Comparisons of EQ-5D-Y and PedsQL in pediatric patients with mild-to-moderate chronic kidney disease in longitudinal analyses.

OBJECTIVE: To characterize longitudinal changes and correlations between the measures of EQ-5D-Y and generic PedsQL and their associations with clinical changes in children and adolescents with mild-to-moderate chronic kidney disease (CKD). METHODS: Participants were recruited from January 2017 to September 2021 in a medical center in Taiwan. Both instruments were administered in their initial visits and every 6-month subsequent visits. Spearman's Rho (ρ) was used to assess correlations between the scores of EQ-5D-Y and PedsQL measures in longitudinal changes. Cohen's effect size (ES) was used to evaluate the changes of scores/subscales over time. In addition, factors associated with longitudinal changes in the score/subscales were explored. RESULTS: A total of 121 participants were enrolled, and 83 with ≥ 3 HRQOL measures during the 3.5 years follow-up were assessed their changes of HRQOL measures. The correlations (ρ > 0.3) appeared between the changes in the visual analog scale (VAS) of EQ-5D-Y and emotional and social subscales of PedsQL. ES was small (< 0.5) in the VAS and level-sum-score (LSS) of EQ-5D-Y scores for the clinical changes in comorbidities, while some PedsQL subscales were medium to high (0.5-0.8 or > 0.8). Hypertension, mineral bone disorder/anemia, and hyperuricemia associated with the changes in both HRQOL scores were varied by their various domains. CONCLUSION: Both EQ-5D-Y and PedsQL of HRQOL measures were responsive to worsened childhood CKD-related comorbidities during the follow-up; however, convergent validity between them was limited in some domains. The LSS of EQ-5D-Y showed greater changes than the VAS by comorbidity status; further comparison with utility weight is needed to determine the better performance of EQ-5D-Y.

Differences in health-related quality of life in children with chronic kidney disease as reported by children and parent proxies.

BACKGROUND: Correlation between reports of children and parent for health-related quality of life (HRQOL) is not well studied. This study aims to assess the degree of agreement between child self- and parent proxy-rated HRQOL and to identify factors associated with discordance at baseline and during follow-up in Taiwanese children with chronic kidney disease (CKD). METHODS: This study includes pediatric patients aged 5-18 years with confirmed CKD. Participants completed the generic version of the Pediatric Quality of Life Inventory (PedsQL) at baseline and every 6 months during follow-up. Child-parent agreement on HRQOL reports was assessed using intraclass correlation coefficient (ICC). Multivariate regression models were used to determine factors associated with child-parent discordance. RESULTS: Of the 112 child-parent dyads included in the analysis, 97 dyads with 640 patient visits were assessed in 4.5 years. Children reported higher total scores on the physical and psychosocial domains as compared to their parent proxies. ICC was low (< 0.5) for the psychosocial domain and moderate for the physical health domain at initial assessment and slightly increased for the physical health (0.62) and for school functioning (0.51) during follow-up. Development of mineral bone disorder/anemia (ß, 11.75 [3.77-19.72]) and proteinuria (ß, 8.48 [1.15-15.81]) in the follow-up were associated with increased discordance in school functioning, and fathers with chronic disease were associated with increased discordance in social functioning (ß, 4.21 [0.68-7.74]). CONCLUSIONS: Parent proxy consistently estimated lower PedsQL score compared to self-reports of children. Child self-rated psychosocial health domains should be evaluated whenever possible to better elucidate treatment outcome over time. A higher resolution version of the Graphical abstract is available as Supplementary information.

Gut Microbiome-Estrobolome Profile in Reproductive-Age Women with Endometriosis.

Microbiota is associated with our bodily functions and microenvironment. A healthy, balanced gut microbiome not only helps maintain mucosal integrity, prevents translocation of bacterial content, and contributes to immune status, but also associates with estrogen metabolism. Gut dysbiosis and estrobolome dysfunction have hence been linked to certain estrogen-dependent diseases, including endometriosis. While prior studies on microbiomes and endometriosis have shown conflicting results, most of the observed microbial differences are seen in the genital tract. This case-control study of reproductive-age women utilizes their fecal and urine samples for enzymatic, microbial, and metabolic studies to explore if patients with endometriosis have distinguishable gut microbiota or altered estrogen metabolism. While gut ß-glucuronidase activities, microbial diversity, and abundance did not vary significantly between patients with or without endometriosis, fecal samples of patients with endometriosis were more enriched by the Erysipelotrichia class and had higher folds of four estrogen/estrogen metabolites. Further studies are needed to elucidate what these results imply and whether there indeed is an association or causation between gut microbiota and endometriosis.

