Cystatin C-Based Equation to Estimate GFR without the Inclusion of Race and Sex.

BACKGROUND: The accuracy of estimation of kidney function with the use of routine metabolic tests, such as measurement of the serum creatinine level, has been controversial. The European Kidney Function Consortium (EKFC) developed a creatinine-based equation (EKFC eGFRcr) to estimate the glomerular filtration rate (GFR) with a rescaled serum creatinine level (i.e., the serum creatinine level is divided by the median serum creatinine level among healthy persons to control for variation related to differences in age, sex, or race). Whether a cystatin C-based EKFC equation would increase the accuracy of estimated GFR is unknown. METHODS: We used data from patients in Sweden to estimate the rescaling factor for the cystatin C level in adults. We then replaced rescaled serum creatinine in the EKFC eGFRcr equation with rescaled cystatin C, and we validated the resulting EKFC eGFRcys equation in cohorts of White patients and Black patients in Europe, the United States, and Africa, according to measured GFR, levels of serum creatinine and cystatin C, age, and sex. RESULTS: On the basis of data from 227,643 patients in Sweden, the rescaling factor for cystatin C was estimated at 0.83 for men and women younger than 50 years of age and 0.83 + 0.005 × (age - 50) for those 50 years of age or older. The EKFC eGFRcys equation was unbiased, had accuracy that was similar to that of the EKFC eGFRcr equation in both White patients and Black patients (11,231 patients from Europe, 1093 from the United States, and 508 from Africa), and was more accurate than the Chronic Kidney Disease Epidemiology Collaboration eGFRcys equation recommended by Kidney Disease: Improving Global Outcomes. The arithmetic mean of EKFC eGFRcr and EKFC eGFRcys further improved the accuracy of estimated GFR over estimates from either biomarker equation alone. CONCLUSIONS: The EKFC eGFRcys equation had the same mathematical form as the EKFC eGFRcr equation, but it had a scaling factor for cystatin C that did not differ according to race or sex. In cohorts from Europe, the United States, and Africa, this equation improved the accuracy of GFR assessment over that of commonly used equations. (Funded by the Swedish Research Council.).

Performance of the European Kidney Function Consortium (EKFC) creatinine-based equation in United States cohorts.

Estimating glomerular filtration rate (GFR) is important in daily practice to assess kidney function and adapting the best clinical care of patients with and without chronic kidney disease. The new creatinine-based European Kidney Function Consortium (EKFC) equation is used to estimate GFR. This equation was developed and validated mainly in European individuals and based on a rescaled creatinine, with the rescaling factor (Q-value) defined as the median normal value of serum creatinine in a given population. The validation was limited in Non-Black Americans and absent in Black Americans. Here, our cross-sectional analysis included 12,854 participants from nine studies encompassing large numbers of both non-Black and Black Americans with measured GFR by clearance of an exogenous marker (reference method), serum creatinine, age, sex, and self-reported race available. Two strategies were considered with population-specific Q-values in Black and non-Black men and women (EKFCPS) or a race-free Q-value (EKFCRF). In the whole population, only the EKFCPS equation showed no statistical median bias (0.14, 95% confidence interval [-0.07; 0.35] mL/min/1.73m2), and the bias for the EKFCRF (0.74, [0.51; 0.94] mL/min/1.73m2) was closer to zero than that for the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI2021) equation (1.22, [0.99; 1.47]) mL/min/1.73m2]. The percentage of estimated GFR within 30% of measured GFR was similar for CKD-EPI2021 (79.2% [78.5%; 79.9%]) and EKFCRF (80.1% [79.4%; 80.7%]), but improved for the EKFCPS equation (81.1% [80.5%; 81.8%]). Thus, our EKFC equations can be used to estimate GFR in the United States incorporating either self-reported race or unknown race at the patient's discretion per hospital registration records.

Unveiling a new era with liquid chromatography coupled with mass spectrometry to enhance parathyroid hormone measurement in patients with chronic kidney disease.

