Mineral Disorders Research Articles

NEONATAL SEIZURES: ETIOLOGY, TREATMENT AND PROGNOSIS

Introduction: Seizures are one of the most common pathologies in newborns. Their incidence is 1.5–3.5/1000 for term infants and 10–130/1000 for preterms. The most common causes of seizures in term infants are hypoxic-ischemic encephalopathy (HIE), cerebrovascular insult (CVI), cerebral malformations (CM), and metabolic disorders. For preterm infants: intraventricular hemorrhage (IVH), periventricular leukomalacia (PVL) and infections. Clinical characteristics are diverse and subtle, and subclinical forms are common. The drug of the first choice is phenobarbitone. Newborns with seizures are more prone to developing neurological disturbances such as epilepsy and cerebral palsy.
 Methods: This is a clinical, observational research, one-year, retrospective, cross-sectional study conducted in the Department of neonatal intensive care and neonatology of the Clinic of Pediatrics KCUS. The study included 43 newborns who met the inclusion criteria.
 Results: We found that 7.19% of hospitalized newborns had seizures. A number of seizures were recorded in the group of term infants with an earlier time of seizures. The most common etiological causes were: HIE, IVH, infections, and CM. There was a frequent occurrence of metabolic disorders such as acidosis, blood sugar, and mineral (Ca, K, Na, and Mg) disorders. The median of the first day of onset of seizures in full-term infants is on the fourth day, while in premature infants it is on the sixth day of life. Phenobarbitone was mainly used to stop seizures, with great success. Overall mortality in children with seizures was 37.21%.
 Conclusions: Seizures are common in newborns, which, depending on the etiological cause, increase mortality, especially in preterm infants. Seizures in term infants occur earlier than in premature infants. The most common etiology of seizures in term infants are infections, hypoxemic-ischemic encephalopathy, intracranial hemorrhage, cerebral malformations, and cerebrovascular insult. In premature infants these are hypoxemic-ischemic encephalopathy, intracranial bleeding, and infections. In the initial treatment of neonatal convulsions, phenobarbitone is most often used, which has proven to be successful in the majority of cases.

Approaches to predicting the risk of acute cerebrovascular accident in patients with stage 5 chronic kidney disease and bone mineral disorders

BACKGROUND. Among the causes of death in patients with chronic kidney disease (CKD) on dialysis, cardiovascular complications play a leading role. One of them is acute incidences of cerebral circulation (AICC). The assessment of the impact of mineral and bone disorders on the risk of developing AICC is interesting and on par with the assessment of the impact of traditional risk factors. THE AIM: to evaluate the effects of bone mineral disorders on the risk of acute cerebrovascular accident in patients with stage 5 D CKD. PATIENTS AND METHODS. A single-center cohort prospective (three-year) study of 85 patients with stage 5D CKD on program hemodialysis was conducted. In the first stage, we evaluated traditional risk factors (blood pressure, echocardiography parameters) and parameters that reflect bone mineral disorders (parathyroid hormone, blood phosphate, calcium levels, 1.25 (OH) D, fibroblast growth factor-FGF-23, a-klotho of blood). Signs of calcification of the heart valves (CHV) and the aortic wall (CAW) were also recorded. In the second stage, three years later, patients were re-examined with the registration of the endpoint, which was identified as cases of fatal and non-fatal AICC. RESULTS. Within three years, 10 cases of AICC were registered. Mineral and bone disorders in patients on hemodialysis, such as hyperphosphatemia, CKD and its severity are risk factors for the development of AICC. It is shown that the severity of CCS and pulse pressure levels determined before the dialysis procedure and intradialytic have a positive effect on the risk of AICC. Factors such as FGF-23 and α-Klotho of blood have not demonstrated their effect on the risk of AICC.

Biochemical markers of bone metabolism in the diagnosis of mineral and bone disorders associated with chronic kidney disease

