Oh, My Gut! New insights on the role of the gastrointestinal tract and the gut microbiome in chronic kidney disease-mineral and bone disorder.

PURPOSE OF REVIEW: The aim of this review is to highlight recent evidence on the role of the gastrointestinal tract and gut microbiome on chronic kidney disease-mineral bone disorder (CKD-MBD) outcomes, including intestinal phosphorus absorption and sensing, and the effect of gut-oriented therapies. RECENT FINDINGS: Recent evidence has revealed a complex interplay among mineral metabolism and novel gut-related factors, including paracellular intestinal phosphate absorption, the gut microbiome, and the immune system, prompting a reevaluation of treatment approaches for CKD-MBD. The inhibition of NHE3 limits phosphate transport in the intestine and may lead to changes in the gut microbiome. A study in rats with CKD showed that the supplementation of the fermentable dietary inulin delayed CKD-MBD, lowering circulating phosphorus and parathyroid hormone, reducing bone remodeling and improving cortical parameters, and lowering cardiovascular calcifications. In non-CKD preclinical studies, probiotics and prebiotics improved bone formation mediated through the effect of butyrate facilitating the differentiation of T cells into Tregs, and Tregs stimulating the osteogenic Wnt10b, and butyrate was also necessary for the parathyroid hormone (PTH) bone effects. SUMMARY: Recent findings support multiple possible roles for gut-oriented therapies in addressing CKD-MBD prevention and management that should be further explored through clinical and translational studies.

Cardiovascular calcifications in dialysis patients / Calcifications cardiovasculaires chez le patient dialysé

Patients with advanced chronic kidney disease and those already on dialysis have an increased prevalence of cardiovascular calcifications. They are the cause of severe complications and are associated with a reduced life expectancy in these patients. Recommendations and imaging scores have been developed to detect and assess their importance, to guide and improve the management of cardiovascular risk. However, despite these recommendations, current practice teaches us that they are only partially applied. The prevention and treatment of cardiovascular calcifications go through the correction of classic risk factors associated with atherosclerosis, mineral and bone metabolism disorders and by optimizing the dose and the efficiency of dialysis. New therapeutic strategies are beginning to emerge, others are being evaluated, such as sodium thiosulfate, rheopheresis, vitamin K, magnesium supplementation, and SNF-472.

Les patients atteints de maladie rénale chronique (MRC) avancée et ceux déjà traités par dialyse présentent une prévalence accrue de calcifications cardiovasculaires. Elles sont à l'origine des complications sévères et s'associent à une diminution de l'espérance de vie chez ces patients. Des recommandations et des scores radiographiques ont été développés pour dépister et évaluer leur importance, afin d'orienter et améliorer la prise en charge du risque cardiovasculaire. Cependant, en dépit de ces recommandations, la pratique courante nous enseigne qu'elles ne sont que partiellement appliquées. La prévention et le traitement de calcifications cardiovasculaires passent par la correction des facteurs de risque classiques associés à l'athérosclérose, des troubles du métabolisme minéral et osseux et en optimisant la dose et l'efficacité de la dialyse. Des nouvelles stratégies thérapeutiques commencent à voir le jour, d'autres sont en cours d'évaluation, comme le thiosulfate de sodium, la rhéophérèse, la vitamine K, la supplémentation en magnésium et le SNF-472.

A meta-analysis of randomized controlled trials of tonifying kidney and strengthen bone therapy on nondialysis patients with chronic kidney disease-mineral and bone disorder.

