The role of irisin in kidney diseases.

Irisin is a hormone that is produced mainly by skeletal muscles in response to exercise. It has been found to have a close correlation with obesity and diabetes mellitus for its energy expenditure and metabolic properties. Recent research has revealed that irisin also possesses anti-inflammatory, anti-oxidative and anti-apoptotic properties, which make it associated with major chronic diseases, such as chronic kidney disease (CKD), liver diseases, osteoporosis, atherosclerosis and Alzheimer s disease. The identification of irisin has not only opened up new possibilities for monitoring metabolic and non-metabolic diseases but also presents a promising therapeutic target due to its multiple biological functions. Studies have shown that circulating irisin levels are lower in CKD patients than in non-CKD patients and decrease with increasing CKD stage. Furthermore, irisin also plays a role in many CKD-related complications like protein energy wasting (PEW), cardiovascular disease (CVD) and chronic kidney disease-mineral and bone disorder (CKD-MBD). In this review, we present the current knowledge on the role of irisin in kidney diseases and their complications.

Sclerostin, Osteocytes, and Wnt Signaling in Pediatric Renal Osteodystrophy.

The pathophysiology of chronic kidney disease-mineral and bone disorder (CKD-MBD) is not well understood. Specific factors secreted by osteocytes are elevated in the serum of adults and pediatric patients with CKD-MBD, including FGF-23 and sclerostin, a known inhibitor of the Wnt signaling pathway. The molecular mechanisms that promote bone disease during the progression of CKD are incompletely understood. In this study, we performed a cross-sectional analysis of 87 pediatric patients with pre-dialysis CKD and post-dialysis (CKD 5D). We assessed the associations between serum and bone sclerostin levels and biomarkers of bone turnover and bone histomorphometry. We report that serum sclerostin levels were elevated in both early and late CKD. Higher circulating and bone sclerostin levels were associated with histomorphometric parameters of bone turnover and mineralization. Immunofluorescence analyses of bone biopsies evaluated osteocyte staining of antibodies towards the canonical Wnt target, ß-catenin, in the phosphorylated (inhibited) or unphosphorylated (active) forms. Bone sclerostin was found to be colocalized with phosphorylated ß-catenin, which suggests that Wnt signaling was inhibited. In patients with low serum sclerostin levels, increased unphosphorylated "active" ß-catenin staining was observed in osteocytes. These data provide new mechanistic insight into the pathogenesis of CKD-MBD and suggest that sclerostin may offer a potential biomarker or therapeutic target in pediatric renal osteodystrophy.

A parathyroid hormone/salt-inducible kinase signaling axis controls renal vitamin D activation and organismal calcium homeostasis.

The renal actions of parathyroid hormone (PTH) promote 1,25-vitamin D generation; however, the signaling mechanisms that control PTH-dependent vitamin D activation remain unknown. Here, we demonstrated that salt-inducible kinases (SIKs) orchestrated renal 1,25-vitamin D production downstream of PTH signaling. PTH inhibited SIK cellular activity by cAMP-dependent PKA phosphorylation. Whole-tissue and single-cell transcriptomics demonstrated that both PTH and pharmacologic SIK inhibitors regulated a vitamin D gene module in the proximal tubule. SIK inhibitors increased 1,25-vitamin D production and renal Cyp27b1 mRNA expression in mice and in human embryonic stem cell-derived kidney organoids. Global- and kidney-specific Sik2/Sik3 mutant mice showed Cyp27b1 upregulation, elevated serum 1,25-vitamin D, and PTH-independent hypercalcemia. The SIK substrate CRTC2 showed PTH and SIK inhibitor-inducible binding to key Cyp27b1 regulatory enhancers in the kidney, which were also required for SIK inhibitors to increase Cyp27b1 in vivo. Finally, in a podocyte injury model of chronic kidney disease-mineral bone disorder (CKD-MBD), SIK inhibitor treatment stimulated renal Cyp27b1 expression and 1,25-vitamin D production. Together, these results demonstrated a PTH/SIK/CRTC signaling axis in the kidney that controls Cyp27b1 expression and 1,25-vitamin D synthesis. These findings indicate that SIK inhibitors might be helpful for stimulation of 1,25-vitamin D production in CKD-MBD.

