Chronic Kidney Disease-mineral Bone Research Articles

Leveraging Quantitative Systems Pharmacology and Artificial Intelligence to advance treatment of Chronic Kidney Disease Mineral Bone Disorder.

Chronic kidney disease mineral bone disorder (CKD-MBD) is a complex clinical syndrome responsible for the accelerated cardiovascular mortality seen in individuals afflicted with CKD. Current approaches to therapy have failed to improve clinical outcomes adequately, likely due to targeting surrogate biochemical parameters as articulated by the guideline developer, KDIGO (Kidney Disease: Improving Global Outcomes). We hypothesized that using a Systems Biology Approach combining machine learning with mathematical modeling, we could test a novel approach to therapy targeting the abnormal movement of mineral out of bone and into soft tissue that is characteristic of CKD-MBD. The mathematical model describes the movement of calcium and phosphate between body compartments in response to standard therapeutic agents. The machine learning technique we applied is Reinforcement Learning (RL). We compared calcium, phosphate, PTH, and mineral movement out of bone and into soft tissue under four scenarios: standard approach (KDIGO), achievement of KDIGO guidelines using RL (RLKDIGO), targeting abnormal mineral flux (RLFLUX), and combining achievement of KDIGO guidelines with minimization of abnormal mineral flux (RLKDIGOFLUX). We demonstrate through simulations that explicitly targeting abnormal mineral flux significantly decreases abnormal mineral movement compared to standard approach while achieving acceptable biochemical outcomes. These investigations highlight the limitations of current therapeutic targets, primarily secondary hyperparathyroidism, and emphasize the central role of deranged phosphate homeostasis in the genesis of the CKD-MBD syndrome.

#3127 Bedside cycling modulated the bone-resorption markers in patients with end-stage renal disease

Abstract Background and Aims Exercise provided multifactorial benefits in improving the health of the CKD patients. The exercise itself improved the bone remodeling. For CKD patients, chronic kidney disease mineral bone disorder (CKD-MBD) is an important complication and the treatment for renal osteodystrophy is unsatisfactory. The aim of study is to validate the role of bedside cycling in bone remodeling markers for patients with end-stage renal disease (ESRD). Method Participants were grouped into 4 groups: health control, chronic kidney disease (GFR 15∼60 ml/min) and ESRD (GFR<15 ml/min with maintenance dialysis). For ESRD patients, 12-week bedside cycling ((30 minutes per session; 3 times per week) were given for subjects. The pre-and post-exercise bone remodeling markers and clinical outcome were compared in ESRD with and without exercise in ESRD subjects. Results Bone formation markers (Bone specific alkaline phosphatase (15.57 ± 1.59 pg/dL) and Procollagen type 1 amino-terminal propeptide (1269.12 ± 116.34 pg/dL) were higher in ESRD patients with correlation with indoxyl sulfate and intact parathyroid hormone concentration(p < 0.05) respectively. In ESRD patients, the post-exercise concentration of Tartrate-resistant acid phosphatase 5b (3.64 ± 0.25 pg/dL to 4.23 ± 0.31 pg/mL, p = 0.003) and N-terminal telopeptide-1 (113.67 ± 20.53 pg/mL to 260.61 ± 30.9 pg/mL, p = 0.001)increased after 12 weeks of bed-side cycling. The hospitalization and mortality were similar between ESRD with or without exercise. Conclusion The bone formation marker concentration increased along with the severity of CKD. Bedside cycling increased the concentration of the bone resorption markers in ESRD patients.

