CKD-MBD Research Articles

Comparative Effectiveness of Dialysis Modality on Laboratory Parameters of Mineral Metabolism

Introduction: Chronic kidney disease-mineral and bone disorders (CKD-MBD) are prevalent in patients undergoing maintenance dialysis. Yet, there are limited and mixed evidence on the effects of different dialysis modalities involving longer treatment times or higher frequencies on CKD-MBD markers. Methods: This cohort study used data from 132,523 incident dialysis patients treated with any of the following modalities: conventional thrice-weekly in-center hemodialysis, nocturnal in-center hemodialysis (NICHD), home hemodialysis (HHD), or peritoneal dialysis (PD) from 2007 to 2011. We used marginal structural models fitted with inverse probability weights to adjust for fixed and time-varying confounding and informative censoring. We estimated the average effects of treatments with different dialysis modalities on time-varying serum concentrations of CKD-MBD markers: albumin-corrected calcium, phosphate, parathyroid hormone (PTH), and alkaline phosphatase (ALP) using pooled linear regression. Results: Most of the cohort were exclusively treated with conventional in-center hemodialysis, while few were ever treated with NICHD or HHD. At the baseline, PD patients had the lowest mean and median values of PTH, while NICHD patients had the highest median values. During follow-up, compared to hemodialysis patients, patients treated with NICHD had lower mean serum PTH (19.8 pg/mL [95% confidence interval: 2.8, 36.8] lower), whereas PD and HHD patients had higher mean PTH (39.7 pg/mL [31.6, 47.8] and 51.2 pg/mL [33.0, 69.3] higher, respectively). Compared to hemodialysis patients, phosphate levels were lower for patients treated with NICHD (0.44 mg/dL [0.37, 0.52] lower), PD (0.15 mg/dL [0.12, 0.19] lower), or HHD (0.33 mg/dL [0.27, 0.40] lower). There were no clinically meaningful associations between dialysis modalities and concentrations of calcium or ALP. Conclusion: In incident dialysis patients, compared to treatment with conventional in-center hemodialysis, treatments with other dialysis modalities with longer treatment times or higher frequency were associated with different patterns of serum phosphate and PTH. Given the recent growth in the use of dialysis modalities other than hemodialysis, the associations between the treatment and the CKD-MBD markers warrant additional study.

Non-Additive Effects of Combined NOX1/4 Inhibition and Calcimimetic Treatment on a Rat Model of Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD).

ABSTRACTChronic kidney disease‐mineral and bone disorder (CKD‐MBD) increases cardiovascular calcification and skeletal fragility in part by increasing systemic oxidative stress and disrupting mineral homeostasis through secondary hyperparathyroidism. We hypothesized that treatments to reduce reactive oxygen species formation and reduce parathyroid hormone (PTH) levels would have additive beneficial effects to prevent cardiovascular calcification and deleterious bone architecture and mechanics before end‐stage kidney disease. To test this hypothesis, we treated a naturally progressive model of CKD‐MBD, the Cy/+ rat, beginning early in CKD with the NADPH oxidase (NOX1/4) inhibitor GKT‐137831 (GKT), the preclinical analogue of the calcimimetic etelcalcetide, KP‐2326 (KP), and their combination. The results demonstrated that CKD animals had elevated blood urea nitrogen, PTH, fibroblast growth factor 23 (FGF23), and phosphorus. Treatment with KP reduced PTH levels compared with CKD animals, whereas GKT treatment increased C‐terminal FGF23 levels without altering intact FGF23. GKT treatment alone reduced aortic calcification and NOX4 expression but did not alter the oxidative stress marker 8‐OHdG in the serum or aorta. KP treatment reduced aortic 8‐OHdG and inhibited the ability for GKT to reduce aortic calcification. Treatments did not alter heart calcification or left ventricular mass. In the skeleton, CKD animals had reduced trabecular bone volume fraction and trabecular number with increased trabecular spacing that were not improved with either treatment. The cortical bone was not altered by CKD or by treatments at this early stage of CKD. These results suggest that GKT reduces aortic calcification while KP reduces aortic oxidative stress and reduces PTH, but the combination was not additive. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

POS-639 PREVALENCE OF FRACTURE AND ASSOCIATED RISK FACTORS IN HEMODIALYSIS PATIENTS IN SHIRAZ HOSPITALS, 2013-2019: A MULTICENTER STUDY

End-stage renal disease (ESRD) is the final stage of CKD, where kidney function has declined and can no longer function independently. ESRD patients must receive dialysis or kidney transplantation to survive. Loss of kidney function leads to metabolic disorders that affect bone and vascular health, known as CKD-mineral and bone disorder (CKD-MBD). The increased risk of fracture in hemodialysis, peritoneal dialysis, and kidney transplant patients compared with the general population has been recognized.