Osteocytic Sclerostin Expression as an Indicator of Altered Bone Turnover.

Renal osteodystrophy (ROD) is a complex and serious complication of chronic kidney disease (CKD), a major global health problem caused by loss of renal function. Currently, the gold standard to accurately diagnose ROD is based on quantitative histomorphometric analysis of trabecular bone. Although this analysis encompasses the evaluation of osteoblast and osteoclast number/activity, tfigurehe interest in osteocytes remains almost nihil. Nevertheless, this cell type is evidenced to perform a key role in bone turnover, particularly through its production of various bone proteins, such as sclerostin. In this study, we aim to investigate, in the context of ROD, to which extent an association exists between bone turnover and the abundance of osteocytes and osteocytic sclerostin expression in both the trabecular and cortical bone compartments. Additionally, the effect of parathyroid hormone (PTH) on bone sclerostin expression was examined in parathyroidectomized rats. Our results indicate that PTH exerts a direct inhibitory function on sclerostin, which in turn negatively affects bone turnover and mineralization. Moreover, this study emphasizes the functional differences between cortical and trabecular bone, as the number of (sclerostin-positive) osteocytes is dependent on the respective bone compartment. Finally, we evaluated the potential of sclerostin as a marker for CKD and found that the diagnostic performance of circulating sclerostin is limited and that changes in skeletal sclerostin expression occur more rapidly and more pronounced. The inclusion of osteocytic sclerostin expression and cortical bone analysis could be relevant when performing bone histomorphometric analysis for diagnostic purposes and to unravel pathological mechanisms of bone disease.

Cambios en el metabolismo óseo y mineral en pacientes con Enfermedad Renal Crónica sometidos a trasplante renal en el Hospital General Plaza de la Salud durante el período comprendido entre enero 2010­agosto 2018 / Changes in bone and mineral metabolism in patients with chronic kidney disease undergoing kidney transplantation at Plaza de la Salud General Hospital during the period between January 2010­August 2018

Introducción: las alteraciones del metabolismo óseo-mineral, son una causa importante de morbilidad en los pacientes con trasplante renal, por lo que el manejo de las complicaciones del paciente trasplantado, a largo plazo, deben de ser seguidas. El estudio intenta demostrar cambios en el metabolismo óseo y mineral en pacientes con enfermedad renal crónica sometidos a trasplante renal en el Hospital General Plaza de la Salud durante el período comprendido entre enero 2010 ­ agosto 2018, Santo Domingo, República Dominicana. Método: estudio observacional, descriptivo, retrospectivo y transversal de 131 trasplantes realizados en el Hospital General Plaza de la Salud, evaluando cambios de calcio (Ca), fósforo (P) y hormona paratiroidea (PTH) antes y tres meses post-trasplante. Resultados: la edad media de los pacientes incluidos fue 43.1 ±13.1 años, 72.51 % pertenecía al sexo masculino, con un tiempo medio en hemodiálisis en meses de 27.0 ± 33.6, 60 % de los trasplantes realizados fueron de donante vivo y un 63 % de los pacientes tenía HTA como comorbilidad. El nivel medio de PTH disminuyó en los primeros 3 meses posteriores al trasplante comparado con el pre-trasplante (779.6 ± 1004.0 vs. 167.9 ± 138.2 pg/ml). El fosfato disminuyó significativamente (4.9 ± 1.6 vs. 3.5 ± 0.8) y el calcio aumentó (9.0 ± 1.2 mg/dl vs. a 9.7± 0.8 mg/dl). Discusión: los cambios generales en los niveles séricos de Ca, P, PTH, BUN y creatinina desde el momento del TR a los 3 meses post TR, fueron todos significativos

