CKD-MBD Research Articles

Hyperparathyroidism Is an Independent Risk Factor for Allograft Dysfunction in Pediatric Kidney Transplantation

Little is known about the consequences of deranged chronic kidney disease-mineral and bone disorder (CKD-MBD) parameters on kidney allograft function in children. We examined a relationship between these parameters over time and allograft outcome. This registry study from the Cooperative European Paediatric Renal Transplant Initiative (CERTAIN) collected data at baseline, months 1, 3, 6, 9, and 12 after transplant; and every 6 months thereafter up to 5 years. Survival analysis for a composite end point of graft loss or estimated glomerular filtration rate (eGFR)≤30 ml/min per 1.73 m2 or a≥50% decline from eGFR at month 1 posttransplant was performed. Associations of parathyroid hormone (PTH), calcium, phosphate, and 25-hydroxyvitamin D (25(OH)D) with allograft outcome were investigated using conventional stratified Cox proportional hazards models and further verified with marginal structural models with time-varying covariates. We report on 1210 patients (61% boys) from 16 European countries. The composite end point was reached in 250 grafts (21%), of which 11 (4%) were allograft losses. In the conventional Cox proportional hazards models adjusted for potential confounders, only hyperparathyroidism (hazard ratio [HR], 2.94; 95% confidence interval [CI], 1.82-4.74) and hyperphosphatemia (HR, 1.94; 95% CI, 1.28-2.92) were associated with the composite end point. Marginal structural models showed similar results for hyperparathyroidism (HR, 2.74; 95% CI, 1.71-4.38), whereas hyperphosphatemia was no longer significant (HR, 1.35; 95% CI, 0.87-2.09), suggesting that its association with graft dysfunction can be ascribed to a decline in eGFR. Hyperparathyroidism is a potential independent risk factor for allograft dysfunction in children.

Management of fracture risk in CKD-traditional and novel approaches.

The coexistence of osteoporosis and chronic kidney disease (CKD) is an evolving healthcare challenge in the face of increasingly aging populations. Globally, accelerating fracture incidence causes disability, impaired quality of life and increased mortality. Consequently, several novel diagnostic and therapeutic tools have been introduced for treatment and prevention of fragility fractures. Despite an especially high fracture risk in CKD, these patients are commonly excluded from interventional trials and clinical guidelines. While management of fracture risk in CKD has been discussed in recent opinion-based reviews and consensus papers in the nephrology literature, many patients with CKD stages 3-5D and osteoporosis are still underdiagnosed and untreated. The current review addresses this potential treatment nihilism by discussing established and novel approaches to diagnosis and prevention of fracture risk in patients with CKD stages 3-5D. Skeletal disorders are common in CKD. A wide variety of underlying pathophysiological processes have been identified, including premature aging, chronic wasting, and disturbances in vitamin D and mineral metabolism, which may impact bone fragility beyond established osteoporosis. We discuss current and emerging concepts of CKD-mineral and bone disorders (CKD-MBD) and integrate management of osteoporosis in CKD with current recommendations for management of CKD-MBD. While many diagnostic and therapeutic approaches to osteoporosis can be applied to patients with CKD, some limitations and caveats need to be considered. Consequently, clinical trials are needed that specifically study fracture prevention strategies in patients with CKD stages 3-5D.

The current status of chronic kidney disease-mineral and bone disorder management in China