BACKGROUND: Correction of calcium, phosphorus, and parathyroid hormone disorders is the standard of treatment in nondialysis patients with chronic kidney disease-mineral and bone disorder (CKD-MBD). However, the side effects and adverse reactions are still the main problems. Moreover, the lack of protection of kidney function in the treatment dramatically affects patients' health. Although Traditional Chinese Medicine, specifically tonifying kidney and strengthen bone (TKSB) therapy, is wildly applied to patients with CKD-MBD in China, the evidence of TKSB therapy in the treatment of CKD-MBD is limited. Thus, we conducted this meta-analysis to evaluate the efficacy and safety of TKSB therapy combined with Western medicine (WM) for nondialysis patients with CKD-MBD. METHODS: Two investigators conducted systematic research of randomized controlled trials of TKSB therapy for CKD-MBD from 7 electronic databases. Methodological quality evaluations were performed using the Cochrane collaboration tool, and data analysis was conducted by RevMan v5.3 software and STATA v15.0. RESULTS: In total, 8 randomized controlled trials involving 310 patients met the criteria of meta-analysis. The complete results showed that compared with WM alone, TKSB treatment could improve the clinical efficacy rate (risk ratio = 4.49, 95% confidence interval [CI]: [2.64, 7.61], P  .00001), calcium (weighted mean difference [WMD] = 0.11, 95% CI: [0.08, 0.14], P < .00001), serum creatinine (WMD = 45.58, 95% CI: [32.35, 58.8], P < .00001) phosphorus (WMD = 0.11, 95% CI: [0.08, 0.13], P < .00001), parathyroid hormone (WMD = 16.72, 95% CI: [12.89, 20.55], P < .00001), blood urea nitrogen levels (WMD = 0.95, 95% CI: [0.26, 1.64], P = .007) on nondialysis patients with CKD-MBD, which was beneficial to improve the patients' bone metabolic state and renal function. In addition, evidence shows that, compared with WM alone, TKSB treatment is safe and does not increase side effects. CONCLUSION: The systematic review found that TKSB therapy combined with WM has a positive effect on improving renal function and correcting bone metabolism disorder in nondialysis patients with CKD-MBD, which shows that Traditional Chinese Medicine is effective and safe in treating CKD-MBD. However, more high-quality, large-sample, multicenter clinical trials should be conducted to assess the safety and efficacy of TKSB therapy in treating nondialysis patients with CKD-MBD.Systematic review registration: INPLASY2020120086.

Long-term benefits of switching from oral to intravenous calcimimetics in patients on hemodialysis.

AIM: In this study, we aimed to investigate the long-term benefits of switching from oral to intravenous calcimimetics in patients on hemodialysis. MATERIALS AND METHODS: Patients on maintenance hemodialysis at our institution who switched from oral to intravenous calcimimetics between March 1, 2017 and October 31, 2018 were enrolled. We compared tablet number; chronic kidney disease-mineral and bone disorder (CKD-MBD)-related drug cost; and serum corrected calcium, serum phosphorous, and serum intact parathyroid hormone levels before and 1, 2, and 3 years after switching from oral to intravenous calcimimetics. RESULTS: There were 15 patients (11 males and 4 females; mean age 60.9 ± 9.2 years). The tablet numbers and CKD-MBD-related drug cost before and 3 years after switching to calcimimetics were 12.1 ± 8.1 tablets/day vs. 8.4 ± 5.0 tablets/day (p = 0.0371) and 9,654.5 ± 6,206.8 yen (87.8 ± 56.4 U.S. dollars)/week vs. 7,231.7 ± 3,490.9 yen (65.7 ± 31.7 U.S. dollars)/week (p = 0.0406), respectively. CONCLUSION: Switching from oral to intravenous calcimimetics decreased intact parathyroid hormone levels and reduced the tablet numbers and CKD-MBD-related drug cost for a long period without significant adverse effects.

