Clinical significance of amphiregulin in patients with chronic kidney disease.

BACKGROUND: Amphiregulin (AREG) is a ligand of epidermal growth factor receptor (EGFR), which plays an important role in injury-induced kidney fibrosis. However, the clinical significance of serum soluble AREG in chronic kidney disease (CKD) is unclear. In this study, we elucidated the clinical significance of serum soluble AREG in CKD by analyzing the association of serum soluble AREG levels with renal function and other clinical parameters in patients with CKD. METHODS: In total, 418 Japanese patients with CKD were enrolled, and serum samples were collected for the determination of soluble AREG and creatinine (Cr) levels, and other clinical parameters. Additionally, these parameters were evaluated after 2 and 3 years. Moreover, immunohistochemical assay was performed ate AREG expression in the kidney tissues of patients with CKD. RESULTS: Soluble AREG levels were positively correlated with serum Cr (p < 0.0001). Notably, initial AREG levels were positively correlated with changes in renal function (ΔCr) after 2 (p < 0.0001) and 3 years (P = 0.048). Additionally, soluble AREG levels were significantly higher (p < 0.05) in patients with diabetic nephropathy or primary hypertension. Moreover, AREG was highly expressed in renal tubular cells in patients with advanced CKD, but only weakly expressed in patients with preserved renal function. CONCLUSION: Serum soluble AREG levels were significantly correlated with renal function, and changes in renal function after 2 and 3 years, indicating that serum soluble AREG levels might serve as a biomarker of renal function and renal prognosis in CKD.

Data on mitochondrial respiratory function in skeletal muscle of adult male mice in response to 3-weeks heat stress.

Chronic heat stress induces mitochondrial adaptation in skeletal muscle. However, the effect of chronic heat stress on the respiratory function per mitochondria in skeletal muscle has not been well studied. Here, the present study reports on the effect of 3-weeks heat stress on muscle mitochondrial respiration using male C57BL/6JJ mice at age 21 weeks. Mice were randomly assigned to either the control group (n = 6) or passive heat group (n = 6). After 3-weeks of heat stress, the right triceps surae was removed and used for biochemical analysis. Protein expression was assessed by immunoblotting. Mitochondrial respiratory function was measured by Oxygraph-2k. The study also shows the impact of the heat stress on daily feeding, body weight, muscle weight, and protein expression of heat shock proteins (heat-response marker).

Prognostic value of initial serum sodium level in predicting disease severity in patients with COVID-19: A multicenter retrospective study.

INTRODUCTION: Early prediction of coronavirus disease (COVID-19) severity is crucial. Hyponatremia has been linked to poor outcomes in hospitalized COVID-19 patients, but its association with mild cases is unclear. This study aimed to investigate whether initial serum sodium level is a risk factor for COVID-19 severity in patients with mild-to-moderate disease. METHODS: A multicenter retrospective cohort study was conducted in 10 hospitals in Fukui City, Japan, from July 1, 2020, to October 31, 2021. The study included 1055 adult patients with asymptomatic, mild, or moderate COVID-19 confirmed by a positive RT-PCR test. The primary outcome was the need for oxygen therapy after hospitalization, and the secondary outcome was the composite of in-hospital death and critical care interventions. The association between initial serum sodium level (at the emergency department or on admission) and outcomes was examined, adjusting for age, sex, hypertension, and pneumonia presence. RESULTS: Of the 1267 patients diagnosed with COVID-19 during the study period, 1055 were eligible (median age: 45 years; 54 % male). Hyponatremia was observed in 5.2 % of patients upon admission. A lower initial serum sodium level was associated with an increased risk of the need for oxygen therapy after hospitalization (adjusted odds ratio [OR] per 1 mmol/L lower, 1.12 [95 % confidence interval {CI}, 1.05-1.19]) and the composite of critical care and in-hospital death (adjusted OR per 1 mmol/L lower, 1.09 [95 % CI, 0.99-1.20]). CONCLUSIONS: Among patients with mild COVID-19, lower initial serum sodium level was a risk factor for COVID-19 progression.

Knockout of Zeb2 ameliorates progression of renal tubulointerstitial fibrosis in a mouse model of renal ischemia-reperfusion injury.

