Kidney Disease-mineral Bone Disorder 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.

Application of artificial intelligence to chronic kidney disease mineral bone disorder.

The global derangement of mineral metabolism that accompanies chronic kidney disease (CKD-MBD) is a major driver of the accelerated mortality for individuals with kidney disease. Advances in the delivery of dialysis, in the composition of phosphate binders, and in the therapies directed towards secondary hyperparathyroidism have failed to improve the cardiovascular event profile in this population. Many obstacles have prevented progress in this field including the incomplete understanding of pathophysiology, the lack of clinical targets for early stages of chronic kidney disease, and the remarkably wide diversity in clinical manifestations. We describe in this review a novel approach to CKD-MBD combining mathematical modelling of biologic processes with machine learning artificial intelligence techniques as a tool for the generation of new hypotheses and for the development of innovative therapeutic approaches to this syndrome. Clinicians need alternative targets of therapy, tools for risk profile assessment, and new therapies to address complications early in the course of disease and to personalize therapy to each individual. The complexity of CKD-MBD suggests that incorporating artificial intelligence techniques into the diagnostic, therapeutic, and research armamentarium could accelerate the achievement of these goals.

#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.

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.

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.

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.

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.

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.

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

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

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

Comparison between Paricalcitol versus cinacalcet therapy in the management of secondary hyperparathyroidism among prevalent hemodialysis patients

Abstract Background Secondary hyperparathyroidism (SHPT) is one of the components of chronic kidney disease–mineral bone disorder (CKD-MBD) with significant contribution to the morbidity and mortality among prevalent hemodialysis (HD) patients. Objectives Multicentric experience study to compare the effectiveness of Intravenous (IV) paricalcitol versus oral cinacalcet and oral cinacalcet plus oral alfacalcidol as treatment regimens of secondary hyperparathyroidism (SHPT) among chronic haemodialysis (HD) patients. Methods Retrospective observational cohort study, 1year time horizon, 130 prevalent HD patients with SHPT were recruited from three main HD centres in Aljouf region in Saudi Arabia. Patients were divided into 3 groups: Group I (50) HD patients were treated by intravenous paricalcitol, group II (50) HD patients who received oral cinacalcet plus oral alfacalcidol, Group III (30) HD patients were on oral cinacalcet. Serum Intact parathyroid hormone, Calcium, Phosphorus and alkaline Phosphatase tests were assessed every 3 months. Results 130 (61 (47%) females, (53%) 69 males) HD patients, mean age 56.30 ± 19.1 years, mean HD duration 4.86±4.15 year. The mean of PTH is significantly reduced in all studied groups (P &amp;lt; 0.001). Mean Δchanges in iPTH concentration in group I, II, III was (-242.11±148.75,225.54±153.91,-254.83±275.17)(P &amp;gt; 0.05) respectively with statistical non-significant differences. Increase of CaxPo4 with paricalcitol group as mean ΔChange in (CaxPO4) was in the group I, II, III(15.39±9.46,1.97±11.74,-2.89 ±9.37) respectively (P &amp;lt; 0.001). Significant increase in serum phosphorus from the baseline in patients in group II. Conclusions Intravenous Paricalcitol based regimen assumed to be equally effective in suppressing SHPT in prevalent hemodialysis patients when compared to the combination of oral Cinacalcet with oral alfacalcidol or treatment with oral cinacalcet alone, with less incidence of hyperphosphatemia with paricalcitol or cinacalcet in comparison to alfacalcidol regimen.

Enteral Ca-Intake May Be Low and Affects Serum-PTH-Levels in Pre-school Children With Chronic Kidney Disease.

