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.

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.

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.

Impact of Cinacalcet and Etelcalcetide on Bone Mineral and Cardiovascular Disease in Dialysis Patients.

PURPOSES OF REVIEW: With chronic kidney disease (CKD) progression, secondary hyperparathyroidism (sHPT) and mineral and bone metabolism disease (MBD) almost inevitably develop and result in renal osteodystrophy and cardiovascular disease (CVD). Together with active vitamin D, calcimimetics are the main therapy for sHPT in CKD. This review provides an overview of the therapeutic effects of oral cinacalcet and intravenous etelcalcetide on CKD-MBD and vascular disease, with a focus on pediatric dialysis patients. RECENT FINDINGS: Randomized controlled trials in adults and children demonstrate efficient lowering of parathyroid hormone (PTH) by the calcimimetics together with a reduction in serum calcium and phosphate when combined with low-dose active vitamin D, while therapy with active vitamin D analogs alone increases serum calcium and phosphate. Cinacalcet and etelcalcetide both improve bone formation and correct adynamic bone, i.e., have a direct bone anabolic effect. They decrease serum calciprotein particles, which are involved in endothelial dysfunction, atherogenesis, and vascular calcification. Clinical trials in adults suggest a modest slowing of the progression of cardiovascular calcification with cinacalcet. Calcimimetic agents represent a major pharmacological tool for improved control of CKD-MBD, by efficiently counteracting sHPT and allowing for better control of calcium/phosphate and bone homeostasis. Albeit definite evidence is lacking, the beneficial effects of calcimimetics on CVD are promising. Routine use of cinacalcet has been suggested in children.

Roxadustat improves renal osteodystrophy by dual regulation of bone remodeling.

PURPOSE: Renal osteodystrophy (ROD), a component of chronic kidney disease-mineral and bone disorder (CKD-MBD) can lead to bone loss increasing fracture risks in CKD patients. Therefore, it is important to prevent and treat ROD. Activation of hypoxia-inducible factor-1α (HIF-1α) signaling was reported to prevent osteoporotic bone loss. Roxadustat, which is used to treat renal anemia in the clinic, is a novel HIF stabilizer. In our study, we aimed to investigate the effects of roxadustat on ROD. METHODS: We established an adenine-induced CKD rat model. Roxadustat was administered intragastrically to normal and CKD rats for 4 weeks. Hemoglobin concentrations and serum biochemical parameters were tested, and bone histomorphometric analysis was performed. RESULTS: CKD rats exhibited impaired renal function with anemia, secondary hyperparathyroidism and high-turnover ROD-induced significant bone loss. Roxadustat ameliorated renal anemia and attenuated the extreme increase in intact parathyroid hormone (iPTH) and fibroblast growth factor 23 (FGF23) in CKD rats. Bone histomorphometric analysis showed that roxadustat significantly alleviated bone loss and bone microarchitecture deterioration in CKD rats by increasing osteoblast activity and inhibiting osteoclast activity. We did not find that roxadustat had significant effects on bone metabolism in normal rats. CONCLUSION: Roxadustat can improve ROD via dual regulation of bone remodeling. The use of roxadustat may be a promising strategy to treat osteoporotic bone disorders, such as ROD.

To what extent can we achieve mineral bone metabolism treatment targets suggested by the KDIGO guidelines among chronic kidney disease stage 3 - 5 non-dialysis patients?