#2296 Time to get calciphylaxis on clinicians’ RaDaR?—a multicentre case series

Abstract Background and Aims Calciphylaxis is a rare, severe complication of chronic kidney disease mineral bone disorder. It is hosphorzed by arteriolar calcification of the subcutaneous fat and dermis, and associated with a mortality rate of approximately 50% within a year of diagnosis. The reported prevalence of calciphylaxis in dialysis patients ranges from 1–4%. Between March 2012 and March 2020 the UK calciphylaxis study (UKCS) recruited 139 patients from 36 enrolled renal centres; an average of 1 case every 2.6 years per centre. The multicentre case series presented here includes patients from two NHS Hospital Trusts in the UK. The aim is to raise awareness of i) calciphylaxis and possible risk factors and ii) the role of registry data in rare kidney diseases. Method Patients were included if they had a diagnosis of calciphylaxis between 01.02.2020 and 01.02.2022. Data regarding demographics, dialysis modality, BMI, medications, and mineral bone parameters were collected from clinical databases. A representative sample of results was recorded from initiation of renal replacement therapy through to diagnosis of calciphylaxis. Data regarding calciphylaxis lesions, treatments and current vital status are hosphorz. Results 17 patients with end stage kidney failure (ESKF) and clinical features of calciphylaxis were included; 8 of 17 (47%) had a skin biopsy of which 6 reported evidence of calcification. Median age was 57 years (IQR: 50-74), BMI 26.8 kg/m2 (IQR: 22.9-31.1), 100% were white, 53% female and 59% had diabetes. Median time from onset of ESKF to calciphylaxis diagnosis was 5.5 years (IQR: 1-16). 53% (9 of 17) had history of recurrent hypercalcaemia (corrected calcium >2.55 mmol/L) and 82% (14 of 17) recurrent hyperphosphatemia (phosphate >1.5 mmol/L). 41% (7 of 17) had refractory secondary hyperparathyroidism. Warfarin therapy exposure was recorded in 47% (8 of 17) patients; a finding consistent with the literature. 76% (13 of 17) had received active vitamin D and 76% (13 of 17) a calcium-based phosphate binder. 76% (13 of 17) had lower leg lesions; 2 of whom also had upper leg lesions. 1 patient had a thigh lesion and 2 patients had an abdominal wound. Median follow up time was 8.5 months (range 1-24). 9 of the 17 patients remain alive, of whom lesions have completely healed in 6 patients. All patients received sodium thiosulphate and 1 (transplant patient) received hyperbaric oxygen therapy and sodium thiosulphate. Only 1 patient has been enrolled into the UK registry of rare kidney diseases (RaDaR). Conclusion Calciphylaxis is a devastating condition for which there are no proven treatments. In this case series a history of hyperphosphataemia, calcium-based binder, alfacalcidol, and warfarin use were common. It remains unknown why some patients develop calciphylaxis and others do not. National registry data, such as RaDaR, plays a crucial role in furthering knowledge and understanding of rare diseases; it helps to determine calciphylaxis incidence, and inform possible prevention and treatment strategies. Yet, in reality, few patients maybe being recruited into RaDaR. The opportunity exists for an international calciphylaxis registry; for this to offer maximum impact individual countries need to explore, and where possible address, barriers to recruitment.

Activin A: a marker of mineral bone disorder in children with chronic kidney disease?

Activin A has been shown to enhance osteoclast activity and its inhibition results in bone growth. The potential role of activin A as a marker of chronic kidney disease-mineral bone disease(CKD-MBD) and its relationship with other markers has not been studied in children with CKD. A cross sectional study was conducted among 40 children aged 2 to 18years with CKD (Stage 2 to 5; 10 in each stage) and 40 matched controls. Activin A, cathepsin K, FGF-23, PTH, serum calcium, phosphorous and alkaline phosphatase in both groups were measured and compared. The correlation of activin A and markers of CKD-MBD was studied. A p value of < 0.05 was considered significant. The mean age of children with CKD was 9.30 ± 3.64years. Mean levels of activin A in cases were 485.55pg/ml compared to 76.19pg/ml in controls (p < 0.001). FGF-23 levels in cases were 133.18pg/ml while in controls it was 6.93pg/ml (p < 0.001). Mean levels of cathepsin K were also significantly higher in cases as compared to controls. There was a progressive increase in activin A and cathepsin K levels with increasing stage of CKD. Activin A had a significant positive correlation with serum creatinine (r = 0.51; p < 0.001). Activin A levels progressively rise with advancing CKD stage. These findings suggest that activin A can be a potential early marker of CKD-MBD in children.

Post-Transplant Bone Disease in Kidney Transplant Recipients: Diagnosis and Management.