Precise determination of circulating parathyroid hormone (PTH) concentration is crucial to diagnose and manage various disease conditions, including the chronic kidney disease-mineral and bone disorder. However, the lack of standardization in PTH assays is challenging for clinicians, potentially leading to medical errors because the different assays do not provide equivalent results and use different reference ranges. Here, we aimed to evaluate the impact of recalibrating PTH immunoassays by means of a recently developed LC-MS/MS method as the reference. Utilizing a large panel of pooled plasma samples with PTH concentrations determined by the LC-MS/MS method calibrated with the World Health Organization (WHO) 95/646 International Standard, five PTH immunoassays were recalibrated. The robustness of this standardization was evaluated over time using different sets of samples. The recalibration successfully reduced inter-assay variability with harmonization of PTH measurements across different assays. By recalibrating the assays based on the WHO 95/646 International Standard, we demonstrated the feasibility for standardizing PTH measurement results and adopting common reference ranges for PTH assays, facilitating a more consistent interpretation of PTH values. The recalibration process aligns PTH results obtained from various immunoassays with the LC-MS/MS method, providing more consistent and reliable measurements. Thus, establishing true standardization across all PTH assays is crucial to ensure consistent interpretation and clinical decision-making.

Vitamin D: Analytical Advances, Clinical Impact, and Ongoing Debates on Health Perspectives.

BACKGROUND: Vitamin D, acknowledged since the 1930s for its role in preventing rickets, gained additional prominence in relation to fragility fracture prevention in the late 1980s. From the early 2000s, connections between vitamin D deficiency and extra-skeletal pathologies emerged, alongside increased awareness of widespread deficits. This prompted crucial debates on optimal serum concentrations, expected to conclude when the outcomes of high-dose supplementation randomized controlled trials were available. Skepticism arose with inconclusive results from these trials. CONTENT: This review begins with an exploration of vitamin D metabolism, followed by a detailed description of the measurement of vitamin D metabolites and the crucial role of standardization. Subsequent sections focus on the association of vitamin D with bone health and explore the extra-skeletal effects. The review concludes with a comprehensive discussion on the definition of vitamin D status and its implications for supplementation. SUMMARY: Despite standardization efforts, assay variations and challenges still exist, especially in specific patient groups. Vitamin D supplementation has a significant impact on bone metabolism and optimal vitamin D status improves the efficacy of antiresorptive drugs such as bisphosphonates. The extra-skeletal effects of vitamin D remain debated, but may include potential benefits in conditions such as respiratory infections and cancer mortality, particularly in deficient individuals. The definition of vitamin D sufficiency is nuanced, especially when variations in population groups and analytical methods are taken into account. Despite ongoing debates and recent mega-trials tempering enthusiasm, vitamin D remains a complex and essential element in human health. Further research is needed to clarify its role in various health outcomes and guide supplementation strategies.

Matrix gla protein, a potential marker of tissue remodelling and physiological ageing of the gut in crohn's disease.

BACKGROUND: The inactive dephosphorylated and uncarboxylated form of the matrix Gla protein (dp-ucMGP) has been shown to be increased in plasma of inflammatory bowel disease (IBD) patients. Our aim was to assess if the plasmatic level of dp-ucMGP could reflect disease endoscopic activity, presence of strictures and cumulative structural bowel damage in Crohn's disease (CD) patients. METHODS: The plasmatic level of dp-ucMGP was measured in a monocentric cohort of prospectively recruited patients. The analysis was done by chemiluminescent immunoassay on blood samples collected the day of a planned ileocolonoscopy. In addition to classical clinical data (gender, age, body mass index (BMI), disease duration, current treatment), endoscopic data (disease location, Crohn's Disease Endoscopic Index of Severity (CDEIS), mucosal healing (MH), presence of 9 CD lesion types) and biological markers (faecal calprotectin and C-reactive protein (CRP)) were collected. The association between dp-ucMGP level and Lémann index was also investigated. Univariate linear regression was used to investigate the relationship between dp-ucMGP level and different parameters collected. RESULTS: A total of 82 ileocolonoscopies and dp-ucMGP assays were performed in 75 CD patients (45 females; 37 ileocolonic, 19 ileal and 19 colonic diseases) between October 2012 and November 2019. A total of 24 patients (29.3%) showed MH. The dp-ucMGP levels were not associated with MH, CDEIS, faecal calprotectin or CRP levels. Plasmatic dp-ucMGP levels increased significantly with age (p = 0.0032), disease duration (p = 0.0033), corticosteroids use (p = 0.019) and tended to increase in patients with intestinal strictures (p = 0.086) but not with the Lémann index. CONCLUSION: The significant increase of plasmatic dp-ucMGP levels with age, disease duration and the trend observed in patients with non-ulcerated strictures may suggest that this extracellular matrix protein could be a marker of tissue remodelling and physiological ageing of the gut.