Integrated network pharmacology, transcriptomics, and metabolomics analysis to reveal the mechanism of salt Eucommiae cortex in the treatment of chronic kidney disease mineral bone disorders via the PPARG/AMPK signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: The skeletal complications associated with chronic kidney diseases from stages 3-5 in individuals are called Chronic Kidney Disease-Mineral Bone Disorder (CKD-MBD), which increases the incidence of cardiovascular diseases drastically and affects the quality of life of patients seriously. Eucommiae cortex has the effect of tonifying kidneys and strengthening bones, and salt Eucommiae cortex is one of the most commonly used traditional Chinese medicines in the clinical treatment of CKD-MBD instead of Eucommiae cortex. However, its mechanism still remains unexplored. AIM OF THE STUDY: The aim of this study was to investigate the effects and mechanisms of salt Eucommiae cortex on CKD-MBD by integrating network pharmacology, transcriptomics, and metabolomics. MATERIALS AND METHODS: The CKD-MBD mice induced by 5/6 nephrectomy and low calcium/high phosphorus diet were treated with salt Eucommiae cortex. The renal functions and bone injuries were evaluated by serum biochemical detection, histopathological analyses, and femur Micro-CT examinations. Differentially expressed genes (DEGs) between the control group and model group, model group and high-dose Eucommiae cortex group, model group and high-dose salt Eucommiae cortex group were analyzed by transcriptomic analysis. The differentially expressed metabolites (DEMs) between the control group and model group, model group and high-dose Eucommiae cortex group, model group and high-dose salt Eucommiae cortex group were analyzed by metabolomics analysis. The common targets and pathways were obtained by integrating transcriptomics, metabolomics, and network pharmacology, which were identified and verified by in vivo experiments. RESULTS: The negative impacts on the renal functions and bone injuries were alleviated with salt Eucommiae cortex treatment effectively. Compared with CKD-MBD model mice, the levels of serum BUN, Ca, and urine Upr were significantly decreased in the salt Eucommiae cortex group. And the Integrated network pharmacology, transcriptomics, and metabolomics analysis revealed that Peroxisome Proliferative Activated Receptor, Gamma (PPARG) was the only common target, mainly involved by AMP-activated Protein Kinase (AMPK) signaling pathways. The activation of PPARG in the kidney tissue was significantly decreased in CKD-MBD mice but increased in the salt Eucommiae cortex treatment. The AMPK signaling pathway was verified and the AMPK expression levels were found to decrease in CKD-MBD mice but increase given salt Eucommiae cortex treatment. CONCLUSIONS: Our study presented that salt Eucommiae cortex alleviated the negative impact of CKD-MBD on the renal injury and bone injury of mice induced by 5/6 nephrectomy with the low calcium/high phosphorus diet effectively, which is highly likely achieved through the PPARG/AMPK signaling pathway.

Dentoalveolar Alterations in an Adenine-Induced Chronic Kidney Disease Mouse Model.

Chronic kidney disease (CKD) is characterized by kidney damage and loss of renal function. CKD mineral and bone disorder (CKD-MBD) describes the dysregulation of mineral homeostasis, including hyperphosphatemia and elevated parathyroid hormone (PTH) secretion, skeletal abnormalities, and vascular calcification. CKD-MBD impacts the oral cavity, with effects including salivary gland dysfunction, enamel hypoplasia and damage, increased dentin formation, decreased pulp volume, pulp calcifications, and altered jaw bones, contributing to clinical manifestations of periodontal disease and tooth loss. Underlying mechanisms are not fully understood, and CKD mouse models commonly require invasive procedures with high rates of infection and mortality. We aimed to characterize the dentoalveolar effects of an adenine diet (AD)-induced CKD (AD-CKD) mouse model. Eight-week-old C57BL/6J mice were provided either a normal phosphorus diet control (CTR) or adenine and high-phosphorus diet CKD to induce kidney failure. Mice were euthanized at 15 weeks old, and mandibles were collected for micro-computed tomography and histology. CKD mice exhibited kidney failure, hyperphosphatemia, and hyperparathyroidism in association with porous cortical bone in femurs. CKD mice showed a 30% decrease in molar enamel volume compared to CTR mice. Enamel wear was associated with reduced ductal components, ectopic calcifications, and altered osteopontin (OPN) deposition in submandibular salivary glands of CKD mice. Molar cusps in CKD mice were flattened, exposing dentin. Molar dentin/cementum volume increased 7% in CKD mice and pulp volume decreased. Histology revealed excessive reactionary dentin and altered pulp-dentin extracellular matrix proteins, including increased OPN. Mandibular bone volume fraction decreased 12% and bone mineral density decreased 9% in CKD versus CTR mice. Alveolar bone in CKD mice exhibited increased tissue-nonspecific alkaline phosphatase localization, OPN deposition, and greater osteoclast numbers. AD-CKD recapitulated key aspects reported in CKD patients and revealed new insights into CKD-associated oral defects. This model has potential for studying mechanisms of dentoalveolar defects or therapeutic interventions. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Role of nutritional vitamin D in chronic kidney disease-mineral and bone disorder: A narrative review.

