Renal Osteodystrophy or Kidney-Induced Osteoporosis?

PURPOSE OF REVIEW: Chronic kidney disease (CKD) affects nearly 10% of the population. The incidence of fractures in population studies demonstrate an increase with worsening stages of kidney disease suggesting specific CKD related causes of fracture. RECENT FINDINGS: The increase in fractures with CKD most likely represents disordered bone quality due to the abnormal bone remodeling from renal osteodystrophy. There is also an increase in fractures with age in patients with CKD, suggesting that patients with CKD also have many fracture risk factors common to patients without known CKD. Osteoporosis is defined by the National Institutes of Health as "A skeletal disorder characterized by compromised bone strength predisposing to an increased risk of fracture. Bone strength reflects the integration of two main features: bone quantity and bone quality." Thus, CKD-related fractures can be considered a type of osteoporosis-where the bone quality is additionally impaired above that of age/hormonal-related osteoporosis. Perhaps using the term CKD-induced osteoporosis, similar to steroid-induced osteoporosis, will allow patients with CKD to be studied in trials investigating therapeutic agents. In this series, we will examine how CKD-induced osteoporosis may be diagnosed and treated

Calcium as a cardiovascular toxin in CKD-MBD

Disordered calcium balance and homeostasis are common in patients with chronic kidney disease. Such alterations are commonly associated with abnormal bone remodeling, directly and indirectly. Similarly, positive calcium balance may also be a factor in the pathogenesis of extra skeletal soft tissue and arterial calcification. Calcium may directly affect cardiac structure and function through direct effects to alter cell signaling due to abnormal intracellular calcium homeostasis 2) extra-skeletal deposition of calcium and phosphate in the myocardium and small cardiac arterioles, 3) inducing cardiomyocyte hypertrophy through calcium and hormone activation of NFAT signaling mechanisms, and 4) increased aorta calcification resulting in chronic increased afterload leading to hypertrophy. Similarly, calcium may alter vascular smooth muscle cell function and affect cell signaling which may predispose to a proliferative phenotype important in arteriosclerosis and arterial calcification. Thus, disorders of calcium balance and homeostasis due to CKD-MBD may play a role in the high cardiovascular burden observed in patients with CKD

Skeletal and cardiovascular consequences of a positive calcium balance during hemodialysis

Patients on hemodialysis are exposed to calcium via the dialysate at least three times a week. Changes in serum calcium vary according to calcium mass transfer during dialysis, which is dependent on the gradient between serum and dialysate calcium concentration (d[Ca]) and the skeleton turnover status that alters the ability of bone to incorporate calcium. Although underappreciated, the d[Ca] can potentially cause positive calcium balance that leads to systemic organ damage, including associations with mortality, myocardial dysfunction, hemodynamic tolerability, vascular calcification, and arrhythmias. The pathophysiology of these adverse effects includes serum calcium changes, parathyroid hormone suppression, and vascular calcification through indirect and direct effects. Some organs are more susceptible to alterations in calcium homeostasis. In this review, we discuss the existing data and potential mechanisms linking the d[Ca] to calcium balance with consequent dysfunction of the skeleton, myocardium, and arteries

How Good Are Provider Annotations?: A Machine Learning Approach

Introduction: CMS-2728 form (Medical Evidence Report) assesses 23 comorbidities chosen to reflect poor outcomes and increased mortality risk. Previous studies questioned the validity of physician reporting on forms CMS-2728. We hypothesize that reporting of comorbidities by computer algorithms identifies more comorbidities than physician completion, and, therefore, is more reflective of underlying disease burden. Methods: We collected data from CMS-2728 forms for all 296 patients who had incident ESRD diagnosis and received chronic dialysis from 2005 through 2014 at Indiana University outpatient dialysis centers. We analyzed patients' data from electronic medical records systems that collated information from multiple health care sources. Previously utilized algorithms or natural language processing was used to extract data on 10 comorbidities for a period of up to 10 years prior to ESRD incidence. These algorithms incorporate billing codes, prescriptions, and other relevant elements. We compared the presence or unchecked status of these comorbidities on the forms to the presence or absence according to the algorithms. Findings: Computer algorithms had higher reporting of comorbidities compared to forms completion by physicians. This remained true when decreasing data span to one year and using only a single health center source. The algorithms determination was well accepted by a physician panel. Importantly, algorithms use significantly increased the expected deaths and lowered the standardized mortality ratios. Discussion: Using computer algorithms showed superior identification of comorbidities for form CMS-2728 and altered standardized mortality ratios. Adapting similar algorithms in available EMR systems may offer more thorough evaluation of comorbidities and improve quality reporting

