Coronavirus disease 2019, vitamin D and kidney function.

PURPOSE OF REVIEW: The purpose of this review is to summarize the emerging studies analyzing the association between vitamin D and risk of COVID-19 infection and severity, as well as the early interventional studies investigating the protective effect of vitamin D supplementation against COVID-19. RECENT FINDINGS: Studies investigating the association between vitamin D levels and risk of COVID-19 infection and risk of severe disease and mortality among those infected have yielded mixed results. Thus far, the majority of studies investigating the association between vitamin D and COVID-19 have been observational and rely on vitamin D levels obtained at the time of admission, limiting causal inference. Currently, clinical trials assessing the effects of vitamin D supplementation in individuals with COVID-19 infection are extremely limited. Randomized, interventional trials may offer more clarity on the protective effects of vitamin D against COVID-19 infection and outcomes. SUMMARY: Decreased levels of vitamin D may amplify the inflammatory effects of COVID-19 infection, yet, data regarding the mortality benefits of vitamin D supplementation in COVID-19-infected individuals are still limited. Current observational data provides the impetus for future studies to including randomized controlled trials to determine whether vitamin D supplementation in COVID-19-infected individuals with kidney disease can improve mortality outcomes.

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.

Impact of Tenofovir-Based Pre-exposure Prophylaxis on Biomarkers of Bone Formation, Bone Resorption, and Bone Mineral Metabolism in HIV-Negative Adults.

BACKGROUND: Pre-exposure prophylaxis (PrEP) with emtricitabine (FTC)/tenofovir disoproxil fumarate (TDF) reduces the risk of HIV seroconversion but may promote bone mineral density (BMD) decline. The mechanisms of BMD decline with FTC/TDF remain unclear, and studies in HIV-positive individuals have been confounded by the effects of HIV and concomitant antiretroviral medications. We evaluated the impact of FTC/TDF on biomarkers of bone remodeling and bone mineral metabolism in HIV-negative men and women enrolled in the Partners PrEP Study. METHODS: In a random sample of HIV-negative participants randomized to FTC/TDF PrEP (n = 50) or placebo (n = 50), serum parathyroid hormone (PTH), bone biomarkers (C-telopeptide, procollagen 1 intact N-terminal propeptide, and sclerostin), and plasma fibroblast growth factor 23 were measured at baseline and month 24, and the percentage change was compared between groups. In a complementary analysis, we compared the change in biomarkers between participants with and without a 25% decline in glomerular filtration rate (GFR) on FTC/TDF. RESULTS: Baseline characteristics were similar between the groups (median age, 38 years; 40% women). Vitamin D insufficiency was common, but baseline GFR and PTH were in the normal range. We observed a significantly greater percent increase in serum C-telopeptide in participants randomized to FTC/TDF vs placebo (P = .03), suggesting an increase in bone remodeling. We observed no differences in the other biomarkers, or in a separate analysis comparing participants with and without a decline in GFR. CONCLUSIONS: Increased bone remodeling may mediate the BMD decline observed with tenofovir-containing PrEP and antiretroviral therapy, independent of a TDF-mediated decrease in kidney function.

Association of Bone Mineral Density With Fractures Across the Spectrum of Chronic Kidney Disease: The Regina CKD-MBD Study.

BACKGROUND: Recent studies have demonstrated that measurement of areal bone mineral density by dual-energy x-ray absorptiometry (DXA) predicts fractures in patients with chronic kidney disease (CKD). However, whether fracture risk prediction through bone mineral density (BMD) is enhanced due to the assessment of biochemical markers of chronic kidney disease and mineral and bone disease (CKD-MBD) or clinical risk factors is not clear. We hypothesized that in a select cohort of patients managed in a CKD clinic, that combining T-Scores with biochemical markers would optimize fracture discrimination than using DXA alone. OBJECTIVE: To examine the relationships among BMD, biochemical markers of CKD-MBD, and fracture risk across Kidney Disease Improving Global Outcomes (KDIGO) glomerular filtration rate (GFR) categories G3a to G5. DESIGN: Retrospective study. SETTING: Patients were recruited from the multidisciplinary CKD clinic, Regina General Hospital, Canada. PATIENTS: A total of 374 patients who received a DXA scan upon initial referral to Regina Multidisciplinary CKD Program from January 31, 2001 to January 31, 2010, were included in this study. The patients were followed for a total of 5 years. METHODS: We conducted a retrospective review of 374 consecutive patients who underwent DXA imaging at the point of entry into our multidisciplinary CKD program. Areal BMD, T- and Z-Scores were obtained at the lumbar spine, total hip, mean of left and right femoral neck, and the one-third radius. We collected data on demographic, cross-sectional biochemical markers of mineral metabolism and fractures (identified through self-reported questionnaires, hospital electronic medical records, and physician billing records). We were able to gather data on 8/11 variables of Fracture Risk Assessment (FRAX) tool. RESULTS: In our cohort, 14.3% of GFR categories G3a and G3b, 15.7% of GFR category G4, and 19.7% of GFR category G5 experienced a clinical fracture during the study period. On multivariate analysis, each decline of 1.0 SD in total hip BMD T-Score was associated with a significant increase in the risk of fracture (OR = 1.46, 95% confidence interval [CI], 1.12-1.89). Adding CKD-MBD markers and clinical risk factors did not further contribute to the model. Low BMD was the only independent risk factor for fracture in patients with CKD. LIMITATIONS: Self-reporting by patients and administrative records were used to identify fractures. We did not perform spine imaging to ascertain morphometric vertebral fractures. We were unable to gather all 11 variables of FRAX score and information on ethnicity. We were unable to capture site of fracture (hips, spine, etc) from billing records. Albumin excretion rates were not collected at baseline. Treatment of the underlying bone disease with pharmacotherapeutic agents may have attenuated patients' fracture risk and thus underestimated the association between BMD and future fracture. CONCLUSIONS: Our findings confirm that BMD predicts fracture. The addition of cross-sectional CKD-MBD parameters and clinical risk factors to BMD did not add to fracture prediction. Prospective studies should investigate the utility of longitudinal biochemical markers on improving fracture risk assessment.