Assessing the status of European laboratories in evaluating biomarkers for chronic kidney diseases (CKD) and recommendations for improvement: insights from the 2022 EFLM Task Group on CKD survey.

OBJECTIVES: Chronic kidney disease (CKD) is a global health issue, ranking as the third leading cause of death worldwide. CKD diagnosis and management depend on clinical laboratory tests, necessitating consistency for precise patient care. Global harmonization of CKD testing through clinical practice guidelines (CPGs) is recommended. Prior to CPG development, assessing the current CKD testing landscape is crucial. In 2022, the European Federation of Laboratory Medicine (EFLM) conducted an online survey among European laboratories associated with EFLM, evaluating CKD testing practices, including new glomerular filtration rate (GFR) estimation methods. This report summarizes the 2022 survey findings and offers recommendations for improving CKD test standardization. METHODS: An online survey was conducted in November 2022 using a questionnaire hosted on LimeSurvey sent to European laboratories affiliated with the EFLM. The survey results were recorded in Excel files and analysed. RESULTS: The results highlight significant discrepancies among countries in unit expression, methods, cystatin C use, and GFR calculation equations. Additionally, limited attention to pediatric renal biology specifics, varied proteinuria and albuminuria result expressions, and limited awareness of GFR measurement methods through iohexol clearance are noted. CONCLUSIONS: In an effort to enhance the standardization of crucial biomarkers utilized in nephrology for evaluating renal function and diagnosing kidney injuries, the EFLM Task Group on CKD suggests nine practical recommendations tailored for European laboratories. The group is confident that implementing these measures will minimize result expression discrepancies, ultimately leading to enhanced patient care.

A global perspective on the status of clinical metabolomics in laboratory medicine - a survey by the IFCC metabolomics working group.

OBJECTIVES: Metabolomics aims for comprehensive characterization and measurement of small molecule metabolites (<1700 Da) in complex biological matrices. This study sought to assess the current understanding and usage of metabolomics in laboratory medicine globally and evaluate the perception of its promise and future implementation. METHODS: A survey was conducted by the IFCC metabolomics working group that queried 400 professionals from 79 countries. Participants provided insights into their experience levels, knowledge, and usage of metabolomics approaches, along with detailing the applications and methodologies employed. RESULTS: Findings revealed a varying level of experience among respondents, with varying degrees of familiarity and utilization of metabolomics techniques. Targeted approaches dominated the field, particularly liquid chromatography coupled to a triple quadrupole mass spectrometer, with untargeted methods also receiving significant usage. Applications spanned clinical research, epidemiological studies, clinical diagnostics, patient monitoring, and prognostics across various medical domains, including metabolic diseases, endocrinology, oncology, cardiometabolic risk, neurodegeneration and clinical toxicology. CONCLUSIONS: Despite optimism for the future of clinical metabolomics, challenges such as technical complexity, standardization issues, and financial constraints remain significant hurdles. The study underscores the promising yet intricate landscape of metabolomics in clinical practice, emphasizing the need for continued efforts to overcome barriers and realize its full potential in patient care and precision medicine.

The role of functional vitamin D deficiency and low vitamin D reservoirs in relation to cardiovascular health and mortality.