Chronic kidney disease-mineral and bone disorder has complex and diverse clinical manifestations, including the simplest abnormalities of calcium, phosphorus and parathyroid hormone detected in blood, abnormalities of bone transformation and mineralization in bone, and calcification of blood vessels or other soft tissues detected on imaging. Patients with CKD-MBD combined low bone mineral density and fragility fractures are referred to as CKD-MBD with low bone mineral density. Vascular calcification refers to ectopic deposition of calcium phosphate in the blood vessel walls and heart valves. The degree of vascular calcification was inversely proportional to bone mineral density. The more severe the degree of vascular calcification, the lower the bone mineral density, and the higher the risk of death, indicating that the bone-vascular axis exists. Activation and alteration of the Wnt signaling pathway are central to the treatment of vascular diseases in uremia. Vitamin D supplementation can prevent secondary hyperparathyroidism, activate osteoblasts, relieve muscle weakness and myalgia, and reduce vascular calcification. Nutritional vitamin D may improve vascular calcification in uremia patients by regulating Wnt signaling pathway.

Effects of Plant-Based Protein Consumption on Kidney Function and Mineral Bone Disorder Outcomes in Adults With Stage 3-5 Chronic Kidney Disease: A Systematic Review.

INTRODUCTION: Plant-based protein is of growing interest for dietary management of chronic kidney disease (CKD) and is hypothesized to preserve kidney function and reduce CKD-mineral bone disorder (MBD) complications, among other benefits. This systematic review aimed to summarize the available clinical trial evidence for the effect of plant-based protein on kidney function and CKD-MBD outcomes in adults with stage 3-5 CKD not on dialysis. METHODS: Searches of Medline, Embase, Agricola, CAB abstracts, Web of Science, Scopus, and hand searching were performed. Clinical trials with ≥8 participants ≥18 years of age with an estimated glomerular filtration rate <60 mL/min/1.73 m2 but not on dialysis were included. Additionally, only clinical trials with ≥1-week interventions with ≥50% dietary protein from plant-based sources and reported at least one outcome for both kidney function and CKD-MBD outcomes were included. Of the 10,962 identified abstracts, 32 met inclusion criteria and were assessed for risk of bias. RESULTS: Results for kidney function and CKD-MBD outcomes were heterogenous, with most studies having suboptimal methodological quality. In most of the studies (27/32), protein source was altered only secondarily to low-protein diet interventions. Thus, data synthesis and interpretation were focused on a subset of five studies that investigated a change in protein source only (i.e., animal vs. plant). Of this subset, four studies reported no change in kidney function, while one study reported a decrease. Three studies reported no change in serum phosphorus, and one study reported lower serum phosphorus following a vegetarian diet. Further, limited data and inconclusive results were observed for phosphaturic hormones, parathyroid hormone, and fibroblast growth factor-23. CONCLUSION: Current clinical trial evidence on plant-based protein interventions for preserving kidney function and preventing CKD-MBD is limited to inform clinical guidelines at this time. This systematic review emphasizes the ongoing need to research the effects of plant-based protein on kidney function and CKD-MBD outcomes.

Serum and Urinary Soluble α-Klotho as Markers of Kidney and Vascular Impairment.

This study was designed to investigate the controversy on the potential role of sKlotho as an early biomarker in Chronic Kidney Disease-Mineral Bone Disorder (CKD-MBD), to assess whether sKlotho is a reliable marker of kidney α-Klotho, to deepen the effects of sKlotho on vascular smooth muscle cells (VSMCs) osteogenic differentiation and to evaluate the role of autophagy in this process. Experimental studies were conducted in CKD mice fed a normal phosphorus (CKD+NP) or high phosphorus (CKD+HP) diet for 14 weeks. The patients' study was performed in CKD stages 2-5 and in vitro studies which used VSMCs exposed to non-calcifying medium or calcifying medium with or without sKlotho. The CKD experimental model showed that the CKD+HP group reached the highest serum PTH, P and FGF23 levels, but the lowest serum and urinary sKlotho levels. In addition, a positive correlation between serum sKlotho and kidney α-Klotho was found. CKD mice showed aortic osteogenic differentiation, together with increased autophagy. The human CKD study showed that the decline in serum sKlotho is previous to the rise in FGF23. In addition, both serum sKlotho and FGF23 levels correlated with kidney function. Finally, in VSMCs, the addition of sKlotho prevented osteogenic differentiation and induced autophagy. It can be concluded that serum sKlotho was the earliest CKD-MBD biomarker, a reliable indicator of kidney α-Klotho and that might protect against osteogenic differentiation by increasing autophagy. Nevertheless, further studies are needed to investigate the mechanisms of this possible protective effect.