Kidney transplantation is the preferred gold standard modality of treatment for kidney failure. Bone disease after kidney transplantation is highly prevalent in patients living with a kidney transplant and is associated with high rates of hip fractures. Fractures are associated with increased healthcare costs, morbidity and mortality. Post-transplant bone disease (PTBD) includes renal osteodystrophy, osteoporosis, osteonecrosis and bone fractures. PTBD is complex as it encompasses pre-existing chronic kidney disease-mineral bone disease and compounding factors after transplantation, including the use of immunosuppression and the development of de novo bone disease. After transplantation, the persistence of secondary and tertiary hyperparathyroidism, renal osteodystrophy, relative vitamin D deficiency and high levels of fibroblast growth factor-23 contribute to post-transplant bone disease. Risk assessment includes identifying both general risk factors and kidney-specific risk factors. Diagnosis is complex as the gold standard bone biopsy with double-tetracycline labelling to diagnose the PTBD subtype is not always readily available. Therefore, alternative diagnostic tools may be used to aid its diagnosis. Both non-pharmacological and pharmacological therapy can be employed to treat PTBD. In this review, we will discuss pathophysiology, risk assessment, diagnosis and management strategies to manage PTBD after kidney transplantation.

Soluble Klotho, a Potential Biomarker of Chronic Kidney Disease-Mineral Bone Disorders Involved in Healthy Ageing: Lights and Shadows.

Shortly after the discovery of Klotho, interest grew in its potential role in chronic kidney disease (CKD). There are three isoforms of the Klotho protein: αKlotho, βKlotho and γKlotho. This review will focus on αKlotho due to its relevance as a biomarker in CKD. αKlotho is synthesized mainly in the kidneys, but it can be released into the bloodstream and urine as soluble Klotho (sKlotho), which undertakes systemic actions, independently or in combination with FGF23. It is usually accepted that sKlotho levels are reduced early in CKD and that lower levels of sKlotho might be associated with the main chronic kidney disease-mineral bone disorders (CKD-MBDs): cardiovascular and bone disease. However, as results are inconsistent, the applicability of sKlotho as a CKD-MBD biomarker is still a matter of controversy. Much of the inconsistency can be explained due to low sample numbers, the low quality of clinical studies, the lack of standardized assays to assess sKlotho and a lack of consensus on sample processing, especially in urine. In recent decades, because of our longer life expectancies, the prevalence of accelerated-ageing diseases, such as CKD, has increased. Exercise, social interaction and caloric restriction are considered key factors for healthy ageing. While exercise and social interaction seem to be related to higher serum sKlotho levels, it is not clear whether serum sKlotho might be influenced by caloric restriction. This review focuses on the possible role of sKlotho as a biomarker in CKD-MBD, highlighting the difference between solid knowledge and areas requiring further research, including the role of sKlotho in healthy ageing.

Real-world usage of Chronic Kidney Disease - Mineral Bone Disorder (CKD-MBD) biomarkers in nephrology practices.

Chronic kidney disease mineral bone disorder (CKD-MBD) is a condition characterized by alterations of calcium, phosphate, parathyroid hormone (PTH), and fibroblast growth factor 23 (FGF-23) metabolism that in turn promote bone disorders, vascular calcifications, and increase cardiovascular (CV) risk. Nephrologists' awareness of diagnostic, prognostic, and therapeutic tools to manage CKD-MBD plays a primary role in adequately preventing and managing this condition in clinical practice. A national survey (composed of 15 closed questions) was launched to inquire about the use of bone biomarkers in the management of CKD-MBD patients by nephrologists and to gain knowledge about the implementation of guideline recommendations in clinical practice. One hundred and six Italian nephrologists participated in the survey for an overall response rate of about 10%. Nephrologists indicated that the laboratories of their hospitals were able to satisfy request of ionized calcium levels, 105 (99.1%) of both PTH and alkaline phosphatase (ALP), 100 (94.3%) of 25(OH)D, and 61 (57.5%) of 1.25(OH)2D; while most laboratories did not support the requests of biomarkers such as FGF-23 (intact: 88.7% and c-terminal: 93.4%), Klotho (95.3%; soluble form: 97.2%), tartrate-resistant acid phosphatase 5b (TRAP-5b) (92.5%), C-terminal telopeptide (CTX) (71.7%), and pro-collagen type 1 N-terminal pro-peptide (P1NP) (88.7%). As interesting data regarding Italian nephrologists' behavior to start treatment of secondary hyperparathyroidism (sHPT), the majority of clinicians used KDOQI guidelines (n=55, 51.9%). In contrast, only 40 nephrologists (37.7%) relied on KDIGO guidelines, which recommended referring to values of PTH between two and nine times the upper limit of the normal range. Results point out a marked heterogeneity in the management of CKD-MBD by clinicians as well as a suboptimal implementation of guidelines in Italian clinical practice.