BACKGROUND: Zeb2, a zinc finger E-box-binding homeobox transcription factor, regulates transforming growth factor (TGF)-ß signaling pathway. However, its role in the pathogenesis of acute kidney injury (AKI) and AKI-to-chronic kidney disease (CKD) transition is unclear. METHODS: We evaluated Zeb2 function in a bilateral renal ischemia-reperfusion injury (IRI)-induced AKI model using proximal tubule-specific Zeb2 conditional knockout (Zeb2-cKO) and wild-type (WT) mice, and in renal biopsy samples. RESULTS: In Zeb2-cKO mice, the levels of plasma creatinine and blood urea nitrogen post-IRI were significantly lower than that in WT mice. Immunohistological analysis revealed mild tubular injury, reduced neutrophil infiltration, fewer fibrotic changes and reduced expression of fibrotic proteins [collagen type IV, α-smooth muscle actin (α-SMA), fibronectin and connective tissue growth factor (CTGF)], at 3-14 days post-IRI. Zeb2 expression was upregulated in proximal tubular cells post-IRI in WT mice. Zeb2 siRNA transfection reduced TGF-ß-stimulated mRNA and protein expression of collagen type IV, α-SMA, fibronectin and CTGF in cultured renal tubular cells. Patients with AKI-to-CKD transition exhibited high Zeb2 expression in renal tubules, as revealed by renal biopsy. Hypoxia and CoCl2-treatment upregulated Zeb2 promoter activity and mRNA and protein expression in cultured renal tubular epithelial cells, suggesting a regulatory role for hypoxia. CONCLUSIONS: Zeb2 was upregulated in renal tissues in both mice and humans with AKI. Zeb2 regulates fibrotic pathways in the pathogenesis of AKI and AKI-to-CKD transition. Therefore, inhibition of Zeb2 could be a potential therapeutic strategy for AKI.

Long-term continuous use of proton-pump inhibitors is associated with renal function decline in patients without acute kidney injury.

BACKGROUND: Proton-pump inhibitors (PPIs) are widely used to treat gastroesophageal reflex disease, peptic ulcer disease, and stress ulcer prophylaxis. This study estimated the progress rate of renal dysfunction in patients taking PPIs in clinical settings and compared the results with those of patients taking histamine-2 receptor antagonists (H2RAs). METHODS: We retrospectively reviewed patients' data collected from Kochi Medical School Hospital's information system between 2001 and 2019. Patients were classified into PPI and H2RA groups, and survival time was defined as the period between initial drug administration and a 30% decrease in estimated glomerular filtration rate (eGFR). RESULTS: On survival analysis, the PPI group was associated with higher event incidence rates compared to that in the H2RA group. The rate of underlying disease was significantly higher in the PPI group than in the H2RA group, with no significant differences in age and sex between the groups. Comparing the PPI group to the H2RA group, the use of aspirin, clopidogrel, statin, and angiotensin II receptor blocker was significantly higher, whereas the use of non-steroidal anti-inflammatory drugs and steroids was significantly less. Regarding survival rate and 30% decrease in eGFR, the PPI group had a significantly higher survival rate compared to that in the H2RA group at 730 days, but not earlier. PPI use, older age, and eGFR ≥ 90 mL/min/1.73 m2 exhibited high hazard ratios. CONCLUSIONS: PPI use was significantly associated with an increased risk of chronic kidney disease development compared to that with H2RA use.

Effects of transient acute kidney injury, persistent acute kidney injury and acute kidney disease on the long-term renal prognosis after an initial acute kidney injury event.

AIM: To clarify the effects of the duration of acute damage and/or loss of renal function following an acute kidney injury event on the renal prognosis after recovery. METHODS: We retrospectively reviewed data collected between 1995 and 2016 from the Kochi Medical School Hospital. Patients were stratified according to the time required for recovery with fluid therapy (expected to reflect the presence of renal dysfunction): ≤2 days after onset, transient injury group (n = 491); 3 to 7 days after onset, persistent injury group (n = 1076); and ≥ 8 days after onset, acute kidney disease group (n = 1046). The healthy group comprised 1000 randomly selected adult patients without acute kidney injury with at least two creatinine measurement results during the study. Survival time was defined as the time from recovery to a 30% decrease in the estimated glomerular filtration rate (primary endpoint). Kaplan-Meier and Cox proportional hazards analyses were conducted. RESULTS: Event incidence rates were higher for the transient injury, persistent injury and acute kidney disease groups than for the healthy group. Persistent injury and acute kidney disease presented a higher risk of renal function decline than transient injury following recovery. CONCLUSION: Transient acute kidney injury, persistent acute kidney injury and acute kidney disease resulted in functional decline and rapid chronic kidney disease progression risks despite recovery. Transient acute kidney injury recovery within 2 days could be associated with better long-term prognoses than persistent acute kidney injury and acute kidney disease persisting beyond 2 days.

Influence of hyperuricemia treatment on postoperative acute kidney injury among hyperuricemia patients: a single-center retrospective database analysis.

OBJECTIVE: Hyperuricemia has been reported to be associated with the development of postoperative acute kidney injury (pAKI). However, it remains underdetermined whether hyperuricemia treatment could decrease the potential risk of pAKI. Here, we investigated this hypothesis among hyperuricemia patients with previously normal renal function by performing a retrospective database analysis. RESULTS: The study screened 18,169 patients, and were examined preoperative serum creatinine, uric acid, and postoperative serum creatinine. Eight hundred thirty-six patients were finally analyzed for the study, of whom 232 were in the treatment group and 604 were in the non-treatment control group. After adjustment for multi-covariates including baseline (pre-treatment) serum uric acid (SUA) levels, the incidence of pAKI in the treatment group (9.05%; 95% CI 6.04-12.1%) was significantly lower than that in the control group (14.2%; 95% CI 11.2-17.2%). On the other hand, further adjusting for preoperative SUA levels, there was no significant difference in the expected incidence of pAKI between the groups.