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.

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.

The Dietary Fermentable Fiber Inulin Alters the Intestinal Microbiome and Improves Chronic Kidney Disease Mineral-Bone Disorder in a Rat Model of CKD.

Background: Dietary fiber is important for a healthy diet, but intake is low in CKD patients and the impact this has on the manifestations of CKD-Mineral Bone Disorder (MBD) is unknown. Methods: The Cy/+ rat with progressive CKD was fed 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). We assessed CKD-MBD, cecal microbiota, and serum gut-derived uremic toxins. Two-way ANOVA was used to evaluate the effect of age and inulin diet, and their interaction. Results: In CKD animals, dietary inulin led to changes in microbiota alpha and beta diversity at 30 and 32 weeks, with higher relative abundance of several taxa, including Bifidobacterium and Bacteroides , and lower Lactobacillus . Inulin reduced serum levels of gut-derived uremic toxins, phosphate, and parathyroid hormone, but not fibroblast growth factor-23. Dietary inulin decreased aorta and cardiac calcification and reduced left ventricular mass index and cardiac fibrosis. Bone turnover and cortical bone parameters were improved with inulin; however, bone mechanical properties were not altered. Conclusions: The addition of the fermentable fiber inulin to the diet of CKD rats led to changes in the gut microbiota composition, lowered gut-derived uremic toxins, and improved most parameters of CKD-MBD. Future studies should assess this fiber as an additive therapy to other pharmacologic and diet interventions in CKD. Significance Statement: Dietary fiber has well established beneficial health effects. However, the impact of fermentable dietary fiber on the intestinal microbiome and CKD-MBD is poorly understood. We used an animal model of progressive CKD and demonstrated that the addition of 10% of the fermentable fiber inulin to the diet altered the intestinal microbiota and lowered circulating gut-derived uremic toxins, phosphorus, and parathyroid hormone. These changes were associated with improved cortical bone parameters, lower vascular calcification, and reduced cardiac hypertrophy, fibrosis and calcification. Taken together, dietary fermentable fiber may be a novel additive intervention to traditional therapies of CKD-MBD.