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Effects of Vitamin D Replacement on Hormones Regulating Iron Metabolism in Individuals With Chronic Kidney Disease

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01988116
Recruitment Status : Completed
First Posted : November 20, 2013
Last Update Posted : August 24, 2015
Information provided by (Responsible Party):
University of Alabama at Birmingham

Brief Summary:

The purpose of the study is to learn more about how treatment with vitamin D can affect iron metabolism and blood levels of two hormones that control iron levels, hepcidin and hemojuvelin in people with chronic kidney disease (CKD).

Iron is an essential mineral which is a major component of proteins that carry oxygen in the blood. Problems with iron metabolism can lead to low blood levels (anemia), which can commonly happen in people with CKD.

New research over the last decade has uncovered a new hormone called `hepcidin', which is made in the liver and released into the blood. Hepcidin controls how much iron is in the blood by preventing the absorption of iron from food. Blood levels of hepcidin C are found to be high in people with CKD, and a recent small study in people with normal kidney function showed that treatment with vitamin D decreased hepcidin levels.

Another protein, known as `hemojuvelin', has been recently discovered and is also thought to control the amount of iron in the blood. The relationship between vitamin D and hemojuvelin has never been studied before.

In this study, investigators would like to examine the effects of vitamin D on iron metabolism and blood levels of hepcidin C and hemojuvelin in individuals with CKD.

Condition or disease Intervention/treatment Phase
Chronic Kidney Disease Anemia of Chronic Disease Drug: Oral Calcitriol 0.5 mcg once daily for 6 weeks Drug: Placebo Early Phase 1

Detailed Description:

Iron homeostasis is tightly regulated in humans. Iron is mostly recycled from hemoglobin, myoglobin and other enzymes. Since humans lack the capacity to excrete excess iron, it must be intricately regulated at the site of its absorption in the duodenum and proximal jejunum. In the last decade, hepcidin has emerged as a master regulator of iron homeostasis. It decreases iron absorption from the gut mucosa by limiting its transport from the enterocyte across the basolateral membrane into the circulation. It does so by down-regulating the synthesis or promoting internalization of a basolateral membrane protein `Ferroportin', the only known cellular iron exporter.

Vitamin D is hypothesized to exert a significant and independent effect on the iron metabolism. In the CKD population, low vitamin-D levels independently correlate with the severity of anemia. Hepcidin C levels are found to be elevated in the CKD population. Mechanisms underlying the effect of vitamin D on iron homeostasis potentially include vitamin D induced expression of erythropoietin receptors, increased proliferation of erythroid precursors, and reduction in hepcidin C levels due to reduction in IL-6 from the anti-inflammatory effects of vitamin D. More recently, a study revealed direct relationship between vitamin D replacement and a sustained fall in hepcidin C levels. The same group of researchers found the above relationship to be due to a direct effect of vitamin D on hepcidin expression.

Hemojuvelin (HJV) is a protein encoded by the HFE2 gene and is found in the membrane bound and the soluble form (sHJV) in the humans. Mutations in the HJV gene are responsible for Juvenile Hemochromatosis. It is an upstream regulator of hepcidin transcription and appears to be essential for hepcidin expression in the hepatocytes and has important role to play in iron homeostasis. Recently, an assay has become available to measure the sHJV levels in the serum.

Although, we know that hepcidin plays a central role in iron homeostasis and recent studies have given us insight into the role hemojuvelin and vitamin D play in iron metabolism, to date, no studies have examined the effect on vitamin D replacement on hepcidin, hemojuvelin levels and iron metabolism in individuals with CKD.

Hypothesis 1: Treatment with an activated vitamin D analog in the individuals with CKD results in a statistically significant fall in hepcidin C levels as compared to individuals provided with placebo.

Hypothesis 2: Treatment with an activated vitamin D analog results in decreased levels of soluble hemojuvelin in individuals with chronic kidney disease.