Introduction: Alterations of bone-mineral metabolism are an important cause of morbidity in patients with kidney transplantation, so the management of long-term transplant patient complications should be followed. The study tries to demonstrate changes in bone and mineral metabolism in patients with chronic renal disease undergoing kidney transplant in the Hospital General Plaza de la Salud during the period January 2010 to August 2018, Santo Domingo, Dominican Republic. Method: Observational, Descriptive, Retrospective and Cross-sectional Study of 131 transplants performed at Hospital General Plaza de la Salud, evaluating changes of calcium (Ca), phosphorus (P) and parathyroid hormone (PTH) before and 3 months post-transplant. Results: The mean age of the patients included was 43.1 ± 13.1 years, 72.51% belonged to the male sex, with a mean time on hemodialysis in months of 27.0 ± 33.6, 60% of the transplants performed were from live donors and 63% from the patients had hypertension as comorbidity. The mean PTH level decreased in the first 3 months after transplantation compared to the pre-transplant (779.6 ± 1004.0 vs 167.9 ± 138.2 pg/ml). Phosphate decreased significantly (4.9 ± 1.6 vs 3.5 ± 0.8) and calcium increased (9.0 ± 1.2 mg / dl vs. 9.7 ± 0.8 mg / dl). Discussion: The general changes in serum levels of Ca, P, PTH, BUN and Creatinine from the time of TR to 3 months post TR were all significant

Cinacalcet Improves Bone Parameters Through Regulation of Osteoclast Endoplasmic Reticulum Stress, Autophagy, and Apoptotic Pathways in Chronic Kidney Disease-Mineral and Bone Disorder.

The possible mechanisms underlying the quantitative and qualitative effects of cinacalcet on bone were explored in a chronic kidney disease-mineral and bone disorder (CKD-MBD) mouse model in relation to the influence of the interactions among the osteoclast (OC) endoplasmic reticulum (ER) stress, autophagy and apoptosis pathways on OC differentiation. Body weight and biochemical parameters improved significantly in the CKD + cinacalcet groups compared to the CKD group. Micro-computed tomography (µCT) revealed both cortical and trabecular parameters deteriorated significantly in the CKD group and were reversed by cinacalcet in a dose-dependent manner. Nanoindentation analysis of bone quality proved that both cortical hardness and elastic modulus improved significantly with high dose cinacalcet treatment. In vitro studies revealed that cinacalcet inhibited receptor activator of NF-κB ligand (RANKL)/receptor activator of NF-κB (RANK)-induced OC differentiation in a concentration-dependent manner through a close interaction between activation of caspase-related apoptosis, reversal of OC autophagy through the protein kinase B (Akt)/mammalian target of rapamycin (mTOR) and adenosine monophosphate-activated protein kinase (AMPK) pathways, and attenuation of the OC ER stress/CREBH/NFATc1 signaling pathway. Cinacalcet improves both bone quantity and bone quality in CKD mouse model and inhibits OC differentiation through regulation of the interactions among the apoptosis, ER stress, and autophagy pathways within OCs. © 2021 American Society for Bone and Mineral Research (ASBMR).

A feline-focused review of chronic kidney disease-mineral and bone disorders - Part 1: Physiology of calcium handling.

Mineral derangements are a common consequence of chronic kidney disease (CKD). Despite the well-established role of phosphorus in the pathophysiology of CKD, the implications of calcium disturbances associated with CKD remain equivocal. Calcium plays an essential role in numerous physiological functions in the body and is a fundamental structural component of bone. An understanding of calcium metabolism is required to understand the potential adverse clinical implications and outcomes secondary to the (mal)adaptation of calcium-regulating hormones in CKD. The first part of this two-part review covers the physiology of calcium homeostasis (kidneys, intestines and bones) and details the intimate relationships between calcium-regulating hormones (parathyroid hormone, calcitriol, fibroblast growth factor 23, α-Klotho and calcitonin) and the role of the calcium-sensing receptor.

The Role of DMP1 in CKD-MBD.

PURPOSE OF REVIEW: Chronic kidney disease-mineral and bone disorder (CKD-MBD) has become a global health crisis with very limited therapeutic options. Dentin matrix protein 1 (DMP1) is a matrix extracellular protein secreted by osteocytes that has generated recent interest for its possible involvement in CKD-MBD pathogenesis. This is a review of DMP1 established regulation and function, and early studies implicating DMP1 in CKD-MBD. RECENT FINDINGS: Patients and mice with CKD show perturbations of DMP1 expression in bone, associated with impaired osteocyte maturation, mineralization, and increased fibroblast growth factor 23 (FGF23) production. In humans with CKD, low circulating DMP1 levels are independently associated with increased cardiovascular events. We recently showed that DMP1 supplementation lowers circulating FGF23 levels and improves bone mineralization and cardiac outcomes in mice with CKD. Mortality rates are extremely high among patients with CKD and have only marginally improved over decades. Bone disease and FGF23 excess contribute to mortality in CKD by increasing the risk of bone fractures and cardiovascular disease, respectively. Previous studies focused on DMP1 loss-of-function mutations have established its role in the regulation of FGF23 and bone mineralization. Recent studies show that DMP1 supplementation may fill a crucial therapeutic gap by improving bone and cardiac health in CKD.

