Bone Quality in Chronic Kidney Disease: Definitions and Diagnostics

PURPOSE OF REVIEW: In this paper, we review the epidemiology, diagnosis, and pathogenesis of fractures and renal osteodystrophy. RECENT FINDINGS: The role of bone quality in the pathogenesis of fracture susceptibility in chronic kidney disease (CKD) is beginning to be elucidated. Bone quality refers to bone material properties, such as cortical and trabecular microarchitecture, mineralization, turnover, microdamage, and collagen content and structure. Recent data has added to our understanding of the effects of CKD on alterations to bone quality, emerging data on the role of abnormal collagen structure on bone strength, the potential of non-invasive methods to inform our knowledge of bone quality, and how we can use these methods to inform strategies that protect against bone loss and fractures. However, more prospective data is required. CKD is associated with abnormal bone quality and strength which results in high fracture incidence

Early Miocene gastropod and ectothermic vertebrate remains from the Lesvos Petrified Forest (Greece)

The Lesvos Petrified Forest (western Lesvos, Greece) has long been famous for its plant fossils. Recently, one proboscidean (from the Gavathas locality) and seven micromammalian species (from the Lapsarna locality) were described; these were the first animals to be found in the Early Miocene subtropical forest. For the first time, a fauna of gastropods and ectothermic vertebrates from the Lapsarna locality is now available. This fauna derives from lacustrine sediments under the pyroclastic material that contains the petrified plants. Based on fragmented mollusc remains, isolated fish pharyngeal teeth and utricular otoliths (lapilli), fragmented amphibian vertebrae and a tooth-bearing element, and reptile fragmented dentaries, teeth, osteoderms and vertebrae, the presence of eight freshwater and three terrestrial gastropod species, three freshwater cyprinid species, and two amphibian and five reptile taxa has been confirmed. Stratigraphical and radiometric data suggest an age older than 18.4 ± 0.5 Ma (latest Early Miocene), in good agreement with the faunal composition. This paper is the first report of the concurrent presence of three cyprinid fish species in a Greek Early Miocene locality, as well as the first documentation of an Early Miocene proteid amphibian in southeastern Europe. The present findings represent one of the best- documented Early Miocene gastropod and fish faunas in the Aegean/southern Balkans, thus adding to our knowledge of Early Miocene amphibians and reptiles from that region and providing valuable information on the local subtropical ecosystem

Skeletal levels of bisphosphonate in the setting of chronic kidney disease are independent of remodeling rate and lower with fractionated dosing

Background Chronic kidney disease (CKD) results in a dramatic increase in skeletal fracture risk. Bisphosphates (BP) are an effective treatment for reducing fracture risk but they are not recommended in advanced CKD. We have recently shown higher acute skeletal accumulation of fluorescently-tagged zoledronate (ZOL) in the setting of CKD but how this accumulation is retained/lost over time is unclear. Furthermore, it is unknown if alternative dosing approaches can modulate accumulation in the setting of CKD. Methods To address these two questions normal (NL) and Cy/+ (CKD) rats were divided into control groups (no dosing), a single dose of a fluorescent-tagged ZOL (FAM-ZOL), a single dose of non-labelled zoledronate (ZOL) or ten weekly doses of FAM-ZOL each at 1/10th the dose of the single dose group. Half of the CKD animals in each group were provided water with 3% calcium in drinking water (CKD + Ca) to suppress PTH and remodeling. At 30 or 35 weeks of age, serum, tibia, ulna, radius, vertebra, femora, and mandible were collected and subjected to assessment methods including biochemistry, dynamic histomorphometry and multi-spectral fluorescence levels (using IVIS SpectrumCT). Results FAM-ZOL did not significantly reduce bone remodeling in either NL or CKD animals while Ca supplementation in CKD produced remodeling levels comparable to NL. At five- and ten-weeks post-dosing, both CKD and CKD + Ca groups had higher levels of FAM-ZOL in most, but not all, skeletal sites compared to NL with no difference between the two CKD groups suggesting that the rate of remodeling did not affect skeletal retention of FAM-ZOL. Fractionating the FAM-ZOL into ten weekly doses led to 20–32% less (p < 0.05) accumulation/retention of compound in the vertebra, radius, and ulna compared to administration as a single dose. Conclusions The rate of bone turnover does not have significant effects on levels of FAM-ZOL accumulation/retention in animals with CKD. A lower dose/more frequent administration paradigm results in lower levels of accumulation/retention over time. These data provide information that could better inform the use of bisphosphonates in the setting of CKD in order to combat the dramatic increase in fracture risk

NGAL (Lcn2) monomer is associated with tubulointerstitial damage in chronic kidney disease

The type and the extent of tissue damage inform the prognosis of chronic kidney disease (CKD), but kidney biopsy is not a routine test. Urinary tests that correlate with specific histological findings might serve as surrogates for the kidney biopsy. We used immunoblots and ARCHITECT-NGAL assays to define the immunoreactivity of urinary neutrophil gelatinase–associated lipocalin (NGAL) in CKD, and we used mass spectroscopy to identify associated proteins. We analyzed kidney biopsies to determine whether specific pathological characteristics associated with the monomeric NGAL species. Advanced CKD urine contained the NGAL monomer as well as novel complexes of NGAL. When these species were separated, we found a significant correlation between the NGAL monomer and glomerular filtration rate (r=-0.53, P<0.001), interstitial fibrosis (mild vs. severe disease; mean 54 vs. 167μg uNGAL/g Cr, P<0.01), and tubular atrophy (mild vs. severe disease; mean 54 vs. 164μg uNGAL/g Cr, P<0.01). Monospecific assays of the NGAL monomer demonstrated a correlation with histology that typifies progressive, severe CKD