The diagnostic possibilities of using biochemical markers of bone metabolism in patients with secondary hyperparathyroidism (SHPT) and chronic kidney disease (CKD) have not yet been properly evaluated.We analyzed indicators of bone mineral density according to double X-ray absorptiometry, as well as biochemical markers of bone metabolism (OC, CTx, ALP), incl. using a neural network algorithm, in 452 patients with various stages of CKD and in 60 persons of the comparison group (control).It has been established that the levels of biochemical markers of bone metabolism in patients with CKD progressively increase with aggravation of renal failure, and are interrelated with PTH and the presence of SHPT, as well as with the presence of osteoporosis. Estimation of OC, CTx, ALP can be used as a source of additional information about the state of bone metabolism in patients with SHPT and CKD. It should be taken into account that in patients with CKD 4–5, the levels of OC, CTx significantly exceed those in a healthy population, due to both an increase in bone metabolism and a slowdown in the process of degradation and elimination of these markers.Using a neural network algorithm, we proposed reference intervals for these indicators depending on the stage of CKD. The data obtained are the basis for the development of recommendations for the diagnosis of osteopathy in SHPT and CKD, as well as multifactorial prevention and correction of this pathology. Only a comprehensive assessment of the state of the bone will make it possible to objectively assess its condition and choose an effective and safe way to correct the identified violations.

Treatment of Diabetes and Osteoporosis-A Reciprocal Risk?

Diabetes mellitus is a metabolic and systematic disorder that requires individualized therapy. The disease leads to various consequences, resulting in the destruction of tissues and organs. The aforementioned outcomes also include bone mineral disorders, caused by medications as well as diet therapy and physical activity. Some drugs may have a beneficial effect on both bone mineral density and the risk of fractures. Nevertheless, the impact of other medications remains unknown. Focusing on pharmacotherapy in diabetes may prevent bone mineral disorders and influence both the treatment and quality of life in patients suffering from diabetes mellitus. On the other hand, anti-osteoporosis drugs, such as antiresorptive or anabolic drugs, as well as drugs with a mixed mechanism of action, may affect carbohydrate metabolism, particularly in patients with diabetes. Therefore, the treatment of diabetes as well as osteoporosis prevention are vital for this group of patients.

Older Patients on Hemodiafiltration: Behavior of Uremic Toxins, Inflammation, Endothelium, and Bone Mineral Disorder

Chronic kidney disease (CKD) affects 10% of the world’s population. Uremic toxins, such as indoxyl sulfate (IS), p-Cresylsulfate (PCS) and indole acetic acid (IAA), are not sufficiently removed by conventional hemodialysis (HD) and have been associated with inflammation, poor quality of life, bone mineral disease (BMD) and endothelial injury. Online hemodiafiltration (OL-HDF) may promote greater clearance of uremic toxins than HD. However, there are few studies evaluating the effect of OL-HDF on serum levels of IS, PCS, IAA, and biomarkers associated with inflammatory, endothelial, and bone and mineral disorder in the elderly population. We evaluated the effect of 6 months of OL-HDF on the serum concentration of uremic toxins, biomarkers of inflammation, endothelial and bone mineral disorder in older patients on OL-HDF. IS, PCS, and IAA were measured by high-performance liquid chromatography. We included 31 patients (77.4 ± 7.1 years, 64.5% male, 35.5% diabetic, on maintenance dialysis for 45 ± 20 days). From baseline to 6 months there was a decrease in serum concentration of IS but not PCS and IAA. We found no change in serum concentration of inflammatory, endothelial, or mineral and bone biomarkers. In summary, OL-HDF was capable to reduce IS in older patients. Whether this reduction may have an impact on clinical outcomes deserves further evaluation.

Investigation on maintenance hemodialysis patients with mineral and bone disorder in Anhui province, China.

Chronic kidney disease-mineral bone disorder (CKD-MBD) is a common comorbidity in patients with CKD. The study aims to describe the control rates of serum-corrected calcium (Ca), phosphate (P) and intact parathyroid hormone (iPTH) and its risk factors among maintenance hemodialysis (MHD) patients in Anhui Province of China. The study was conducted in 27 hemodialysis centers of Anhui Province between January 1st 2020 and December 31th 2020. Chi-square test was used to compare the control rates of serum-corrected Ca, P and iPTH between the present study and DOPPS 4 or Anhui Province in 2014. Binary logistic regression analysis was used to explore the risk factors of the control rates of serum-corrected Ca, P and iPTH. A total of 3 025 MHD patients were recruited in this study, with a mean age of 54.8 (SD: 12.8) years, and 60.1% were males. According to the Chinese Diagnosis and Treatment Guidelines for CKD-MBD, the control rates of serum-corrected Ca, P and iPTH in the present study were 57.9%, 20.0% and 56.0%, respectively. Based on KDOQI guidelines (2003), the control rates of the above indicators were 43.1%, 35.3% and 22.3%, respectively. The control rates of serum-corrected Ca, P and iPTH in this study were lower than those of DOPPS 4 (P < 0.001). Compared to the results of Anhui Province in 2014, the control rate of corrected Ca was higher (P < 0.001) and the control rate of iPTH was lower (P = 0.005). Age, residential area, BMI, dialysis vintage, albumin and hemoglobin levels were factors of serum-corrected Ca, P and iPTH not within target range. The control rates of serum-corrected Ca, P and iPTH in MHD patients in Anhui Province are relatively low. Monitoring and management should be strengthened to improve the prognosis of patients undergoing dialysis.