Utility of Trabecular Bone Score (TBS) in Bone Quality and Fracture Risk Assessment in Patients on Maintenance Dialysis.

Maintenance dialysis is associated with almost universal changes in bone metabolism collectively known as chronic kidney disease—mineral and bone disorder (CKD-MBD). These are accompanied in various proportions by bone loss and altered bone quality that led to an increased risk of fracture. Osteoporosis, age-related or postmenopausal, a condition that often coexists with CKD, is also a leading cause of fracture. Dual-energy X-ray densitometry (DXA) is the main tool for assessing the bone quantity and bone loss and the associated fracture risk. It has been validated in both CKD-MBD and osteoporosis. Trabecular bone score (TBS) is a DXA-derived algorithm for the evaluation of bone microarchitecture, and its clinical value has been repeatedly demonstrated in large cohorts of osteoporotic patients. However, its utility in patients on maintenance dialysis has not been conclusively shown. Published studies showed a lower TBS score and implicitly an altered bone microarchitecture in patients on maintenance dialysis, even after adjusting for various variables. Moreover, FRAX-based fracture risk is higher after adjusting for TBS, showing promise on an algorithm better estimating the clinical fracture risk in dialysis patients. However, TBS has not been demonstrated to independently predict clinical fractures in prospective studies on dialysis patients. Also, aortic calcifications and altered fluid balance could significantly affect TBS score and could hamper the widespread clinical use in patients on maintenance dialysis. In this mini-review, we focus on the benefits and pitfalls of TBS in the management of CKD-MBD and fracture risk assessment in patients on maintenance dialysis.

Extraskeletal Calcifications in Children with Maintenance Peritoneal Dialysis

Chronic kidney disease (CKD)-mineral and bone disorder (CKD-MBD) is a common complication of CKD, often accompanied by extra-skeletal calcification in adult patients. As increased vascular calcification is predicted to increase cardiovascular mortality and morbidity, the revised Kidney Disease: Improving Global Outcomes guidelines recommend avoiding calcium-containing phosphate chelators. However, extra-skeletal calcification is less commonly noticed in pediatric patients. Here, we report our experience of such a complication in pediatric patients receiving maintenance peritoneal dialysis. Extra-skeletal calcification was noticed at the corneas, pelvic cavity, and soft tissues of the lower leg in 4 out of 32 patients on maintenance peritoneal dialysis. These patients experienced the aggravation of extra-skeletal calcifications during peritoneal dialysis, and 2 of them underwent excisional operations. It is required to monitor extra-skeletal calcifications in children on kidney replacement therapy.

Clinical Decision Support System Based on Hybrid Knowledge Modeling: A Case Study of Chronic Kidney Disease-Mineral and Bone Disorder Treatment.

Clinical decision support systems (CDSSs) represent the latest technological transformation in healthcare for assisting clinicians in complex decision-making. Several CDSSs are proposed to deal with a range of clinical tasks such as disease diagnosis, prescription management, and medication ordering. Although a small number of CDSSs have focused on treatment selection, areas such as medication selection and dosing selection remained under-researched. In this regard, this study represents one of the first studies in which a CDSS is proposed for clinicians who manage patients with end-stage renal disease undergoing maintenance hemodialysis, almost all of whom have some manifestation of chronic kidney disease–mineral and bone disorder (CKD–MBD). The primary objective of the system is to aid clinicians in dosage prescription by levering medical domain knowledge as well existing practices. The proposed CDSS is evaluated with a real-world hemodialysis patient dataset acquired from Kyung Hee University Hospital, South Korea. Our evaluation demonstrates overall high compliance based on the concordance metric between the proposed CKD–MBD CDSS recommendations and the routine clinical practice. The concordance rate of overall medication dosing selection is 78.27%. Furthermore, the usability aspects of the system are also evaluated through the User Experience Questionnaire method to highlight the appealing aspects of the system for clinicians. The overall user experience dimension scores for pragmatic, hedonic, and attractiveness are 1.53, 1.48, and 1.41, respectively. A service reliability for the Cronbach’s alpha coefficient greater than 0.7 is achieved using the proposed system, whereas a dependability coefficient of the value 0.84 reveals a significant effect.