Effect of Advanced Glycation End‐Products (AGE) Lowering Drug ALT‐711 on Biochemical, Vascular, and Bone Parameters in a Rat Model of CKD‐MBD

Chronic kidney disease–mineral bone disorder (CKD‐MBD) is a systemic disorder that affects blood measures of bone and mineral homeostasis, vascular calcification, and bone. We hypothesized that the accumulation of advanced glycation end‐products (AGEs) in CKD may be responsible for the vascular and bone pathologies via alteration of collagen. We treated a naturally occurring model of CKD‐MBD, the Cy/+ rat, with a normal and high dose of the AGE crosslink breaker alagebrium (ALT‐711), or with calcium in the drinking water to mimic calcium phosphate binders for 10 weeks. These animals were compared to normal (NL) untreated animals. The results showed that CKD animals, compared to normal animals, had elevated blood urea nitrogen (BUN), PTH, FGF23 and phosphorus. Treatment with ALT‐711 had no effect on kidney function or PTH, but 3 mg/kg lowered FGF23 whereas calcium lowered PTH. Vascular calcification of the aorta assessed biochemically was increased in CKD animals compared to NL, and decreased by the normal, but not high dose of ALT‐711, with parallel decreases in left ventricular hypertrophy. ALT‐711 (3 mg/kg) did not alter aorta AGE content, but reduced aorta expression of receptor for advanced glycation end products (RAGE) and NADPH oxidase 2 (NOX2), suggesting effects related to decreased oxidative stress at the cellular level. The elevated total bone AGE was decreased by 3 mg/kg ALT‐711 and both bone AGE and cortical porosity were decreased by calcium treatment, but only calcium improved bone properties. In summary, treatment of CKD‐MBD with an AGE breaker ALT‐711, decreased FGF23, reduced aorta calcification, and reduced total bone AGE without improvement of bone mechanics. These results suggest little effect of ALT‐711 on collagen, but potential cellular effects. The data also highlights the need to better measure specific types of AGE proteins at the tissue level in order to fully elucidate the impact of AGEs on CKD‐MBD. © 2019 American Society for Bone and Mineral Research

Systematics of Inclusive Photon Production in 158 AGeV Pb Induced Reactions on Ni, Nb, and Pb Targets

The multiplicity of inclusive photons has been measured on an event-by-event basis for 158 AGeV Pb induced reactions on Ni, Nb, and Pb targets. The systematics of the pseudorapidity densities at midrapidity (rho_max) and the width of the pseudorapidity distributions have been studied for varying centralities for these collisions. A power law fit to the photon yield as a function of the number of participating nucleons gives a value of 1.13+-0.03 for the exponent. The mean transverse momentum, , of photons determined from the ratio of the measured electromagnetic transverse energy and photon multiplicity, remains almost constant with increasing rho_max. Results are compared with model predictions.Comment: 16 pages including 4 figure

Scaling of Particle and Transverse Energy Production in 208Pb+208Pb collisions at 158 A GeV

Transverse energy, charged particle pseudorapidity distributions and photon transverse momentum spectra have been studied as a function of the number of participants (N_{part}) and the number of binary nucleon-nucleon collisions (N_{coll}) in 158 A GeV Pb+Pb collisions over a wide impact parameter range. A scaling of the transverse energy pseudorapidity density at midrapidity as N_{part}^{1.08 \pm 0.06} and N_{coll}^{0.83 \pm 0.05} is observed. For the charged particle pseudorapidity density at midrapidity we find a scaling as N_{part}^{1.07 \pm 0.04} and N_{coll}^{0.82 \pm 0.03}. This faster than linear scaling with N_{part} indicates a violation of the naive Wounded Nucleon Model.Comment: 13 pages, 16 figures, submitted to European Physical Journal C (revised results for scaling exponents

Aptamer-based multiplexed proteomic technology for biomarker discovery

Interrogation of the human proteome in a highly multiplexed and efficient manner remains a coveted and challenging goal in biology. We present a new aptamer-based proteomic technology for biomarker discovery capable of simultaneously measuring thousands of proteins from small sample volumes (15 [mu]L of serum or plasma). Our current assay allows us to measure ~800 proteins with very low limits of detection (1 pM average), 7 logs of overall dynamic range, and 5% average coefficient of variation. This technology is enabled by a new generation of aptamers that contain chemically modified nucleotides, which greatly expand the physicochemical diversity of the large randomized nucleic acid libraries from which the aptamers are selected. Proteins in complex matrices such as plasma are measured with a process that transforms a signature of protein concentrations into a corresponding DNA aptamer concentration signature, which is then quantified with a DNA microarray. In essence, our assay takes advantage of the dual nature of aptamers as both folded binding entities with defined shapes and unique sequences recognizable by specific hybridization probes. To demonstrate the utility of our proteomics biomarker discovery technology, we applied it to a clinical study of chronic kidney disease (CKD). We identified two well known CKD biomarkers as well as an additional 58 potential CKD biomarkers. These results demonstrate the potential utility of our technology to discover unique protein signatures characteristic of various disease states. More generally, we describe a versatile and powerful tool that allows large-scale comparison of proteome profiles among discrete populations. This unbiased and highly multiplexed search engine will enable the discovery of novel biomarkers in a manner that is unencumbered by our incomplete knowledge of biology, thereby helping to advance the next generation of evidence-based medicine