Diagnosis and management of mineral and bone disorders in infants with CKD: clinical practice points from the ESPN CKD-MBD and Dialysis working groups and the Pediatric Renal Nutrition Taskforce.

BACKGROUND: Infants with chronic kidney disease (CKD) form a vulnerable population who are highly prone to mineral and bone disorders (MBD) including biochemical abnormalities, growth retardation, bone deformities, and fractures. We present a position paper on the diagnosis and management of CKD-MBD in infants based on available evidence and the opinion of experts from the European Society for Paediatric Nephrology (ESPN) CKD-MBD and Dialysis working groups and the Pediatric Renal Nutrition Taskforce. METHODS: PICO (Patient, Intervention, Comparator, Outcomes) questions were generated, and relevant literature searches performed covering a population of infants below 2 years of age with CKD stages 2-5 or on dialysis. Clinical practice points (CPPs) were developed and leveled using the American Academy of Pediatrics grading matrix. A Delphi consensus approach was followed. RESULTS: We present 34 CPPs for diagnosis and management of CKD-MBD in infants, including dietary control of calcium and phosphate, and medications to prevent and treat CKD-MBD (native and active vitamin D, calcium supplementation, phosphate binders). CONCLUSION: As there are few high-quality studies in this field, the strength of most statements is weak to moderate, and may need to be adapted to individual patient needs by the treating physician. Research recommendations to study key outcome measures in this unique population are suggested. A higher resolution version of the Graphical abstract is available as Supplementary information.

[Diagnosis and treatment of osteoporosis in patients with chronic kidney disease : Joint guidelines of the Austrian Society for Bone and Mineral Research (ÖGKM), the Austrian Society of Physical and Rehabilitation Medicine (ÖGPMR) and the Austrian Society of Nephrology (ÖGN)]. / Diagnose und Therapie der Osteoporose bei Patienten mit chronischer Niereninsuffizienz : Gemeinsame Leitlinie der Österreichischen Gesellschaft für Knochen- und Mineralstoffwechsel (ÖGKM), der Österreichischen Gesellschaft für Physikalische Medizin und Rehabilitation (ÖGPMR) und der Österreichischen Gesellschaft für Nephrologie (ÖGN).

DEFINITION AND EPIDEMIOLOGY: Chronic kidney disease (CKD): abnormalities of kidney structure or function, present for over 3 months. Staging of CKD is based on GFR and albuminuria (not graded). Osteoporosis: compromised bone strength (low bone mass, disturbance of microarchitecture) predisposing to fracture. By definition, osteoporosis is diagnosed if the bone mineral density T­score is ≤ -2.5. Furthermore, osteoporosis is diagnosed if a low-trauma (inadequate trauma) fracture occurs, irrespective of the measured T­score (not graded). The prevalence of osteoporosis, osteoporotic fractures and CKD is increasing worldwide (not graded). PATHOPHYSIOLOGY, DIAGNOSIS AND TREATMENT OF CHRONIC KIDNEY DISEASE-MINERAL AND BONE DISORDER (CKD-MBD): Definition of CKD-MBD: a systemic disorder of mineral and bone metabolism due to CKD manifested by either one or a combination of the following: abnormalities of calcium, phosphorus, PTH, or vitamin D metabolism; renal osteodystrophy; vascular calcification (not graded). Increased, normal or decreased bone turnover can be found in renal osteodystrophy (not graded). Depending on CKD stage, routine monitoring of calcium, phosphorus, alkaline phosphatase, PTH and 25-OH-vitamin D is recommended (2C). Recommendations for treatment of CKD-MBD: Avoid hypercalcemia (1C). In cases of hyperphosphatemia, lower phosphorus towards normal range (2C). Keep PTH within or slightly above normal range (2D). Vitamin D deficiency should be avoided and treated when diagnosed (1C). DIAGNOSIS AND RISK STRATIFICATION OF OSTEOPOROSIS IN CKD: Densitometry (using dual X­ray absorptiometry, DXA): low T­score correlates with increased fracture risk across all stages of CKD (not graded). A decrease of the T­score by 1 unit approximately doubles the risk for osteoporotic fracture (not graded). A T-score ≥ -2.5 does not exclude osteoporosis (not graded). Bone mineral density of the lumbar spine measured by DXA can be increased and therefore should not be used for the diagnosis or monitoring of osteoporosis in the presence of aortic calcification, osteophytes or vertebral fracture (not graded). FRAX can be used to aid fracture risk estimation in all stages of CKD (1C). Bone turnover markers can be measured in individual cases to monitor treatment (2D). Bone biopsy may be considered in individual cases, especially in patients with CKD G5 (eGFR < 15 ml/min/1.73 m2) or CKD 5D (dialysis). SPECIFIC TREATMENT OF OSTEOPOROSIS IN PATIENTS WITH CKD: Hypocalcemia should be treated and serum calcium normalized before initiating osteoporosis therapy (1C). CKD G1-G2 (eGFR ≥ 60 ml/min/1.73 m2): treat osteoporosis as recommended for the general population (1A). CKD G3-G5D (eGFR < 60 ml/min/1.73 m2 to dialysis): treat CKD-MBD first before initiating osteoporosis treatment (2C). CKD G3 (eGFR 30-59 ml/min/1.73 m2) with PTH within normal limits and osteoporotic fracture and/or high fracture risk according to FRAX: treat osteoporosis as recommended for the general population (2B). CKD G4-5 (eGFR < 30 ml/min/1.73 m2) with osteoporotic fracture (secondary prevention): Individualized treatment of osteoporosis is recommended (2C). CKD G4-5 (eGFR < 30 ml/min/1.73 m2) and high fracture risk (e.g. FRAX score > 20% for a major osteoporotic fracture or > 5% for hip fracture) but without prevalent osteoporotic fracture (primary prevention): treatment of osteoporosis may be considered and initiated individually (2D). CKD G4-5D (eGFR < 30 ml/min/1.73 m2 to dialysis): Calcium should be measured 1-2 weeks after initiation of antiresorptive therapy (1C). PHYSICAL MEDICINE AND REHABILITATION: Resistance training prioritizing major muscle groups thrice weekly (1B). Aerobic exercise training for 40 min four times per week (1B). Coordination and balance exercises thrice weekly (1B). Flexibility exercise 3-7 times per week (1B).

