OPG and RANKL Plasma Level After Administration of Unfractionated Heparin (UFH) and Low-Molecular-Weight Heparin (LMWH) in Hemodialysis

April 28, 2008 updated by: IRCCS Azienda Ospedaliero-Universitaria di Bologna

Effects of UFH and LMWH on Osteoprotegerin and RANKL Plasma Levels in Hemodialysis Patients

A randomised, prospective, cross over study will be done to determine whether the anticoagulation therapy with UFH or LMWH used for hemodialysis sessions modifies osteoprotegerin and RANKL plasma levels.

Study Overview

Status

Unknown

Conditions

Intervention / Treatment

Detailed Description

It's well known that treatment with heparin can lead to a reduction in bone density and the development of osteoporosis [ 1 ]. Until now, it's not clear the mechanism by which heparin produces this side effect, but several studies in animals [ 2,3] and in humans [ 4 ] have shown that LMWH may induce less osteoporosis than UFH.

Recently it was observed that heparin interferes with RANK/RANKL/POG system [5,6]. RANK, RANKL and OPG are members of TNF alfa receptor superfamily. The pathways involving them in conjunction with various cytokines and calciotrophic hormones play a pivotal role in bone remodelling. In addiction experimental and clinical studies established a consistent relationship between the RANK/RANKL/OPG pathway and both skeletal lesion related to disorders of mineral metabolism [7,8,9] and vascular calcification [7,10]. OPG exists either as active soluble form or is expressed by osteoblast, stromal and cardiovascular cells, acting as decoy receptor that competes with RANKL for RANK.

This interaction inhibits osteoclastic proliferation and differentiation and consequently prevents bone resorption . OPG is also produced by both endothelial cells (EC) and Vascular Smooth Muscle Cells (VSMCs ). EC-derived OPG seems to act as an important autocrine / paracrine factor able to protect against arterial calcification blocking the effects of RANKL that promotes monocytes differentiation in osteoclast -like cells and an osteogenic differentiation program in VSMC. This process leads to the synthesis of bone proteins and matrix calcification within the arterial vessel. OPG levels increase with aging and are higher in ESRD patient [11,12].

Recently it was demonstrated in cultures of murine bone marrow that the heparin inhibits osteoprotegerin activity binding OPG competitively and in this way inhibiting the interaction between OPG and RANKL [5].

On the other side heparin seems cause the mobilization of OPG into the circulation. It was reported that OPG is co-localized with vWF in Weibel Palade bodies in endothelial cells [13] and binds to Glucosaminoglycans (GAGs) at cellular membranes through its highly basic heparin binding domain [14,15]. Heparin treatment causes an immediate mobilization of these protein in to the circulation by displacement from the endothelial surface since they have higher affinity for heparins than GAGs at the endothelial surface[16,17]. UFH cause a more pronounced vascular mobilization of OPG than LMWH, indicating that UFH have an higher affinity for OPG than LMWH [6].

Study Type

Interventional

Enrollment (Anticipated)

40

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Italy
      • Bologna, Italy, 40100
        • Recruiting
        • St.Orsola University Hospital
        • Contact:
        • Principal Investigator:
          • Sergio Stefoni, Prof.

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  1. hemodialysis patients with age > 18 years on regular bicarbonate hemodialysis or hemodiafiltration treatment three times a week;
  2. clinical stability at least three months before the study started;

Exclusion Criteria:

  1. active gastrointestinal bleeding (one ore more positive hemoccult test in the last 8 weeks, melena or proctoraggia in the last 6 months )
  2. hemorrhagic stroke
  3. Myeloproliferative disorders
  4. Hereditary deficiency of coagulation factors, LAC phenomenon or antiphospholipid syndrome
  5. Malignant disease
  6. Patient submitted to antithrombotic prophylaxis with LMWH
  7. Immunosuppressive therapy
  8. Participation in other clinical trials

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Basic Science
  • Allocation: Randomized
  • Interventional Model: Crossover Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: A
This patients start a run in period with LMWH schedule as hemodialysis circuit anticoagulation. Then they'll undergo hemodialysis with LMWH for a second period of two weeks: in this checking phase samples will be collected during the midweek hemodialysis sessions. After the checking phase the patients will be crossed to UFH schedule. A wash out period of two weeks with UFH will be done. At the end of this period two weeks of checking phase will starts.
Drug: law molecular weigth heparin
administration of LMWH as anticoagulation for hemodialysis circuit;nadroparin is administred ad the dosage of 65 IU/kg on starting dialysis and in the arterial hemodialytic line after a washing phase with 2 litres of a heparin-free saline solution 0.9%.
Other Names:
  • nadroparin
Active Comparator: B
The patients randomized to receive UFH will start a run in period with this heparin schedule. Then they'll undergo hemodialysis with UFH for a second period of two weeks: in this checking phase samples will be collected during the midweek hemodialysis sessions. After the checking phase the patients will be crossed to LMWH. A wash out period of two weeks with UFH will be done. At the end of this period two weeks of checking phase will starts.
Drug: unfractioned heparin
administration of UFH as anticoagulation of hemodialysis circuit; standard heparin ( Sodic Heparin, Vister by Parke-Davis) 1500 IU on starting dialysis and 1500 ± 500 IU in continues intradialytic infusion per dialysis session
Other Names:
  • standard heparin, Sodic Heparin

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
Levels of osteoprotegerin after administration of UFH or LMWH used as anticoagulant therapy for hemodialysis
Time Frame: during and after dialysis sessions
during and after dialysis sessions

Secondary Outcome Measures

Outcome Measure
Time Frame
Secondary aim of the study is to verify the safety of anticoagulation therapy with UFH and LMWH.
Time Frame: during and after dialysis sessions
during and after dialysis sessions

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

IRCCS Azienda Ospedaliero-Universitaria di Bologna

Investigators

  • Principal Investigator: Sergio Stefoni, Prof, St.Orsola University Hospital

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

March 1, 2008

Primary Completion (Anticipated)

June 1, 2008

Study Completion (Anticipated)

June 1, 2008

Study Registration Dates

First Submitted

April 25, 2008

First Submitted That Met QC Criteria

April 28, 2008

First Posted (Estimate)

April 30, 2008

Study Record Updates

Last Update Posted (Estimate)

April 30, 2008

Last Update Submitted That Met QC Criteria

April 28, 2008

Last Verified

April 1, 2008

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • LWH-INT-79

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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