Interplay between gut microbiota, bone health and vascular calcification in chronic kidney disease.

Deregulations in gut microbiota may play a role in vascular and bone disease in chronic kidney disease (CKD). As glomerular filtration rate declines, the colon becomes more important as a site of excretion of urea and uric acid, and an increased bacterial proteolytic fermentation alters the gut microbial balance. A diet with limited amounts of fibre, as well as certain medications (eg phosphate binders, iron supplementation, antibiotics) further contribute to changes in gut microbiota composition among CKD patients. At the same time, both vascular calcification and bone disease are common in patients with advanced kidney disease. This narrative review describes emerging evidence on gut dysbiosis, vascular calcification, bone demineralization and their interrelationship termed the 'gut-bone-vascular axis' in progressive CKD. The role of diet, gut microbial metabolites (ie indoxyl sulphate, p-cresyl sulphate, trimethylamine N-oxide (TMAO) and short-chain fatty acids (SCFA)), vitamin K deficiency, inflammatory cytokines and their impact on both bone health and vascular calcification are discussed. This framework may open up novel preventive and therapeutic approaches targeting the microbiome in an attempt to improve cardiovascular and bone health in CKD.

Effects of triangle grass decoction on bone metabolism in rats with chronic kidney disease complicated with mineral and bone abnormalities.

ETHNOPHARMACOLOGICAL RELEVANCE: Triangle grass is a liliaceous Chlorophytum perennial herb of ChlorophytumlaxumR.Br. It is distributed mainly in Guangdong and Guangxi Provinces of China. The initial use of triangle grass was mainly to treat bone pain and swelling caused by a fall injury. Triangle grass tablets (NO. Z20070544) are also used as a preparation in our hospital because of their analgesic, anti-inflammatory, anti-snake venom and microcirculation improvement properties and other pharmacological effects (Mei et al., 2006). Triangle grass tablets have been widely used in our hospital to treat patients with bone pain from chronic kidney disease-mineral and bone disorder (CKD-MBD). However, the effects and mechanism of triangle grass on bone metabolism in chronic kidney disease complicated with mineral and bone abnormalities are unclear. AIM OF THE STUDY: The aim of the present study was to investigate the effects of a triangle grass decoction on bone metabolism in CKD-MBD rats. MATERIALS AND METHODS: CKD-MBD model rats were subjected to 5/6 nephrectomy combined with 0.5 g NaH2PO4/rat. Serum blood urea nitrogen (BUN), creatinine (Cr), phosphorus (P), calcium (Ca), and intact parathyroid hormone (iPTH) levels were measured with an automatic biochemical analyser. Bone mineral density was determined with a Viva CT 40 system. Bone morphogenetic protein 7(BMP-7),runt-related transcription factor 2 (Runx2) and Osterix protein levels were measured by Western blot analysis. Kidney, vertebra and thoracic aorta tissue samples were assessed by histopathology and immunohistochemistry (IHC). RESULTS: The degrees of membrane thickening, necrosis, swelling and cast deposition were significantly reduced in high-dose rats and Low-dose rats. Serum BUN levels were significantly reduced in the Pre-H group (P < 0.05). Hypocalcaemia and hyperphos phataemia were detected in triangle grass (P < 0.05, P < 0.05). In addition, iPTH levels were significantly increased in the Pre-H group (P < 0.05). Alkaline phosphatase (ALP)levels were significantly decreased in the Pre-H group (P < 0.05). The bone mineral density was improved in the Pre-H and Pre-L groups. BMP-7 protein levels were significantly increased in the Pre-H group (P < 0.05). The pathological changes in muscle fibres in the thoracic aorta middle membranes were significantly alleviated in rats in the Pre-H and Pre-L groups. Changes in SM22α and SMα-act in protein levels were significantly attenuated in the Pre-H group (P < 0.05, P < 0.05). Changes in Runx2 and Osterix protein levels were also significantly attenuated in the Pre-H and Pre-L groups (P < 0.05, P < 0.05). CONCLUSIONS: Triangle grass can simultaneously ameliorate vertebral bone loss and abnormal calcification in the thoracic aorta. Triangle grass has a definite effect on bone metabolism disorder in CKD-MBD rats.

