Plasma metabolites and physical function in patients undergoing hemodialysis.

Impaired physical function contributes to falls, fractures, and mortality among patients undergoing dialysis. Using a metabolomic approach, we identified metabolite alterations and effect size-based composite scores for constructs of impaired gait speed and grip strength. 108 participants incident to dialysis had targeted plasma metabolomics via liquid chromatography-mass spectrometry and physical function assessed (i.e., 4 m walk, handgrip strength). Physical function measures were categorized as above/ below median, with grip utilizing sex-based medians. To develop composite scores, metabolites were identified via Wilcoxon uncorrected p < 0.05 and effect size > 0.40. Receiver operating characteristic analyses tested whether scores differentiated between above/below function groups. Participants were 54% male, 77% Black and 53 ± 14 y with dialysis vintage of 101 ± 50 days. Median (IQR) grip strength was 35.5 (11.1) kg (males) and 20 (8.4) kg (females); median gait speed was 0.82 (0.34) m/s. Of 246 measured metabolites, composite scores were composed of 22 and 12 metabolites for grip strength and gait speed, respectively. Area under the curve for metabolite composite was 0.88 (gait) and 0.911 (grip). Composite scores of physical function performed better than clinical parameters alone in patients on dialysis. These results provide potential pathways for interventions and needed validation in an independent cohort.

Musculoskeletal Health Worsened from Carnitine Supplementation and Not Impacted by a Novel Individualized Treadmill Training Protocol.

INTRODUCTION: Chronic kidney disease (CKD) negatively affects musculoskeletal health, leading to reduced mobility, and quality of life. In healthy populations, carnitine supplementation and aerobic exercise have been reported to improve musculoskeletal health. However, there are inconclusive results regarding their effectiveness and safety in CKD. We hypothesized that carnitine supplementation and individualized treadmill exercise would improve musculoskeletal health in CKD. METHODS: We used a spontaneously progressive CKD rat model (Cy/+ rat) (n = 11-12/gr): (1) Cy/+ (CKD-Ctrl), (2) CKD-carnitine (CKD-Carn), and (3) CKD-treadmill (CKD-TM). Carnitine (250 mg/kg) was injected daily for 10 weeks. Rats in the treadmill group ran 4 days/week on a 5° incline for 10 weeks progressing from 30 min/day for week one to 40 min/day for week two to 50 min/day for the remaining 8 weeks. At 32 weeks of age, we assessed overall cardiopulmonary fitness, muscle function, bone histology and architecture, and kidney function. Data were analyzed by one-way ANOVA with Tukey's multiple comparisons tests. RESULTS: Moderate to severe CKD was confirmed by biochemistries for blood urea nitrogen (mean 43 ± 5 mg/dL CKD-Ctrl), phosphorus (mean 8 ± 1 mg/dL CKD-Ctrl), parathyroid hormone (PTH; mean 625 ± 185 pg/mL CKD-Ctrl), and serum creatinine (mean 1.1 ± 0.2 mg/mL CKD-Ctrl). Carnitine worsened phosphorous (mean 11 ± 3 mg/dL CKD-Carn; p < 0.0001), PTH (mean 1,738 ± 1,233 pg/mL CKD-Carn; p < 0.0001), creatinine (mean 1 ± 0.3 mg/dL CKD-Carn; p < 0.0001), cortical bone thickness (mean 0.5 ± 0.1 mm CKD-Ctrl, 0.4 ± 0.1 mm CKD-Carn; p < 0.05). Treadmill running significantly improves maximal aerobic capacity when compared to CKD-Ctrl (mean 14 ± 2 min CKD-TM, 10 ± 2 min CKD-Ctrl; p < 0.01). CONCLUSION: Carnitine supplementation worsened CKD progression, mineral metabolism biochemistries, and cortical porosity and did not have an impact on physical function. Individualized treadmill running improved maximal aerobic capacity but did not have an impact on CKD progression or bone properties. Future studies should seek to better understand carnitine doses in conditions of compromised renal function to prevent toxicity which may result from elevated carnitine levels and to optimize exercise prescriptions for musculoskeletal health.

Phosphate in Cardiovascular Disease: From New Insights Into Molecular Mechanisms to Clinical Implications.