Matrix vesicles induce calcification of recipient vascular smooth muscle cells through multiple signaling pathways

In patients with chronic kidney and end-stage renal diseases, the major risk factor for progression of arterial calcification is the presence of existing (baseline) calcification. Here, we tested whether calcification of arteries is extended from calcified vascular smooth muscle cells (VSMCs) to adjacent normal cells by matrix vesicle–induced alteration of cell signaling. Matrix vesicles isolated from VSMC of rats with chronic kidney disease were co-cultured with VSMCs from normal littermates. Endocytosis of vesicles by recipient cells was confirmed by confocal microscopy. The addition of cellular matrix vesicles with characteristics of exosomes and low fetuin-A content enhanced the calcification of recipient VSMC. Further, only cellular-derived matrix vesicles induced an increase in intracellular calcium ion concentration, NOX1 (NADPH oxidase) and the anti-oxidant superoxide dismutase-2 in recipient normal VSMC. The increase in intracellular calcium ion concentration was due to release from endoplasmic reticulum and partially attributed to the activation of both NOX1 and mitogen-activated protein kinase (MEK1 and Erk1/2) signaling, since inhibiting both pathways blocked the increase in intracellular calcium ion in recipient VSMC. In contrast, matrix vesicles isolated from the media had no effect on the intracellular calcium ion concentration or MEK1 signaling, and did not induce calcification. However, media matrix vesicles did increase Erk1/2, although not to the level of cellular matrix vesicles, and NOX1 expression. Blockade of NOX activity further inhibited the cellular matrix vesicle–induced accelerated calcification of recipient VSMC, suggesting a potential therapeutic role of such inhibition. Thus, addition of cellular-derived matrix vesicles from calcifying VSMC can accelerate calcification by inducing cell signaling changes and phenotypic alteration of recipient VSMC

Nicotinamide treatment in a murine model of familial tumoral calcinosis reduces serum Fgf23 and raises heart calcium

Mutations in the GALNT3 gene result in familial tumoral calcinosis, characterized by persistent hyperphosphatemia and ectopic calcific masses in soft tissues. Since calcific masses often recur after surgical removal, a more permanent solution to the problem is required. Nicotinamide is reported to lower serum phosphate by decreasing sodium-dependent phosphate co-transporters in the gut and kidney. However, its effectiveness in tumoral calcinosis remains unknown. In this study, we investigated nicotinamide as a potential therapy for tumoral calcinosis, using a murine model of the disease-Galnt3 knockout mice. Initially, five different doses of nicotinamide were given to normal heterozygous mice intraperitoneally or orally. Treatment had no effect on serum phosphate levels, but serum levels of a phosphaturic hormone, fibroblast growth factor 23 (Fgf23), decreased in a dose-dependent manner. Subsequently, high-dose nicotinamide (40mM) was tested in Galnt3 knockout mice fed a high phosphate diet. The radiographic data pre- and post-treatment showed that nicotinamide did not reverse the calcification. However, the treatment retarded calcification growth after 4weeks, while in the untreated animals, calcifications increased in size. The therapy did not affect serum phosphate levels, but intact Fgf23 decreased in the treated mice. The treated mice also had increased calcium in the heart. In summary, nicotinamide did not alter serum phosphate levels, likely due to compensatory decrease in Fgf23 to counteract the phosphate lowering effect of nicotinamide. Although increased calcium accumulation in the heart is a concern, the therapy appears to slow down the progression of ectopic calcifications

Effects of etelcalcetide on fibroblast growth factor 23 in patients with secondary hyperparathyroidism receiving hemodialysis