Chronic kidney disease-mineral and bone disorder (CKD-MBD) is one of the most common complications of patients with chronic kidney disease (CKD). After considering updated international and domestic CKD-MBD management guidelines, the current management status of CKD-MBD in China remains unclear. We aimed to investigate the management status of CKD-MBD in China. A nationwide survey was combined with a real-world study from Sichuan. Targets recommended in KDIGO 2017 and Chinese 2019 guidelines were used as targets. We compared the data between Sichuan from western China and the eastern developed areas of China, and also compared the results of the real-world data from Sichuan with those of DOPPS5. In the questionnaire, a total of 51,039 maintenance hemodialysis (MHD) patients from 272 centers were involved. Estimated achievement rates for Ca (2.1–2.5 mmol/L), P (1.13–1.78 mmol/L), and iPTH (150–600 pg/mL) levels were 57.1%, 41.1% and 52.0%, respectively. Differences in MBD management between Sichuan from questionnaire and central region. In the real-world survey, a total of 7,053 patients were enrolled. Among them, 57.6%, 24.3%, and 55.0% of patients met corrected Ca, serum P, and iPTH targets specified in Chinese 2019 guidelines, respectively. The comprehensive achievement rate was 7.5%. There are differences in MBD management between Sichuan and DOPPS5 regions, with Sichuan being relatively poorer. The level of the above parameters varies among different genders, age groups, and hospital grades. The achievement rate of serum P was higher in tertiary hospitals and elderly patients (P < 0.05). Current MBD management is poor. Phosphate levels in patients treated in secondary and lower hospitals and young dialysis patients should be strengthened.

Roxadustat improves renal osteodystrophy by dual regulation of bone remodeling.

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. 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. 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. 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.

Mitochondria and vascular calcification in chronic kidney disease: Lessons learned from the past to improve future therapy.

Chronic kidney disease-mineral and bone disorders (CKD-MBD) is a common complication of CKD Stages 3-5. Hyperphosphatemia is one of the major metabolic components of CKD-MBD, frequently resulting in vascular calcification (VC) in advanced-stage patients. Also, a long duration of renal replacement therapy can cause the worsening of VC, leading to increased cardiovascular morbidity and mortality. Vascular smooth muscle cells play an important role in the development of VC through osteochondrogenic transformation and the apoptotic process. It has been shown that mitochondrial dysfunction is involved with CKD progression, and excessive oxidative stress can aggravate osteoblastic transformation and VC. Currently, novel interventions targeting mitochondrial function and dynamics, in addition to mitochondrial antioxidants, have been studied with the aim of attenuating VC. This review aims to comprehensively summarize and discuss the experimental and clinical reports concerning mitochondrial studies, along with the purpose of interventions that can improve the outcomes of VC among CKD patients.

Association between depressive symptoms and bone density in elderly patients with non-dialysis dependent chronic kidney disease

BackgroundDepression is a disease that is commonly accompanied by elderly chronic kidney disease (CKD) patients, but when the two diseases are accompanied, etiology or combination are not well known. We aimed to evaluate the etiology of CKD and comorbid depression by investigating bone disorders that are observed in persons affected by both CKD and depression. MethodsWe conducted a cross-sectional study with a total of 646 patients with CKD. We compared the sociodemographic factors, kidney function, markers for CKD-Mineral and Bone Disorder (CKD-MBD) and bone mineral density according to the depressive symptoms. We conducted a univariate and multivariate logistic regression analysis to calculate odd ratios (95 % confidence interval) between depressive symptoms and low bone mineral density. ResultsIndividuals with CKD and depressive symptoms were associated with lower level of education attained, living alone, exercising less, low 24-hour urine phosphorus, and low bone density. Depressive symptoms were significantly associated with low bone density in lowest parts (1.55 [1.06–2.29]) and in total hip (1.72 [1.17–2.53]) even after adjusting for diabetes mellitus, hypertension, kidney function, proteinuria, age, sex, smoking, and body mass index. LimitationsA cross-sectional design was used in this study and the bone biopsy for diagnosis of CKD-MBD was not done because of invasiveness and practical difficulties. ConclusionLow bone density was associated with depressive symptoms in elderly patients with non-dialysis chronic kidney disease.

Dialysate calcium, alfacalcidol, and clinical outcomes: A post-hoc analysis of the J-DAVID trial.