OBJECTIVES: The role of vitamin D deficiency in cardiovascular disease (CVD) is controversial. Inherent biological and analytical limitations compromise the specificity of widely used 25-hydroxyvitamin D [25(OH)D] cut-offs. Simultaneous determination of 25(OH)D and 24,25-dihydroxyvitamin D [24,25(OH)2D] permits a functional assessment of vitamin D metabolism. The present study compared the associations of functional vitamin D deficiency and low vitamin D reservoirs with CVD mortality and CVD burden. METHODS: 25(OH)D, 24,25(OH)2D, the degree of coronary obstruction on angiography, high-sensitive cardiac troponin T (hs-cTnT), N-terminal brain natriuretic peptide (NT-proBNP), and 10-year CVD mortality were obtained from 2,456 participants of the LURIC (Ludwigshafen Risk and Cardiovascular Health) study. RESULTS: Neither low 25(OH)D concentrations nor functional vitamin D deficiency were associated with the number of atherosclerotic coronary arteries or the degree of coronary obstruction. Over a median follow-up of 9.9 years, 454 participants died (23.6 %) due to CVD. CVD mortality was doubled in individuals with 25(OH)D concentrations below the widely used cut-off for deficiency of <50 nmol/L [20 ng/mL] (21.6 vs. 11.5 %). In individuals with and without functional vitamin D deficiency, CVD mortality was 25.0 and 16.7 %, respectively. NT-proBNP and heart failure prevalence were also higher in vitamin D deficient individuals. CONCLUSIONS: Vitamin D deficient individuals have markedly higher CVD mortality, but only marginally higher hs-cTnT concentrations. A higher prevalence of heart failure and higher NT-proBNP concentrations suggest a link between vitamin D deficiency and cardiac function. The traditional and metabolic assessment of vitamin D status showed comparable associations for the different parameters of cardiac health.

Confounding factors of the expression of mTBI biomarkers, S100B, GFAP and UCH-L1 in an aging population.

OBJECTIVES: To evaluate some confounding factors that influence the concentrations of S100 calcium binding protein B (S100B), glial fibrillary acidic protein (GFAP), and ubiquitin carboxyl-terminal hydrolase L-1 (UCH-L1) in older individuals. Indeed, recent guidelines have proposed the combined use of S100B and the "GFAP-UCH-L1" mTBI test to rule out mild traumatic brain injuries (mTBI). As older adults are the most at risk of mTBI, it is particularly important to understand the confounding factors of those mTBI rule-out biomarkers in aging population. METHODS: The protein S100B and the "GFAP and UCH-L1" mTBI test were measured using Liaison XL (Diasorin) and Alinity I (Abbott), respectively, in 330 and 341 individuals with non-suspected mTBI from the SarcoPhAge cohort. RESULTS: S100B, GFAP and UCH-L1 were all significantly correlated with renal function whereas alcohol consumption, Geriatric Depression Score (GDS), smoking habits and anticoagulant intake were not associated with any of these three biomarkers. Body mass index (BMI) and age were associated with GFAP and UCH-L1 expression while sex and mini-mental state examination (MMSE) were only associated with GFAP. According to the manufacturer's cut-offs for mTBI rule-out, only 5.5 % of participants were positive for S100B whereas 66.9 % were positive for the "GFAP-UCH-L1" mTBI test. All positive "GFAP-UCH-L1" mTBI tests were GFAP+/UCH-L1-. Among individuals with cystatin C>1.55 mg/L, 25 % were positive for S100B while 90 % were positive for the mTBI test. CONCLUSIONS: Our data show that confounding factors have different impacts on the positivity rate of the "GFAP-UCH-L1" mTBI test compared to S100B.

Nitrous oxide abuse direct measurement for diagnosis and follow-up: update on kinetics and impact on metabolic pathways.

Recreational use of nitrous oxide (N2O) has become a major health issue worldwide, with a high number of clinical events, especially in neurology and cardiology. It is essential to be able to detect and monitor N2O abuse to provide effective care and follow-up to these patients. Current recommendations for detecting N2O in cases of recreational misuse and consumption markers are lacking. We aimed to update current knowledge through a review of the literature on N2O measurement and kinetics. We reviewed the outcomes of experiments, whether in preclinical models (in vitro or in vivo), or in humans, with the aim to identify biomarkers of intoxication as well as biomarkers of clinical severity, for laboratory use. Because N2O is eliminated 5 min after inhalation, measuring it in exhaled air is of no value. Many studies have found that urine and blood matrices concentrations are connected to ambient concentrations, but there is no similar data for direct exposure. There have been no studies on N2O measurement in direct consumers. Currently, patients actively abusing N2O are monitored using effect biomarkers (biomarkers related to the effects of N2O on metabolism), such as vitamin B12, homocysteine and methylmalonic acid.

