Background: Previous studies from our laboratory have shown that hyperinsulinemia and insulin resistance (IR) are elevated in obese Dahl salt-sensitive (SS) leptin receptor mutant (SS LepR mutant) rats compared to SS rats before puberty. Clinical studies suggest that time-restricted feeding improves insulin sensitivity and is considered beneficial in obese patients. Therefore, the current study examined whether time-restricted feeding improves IR and reduces renal injury in obese SS LepR mutant rats prior to puberty. Methods: Four-week-old SS and SS LepR mutant rats were given either ad libitum access to food for 24 hours (control) or 8 hours each day during their active phase time-restricted feeding for 4 weeks. Metabolic parameters, insulin sensitivity, renal function and injury, proximal tubular SGLT2 expression, inflammation, and mitochondrial bioenergetics were assessed at the end of the study. Results: Body weight and food intake were significantly elevated in SS LepR mutant compared to SS rats, and time-restricted feeding did not affect either parameter. Fasting blood glucose levels were normal (≤120 mg/dL) in all groups. HOMA-IR (marker of IR) was significantly elevated in SS LepR mutant rats versus SS rats, and time-restricted feeding significantly reduced HOMA-IR only in SS LepR mutant rats. Proteinuria was significantly higher in SS LepR mutant rats vs SS rats (361±32 vs. 17±4 mg/day, respectively), and time-restricted feeding markedly reduced proteinuria in SS LepR mutant rats (144±19 mg/day). We observed a 2-fold increase in GFR in SS LepR mutant rats compared to SS rats indicating renal hyperfiltration. Time-restricted feeding prevented renal hyperfiltration in SS LepR mutant rats. Renal tubular sodium–glucose cotransporter 2 (SGLT2) expression was markedly increased in SS LepR mutant rats relative to SS rats and was notably reduced by time-restricted feeding in the SS LepR mutant rats. When measuring mitochondrial function, there was a tendency of OCR to be reduced in SS LepR mutant rats compared to SD rats, indicating impaired mitochondrial function, but time-restricted feeding significantly increased baseline OCR in SS LepR mutant rats. Conclusions: Overall, these data suggest that time-restricted feeding reduces proteinuria by potentially improving insulin sensitivity and tubular mitochondrial function indicating TRF could be of great potential in obese children with early signs of renal injury.
Background: Arteriovenous fistulas (AVFs) and grafts (AVGs) are the preferred long-term hemodialysis access for the majority of patients, but produce hemodynamic changes that contribute to cardiac complications including heart failure, pulmonary hypertension, and atrial arrhythmia. This cohort study leverages nationwide claims data to examine adverse cardiac events associated with AVGs and AVFs among patients with ESKD. Methods: We performed a retrospective cohort study using 100% Medicare fee-for-service claims to identify adults with ESKD undergoing AVF or AVG creation from 2017−2024. The primary outcome was hospitalization for a composite adverse cardiac event (heart failure, pulmonary hypertension, or atrial fibrillation or flutter) within 1 year. Secondary outcomes included the composite outcome through 5 years, its individual components, all-cause hospitalization, and flow-reduction procedures. Cumulative incidence functions were estimated using Fine-Gray subdistribution hazard models. Independent variable analyses were conducted for the primary outcome. Results: We identified 210,002 accesses (mean age 66.3 years; 43% female) including 147,709 (70%) AVFs and 62,293 (30%) AVGs. AVG recipients had a greater burden of baseline comorbidity and cardiovascular disease. Through 1 year, the cumulative incidence of hospitalization for an adverse cardiac event was 40% (AVF 39%, AVG 44%, P < .001), constituting 61% of all-cause hospitalizations. Heart failure predominated (AVF 33%, AVG 37%, P < .001), followed by atrial fibrillation or flutter (AVF 19%, AVG 21%, P < .001), and pulmonary hypertension (AVF 8%, AVG 9%, P < .001). Older age (≥ 50 years), AVG creation, pre-existing pulmonary hypertension, and atrial arrhythmia were independently associated with a higher hazard of the primary outcome (P < .05). Conclusions: The high rate of hospitalization for adverse cardiac events in the first year after arteriovenous access creation supports consideration of strategies (e.g., lower-flow forearm access, flow-volume surveillance) to mitigate the hemodynamic consequences of long-term arteriovenous access.
