Chronic kidney disease (CKD) poses a significant epidemiological challenge, necessitating effective patient management strategies. Nutritional intervention, particularly vitamin D supplementation, has garnered attention for its potential therapeutic utility in CKD. Despite widespread acknowledgment of the importance of vitamin D, particularly in bone and mineral metabolism, its supplementation in CKD patients for non-skeletal purposes remains contentious due to limited evidence. Hypovitaminosis D linked with CKD substantially contributes to disturbances in mineral and bone metabolism, increasing the risks of cardiovascular complications and skeletal disorders. Notably, CKD patients experience progressive vitamin D deficiency, exacerbating as the disease progresses. Guidelines recommend monitoring 25-hydroxyvitamin D (25 (OH)-D) levels due to their correlation with mineral metabolism parameters, although robust evidence for recommending supplementation is lacking. The primary aim of this paper is to focus on the main open questions regarding vitamin D supplementation in CKD, reporting the current evidence concerning the role of vitamin D supplementation in CKD and in renal transplant recipients.

OBJECTIVE: This review is a critical analysis of treatment results obtained in clinical trials conducted in patients with chronic kidney disease (CKD) and secondary hyperparathyroidism (SHPT), hyperphosphatemia, or both.
RESULTS: Patients with CKD have a high mortality rate. The disorder of mineral and bone metabolism (CKD-MBD), which is commonly present in these patients, is associated with adverse outcomes, including cardiovascular events and mortality. Clinical trials aimed at improving these outcomes by modifying CKD-MBD associated factors have most often resulted in disappointing results. The complexity of CKD-MBD, where many players are closely interconnected, might explain these negative findings. We first present an historical perspective of current knowledge in the field of CKD-MBD and then examine potential flaws of past and ongoing clinical trials targeting SHPT and hyperphosphatemia respectively in patients with CKD.

In people with chronic kidney disease (CKD), the physiology of vitamin D is altered and leads to abnormalities in bone and mineral metabolism which contribute to CKD mineral and bone disorder (CKD-MBD). Observational studies show an association between vitamin D deficiency and increased risk of mortality, cardiovascular disease and fracture in CKD. Although vitamin D therapy is widely prescribed in people with CKD, clinical trials to date have failed to demonstrate a clear benefit of either nutritional vitamin D supplementation or active vitamin D therapy in improving clinical outcomes in CKD. This review provides an updated critical analysis of recent trial evidence on vitamin D therapy in people with CKD.

UNASSIGNED: Fibroblast growth factor 23 (FGF-23) and other markers of chronic kidney disease-mineral and bone disorder (CKD-MBD) provide valuable insights into disease processes, treatment options and patient prognosis. However, limited research has explored potential associations with ethnicity or season, particularly in multi-ethnic populations residing in high-latitude regions.
UNASSIGNED: We evaluated CKD-BMD markers in a diverse cohort of CKD patients, who were participants of The CANADIAN AIM to PREVENT (the CAN AIM to PREVENT) study. FGF-23, calcium, phosphate, 25-hydroxyvitamin D (25-OHD) and intact parathyroid hormone (iPTH) in 1234 participants with pre-dialysis CKD (mean estimated glomerular filtration rate: 41.8 ± 14.3 mL/min) were analyzed. Mixed-effects general linear regression models adjusted for demographic and biological factors were used to compare repeated measurements across patient groups categorized by ethnicity (East Asian, White, South Asian, Black, Southeast Asian) and seasons.
UNASSIGNED: Compared with other groups, White participants exhibited 8.0%-18.5% higher FGF-23 levels, Black participants had 0.17-0.32 mg/dL higher calcium levels, White participants had 10.0%-20.1% higher 25-OHD levels, South Asian participants had 7.3%-20.1% lower 25-OHD levels and Black participants had 22.1-73.8% higher iPTH levels, while East Asian participants had 10.7%-73.8% lower iPTH levels. Seasonal variations were also observed. FGF-23 levels were 11.9%-15.5% higher in summer compared with other seasons, while calcium levels were 0.03-0.06 mg/dL lower in summer. 25-OHD levels were 5.6%-10.6% higher in summer and autumn compared with other seasons.
UNASSIGNED: This study shows that FGF-23 and CKD-MBD markers in a Canadian pre-dialysis CKD cohort vary independently by ethnicity and season. Further research is needed to understand the reasons and clinical significance of these findings.