The selection of dialysate calcium concentration (D-Ca) is still controversial among chronic hemodialysis (HD) regimens. We examined the trajectories of CKD MBD parameters among the J-DAVID trial participants to see the effect of D-Ca and alfacalcidol. The trial was an open-label randomized clinical trial including 976 HD patients with intact PTH of 180 pg/mL or lower which compared the users of vitamin D receptor activator (oral alfacalcidol) and non-users over a median of 4 years. The main D-Ca used at baseline were 3.0 mEq/L in 70% and 2.5 mEq/L in 25%, respectively. The primary endpoint was the composite of fatal and non-fatal cardiovascular events and the secondary endpoint was all-cause mortality. Multivariable Cox proportional hazard regression analyses in which D-Ca was included as a possible effect modifier and serum laboratory data as time-varying covariates showed no significant effect modification for composite cardiovascular events or all-cause mortality. This post hoc analysis showed that the effects of alfacalcidol on cardiovascular outcomes were not significantly modified by D-Ca.

CKD-MBD biomarkers and CKD progression: an analysis by the joint model.

Biomarkers of chronic kidney disease-mineral and bone disorder (CKD-MBD) have been implicated in CKD progression in follow-up studies focusing on single measurements of individual biomarkers made at baseline only. The simultaneous relationship between the time trend of these biomarkers over the course of CKD and renal outcomes has never been tested. We applied the joint model (JM) to investigate the longitudinal relationship between repeated measurements of CKD-MBD biomarkers and a combined renal endpoint (estimated glomerular filtration rate reduction>30%, dialysis or transplantation) in 729 stage 2-5 CKD patients over a 36-month follow-up. In the survival submodel of the JM, the longitudinal series of parathyroid hormone (PTH) values was directly and independently related to the risk of renal events [hazard ratio (HR) (1 ln increase in parathyroid hormone (PTH) 2.0 (range 1.5-2.8), P<.001)] and this was also true for repeated measurements of serum phosphate [HR (1mg/dl) 1.3924 (range 1.1459-1.6918), P=.001], serum calcium [HR (1mg/dl) 0.7487 (range 0.5843-0.9593), P=.022], baseline fibroblast growth factor 23 [HR (1 pg/ml) 1.001 (range 1.00-1.002), P=.045] and 1,25-dihydroxyvitamin D [HR (1 pg/ml) 0.9796 (range 0.9652-0.9942), P=.006]. Repeated measurements of serum PTH, calcium and phosphate as well as baseline FGF23 and 1,25-dihydroxyvitamin D are independently related with the progression to kidney failure in a cohort of stage 2-5 CKD patients. This longitudinal study generates the hypothesis that interventions at multiple levels on MBD biomarkers can mitigate renal function loss in this population.

Impact of adherence to CKD-MBD guidelines on mortality among Japanese dialysis patients: an ecological study.

This study evaluated the association between prefecture-level achievement of chronic kidney disease-mineral and bone disorder (CKD-MBD) parameter targets and mortality in Japanese dialysis patients. We conducted an ecological study of all prefectures in Japan using data from the Japanese Society of Dialysis Therapy and National Vital Statistics between 2016 and 2017. We calculated adherence rates to recommend target ranges for CKD-MBD parameters, including phosphate, corrected calcium, and parathyroid hormone (PTH), and explored associations of these rates with prefecture-specific standardized mortality rates (SMRs) among the general population and among prevalent dialysis patients using bivariate association analysis and structural equation modeling. Prefecture-level adherence to the target phosphate range was significantly and negatively associated with prefecture-specific SMRs in men (standardized estimate (β) = -0.61, p < 0.001) and women (β = -0.41, p < 0.001). However, prefecture-level adherence to the target corrected calcium range was significantly and negatively associated with prefecture-specific SMRs only in men (β = -0.28, p = 0.01). Meanwhile, prefecture-level adherence to the target PTH range was significantly and positively associated with prefecture-specific SMRs in men (β = 0.23, p = 0.04). Prefecture-level SMRs of females in the general population had a significant impact on prefecture-level SMRs of female dialysis patients (β = 0.27, p = 0.03). The models explained 52% of variance in SMR for men and 33% for women. A higher prefecture-level achievement rate of the target phosphate range recommended by the Japanese CKD-MBD guidelines was associated with a lower prefecture-specific SMR in the Japanese dialysis population.

