Diurnal Variation in Markers of Mineral and Bone Disease in Chronic Kidney Disease

Study Overview
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Brief Summary
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The purpose of this study is to examine whether there are diurnal variations in magnesium and other markers related to mineral metabolism in blood from patients with chronic kidney disease (CKD) compared to healthy controls.

Detailed Description
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CKD is associated with a mortality rate 5-10 times higher than in the general population, which is driven by a high rate of cardiovascular disease. Several cohort studies have revealed an association between hypomagnesaemia and increased mortality in patients with CKD as well as faster progression of CKD. Additionally, studies in cultured vascular smooth muscle cells (VSMC) and in rodents with CKD have shown that Mg inhibits vascular calcification. The exact mechanism behind the inhibitory effect of Mg on vascular calcification is incompletely understood, but seems to be related to an inhibitory effect on the formation and precipitation of hydroxyapatite and delayed formation of secondary calciprotein particles, both of which have been shown to induce calcification of VSMC in vitro. Mg blocks the calcium (Ca) influx across the cell membrane in the VSMC. Mg has some affinity for the Ca sensing receptor, which has been shown to be involved in the calcification of VSMC, and might thus inhibit vascular calcification in a manner similar to other calcimimetics. Thus, increasing serum Mg has been proposed as a possible treatment to prevent vascular calcification in CKD. However, any diurnal variation in serum Mg and other markers of mineral metabolism related to vascular calcification in CKD have not previously been described. This is relevant as monitoring of treatment with Mg supplementation might potentially be dangerous, if there are significant diurnal changes in serum Mg. Therefore, we wish to conduct a prospective controlled clinical trial to investigate any diurnal changes in Mg other markers of mineral metabolism in healthy controls, patients with predialysis CKD and patients with end-stage kidney disease (ESKD).

Official Title
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Diurnal Variation in Markers of Mineral and Bone Disease in Chronic Kidney Disease - An Observational Study

Conditions
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Chronic Kidney Diseases, Mineral Metabolism Disorder

Intervention / Treatment
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* Diagnostic Test: Blood and urine samples


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18 years. Serum Mg between 0.7 and 1.1 mmol/L on average of previous measurements over the last 6 months. Serum ionised Ca between 1.10 and 1.35 mmol/L on average of previous measurements over the last 6 months. Serum phosphate (PO4) between 0.7 and 1.8 mmol/L on average of previous measurements over the last 6 months. A negative pregnancy test for women of childbearing age. Written informed consent. For healthy controls - estimated glomerular filtration rate (eGFR) > 60 mL/min for > 3 months and no known current or chronic medical or surgical conditions. For predialysis CKD subjects - estimated glomerular filtration rate (eGFR) between 30 and 15 mL/min for > 3 months (i.e. CKD stage 4). For ESKD subjects - maintenance haemodialysis treatment for > 3 months for ESKD and with anuria (urine excretion < 100 mL/day). Exclusion Criteria: Diagnosis of diabetes mellitus. Kidney transplant recipient. Parathyroid hormone (PTH) > 66 ρmol/L during the previous 3 months. Previous parathyroidectomy. Current treatment with Mg containing medication or supplements. Current treatment with calcimimetics. Current treatment with immunosuppressive drugs. Active malignant disease. Blood haemoglobin < 6.0 mmol/L Any condition impairing Mg absorption from the gastrointestinal tract (e.g. short bowel syndrome, chronic pancreatitis). Other diseases or conditions, which, in the opinion of the site investigator, would prevent participation in or completion of trial. Pregnancy or breastfeeding.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Healthy controls<br>Estimated glomerular filtration rate (eGFR) > 60 mL/min for > 3 months and no known current or chronic medical or surgical conditions. Blood and urine samples are collected for every 3rd hour during 24 hours | Diagnostic Test: Blood and urine samples<br>* Subjects will be admitted to the Department of Nephrology, Herlev and Gentofte Hospital, Herlev, Denmark, for 24-hour observation with measurements of serum and urine at three-hour intervals.<br>|
| Predialysis CKD subjects<br>Estimated glomerular filtration rate (eGFR) between 30 and 15 mL/min for > 3 months (i.e. CKD stage 4). Blood and urine samples are collected for every 3rd hour during 24 hours | Diagnostic Test: Blood and urine samples<br>* Subjects will be admitted to the Department of Nephrology, Herlev and Gentofte Hospital, Herlev, Denmark, for 24-hour observation with measurements of serum and urine at three-hour intervals.<br>|
| ESKD subjects<br>Maintenance haemodialysis treatment for > 3 months for ESKD and with anuria (urine excretion < 100 mL/day). Blood and urine samples are collected for every 3rd hour during 24 hours | Diagnostic Test: Blood and urine samples<br>* Subjects will be admitted to the Department of Nephrology, Herlev and Gentofte Hospital, Herlev, Denmark, for 24-hour observation with measurements of serum and urine at three-hour intervals.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Diurnal change in serum magnesium within groups | change in serum magnesium (mmol/l) within Groups The changes within groups over several timepoints will be compared with linear mixed effect models | 24 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in serum magnesium between groups | Change in serum magnesium (mmol/l) between Groups The overall magnesium levels will be compared between groups by comparing the total mean of measurements for each group. | 24 hours | 
| Change in ionized calcium | Change in p-ionized calcium within and between groups | 24 hours | 
| Change in p-phosphate | Change in p-phosphate within and between groups | 24 hours | 
| Change in p-PTH | Change in p-PTH within and between groups | 24 hours | 
| Change in p-FGF23 | Change in p-FGF23 within and between groups | 24 hours | 
| Change in s-calcification propensity score | Change in s-calcification propensity score within and between groups | 24 hours | 
| Change in u-magnesium | Change in u-magnesium within and between groups | 24 hours |