Mineral and bone disorder and longterm survival in a chronic kidney disease grade 3b-4cohort

Mineral and bone disorder biomarkers ‘normal ranges’ are controversial. The aim of the study was to evaluate the association between serum calcium (Ca), phosphate (P), intact parathyroid hormone (iPTH), and 25(OH) vitamin D levels and mortality risk, in a chronic kidney disease (CKD) grade (G) 3b-4 cohort. The Uruguayan National Renal Healthcare Program (NRHP-UY) CKD patients’ cohort, included between 1 October 2004 and 1 March 2020 and followed-up until 1 March 2021, was analyzed with the Ethics Committee approval. A total of 6473 patients were analyzed: 56% men, median age 73 (65–79) years, 55% on CKD G3b. At the end of the follow-up, 2459 (37.7%) patients had died (6.4/100 patient–year). There were iPTH data on 2013 patients (younger, with lower estimated glomerular filtration rate (eGFR) and lesser comorbidities). By bivariate Cox analysis the lowest death risk was observed with mean Ca between 9.01 and 10.25 mg/dl, P between 2.76 and 4.0 mg/dl, iPTH ≤ 105 pg/ml, and 25(OH) vitamin D >10 ng/ml. The multivariate Cox regression mortality risk adjusted to age, sex, CKD etiology, diabetes, smoking, cardiovascular comorbidity, blood pressure, proteinuria, eGFR, renin-angiotensin system blockers and vitamin D treatments, serum Ca, P, iPTH, and 25(OH) vitamin D (n = 964) showed that a higher mortality risk was associated with p > 4.00 mg/dl (HR 1.668, CI 95%: 1.201–2.317), iPTH >105 pg/ml (HR 1.386, CI 95%: 1.012–1.989), and 25(OH) vitamin D ≤ 10 ng/ml (HR 1.958, CI 95%: 1.238–3.098) and a lower mortality risk with 1,25(OH)2 vitamin D treatment (HR 0.639, CI 95%: 0.451–0.906). These data may contribute to the precise G3b-4 CKD-MBD biomarkers levels definition.

Bone pathology in chronic kidney disease

The article presents current data on mineral and bone disorders in patients with various stages of chronic kidney disease. The key points of bone lesions pathology are reflected, which include impaired secretion of parathyroid hormone and phosphorus-calcium metabolism, specific osteopathy and extraskeletal calcification, the relationship between bone pathology and cardiovascular complications is indicated. The role of diagnostic tools (FRAX questionnaire, bone densitometry, biochemical parameters and new biological markers) is discussed, approaches to the interpretation of research results are defined. Both general population and specific risk factors for bone strength decrease and occurrence of osteoporotic fractures pathology in chronic kidney disease are described.

The short test with hydrochlorothiazide in differential diagnosis between primary normocalcemic and secondary hyperparathyroidism for inpatient treatment