THU416 Trabecular Bone Score, Bone Mineral Density, And Fractures In Patients Of Chronic Kidney Disease With And Without Diabetes Mellitus

Abstract Disclosure: V. Suryadevara: None. R. Kg: None. A. Prasad: None. V. Sunthoju: None. P. Ps: None. R. Govindarajalou: None. J. Sahoo: None. S. Kamalanathan: None. D. Naik: None. Background and objectives: Chronic kidney disease-mineral bone disease (CKD-MBD) is a common yet neglected long-term complication of CKD. The primary objective of this study was to compare the proportion of patients with low trabecular bone score (TBS) in the CKD patients with diabetes mellitus (CKD-DM) and the CKD patients without DM (CKD-NDM). The secondary objectives were to compare bone mineral density (BMD) and morphometric vertebral fractures (VF) between the two groups. Methods: Patients of CKD with an estimated glomerular filtration rate (eGFR) &amp;lt; 60 mL/min/1.73m2, and not initiated on maintenance hemodialysis were recruited in the study. They were classified into the CKD-DM or the CKD-NDM group based on the presence of DM. Both groups were matched for age and gender. A detailed history was taken, and a physical examination was done to rule out secondary causes of osteoporosis. Serum creatinine, electrolytes, 25 hydroxy vitamin [25 (OH)D], and intact parathyroid hormone (iPTH) were analysed. Areal BMD was assessed using Hologic Discovery Wi dual-energy X-ray absorptiometer. TBS was estimated from spine BMD images using TBS iNsight software v 3.1.1 (Medimaps, Geneva). A dorsolumbar spine radiograph was performed to look for morphometric VFs. Results: 306 participants with CKD (153- diabetic and 153 non-diabetic) were included. The baseline characteristics were comparable between the two groups except for a higher BMI [24.13 (21.9-27.5) vs 21.86 (19.7-24.4) kg/m2], higher waist circumference [92.5 (85-99) vs 85 (80-93) cm], higher eGFR [31 (15.5-42.5) vs 25 (13-34) ml/min/1.73m2], lower magnesium [2 (1.8-2.2) vs 2.1 (1.8-2.4) mg/dl], and lower 25(OH)D [28.82 (21.3-38.6) vs 36.11 (28.4-47.3) ng/ml] in the CKD-DM group. The proportion of patients with low bone turnover (iPTH levels &amp;lt; 80 pg/ml) was higher in the CKD-DM group (34.2% vs 27.1%). The proportion of patients with low TBS was similar between the two groups (39.86% vs 41.83%; p=0.727). The BMD at lumbar spine (LS) [0.977 (0.877-1.128) vs 0.945 (0.814-1.148) g/cm2; p=0.219] and distal forearm (FA) [0.689 (0.618-0.736) vs 0.661 (0.576-0.731) g/cm2; p = 0.053] were also comparable between the two groups. However, BMD at femur neck (FN) [0.707 (0.624-0.798) vs 0.665 (0.586-0.768) g/cm2; p=0.012] and total hip (TH) [0.862 (0.760-0.951) vs 0.811 (0.713-0.916) g/cm2; p=0.006] were higher in the CKD-DM group. The prevalence of morphometric VF was similar between the two groups (8.5% vs 5.2%; p=0.258). Conclusion: In this cohort of pre-dialysis stage 3-5 CKD patients, the prevalence of low TBS, BMD at LS and distal FA were similar between the CKD-DM and the CKD-NDM groups. The BMD at FN and TH was higher in CKD with DM compared to CKD without DM. Presentation: Thursday, June 15, 2023

Vitamin K Status of Patients Undergoing Hemodialysis: Insights from a Cross-Sectional Study