INTRODUCTION: Real-life data on the predialysis management of chronic kidney disease (CKD) is scarce. In this study, our aim was to investigate the current clinical practice and compliance among nephrologists with the KDIGO chronic kidney disease-mineral and bone disorder (CKD-MBD) guidelines. MATERIALS AND METHODS: In this multicenter cross-sectional study, we recruited stage 3 - 5 non-dialysis (ND) CKD patients and recorded the data related to CKD-MBD from two consecutive outpatient clinical visits 3 - 6 months apart. We calculated the therapeutic inertia for hyperphosphatemia, hypocalcemia, hyperparathyroidism, and hypovitaminosis D, in addition to overtreatment for hypophosphatemia, hypercalcemia, hypoparathyroidism, and hypervitaminosis D. RESULTS: We examined a total of 302 patients (male: 48.7%, median age: 67 years). The persistence of low 25-hydroxy vitamin D levels was the most common laboratory abnormality related to CKD-MBD (61.7%), followed by hyperparathyroidism (14.8%), hyperphosphatemia (7.9%), and hypocalcemia (0.0%). According to our results, therapeutic inertia seems to be a more common problem than overtreatment for all the CKD-MBD laboratory parameters that we examined. Therapeutic inertia frequency was highest for hypovitaminosis D (81.1%), followed by hypocalcemia (75.0%), hyperparathyroidism (59.0%), and hyperphosphatemia (30.4%). CONCLUSION: We concluded that CKD-MBD is not optimally managed in CKD stage 3 - 5 ND patients. Clinicians should have an active attitude regarding the correction of MBD even at the earlier stages of CKD.

Calcimimetics Alter Periosteal and Perilacunar Bone Matrix Composition and Material Properties in Early Chronic Kidney Disease.

Chronic kidney disease (CKD) affects 15% of Americans and greatly increases fracture risk due to elevated parathyroid hormone, cortical porosity, and reduced bone material quality. Calcimimetic drugs are used to lower parathyroid hormone (PTH) in CKD patients, but their impact on bone matrix properties remains unknown. We hypothesized that tissue-level bone quality is altered in early CKD and that calcimimetic treatment will prevent these alterations. To test this hypothesis, we treated Cy/+ rats, a model of spontaneous and progressive CKD-mineral and bone disorder (CKD-MBD), with KP-2326, a preclinical analogue of etelcalcetide, early in the CKD disease course. To measure tissue-level bone matrix composition and material properties, we performed colocalized Raman spectroscopy and nanoindentation on new periosteal bone and perilacunar bone using hydrated femur sections. We found that CKD and KP treatment lowered mineral type B carbonate substitution whereas KP treatment increased mineral crystallinity in new periosteal bone. Reduced elastic modulus was lower in CKD but was not different in KP-treated rats versus CTRL. In perilacunar bone, KP treatment lowered type B carbonate substitution, increased crystallinity, and increased mineral-to-matrix ratio in a spatially dependent manner. KP treatment also increased reduced elastic modulus and hardness in a spatially dependent manner. Taken together, these data suggest that KP treatment improves material properties on the tissue level through a combination of lowering carbonate substitution, increasing mineral crystallinity, and increasing relative mineralization of the bone early in CKD. As a result, the mechanical properties were improved, and in some regions, were the same as control animals. Therefore, calcimimetics may help prevent CKD-induced bone deterioration by improving bone quality in new periosteal bone and in bone tissue near osteocyte lacunae. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

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.

Chronic Kidney Disease-Mineral Bone Disease Biomarkers in Kidney Transplant Patients.

BACKGROUND: Kidney transplant patients frequently suffer from Chronic Kidney Disease associated with Mineral Bone Disease (CKD-MBD), a complex condition that affects mainly kidney transplant patients. Post-transplantation bone disease is complex, especially in patients with pre-existing metabolic bone disorders that are further affected by immunosuppressive medications and changes in renal allograft function. Main biochemical abnormalities of mineral metabolism in kidney transplantation (KTx) include hypophosphatemia, hyperparathyroidism (HPTH), insufficiency or deficiency of vitamin D, and hypercalcemia. OBJECTIVE: This review aims to summarize the pathophysiology and main biomarkers of CKD-MBD in KTx. METHODS: A comprehensive and non-systematic search in PubMed was independently made, emphasizing biomarkers in mineral bone disease in KTx. RESULTS: CKD-MBD can be associated with numerous factors, including secondary HPTH, metabolic dysregulations before KTx, and glucocorticoid therapy in post-transplant subjects. Fibroblast growth factor 23 (FGF23) reaches normal levels after KTx with good allograft function, while calcium, vitamin D, and phosphorus, ultimately result in hypercalcemia, persistent vitamin D insufficiency, and hypophosphatemia, respectively. As for PTH levels, there is an initial tendency of a significant decrease, followed by a rise due to secondary or tertiary HPTH. In regard to sclerostin levels, there is no consensus in the literature. CONCLUSION: KTx patients should be continuously evaluated for mineral homeostasis and bone status, both in cases with successful kidney transplantation and those with reduced functionality. Additional research on CKD-MBD pathophysiology, diagnosis, and management is essential to guarantee long-term graft function, better prognosis, good quality of life, and reduced mortality for KTx patients.

