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

Study Overview
=================
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.

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].

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

Conditions
-----------------
Renal Failure, Hemodialysis

Intervention / Treatment
-----------------
* Drug: law molecular weigth heparin
* Drug: unfractioned heparin


Participation Criteria
=================
Eligibility Criteria
-----------------
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: A<br>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<br>* 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%.<br>* Other names: nadroparin;|
| Active Comparator: B<br>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<br>* 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<br>* Other names: standard heparin, Sodic Heparin;|

What is the study measuring?
-----------------
Primary Outcome Measures

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

Secondary Outcome Measures

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

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
osteoprotegerin, RANKL, heparin, hemodialysis, anticoagulation, vascular calcification