Association between Acrylamide Metabolites and Cardiovascular Risk in Children With Early Stages of Chronic Kidney Disease.

Cardiovascular disease (CVD) begins early in children with chronic kidney disease (CKD). Reduced nitric oxide (NO) bioavailability has been associated with increased CVD in CKD patients. Children tend to have more exposure to acrylamide, one of the most common toxins in food. We aimed to determine whether urinary levels of acrylamide metabolites N-acetyl-S-(2-carbamoylethyl)-cysteine (AAMA) and N-acetyl-S-(2-carbamoyl-2-hydroxyethyl)-cysteine (GAMA) are associated with CV risk markers in children with CKD. Data on 112 children and adolescents ages three to 18 years old with CKD stage G1-G4 are reported. We observed that 24 h ambulatory blood pressure monitoring (ABPM) abnormalities were greater, and left ventricular (LV) mass and ambulatory arterial stiffness index (AASI) were higher in children with CKD stage G2-G4 versus G1. Patients with CKD stage G2-G4 had a lower urinary acrylamide level, but a higher AAMA-to-GAMA ratio than those with CKD stage G1. Urinary acrylamide level was negatively associated with high systolic blood pressure (SBP) and diastolic BP (DBP) load on 24 h ABPM. Lower urinary levels of acrylamide, AAMA, and GAMA were correlated with LV mass. Additionally, GAMA are superior to AAMA related to NO-related parameters, namely citrulline and symmetric dimethylarginine (SDMA). This study suggests that determinations of urinary acrylamide level and its metabolites in the early stages of pediatric CKD may identify patients at risk of CVD. Further studies should clarify mechanisms underlying acrylamide exposure to define the treatment for protection against CVD.

Evaluation of endothelial dysfunction, endothelial plasma markers, and traditional metabolic parameters in children with adiposity.

BACKGROUND/PURPOSE: To investigate the correlations among endothelial function assessment parameters, asymmetric dimethylarginine (ADMA)-related biomarkers, and traditional risk factors in adipose children. METHODS: We enrolled adipose children aged 7-18 years between July 2014 and August 2016 as well as normal-weight controls from the outpatient clinic. Vascular measurements including echocardiography, carotid intima media thickness, pulse wave velocity (PWV), and flow-mediated dilation (FMD) were measured. Venous blood samples including traditional metabolic and endothelial dysfunction parameters were analyzed. Participants were grouped as adipose vs. normal-weight and as adipose with hypertension vs. adipose without hypertension. Clinical presentations, laboratory data, and cardiovascular measurement were compared. RESULTS: Of the 105 enrolled children, 85 were adipose. Adipose children had higher systolic blood pressure, larger left ventricular (LV) mass, and adverse traditional metabolic biomarkers. FMD was significantly reduced (8.25 (5.32-12.06) % vs. 12.49 (7.18-16.58) %, p = 0.018) in the adipose group. PWV was markedly increased (4.65 (4.2-5.5) m/sec vs. 3.95 (3.38-4.35) m/sec, p < 0.001) in the hypertensive adipose children. Endothelial dysfunction parameters were not significantly changed in this study. CONCLUSION: Adipose children were at higher risk of hypertension and LV hypertrophy. FMD, PWV and traditional cardiovascular biomarkers can detect subtle vascular changes. Hypertension is an important sign of arterial involvement in adipose children. Although ADMA-related biomarkers were not statistically significant, future studies are needed to confirm its correlation with adiposity and hypertension in children. The early detection and prevention of endothelial dysfunction may decrease the rate of progression to cardiovascular consequences in later life.

The Association between Nitric Oxide Pathway, Blood Pressure Abnormalities, and Cardiovascular Risk Profile in Pediatric Chronic Kidney Disease.