Contribution of Gut Microbiota-Derived Uremic Toxins to the Cardiovascular System Mineralization.

Chronic kidney disease (CKD) affects more than 10% of the world population and leads to excess morbidity and mortality (with cardiovascular disease as a leading cause of death). Vascular calcification (VC) is a phenomenon of disseminated deposition of mineral content within the media layer of arteries preceded by phenotypic changes in vascular smooth muscle cells (VSMC) and/or accumulation of mineral content within the atherosclerotic lesions. Medial VC results in vascular stiffness and significantly contributes to increased cardio-vascular (CV) morbidity, whereas VC of plaques may rather increase their stability. Mineral and bone disorders of CKD (CKD-MBD) contribute to VC, which is further aggravated by accumulation of uremic toxins. Both CKD-MBD and uremic toxin accumulation affect not only patients with advanced CKD (glomerular filtration rate (GFR) less than 15 mL/min./1.72 m2, end-stage kidney disease) but also those on earlier stages of a disease. The key uremic toxins that contribute to VC, i.e., p-cresyl sulphate (PCS), indoxyl sulphate (IS) and trimethylamine-N-oxide (TMAO) originate from bacterial metabolism of gut microbiota. All mentioned toxins promote VC by several mechanisms, including: Transdifferentiation and apoptosis of VSMC, dysfunction of endothelial cells, oxidative stress, interaction with local renin-angiotensin-aldosterone system or miRNA profile modification. Several attractive methods of gut microbiota manipulations have been proposed in order to modify their metabolism and to limit vascular damage (and VC) triggered by uremic toxins. Unfortunately, to date no such method was demonstrated to be effective at the level of "hard" patient-oriented or even clinically relevant surrogate endpoints.

Phosphate, Microbiota and CKD.

Phosphate is a key uremic toxin associated with adverse outcomes. As chronic kidney disease (CKD) progresses, the kidney capacity to excrete excess dietary phosphate decreases, triggering compensatory endocrine responses that drive CKD-mineral and bone disorder (CKD-MBD). Eventually, hyperphosphatemia develops, and low phosphate diet and phosphate binders are prescribed. Recent data have identified a potential role of the gut microbiota in mineral bone disorders. Thus, parathyroid hormone (PTH) only caused bone loss in mice whose microbiota was enriched in the Th17 cell-inducing taxa segmented filamentous bacteria. Furthermore, the microbiota was required for PTH to stimulate bone formation and increase bone mass, and this was dependent on bacterial production of the short-chain fatty acid butyrate. We review current knowledge on the relationship between phosphate, microbiota and CKD-MBD. Topics include microbial bioactive compounds of special interest in CKD, the impact of dietary phosphate and phosphate binders on the gut microbiota, the modulation of CKD-MBD by the microbiota and the potential therapeutic use of microbiota to treat CKD-MBD through the clinical translation of concepts from other fields of science such as the optimization of phosphorus utilization and the use of phosphate-accumulating organisms.

Osteoporosis and Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD): Back to Basics.