Effect of CKD-MBD therapies on the gastrointestinal expression of phosphate transporters

Background: Chronic kidney disease-mineral and bone disorder (CKD-MBD) is prevalent and encompasses biochemical abnormalities, bone alterations, and vascular calcifications. CKD-MBD treatments include phosphate binders and calcimimetics that effectively lower phosphorus and PTH, respectively, but the impact of these treatments on phosphate transporters in the gastrointestinal tract is still unknown. NaPi2B is considered the primary intestinal phosphate transporter. However, NaPi2B inhibition shows limited effectiveness, thus the importance of PIT1 and PIT2 requires further investigation.
 Methods: We tested the effects phosphate binders (ferric citrate (FC) and calcium gluconate (Ca)) and the calcimimetic KP2326 (KP) in (Cy/+ male rat; CKD) and untreated normal littermates (NL). Treatments lasted 10 weeks until euthanasia at 28 weeks (moderate-to-advanced CKD), where we collected mucosa samples from duodenum, jejunum, and ileum. Blood was collected for biochemistry measurements. Total RNA was isolated, and qPCR performed to assess phosphate transporters expression (NaPi2B, PIT1, PIT2) normalized to b-actin. Results were analyzed via 2-way ANOVA.
 Results: As expected, CKD had abnormal plasma concentrations of phosphorus, PTH, and FGF23. FC and KP effectively lowered phosphorus. KP and Ca lowered PTH, but Ca increased FGF23. NaPi2B was expressed in the duodenum and jejunum but not in the ileum, and its expression was upregulated with FC compared to NL. PIT1 was expressed in all segments, but the expression was the highest in the ileum, while PIT2 was constitutively expressed in all segments. Ca led to higher PIT1 and PIT2 expression in the duodenum and jejunum compared to NL, CKD, or KP. KP led to higher expression of PIT1 in the ileum compared to CKD, FC, and Ca.
 Conclusions: CKD-MBD therapies differentially impacted biochemistries and phosphate transporters expression. The effect of Ca on gastrointestinal expression of PIT1 and PIT2 may explain the higher plasma phosphorus and should be further explored.

New Insights to the Crosstalk between Vascular and Bone Tissue in Chronic Kidney Disease-Mineral and Bone Disorder.

Vasculature plays a key role in bone development and the maintenance of bone tissue throughout life. The two organ systems are not only linked in normal physiology, but also in pathophysiological conditions. The chronic kidney disease–mineral and bone disorder (CKD-MBD) is still the most serious complication to CKD, resulting in increased morbidity and mortality. Current treatment therapies aimed at the phosphate retention and parathyroid hormone disturbances fail to reduce the high cardiovascular mortality in CKD patients, underlining the importance of other factors in the complex syndrome. This review will focus on vascular disease and its interplay with bone disorders in CKD. It will present the very late data showing a direct effect of vascular calcification on bone metabolism, indicating a vascular-bone tissue crosstalk in CKD. The calcified vasculature not only suffers from the systemic effects of CKD but seems to be an active player in the CKD-MBD syndrome impairing bone metabolism and might be a novel target for treatment and prevention.

Comparison of [18F] NaF PET/CT dynamic analysis methods and a static analysis method including derivation of a semi-population input function for site-specific measurements of bone formation in a population with chronic kidney disease-mineral and bone disorder

PurposeThe purpose of this study is to compare dynamic and static whole-body (WB) [18F]NaF PET/CT scan methods used for analysis of bone plasma clearance in patients with chronic kidney disease-mineral and bone disorder (CKD-MBD).MethodsSeventeen patients with CKD-MBD underwent a 60-min dynamic scan followed by a 30-min static WB scan. Tracer kinetics in four thoracic vertebrae were analysed using nonlinear regression and Patlak analysis using image-derived arterial input functions. The static WB scan was analysed using a simplified Patlak method requiring only a single data point in combination with a fixed y-intercept value (V0), both obtained using a semi-population function. The semi-population function was constructed by combining a previously derived population input function in combination with data from venous blood samples. Static WB scan analysis data, obtained from the semi-population input functions, was compared with paired data obtained using dynamic input functions.ResultsBone plasma clearance (Ki) from Patlak analyses correlated well with nonlinear regression analysis, but Ki results using Patlak analysis were lower than Ki results using nonlinear regression analysis. However, no significant difference was found between Ki obtained by static WB scans and Ki obtained by dynamic scans using nonlinear regression analysis (p = 0.29).ConclusionBone plasma clearance measured from static WB scans correlates with clearance data measured by dynamic analysis. Static [18F]NaF PET/CT scans can be applied in future studies to measure Ki in patients with CKD-MBD, but the results should not be compared uncritically with results obtained by dynamic scan analysis.