Cardiovascular disease (CVD) is common in chronic kidney disease (CKD), while major CV events are rare in young CKD patients. In addition to nitric oxide (NO)-related biomarkers, several surrogate markers have been assessed to stratify CV risk in youth with CKD, including 24-h ambulatory blood pressure monitoring (ABPM), carotid artery intima-media thickness (cIMT), pulse wave velocity (PWV), ABPM-derived arterial stiffness index (AASI), flow-mediated dilatation (FMD), and left ventricular mass index (LVMI). The aim of this study was to identify subclinical CVD through the analysis of indices of CV risk in children and adolescents with CKD. Between 2016 and 2018, the prospective observational study enrolled 125 patients aged 3 to 18 years with G1-G4 CKD stages. Close to two-thirds of young patients with CKD exhibited blood pressure (BP) abnormalities on ABPM. CKD children with abnormal office BP showed lower plasma arginine levels and arginine-to-asymmetric dimethylarginine (ADMA) ratio, but higher ratios of ADMA-to-symmetric dimethylarginine (SDMA) and citrulline-to-arginine. High PWV and AASI, indices of arterial stiffness, both strongly correlated with high BP load. Additionally, LV mass and LVMI exhibited strong correlations with high BP load. Using an adjusted regression model, we observed the citrulline-to-arginine ratio was associated with 24-h systolic and diastolic BP, systolic blood pressure (SBP) load, and diastolic blood pressure (DBP) load. Early assessments of NO-related parameters, BP load abnormalities, arterial stiffness indices, and LV mass will aid in early preventative care toward decreasing CV risk later in life for children and adolescents with CKD.

Early short-term treatment with exogenous hydrogen sulfide postpones the transition from prehypertension to hypertension in spontaneously hypertensive rat.

ABSTACT Hydrogen sulfide (H2S), nitric oxide (NO), and renin-angiotensin system (RAS) are involved in hypertension. We examined whether early treatment with sodium hydrosulfide (NaHS), an exogenous H2S donor, can regulate H2S-generating pathway, NO pathway, and the RAS, to prevent the transition from prehypertension to hypertension in spontaneously hypertensive rats (SHRs). Four-week-old SHRs and control normotensive Wistar-Kyoto (WKY) rats were assigned into three groups: WKY, SHRs, and SHR + NaHS; SHRs were injected intraperitoneally with sodium hydrosulfide (14 µmol/kg/day) for 4 weeks. SHRs exhibited hypertension at 12 weeks of age, which was blocked by early sodium hydrosulfide administration. Concentrations of H2S were increased in the kidney in SHR + NaHS group versus WKY. Sodium hydrosulfide reduces mRNA expression of four H2S-generating enzymes and decreased 3-mercaptopyruvate sulphurtransferase protein level in SHRs. Early administration of sodium hydrosulfide decreases plasma NG monomethyl-l-arginine (l-NMMA, an inhibitor of NO synthase) level and increases plasma NO level in SHRs. Next, sodium hydrosulfide administration reduces renal mRNA expression of Ren, Atp6ap2, Agt, Ace, and Agtr1a in SHRs. We conclude that early short-term sodium hydrosulfide treatment increases renal H2S concentrations, restores NO bioavailability, and blocks the RAS in the kidney, in favor of vasodilatation to prevent the development of hypertension in adult SHRs.

Maternal Resveratrol Therapy Protects Male Rat Offspring against Programmed Hypertension Induced by TCDD and Dexamethasone Exposures: Is It Relevant to Aryl Hydrocarbon Receptor?

Hypertension can originate from early-life adverse environmental in utero exposure to dexamethasone (DEX) or 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Since DEX and TCDD are related to the aryl hydrocarbon receptor (AHR) signaling pathway, we examined whether resveratrol, an AHR modulator and antioxidant, could prevent programmed hypertension via regulating AHR signaling and oxidative stress. Groups of four-month-old male rat offspring were studied (n = 7⁻8 per group): control, DEX (0.1 mg/kg i.p. from a gestational age of 16 to 22 days), TCDD (200 ng/kg in four once-weekly oral doses), DEX + TCDD, and DEX + TCDD + R (resveratrol 0.05% in drinking water throughout pregnancy and lactation). Maternal TCDD exposure aggravated prenatal DEX-induced hypertension in adult male offspring, which maternal resveratrol therapy prevented. Maternal TCDD exposure aggravated DEX-induced oxidative damage in offspring kidneys, which was prevented by resveratrol therapy. Maternal resveratrol therapy decreased asymmetric and symmetric dimethylarginine (ADMA and SDMA) levels, thereby preventing combined DEX and TCDD exposure-induced programmed hypertension. Increases in renal Ahrr and Cyp1a1 expression induced by DEX + TCDD exposure were restored by resveratrol therapy. The beneficial effects of resveratrol on DEX + TCDD-induced hypertension relate to reduced renal mRNA expression of Ren, Ace, and Agtr1a expression. Thus, the beneficial effects of resveratrol on DEX + TCDD-induced hypertension include reduction of oxidative stress, restoration of nitric oxide (NO) bioavailability, blockade of the renin⁻angiotensin system (RAS), and antagonizing AHR signaling pathway.