Differential diagnosis between the normocalcemic primary hyperparathyroidism (nPHPT) and secondary hyperparathyroidism (SHPT) due to hypercalciuria remains a challenge. The aim of this study was to investigate the capability of short test with hydrochlorothiazide for the differential diagnosis of nPHPT and SHPT. A retrospective study was conducted with the participation of 28 patients who underwent a functional test with thiazide diuretics during hospitalization in the Department of parathyroid glands pathology and mineral disorders of the Endocrinology Research Centre, Russia. Parameters of mineral metabolism were evaluated before and 3-5 days after taking hydrochlorothiazide 50 mg/day. According to baseline and dynamic biochemical evaluation patients were divided into 3 groups. Group 1 (n=21) included patients with confirmed PHPT, who reached hypercalcemia accompanying with an elevated level of iPTH (n=19) or an increased level of iPTH accompanying with normocalcemia (n=2). In group 1, baseline Caadj. was 2.48 mmol/l [2.47; 2.52], iPTH 107.5 pg/ml [86.8; 133.0], after short test - 2.63 mmol/l [2.59; 2.66] and 102.1 pg/ml [95,7; 124,1]. Group 2 included only one who was diagnosed with SHPT, a normal value of iPTH with concomitant normocalcemia was achieved after 4 days of hydrochlorothiazide therapy (baseline Caadj. 2.35 mmol/l, iPTH 74.5 pg/ml vs at 2.27 mmol/l and 50.7 pg/ml respectively). Patients with doubtful results of the test entered in group 3 (n=6), they did not achieve significant changes in the calcium and iPTH levels, so it was recommended to continue the test on an outpatient basis (baseline Caadj. 2.39 mmol/l [2.33;2.45], iPTH 97.0 pg/ml [83.1;117.0]); after short test - 2.47 mmol/l [2.42; 2.48] and 91.3 pg/ml [86.9; 124.0] respectively). Groups with PHPT and SHPT and doubtful results significantly differed from each other in Caadj (р=0.003, U-test, Bonferroni correction Р0=0.006), but not in iPTH, daily calciuria, eGFR, and phosphorus. There were no significant differences in the incidence of classical complications of PHPT. The diagnosis of PHPT was confirmed in 21/28 patients 3-5 days after taking hydrochlorothiazide 50 mg/day. The obtained results are significant for the differential diagnosis in hospitalized patients with an unspecified genesis of hyperparathyroidism.

Role of Calcimimetics in Treating Bone and Mineral Disorders Related to Chronic Kidney Disease.

Renal osteodystrophy is common in patients with chronic kidney disease and end-stage renal disease and leads to the risks of fracture and extraosseous vascular calcification. Secondary hyperparathyroidism (SHPT) is characterized by a compensatory increase in parathyroid hormone (PTH) secretion in response to decreased renal phosphate excretion, resulting in potentiating bone resorption and decreased bone quantity and quality. Calcium-sensing receptors (CaSRs) are group C G-proteins and negatively regulate the parathyroid glands through (1) increasing CaSR insertion within the plasma membrane, (2) increasing 1,25-dihydroxy vitamin D3 within the kidney and parathyroid glands, (3) inhibiting fibroblast growth factor 23 (FGF23) in osteocytes, and (4) attenuating intestinal calcium absorption through Transient Receptor Potential Vanilloid subfamily member 6 (TRPV6). Calcimimetics (CaMs) decrease PTH concentrations without elevating the serum calcium levels or extraosseous calcification through direct interaction with cell membrane CaSRs. CaMs reduce osteoclast activity by reducing stress-induced oxidative autophagy and improving Wnt-10b release, which promotes the growth of osteoblasts and subsequent mineralization. CaMs also directly promote osteoblast proliferation and survival. Consequently, bone quality may improve due to decreased bone resorption and improved bone formation. CaMs modulate cardiovascular fibrosis, calcification, and renal fibrosis through different mechanisms. Therefore, CaMs assist in treating SHPT. This narrative review focuses on the role of CaMs in renal osteodystrophy, including their mechanisms and clinical efficacy.

Prevalence of Bone Mineral Disorder in Hemodialysis patients: A Single Centered Study of Local Population

Background: Mineral homeostasis deteriorates when kidney function diminishes, manifesting as variations in blood and tissue levels of calcium and phosphate, followed by the change in circulating parathyroid hormone (PTH). Mineral bone disorders (MBD) are a clinical illness caused by chronic renal disease that expresses as a systemic impairment of mineral and bone metabolism. Aim: To find out prevalence of bone mineral disorders in hemodialysis patients presenting in Nephrology Ward, SIMS. Lahore Methodology: This observational analysis included a total of 88 patients, who were on dialysis at the nephrology department of SHL for the period of more than six months. The study was conducted from 17 September 2021 to 10 March 2022 after the approval of the ethical review board of the Department. According to their blood PTH levels, the patients were split into three groups: those with PTH levels less than 150 pg/ml (low bone turnover), those with PTH levels between 150 and 300 pg/ml (normal bone turnover), and those with PTH levels greater than 300 pg/ml (high bone turnover). Results: The prevalence of bone mineral disorder was 87.5% in hemodialysis patients presenting at the nephrology department, in which prevalence of high turnover bone disorder was 73.9% whereas the prevalence of low turnover bone disorder was 13.6%. In the early dialysis period (0.5-5 years) the prevalence of bone mineral disorders was more prominent as compared to the patients on dialysis for more than 5 years. Conclusion: There was a high prevalence of bone mineral disorders, in which patients with high turnover were found to be more prevalent. Similarly, patients in the early years of dialysis are more prone to develop bone mineral disorders. Thus, we should keep these findings in mind while doing the follow up and adjust the medication accordingly. Keywords: Bone Mineral Disorders, Low Turnover Bone Disorders, Hyper Para Thyroid Disorder, Prevalence of Disease

Parkinson's Disease Etiology: Insights and Associations with Phosphate Toxicity.