Treatment of chronic kidney disease (CKD) mineral bone disorder (MBD) is challenging in growing children due to the high amount of calcium needed for normal bone mineralization and the required dietary phosphate restriction, which often includes intake of calcium-rich products such as milk. Therefore, enteral calcium-intake (Ca-I) was calculated.Patients: We looked at pediatric CKD-Patients aged 0–6 years.Design: We used a retrospective analysis of Ca-I from dietary data collections. Ca-I below 60% or above 100% of the D-A-CH and the KDOQI reference values were considered as severe Ca deficiency or Ca overload, respectively.Results: We had 41 children, median age 1.1 (range 0-5.8) years, body weight 7.3 (2.4–19.9) kg, and length 68 (48-105) cm at the time of first dietary data collection. Renal function was classified as CKD stage III in 20, IV in 28, V in 44, and VD in 142 dietary data collections. At the first dietary data collection, 5 children were in the CKD stage III, 10 in IV, 9 in V, and 17 were on dialysis. Only one child progressed to a higher CKD stage. In total, 234 dietary data collections were analyzed, and 65 follow-up collections were available from 33 children after a time interval of 26 (1–372) days. The median caloric intake was 120 (47–217)% of D-A-CH RDI. In 149 (63.6%) of the dietary data collections, enteral Ca-I was below the target (<100% of the D-A-CH and KDOQI RDI). Severe Ca-deficiency was found in 11 (26%) and 4 (12%) of the children at the first and second dietary data collection, respectively. In total, 11 children were on Ca-containing phosphate binders. In dietary data collection 1 and 2, there were seven children. From these, 4/7 and 4/7 patients had an enteral total Ca-I above the 100% D-A-CH-limit or above the KDOQI limit, respectively. Absolute dietary Ca-I and Ca-I normalized to body weight correlated negatively with PTH (r = −0.196, p < 0.005 and r = −0.13, p < 0.05).Conclusion: Enteral Ca-I should repeatedly be monitored in CKD children because many may may otherwise be underexposed to enteral calcium and overexposed when calcium-containing phosphate binders are given. Our findings suggest a major impact of dietary calcium supply on bone health in pediatric CKD.

Fat-Bone Relationship in Chronic Kidney Disease-Mineral Bone Disorders: Adiponectin Is Associated with Skeletal Events among Hemodialysis Patients.

Background: The risk of skeletal events is rising in parallel with the burden of chronic kidney disease and mineral bone disorder (CKD-MBD), whilst the role of the fat-bone axis in CKD-MBD remains elusive. Adiponectin derived from adipocytes has emerged as a valid biomarker of low bone mineral density and increased marrow adiposity. We aimed to explore the association between adiponectin and bone fracture (BF) risks in patients with maintenance hemodialysis (MHD). Methods: Serum concentrations of adiponectin and bio-clinical data were determined at study entry. The Cox proportional hazard regression analyses were used to assess unadjusted and adjusted hazard ratios (aHRs) of adiponectin and various clinical predictors for BF risks. The predictive accuracy of adiponectin for BF events was evaluated by receiver operating characteristic (ROC) curve analysis. Results: Age and serum concentrations of adiponectin, phosphate, and intact parathyroid hormone were significantly associated with higher risks of BF. With respect to the risk of BF events, the cumulative event-free survival curves differed significantly between the high and low concentration groups of adiponectin (p = 0.02). In multivariable analysis, higher adiponectin levels were associated with an incremental risk of BF (adjusted hazard ratios (aHRs): 1.08 (95% confidence interval (CI): 1.01–1.15, p < 0.05). The ROC analysis of adiponectin cutoff point concentration (18.15 ug/mL) for prediction of BF showed 0.66 (95% CI = 0.49 to 0.84). Conclusion: Adiponectin was associated with an incremental risk of BF that could serve as a potential predictor of BF in MHD patients. In the high-risk population with hyperphosphatemia, an elevated adiponectin level could alert clinicians to the urgent need to correct mineral dysregulation and undertake further bone survey.

Misclassification of calcium status in end-stage kidney disease using albumin-adjusted calcium levels.

Albumin-adjusted calcium remains widely used in clinical practice with guidelines for chronic kidney disease (CKD) mineral bone disorder recommending the use of serum calcium for monitoring. This is despite ionized calcium being the biologically active fraction. This study aimed to investigate the ability of total calcium and albumin-adjusted calcium to correctly assign calcium status in stage 5/5D CKD across non-dialysis, haemodialysis and peritoneal dialysis patients. Over a 6-months, 352 paired serum and ionized calcium samples were collected from stage 5 (n= 58) and 5D (n= 294, 196 haemodialysis, 98 peritoneal dialysis) CKD patients in a tertiary-hospital setting. Albumin-adjusted calcium was calculated using the modified-Payne formula. Ionized calcium was the reference standard. The agreement between the two methods in assigning calcium status was assessed using Cohen's weighted kappa (κ) statistic. Albumin-adjusted calcium was a poor predictor of calcium status compared to ionized calcium in stage 5/5D CKD (observed agreement 0.42, weighted κ 0.20, 95% CI 0.15-0.26). Dialysis dependence was associated with worse agreement (observed agreement 0.38, weighted κ 0.14, 95% CI 0.09-0.19). Total calcium was more reliable, however, remained inaccurate. Calcium status was not more accurately classified in those with higher albumin levels ≥30 g/L (observed agreement 0.47, weighted κ 0.23, 95% CI 0.10-0.36). Total calcium provides better approximation of calcium status than albumin-adjusted calcium in stage 5/5D CKD. Albumin-adjusted calcium tends to 'overcorrect' serum calcium upward. Clinicians should use ionized calcium where accurate measure of calcium is indicated, with total calcium used as the next best option where resources are limited.

