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

Sponsor

IRCCS Azienda Ospedaliero-Universitaria di Bologna (Other)

Overall Status

Unknown status

CT.gov ID

NCT00669721

Collaborator

(none)

Enrollment

Location

Arms

Duration (Months)

13.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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 or Disease	Intervention/Treatment	Phase
Renal Failure Hemodialysis	Drug: law molecular weigth heparin Drug: unfractioned heparin	N/A

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 Design

Study Type:

Interventional

Anticipated Enrollment :

40 participants

Allocation:

Randomized

Intervention Model:

Crossover Assignment

Masking:

None (Open Label)

Primary Purpose:

Basic Science

Official Title:

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

Study Start Date :

Mar 1, 2008

Anticipated Primary Completion Date :

Jun 1, 2008

Anticipated Study Completion Date :

Jun 1, 2008

Arms and Interventions

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

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

Outcome Measures

Primary Outcome Measures

Levels of osteoprotegerin after administration of UFH or LMWH used as anticoagulant therapy for hemodialysis [during and after dialysis sessions]

Secondary Outcome Measures

Secondary aim of the study is to verify the safety of anticoagulation therapy with UFH and LMWH. [during and after dialysis sessions]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

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

Exclusion Criteria:

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