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.

Effect of vitamin D sterols on bone histology in pre-dialysis patients: A prospective controlled study.

BACKGROUND: Abnormalities related to mineral and bone metabolism are a common finding in chronic kidney disease (CKD). Vitamin D compounds are often prescribed to CKD patients with the purpose to control secondary hyperparathyroidism and reduce the risk of high-turnover bone disease. However, data on the effect of vitamin D sterols on bone histology in non-dialysis CKD is limited. MATERIALS AND METHODS: A prospective controlled study was conducted on a cohort of 56 patients with CKD stages 3 and 4. 19 patients on calcitriol and 12 patients on cholecalciferol were compared to a group of 25 age- and sex-matched controls. Participants underwent a tetracycline double-labelled transiliac bone biopsy before starting therapy and again 12 months later. Changes from baseline in circulating biomarkers and bone histomorphometric parameters were analyzed. RESULTS: Low-turnover bone disease was the most common pattern of renal osteodystrophy on the initial biopsy. There was no difference in biochemical or histomorphometric values between the three study groups at baseline. Serum intact parathormone (iPTH) and bone formation rate decreased significantly in calcitriol-treated patients, with prevalence of low-turnover bone disease doubling from baseline. In contrast, no significant changes were noted in cholecalciferol-treated and control subjects. CONCLUSION: Calcitriol was effective in preventing secondary hyperparathyroidism and high-turnover bone disease. However, it was associated with an increased risk of developing or aggravating low-turnover bone disease. In the absence of a bone biopsy, calcitriol use in pre-dialysis CKD should be reserved for patients with a progressive rise in iPTH levels, in whom high-turnover bone disease is suspected.

Pediatric CKD-MBD: existing and emerging treatment approaches.

The effects of bone and mineral metabolism on skeletal formation, as well as vascular and soft tissue calcifications, define chronic kidney disease-metabolic bone disease (CKD-MBD). Treatment recommendations center on establishing adequate vitamin D status, phosphate control through diet restriction and phosphate binders, and the use of vitamin D analogs for specific indications. Several emerging bone-promoting therapies have now been studied in adults with CKD, including bisphosphonates and denosumab. These approaches are associated with improved bone mass and, in some cases, decreased fracture rates in adults with CKD-MBD and are of potential interest for some children with CKD-MBD. In children with CKD and immobilization and/or muscle weakness, bisphosphonates appear to be an effective treatment to increase bone mass; baseline assessment and careful monitoring of bone density and/or bone biopsy findings are important in consideration of any new bone therapies for children with CKD-MBD.

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.

Etelcalcetide Utilization, Dosing Titration, and Chronic Kidney Disease-Mineral and Bone Disease (CKD-MBD) Marker Responses in US Hemodialysis Patients.

