Renal Effects of Erythropoietin in Humans

NCT01584921 | Completed Phase 1 DMC

• 1 other identifier: H-2-2011-068
• Study Type: interventional
• Target: 16
• Locations: 1 country
• Sites: 1

Brief Summary

Erythropoietin (EPO) is a glycoprotein produced mainly in the kidney. After its release to the bloodstream EPO binds to its receptor predominantly located within the bone marrow where erythropoiesis is stimulated. Recently, we have shown that recombinant human EPO (rHuEPO) down-regulates circulating levels of renin and aldosterone. Concomitant clearance studies revealed a decrease in proximal tubular reabsorption of sodium and water and a fall in glomerular filtration rate (GFR). These results for the first time demonstrate a link between EPO and renal function: By inhibiting proximal tubular reabsorption, which in turn results in rapid declines in GFR and renin/aldosterone levels, EPO may directly reduce the major oxygen consuming factor in the kidney. The expected result will be an increase of the oxygen tension in the environment of renal EPO producing cells, in this way initiating an appropriate signal for down-regulation of endogenous EPO synthesis when circulating levels of EPO are high. The aim of this project is to test this hypothesis by investigating the renal effects of rHuEPO in humans. In a double-blinded manner healthy subjects will be tested with placebo, or low-dose rHuEPO for two weeks, or high-dose rHuEPO for three days. Accurate sodium balance studies will be conducted together with renal clearance studies for measurements of renal plasma flow (131I-Hippuran clearance with renal venous sampling), GFR (51Cr-EDTA clearance) and the segmentel tubular handling of sodium and water (lithium clearance). EPO is the sole haematopoietic growth factor that is mainly produced in the kidneys and the project will provide new information about basic physiological issues regarding the association between renal function and the regulation of EPO synthesis.

Conditions

Renal Effects

Keywords

Erythropoietin; Glomerular filtration rate; Tubular reabsorption; Renal function; Renal perfusion

Outcome Measures

Primary Outcomes (1)

• Change in the Renal Blood Flow (RBF ml/min).

  Renal clearance studies with timed urine collections and renal venous catherization for measurements of renal perfusion (131I-Hippuran).

  Day 4 and 25

Secondary Outcomes (5)

• Glomerular filtration rate (GFR ml/min)

  Day 4, 11 and 25

• Segmental renal handling of sodium and water (lithium clearance).

  Day 4, 11 and 25.

• Blood and plasma volume

  Day 4, 11 and 25

• Analysis of hormones and proteins.

  Day 4, 11 and 25.

• Endothel function

  Day 4, 11 and 25

Study Arms (3)

Placebo

PLACEBO COMPARATOR

1 ml of saline (Sodium Chloride 9 mg/ml) is given subcutaneously before 10 O-clock a.m. on day 1,2,3,5,7,9,11 and 13. On day 1,2 and 3 six ml in total is given in six syringes in order to maintain the double blinding.

Drug: Placebo

Low dose Erythropoietin

ACTIVE COMPARATOR

Drug: Erythropoietin (Epoetin-beta, NeoRecormon®)

High dose Eryhropoietin

ACTIVE COMPARATOR

Drug: Erythropoietin (Epoetin-beta, NeoRecormon®)

Interventions

Erythropoietin (Epoetin-beta, NeoRecormon®) DRUG

5000 IU/ml of NeoRecormon (Epoetin beta) is given subcutaneously as one ml before 10 O-clock a.m. on day 1,3,5,7,9,11 and 13. On day 1 and 3 5000 IU is given in one syringe and five ml of saline in total is given in five other syringes in order to maintain the double blinding. On day 2 six syringes of a total of 6 ml of saline is given in six syringes.

Low dose Erythropoietin

Placebo DRUG

1 ml of saline (Sodium Chloride 9 mg/ml) is given subcutaneously before 10 O-clock a.m. on day 1,2,3,5,7,9,11 and 13. On day 1,2 and 3 six ml in total is given in six syringes in order to maintain the double blinding.