(1) Background: Vitamin K deficiency is a common feature of chronic kidney disease (CKD), leading to impaired bone quality and an increased risk of vascular calcifications. A method to indirectly assess the vitamin K status is measuring the blood level of vitamin K-dependent proteins (VKDP): osteocalcin (OC) and matrix GLA protein (MGP). The aim of this study is to correlate the level of total OC and inactive MGP (dp-uc MGP) with markers of CKD mineral bone disorder (CKD-MBD). (2) Methods: We conducted a single-center cross-sectional study that included 45 CKD G5D patients and measured their blood biochemistry, complete blood count and total osteocalcin and dp-uc MGP contents. (3) Results: We found a strong, statistically significant correlation of the total OC with the markers of CKD-MBD, such as: iPTH, serum calcium and serum phosphorus, and a strong, indirect statistically significant correlation with abdominal circumference. There was also a statistically significant correlation of dp-uc MGP with the markers of inflammation (CRP). Higher levels of dp-uc MGP were found in the patients treated with vitamin K antagonists, non-calcium-based phosphate binders and the vitamin D receptor activator, paricalcitol. (4) Conclusions: In our study, we found that when it is measured indirectly using VKDP levels, vitamin K deficiency is associated with CKD-MBD. Certain widely used medications such as phosphate binders reduce vitamin K absorption, supplementary vitamin D increases vitamin K requirements, and also vitamin K antagonists influence the blood level of VKDPs.

Chronic kidney disease mineral bone disorder in childhood and young adulthood: a ‘growing’ understanding

Chronic kidney disease (CKD) mineral and bone disorder (MBD) comprises a triad of biochemical abnormalities (of calcium, phosphate, parathyroid hormone and vitamin D), bone abnormalities (turnover, mineralization and growth) and extra-skeletal calcification. Mineral dysregulation leads to bone demineralization causing bone pain and an increased fracture risk compared to healthy peers. Vascular calcification, with hydroxyapatite deposition in the vessel wall, is a part of the CKD-MBD spectrum and, in turn, leads to vascular stiffness, left ventricular hypertrophy and a very high cardiovascular mortality risk. While the growing bone requires calcium, excess calcium can deposit in the vessels, such that the intake of calcium, calcium- containing medications and high calcium dialysate need to be carefully regulated. Normal physiological bone mineralization continues into the third decade of life, many years beyond the rapid growth in childhood and adolescence, implying that skeletal calcium requirements are much higher in younger people compared to the elderly. Much of the research into the link between bone (de)mineralization and vascular calcification in CKD has been performed in older adults and these data must not be extrapolated to children or younger adults. In this article, we explore the physiological changes in bone turnover and mineralization in children and young adults, the pathophysiology of mineral bone disease in CKD and a potential link between bone demineralization and vascular calcification.Graphical abstractA higher resolution version of the Graphical abstract is available as Supplementary information

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 relevanceThe 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 studyThe 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 methodsThe 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. ResultsThe 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. ConclusionsOur 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.

Parathyroidectomy versus oral cinacalcet on cardiovascular parameters in peritoneal dialysis patients with advanced secondary hyperparathyroidism (PROCEED): A randomized trial.

This trial aimed to evaluate oral cinacalcet versus total parathyroidectomy with forearm autografting (PTx) on cardiovascular surrogate outcomes and health-related quality of life (HRQOL) measures in dialysis patients with advanced SHPT. In this pilot prospective randomized trial conducted in two university-affiliated hospitals, 65 adult peritoneal dialysis patients with advanced SHPT were randomized to receive either oral cinacalcet or PTx. Primary endpoints were changes in left ventricular (LV) mass index by cardiac magnetic resonance imaging and coronary artery calcium scores (CACS) over 12 months. Secondary endpoints included changes in heart valves calcium scores, aortic stiffness, biochemical parameters of chronic kidney disease-mineral bone disease (CKD-MBD) and HRQOL measures over 12 months. Changes in LV mass index, CACS, heart valves calcium score, aortic pulse wave velocity and HRQOL did not differ between-groups or within-groups, despite significant reductions in plasma calcium, phosphorus and intact parathyroid hormone in both groups. Cinacalcet-treated patients experienced more cardiovascular-related hospitalizations than those who underwent PTx (P=0.008) but the difference became insignificant after adjusting for baseline difference in heart failure (P=0.43). With the same monitoring frequency, cinacalcet-treated patients had fewer hospitalizations due to hypercalcemia (1.8%) than patients who underwent PTx (16.7%) (P=0.005). No significant changes were observed in HRQOL measures in either group. Both cinacalcet and PTx effectively improved various biochemical abnormalities of CKD-MBD and stabilized but did not reduce LV mass, coronary artery and heart valves calcification, arterial stiffness or improve patient-centered HRQOL measures in PD patients with advanced SHPT. Cinacalcet may be used in place of PTx for treating advanced SHPT. Long-term and powered studies are required to evaluate PTx versus cinacalcet on hard cardiovascular outcomes in dialysis patients.