CONTEXTE: Des études récentes ont démontré qu'il était possible de prédire les fractures chez les patients atteints d'insuffisance rénale chronique (IRC) avec une mesure de la densité minérale osseuse (DMO) surfacique par absorptiométrie biénergétique à rayons X (DXA). On ignore cependant si la valeur prédictive de la DMO est améliorée par l'analyze des biomarqueurs des troubles minéraux et osseux associés à l'IRC (TMO-IRC) ou des facteurs de risque cliniques. Nous avons émis l'hypothèse que, dans une cohorte choisie de patients suivis en clinique d'IRC, la combinaison des scores T et des marqueurs biochimiques optimiserait la discrimination des fractures par rapport à l'utilization de la DXA seule. OBJECTIF: L'étude visait à établir un lien entre la DMO, les biomarqueurs des TMO-IRC et le risque de fractures chez les patients présentant un débit de filtration glomérulaire (DFG) de catégories G3a à G5 selon la classification du KDIGO (Kidney Disease Improving Global Outcomes). TYPE D'ÉTUDE: Étude rétrospective. CADRE: Les patients ont été recrutés à la clinique multidisciplinaire d'IRC de l'hôpital général de Régina (Canada). SUJETS: Ont été inclus les 374 patients ayant passé un test d'imagerie DXA entre le 31 janvier 2001 et le 31 janvier 2010 lors de leur aiguillage vers le program multidisciplinaire d'IRC de Régina. Les patients ont été suivis sur une période de cinq ans. MÉTHODOLOGIE: Nous avons mené une étude rétrospective portant sur 374 patients consécutifs examinés par DXA à leur admission au program. La DMO surfacique et les scores T et Z ont été mesurés au rachis lombaire, à la hanche totale, à la moyenne des cols fémoraux droit et gauche, et au tiers du radius. On a recueilli les caractéristiques démographiques des patients, les données sur les marqueurs biochimiques transversaux du métabolisme minéral et les fractures subies (recensées à l'aide d'un questionnaire d'auto-déclaration et par consultation des dossiers médicaux électroniques et des registres de facturation des médecins). Nous sommes parvenus à rassembler des données sur huit variables des onze de l'outil FRAX (Fracture Risk Assessment tool). RÉSULTATS: Dans notre cohorte, 14,3 % des patients avec un DFG de catégorie G3a-G3b, 15,7 % des patients avec un DFG de catégorie G4 et 19,7 % des patients avec un DFG de catégorie G5 ont subi une fracture clinique au cours de la période d'étude. Dans l'analyze multivariée, chaque déclin d'un point d'écart-type au score T de la DMO à la hanche a été associé à une augmentation significative du risque de fracture (RR = 1,46; IC 95 %: 1,12-1,89). L'ajout des marqueurs des TMO-IRC et des facteurs de risque cliniques n'a pas contribué davantage au modèle. Une faible DMO s'est avérée le seul facteur de risque indépendant de subir une fracture chez les patients atteints d'IRC. LIMITES: Les fractures ont été identifiées à partir des dossiers administratifs et par auto-déclaration des patients. Nous n'avons pas procédé à l'imagerie de la colonne vertébrale pour confirmer les fractures vertébrales morphométriques. Nous n'avons pas été en mesure de rassembler les onze variables du score FRAX ni les informations sur l'origine ethnique des patients. Les registres de facturation ne nous ont pas permis d'établir le site de la fracture (hanche, rachis ou autre). Les taux initiaux d'excrétion de l'albumine n'ont pas été mesurés. Le traitement de l'ostéopathie sous-jacente à l'aide d'agents pharmacothérapeutiques pourrait avoir atténué le risque de fracture des patients et ainsi, sous-évalué l'association entre la DMO et de futures fractures. CONCLUSION: Nos résultats confirment que la DMO est prédictive du risque de fractures. L'ajout des paramètres transversaux des TMO-IRC et des facteurs de risque cliniques à la mesure de DMO n'en a pas amélioré la valeur prédictive. Des études prospectives devraient examiner l'intérêt des marqueurs biochimiques longitudinaux pour améliorer l'évaluation du risque de fracture.

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.

MC4R-dependent suppression of appetite by bone-derived lipocalin 2.

Bone has recently emerged as a pleiotropic endocrine organ that secretes at least two hormones, FGF23 and osteocalcin, which regulate kidney function and glucose homeostasis, respectively. These findings have raised the question of whether other bone-derived hormones exist and what their potential functions are. Here we identify, through molecular and genetic analyses in mice, lipocalin 2 (LCN2) as an osteoblast-enriched, secreted protein. Loss- and gain-of-function experiments in mice demonstrate that osteoblast-derived LCN2 maintains glucose homeostasis by inducing insulin secretion and improves glucose tolerance and insulin sensitivity. In addition, osteoblast-derived LCN2 inhibits food intake. LCN2 crosses the blood-brain barrier, binds to the melanocortin 4 receptor (MC4R) in the paraventricular and ventromedial neurons of the hypothalamus and activates an MC4R-dependent anorexigenic (appetite-suppressing) pathway. These results identify LCN2 as a bone-derived hormone with metabolic regulatory effects, which suppresses appetite in a MC4R-dependent manner, and show that the control of appetite is an endocrine function of bone.