Biomarkers of heart and vascular lesions in the framework of mineral and bone disorders in chronic kidney disease, correction possibilities

Сardiovascular disease (СVD) is the most common complication of chronic kidney disease (СKD). In patients with the earlier stages of CKD, the risk of death from CVD greatly exceeds the risk of progression to end-stage renal disease. In recent years, accumulated data suggest that chronic kidney disease — mineral and bone disorders (CKD-MBD) are strongly associated with cardiovascular events and mortality. Among cardiovascular damage in CKD, both, the progressive cardiac remodeling and vascular calcifi cation, contribute immensely, and lead to an urgently high cardiovascular mortality in patients with CKD. Clarifi cation of CKD progression mechanisms and possible early markers of CVD has led to interest in studying the identifi ed factors such as fi broblast growth factor-23 (FGF-23), Klotho and sclerostin in recent years. Results of studies show that disorders in the system of FGF-23–Klotho–sclerostin correlate with the frequency and severity of hypertension, cardiac remodeling, vascular calcifi cation, anaemia, malnutrition, infl ammation, and strongly aggravate cardiovascular risk in CKD. This review represents an analysis of the available data showing the potential association of СVD with established (phosphate, parathyroid hormone (PTH), Vitamin D) and newer (FGF-23, Klotho, sclerostin) СKD-MBD biomarkers. In addition, it has been shown that renoprotective therapy, including renin-angiotensin blockers, low-protein diet with amino/keto acid supplementation, phosphate binders, erythropoiesis stimulators, vitamin D metabolites used to reach the target levels of blood pressure, serum phosphorus, haemoglobin, PTH and nutritional status disorders, can aff ect CKD-MBD biomarkers and reduce the risk of cardiovascular events in CKD patients.

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

Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD Update Work Group. KDIGO 2017 Clinical Practice Guideline Update for the Diagnosis, Evaluation, Prevention, and Treatment of Chronic Kidney Disease — Mineral and BoneDisorder (CKD-MBD). Kidney Int Suppl. 2017;7:1-59.

A New Disease Concept in the Age of Processed Foods-Phosphorus-Burden Disease; including CKD-MBD Concrete Analysis and the Way to Solution.

In 2012, the Japanese Society for Dialysis Therapy (JSDT) established the order of correction of P, corrected Ca (cCa), and whole PTH (w-PTH) in the treatment of Chronic Kidney Disease-Metabolic Bone Disorder (CKD-MBD) as P-first. However, there is no report that analyzes whether this rule is in line with reality and what the adequate rate of P is. Therefore, we analyzed the test values of our 48 patients during the year of 2019 and examined the validity of the results. The results showed that the adequate range rates were 70.8% for P, 100% for cCa, and 89.6% for w-PTH. This result is better than the JSDT Web-based Analysis of Dialysis Data Archives (WADDA) P adequacy rate of 66.2%. Although the guideline is P-first, it is often the case that we cannot reach the adequate level; therefore, healthcare professionals and patients often blame each other. We believe that this is due to the mismatch between the modern era of processed foods covered with P additives and treatment methods (P intake restriction and P-binders). The development of processed foods with P additives has brought light and darkness to mankind. The light side is freedom from starvation, and the dark side is a new condition caused by P burden: P burden disease including CKD-MBD.

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.

The Role of DMP1 in CKD-MBD.

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. 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.

Circulating p-Cresyl Sulfate, Non-Hepatic Alkaline Phosphatase and Risk of Bone Fracture Events in Chronic Kidney Disease-Mineral Bone Disease.