Hyperphosphataemia represents a significant challenge in the management of chronic kidney disease, exerting a pronounced influence on the pathogenesis of cardiovascular complications and mineral bone disorders. Traditional approaches to address hyperphosphataemia involve implementing dietary phosphate restrictions, administering phosphate binders, and, in cases of end-stage renal disease, resorting to dialysis. Unfortunately, these interventions frequently prove inadequate in maintaining phosphate levels within recommended ranges. Additionally, commonly employed pharmacological agents are not immune to eliciting adverse events, thereby limiting their prescription and therapeutic adherence. There is a growing focus on exploring novel therapeutic strategies in this context. The current discussion centres on tenapanor, a pharmacological agent predominantly acting as a selective inhibitor of sodium/hydrogen exchanger isoform 3 (NHE3). Its mechanism of action involves modulating tight junctions, resulting in reduced sodium absorption and intestinal paracellular permeability to phosphate. Furthermore, tenapanor downregulates sodium-dependent phosphate 2b transport protein (NaPi2b) expression, thereby impeding active transcellular phosphate transport. Clinical trials have elucidated the efficacy and safety profile of tenapanor. This evidence hints at a potential paradigm shift in the management of hyperphosphataemia. However, the burgeoning optimism surrounding tenapanor warrants tempered enthusiasm, as further research remains indispensable. The imperative lies in meticulously delineating its efficacy and safety contours within the crucible of clinical practice. In this review, we synthesize the intricate interplay between hyperphosphataemia and Chronic Kidney Disease-Mineral Bone Disorder, and we discuss the existing pharmacological interventions for hyperphosphataemia and explore emerging treatment paradigms that offer novel perspectives in managing elevated phosphate levels in CKD patients.

Background: Osteoporosis is common in hemodialysis (HD) patients, contributing to cardiovascular risks. Limited research exists on denosumab\'s efficacy in this group. Our study explores denosumab\'s effects on bone turnover markers (BTMs) and vascular calcification in chronic kidney disease-mineral bone disorder (CKD-MBD) patients. Methods: In a prospective single-center study, we investigated the effects of denosumab over 2 years on 30 HD patients from a cohort of 185. Annual assessments of bone mineral density (BMD), vascular calcification, and health-related quality of life (HRQL) were conducted and compared with an untreated group. Mineral and bone parameters were analyzed at specific intervals in the treatment group. Results: Denosumab notably raised femoral BMD in the initial year. Most bone turnover markers (BTMs) decreased, except for osteocalcin. Changes in T50 correlated with BTMs. Pre-denosumab supplementation of calcium and vitamin D helped manage mineral imbalances. Post denosumab, parathyroid hormone (PTH) levels increased initially, stabilizing after 3 months. No significant changes occurred in vascular calcification or HRQL. Conclusions: Denosumab exhibited varying effects on BMD improvement, with a stronger impact in the first year that diminished in the second year. Early PTH monitoring was crucial, and extending the administrative period may enhance BMD outcomes compared to the general population.

UNASSIGNED: Encapsulating peritoneal sclerosis (EPS) is a rare complication of prolonged peritoneal dialysis (PD) exposure, characterised by peritoneal thickening, calcification, and fibrosis ultimately presenting with life-threatening bowel obstruction. The presence or role of peritoneal calcification in the pathogenesis of EPS is poorly characterised. We hypothesise that significantly aberrant bone mineral metabolism in patients on PD can cause peritoneal calcification which may trigger the development of EPS. We compared the temporal evolution of bone mineral markers during PD in EPS patients with non-EPS long-term PD controls.
UNASSIGNED: Linear mixed model and logistic regression analysis were used to compare four-monthly serum levels of calcium, phosphate, parathyroid hormone, and alkaline phosphatase (ALP) over the duration of PD exposure in 46 EPS and 46 controls (PD, non-EPS) patients.
UNASSIGNED: EPS patients had higher mean calcium (2.51 vs. 2.41 mmol/L) and ALP (248.00 vs. 111.13 IU/L) levels compared with controls (p=0.01 and p<0.001 respectively, maximum likelihood estimation). Logistic regression analysis demonstrated that high serum calcium and phosphate levels during PD were associated with a 4.5 and 2.9 fold increase in the risk of developing EPS respectively.
UNASSIGNED: High levels of calcium and phosphate in patients on PD were identified to be risk factors for EPS development. Possible reasons for this may be an imbalance of pro-calcifying factors and calcification inhibitors promoting peritoneal calcification which increases peritoneal stiffness. Mechanical alterations may trigger, unregulated fibrosis and subsequent development of EPS. Improved management of secondary hyperparathyroidism during PD may ultimately diminish the EPS risk.