Hyperphosphatemia is a common feature in patients with impaired kidney function and is associated with increased risk of cardiovascular disease. This phenomenon extends to the general population, whereby elevations of serum phosphate within the normal range increase risk; however, the mechanism by which this occurs is multifaceted, and many aspects are poorly understood. Less than 1% of total body phosphate is found in the circulation and extracellular space, and its regulation involves multiple organ cross talk and hormones to coordinate absorption from the small intestine and excretion by the kidneys. For phosphate to be regulated, it must be sensed. While mostly enigmatic, various phosphate sensors have been elucidated in recent years. Phosphate in the circulation can be buffered, either through regulated exchange between extracellular and cellular spaces or through chelation by circulating proteins (ie, fetuin-A) to form calciprotein particles, which in themselves serve a function for bulk mineral transport and signaling. Either through direct signaling or through mediators like hormones, calciprotein particles, or calcifying extracellular vesicles, phosphate can induce various cardiovascular disease pathologies: most notably, ectopic cardiovascular calcification but also left ventricular hypertrophy, as well as bone and kidney diseases, which then propagate phosphate dysregulation further. Therapies targeting phosphate have mostly focused on intestinal binding, of which appreciation and understanding of paracellular transport has greatly advanced the field. However, pharmacotherapies that target cardiovascular consequences of phosphate directly, such as vascular calcification, are still an area of great unmet medical need.

Am I big boned? Bone length scaled reference data for HRpQCT measures of the radial and tibial diaphysis in White adults.

Cross-sectional size of a long bone shaft influences its mechanical properties. We recently used high-resolution peripheral quantitative computed tomography (HRpQCT) to create reference data for size measures of the radial and tibial diaphyses. However, data did not take into account the impact of bone length. Human bone exhibits relatively isometric allometry whereby cross-sectional area increases proportionally with bone length. The consequence is that taller than average individuals will generally have larger z-scores for bone size outcomes when length is not considered. The goal of the current work was to develop a means of determining whether an individual's cross-sectional bone size is suitable for their bone length. HRpQCT scans performed at 30 % of bone length proximal from the distal end of the radius and tibia were acquired from 1034 White females (age = 18.0 to 85.3 y) and 392 White males (age = 18.4 to 83.6 y). Positive relationships were confirmed between bone length and cross-sectional areas and estimated mechanical properties. Scaling factors were calculated and used to scale HRpQCT outcomes to bone length. Centile curves were generated for both raw and bone length scaled HRpQCT data using the LMS approach. Excel-based calculators are provided to facilitate calculation of z-scores for both raw and bone length scaled HRpQCT outcomes. The raw z-scores indicate the magnitude that an individual's HRpQCT outcomes differ relative to expected sex- and age-specific values, with the scaled z-scores also considering bone length. The latter enables it to be determined whether an individual or population of interest has normal sized bones for their length, which may have implications for injury risk. In addition to providing a means of expressing HRpQCT bone size outcomes relative to bone length, the current study also provides centile curves for outcomes previously without reference data, including tissue mineral density and moments of inertia.

The Dietary Fiber Inulin Slows Progression of Chronic Kidney Disease-Mineral Bone Disorder (CKD-MBD) in a Rat Model of CKD.

Chronic kidney disease (CKD)-mineral bone disorder (CKD-MBD) leads to fractures and cardiovascular disease. Observational studies suggest beneficial effects of dietary fiber on both bone and cardiovascular outcomes, but the effect of fiber on CKD-MBD is unknown. To determine the effect of fiber on CKD-MBD, we fed the Cy/+ rat with progressive CKD a casein-based diet of 0.7% phosphate with 10% inulin (fermentable fiber) or cellulose (non-fermentable fiber) from 22 weeks to either 30 or 32 weeks of age (~30% and ~15% of normal kidney function; CKD 4 and 5). We assessed CKD-MBD end points of biochemistry, bone quantity and quality, cardiovascular health, and cecal microbiota and serum gut-derived uremic toxins. Results were analyzed by two-way analysis of variance (ANOVA) to evaluate the main effects of CKD stage and inulin, and their interaction. The results showed that in CKD animals, inulin did not alter kidney function but reduced the increase from stage 4 to 5 in serum levels of phosphate and parathyroid hormone, but not fibroblast growth factor-23 (FGF23). Bone turnover and cortical bone parameters were similarly improved but mechanical properties were not altered. Inulin slowed progression of aorta and cardiac calcification, left ventricular mass index, and fibrosis. To understand the mechanism, we assessed intestinal microbiota and found changes in alpha and beta diversity and significant changes in several taxa with inulin, together with a reduction in circulating gut derived uremic toxins such as indoxyl sulfate and short-chain fatty acids. In conclusion, the addition of the fermentable fiber inulin to the diet of CKD rats led to a slowed progression of CKD-MBD without affecting kidney function, likely mediated by changes in the gut microbiota composition and lowered gut-derived uremic toxins. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.