Comprehensive Associations between Acidosis and the Skeleton in Patients with Kidney Disease.

SIGNIFICANCE STATEMENT: Renal osteodystrophy (ROD) contributes substantially to morbidity in CKD, including increased fracture risk. Metabolic acidosis (MA) contributes to the development of ROD, but an up-to-date skeletal phenotype in CKD-associated acidosis has not been described. We comprehensively studied associations between acidosis and bone in patients with CKD using advanced methods to image the skeleton and analyze bone-tissue, along with biochemical testing. Cross-sectionally, acidosis was associated with higher markers of bone remodeling and female-specific impairments in cortical and trabecular bone quality. Prospectively, acidosis was associated with cortical expansion and trabecular microarchitectural deterioration. At the bone-tissue level, acidosis was associated with deficits in bone mineral content. Future work investigating acidosis correction on bone quality is warranted. BACKGROUND: Renal osteodystrophy is a state of impaired bone quality and strength. Metabolic acidosis (MA) is associated with alterations in bone quality including remodeling, microarchitecture, and mineralization. No studies in patients with CKD have provided a comprehensive multimodal skeletal phenotype of MA. We aim to describe the structure and makeup of bone in patients with MA in the setting of CKD using biochemistry, noninvasive imaging, and histomorphometry. METHODS: The retrospective cross-sectional analyses included 180 patients with CKD. MA was defined as bicarbonate ≤22 mEq/L. We evaluated circulating bone turnover markers and skeletal imaging with dual energy x-ray absorptiometry and high-resolution peripheral computed tomography. A subset of 54 participants had follow-up. We assessed associations between baseline and change in bicarbonate with change in bone outcomes. Histomorphometry, microCT, and quantitative backscatter electron microscopy assessed bone biopsy outcomes in 22 participants. RESULTS: The mean age was 68±10 years, 54% of participants were male, and 55% were White. At baseline, acidotic subjects had higher markers of bone turnover, lower areal bone mineral density at the radius by dual energy x-ray absorptiometry, and lower cortical and trabecular volumetric bone mineral density and impaired trabecular microarchitecture. Over time, acidosis was associated with opposing cortical and trabecular effects: cortical expansion but trabecular deterioration. Bone-tissue analyses showed reduced tissue mineral density with increased heterogeneity of calcium distribution in acidotic participants. CONCLUSIONS: MA is associated with multiple impairments in bone quality. Future work should examine whether correction of acidosis improves bone quality and strength in patients with CKD.

Renal osteodystrophy: something old, something new, something needed.

PURPOSE OF REVIEW: Renal osteodystrophy (ROD) is a complex disorder of bone metabolism that affects virtually all adults and children with chronic kidney disease (CKD). ROD is associated with adverse clinical outcomes including bone loss, mineralization and turnover abnormalities, skeletal deformities, fractures, cardiovascular events, and death. Despite current therapies, fracture incidence is 2-fold to 100-fold higher in adults and 2-fold to 3-fold higher in children when compared to without CKD. Limited knowledge of ROD pathogenesis, due to the lack of patient-derived large-scale multimodal datasets, impedes development of therapeutics aimed at reducing morbidity and mortality of CKD patients. The purpose of the review is to define the much needed infrastructure for the advancement of RDO treatment. RECENT FINDINGS: Recently, we created a large-scale data and tissue biorepository integrating clinical, bone quality, transcriptomic, and epigenomic data along with stored urine, blood, and bone samples. This database will provide the underpinnings for future research endeavors leading to the elucidation and characterization of the pathogenesis of ROD in CKD patients with and without dialysis. SUMMARY: The availability of an open-access NIH-funded resource that shares bone-tissue-based information obtained from patients with ROD with the broad scientific community represents a critical step in the process of discovering new information regarding unrecognized bone changes that have severe clinical complications. This will facilitate future high-impact hypothesis-driven research to redefine our understanding of ROD pathogenesis and pathophysiology and inform the development of disease-modifying and prevention strategies.

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.

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

This corrects the article DOI: 10.1038/nature21697.

The Role of Vitamin K in CKD-MBD.