Fracture risk assessment in patients with chronic kidney disease (CKD) has been included in the CKD-MBD (\"Chronic Kidney Disease-Mineral and Bone Disorders\") complex in international and national nephrology guidelines, suggesting for the first time the assessment of bone mineral density (BMD) if the results can influence therapeutic decision-making. However, there is very little information on actual clinical practice in this population. The main objective of the ERCOS (ERC-Osteoporosis) study is to describe the profile of patients with CKD G3-5D with osteoporosis (OP) and/or fragility fractures treated in specialized nephrology, rheumatology and internal medicine clinics in Spain. Fifteen centers participated and 162 patients (mostly women [71.2%] postmenopausal [98.3%]) with a median age of 77 years were included. Mean estimated glomerular filtration rate (eGFR) was 36 mL/min/1.73 m2 and 38% of the included patients were on dialysis. We highlight the high frequency of prevalent fragility fractures [37.7%), mainly vertebral (52.5%) and hip (24.6%)], the disproportionate history of patients with glomerular disease compared to purely nephrological series (corticosteroids) and undertreatment for fracture prevention, especially in nephrology consultations. This study is an immediate call to action with the dissemination of the new, more proactive, clinical guidelines, and underlines the need to standardize a coordinated and multidisciplinary care/therapeutic approach to these patients in an efficient way to avoid current discrepancies and therapeutic nihilism.

Purpose of review: Mineral and bone disorder (MBD) is a prevalent complication in chronic kidney disease (CKD), significantly impacting overall health with multifaceted implications including fractures, cardiovascular events, and mortality. Despite its pervasive nature, effective treatments for CKD-MBD are lacking, emphasizing the urgency to advance understanding and therapeutic interventions. Bone metabolism intricacies, influenced by factors like 1,25 dihydroxy vitamin D, parathyroid hormone (PTH), and fibroblast growth factor 23 (FGF23), along with intrinsic osseous mechanisms, play pivotal roles in CKD. Skeletal abnormalities precede hormonal changes, persisting even with normalized systemic mineral parameters, necessitating a comprehensive approach to address both aspects. Recent findings: In this review, we explore novel pathways involved in the regulation of systemic mineral bone disease factors, specifically examining anemia, inflammation, and metabolic pathways. Special emphasis is placed on internal bone mechanisms, such as hepatocyte nuclear factor 4α, transforming growth factor-β1, and sclerostin, which play crucial roles in the progression of renal osteodystrophy. Summary: Despite advancements, effective treatments addressing CKD-MBD morbidity and mortality are lacking, necessitating ongoing research for novel therapeutic targets.

BACKGROUND: The consequences of chronic kidney disease (CKD) can be addressed with a range of pharmacotherapies primarily prescribed by nephrologists. More accurate information regarding future CKD-related pharmacotherapy requirements could guide clinical decisions including follow-up frequency.
METHODS: Following assignment to derivation and validation groups (2,1), variables predicting individually future use of vitamin D receptor agonists (VDRA), phosphate binders, erythropoiesis stimulating agents (ESAs) and iron were identified using logistic regression in a prospective cohort study containing demography, comorbidity, hospitalization, laboratory, and mortality data in patients with CKD stage G4/G5 across six European countries. Discriminative ability was measured using C-statistics, and predicted probability of medication use used to inform follow-up frequency.
RESULTS: A total of 2196 patients were included in the analysis. During a median follow-up of 735 days 648 initiated hemodialysis and 1548 did not. Combinations of age, diabetes status and iPTH, calcium, hemoglobin and serum albumin levels predicted the use of ESA, iron, phosphate binder or VDRA, with C-statistics of 0.70, 0.64, 0.73 and 0.63 in derivation cohorts respectively. Model performance in validation cohorts were similar. Sixteen percent of patients were predicted to have a likelihood of receiving any of these medications of less than 20%.
CONCLUSIONS: In a multi-country CKD cohort, prediction of ESA and phosphate binder use over a two-year period can be made based on patient characteristics with the potential to reduce frequency of follow-up in individuals with low risk for requiring these medications.