Investigation on maintenance hemodialysis patients with mineral and bone disorder in Anhui province, China.

BACKGROUND: Chronic kidney disease-mineral bone disorder (CKD-MBD) is a common comorbidity in patients with CKD. The study aims to describe the control rates of serum-corrected calcium (Ca), phosphate (P) and intact parathyroid hormone (iPTH) and its risk factors among maintenance hemodialysis (MHD) patients in Anhui Province of China. METHODS: The study was conducted in 27 hemodialysis centers of Anhui Province between January 1st 2020 and December 31th 2020. Chi-square test was used to compare the control rates of serum-corrected Ca, P and iPTH between the present study and DOPPS 4 or Anhui Province in 2014. Binary logistic regression analysis was used to explore the risk factors of the control rates of serum-corrected Ca, P and iPTH. RESULTS: A total of 3 025 MHD patients were recruited in this study, with a mean age of 54.8 (SD: 12.8) years, and 60.1% were males. According to the Chinese Diagnosis and Treatment Guidelines for CKD-MBD, the control rates of serum-corrected Ca, P and iPTH in the present study were 57.9%, 20.0% and 56.0%, respectively. Based on KDOQI guidelines (2003), the control rates of the above indicators were 43.1%, 35.3% and 22.3%, respectively. The control rates of serum-corrected Ca, P and iPTH in this study were lower than those of DOPPS 4 (P < 0.001). Compared to the results of Anhui Province in 2014, the control rate of corrected Ca was higher (P < 0.001) and the control rate of iPTH was lower (P = 0.005). Age, residential area, BMI, dialysis vintage, albumin and hemoglobin levels were factors of serum-corrected Ca, P and iPTH not within target range. CONCLUSION: The control rates of serum-corrected Ca, P and iPTH in MHD patients in Anhui Province are relatively low. Monitoring and management should be strengthened to improve the prognosis of patients undergoing dialysis.

FGF23 Actions in CKD-MBD and other Organs During CKD.