Osteoporosis is defined as a skeletal disorder of compromised bone strength predisposing those affected to an elevated risk of fracture. However, based on bone histology, osteoporosis is only part of a spectrum of skeletal complications that includes osteomalacia and the various forms of renal osteodystrophy of chronic kidney disease-mineral and bone disorder (CKD-MBD). In addition, the label "kidney-induced osteoporosis" has been proposed, even though the changes caused by CKD do not qualify as osteoporosis by the histological diagnosis. It is clear, therefore, that such terminology may not be helpful diagnostically or in making treatment decisions. A new label, "CKD-MBD/osteoporosis" could be a more appropriate term because it brings osteoporosis under the official label of CKD-MBD. Neither laboratory nor noninvasive diagnostic investigations can discriminate osteoporosis from the several forms of renal osteodystrophy. Transiliac crest bone biopsy can make the diagnosis of osteoporosis by exclusion of other kidney-associated bone diseases, but its availability is limited. Recently, a classification of metabolic bone diseases based on bone turnover, from low to high, together with mineralization and bone volume, has been proposed. Therapeutically, no antifracture treatments have been approved by the US Food and Drug Administration for patients with kidney-associated bone disease. Agents that suppress parathyroid hormone (vitamin D analogues and calcimimetics) are used to treat hyperparathyroid bone disease. Antiresorptive and osteoanabolic agents approved for osteoporosis are being used off-label to treat CKD stages 3b-5 in high-risk patients. It has now been suggested that intermittent administration of parathyroid hormone as early as CKD stage 2 could be an effective management strategy. If confirmed in clinical trials, it could mitigate the retention of phosphorus and subsequently the rise in fibroblast growth factor 23 and may be beneficial for coexisting osteoporosis.

Dietary Phosphorus as a Marker of Mineral Metabolism and Progression of Diabetic Kidney Disease.

Phosphorus is an essential nutrient that is critically important in the control of cell and tissue function and body homeostasis. Phosphorus excess may result in severe adverse medical consequences. The most apparent is an impact on cardiovascular (CV) disease, mainly through the ability of phosphate to change the phenotype of vascular smooth muscle cells and its contribution to pathologic vascular, valvular and other soft tissue calcification. Chronic kidney disease (CKD) is the most prevalent chronic disease manifesting with the persistent derangement of phosphate homeostasis. Diabetes and resulting diabetic kidney disease (DKD) remain the leading causes of CKD and end-stage kidney disease (ESRD) worldwide. Mineral and bone disorders of CKD (CKD-MBD), profound derangement of mineral metabolism, develop in the course of the disease and adversely impact on bone health and the CV system. In this review we aimed to discuss the data concerning CKD-MBD in patients with diabetes and to analyze the possible link between hyperphosphatemia, certain biomarkers of CKD-MBD and high dietary phosphate intake on prognosis in patients with diabetes and DKD. We also attempted to clarify if hyperphosphatemia and high phosphorus intake may impact the onset and progression of DKD. Careful analysis of the available literature brings us to the conclusion that, as for today, no clear recommendations based on the firm clinical data can be provided in terms of phosphorus intake aiming to prevent the incidence or progression of diabetic kidney disease.

P-cresol and Indoxyl Sulfate Impair Osteogenic Differentiation by Triggering Mesenchymal Stem Cell Senescence.

Chronic kidney disease (CKD) patients obtained high levels of uremic toxins progressively develop several complications including bone fractures. Protein-bound uremic toxins especially p-cresol and indoxyl sulfate are hardly eliminated due to their high molecular weight. Thus, the abnormality of bone in CKD patient could be potentially resulted from the accumulation of uremic toxins. To determine whether protein-bound uremic toxins have an impact on osteogenesis, mesenchymal stem cells were treated with either p-cresol or indoxyl sulfate under in vitro osteogenic differentiation. The effects of uremic toxins on MSC-osteoblastic differentiation were investigated by evaluation of bone phenotype. The results demonstrated that p-cresol and indoxyl sulfate down-regulated the transcriptional level of collagen type I, deceased alkaline phosphatase activity, and impaired mineralization of MSC-osteoblastic cells. Furthermore, p-cresol and indoxyl sulfate gradually increased senescence-associated beta-galactosidase positive cells while upregulated the expression of p21 which participate in senescent process. Our findings clearly revealed that the presence of uremic toxins dose-dependently influenced a gradual deterioration of osteogenesis. The effects partially mediate through the activation of senescence-associated gene lead to the impairment of osteogenesis. Therefore, the management of cellular senescence triggered by uremic toxins could be considered as an alternative therapeutic approach to prevent bone abnormality in CKD patients.

Osteoporosis in Patients with Chronic Kidney Diseases: A Systemic Review.