Extending the cystatin C based EKFC-equation to children - validation results from Europe.

BACKGROUND: A new cystatin C based European Kidney Function Consortium (EKFCCysC) equation was recently developed for adults, using the same mathematical form as the previously published full age spectrum creatinine based EKFC-equation (EKFCCrea). In the present study the cystatin C based EKFC-equation is extended to children, by defining the appropriate cystatin C rescaling factor QCysC. METHODS: Rescaling factor QCysC for cystatin C was defined as: a) 0.83 mg/L, exactly as it was defined for young adults in the adult equation, and b) a more complex QCysC-age relationship based on 4th degree cystatin C-age polynomials after evaluation of data from Uppsala, Stockholm and Canada and aggregated data from Germany. The EKFCCysC equation was then validated in an independent dataset in European children (n = 2,293) with measured GFR, creatinine, cystatin C, age, height and sex available. RESULTS: The EKFCCysC with the simple QCysC-value of 0.83 had a bias of -7.6 [95%CI -8.4;-6.5] mL/min/1.73 m2 and a P30-value of 85.8% [95%CI 84.4;87.3] equal to the EKFCCysC with the more complex 4th degree QCysC-value. The arithmetic mean of the EKFCCrea and EKFCCysC with the simple QCysC of 0.83 had a bias of -4.0 [95%CI -4.5;-3.1] mL/min/1.73 m2 and P30 of 90.4% [95%CI 89.2;91.6] similar to using the more complex 4th degree QCysC-polynomial. CONCLUSION: Using exactly the same QCysC of 0.83 mg/L, the adult EKFCCysC can easily be extended to children, with some bias but acceptable P30-values. The arithmetic mean of EKFCCrea and EKFCCysC results in bias closer to zero and P30 slightly over 90%.

Estimated glomerular filtration rate: applicability of creatinine-based equations in African children.

BACKGROUND: The Schwartz equation is the most widely used serum creatinine (SCr)-based formula to estimate the glomerular filtration rate (GFR) in children of European descent, but whether this applies to African children is unclear. METHODS: In a cross-sectional study, 513 apparently healthy African children aged 6 to 16 years were randomly recruited in school area of Kinshasa, the Democratic Republic of Congo (DRC). SCr was measured using calibrated enzymatic method. SCr was normalized using Q-values designed for European descent children, due to the absence of Q-values for African children. Commonly used eGFR equations were applied in this population. RESULTS: Normalization of SCr using Q-values for European descent children was effective in this cohort. The majority of African children (93.4%) have normalized SCr (SCr/Q) values within the reference interval (0.67-1.33) of children of European descent. The bedside-Schwartz equation was associated with significant age and sex dependency. However, the FAS-Age formula showed no sex and age dependency. The new CKiDU25 equation did not show a significant sex dependency. The recently introduced EKFC and LMR18 equations also showed no age and sex dependency, although the distribution of eGFR-values was not symmetrical. On the other hand, the FAS-Height and the Schwartz-Lyon equations showed significant sex dependency but no age dependency. CONCLUSIONS: The reference interval for SCr designed for European descent children can be applied to African children. Of all the equations studied, FAS-Age performed best and is most suitable because no height measurements are required. Establishment of specific Q-values for the widespread Jaffe-measured creatinine in Africa can further broaden applicability.

Association of circulating hsa-miRNAs with sarcopenia: the SarcoPhAge study.