The present paper investigated the association of Parkinson’s disease etiology with phosphate toxicity, a pathophysiological condition in which dysregulated phosphate metabolism causes excessive inorganic phosphate sequestration in body tissue that damages organ systems. Excessive phosphate is proposed to reduce Complex I function of the mitochondrial electron transport chain in Parkinson’s disease and is linked to opening of the mitochondrial permeability transition pore, resulting in increased reactive oxygen species, inflammation, DNA damage, mitochondrial membrane depolarization, and ATP depletion causing cell death. Parkinson’s disease is associated with α-synuclein and Lewy body dementia, a secondary tauopathy related to hyperphosphorylation of tau protein, and tauopathy is among several pathophysiological pathways shared between Parkinson’s disease and diabetes. Excessive phosphate is also associated with ectopic calcification, bone mineral disorders, and low levels of serum vitamin D in patients with Parkinson’s disease. Sarcopenia and cancer in Parkinson’s disease patients are also associated with phosphate toxicity. Additionally, Parkinson’s disease benefits are related to low dietary phosphate intake. More studies are needed to investigate the potential mediating role of phosphate toxicity in the etiology of Parkinson’s disease.

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.

Assessment of osteoprotegerin as bone marker in chronic kidney disease patients

Chronic kidney disease is a chronic impairment in the structure or function of the kidney. (eg, glomerular filtration rate [GFR] &lt;60 mL/min/1.73 m2 or albuminuria ≥30 mg per 24 hours) for more than 3 months.Renal osteodystrophy is a change in bone morphology in CKD patients, and it is one marker of the skeletal component of the systemic condition of chronic kidney disease mineral bone disease (CKD-MBD) that can be quantified using histomorphometry on bone biopsies chronic kidney disease mineral bone disease (CKD-MBD) defines a complex syndrome of renal osteodystrophy, mineral disorders and cardiovascular disease in patients with chronic kidney disease. The study was a case –control design which conducted in Dialysis Unit in AL-Mahmoodia General Hospital and ALyarmook Teaching Hospital in Baghdad. This study was carried out in private laboratories between September 2021to march 2022. In this investigation,the total subjects were 90, the patient group was Consist of 45 Hemodialysis (HD) (CKD) ( 18 males and 27 females).

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.

Bone Turnover, Mineralization, and Volume Estimated by 18F-Sodium Fluoride PET/CT and Biomarkers in Chronic Kidney Disease: Mineral and Bone Disorder Compared with Bone Biopsy

Introduction: Invasive bone biopsy to assess bone metabolism in patients with chronic kidney disease-mineral and bone disorder may be replaced by the noninvasive ¹⁸F-NaF PET/CT and biomarkers of bone metabolism. We aimed to compare parameters of bone turnover, mineralization, and volume assessed by bone biopsies with results derived from ¹⁸F-NaF PET/CT and biomarkers (bone-specific alkaline phosphatase, osteocalcin, fibroblast growth factor 23, and osteoprotegerin). Methods: A cross-sectional study included 17 dialysis patients, and results from ¹⁸F-NaF PET/CT scans and the biomarkers were directly compared with the results of histomorphometric analyses of tetracycline double-labeled trans-iliac bone biopsies. Results: Bone biopsies showed 40% high, 20% normal, and 40% low bone turnover. No biopsies had generalized abnormal mineralization, and the bone volume/total tissue volume was low in 80% and high in 7%. The pelvic skeletal plasma clearance (K_i) from ¹⁸F-NaF PET/CT correlated with bone turnover parameters obtained by bone biopsy (activation frequency: r = 0.82, p < 0.01; bone formation rate/bone surface: r = 0.81, p < 0.01), and K_i defined low turnover with high sensitivity (83%) and specificity (100%). CT-derived radiodensity correlated with bone volume, r = 0.82, p < 0.01. Of the biomarkers, only osteocalcin showed a correlation with turnover assessed by histomorphometry. Conclusion: In conclusion, ¹⁸F-NaF PET/CT may be applicable for noninvasive assessment of bone turnover and volume in CKD-MBD.