Placebo

Eligibility Criteria

• Age: 20 Years - 40 Years
• Sex: male
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Male
• Age between 20-40 years
• Non smoker for min. a year
• BP below 140/90
• No medicine use
• BMI below 25

You may not qualify if:

• Participation in other medical trails
• Allergi towards Erythropoietin
• Malignity diseases
• Epilepsy
• Staying above 1500 meters within the last 3 months
• Polycythemia
• Elite athlete
• Haematocrit above 55%

Sponsors & Collaborators

• University of Copenhagen: lead
• Rigshospitalet, Denmark: collaborator

Study Sites (1)

Department of Clinical Physiology and Nuclear Medicine and PET, Rigshospitalet

Copenhagen, Copenhagen East, 2100, Denmark

Location

Related Publications (8)

• Olsen NV, Aachmann-Andersen NJ, Oturai P, Munch-Andersen T, Borno A, Hulston C, Holstein-Rathlou NH, Robach P, Lundby C. Erythropoietin down-regulates proximal renal tubular reabsorption and causes a fall in glomerular filtration rate in humans. J Physiol. 2011 Mar 15;589(Pt 6):1273-81. doi: 10.1113/jphysiol.2010.194241. Epub 2010 Aug 19.

  PMID: 20724370 BACKGROUND

• Lundby C, Olsen NV. Effects of recombinant human erythropoietin in normal humans. J Physiol. 2011 Mar 15;589(Pt 6):1265-71. doi: 10.1113/jphysiol.2010.195917. Epub 2010 Aug 31.

  PMID: 20807784 BACKGROUND

• Holstein-Rathlou NH. A closed-loop analysis of the tubuloglomerular feedback mechanism. Am J Physiol. 1991 Nov;261(5 Pt 2):F880-9. doi: 10.1152/ajprenal.1991.261.5.F880.

  PMID: 1951720 BACKGROUND

• Jelkmann W. Erythropoietin: structure, control of production, and function. Physiol Rev. 1992 Apr;72(2):449-89. doi: 10.1152/physrev.1992.72.2.449. No abstract available.

  PMID: 1557429 BACKGROUND

• Hutchings M, Hesse B, Gronvall J, Olsen NV. Renal 131I-hippuran extraction in man: effects of dopamine. Br J Clin Pharmacol. 2002 Dec;54(6):675-7. doi: 10.1046/j.1365-2125.2002.t01-5-01689.x.

  PMID: 12492618 BACKGROUND

• Krapf R, Hulter HN. Arterial hypertension induced by erythropoietin and erythropoiesis-stimulating agents (ESA). Clin J Am Soc Nephrol. 2009 Feb;4(2):470-80. doi: 10.2215/CJN.05040908.

  PMID: 19218474 BACKGROUND

• Rasmussen P, Foged EM, Krogh-Madsen R, Nielsen J, Nielsen TR, Olsen NV, Petersen NC, Sorensen TA, Secher NH, Lundby C. Effects of erythropoietin administration on cerebral metabolism and exercise capacity in men. J Appl Physiol (1985). 2010 Aug;109(2):476-83. doi: 10.1152/japplphysiol.00234.2010. Epub 2010 Jun 3.

  PMID: 20522733 BACKGROUND

• Kristensen PL, Hoi-Hansen T, Olsen NV, Pedersen-Bjergaard U, Thorsteinsson B. Erythropoietin during hypoglycaemia in type 1 diabetes: relation to basal renin-angiotensin system activity and cognitive function. Diabetes Res Clin Pract. 2009 Jul;85(1):75-84. doi: 10.1016/j.diabres.2009.01.008. Epub 2009 Feb 10.

  PMID: 19211168 BACKGROUND

MeSH Terms

Interventions

Erythropoietin; epoetin beta

Intervention Hierarchy (Ancestors)

Colony-Stimulating Factors; Glycoproteins; Glycoconjugates; Carbohydrates; Hematopoietic Cell Growth Factors; Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Biological Factors

Study Officials

• Niels Vidiendal Olsen, M.D., D.M.Sc.

  Department of Neuroscience and Pharmacology, University of Copenhagen

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Medical doctor, phd.-student

Study Record Dates

• First Submitted: April 24, 2012
• First Posted: April 25, 2012
• Study Start: March 1, 2012
• Primary Completion: August 1, 2013
• Study Completion: September 1, 2013
• Last Updated: November 5, 2013

Record last verified: 2013-11

Locations

DK (1)