In-center Nocturnal Hemodialysis Reduced the Circulating FGF23, Left Ventricular Hypertrophy, and All-Cause Mortality: A Retrospective Cohort Study.

Fibroblast growth factor 23(FGF23) is the most important biomarker and pathogenic factor in Chronic Kidney Disease–Mineral and Bone Disorder (CKD–MBD). In the moderate and severe stages of chronic renal failure, abnormally elevated circulating FGF23 can lead to some complications, including myocardial hypertrophy, which is positively correlated with all-cause mortality. However, the circulating FGF23 level of different hemodialysis modalities, the underlying essential regulatory factors, and potential clinical benefits remain to be elucidated. In this retrospective cohort study, 90 in-center nocturnal hemodialysis (INHD) and 90 matched conventional hemodialysis (CHD) patients were enrolled. The complete blood count, intact FGF23(iFGF23), calcium, phosphorus, PTH, and other biochemical and echocardiographic parameters of INHD and CHD patients were collected and analyzed at 1-year follow-up. The all-cause mortality was recorded during the 7-year follow-up. Furthermore, the regulatory factors of iFGF23 and its association with echocardiographic parameters and mortality were investigated by multivariate regression. The levels of iFGF23 and serum phosphate in patients undergoing INHD were significantly lower than those in patients undergoing CHD. The left ventricular volume index (LVMI) in patients with INHD was significantly attenuated and positively correlated with the drop of serum iFGF23. The INHD group had reduced all-cause mortality compared to the CHD group. Multivariate analysis showed that iFGF23 was positively correlated with serum calcium, serum phosphorus, and calcium-phosphate product. The calcium-phosphate product is an independent determining factor of serum iFGF23. Compared with the CHD group, the INHD group presented with a significantly reduced circulating iFGF23 level, which was closely associated with attenuation of left ventricular hypertrophy, but INHD reduced all-cause mortality in an FGF23 independent manner.

Alkaline Phosphatase: An Old Friend as Treatment Target for Cardiovascular and Mineral Bone Disorders in Chronic Kidney Disease.

Alkaline phosphatase (ALP) is an evolutionary conserved enzyme and widely used biomarker in clinical practice. Tissue-nonspecific alkaline phosphatase (TNALP) is one of four human isozymes that are expressed as distinct TNALP isoforms after posttranslational modifications, mainly in bone, liver, and kidney tissues. Beyond the well-known effects on bone mineralization, the bone ALP (BALP) isoforms (B/I, B1, B1x, and B2) are also involved in the pathogenesis of ectopic calcification. This narrative review summarizes the recent clinical investigations and mechanisms that link ALP and BALP to inflammation, metabolic syndrome, vascular calcification, endothelial dysfunction, fibrosis, cardiovascular disease, and mortality. The association between ALP, vitamin K, bone metabolism, and fracture risk in patients with chronic kidney disease (CKD) is also discussed. Recent advances in different pharmacological strategies are highlighted, with the potential to modulate the expression of ALP directly and indirectly in CKD–mineral and bone disorder (CKD-MBD), e.g., epigenetic modulation, phosphate binders, calcimimetics, vitamin D, and other anti-fracture treatments. We conclude that the significant evidence for ALP as a pathogenic factor and risk marker in CKD-MBD supports the inclusion of concrete treatment targets for ALP in clinical guidelines. While a target value below 120 U/L is associated with improved survival, further experimental and clinical research should explore interventional strategies with optimal risk–benefit profiles. The future holds great promise for novel drug therapies modulating ALP.

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.