OBJECTIVE: To identify a microRNA signature associated to sarcopenia in community-dwelling older adults form the SarcoPhAge cohort. METHODS: In a screening phase by next generation sequencing (NGS), we compared the hsa-miRome expression of 18 subjects with sarcopenia (79.6 ± 6.8 years, 9 men) and 19 healthy subjects without sarcopenia (77.1 ± 6 years, 9 men) at baseline. Thereafter, we have selected eight candidate hsa-miRNAs according to the NGS results and after a critical assessment of previous literature. In a validation phase and by real-time qPCR, we then analyzed the expression levels of these 8 hsa-miRNAs at baseline selecting 92 healthy subjects (74.2 ± 10 years) and 92 subjects with sarcopenia (75.3 ± 6.8 years). For both steps, the groups were matched for age and sex. RESULTS: In the validation phase, serum has-miRNA-133a-3p and has-miRNA-200a-3p were significantly decreased in the group with sarcopenia vs controls [RQ: relative quantification; median (interquartile range)]: -0.16 (-1.26/+0.90) vs +0.34 (-0.73/+1.33) (p < 0.01) and -0.26 (-1.07/+0.68) vs +0.27 (-0.55/+1.10) (p < 0.01) respectively. Has-miRNA-744-5p was decreased and has-miRNA-151a-3p was increased in the group with sarcopenia vs controls, but this barely reached significance: +0.16 (-1.34/+0.79) vs +0.44 (-0.31/+1.00) (p = 0.050) and +0.35 (-0.22/+0.90) vs +0.03 (-0.68/+0.75) (p = 0.054). CONCLUSION: In subjects with sarcopenia, serum hsa-miRNA-133a-3p and hsa-miRNA-200a-3p expression were downregulated, consistent with their potential targets inhibiting muscle cells proliferation and differentiation.

[Clinical metabolomics : an innovative approach towards preventive and personalized medicine]. / La métabolomique clinique : une approche novatrice vers une médecine préventive et personnalisée.

In order to improve our healthcare system, it is undeniable that the future of modern medicine must focus on a more preventive and personalized approach, notably based on the individual characteristics specific to each patient. In this perspective, clinical metabolomics, which focuses on metabolites, emerges as a particularly interesting and promising approach. Indeed, this science reflects the internal and external stimuli received by an individual, thus capturing their physiological and/or pathological state. Close to the phenotype, it represents the interface between the patient, their genes, and their environment in the broadest sense. Its translational nature requires the conjunction of several expertise areas, both in analytical, biostatistical, and clinical levels. Combined with other data, it allows the generation of predictive or diagnostic models useful for early detection and monitoring of pathologies, taking into account notably the individual characteristics of patients. There are, of course, many obstacles and challenges to overcome for metabolomics to transition into clinical practice, but it is evident that this innovative approach will, in the years to come, find its place among the tools available to clinicians in a more personalized vision of patient care.

Dans le but d'améliorer notre système de santé, il est indéniable que l'avenir de la médecine moderne doit se porter sur une approche plus préventive et personnalisée, basée, notamment, sur les caractéristiques individuelles propres au patient. Dans cette optique, la métabolomique clinique, qui s'intéresse aux métabolites, apparaît comme une approche particulièrement intéressante et prometteuse. En effet, cette science est le reflet des stimuli internes et externes que reçoit un individu et permet donc de capturer son état physiologique et/ou pathologique. Proche du phénotype, elle représente l'interface entre le patient, ses gènes et son environnement au sens large. Sa nature translationnelle nécessite la conjonction de plusieurs expertises, tant au niveau analytique que bio-statistique et clinique. Combinée à d'autres données, elle permet de générer des modèles prédictifs ou diagnostiques utiles pour détecter précocement et suivre des pathologies, en tenant compte, notamment, des caractéristiques individuelles des patients. Il reste, bien entendu, de nombreux obstacles et défis à relever pour que la métabolomique passe dans la pratique clinique. Cependant, il apparaît évident que cette approche novatrice trouvera, dans les années à venir, sa place parmi les outils à disposition des cliniciens dans une vision préventive et plus personnalisée de la prise en charge du patient.

Functional Assessment of Vitamin D Status by a Novel Metabolic Approach: The Low Vitamin D Profile Concept.