Inositol 1,4,5-trisphosphate receptor type 2 is associated with the bone–vessel axis in chronic kidney disease–mineral bone disorder

Objective The pathogenesis of renal osteopathy and cardiovascular disease suggests the disordered bone–vessel axis in chronic kidney disease–mineral bone disorder (CKD–MBD). However, the mechanism of the bone–vessel axis in CKD–MBD remains unclear. Methods We established a CKD–MBD rat model to observe the pathophysiological phenotype of the bone–vessel axis and performed RNA sequencing of aortas to identify novel targets of the bone–vessel axis in CKD–MBD. Results The microarchitecture of the femoral trabecular bone deteriorated and alveolar bone loss was aggravated in CKD–MBD rats. The intact parathyroid hormone and alkaline phosphatase levels increased, 1,25-dihydroxyvitamin D3 levels decreased, and intact fibroblast growth factor-23 levels did not increase in CKD–MBD rats at 16 weeks; other bone metabolic parameters in the serum demonstrated dynamic characteristics. With calcium deposition in the abdominal aortas of CKD–MBD rats, RNA sequencing of the aortas revealed a significant decrease in inositol 1,4,5-trisphosphate receptor type 2 (ITPR2) gene levels in CKD–MBD rats. A similar trend was observed in rat aortic smooth muscle cells. As a secretory protein, ITPR2 serum levels decreased at 4 weeks and slightly increased without statistical differences at 16 weeks in CKD–MBD rats. ITPR2 serum levels were significantly increased in patients with vascular calcification, negatively correlated with blood urea nitrogen levels, and positively correlated with serum tartrate-resistant acid phosphatase 5b levels. Conclusion These findings provide preliminary insights into the role of ITPR2 in the bone–vessel axis in CKD–MBD. Thus, ITPR2 may be a potential target of the bone–vessel axis in CKD–MBD.

Differences in prevalence of reduced and low bone mineral density between lumbar spine and femoral neck in peritoneal dialysis patients using dual-energy X-ray absorptiometry (DXA).

The pattern of chronic kidney disease-mineral bone disease has changed following the increase in elderly patients receiving dialysis, with escalating likelihood of osteoporosis, with associated increased fracture risk and mortality. Thus, we wished to determine the prevalence of osteoporosis in our peritoneal dialysis (PD) cohort. Lumbar spine (LS) and femoral neck (FN) bone mineral density (BMD) measured by dual-energy X-ray absorptiometry (DXA), and low BMD (osteoporosis) and reduced BMD (osteopenia) defined according to the World Health Organisation T scores. DXA scans from 734 patients, 57.2% male, mean age 61.0 ±16.0 years, 34.6% diabetic, with a median 8.0 (2-24) months of treatment with PD were reviewed. Fewer patients had normal BMD at the FN vs. LS (24.1 vs. 55%), and more classified as reduced (FN 55.9 vs. 34% LS) and low BMD (FN 17 vs. 11% LS), χ 2 112.2, p < 0.001. Agreement between FN and LS T scores was r = 0.36 with Spearman rank correlation, and 0.34 by Kendall's tau b, Cohen's kappa score 0.17, and Bland-Altman bias -0.37 (95% limits of agreement -1.8 to 1.08). The prevalence of reduced and low BMD was much greater when using FN T scores compared to LS, with LS T scores a mean of 0.34 higher than FN. DXA scanning at the LS can be affected by overlying vascular calcification and electron densities in the bowel, and as such we suggest that FN T scores are used to report BMD in PD patients.

