjunctival injection-a relatively rare presentation-was associated with a lower cumulative incidence of CA sequelae. This finding may help identify distinct low-risk phenotypes of KD and support risk stratification.<h4>Impact</h4>This study emphasizes the importance of feature-specific risk for coronary artery (CA) sequelae among patients with complete Kawasaki Disease (KD). We found that among patients with complete KD, those with conjunctival injection were more likely to develop CA sequelae than were those lacking it. The absence of conjunctival injection-a relatively rare presentation in KD-is associated with a markedly lower cumulative incidence of CA sequelae. This finding may help identify a distinct low-risk phenotype of KD and aid risk stratification.