Comparison between paricalcitol versus cinacalcet therapy in the management of secondary hyperparathyroidism among prevalent hemodialysis patients

Introduction: Secondary hyperparathyroidism (SHPT) is one of the components of chronic kidney disease–mineral bone disorder (CKD-MBD) with significant contribution to the morbidity and mortality among prevalent hemodialysis (HD) patients. Objectives: This multi-centric experience study aims to compare the effectiveness of intravenous (IV) paricalcitol versus oral cinacalcet and oral cinacalcet plus oral alfacalcidol as treatment regimens of SHPT among chronic HD patients. Patients and Methods: This is a retrospective observational cohort study, in which 130 prevalent HD patients with SHPT was recruited from three main HD centres of Aljouf region in Saudi Arabia. Patients were divided into three groups; group I (50) HD patients were treated by IV paricalcitol, group II (50) HD patients who received oral cinacalcet plus oral alfacalcidol, group III (30) HD patients were on oral cinacalcet. Serum intact parathyroid hormone (iPTH), calcium (Ca), phosphorus (Po4) and alkaline phosphatase (ALP) tests were assessed at 0, 3, 6, and 9 months. Results: A total of 130 (61 (47%) females, (53%) 69 males) HD patients with mean age 56.30 ± 19.1 years, and with mean HD duration of 4.86±4.15 years were enrolled in the study. The mean of iPTH is significantly reduced in all studied groups (P&lt;0.001). Mean Δchanges in iPTH concentration in groups I, II, III were -242.11±148.75, -225.54±153.91 and -254.83±275.17 respectively; P&gt;0.05) with statistical non-significant differences. Increase of Ca×Po4 with paricalcitol group as mean ΔChange in (Ca×PO4) was in the groups I, II, III (15.39±9.46, 1.97±11.74, -2.89±9.37) respectively (P&lt;0.001). Our study showed a significant increase in serum phosphorus from the baseline in patients of group II. Conclusion: IV paricalcitol based regimen assumed to be equally effective in suppressing SHPT in HD patients when compared to the combination of oral cinacalcet with oral alfacalcidol or treatment with oral cinacalcet alone.

Testing Patterns for CKD-MBD Abnormalities in a Sample US Population

IntroductionPatterns of testing, treatment, and retesting following treatment for disorders of chronic kidney disease mineral bone disorder (CKD-MBD) have not been explored using a large electronic database.MethodsTo determine concordance with CKD-MBD management guidelines, we used 2010 to 2019 data from an electronic health record (>50 million patients) to create cohorts of incident CKD stage 3, 4, and 5 patients using diagnosis codes and estimated glomerular filtration rates. The CKD-MBD test ordering and relevant drug prescribing were assessed during follow-up. We estimated cumulative incidence of posttreatment retesting (death as competing risk). We used multivariable Cox regression to examine baseline characteristics and pretreatment test results as predictors of retesting.ResultsFor 215,553 stage 3, 43,576 stage 4, and 11,407 stage 5 CKD patients, the mean follow-up was 2.3, 1.7, and 0.6 years, respectively. Only 46% of stage 4 and 41% of stage 5 patients underwent parathyroid hormone (PTH) testing, 74% and 73% had phosphorus testing, and 38% and 25% had 25D testing. By 1 year after vitamin D sterol treatment, only 50%, 53%, and 60% of stage 3, 4, and 5 patients had been retested for PTH. By 1 year after treatment with ergocalciferol or cholecalciferol, only 46%, 49%, and 55% had 25D reassessed. Pretreatment levels of PTH and 25D were not associated in a graded fashion with likelihood of retesting after treatment. Rates of retesting were not highest for patients with the highest and lowest pre-treatment PTH and 25D levels, respectively.ConclusionFrequency of testing for CKD-MBD abnormalities and posttreatment retesting appears to be suboptimal.