Klotho and Clinical Outcomes in CKD: Findings From the Chronic Renal Insufficiency Cohort (CRIC) Study.

RATIONALE & OBJECTIVE: Klotho deficiency may affect clinical outcomes in chronic kidney disease (CKD) through fibroblast growth factor-23 (FGF23)-dependent and -independent pathways. However, the association between circulating Klotho and clinical outcomes in CKD remains unresolved and was the focus of this study. STUDY DESIGN: Prospective observational study. SETTING & PARTICIPANTS: 1,088 participants in the Chronic Renal Insufficiency Cohort (CRIC) Study with an estimated glomerular filtration rate (eGFR) of 20-70mL/min/1.73m2. EXPOSURE: Plasma Klotho level at the year-1 study visit. OUTCOMES: 5-year risks of all-cause mortality, heart failure hospitalization, atherosclerotic cardiovascular events, and a composite kidney end point that comprised a sustained 50% decrease in eGFR, dialysis, kidney transplant, or eGFR<15mL/min/1.73m2. ANALYTICAL APPROACH: We divided Klotho into 6 groups to account for its nonnormal distribution. We used Cox proportional hazards regression and subdistribution hazards models to compare survival and clinical outcomes, respectively, between Klotho groups. We sequentially adjusted for demographic characteristics, kidney function, cardiovascular risk factors, sample age, and FGF23. RESULTS: Mean eGFR was 42mL/min/1.73m2, and median Klotho concentration was 0.31ng/mL (IQR, 0.10-3.27ng/mL). When compared with the lowest Klotho group, survival (HR, 0.77; 95% CI, 0.32-1.89), heart failure hospitalization (HR, 1.10; 95% CI, 0.38-3.17), atherosclerotic cardiovascular events (HR, 1.19; 95% CI, 0.57-2.52), and CKD progression (HR, 1.05; 95% CI, 0.58-1.91) did not differ in the high Klotho group. In contrast, FGF23 was significantly associated with mortality and heart failure hospitalization independent of Klotho levels. LIMITATIONS: Despite adjustments, we cannot exclude the potential influence of residual confounding or sample storage on the results. A single measurement of plasma Klotho concentration may not capture Klotho patterns over time. CONCLUSIONS: In a large, diverse, well-characterized CKD cohort, Klotho was not associated with clinical outcomes, and Klotho deficiency did not confound the association of FGF23 with mortality or heart failure hospitalization. PLAIN-LANGUAGE SUMMARY: Klotho is a protein that is vital to mineral metabolism and aging and may protect against cardiovascular disease. Klotho levels decrease in chronic kidney disease (CKD), but the association between Klotho and clinical outcomes in CKD remains uncertain. In a prospective cohort study of more than 1,000 people with CKD, circulating Klotho levels were not associated with kidney disease progression, cardiovascular outcomes, or mortality. These results suggest that the decrease in circulating Klotho levels in CKD does not play a prominent role in the development of poor clinical outcomes.

Fibroblast Growth Factor (FGF) 23 and FGF Receptor 4 promote cardiac metabolic remodeling in chronic kidney disease.

Chronic kidney disease (CKD) is a global health epidemic that significantly increases mortality due to cardiovascular disease. Left ventricular hypertrophy (LVH) is an important mechanism of cardiac injury in CKD. High serum levels of fibroblast growth factor (FGF) 23 in patients with CKD may contribute mechanistically to the pathogenesis of LVH by activating FGF receptor (FGFR) 4 signaling in cardiac myocytes. Mitochondrial dysfunction and cardiac metabolic remodeling are early features of cardiac injury that predate development of hypertrophy, but these mechanisms of disease have been insufficiently studied in models of CKD. Wild-type mice with CKD induced by adenine diet developed LVH that was preceded by morphological changes in mitochondrial structure and evidence of cardiac mitochondrial and metabolic dysfunction. In bioengineered cardio-bundles and neonatal rat ventricular myocytes grown in vitro, FGF23-mediated activation of FGFR4 caused a mitochondrial pathology, characterized by increased bioenergetic stress and increased glycolysis, that preceded the development of cellular hypertrophy. The cardiac metabolic changes and associated mitochondrial alterations in mice with CKD were prevented by global or cardiac-specific deletion of FGFR4. These findings indicate that metabolic remodeling and eventually mitochondrial dysfunction are early cardiac complications of CKD that precede structural remodeling of the heart. Mechanistically, FGF23-mediated activation of FGFR4 causes mitochondrial dysfunction, suggesting that early pharmacologic inhibition of FGFR4 might serve as novel therapeutic intervention to prevent development of LVH and heart failure in patients with CKD.

Accuracy of non-invasive blood pressure monitoring in very preterm infants.

PURPOSE: Blood pressure (BP) monitoring is an essential procedure in intensive care. There is controversy about the reliability of non-invasive BP measurements in very preterm infants. This prospective trial compared non-invasive BP monitoring with BP monitoring via an umbilical arterial catheter (UAC) in this population. METHODS: Preterm infants born at less than 32 weeks gestation requiring a UAC for clinical management were eligible. Enrolled infants had up to three BP measurements on the right arm (RA) and right leg (RL) when in a resting state. UAC-BP measurements were noted immediately after the non-invasive BP was displayed on the monitor. Measurements were analysed in subgroups according to birth weight: no greater than 750 g, 751-1,000 g, above 1,000 g. Statistical analysis reports median, range, and Bland-Altman analysis. RESULTS: Sixty infants were included. Median (range) gestational age was 26.4 weeks (23.6, 31.2); birth weight 924 g (581, 1,518). A total of 1,865 measurements were performed (RA: 935, RL: 930). Mean difference (95% limits of agreement) for infants no greater than 750 g: RA 2.53 mmHg (-11.18, 16.24), RL -0.804 mmHg (-12.65, 11.04); for infants 751-1,000 g: RA 3.535 mmHg (-9.6, 16.7), RL -1.239 mmHg (-13.14, 10.66); for infants above 1,000 g: RA -1.65 mmHg (-13.47, 10.17), RL -4.101 mmHg (-14.17, 5.96). CONCLUSIONS: Although the average differences between invasive and non-invasive BP measurements are acceptable, the range of under- and overestimation of non-invasive BP measurements is large and not consistent, making reliance on non-invasive modalities to guide circulatory management problematic. If arterial BP monitoring is not available, our results suggest measuring non-invasive BP on the leg in preterm infants with a birth weight no greater than 1,000 g.