Hypothesis 3: Vitamin D replacement in the individuals with CKD results in improved iron parameters as compared to the placebo.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 40 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Official Title: Vitamin D Replacement in Chronic Kidney Disease and Its Effects on Iron Homeostasis, Serum Hepcidin, and Hemojuvelin Levels.
Study Start Date : October 2013
Actual Primary Completion Date : June 2015
Actual Study Completion Date : June 2015

Resource links provided by the National Library of Medicine

Drug Information available for: Calcitriol

Arm Intervention/treatment
Experimental: Oral Calcitriol
Oral Calcitriol 0.5 mcg once daily for 6 weeks
Drug: Oral Calcitriol 0.5 mcg once daily for 6 weeks
Other Name: Rocaltrol

Placebo Comparator: Placebo Arm
Placebo capsule 1 Capsule once daily for 6 weeks
Drug: Placebo

Primary Outcome Measures :
  1. Change in serum hepcidin levels [ Time Frame: At Day 0, Day 3, 1 week, 4 weeks and 6 weeks ]
  2. Change in soluble hemojuvelin [ Time Frame: At Day 0, Day 3, 1 week, 4 weeks and 6 weeks ]
  3. Change in other indices of iron metabolism [ Time Frame: At Day 0, Day 3, 1 week, 4 weeks and 6 weeks ]
    Including, Serum Ferritin, Iron level, Percent transferrin saturation and TIBC

Secondary Outcome Measures :
  1. Change in serum hemoglobin [ Time Frame: At Day 0, Day 3, 1 week, 4 weeks and 6 weeks ]

Information from the National Library of Medicine

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Ages Eligible for Study:   19 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Patients with mild to moderate CKD (eGFR 15 - 60 ml/min/1.73 m2) as estimated by the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) formula.

Exclusion Criteria:

  • Subjects currently receiving active vitamin D analog therapy or history of recent (< 3 months) use.
  • Subjects currently receiving nutritional vitamin D (cholecalciferol or ergocalciferol) in dosages greater than 2000 IU/day.
  • Subjects receiving erythropoiesis stimulating agents.
  • Subjects receiving intravenous iron therapy.
  • Subjects receiving oral iron therapy started within 3 months prior to recruitment.
  • Subjects with severe anemia defined as Hb < 8.0 g/dL for males and Hb <7.0 g/dL for females.
  • Subjects with iron deficiency anemia defined as serum ferritin <100ng/ml and Transferring Saturation < 20%.
  • Pregnancy and lactation.
  • Subjects with hypercalcemia defined as serum calcium level of > 10.0 mg/dL.
  • Subjects with serum phosphorus concentration of > 4.5 mg/dL.
  • Subjects with acute kidney injury or rapidly declining GFR.
  • Subjects receiving any form of renal replacement therapy including hemodialysis, peritoneal dialysis, and patients with renal transplant.
  • Subjects with focus of active inflammation or infection determined clinically.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01988116

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United States, Alabama
University of Alabama
Birmingham, Alabama, United States, 35294
Sponsors and Collaborators
University of Alabama at Birmingham
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Principal Investigator: Bhupesh Panwar, MD University of Alabama, Nephrology Division
Study Director: Orlando M Gutierrez, MD,MMSc University of Alabama, Nephrology Division

Publications automatically indexed to this study by Identifier (NCT Number):
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Responsible Party: University of Alabama at Birmingham Identifier: NCT01988116     History of Changes
Other Study ID Numbers: F130725013
First Posted: November 20, 2013    Key Record Dates
Last Update Posted: August 24, 2015
Last Verified: August 2015
Keywords provided by University of Alabama at Birmingham:
Chronic kidney disease
Anemia of chronic disease
Iron Metabolism
Iron Homeostasis
Vitamin D
Additional relevant MeSH terms:
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Kidney Diseases
Renal Insufficiency, Chronic
Chronic Disease
Hematologic Diseases
Urologic Diseases
Renal Insufficiency
Disease Attributes
Pathologic Processes
Vitamin D
Growth Substances
Physiological Effects of Drugs
Bone Density Conservation Agents
Calcium-Regulating Hormones and Agents
Trace Elements
Calcium Channel Agonists
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action
Vasoconstrictor Agents
Anti-Infective Agents