Background: Large-scale genome-wide association studies (GWAS) have identified hundreds of genetic loci associated with kidney function. However, most polygenic risk score models for kidney function were developed in European populations, limiting their accuracy in non-European groups. This study aimed to validate the clinical utility of polygenic risk scores for kidney function decline in the Japanese general population. Methods: We analyzed the Shika resident cohort cross-sectional and the Toshiba worker cohort prospectively to construct polygenic risk score models based on GWAS data from Japanese populations incorporating 344,577 and 352,151 genetic variants, respectively. The primary outcome was kidney function decline, defined as eGFR <60 mL/min/1.73 m 2 . With adjustments for traditional risk factors, multivariate logistic regression and Cox proportional hazards models were used to assess associations between the polygenic risk score and kidney function decline. Results: In the Shika resident cohort (n = 895, mean age 62 years), 157 participants (18%) had eGFR <60 mL/min/1.73 m 2 ; each standard deviation (SD) increase in the polygenic risk score conferred 55% higher odds (OR 1.55, 95% CI 1.28–1.89). In the Toshiba worker cohort (n = 6,769, mean age 40 years), 1,593 participants (24%) developed eGFR <60 mL/min/1.73 m 2 over median 8.3-year follow-up; each SD increase in the polygenic risk score was associated with 16% higher risk (HR 1.16, 95% CI 1.10–1.22). Adding the polygenic risk score to clinical models was associated with improved integrated discrimination in both cohorts, but the overall improvement in predictive ability was limited. Conclusions: The polygenic risk score was independently associated with kidney function decline beyond established risk factors and was associated with modestly improved risk prediction accuracy in Japanese populations, supporting its potential utility for personalized chronic kidney disease management.
Background: Gitelman syndrome and pseudo-Gitelman syndrome share overlapping biochemical abnormalities, complicating clinical differentiation and genetic testing allocation. While Gitelman syndrome impairs health-related quality of life (QOL), the comparable burden in pseudo-Gitelman syndrome remains unclear. We compared QOL burden and symptom profiles between individuals with genetically confirmed Gitelman syndrome and those classified as pseudo-Gitelman syndrome. Methods: We evaluated 128 participants aged ≥10 years referred for genetic testing due to suspected Gitelman syndrome (hypokalemia and metabolic alkalosis). Participants were divided into a Gitelman syndrome subgroup (genetically confirmed biallelic SLC12A3 variants; n=66) and a pseudo-Gitelman syndrome subgroup (no disease-causing variants; n=62). Seventy controls were frequency-matched to Gitelman syndrome by age and sex. QOL and clinical manifestations were assessed using a structured 21-item questionnaire covering taste, urinary, muscle, and nonspecific symptom domains. To limit false-positive findings from multiple comparisons, P values were adjusted using the Benjamini–Hochberg procedure; the resulting adjusted P values (q values) <0.05 were considered statistically significant. Results: Total QOL scores indicated significant and comparable impairment in both the Gitelman syndrome and pseudo-Gitelman syndrome subgroups versus controls (both q <0.001), with no significant difference between the affected groups ( q = 0.33). Despite similar overall burdens, specific clinical features differed between the groups. Nocturnal enuresis scores were higher in Gitelman syndrome group than in pseudo-Gitelman syndrome group and controls (both q < 0.001); 50% of Gitelman syndrome participants reported persistence at least until elementary school entry. The taste-related domain was higher in Gitelman syndrome group than in pseudo-Gitelman syndrome group ( q = 0.01), but no individual taste item differed after correction. Conclusions: Individuals with pseudo-Gitelman syndrome experienced QOL impairment comparable to those with genetically confirmed Gitelman syndrome. However, the severity and duration of nocturnal enuresis and overall taste-related symptom burden were prominent descriptive features of Gitelman syndrome. Systematic symptom assessment may contribute to a more comprehensive clinical characterization of individuals with suspected Gitelman syndrome.