Fibroblast growth factor 23 (FGF23) is a new endocrine product discovered in the past decade. In addition to being related to bone diseases, it has also been found to be related to kidney metabolism and parathyroid metabolism, especially as a biomarker and a key factor to be used in kidney diseases. FGF23 is upregulated as early as the second and third stages of chronic kidney disease (CKD) in response to relative phosphorus overload. The early rise of FGF23 has a protective effect on the body and is essential for maintaining phosphate balance. However, with the decline in renal function, eGFR (estimated glomerular filtration rate) declines, and the phosphorus excretion effect caused by FGF23 is weakened. It eventually leads to a variety of complications, such as bone disease (Chronic Kidney Disease-Mineral and Bone Metabolism Disorder), vascular calcification (VC), and more. Monoclonal antibodies against FGF23 are currently used to treat genetic diseases with increased FGF23. CKD is also a state of increased FGF23. This article reviews the current role of FGF23 in CKD and discusses the crosstalk between various organs under CKD conditions and FGF23. Studying the effect of hyperphosphatemia on different organs of CKD is important. The prospect of FGF23 for therapy is also discussed.

Increased PHOSPHO1 expression mediates cortical bone mineral density in renal osteodystrophy.

Patients with advanced chronic kidney disease (CKD) often present with skeletal abnormalities, a condition known as renal osteodystrophy (ROD). While tissue non-specific alkaline phosphatase (TNAP) and PHOSPHO1 are critical for bone mineralization, their role in the etiology of ROD is unclear. To address this, ROD was induced in both WT and Phospho1 knockout (P1KO) mice through dietary adenine supplementation. The mice presented with hyperphosphatemia, hyperparathyroidism, and elevated levels of FGF23 and bone turnover markers. In particular, we noted that in CKD mice, bone mineral density (BMD) was increased in cortical bone (P < 0.05) but decreased in trabecular bone (P < 0.05). These changes were accompanied by decreased TNAP (P < 0.01) and increased PHOSPHO1 (P < 0.001) expression in WT CKD bones. In P1KO CKD mice, the cortical BMD phenotype was rescued, suggesting that the increased cortical BMD of CKD mice was driven by increased PHOSPHO1 expression. Other structural parameters were also improved in P1KO CKD mice. We further investigated the driver of the mineralization defects, by studying the effects of FGF23, PTH, and phosphate administration on PHOSPHO1 and TNAP expression by primary murine osteoblasts. We found both PHOSPHO1 and TNAP expressions to be downregulated in response to phosphate and PTH. The in vitro data suggest that the TNAP reduction in CKD-MBD is driven by the hyperphosphatemia and/or hyperparathyroidism noted in these mice, while the higher PHOSPHO1 expression may be a compensatory mechanism. Increased PHOSPHO1 expression in ROD may contribute to the disordered skeletal mineralization characteristic of this progressive disorder.

Role of Vitamin K in Chronic Kidney Disease: A Focus on Bone and Cardiovascular Health.

Chronic kidney disease (CKD) is commonly associated with vitamin K deficiency. Some of the serious complications of CKD are represented by cardiovascular disease (CVD) and skeletal fragility with an increased risk of morbidity and mortality. A complex pathogenetic link between hormonal and ionic disturbances, bone tissue and metabolism alterations, and vascular calcification (VC) exists and has been defined as chronic kidney disease-mineral and bone disorder (CKD-MBD). Poor vitamin K status seems to have a key role in the progression of CKD, but also in the onset and advance of both bone and cardiovascular complications. Three forms of vitamin K are currently known: vitamin K1 (phylloquinone), vitamin K2 (menaquinone), and vitamin K3 (menadione). Vitamin K plays different roles, including in activating vitamin K-dependent proteins (VKDPs) and in modulating bone metabolism and contributing to the inhibition of VC. This review focuses on the biochemical and functional characteristics of vitamin K vitamers, suggesting this nutrient as a possible marker of kidney, CV, and bone damage in the CKD population and exploring its potential use for promoting health in this clinical setting. Treatment strategies for CKD-associated osteoporosis and CV disease should include vitamin K supplementation. However, further randomized clinical studies are needed to assess the safety and the adequate dosage to prevent these CKD complications.

Effects of ferric citrate and intravenous iron sucrose on markers of mineral, bone, and iron homeostasis in a rat model of CKD-MBD.