Patients with chronic kidney disease (CKD), especially those undergoing hemodialysis, are at a considerably high risk of bone fracture events. Experimental data indicate that uremic toxins intricately involved in bone-related proteins exert multi-faced toxicity on bone cells and tissues, leading to chronic kidney disease–mineral and bone disorder (CKD-MBD). Nonetheless, information regarding the association between p-cresyl sulfate (PCS), non-hepatic alkaline phosphatase (NHALP) and skeletal events remains elusive. We aim to explore the association between PCS, NHALP and risk of bone fracture (BF) in patients with hemodialysis. Plasma concentrations of PCS and NHALP were ascertained at study entry. Cox proportional hazard regression analyses were used to determine unadjusted and adjusted hazard ratios (aHRs) of PCS for BF risk. In multivariable analysis, NHALP was associated with incremental risks of BFs [aHR: 1.06 (95% CI: 1.01–1.11)]. The association between the highest PCS tertile and BF risk remained robust [aHR: 2.87 (95% CI: 1.02–8.09)]. With respect to BF events, the interaction between NHALP and PCS was statistically significant (p value for the interaction term < 0.05). In addition to mineral dysregulation and hyperparathyroidism in hemodialysis patients, higher circulating levels of PCS and NHALP are intricately associated with incremental risk of BF events, indicating that a joint evaluation is more comprehensive than single marker. In light of the extremely high prevalence of CKD-MBD in the hemodialysis population, PCS may act as a pro-osteoporotic toxin and serve as a potential surrogate marker for skeletal events.

The Influence of Dietary Interventions on Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD).

Chronic kidney disease is a health problem whose prevalence is increasing worldwide. The kidney plays an important role in the metabolism of minerals and bone health and therefore, even at the early stages of CKD, disturbances in bone metabolism are observed. In the course of CKD, various bone turnover or mineralization disturbances can develop including adynamic hyperparathyroid, mixed renal bone disease, osteomalacia. The increased risk of fragility fractures is present at any age in these patients. Nutritional treatment of patients with advanced stages of CKD is aiming at prevention or correction of signs, symptoms of renal failure, avoidance of protein-energy wasting (PEW), delaying or prevention of the occurrence of mineral/bone disturbances, and delaying the start of dialysis. The results of studies suggest that progressive protein restriction is beneficial with the progression of renal insufficiency; however, other aspects of dietary management of CKD patients, including changes in sodium, phosphorus, and energy intake, as well as the source of protein and lipids (animal or plant origin) should also be considered carefully. Energy intake must cover patients’ energy requirement, in order to enable correct metabolic adaptation in the course of protein-restricted regimens and prevent negative nitrogen balance and protein-energy wasting.

THE EFFECT OF INTRADIALYTIC AEROBIC TRAINING ON PHYSICAL PERFORMANCE AND QUALITY OF LIFE AMONGHEMODIALYSIS PATIENTS

Chronic kidney disease (CKD) and end stage renal disease (ESRD) are worldwide public health problems.(1)The prevalence of CKD (stages 1-5) in the general United States adult population was 14.8% in 2013-2016, CKD and ESRD patients have increased risk of functional impairment, regardless of their age, gender, associated co-morbidities, and cardiovascular events.(3) This high level of functional limitations in patients with CKD and ESRD is not necessarily improved by dialysis. Rehabilitationprinciples need to be integrated into the routine management of patients. (5)Rehabilitation of CKD and ESRD patients involves many aspects as psychological, nutritional, and exercise training.(6)Various exercise programs, such as aerobic exercise, resistance exercise, combined aerobic and resistance exercise, and passive exercise including electrical stimulation have been developed for hemodialysis patientsThe aim of the current study was to assess the effect of intradialytic aerobic training on physical performance and quality of life in patients maintained on haemodialysis therapy.The study included thirty patients on maintenance hemodialysis therapy for more than three months in Alexandria University Hospitals.Patients were divided into two groups: Group (A): Fifteen patients performed exercise during hemodialysis session.Group (B): Fifteen patients were not assigned to any exercise program (as a control group).Mentally or physically unfit patients,patients with overt ischemic heart disease or cardiac decompensation, severe anaemic patients (Hb ≤ 8 g/dl),patients with advanced chronic kidney disease-mineral and bone disorder (CKD-MBD), patients with advanced lower limbs joints disease or amputation of lower limb were excluded.

Circulating Osteoprotegerin in Chronic Kidney Disease and All-Cause Mortality.