PURPOSE OF REVIEW: We describe the mechanism of action of vitamin K, and its implication in cardiovascular disease, bone fractures, and inflammation to underline its protective role, especially in chronic kidney disease (CKD). RECENT FINDINGS: Vitamin K acts as a coenzyme of y-glutamyl carboxylase, transforming undercarboxylated in carboxylated vitamin K-dependent proteins. Furthermore, through the binding of the nuclear steroid and xenobiotic receptor, it activates the expression of genes that encode proteins involved in the maintenance of bone quality and bone remodeling. There are three main types of K vitamers: phylloquinone, menaquinones, and menadione. CKD patients, for several conditions typical of the disease, are characterized by lower levels of vitamin K than the general populations, with a resulting higher prevalence of bone fractures, vascular calcifications, and mortality. Therefore, the definition of vitamin K dosage is an important issue, potentially leading to reduced bone fractures and improved vascular calcifications in the general population and CKD patients.

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.

Overweight-obesity is associated with decreased vitamin K2 levels in hemodialysis patients.

OBJECTIVES: Obesity is an important risk factor for morbidity and mortality. Vitamin K2 is involved in the production of bone and matrix amino acid g-carboxy-glutamic acid (Gla) proteins (vitamin K-dependent proteins [VKDPs]), regulating bone and vascular calcification (VC). Bone Gla protein (BGP) is involved both in bone mineralization and VCs. We assessed the relationships between vitamin K levels and body mass index (BMI) according to the hypothesis that the impact of BMI on mortality is partly driven by low vitamin K levels. METHODS: The Vitamin K Italian (VIKI) study included 387 hemodialysis patients from 18 dialysis centers in Italy. We determined plasma levels of bone markers: vitamin K levels, VKDPs, vitamin 25(OH)D, alkaline phosphatase (ALP), parathyroid hormone (PTH), calcium (Ca), phosphorus (P) and routine biochemistry. BMI was classified into the following categories: underweight (BMI < 18.5 kg/m2), normal weight (18.5 ≤ BMI < 25 kg/m2), overweight (25 ≤ BMI < 30 kg/m2) and obese (BMI ≥ 30 kg/m2). RESULTS: 45.2% of patients were overweight or obese. Stratification by BMI demonstrated lower median menaquinone-7 (MK7)/triglycerides levels in obese patients (0.42 ng/mg [0.19, 0.87], p = 0.005). BGP levels were lower in overweight and obese patients (152 mcg/L [83.2, 251] and 104 mcg/L [62.7, 230], p = <0.001). Furthermore, there was an inverse correlation between MK7/triglycerides levels and BMI (regression coefficient ß = -0.159; p = 0.003). In multiple linear regression, there was an inverse relationship between BGP levels and BMI (ß = - 0.119; p = 0.012). CONCLUSIONS: These data are the first to report an inverse relationship between Vitamin K2 levels and BMI in hemodialysis patients. Further studies are needed to confirm these findings and to determine if lower levels of Vitamin K are related to greater morbidity and mortality in this at-risk population.

Bisphosphonate therapy in CKD: the current state of affairs.

PURPOSE OF REVIEW: Chronic kidney disease (CKD) is associated with the development of mineral and bone disorders (MBD), including renal osteodystrophy (ROD). ROD is a global disorder of bone strength that is associated with an increased fracture risk. The use of bisphosphonates for fracture risk reduction in CKD remains controversial. This review provides a synopsis of the state-of-the literature regarding the safety and potential antifracture benefits of bisphosphonates in CKD patients. RECENT FINDINGS: In preclinical studies of animals with CKD 3-4 and evidence of CKD-MBD, bisphosphonates resulted in changes in bone quality that improve bone strength. Bone turnover was generally reduced to a similar extent in animals with and without CKD. Post hoc analyses of randomized trials in patients with CKD 3-4 reported increases in bone mineral density (BMD) and fracture reduction that were similar in patients with and without CKD. There are no primary clinical trial data in patients with CKD-MBD. SUMMARY: In patients with CKD without evidence of CKD-MBD, the use of bisphosphonates should follow general population guidelines. The lack of data for patients with CKD 4-5D and evidence of CKD-MBD makes treatment decisions challenging. Clinical studies are urgently needed to provide data on the safety and antifracture benefits of bisphosphonates in these cohorts.

Neutrophil Gelatinase-Associated Lipocalin Measured on Clinical Laboratory Platforms for the Prediction of Acute Kidney Injury and the Associated Need for Dialysis Therapy: A Systematic Review and Meta-analysis.