MO833: Patient Benefits of Nephrological Follow-Up Before the Initiation of Rrt—An Observational Retrospective Analysis

Abstract BACKGROUND AND AIMS The clinical follow-up of CKD patients by nephrologists before RRT initiation (RRTi) is recommended by the practice guidelines starting with stage 3b CKD [1]. Despite this, the real-life implementation in clinical practice suggests otherwise, based on the paucity of papers reporting on the matter [2, 3]. In Romania, where the representation of the nephrology outpatient care is scarce, partly because of the low number of specialists, the establishment of outpatient clinics attached to dialysis units could be a solution. The purpose of this analysis is to evaluate, for the first time, if nephrological monitoring through the Diaverum outpatient clinics has benefits for CKD patients. METHOD A total of 344 patients from 9 Diaverum clinics have been evaluated (335 haemodialysis, 9 peritoneal dialysis), our present analysis retaining only those starting haemodialysis, of which 118 started RRT in the 3 years between 1 January 2015 and 31 December 2017 and were monitored through the nephrology outpatient and 217 were patients there were not referred to a nephrology unit until RRTi, in the 2 years between 1 July 2016 and 1 July 2018. Clinical and laboratory data were gathered at RRTi and the follow up was investigated over a period of 3 years for both groups, starting from the end of the inclusion period, using anonymized records from the electronic database of Diaverum. Collected data were compared using the Pearson test for nominal variables and the Student's t-test and Wilcoxon Mann—Whitney U-tests for continuous variables. Survival analysis was employed using the Kaplan–Meier estimate and Cox regression models. RESULTS The patient groups had similar general characteristics: most were men, &amp;gt;40% being elder (&amp;gt;65 yo), ∼30% had DM and both groups were comprised of subjects with multiple comorbidities (a mean Charlson score of 6). For patients that were not nephrologically referred, RRT was started in 100% of the cases using a CVC, while AVFs were employed in a majority of those followed through the outpatient clinics. In both groups, the mean eGFR was similarly &amp;lt;10 mL/min/1/73 m2 but &amp;gt;7 mL/min/1.73 m2 reflecting an alignment to clinical practice guidelines [1]. The median level of haemoglobin and the percentage of those with an optimal level of haemoglobin were higher in the group of monitored patients (9.9 versus 8.4 g/dL, respectively, 42% versus 15%). The nutrition status faired better in monitored patients: BMI (26 versus 23.3 kg/m2) and serum albumin (3.8 versus 3.5 g/dL). Serum calcium levels were higher (8.8 versus 8.3 mg/dL) and serum iPTH levels were lower (264 versus 331 pg/mL) in monitored patients, suggesting a better control of CKD-MBD, but serum phosphate was higher (5.7 versus 4.64 mg/dL), possibly reflecting a better nutrition status. The number of hospital admissions, COVID-19 cases and deaths are hard to compare, given the different observation periods that covered different periods and waves of the COVID-19 pandemic. However, hospital admissions and COVID-19 cases seemed more frequent in those that were not monitored. The 4 year survival rate was significantly higher (59% versus 51%) in the Kaplan–Meier analysis for those monitored through the outpatient. In the multivariate analysis, statistically significant associations with mortality were observed for diabetic and unmonitored patients. A major bias in our analysis is the difference between the periods of follow-up, which featured different periods of the COVID-19 pandemic. CONCLUSION This is the first observational analysis on a nephrological patient population from Romania, which was followed through outpatient units until the initiation of RRT. Patient monitoring before RRTi potentially allows: for a better control of the main complications of CKD (anaemia, CKD-MBD), a better preparation for RRTi (a more frequent use of an AVF) and possibly for an improvement in morbidity and mortality, as suggested by previous studies on the benefits of nephrological monitoring before RRTi [4, 5].