BackgroundChronic kidney disease (CKD) is associated with cardiovascular disease (CKD), mineral and bone disorder (CKD-MBD) and high mortality. Bone-related factors such as osteopontin (OPN), osteocalcin (OC), osteoprotegerin (OPG) and fibroblast growth factor 23 (FGF23) were linked to cardiovascular complications of CKD and are expected to have predictive value in CKD patients.PurposeThe aim of this study was to assess the relationship of OPN, OC, OPG and FGF23 to clinical characteristics and to evaluate their ability to predict mortality in patients with different CKD stages.MethodsThe following study groups were enrolled: subjects with end-stage renal disease (38 ESRD), CKD stages 3 and 4 (19 CKD3-4) and non-CKD controls (19), respectively. Blood was withdrawn once to perform the measurements and cardiac computed tomography was used to evaluate coronary calcium score (CS). Patients were followed for 5 years for the ascertainment of their all-cause mortality.ResultsSerum OPN, OC and OPG concentrations increased significantly along with the progression of renal disease. We found a significant positive correlation among these proteins. Additionally, OPN and OPG were significantly and positively correlated to CS. Serum OPG revealed the strongest correlation to the calcium turnover markers of GFR decline and was significantly associated with an increased risk of death in subjects with CKD3-4 or ESRD (HR 5.8, CI 95%).ConclusionSingle measurement of osteoprotegerin is associated with 5-year all-cause mortality in patients with CKD3-4 or ESRD. We suggest assessing its concentration, preferably in combination with calcium score, to stratify mortality risks in CKD patients.

MO797JUXTAPOSING THE EFFICACIES BETWEEN IRON-BASED AND NON-CALCIUM PHOSPHATE BINDERS FOR IMPROVING MINERAL AND BONE DISORDER PARAMETERS IN DIALYSIS-DEPENDENT CHRONIC KIDNEY DISEASE PATIENTS: A META-ANALYSIS OF RANDOMIZED CONTROLLED TRIALS

Abstract Background and Aims Hyperphosphatemia is a serious complication in chronic kidney disease (CKD) patients that serves as the main risk factor of CKD–mineral and bone disorder (CKD-MBD) progression. Previous studies suggested that iron-based phosphate binder showed better improvement in CKD-MBD parameters although the results were still inconclusive. This study aims to juxtapose the efficacies between iron-based and non-calcium phosphate binders for improving CKD-MBD parameters in dialysis-dependent (DD)-CKD patients. Method We did comprehensive searching to screen all relevant literature until November 2020 in online databases of Pubmed, EMBASE, ScienceDirect, and The Cochrane Library. We included all randomized controlled trials (RCTs) accessing the efficacies of iron-based phosphate binders (sucroferric oxyhydroxide, ferric citrate) in improving CKD-MBD parameters compared with non-calcium phosphate binders (sevelamer) in DD-CKD patients. The parameters compared in this study are changes in serum phosphate (P), serum calcium ions (Ca), fibroblast growth factors-23 (FGF23), intact parathyroid hormone (iPTH), 25-hydroxyvitamin D (calcidiol), and 1,25-dihydroxyvitamin D (calcitriol). Bias risk was accessed by using the revised Cochrane Risk-of-bias (RoB-2) tool. Analysis was performed to provide standard mean difference (SMD) with 95% confidence interval (CI) using random-effect heterogeneity test. Results Ten RCTs with total of 1,139 participants were included in this analysis. The sucroferric oxyhydroxide decreases FGF23 although not statistically significant (SMD = 0.22. 95% CI = -0.49 to 0.05, p = 0.11, I2 = 52%), but ferric citrate (SMD = -0.92. 95%CI = -1.56 to -0.29, p = 0.004, I2 = 69%) and the overall estimate (SMD = -0.45. 95% CI = -0.82 to -0.09, p = 0.02, I2 = 79%) showed significant FGF23 decline compared with sevelamer. The sucroferric oxyhydroxide showed no significant improvement of calcidiol (SMD = 0.08. 95%CI = -0.02 to 0.17, p = 0.13, I2 = 0%) and calcitriol (SMD = 0.02. 95% CI = -0.08 to 0.12, p = 0.74, I2 = 0%) compared with selevamer. There is also no significant improvement of iPTH in sucroferric oxyhydroxide subgroup (SMD = -0.14. 95%CI = -0.43 to 0.14, p = 0.32, I2 = 85%), ferric citrate subgroup (SMD = -0.02. 95%CI = -0.16 to 0.12, p = 0.80, I2 = 0%), and pooled group analysis (SMD = -0.10. 95%CI = -0.27 to 0.07, p = 0.27, I2 = 75%). Besides, this study also suggests no significant improvement comparison of serum P (SMD = -0.09. 95%CI = -0.19 to 0.02, p = 0.12, I2 = 38%) and Ca (SMD = 0.04. 95%CI = -0.12 to 0.20, p = 0.61, I2 = 57%). Conclusion There is no significant efficacies differences between iron-based and non-calcium phosphate binders for improving serum phosphate, serum calcium ions, iPTH, calcidiol, and calcitriol in dialysis-dependent chronic kidney disease patients, except for the FGF-23 parameter. However, further trials are needed to establish the juxtaposition.