Background: Etelcalcetide is an intravenous calcimimetic approved for treatment of secondary hyperparathyroidism (sHPT) in patients receiving hemodialysis. Besides lowering parathyroid hormone (PTH), etelcalcetide also significantly reduces fibroblast growth factor 23 (FGF23), but the mechanisms are unknown. Methods: To investigate potential mediators of etelcalcetide-induced FGF23 reduction, we performed secondary analyses of the 26-week randomized trials that compared the effects on PTH of etelcalcetide (n = 509) versus placebo (n = 514) and etelcalcetide (n = 340) versus cinacalcet (n = 343) in adults with sHPT receiving hemodialysis. We analyzed changes in FGF23 in relation to changes in PTH, calcium, phosphate and bone turnover markers. We also investigated how concomitant treatments aimed at mitigating hypocalcemia altered the FGF23-lowering effects of etelcalcetide. Results: Etelcalcetide reduced FGF23 [median % change (quartile 1-quartile 3)] from baseline to the end of the trial significantly more than placebo [-56% (-85 to -7) versus +2% (-40 to +65); P < 0.001] and cinacalcet [-68% (-87 to -26) versus -41% (-76 to +25); P < 0.001]. Reductions in FGF23 correlated strongly with reductions in calcium and phosphate, but not with PTH; correlations with bone turnover markers were inconsistent and of borderline significance. Increases in concomitant vitamin D administration partially attenuated the FGF23-lowering effect of etelcalcetide, but increased dialysate calcium concentration versus no increase and increased dose of calcium supplementation versus no increase did not attenuate the FGF23-lowering effects of etelcalcetide. Conclusion: These data suggest that etelcalcetide potently lowers FGF23 in patients with sHPT receiving hemodialysis and that the effect remains detectable among patients who receive concomitant treatments aimed at mitigating treatment-associated decreases in serum calcium

Effects of switching from efavirenz to raltegravir on endothelial function, bone mineral metabolism, inflammation, and renal function: a randomized, controlled trial

We performed a randomized controlled trial in 30 HIV-infected participants to either continue tenofovir/emtricitabine/efavirenz (Continuation Group) or switch to tenofovir/emtricitabine/raltegravir (Switch Group) for 24 weeks. There were no significant differences in the changes in flow-mediated dilation, 25(OH) vitamin D, or parathyroid hormone levels. Total cholesterol, high sensitivity C-reactive protein, serum alkaline phosphatase, sCD14 levels, and renal function significantly declined in the Switch Group compared with the Continuation Group; however, sCD163 levels significantly increased in the Switch Group. These findings suggest that raltegravir is not inherently more beneficial to endothelial function compared with efavirenz but may impact renal function and monocyte activation

Adverse mandibular bone effects associated with kidney disease are only partially corrected with bisphosphonate and/or calcium treatment

Bone Biology Laboratory http://www.iupui.edu/~bonelab/ Department of Anatomy and Cell Biology Indiana University School of Medicine Department of Biomedical Engineering IUPUIBackground/Aims: Patients with chronic kidney disease (CKD) have high prevalence of periodontal disease that may predispose to tooth loss and inflammation. The goal of this study was to test the hypotheses that a genetic rat model of progressive CKD would exhibit altered oral bone properties and that treatment with either bisphosphonates or calcium could attenuate these adverse changes. Methods: At 25 weeks of age, rats were treated with zoledronate, calcium gluconate, or their combination for 5 or 10 weeks. Mandible bone properties were assessed using micro-computed tomography to determine bone volume (BV/TV) and cementenamel junction to alveolar crest distance (CEJ-AC). Results: Untreated CKD animals had significantly lower BV/TV at both 30 (-5%) and 35 (-14%) weeks of age and higher CEJ-AC (+27 and 29%) compared to normal animals. CKD animals had significantly higher PTH compared to normal animals yet similar levels of C-reactive protein. Zoledronate-treatment normalized BV/TV over the first 5 weeks but this benefit was lost by 10 weeks. Calcium treatment, alone or in combination with zoledronate, was effective in normalizing BV/TV at both time points. Neither zoledronate nor calcium was able to correct the higher CEJ-AC caused by CKD. Calcium, but not zoledronate, significantly reduced serum parathyroid hormone (PTH) while neither treatment affected C-reactive protein. Conclusions: 1) this progressive animal model of chronic kidney disease shows a clear mandibular skeletal phenotype consistent with periodontitis, 2) the periodontitis is not associated with systemic inflammation as measured by C-reactive protein, and 3) reducing PTH has positive effects on the mandible phenotype.This work was supported by NIH grant (AR058005). We would like to thank Dr. Xianming Chen, Mr. Alex Carr and Mr. Drew Brown for their assistance with the biochemical assays, breeding colony and micro CT scanning/analysis, respectively