Gut Microbiota-Dependent Trimethylamine N-Oxide Pathway Associated with Cardiovascular Risk in Children with Early-Stage Chronic Kidney Disease.

Despite cardiovascular disease (CVD) being the leading cause of morbidity and mortality in chronic kidney disease (CKD), less attention has been paid to subclinical CVD in children and adolescents with early CKD stages. Gut microbiota and their metabolite, trimethylamine N-oxide (TMAO), have been linked to CVD. Ambulatory blood-pressure monitoring (ABPM) and arterial-stiffness assessment allow for early detection of subclinical CVD. We therefore investigated whether gut microbial composition and TMAO metabolic pathway are correlated with blood-pressure (BP) load and vascular abnormalities in children with early-stage CKD. We enrolled 86 children with G1⁻G3 CKD stages. Approximately two-thirds of CKD children had BP abnormalities on ABPM. Children with CKD stage G2⁻G3 had a higher uric acid level (6.6 vs. 4.8 mg/dL, p < 0.05) and pulse-wave velocity (4.1 vs. 3.8 m/s, p < 0.05), but lower TMAO urinary level (209 vs. 344 ng/mg creatinine, p < 0.05) than those with stage G1. Urinary TMAO level was correlated with the abundances of genera Bifidobacterium (r = 0.307, p = 0.004) and Lactobacillus (r = 0.428, p < 0.001). CKD children with abnormal ABPM profile had a lower abundance of the Prevotella genus than those with normal ABPM (p < 0.05). Our results highlight the link between gut microbiota, microbial metabolite TMAO, BP load, and arterial-stiffness indices in children with early-stage CKD. Early assessments of these surrogate markers should aid in decreasing cardiovascular risk in childhood CKD.

Early postnatal treatment with soluble epoxide hydrolase inhibitor or 15-deoxy-Δ(12,14)-prostagandin J2 prevents prenatal dexamethasone and postnatal high saturated fat diet induced programmed hypertension in adult rat offspring.

Prenatal dexamethasone (DEX) exposure, postnatal high-fat (HF) intake, and arachidonic acid pathway are closely related to hypertension. We tested whether a soluble epoxide hydrolase (SEH) inhibitor, 12-(3-adamantan-1-yl-ureido)-dodecanoic acid (AUDA) or 15-deoxy-Δ(12,14)-prostagandin J2 (15dPGJ2) therapy can rescue programmed hypertension in the DEX+HF two-hit model. Four groups of Sprague Dawley rats were studied: control, DEX+HF, AUDA, and 15dPGJ2. Dexamethasone (0.1mg/kg body weight) was intraperitoneally administered to pregnant rats from gestational day 16-22. Male offspring received high-fat diet (D12331, Research Diets) from weaning to 4 months of age. In AUDA group, mother rats received 25mg/L in drinking water during lactation. In the 15dPGJ2 group, male offspring received 15dPGJ2 1.5mg/kg BW by subcutaneous injection once daily for 1 week after birth. We found postnatal HF diet aggravated prenatal DEX-induced programmed hypertension, which was similarly prevented by early treatment with AUDA or 15dPGJ2. The beneficial effects of AUDA and 15d-PGJ2 therapy include inhibition of SEH, increases of renal angiotensin converting enzyme-2 (ACE2) and angiotensin II type 2 receptor (AT2R) protein levels, and restoration of nitric oxide bioavailability. Better understanding of the impact of arachidonic acid pathway in the two-hit model will help prevent programmed hypertension in children exposed to corticosteroids and postnatal HF intake.