MO790: Arteriovenous Fistula Calcifications—Risk Factors and Impact on Arteriovenous Fistula Functionality

Abstract BACKGROUND AND AIMS Vascular calcifications have been recognized as frequent findings in patients with end-stage renal disease (ESRD) and have intricate mechanisms, including chronic kidney disease—mineral and bone disorders (CKD-MBD), inflammation and advanced atherosclerosis. The pathogenesis of arteriovenous fistula (AVF) calcifications is not fully understood, since it involves many other factors related to haemodialysis (HD) such as haemodynamic variables or vessel wall shear stress. The current study aims to assess the risk factors related to AVF calcifications and the impact on AVF functionality. METHOD The study included 174 chronic HD patients, mean age 58 ± 12 years, 35% female, median AVF duration 44 ± 52 months, with 35.9% radio-cephalic AVF, 12.1% brachio-basilic AVF, 52% brachio-cephalic AVF. The same nephrologist performed Doppler and B-mode AVF US scans in order to record AVF calcifications (defined as areas of hyperechogenicity with or without posterior shadowing within the arterial wall), as well as other complications (stenosis, partial thrombosis, aneurysms). In the same month of the AVF ultrasound assessment, cardiac echocardiography was performed in order to assess valvular calcifications. Laboratory parameters were analysed in the same month (Hb, calcium, phosphorus, serum bicarbonate, iPTH, albumin, ferritin, CRP). Dialysis efficiency (mean eKt/V in the month of ultrasound assessment) was recorded. The AVF survival was followed for 1 year after the initial evaluation, or up to the patient's death/transplantation. Statistical analysis was performed using MedCalc 14.8.1.0. RESULTS In our group, we found that the prevalence of AVF calcifications was 38% (66/174). Significantly more radiocephalic AVFs (47%) had calcifications than brachio-cephalic (38%) or brachio-basilic AVFs (15%), P = 0.04. The presence of calcifications was associated with longer AVF duration (P &amp;lt; .001), the presence of concomitant AVF stenosis (P = .04) and lower Hb levels (P = .02). The presence of AVF calcifications was not significantly associated with age, cardiac calcifications, or the presence of diabetes mellitus. Moreover, there was no statistically significant difference between the eKT/v values obtained in the group with AVF calcifications versus without AVF calcifications. We used the Cox proportional hazards model adjusted for standardized predicted values to determine whether patients with AVF calcifications had an increased risk of AVF failure. We found that after 1 year, 18,1% AVFs with calcifications had failed (12/66) while only 4.6% AVFs without calcifications had failed (5/108) [P = 0.02, hazard ratio (HR) 3.5, 95% confidence interval (95% CI) 1–11.3]. CONCLUSION The prevalence of AVF calcifications was 38% and affects radio-cephalic AVFs the most. AVF calcifications detected through ultrasound represent a risk factor for AVF failure, but the mechanism might be different from the pathways engaged in other vascular calcifications associated with CKD. We found no correlation with concomitant cardiac calcifications or CKD-MBD related biochemical changes. We found that AVF calcifications rather associate with HD-related factors (longer AVF duration and the presence of AVF stenosis). We suggest that periodic screening via ultrasound may be an easy method to diagnose AVF calcifications.

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

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. 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. 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. 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.

An optimized machine learning framework for predicting intradialytic hypotension using indexes of chronic kidney disease-mineral and bone disorders

Intradialytic hypotension (IDH) is the most common acute complication in hemodialysis (HD) sessions and is associated with increased morbidity and mortality in HD patients. To prevent the episode of IDH, it is critical to predict its occurrence. Chronic kidney disease-mineral and bone disorders (CKD-MBD) induce cardiac and vascular calcification, which impairs the compensatory mechanisms of blood pressure during HD. In this study, we proposed a feature selection framework called BSWEGWO_KELM to analyze 1940 records from 178 HD patients, which was based on an enhanced grey wolf optimization (GWO) algorithm and the kernel extreme learning machine (KELM). Then, global optimization experiments, together with feature selection experiments on public data sets and HD dataset, were performed to verify the effectiveness of the BSWEGWO_KELM method. The experimental results showed that the established BSWEGWO_KELM had the capability of screening out the key indicators such as dialysis vintage, mean arterial pressure (MAP), alkaline phosphatase (ALP), and intact parathyroid hormone (iPTH). Consequently, BSWEGWO_KELM can be applied as a practical and accurate method to predict IDH.

