Fibroblast growth factor-23 (FGF23) was initially identified as the causative factor of autosomal dominant hypophosphatemic rickets. Further studies confirmed that FGF23 is predominantly expressed in the osteocytes and osteoblasts of bone and that circulating FGF23 acts on the kidney to inhibit renal phosphate reabsorption and 1,25(OH)2D3 hydroxylation. With the progression of chronic kidney disease (CKD), the kidneys become insufficient to maintain a normal systemic mineral homeostasis, resulting in various abnormalities of bone and mineral metabolism, generally referred to as Chronic Kidney Disease – Mineral and Bone Disorders (CKD-MBD). FGF23 increases early in the course of CKD in order to maintain normal serum phosphate levels; long before a significant increase in serum phosphate can be detected. Recent studies suggest that increased FGF23 levels are associated with progression of CKD, mortality, and the development of refractory secondary hyperparathyroidism. Because FGF23 is the very earliest marker of CKD-MBD, it is of particular interest to evaluate the relation between FGF23 and CKD-MBD abnormalities, in the setting of early CKD and also in individuals with normal renal function. In the present work, we show that FGF23 is linked to several dynamic measurements of vascular function, including endothelial dysfunction, arterial stiffness, and atherosclerosis. FGF23 is also positively associated with left ventricular mass index and an increased risk of having left ventricular hypertrophy. All associations were independent of serum phosphate and were strengthened in subjects with diminished renal function. Furthermore, we found significant evidence for an association between higher FGF23 and increased fat mass and dyslipidemia, which could represent a novel pathway linking FGF23 to cardiovascular disease. Finally, we show that FGF23 is a significant predictor of future fracture risk. Although these associations could be reflecting the increased risk associated with hyperphosphatemia and calcitriol deficiency, current evidence points towards FGF23 being more than an innocent bystander. At the very least, FGF23 holds promise of being a bio-marker of cardiovascular status and phosphate-related toxicity both in CKD and in the general population, and might be a therapeutic target that could improve the fatal prognosis in CKD patients.

Background: Amyloid transthyretin (ATTR) cardiomyopathy is caused by the deposition of misfolded proteins, known as amyloid fibrils, in the myocardium. Quantitative Single Photon Emission Computed Tomography (QSPECT) utilizing 99mTc-DPD scintigraphy has the potential to assess ATTR-suspected cardiac amyloidosis (CA). This method could offer improved risk stratification and therapy response monitoring compared to the established Perugini score system. The primary objective of this study is to evaluate the feasibility of employing a quantitative approach and correlating various parameters with LVMI (left ventricular mass index). Method: Initially, planar and volumetric sensitivity measurements were conducted, followed by verification of accuracy measurements. Several torso phantom acquisitions were then performed to evaluate the accuracy and repeatability in terms of recovery coefficient (RC) and repeatability deviation (RD). This served as the foundation for the subsequent in vivo quantification. In this retrospective study, 10 patients underwent 99mTc-DPD scintigraphy, including SPECT/CT of the thorax and echocardiography examinations, as part of a clinical routine for suspected CA. The myocardial SUVmax was determined using a semi-automatic segmentation of the entire heart, excluding the descending and ascending aortas. The bone uptake was also quantified using the SUVmean parameter within the automatically delineated volume of all bones. This enabled the determination of the normalized uptake value nSUVmax, (SUVmax to SUVmean bone). Moreover, an attempt was made to apply an automatic segmentation of the myocardium based on 26% and 36% thresholds, which were developed from the torso phantom acquisitions. This approach allowed for the utilization of the injected dose (ID). Results: The planar calibration factor (CF) exceeded the volumetric cross-calibration factor (CCF) by 3.4%. The anthropomorphic phantom exhibited an underestimation of approximately 50% in the myocardium and around 21% in the kidneys. The average RD in the myocardium and kidneys was 2.3% and 1.6%, respectively. A significant quantitative separation was observed between the ATTR and control groups, comprising 6 and 4 patients, respectively (p<0.01 for SUVmax and nSUVmax, and p<0.02 for SUVmean bone). Correlation analysis revealed a weak positive correlation between SUVmax and LVMI; however, the correlation was not statistically significant (ρ = 0.31, p = 0.39). The ID in the 26% and 36% threshold-based segmented myocardium showed a relatively lower negative correlation with LVMI; although this was observed in the small ATTR cohort and was not statistically significant. The latter outcome resulted from the automatic-delineation method, which was unable to segment grade 0 and 1 patients. Conclusion: This study suggests that both CFs can be used in QSPECT. The phantom measurements indicate good repeatability and a significant quantitative underestimation, primarily due to the partial volume effect (PVE). Size and shape-specific PVE corrections, encompassing various activity concentrations of myocardium-to-blood pool ratios, are essential in QSPECT of the myocardium. Moreover, quantitative SPECT/CT utilizing 99mTc-DPD scintigraphy can effectively distinguish between patients with grade 0/1 and those with grade 2/3. This approach has the potential to enhance diagnostic accuracy and improve risk stratification.

Short summary: Background: High cardiovascular risk in patients with chronic kidney disease is partly due to mineral dysbalance, microinflammation and oxidative stress. CKD patients accumulate traditional and non-traditional CV risk factors. FGF23, MMPs and PlGF belong among these non-traditional biomarkers of CV risk. FGF23 is a phosphaturic hormone and inhibitor of calcitriol synthesis. It is associated with vascular calcifications. Matrix-metalloproteinases (e.g. MMP-2, MMP-9) are proteolytic, proinflammatory enzymes, contributing to myocardial remodelation. Placental growth factor (PlGF) is a proangiogenic cytokine that is associated with LV hypertrophy in animal model. Plasmatic FGF23, MMPs and PlGF are elevated in CKD. Aim: We aimed to describe dynamic changes between several novel biomarkers of CV risk (FGF23, MMP-2, MMP-9 and PlGF) in CKD stages 1-5, to describe their mutual correlations and possible association with traditional CV risk markers. We studied possible association of laboratory and echocardiographic parameters in patients with CKD stages 2-4. Methods: In a cross-sectional study we evaluated 80 patiens with CKD 1-5 and 44 healthy controls. In a prospective study we evaluated echocardiographic and laboratory parameters in 62 patients with CKD 2-4 for an average study period of 36±10...

Short summary: Background: High cardiovascular risk in patients with chronic kidney disease is partly due to mineral dysbalance, microinflammation and oxidative stress. CKD patients accumulate traditional and non-traditional CV risk factors. FGF23, MMPs and PlGF belong among these non-traditional biomarkers of CV risk. FGF23 is a phosphaturic hormone and inhibitor of calcitriol synthesis. It is associated with vascular calcifications. Matrix-metalloproteinases (e.g. MMP-2, MMP-9) are proteolytic, proinflammatory enzymes, contributing to myocardial remodelation. Placental growth factor (PlGF) is a proangiogenic cytokine that is associated with LV hypertrophy in animal model. Plasmatic FGF23, MMPs and PlGF are elevated in CKD. Aim: We aimed to describe dynamic changes between several novel biomarkers of CV risk (FGF23, MMP-2, MMP-9 and PlGF) in CKD stages 1-5, to describe their mutual correlations and possible association with traditional CV risk markers. We studied possible association of laboratory and echocardiographic parameters in patients with CKD stages 2-4. Methods: In a cross-sectional study we evaluated 80 patiens with CKD 1-5 and 44 healthy controls. In a prospective study we evaluated echocardiographic and laboratory parameters in 62 patients with CKD 2-4 for an average study period of 36±10...