Chronic kidney disease (CKD) is associated with the development of mineral bone disorder (MBD), osteoporosis, and fragility fractures. Among CKD patients, adynamic bone disease or low bone turnover is the most common type of renal osteodystrophy. The consequences of CKD-MBD include increased fracture risk, greater morbidity, and mortality. Thus, the goal is to prevent the occurrences of fractures by means of alleviating CKD-induced MBD and treating subsequent osteoporosis. Changes in mineral and humoral metabolism as well as bone structure develop early in the course of CKD. CKD-MBD includes abnormalities of calcium, phosphorus, PTH, and/or vitamin D; abnormalities in bone turnover, mineralization, volume, linear growth, or strength; and/or vascular or other soft tissue calcification. In patients with CKD-MBD, using either DXA or FRAX to screen fracture risk should be considered. Biomarkers such as bALP and iPTH may assist to assess bone turnover. Before initiating an antiresorptive or anabolic agent to treat osteoporosis in CKD patients, lifestyle modifications, such as exercise, calcium, and vitamin D supplementation, smoking cessation, and avoidance of excessive alcohol intake are important. Managing hyperphosphatemia and SHPT are also crucial. Understanding the complex pathogenesis of CKD-MBD is crucial in improving one's short- and long-term outcomes. Treatment strategies for CKD-associated osteoporosis should be patient-centered to determine the type of renal osteodystrophy. This review focuses on the mechanism, evaluation and management of patients with CKD-MBD. However, further studies are needed to explore more details regarding the underlying pathophysiology and to assess the safety and efficacy of agents for treating CKD-MBD.

Nephropathic Cystinosis: A Distinct Form of CKD-Mineral and Bone Disorder that Provides Novel Insights into the Regulation of FGF23.

BACKGROUND: The rare lysosomal storage disease nephropathic cystinosis presents with renal Fanconi syndrome that evolves in time to CKD. Although biochemical abnormalities in common causes of CKD-mineral and bone disorder have been defined, it is unknown if persistent phosphate wasting in nephropathic cystinosis is associated with a biochemical mineral pattern distinct from that typically observed in CKD-mineral and bone disorder. METHODS: We assessed and compared determinants of mineral homeostasis in patients with nephropathic cystinosis across the predialysis CKD spectrum to these determinants in age- and CKD stage-matched patients, with causes of CKD other than nephropathic cystinosis. RESULTS: The study included 50 patients with nephropathic cystinosis-related CDK and 97 with CKD from other causes. All major aspects of mineral homeostasis were differentially effected in patients with CKD stemming from nephropathic cystinosis versus other causes. Patients with nephropathic cystinosis had significantly lower percent tubular reabsorption of phosphate and fibroblast growth factor-23 (FGF23) at all CKD stages, and lower blood phosphate in CKD stages 3-5. Linear regression analyses demonstrated lower FGF23 levels in nephropathic cystinosis participants at all CKD stages when corrected for eGFR and age, but not when adjusted for serum phosphate. CONCLUSIONS: Nephropathic cystinosis CKD patients have mineral abnormalities that are distinct from those in CKD stemming from other causes. Persistently increased urinary phosphate excretion maintains serum phosphate levels within the normal range, thus protecting patients with nephropathic cystinosis from elevations of FGF23 during early CKD stages. These findings support the notion that phosphate is a significant driver of increased FGF23 levels in CKD and that mineral abnormalities associated with CKD are likely to vary depending on the underlying renal disease.

Trabecular bone score may indicate chronic kidney disease-mineral and bone disorder (CKD-MBD) phenotypes in hemodialysis patients: a prospective observational study.