Optimal targets of chronic kidney disease-mineral and bone disorder markers for Chinese patients with maintenance peritoneal dialysis: a single-center retrospective cohort study

Background The chronic kidney disease-mineral and bone disorder（CKD-MBD) is known to be associated with increased mortality in dialysis patients, but whether current global guidelines for CKD-MBD, which were primarily developed from hemodialysis, are suitable for peritoneal dialysis (PD) patients practice require further investigation. Methods This is a single-center retrospective cohort study. In total 491 prevalent PD patients (median follow-ups: 34 months) from Peking Union Medical College Hospital (PUMCH) from January 2004 to December 2017 were included and followed until 30 June 2018. In the first dialysis year, the average levels of serum calcium, albumin-corrected calcium (CorCa), phosphorus, and parathyroid hormone (PTH) levels were the interested predictors in Cox proportional regression model. Results Of these PD patients (age 58 ± 17 years), 52% were male and 36% had diabetic nephropathy. In Cox regression over first-year mean parameters, PTH <100 pg/mL (HR = 1.97, 95% CI 1.32 to 2.94, p < 0.001) and ≥300 pg/mL (HR = 2.24, 95% CI 1.32 to 3.81, p = 0.003) were associated with increased all-cause mortality than that of PTH 100–200 pg/mL. Patients with albumin-corrected serum calcium level < 2.13 mmol/L also had higher risk of death than patients with level of 2.13 to 2.38 mmol/L (HR = 2.06, 95% CI 1.06 to 4.01, p = 0.02). Serum phosphorus ≥1.45 mmol/L were associated with increased all-cause mortality. However, lacking of data on 25-hydroxy vitamin D, alkaline phosphatase, and activated vitamin-D are limitations of our analysis. Conclusions As one of the largest PD cohort study focusing on CKD-MBD, we demonstrated that the level of CKD-MBD markers in the first PD year are independent predictors of all-cause mortality. PTH 100–300 pg/mL might be the best target for Chinese PD patients.

Usefulness of the trabecular bone score in maintenance dialysis patients : A single center observational study.

BackgroundThe number of dialysis patients is steadily increasing. Associated comorbidities include impaired bone and mineral metabolism, termed chronic kidney disease-mineral and bone disorder (CKD-MBD), leading to a high fracture risk, increased morbidity and mortality and impaired quality of life. While the bone density is assessed with dual-energy X‑ray absorptiometry (DXA), the trabecular bone score (TBS) captures the image texture as a potential index of skeletal microarchitecture. The aim of this study was to evaluate the clinical relevance of DXA and TBS in dialysis patients with and without prevalent fractures.MethodsBone disorders were evaluated in 82 dialysis patients (37% female) at the University Hospital of Graz, Austria, by DXA including the assessment of the TBS based on a patient interview and the local routine patient database software. The patient cohort was stratified by having sustained a fragility fracture in the past or not. Descriptive statistics, t‑tests for continuous variables and χ2-tests for nominal variables including results of DXA and TBS were performed to compare these groups considering the dialysis modality and duration as well as the number of kidney transplantations.ResultsOf the 82 patients, 32 (39%) had a positive history of fractures. There was a significant association between dialysis duration and fracture prevalence (p < 0.05) as well as musculoskeletal pain (p < 0.01). No significant correlation between DXA/TBS parameters and musculoskeletal pain could be established. The DXA scores did not correlate with fracture prevalence with the exception of DXA radius measurements; however, fracture prevalence significantly correlated inversely with TBS (p < 0.001).ConclusionThe use of DXA has a limited role in fracture prediction in dialysis patients; however, the TBS seems to add information as an additional tool for fracture risk estimation in this patient population.

