FGF23-klotho axis, bone fractures, and arterial stiffness in dialysis: a case-control study.

We performed a case-control study on 130 age- and sex-matched hemodialysis patients. In multivariate analysis, we observed that FGF23 levels were associated with fracture incidence and that soluble α-klotho levels were associated with the aortic-brachial arterial stiffness ratio. INTRODUCTION: New bone markers such as sclerostin, Dickkopf-related protein 1 (DKK1), fibroblast growth factor-23 (FGF23), and α-klotho have been identified as potential key players in bone and vascular abnormalities of chronic kidney disease. Therefore, we aimed to assess whether these markers are associated with fractures, bone metabolism, and vascular stiffness in dialysis patients. METHODS: In a prospective hemodialysis cohort, where plasma samples and vascular assessment were performed at baseline, we matched patients who experienced a fracture during follow-up with sex- and age-matched non-fractured patients on a 1:4 ratio. Sclerostin, DKK1, α-klotho, FGF23, and markers of bone formation (alkaline phosphatase and procollagen type 1-N terminal propeptide [P1NP]) and bone resorption (tartrate-resistant acid phosphatase 5b [TRAP5b]) were measured in baseline plasma samples. Aortic-brachial pulse wave velocity ratio, a blood pressure independent measure of arterial stiffness, was used to assess vascular stiffness at baseline. RESULTS: We included 130 hemodialysis patients (26 fractured, 104 non-fractured) with a median follow-up of 42 months and a median age of 72 years. In multivariate Cox regression models, high FGF23 levels were associated with increased fracture incidence (adjusted HR = 2.97; 95% CI 1.18, 7.43). α-Klotho levels were associated with bone formation but not resorption markers. In both univariate and multivariable adjusted models, α-klotho levels were inversely associated with the aortic-brachial pulse wave velocity ratio (ß = - 0.070; 95% CI - 0.133, - 0.006). CONCLUSIONS: These results suggest a role for FGF23/klotho axis on bone and vascular metabolism in dialysis populations.

Tacrolimus prevents von Willebrand factor secretion by allostimulated human glomerular endothelium.

Little is known about the endothelial injury caused directly by circulating donor-specific antibodies (DSAs) during antibody-mediated rejection. von Willebrand factor (vWF) is a highly thrombotic glycoprotein stored in Weibel-Palade bodies in endothelial cells. It has been shown that its secretion is triggered by allostimulation. Calcineurin-like phosphatases regulate pathways involved in vWF secretion. Therefore, we hypothesized that tacrolimus would prevent alloantibody-induced glomerular lesions, in part via inhibition of vWF secretion from endothelial cells. Here, we used a human in vitro model of glomerular endothelium expressing HLA class I and II antigens and demonstrated that anti-HLA class II antibodies elicit a higher endothelial release of vWF than do anti-HLA class I antibodies in cell supernatants. We observed that tacrolimus treatment decreased vWF secretion after stimulation with both classes of anti-HLA antibodies and decreased platelet adhesion on allostimulated endothelial cells in a microfluidic chamber. In kidney recipients, tacrolimus trough levels were negatively associated with vWF blood levels. These results indicate that direct disruption of hemostasis via vWF secretion is a potential mechanism of antibody-mediated injury in patients with DSAs. Our results further suggest that the targeting of microcirculation hemostasis may be beneficial to prevent the development of microangiopathic lesions in antibody-mediated rejection.

Non-assisted treadmill training does not improve motor recovery and body composition in spinal cord-transected mice.

STUDY DESIGN: Experiments in a mouse model of complete paraplegia. OBJECTIVES: To evaluate the effect of non-assisted treadmill training on motor recovery and body composition in completely spinal cord-transected mice. SETTINGS: Laval University Medical Center, Neuroscience Unit, Quebec City, Quebec, Canada. METHODS: Following a complete low-thoracic (Th9/10) spinal transection (Tx), mice were divided into two groups that were either untrained or trained with no assistance. Training consisted of placing the mice during 15 min with no further intervention (that is no tail pinching or body weight support) on a motorized treadmill (8-10 cm s(-1)) five times per week for 5 weeks. Locomotor performances were assessed weekly in both groups using two complementary locomotor rating scales. After 5 weeks, all mice were killed and adipose tissue, soleus, and extensor digitorum longus muscles were dissected for analyses. RESULTS: No significant difference in locomotor performances or in muscle fibre type conversion was found between trained and untrained mice. In contrast, body weight, adipose tissue, whole muscle, and individual fibre cross-sectional area (CSA) values were significantly lower in trained compared with untrained animals. CONCLUSIONS: Non-assisted treadmill training in these conditions did not improve motor performances and contributed to further accentuate body composition changes post-Tx, suggesting that assistance provided manually, robotically, or pharmacologically may be key to spinal learning and recovery of locomotor function and body composition.

Early adaptive changes in chronic paraplegic mice: a model to study rapid health degradation after spinal cord injury.

STUDY DESIGN: Literature review. OBJECTIVE: To describe quantitatively some of most important anatomic, systemic, and metabolic changes occurring soon (one month) after spinal cord trauma in mice. SETTING: University Laval Medical Center. RESULTS: Significant changes in weight, mechanical and contractile muscle properties, bone histomorphometry and biomechanics, deep-vein morphology, complete blood count, immune cell count, lipid metabolism and anabolic hormone levels were found occurring within 1 month in completely spinal cord transected (Th9/10) mice. CONCLUSION: These data reveal that many changes in mice and humans are comparable suggesting, in turn, that this model may be a valuable tool for neuroscientists to investigate the specific mechanisms associated with rapid health degradation post-SCI.

Spontaneous recovery of hindlimb movement in completely spinal cord transected mice: a comparison of assessment methods and conditions.

STUDY DESIGN: To compare results obtained with a variety of locomotor rating scales in Th9/10 spinal cord transected (Tx) mice. OBJECTIVES: To assess spontaneous recovery with a variety of rating scales to find the most sensitive methods for assessing recovery levels in Tx mice and differences associated with gender and condition. SETTING: Laval University Medical Center, Neuroscience Unit & Laval University, Department of Anatomy and Physiology, Quebec City, Quebec, Canada. METHODS: Scales including the Basso, Beattie and Bresnahan (BBB), the Basso Mouse Score (BMS), the Antri, Orsal and Barthe (AOB), the Motor Function Score (MFS) and the Averaged Combined Score (ACOS) were used to assess, in open-field and treadmill conditions, spontaneous locomotor recovery in male and female Tx mice. RESULTS: The ACOS scale revealed a progressive increase of spontaneous recovery during 5-weeks post-Tx. The other methods detected a progressive increase for the first 2-3 weeks post-Tx without any significant progress in weeks 4 and 5. Generally, scores obtained with each method were nonsignificantly different between males and females or between open-field and treadmill conditions. CONCLUSION: These results further confirm the existence of a limited but significant increase of locomotor function recovery, occurring without intervention, in Tx animals. Although each method could detect small levels of recovery, the ACOS method was discriminative enough to detect progressive changes up to 5 weeks post-Tx. In conclusion, the ACOS rating scale was the most discriminative method for assessing the spontaneous return of hindlimb movements found in Tx mice, both in open-field and treadmill conditions.