BACKGROUND: Determining serum 25-hydroxyvitamin D [25(OH)D], 24,25-dihydroxyvitamin D [24,25(OH)2D] and the vitamin D metabolite ratio (VMR) allows the identification of individuals with a low vitamin D metabolite profile. Here, we evaluated if such a functional approach provides superior diagnostic information to serum 25(OH)D alone. METHODS: 25(OH)D, 24,25(OH)2D, and the VMR were determined in participants of the DESIRE (Desirable Vitamin D Concentrations, n = 2010) and the LURIC (Ludwigshafen Risk and Cardiovascular Health, n = 2456) studies. A low vitamin D metabolite profile (vitamin D insufficiency) was defined by a 24,25(OH)2D concentration <1.2 ng/mL (<3 nmol/L) and a VMR <4%. Parathyroid hormone (PTH) and bone turnover markers were measured in both cohorts, whereas 10-year mortality data was recorded in LURIC only. RESULTS: The median age in DESIRE and LURIC was 43.3 and 63.8 years, respectively. Median 25(OH)D concentrations were 27.2 ng/mL (68.0 nmol/L) and 15.5 ng/mL (38.8 nmol/L), respectively. Serum 25(OH)D deficiency, defined as <20.2 ng/mL (<50 nmol/L), was present in 483 (24.0%) and 1701 (69.3%) participants of DESIRE and LURIC, respectively. In contrast, only 77 (3.8%) and 521 (21.2%) participants had a low vitamin D metabolite profile. Regardless of the serum 25(OH)D concentration, a low vitamin D metabolite profile was associated with a significantly higher PTH, accelerated bone metabolism, and higher all-cause mortality than an unremarkable vitamin D metabolite profile. CONCLUSIONS: The personalized assessment of vitamin D status using a functional approach better identifies patients with accelerated bone metabolism and increased mortality than the use of a fixed 25(OH)D cutoff of 20 ng/mL (50 nmol/L).

The Measurement and Interpretation of Fibroblast Growth Factor 23 (FGF23) Concentrations.

Two decades after the discovery of the hormone FGF23, we know more about phosphate homeostasis as it turned out that FGF23 is the central hormone that regulates this. Hereditary hypophosphatemic rickets and tumor-induced osteomalacia could by then be explained, by autonomous FGF23 production, and the nephrology field was excited by this new marker as it turned out to be independently associated with mortality in people treated by hemodialysis. This led to the development of several immunoassays to be able to measure FGF23 in blood. In the past years we learned that FGF23 is a rather stable peptide, the precision of the assays is acceptable but assays are not standardized and therefore not comparable. This means that reference values and cutoff values need to be assay specific. For several assays reference values have been established and gender and age did not seem of high importance. The phosphate content of the diet, which can be culturally dependent, however, should be taken into account when interpreting results, but to what extent is not totally clear. Currently, clinical application of the immunoassays is established in the diagnosis of hereditary hypophosphatemic rickets and diagnosis and follow-up of tumor-induced osteomalacia. Definite conclusions on the usefulness of the FGF23 measurement in people with CKD either as a marker for risk prediction or a as target for treatment remains to be determined. The latter applications would require dedicated prospective clinical trials, which may take years, before providing answers. To improve the standardization of the FGF23 assays and to shed light on the biological functions that fragments might have we might aim for an LC-MS/MS-based method to quantify both intact and fragmented FGF23. In this literature review we will summarize the current knowledge on the physiological role of FGF23, its quantification, and the clinical usefulness of its determination.

Alkaline Phosphatases: Biochemistry, Functions, and Measurement.

Alkaline phosphatases (ALPs) are a group of isoenzymes, situated on the external layer of the cell membrane; they catalyze the hydrolysis of organic phosphate esters present in the extracellular space. Zinc and magnesium are significant co-factors for the biological activity of these enzymes. Although ALPs are available in various body tissues and have distinct physiochemical properties, they are true isoenzymes since they catalyze a similar reaction. In the liver, ALP is cytosolic and present in the canalicular membrane of the hepatocytes. ALPs are available in placenta, ileal mucosa, kidney, bone, and liver. However, most of the ALPs in serum (over 80%) are delivered from liver and bone and in more modest quantities from the intestines. Despite the fact that alkaline phosphatases are found in numerous tissues all through the body, their exact physiological function remains largely unknown.

Bone Turnover Markers in Children: From Laboratory Challenges to Clinical Interpretation.