RATIONALE & OBJECTIVE: The usefulness of measures of neutrophil gelatinase-associated lipocalin (NGAL) in urine or plasma obtained on clinical laboratory platforms for predicting acute kidney injury (AKI) and AKI requiring dialysis (AKI-D) has not been fully evaluated. We sought to quantitatively summarize published data to evaluate the value of urinary and plasma NGAL for kidney risk prediction. STUDY DESIGN: Literature-based meta-analysis and individual-study-data meta-analysis of diagnostic studies following PRISMA-IPD guidelines. SETTING & STUDY POPULATIONS: Studies of adults investigating AKI, severe AKI, and AKI-D in the setting of cardiac surgery, intensive care, or emergency department care using either urinary or plasma NGAL measured on clinical laboratory platforms. SELECTION CRITERIA FOR STUDIES: PubMed, Web of Science, Cochrane Library, Scopus, and congress abstracts ever published through February 2020 reporting diagnostic test studies of NGAL measured on clinical laboratory platforms to predict AKI. DATA EXTRACTION: Individual-study-data meta-analysis was accomplished by giving authors data specifications tailored to their studies and requesting standardized patient-level data analysis. ANALYTICAL APPROACH: Individual-study-data meta-analysis used a bivariate time-to-event model for interval-censored data from which discriminative ability (AUC) was characterized. NGAL cutoff concentrations at 95% sensitivity, 95% specificity, and optimal sensitivity and specificity were also estimated. Models incorporated as confounders the clinical setting and use versus nonuse of urine output as a criterion for AKI. A literature-based meta-analysis was also performed for all published studies including those for which the authors were unable to provide individual-study data analyses. RESULTS: We included 52 observational studies involving 13,040 patients. We analyzed 30 data sets for the individual-study-data meta-analysis. For AKI, severe AKI, and AKI-D, numbers of events were 837, 304, and 103 for analyses of urinary NGAL, respectively; these values were 705, 271, and 178 for analyses of plasma NGAL. Discriminative performance was similar in both meta-analyses. Individual-study-data meta-analysis AUCs for urinary NGAL were 0.75 (95% CI, 0.73-0.76) and 0.80 (95% CI, 0.79-0.81) for severe AKI and AKI-D, respectively; for plasma NGAL, the corresponding AUCs were 0.80 (95% CI, 0.79-0.81) and 0.86 (95% CI, 0.84-0.86). Cutoff concentrations at 95% specificity for urinary NGAL were>580ng/mL with 27% sensitivity for severe AKI and>589ng/mL with 24% sensitivity for AKI-D. Corresponding cutoffs for plasma NGAL were>364ng/mL with 44% sensitivity and>546ng/mL with 26% sensitivity, respectively. LIMITATIONS: Practice variability in initiation of dialysis. Imperfect harmonization of data across studies. CONCLUSIONS: Urinary and plasma NGAL concentrations may identify patients at high risk for AKI in clinical research and practice. The cutoff concentrations reported in this study require prospective evaluation.

Updates in CKD-Associated Osteoporosis.

PURPOSE OF REVIEW: Chronic kidney disease (CKD) is associated with bone loss and fractures. The purpose of this review is to provide clinicians with an overview of the underlying pathogenesis of CKD-associated osteoporosis, and a summary of the current diagnostic and therapeutic approaches to this disease. RECENT FINDINGS: In 2017, the Kidney Disease Improving Global Outcomes Committee on Bone Quality updated their guidelines to include screening for osteoporosis and fracture risk by dual energy X-ray absorptiometry in patients with CKD. Once a diagnosis of osteoporosis and/or fracture risk is established, it is not clear how nephrologists should manage their patients. Patients with CKD should be screened for CKD-associated osteoporosis and considered for strategies that prevent bone loss and fractures. Assessment of bone turnover via imaging, biochemical testing, or bone biopsy can help guide the choice of therapy. Randomized controlled trials are needed to assess safety and efficacy of treatments to prevent bone loss and fractures.

KDOQI US Commentary on the 2017 KDIGO Clinical Practice Guideline Update for the Diagnosis, Evaluation, Prevention, and Treatment of Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD).

Chronic kidney disease-mineral and bone disorder (CKD-MBD) encompasses laboratory and bone abnormalities and vascular calcification and has deleterious effects on clinical outcomes. KDOQI (Kidney Disease Outcomes Quality Initiative), an initiative of the National Kidney Foundation, addressed this issue with the publication of a clinical practice guideline for bone metabolism and disease in CKD in 2003, and 2 years later, a new definition and classification scheme for CKD-MBD was developed following a KDIGO (Kidney Disease: Improving Global Outcomes) Controversies Conference. The initial KDIGO guideline on CKD-MBD was then published in 2009. New evidence was subsequently reviewed at the 2013 KDIGO Controversies Conference, and in 2017, KDIGO issued a clinical practice guideline update for the diagnosis, evaluation, prevention, and treatment of CKD-MBD. This commentary presents the views of the KDOQI CKD-MBD work group convened by the National Kidney Foundation. The KDOQI work group agrees with most of the KDIGO guideline update recommendations, particularly the suggestions regarding bone mineral density testing, joint assessments of longitudinal trends in mineral metabolism markers, and dietary phosphate counseling focused on phosphate additives. However, the KDOQI work group has some concerns about the suggestions related to hypocalcemia and hypercalcemia, phosphate-binder choice, and treatment of abnormal parathyroid hormone concentrations. The overall goal of this commentary is to provide a broad discussion for the US nephrology community regarding CKD-MBD and its diagnosis, prevention, and treatment.