RATIONALE & OBJECTIVE: Clinical trial data have demonstrated the efficacy of etelcalcetide for reducing parathyroid hormone (PTH) levels in hemodialysis (HD) patients. We provide a real-world summary of etelcalcetide utilization, dosing, effectiveness, and discontinuation since its US introduction in April 2017. STUDY DESIGN: New-user design within prospective cohort. SETTING & PARTICIPANTS: 2,596 new users of etelcalcetide from April 2017 through August 2019 in a national sample of adult maintenance HD patients in the US Dialysis Outcomes and Practice Patterns Study (DOPPS). PREDICTORS: Baseline PTH, prior cinacalcet use, initial etelcalcetide dose. OUTCOME: Trajectories of etelcalcetide dose, chronic kidney disease-mineral and bone disease (CKD-MBD) medications, and levels of PTH, serum calcium, and phosphorus in the 12 months after etelcalcetide initiation. ANALYTICAL APPROACH: Cumulative incidence methods for etelcalcetide discontinuation and linear generalized estimating equations for trajectory analyses. RESULTS: By August 2019, etelcalcetide prescriptions increased to 6% of HD patients from their first use in April 2017. Starting etelcalcetide dose was 15 mg/wk in 70% of patients and 7.5 mg/wk in 27% of patients; 49% of new users were prescribed cinacalcet in the prior 3 months. Etelcalcetide discontinuation was 9%, 17%, and 27% by 3, 6, and 12 months after initiation. One year after etelcalcetide initiation, mean PTH levels declined by 40%, from 948 to 566 pg/mL, and the proportion of patients with PTH within target (150-599 pg/mL) increased from 33% to 64% overall, from 0 to 60% among patients with baseline PTH ≥ 600 pg/mL, and from 30% to 63% among patients with prior cinacalcet use. The proportion of patients with serum phosphorus > 5.5 mg/dL decreased from 55% to 45%, while the prevalence of albumin-corrected serum calcium < 7.5 mg/dL remained at 1%-2%. There were increases in use of active vitamin D (from 77% to 87%) and calcium-based phosphate binders (from 41% to 50%) in the 12 months after etelcalcetide initiation. LIMITATIONS: Data are unavailable for provider dosing protocols, dose holds, or reasons for discontinuation. CONCLUSIONS: In the 12 months after etelcalcetide initiation, patients had large and sustained reductions in PTH levels. These results support the utility of etelcalcetide as an effective therapy to achieve the KDIGO-recommended guidelines for CKD-MBD markers in HD patients.

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).

Characterization of Medication Trends for Chronic Kidney Disease: Mineral and Bone Disorder Treatment Using Electronic Health Record-Based Common Data Model.

Chronic kidney disease-mineral bone disorder (CKD-MBD) is the most common complication in CKD patients. Although there is a consensus on treatment guidelines for CKD-MBD, it remains uncertain whether these treatment recommendations reflect actual practice. Therefore, the aim of this study was to investigate the CKD-MBD medication trend in real-world practice. This was a retrospective and observational study using a 12-year period database transformed into a common data model from three tertiary university hospitals. Study populations were subjects initially diagnosed as CKD. The date of diagnosis was designated as the index date. New patients were categorized year to year from 2008 to 2019 with a fixed observation period of 365 days to check the prescription of CKD-MBD medications including calcium-containing phosphate binder, noncalcium-containing phosphate binder, aluminium hydroxide, vitamin D receptor activator (VDRA), and cinacalcet. The numbers of CKD patients in the three hospitals were 7555, 2424, and 5351, respectively. The proportion for patients with CKD-MBD medication prescription decreased yearly regardless of hospital and CKD stage (p for trend < 0.05). The use of aluminium hydroxide disappeared steadily while the use of VDRA increased annually in all settings. Despite these changes in prescription patterns, the mean value for CKD-MBD-related serologic markers was almost within target range. The proportion of the population within the target value was not significantly changed. Irrespective of hospital and CKD stage, similar trends of prescription for CKD-MBD medications were observed in real-world practice. Further research with a distributed network study may be helpful to understand medication trends in CKD-MBD treatment.

Safety and effectiveness of lanthanum carbonate for hyperphosphatemia in chronic kidney disease (CKD) patients: a meta-analysis.

