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

The recruitment status of this study is unknown because the information has not been verified recently.
Verified April 2008 by St. Orsola Hospital.
Recruitment status was  Recruiting
Sponsor:
Information provided by:
St. Orsola Hospital
ClinicalTrials.gov Identifier:
NCT00669721
First received: April 25, 2008
Last updated: April 28, 2008
Last verified: April 2008
  Purpose

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.


Condition Intervention
Renal Failure
Hemodialysis
Drug: law molecular weigth heparin
Drug: unfractioned heparin

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Bio-equivalence Study
Intervention Model: Crossover Assignment
Masking: Open Label
Primary Purpose: Basic Science
Official Title: Effects of UFH and LMWH on Osteoprotegerin and RANKL Plasma Levels in Hemodialysis Patients

Resource links provided by NLM:


Further study details as provided by St. Orsola Hospital:

Primary Outcome Measures:
  • Levels of osteoprotegerin after administration of UFH or LMWH used as anticoagulant therapy for hemodialysis [ Time Frame: during and after dialysis sessions ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Secondary aim of the study is to verify the safety of anticoagulation therapy with UFH and LMWH. [ Time Frame: during and after dialysis sessions ] [ Designated as safety issue: Yes ]

Estimated Enrollment: 40
Study Start Date: March 2008
Estimated Study Completion Date: June 2008
Estimated Primary Completion Date: June 2008 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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 Name: 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 Name: standard heparin, Sodic Heparin

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].

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00669721

Locations
Italy
St.Orsola University Hospital Recruiting
Bologna, Italy, 40100
Contact: Sergio Stefoni, Prof.    +390516362111    emodia@aosp.bo.it   
Principal Investigator: Sergio Stefoni, Prof.         
Sponsors and Collaborators
St. Orsola Hospital
Investigators
Principal Investigator: Sergio Stefoni, Prof St.orsola University Hospital
  More Information

Publications:
Vescini F, Buffa A, Sinicropi G. Osteoprotegerina RANKL e RANK nella regolazione dell'ostoclastogenesi. Riv It Biol Med 22: 64-67, 2002.

Responsible Party: Prof. Sergio Stefoni, St. Orsola University Hospital
ClinicalTrials.gov Identifier: NCT00669721     History of Changes
Other Study ID Numbers: LWH-INT-79
Study First Received: April 25, 2008
Last Updated: April 28, 2008
Health Authority: Italy: National Monitoring Centre for Clinical Trials - Ministry of Health

Keywords provided by St. Orsola Hospital:
osteoprotegerin
RANKL
heparin
hemodialysis
anticoagulation
vascular calcification

Additional relevant MeSH terms:
Renal Insufficiency
Kidney Diseases
Urologic Diseases
Calcium heparin
Dalteparin
Heparin
Heparin, Low-Molecular-Weight
Anticoagulants
Cardiovascular Agents
Fibrin Modulating Agents
Fibrinolytic Agents
Hematologic Agents
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Therapeutic Uses

ClinicalTrials.gov processed this record on November 23, 2014