MO574MINERAL AND BONE DISORDERS CHANGES IN RENAL TRANSPLANTED PATIENTS

Abstract Background and Aims Successful renal transplant restores many physiologic abnormalities, including improvement of chronic kidney disease- mineral and bone disorder (CKD-MBD) syndrome. The primary aims of this study were: analyse the changes and evolution of the 3 components of CKD-MBD pre and 1 year post renal transplantation: the mineral abnormalities, the bone disorders and the vascular calcifications; and to correlate fibroblast grow factor 23 (FGF23), klotho and sclerostin serum levels with bone histomorphometric parameters and CV disease. The secondary aims were to study the evolution of other bone related parameters and correlate those with bone biopsies data, as well as to validate Adragão vascular calcification score in a population of renal transplant patients. Method We performed a prospective cohort study of a consecutive sample of de novo single renal transplanted patients in our unit. At inclusion, demographic, clinical and transplant-related data were collected, X-ray of the pelvis and hands (for Adragão score) and echocardiographic findings were recorded. All patients were submitted to a bone biopsy and laboratorial evaluation at baseline (time 0 – T0). Patients were followed for 12 months (time 1 – T1), after which performed laboratorial evaluation, a 2nd bone biopsy, echocardiogram, X-ray of pelvis and hands, bone densitometry and non-contrast cardiac CT (Agatston score). Continuous variables are presented as medians and categorical variables as frequencies. Differences between T0 and T1 were accessed by Wilcoxon matched-pairs test and paired McNemar test. Correlations between bone histomorphometric findings and severity of vascular calcifications with demographic and laboratorial parameters were obtained with Wilcoxon rank-sum test or Kruskall Wallis test. STATA software was used and p &amp;lt; 0.05 was considered statistically significant. Results We recruited 84 patients in a 28 month-period. At the end of 12 months, 69 patients performed a 2nd evaluation. Median age 53 years, 48 men, 53 caucasian, median dialysis vintage 55 months. We observe a significant reduction on phosphorus, magnesium, PTH, calcitonin, sclerostin, bone alkaline phosphatase and FGF23. Both calcium and alpha-klotho serum levels increase, with no significant changes in vitamin D levels. 68% of the patients presented renal osteodystrophy at the 2nd bone biopsy, and we observed a significant increase in the development of low turnover bone disorder, with no major changes in volume or mineralization. Changes in alpha-klotho, bAP and sclerostin (from T0 to T1) were important determinants of changes in turnover, mineralization and volume, respectively. Despite not being statistically significant, we were able to observe an improvement in the cortical bone porosity. Vascular calcifications and echocardiographic findings weren’t different comparing to the baseline (Median Adragão score was 1 in both evaluations, and valve calcifications were present in 22% and 23% of patients, with no changes in LVMI). The median Agatston score was 48.5, being the median adjusted percentile of 82%. FGF23 and sclerostin were found to be independent risk factors for extra-osseous calcifications, as well as low bone volume, cortical porosity and osteoid volume. Adragão score and valve calcifications correlated well with the increased severity of coronary calcifications determined by Agatston score (absolute and percentile). Conclusion In conclusion, renal transplantation improves two of the three components of CKD-MBD (biochemical and bone disorders), slowing the progression of vascular calcifications. FGF23, sclerostin and bAP seemed to be key parameters in understanding the bone changes observed in post transplant period, and these hormones also interfere with extra osseous calcification severity. Adragão score seems to be a good tool to access vascular calcifications in renal transplanted patients.