Bone Turnover Markers: Basic Biology to Clinical Applications.

Bone turnover markers (BTMs) are used widely, in both research and clinical practice. In the last 20 years, much experience has been gained in measurement and interpretation of these markers, which include commonly used bone formation markers (bone alkaline phosphatase, osteocalcin, and procollagen I N-propeptide); and commonly used resorption markers (serum C-telopeptides of type I collagen, urinary N-telopeptides of type I collagen, and tartrate-resistant acid phosphatase type 5b). BTMs are usually measured by enzyme-linked immunosorbent assay or automated immunoassay. Sources contributing to BTM variability include uncontrollable factors (eg, age, gender, ethnicity) and controllable factors, particularly relating to collection conditions (eg, fasting/feeding state, and timing relative to circadian rhythms, menstrual cycling, and exercise). Pregnancy, season, drugs, and recent fracture(s) can also affect BTMs. BTMs correlate with other methods of assessing bone turnover, such as bone biopsies and radiotracer kinetics, and can usefully contribute to diagnosis and management of several diseases such as osteoporosis, osteomalacia, Paget's disease, fibrous dysplasia, hypophosphatasia, primary hyperparathyroidism, and chronic kidney disease-mineral bone disorder.

Hyperphosphatemia in Chronic Kidney Disease: Drug Treatment and Effects on Metabolic Acidosis. A Mini Review

Hyperphosphatemia is a highly prevalent component of CKD and chronic kidney disease mineral bone disease (CKD-MBD). Its association with metabolic acidosis, hypertension, cardiovascular disease and chronic inflammation is common. Treatment is commonly with calcium based phosphate binder (PB) as the high cost of sevelamer makes it readily unavailable particularly in low income settings. Sevelamer has several comparative advantage over calcium based PBs, many of which, in addition to its non-worsening of tissue calcification contributes significantly to positive treatment outcome. The ability of sevelamer to reduce many cytokines and inflammatory mediators such as TNF-α, IL-1, IL-6, FGF-23 and high sensitivity CRP among others, contributes significantly to its renoprotection prowess.

Correction of Vascular Calcification and Hyperphosphatemia in CKD Rats Treated with ASARM Peptide.

Abnormalities in calcium, phosphorus, PTH, vitamin D metabolism, bone, and vascular calcification occur in chronic kidney disease mineral bone disorder (CKD-MBD). Calciphylaxis, involving painful, ulcerative skin lesions, is also a major problem associated with CKD-MBD. There are no quality medical interventions to address these clinical issues. Bone ASARM peptides are strong inhibitors of mineralization and induce hypophosphatemia by inhibiting phosphate uptake from the gut. We hypothesize treatment of CKD-MBD rats with ASARM peptides will reverse hyperphosphatemia, reduce soft-tissue calcification, and prevent calciphylaxis. To test our hypothesis, we assessed the effects of synthetic ASARM peptide in rats that had undergone a subtotal 5/6th nephrectomy (56NEPHREX), a rodent model of CKD-MBD. All rats were fed a high phosphate diet (2% Pi) to worsen mineral metabolism defects. Changes in serum potassium, phosphate, BUN, creatinine, PTH, FGF23, and calcium were assessed in response to 28 days of ASARM peptide infusion. Also, changes in bone quality, soft-tissue calcification, and expression of gut Npt2b (Slc34a2) were studied following ASARM peptide treatment. Rats that had undergone 56NEPHREX treated with ASARM peptide showed major improvements in hyperphosphatemia, blood urea nitrogen (BUN), and bone quality compared with vehicle controls. Also, ASARM-infused 56NEPHREX rats displayed improved renal, brain, and cardiovascular calcification. Notably, ASARM peptide infusion prevented the genesis of subdermal medial blood vessel calcification and calciphylaxis-like lesions in 56NEPHREX rats compared with vehicle controls. ASARM peptide infusion corrects hyperphosphatemia and improves vascular calcification, renal calcification, brain calcification, bone quality, renal function, and skin mineralization abnormalities in 56NEPHREX rats. These findings confirm our hypothesis and support the utility of ASARM peptide treatment in patients with CKD-MBD.