BACKGROUND: In the general population, the trabecular bone score (TBS) represents the bone microarchitecture and predicts fracture risk independent of bone mineral density (BMD). A few studies reported that TBS is significantly reduced in dialysis patients. Chronic kidney disease-mineral and bone disorder (CKD-MBD) are accompanied by increased fracture risk, cardiovascular morbidity, and mortality. We investigated whether TBS is associated with comorbidity related to CKD-MBD or frailty in hemodialysis patients. METHODS: In this prospective observational study, TBS was obtained using the TBS iNsight software program (Med-Imaps) with BMD dual energy x-ray absorptiometry (DXA) images (L1-L4) from prevalent hemodialysis patients. A Tilburg frailty indicator was used to evaluate frailty, and hand grip strength and bio-impedance (InBody) were measured. A patient-generated subjective global assessment (PG-SGA) was used for nutritional assessment. The history of cardiovascular events (CVE) and demographic, clinical, laboratory, and biomarker data were collated. We then followed up patients for the occurrence of CKD-MBD related complications. RESULTS: We enrolled 57 patients in total. The mean age was 56.8 ± 15.9 years (50.9% female). Prevalence of Diabetes mellitus (DM) was 40.4% and CVE was 36.8%. Mean TBS was 1.44 ± 0.10. TBS significantly reduced in the CVE group (1.38 ± 0.08 vs. 1.48 ± 0.10, p <  0.001). Multivariable regression analysis was conducted adjusting for age, sex, dialysis vintage, DM, CVE, albumin, intact parathyroid hormone, fibroblast growth factor 23, handgrip strength, and phosphate binder dose. Age (ß = - 0.030; p = 0.001) and CVE (ß = - 0.055; p = 0.024) were significant predictors of TBS. During the follow up period after TBS measurements (about 20 months), four deaths, seven incident fractures, and six new onset CVE were recorded. Lower TBS was associated with mortality (p = 0.049) or new onset fracture (p = 0.007, by log-rank test). CONCLUSION: Lower TBS was independently associated with increased age and CVE prevalence in hemodialysis patients. Mortality and fracture incidence were significantly higher in patients with lower TBS values. These findings suggest that TBS may indicate a phenotype of frailty and also a CKD-MBD phenotype reciprocal to CVE.

Circadian rhythms of mineral metabolism in chronic kidney disease-mineral bone disorder.

PURPOSE OF REVIEW: The circadian rhythms have a systemic impact on all aspects of physiology. Kidney diseases are associated with extremely high-cardiovascular mortality, related to chronic kidney disease-mineral bone disorder (CKD-MBD), involving bone, parathyroids and vascular calcification. Disruption of circadian rhythms may cause serious health problems, contributing to development of cardiovascular diseases, metabolic syndrome, cancer, organ fibrosis, osteopenia and aging. Evidence of disturbed circadian rhythms in CKD-MBD parameters and organs involved is emerging and will be discussed in this review. RECENT FINDINGS: Kidney injury induces unstable behavioral circadian rhythm. Potentially, uremic toxins may affect the master-pacemaker of circadian rhythm in hypothalamus. In CKD disturbances in the circadian rhythms of CKD-MBD plasma-parameters, activin A, fibroblast growth factor 23, parathyroid hormone, phosphate have been demonstrated. A molecular circadian clock is also expressed in peripheral tissues, involved in CKD-MBD; vasculature, parathyroids and bone. Expression of the core circadian clock genes in the different tissues is disrupted in CKD-MBD. SUMMARY: Disturbed circadian rhythms is a novel feature of CKD-MBD. There is a need to establish which specific input determines the phase of the local molecular clock and to characterize its regulation and deregulation in tissues involved in CKD-MBD. Finally, it is important to establish what are the implications for treatment including the potential applications for chronotherapy.

Dietary Protein Intake and Bone Across Stages of Chronic Kidney Disease.

PURPOSE OF REVIEW: This review aims to summarize the current evidence on the effect of very-low-, low-, and high-protein diets on outcomes related to chronic kidney disease-mineral and bone disorder (CKD-MBD) and bone health in patients with CKD. RECENT FINDINGS: Dietary protein restriction in the form of low- and very-low-protein diets have been used to slow down the progression of CKD. These diets can be supplemented with alpha-keto acid (KA) analogues of amino acids. Observational and randomized controlled trials have shown improvements in biochemical markers of CKD-MBD, including reductions in phosphorus, parathyroid hormone, and fibroblast growth factor-23. However, few studies have assessed changes in bone quantity and quality. Furthermore, studies assessing the effects of high-protein diets on CKD-MBD are scarce. Importantly, very-low- and low-protein diets supplemented with KA provide supplemental calcium in amounts that surpass current dietary recommendations, but to date there are no studies on calcium balance with KA. Current evidence suggests that dietary protein restriction in CKD may slow disease progression, which may subsequently benefit CKD-MBD and bone health outcomes. However, prospective randomized controlled trials assessing the effects of modulating dietary protein and supplementing with KA on all aspects of CKD-MBD and particularly bone health are needed.