Bone turnover markers (BTMs) have been developed many years ago to study, in combination with imaging techniques, bone remodeling in adults. In children and adolescents, bone metabolism differs from adults since it implies both growth and bone remodeling, suggesting an age- and gender-dependent BTM concentration. Therefore, specific studies have evaluated BTMs in not only physiological but also pathological conditions. However, in pediatrics, the use of BTMs in clinical practice is still limited due to these many children-related specificities. This review will discuss about physiological levels of BTMs as well as their modifications under pathological conditions in children and adolescents. A focus is also given on analytical and clinical challenges that restrain BTM usefulness in pediatrics.

Practical Considerations for the Clinical Application of Bone Turnover Markers in Osteoporosis.

Bone turnover markers (BTMs) are released during the bone remodelling cycle and are measurable in blood or urine, reflecting bone remodelling rate. They have been useful in elucidating the pharmacodynamics and effectiveness of osteoporosis medication in clinical trials and are increasingly used in routine clinical management of osteoporosis, especially for monitoring therapy, in addition to their use in other metabolic bone disease such as Paget's disease of bone and osteomalacia. Serum ß isomerised C-terminal telopeptide of type I collagen and pro-collagen I N-terminal propeptide have been designated as reference BTMs for use in osteoporosis. In addition, bone-specific isoenzyme of alkaline phosphatase (B-ALP) secreted by osteoblasts and tartrate-resistant acid phosphatase 5b (TRACP-5b) secreted by osteoclasts are also found to be specific markers of bone formation and resorption, respectively. The concentrations of the latter enzymes in blood measured by immunoassay provide reliable measures of bone turnover even in the presence of renal failure. B-ALP is recommended for use in the assessment of renal bone disease of chronic kidney disease, and TRACP-5b shows promise as a marker of bone resorption in that condition. BTMs in blood do not suffer from biological variation to the same extent as the older BTMs that were measured in urine. Appropriate patient preparation and sample handling are important in obtaining accurate measures of BTMs for clinical use. Reference change values and treatment targets have been determined for the reference BTMs for their use in monitoring osteoporosis treatment. Further ongoing studies will enhance their clinical applications.

Biochemical Markers of Musculoskeletal Health and Aging to be Assessed in Clinical Trials of Drugs Aiming at the Treatment of Sarcopenia: Consensus Paper from an Expert Group Meeting Organized by the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO) and the Centre Académique de Recherche et d'Expérimentation en Santé (CARES SPRL), Under the Auspices of the World Health Organization Collaborating Center for the Epidemiology of Musculoskeletal Conditions and Aging.

In clinical trials, biochemical markers provide useful information on the drug's mode of action, therapeutic response and side effect monitoring and can act as surrogate endpoints. In pharmacological intervention development for sarcopenia management, there is an urgent need to identify biomarkers to measure in clinical trials and that could be used in the future in clinical practice. The objective of the current consensus paper is to provide a clear list of biochemical markers of musculoskeletal health and aging that can be recommended to be measured in Phase II and Phase III clinical trials evaluating new chemical entities for sarcopenia treatment. A working group of the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO) proposed classifying biochemical markers into 2 series: biochemical markers evaluating musculoskeletal status and biochemical markers evaluating causal factors. For series 1, the group agreed on 4 biochemical markers that should be assessed in Phase II or Phase III trials (i.e., Myostatin-Follistatin, Brain Derived Neurotrophic Factor, N-terminal Type III Procollagen and Serum Creatinine to Serum Cystatin C Ratio - or the Sarcopenia Index). For series 2, the group agreed on 6 biochemical markers that should be assessed in Phase II trials (i.e., the hormones insulin-like growth factor-1 (IGF-I), dehydroepiandrosterone sulphate, and cortisol, and the inflammatory markers C-reactive protein (CRP), interleukin-6 and tumor necrosis factor-α), and 2 in Phase III trials (i.e., IGF-I and CRP). The group also proposed optional biochemical markers that may provide insights into the mode of action of pharmacological therapies. Further research and development of new methods for biochemical marker assays may lead to the evolution of these recommendations.