BACKGROUND: Anemia and chronic kidney disease-mineral and bone disorder (CKD-MBD) are common and begin early in CKD. Limited studies have concurrently compared the effects of ferric citrate (FC) versus intravenous (IV) iron on CKD-MBD and iron homeostasis in moderate CKD. METHODS: We tested the effects of 10 weeks of 2% FC versus IV iron sucrose in rats with moderate CKD (Cy/+ male rat) and untreated normal (NL) littermates. Outcomes included a comprehensive assessment of CKD-MBD, iron homeostasis and oxidative stress. RESULTS: CKD rats had azotemia, elevated phosphorus, parathyroid hormone and fibroblast growth factor-23 (FGF23). Compared with untreated CKD rats, treatment with FC led to lower plasma phosphorus, intact FGF23 and a trend (P = 0.07) toward lower C-terminal FGF23. FC and IV iron equally reduced aorta and heart calcifications to levels similar to NL animals. Compared with NL animals, CKD animals had higher bone turnover, lower trabecular volume and no difference in mineralization; these were unaffected by either iron treatment. Rats treated with IV iron had cortical and bone mechanical properties similar to NL animals. FC increased the transferrin saturation rate compared with untreated CKD and NL rats. Neither iron treatment increased oxidative stress above that of untreated CKD. CONCLUSIONS: Oral FC improved phosphorus homeostasis, some iron-related parameters and the production and cleavage of FGF23. The intermittent effect of low-dose IV iron sucrose on cardiovascular calcification and bone should be further explored in moderate-advanced CKD.

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).

Effect of Magnesium Supplementation on Chronic Kidney Disease-Mineral and Bone Disorder in Hemodialysis Patients: A Meta-Analysis of Randomized Controlled Trials.

OBJECTIVES: Research about the effects of magnesium (Mg) supplementation on chronic kidney disease-mineral bone disorder (CKD-MBD) among hemodialysis (HD) patients is controversial. Thus, we conducted a meta-analysis to examine Mg supplementation's effects on CKD-MBD in patients requiring dialysis. METHODS: The PubMed and EMBASE databases were searched for English language studies up to September 2020. The main indicators of our study were changes in serum Mg, calcium (Ca), phosphate, parathyroid hormone (PTH), and C-reactive protein levels, and carotid intima-media thickness (CIMT) after Mg supplementation. Mg efficacy was evaluated by weighted mean difference (WMD) and confidence intervals (CIs), and subgroup analyses of intervention type and intervention duration were also performed. RESULTS: Eight eligible studies comprising 309 HD patients were included in our meta-analysis. Mg supplementation alone produced a negative effect on serum PTH levels (WMD = -236.56; 95% CI -349.71 to -123.41) and CIMT (WMD = -0.18; 95% CI -0.34 to -0.01). A subgroup analysis based on intervention type showed a significant improvement in serum Mg (WMD = 1.08; 95% CI 0.51-1.64) and Ca (WMD = -0.50; 95% CI -0.77 to -0.23) levels when Mg was administered via dialysate and oral medication, respectively. Different intervention durations had no effect on serum Mg levels. Mg supplementation had no significant effect on serum phosphate (WMD = -0.25; 95% CI -0.64 to 0.14) and C-reactive protein levels (WMD = -0.02; 95% CI -2.80 to 2,76). CONCLUSIONS: Our results showed that Mg supplementation alone could improve CKD-MBD by regulating serum Ca and PTH metabolism and decreasing CIMT among HD patients.

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.

The Importance of Phosphate Control in Chronic Kidney Disease.

A series of problems including osteopathy, abnormal serum data, and vascular calcification associated with chronic kidney disease (CKD) are now collectively called CKD-mineral bone disease (CKD-MBD). The pathophysiology of CKD-MBD is becoming clear with the emerging of αKlotho, originally identified as a progeria-causing protein, and bone-derived phosphaturic fibroblast growth factor 23 (FGF23) as associated factors. Meanwhile, compared with calcium and parathyroid hormone, which have long been linked with CKD-MBD, phosphate is now attracting more attention because of its association with complications and outcomes. Incidentally, as the pivotal roles of FGF23 and αKlotho in phosphate metabolism have been unveiled, how phosphate metabolism and hyperphosphatemia are involved in CKD-MBD and how they can be clinically treated have become of great interest. Thus, the aim of this review is reconsider CKD-MBD from the viewpoint of phosphorus, its involvement in the pathophysiology, causing complications, therapeutic approach based on the clinical evidence, and clarifying the importance of phosphorus management.