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.

Low Risk of Proximal Tubular Dysfunction Associated With Emtricitabine-Tenofovir Disoproxil Fumarate Preexposure Prophylaxis in Men and Women.

OBJECTIVE: Tenofovir disoproxil fumarate (TDF) is associated with proximal tubular dysfunction (tubulopathy) when used in the treatment of human immunodeficiency virus (HIV) infection. We evaluated whether TDF causes tubulopathy when used as HIV preexposure prophylaxis (PrEP) and whether tubulopathy predicts clinically relevant decline (≥25%) in the estimated glomerular filtration rate (eGFR). METHODS: A subgroup analysis of the Partners PrEP Study, a randomized, placebo-controlled trial of daily oral TDF, alone or with emtricitabine (FTC), in HIV-uninfected African men and women (Clinicaltrials.gov NCT00557245). Tubulopathy was assessed in concurrently obtained urine and serum samples at the 24-month or last on-treatment visit, predefined as ≥2 of the following: tubular proteinuria, euglycemic glycosuria, increased urinary phosphate, and uric acid excretion. RESULTS: Of 1549 persons studied (776 receiving FTC-TDF, 773 receiving placebo), 64% were male, and the median age was 37 years. Over a median 24 months of study-drug exposure, the frequency of tubulopathy was 1.7% for FTC-TDF versus 1.3% for placebo (odds ratio, 1.30; 95% confidence interval, .52-3.33; P = .68); Tubulopathy occurred in 2 of 52 persons (3.8%) with versus 3 of 208 (1.4%) without ≥25% eGFR decline (adjusted odds ratio, 1.39; .10-14.0; P > .99). CONCLUSIONS: Daily oral FTC-TDF PrEP was not significantly associated with tubulopathy over the course of 24 months, nor did tubulopathy predict clinically relevant eGFR decline.

Inhibition of leukemia cell engraftment and disease progression in mice by osteoblasts.

The bone marrow niche is thought to act as a permissive microenvironment required for emergence or progression of hematologic cancers. We hypothesized that osteoblasts, components of the niche involved in hematopoietic stem cell (HSC) function, influence the fate of leukemic blasts. We show that osteoblast numbers decrease by 55% in myelodysplasia and acute myeloid leukemia patients. Further, genetic depletion of osteoblasts in mouse models of acute leukemia increased circulating blasts and tumor engraftment in the marrow and spleen leading to higher tumor burden and shorter survival. Myelopoiesis increased and was coupled with a reduction in B lymphopoiesis and compromised erythropoiesis, suggesting that hematopoietic lineage/progression was altered. Treatment of mice with acute myeloid or lymphoblastic leukemia with a pharmacologic inhibitor of the synthesis of duodenal serotonin, a hormone suppressing osteoblast numbers, inhibited loss of osteoblasts. Maintenance of the osteoblast pool restored normal marrow function, reduced tumor burden, and prolonged survival. Leukemia prevention was attributable to maintenance of osteoblast numbers because inhibition of serotonin receptors alone in leukemic blasts did not affect leukemia progression. These results suggest that osteoblasts play a fundamental role in propagating leukemia in the marrow and may be a therapeutic target to induce hostility of the niche to leukemia blasts.

Bone kidney interactions.

The fact that bone disease and kidney disease co-exist is well known. Formally, this inter-relationship is called chronic kidney disease mineral bone disorder or CKD-MBD. Traditionally, it was thought that bone played a passive role in CKD-MBD - specifically that kidney disease caused disordered mineral metabolism which resulted in bone disease and ultimately fractures. More recently however our understanding of bone function in general and the role that bone plays in CKD-MBD in particular, has changed. This chapter will briefly review epidemiology of fractures in chronic kidney disease (CKD) and the roles that imaging and measuring markers of mineral metabolism can play in assessing fracture risk. We will then review more recent data consistent with the concept MBD occurs early in the course of CKD and, via the secretion of novel molecules and/or signalling pathways, the bone can influence other organ systems.