Bisphosphonates and bone mineral density in patients with end-stage kidney disease and renal transplants: A 15-year single-centre experience

Chronic Kidney Disease Stage 5 (CKD-5) imparts a 4-fold increase in minimal trauma fracture with a substantial increase in mortality following hip fracture. Bone disease in CKD is complex, characterised by abnormal levels of PTH, calcium, phosphate, ALP, and vitamin D, manifesting as a condition known as CKD-Mineral and Bone Disorder (CKD-MBD). While bisphosphonates (BPs) are widely used in the management of osteoporosis, their therapeutic role when end-stage renal function and bone disease co-exist remains unclear. This 15-year retrospective cohort study examines the long-term use of BPs in CKD-4 and -5 patients receiving no renal replacement therapy, haemodialysis and renal transplant in a tertiary centre in Sydney, Australia. In multivariate regression adjusting for age, baseline bone mineral density (BMD) and history of fracture, BP use was associated with net gain in lumbar spine bone density in renal transplant recipients over a mean treatment period of 3.5 years (net annual BMD gain of 0.039 g/cm2, p = 0.005). No such benefit was seen in hip BMD in CKD subjects. Regardless of transplant status, CKD patients treated with BPs had no improvement in hip BMD with a general decline in hip BMD across both groups during the study period (hip BMD: transplant recipients decline 0.024 ± 0.81 g/cm2, non-transplant CKD patients decline 0.055 ± 0.84 g/cm2). BP therapy did not result in significant changes in biochemical parameters (ALP, PTH, and phosphate) and no serious adverse effects were detected in association with BP use. In particular, kidney function was not affected by BPs post-transplant (eGFR = 43 ± 29 ml/min/1.73 m2, p = 0.80). BPs preserved lumbar spine bone density in kidney transplant recipients but did not prevent declines in hip bone mineral density in either transplant patients or those with CKD-4 and -5. SummaryThere remains a lack of clarity of the risks vs. benefits of bone-sparing pharmacotherapy in chronic kidney disease Stages 4 and 5. This single-centre 15-year retrospective data analysis showed that bisphosphonates are not associated with any detectable serious adverse effects in CKD-4 and -5 and effective at mitigating lumbar spine bone loss in kidney transplant patients.

The Calcified Vasculature in Chronic Kidney Disease Secretes Factors that Inhibit Bone Mineralization.

ABSTRACTVascular calcification and bone disorder progress simultaneously in chronic kidney disease (CKD). Still, how the complex pathological mechanisms are linked is only sparsely understood. Up to now, the focus has been on the disturbed bone metabolism in developing vascular calcification. However, our group has recently demonstrated that vascular calcification has negative effects on bone formation and mineralization as shown in the bone of normal recipient rats transplanted with the calcified aorta from CKD rats. In the present in vitro study, the hypothesis of a direct crosstalk between the vasculature and bone was examined. Calcified aortas from 5/6 nephrectomized rats and normal aortas from control rats were excised and incubated ex vivo. The calcified aorta secreted large amounts of sclerostin, dickkopf‐1 (Dkk1), and activin A. Both normal and calcified aortas secreted frizzle‐related protein 4 (SFRP4). Aorta rings were co‐incubated with the osteoblast‐like cell line UMR‐106. The calcified aorta strongly inhibited calcium crystal formation in UMR‐106 cells, together with a significant upregulation of the mineralization inhibitors osteopontin and progressive ankylosis protein homolog (ANKH). The strong stimulation of osteopontin was blocked by lithium chloride, indicating involvement of Wnt/β‐catenin signaling. The present in vitro study shows detrimental effects of the calcified aorta on bone cell mineralization. These findings support the hypothesis of an active role of the calcified vasculature in the systemic CKD–mineral and bone disorder (CKD‐MBD), resulting in a pathological vascular–bone tissue crosstalk. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.