Naturally occurring stable calcium isotope ratios are a novel biomarker of bone calcium balance in chronic kidney disease

Dysregulated calcium homeostasis is common in chronic kidney disease and causally associated with disorders of bone mineralization. However, radiological measures and biomarkers do not allow accurate evaluation of bone calcium balance. Non-radioactive calcium isotopes, 42Ca and 44Ca, are present in our diet and sequestered into body compartments following principles of kinetic isotope fractionation. Isotopically light 42Ca is preferentially incorporated into bone, while heavier 44Ca is excreted. The ratio (44/42Caserum) increases when bone formation exceeds resorption and vice versa, reflecting bone calcium balance. We measured these calcium isotopes by inductively coupled plasma mass-spectrometry in blood, urine and feces of 42 children with chronic kidney disease and 92 receiving dialysis therapy. We compared the isotope ratios with bone biomarkers and determined total bone mineral content by dual-energy x-ray absorptiometry and peripheral quantitative CT expressed as age-adjusted z-scores. The 44/42Caserum ratio positively correlated with serum calcium, 25-hydroxyvitamin D and alkaline phosphatases and inversely with serum parathyroid hormone and other bone resorption markers. The 44/42Caserum ratio positively correlated with age-adjusted z-scores of tibial trabecular bone mineral density and total bone mineral content measured by peripheral quantitative CT, and hip bone mineral density measured by dual-energy X-ray absorptiometry. Significant and independent predictors of total bone mineral content, measured by, were the 44/42Caserum ratio and parathyroid hormone. The44/42Caserum ratio, repeated after four weeks, highly correlated with baseline values. When adjusted for calcium-containing medications and kidney impairment, the 44/42Caserum ratio in patients receiving dialysis was 157% lower than that of age-matched children and 29% lower than levels in elderly women with osteoporosis, implying significantly lower bone mineral content. Thus, calcium isotope ratios may provide a novel, sensitive and non-invasive method of assessing bone calcium balance in chronic kidney disease.

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.

Skeletal and extraskeletal disorders of biomineralization.

The physiological process of biomineralization is complex and deviation from it leads to a variety of diseases. Progress in the past 10 years has enhanced understanding of the genetic, molecular and cellular pathophysiology underlying these disorders; sometimes, this knowledge has both facilitated restoration of health and clarified the very nature of biomineralization as it occurs in humans. In this Review, we consider the principal regulators of mineralization and crystallization, and how dysregulation of these processes can lead to human disease. The knowledge acquired to date and gaps still to be filled are highlighted. The disorders of mineralization discussed comprise a broad spectrum of conditions that encompass bone disorders associated with alterations of mineral quantity and quality, as well as disorders of extraskeletal mineralization (hyperphosphataemic familial tumoural calcinosis). Included are disorders of alkaline phosphatase (hypophosphatasia) and phosphate homeostasis (X-linked hypophosphataemic rickets, fluorosis, rickets and osteomalacia). Furthermore, crystallopathies are covered as well as arterial and renal calcification. This Review discusses the current knowledge of biomineralization derived from basic and clinical research and points to future studies that will lead to new therapeutic approaches for biomineralization disorders.

Disorders of phosphate homeostasis in children, part 1: primer on mineral ion homeostasis and the roles of phosphate in skeletal biology.

Phosphate has extensive physiological roles including energy metabolism, genetic function, signal transduction and membrane integrity. Regarding the skeleton, not only do phosphate and calcium form the mineral component of the skeleton, but phosphate is also essential in regulating function of skeletal cells. Although our understanding of phosphate homeostasis has lagged behind and remains less than that for calcium, considerable advances have been made since the recognition of fibroblast growth factor-23 (FGF23) as a bone-derived phosphaturic hormone that is a major regulator of phosphate homeostasis. In this two-part review of disorders of phosphate homeostasis in children, part 1 covers the basics of mineral ion homeostasis and the roles of phosphate in skeletal biology. Part 1 includes phosphate-related disorders of mineralization for which overall circulating mineral ion homeostasis remains normal. Part 2 covers hypophosphatemic and hyperphosphatemic disorders, emphasizing, but not limited to, those related to increased and decreased FGF23 signaling, respectively.