OBJECTIVE: The aim of this study was to determine the efficacy and safety of lanthanum carbonate (LC) versus calcium salts, non-LC phosphate binders (PBs), sevelamer, or placebo in patients with chronic kidney disease (CKD). MATERIALS AND METHODS: A literature search on PubMed, Embase, and Cochrane Library databases was conducted up to 18 June 2021. Data acquisition and quality assessment were performed by two reviewers. Meta-analysis was performed to evaluate the serum biochemical parameters, adverse events, and patient-level outcomes of LC, non-LC PBs, and sevelamer for hyperphosphatemia in patients with CKD. Heterogeneity across studies was assessed utilizing the I2 statistic and Q-test, and a random effect model was selected to calculate the pooled effect size. RESULTS: A total of 26 randomized, controlled trials and 3 observational studies were included. Compared to the other groups, better control effect of serum phosphorus (RR = 2.68, p < 0.001), reduction in serum phosphorus (95%CI = -1.93, -0.99; p < 0.001), Ca × P (95%CI = -13.89, -2.99; p = 0.002), serum intact parathyroid hormone levels (95%CI = -181.17, -3.96, p = 0.041) were found in LC group. Besides, reduced risk of various adverse effects, such as hypotension, abdominal pain, diarrhea, dyspepsia, and a score of coronary artery calcification were identified with LC in comparison to calcium salt, non-LC PBs, or placebo group. Significantly lower risk in mortality with LC treatment vs. non-LC PBs was observed, while no significant difference was identified between LC and calcium salt groups. CONCLUSION: LC might be an alternative treatment for hyperphosphatemia in patients with CKD considering its comprehensive curative effect.

Importance of bone turnover for therapeutic decisions in patients with CKD-MBD.

Patients with chronic kidney disease-mineral and bone disorder (CKD-MBD) frequently have low bone formation rates. A recent review suggested that adynamic bone disease is not always associated with negative outcomes and therefore antiresorptive medications could be used more often. However, there is currently no evidence to support an improvement in fracture risk or mortality in patients with CKD-MBD and low bone turnover who are treated with antiresorptive medication. There is reasonable pathophysiological evidence suggesting that it may even be harmful.

Differentiating the causes of adynamic bone in advanced chronic kidney disease informs osteoporosis treatment.

Patients with chronic kidney disease (CKD) have an increased fracture risk because of impaired bone quality and quantity. Low bone mineral density predicts fracture risk in all CKD stages, including advanced CKD (CKD G4-5D). Pharmacological therapy improves bone mineral density and reduces fracture risk in moderate CKD. Its efficacy in advanced CKD remains to be determined, although pilot studies suggest a positive effect on bone mineral density. Currently, antiresorptive agents are the most commonly prescribed drugs for the prevention and therapy of osteoporosis. Their use in advanced CKD has been limited by the lack of large clinical trials and fear of causing kidney dysfunction and adynamic bone disease. In recent decades, adynamic bone disease has evolved as the most predominant form of renal osteodystrophy, commonly associated with poor outcomes, including premature mortality and progression of vascular calcification. Evolving evidence indicates that reduction of bone turnover by parathyroidectomy or pharmacological therapies, such as calcimimetics and antiresorptive agents, are not associated with premature mortality or accelerated vascular calcification in CKD. In contrast, chronic inflammation, oxidative stress, malnutrition, and diabetes can induce low bone turnover and associate with poor prognosis. Thus, the conditions causing suppression of bone turnover rather than the low bone turnover per se may account for the perceived association with outcomes. Anabolic treatment, in contrast, has been suggested to improve turnover and bone mass in patients with advanced CKD and low bone turnover; however, uncertainty about safety even exceeds that of antiresorptive agents. Here, we critically review the pathophysiological concept of adynamic bone disease and discuss the effect of low bone turnover on the safety and efficacy of anti-osteoporosis pharmacotherapy in advanced CKD.