Mineral Bone Disorders in Kidney Disease Patients: The Ever-Current Topic.

Chronic kidney disease (CKD) is a complex and multifactorial disease, and one of the most prevalent worldwide. Chronic kidney disease–mineral bone disorders (CKD–MBD) with biochemical and hormonal alterations are part of the complications associated with the progression of CKD. Pathophysiology of CKD–MBD focused on abnormalities in serum levels of several biomarkers (such as FGF-23, klotho, phosphate, calcium, vitamin D, and PTH) which are discussed in this review. We therefore examine the prognostic association between CKD–MBD and the increased risk for cardiovascular events, mortality, and CKD progression to end-stage kidney disease (ESKD). Lastly, we present specific treatments acting on CKD to prevent and treat the complications associated with secondary hyperparathyroidism (SHPT): control of hyperphosphatemia (with dietary restriction, intestinal phosphate binders, and adequate dialysis), the use of calcimimetic agents, vitamin D, and analogues, and the use of bisphosphonates or denosumab in patients with osteoporosis.

The controversy of klotho as a potential biomarker in chronic kidney disease.

Klotho is an identified longevity gene with beneficial pleiotropic effects on the kidney. Evidence shows that a decline in serum Klotho level occurs in early chronic kidney disease (CKD) and continues as CKD progresses. Klotho deficiency is associated with poor clinical outcomes and CKD mineral bone disorders (CKD-MBD). Klotho has been postulated as a candidate biomarker in the evaluation of CKD. However, the evidence for the clinical significance of the relationship between Klotho and kidney function, CKD stage, adverse kidney and/or non-kidney outcomes, and CKD-MBD remains inconsistent and in some areas, contradictory. Therefore, there is uncertainty as to whether Klotho is a potential biomarker in CKD; a general consensus regarding the clinical significance of Klotho in CKD has not been reached, and there is limited evidence synthesis in this area. To address this, we have systematically assessed the areas of controversy, focusing on the inconsistencies in the evidence base. We used a PICOM strategy to search for relevant studies and the Newcastle–Ottawa Scale scoring to evaluate included publications. We reviewed the inconsistent clinical findings based on the relationship of Klotho with CKD stage, kidney and/or non-kidney adverse outcomes, and CKD-MBD in human studies. Subsequently, we assessed the underlying sources of the controversies and highlighted future directions to resolve these inconsistencies and clarify whether Klotho has a role as a biomarker in clinical practice in CKD.

Frailty, appendicular lean mass, osteoporosis and osteosarcopenia in peritoneal dialysis patients

IntroductionThe pattern of chronic kidney disease mineral bone disorder (CKD-MBD) is changing with increasing numbers of elderly patients now treated by dialysis. The risk of falls and bone fractures increases with frailty and sarcopenia. As such we wished to review the association between osteoporosis and frailty and loss of appendicular lean mass (ALM).MethodsDual-energy X-ray absorptiometry (DXA) was used to measure lumbar spine and femoral neck bone mineral density (BMD) and body composition. Osteoporosis and osteopenia were defined according to T scores. ALM was indexed to height (ALMI). Frailty was classified using the clinical frailty scale (CFS).ResultsDXA scans from 573 patients, 57.8% male, 36.8% diabetic, mean age 61.0 ± 15.8 years, with a median 6.0 (2–20) months of treatment with PD were reviewed. Forty-two (7.3%) were classified as clinically frail, 115 (20%) osteoporotic, and 198 (34.6%) ALMI meeting sarcopenic criteria, with 43% of osteoporotic patients being osteosarcopenic. In a multivariable model, femoral neck BMD was associated with weight, standardised β (St β) 0.29, p = 0.004, ALM St β 0.11, p = 0.03 and Black vs other ethnicities St β 0.19, p = 0.02, and negatively with age St β −0.24, p < 0.001, and frailty St β −2.1, p = 0.04. Z scores (adjusted for gender and age) were associated with ALMI (r = 0.18, p < 0.001).DiscussionOsteoporosis is increasing with the numbers of elderly dialysis patients. As frailty and sarcopenia increase with age, then the risk of falls and bone fractures increases with osteosarcopenia. Whether interventions with exercise and nutrition can improve bone heath remains to be determined.Graphical abstract