OxLDL: Lipid Lowering Agents to Limit Lipid Oxidation and Activation of Clotting System in Nephrotic Syndrome

Sponsor

University of North Carolina, Chapel Hill (Other)

Overall Status

Completed

CT.gov ID

NCT01845428

Collaborator

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (NIH)

Enrollment

Location

Arm

Actual Duration (Months)

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this research study is to learn if using statin in patients with nephrotic syndrome could lower the risk of blood clots. Nephrotic syndrome is a collection of signs and symptoms that occur when the glomeruli -the tiny filters that work in the kidney- leak protein in the urine.

One of the symptoms associated with nephrotic syndrome is hyperlipidemia: too much bad cholesterol (LDL). This bad cholesterol could be linked to the increased risk of blood clots in patients with nephrotic syndrome. The study doctors would like to see if taking a statin drug to reduce the amount of bad cholesterol could reduce the risk of blood clots.

Condition or Disease	Intervention/Treatment	Phase
Nephrotic Syndrome Hyperlipidemia	Drug: Pravastatin	Phase 1

Detailed Description

Venous thromboembolic (VTE) events are common in the nephrotic syndrome (NS) occurring in up to 30% of patients when systematically screened. The investigator proposes to explore a novel mechanism for the increased clot formation in NS. To date, the only consistently identified underlying risk factor for VTEs is severe hypoalbuminemia related to the NS. The underlying pathophysiology related to VTE in NS remains poorly understood and has previously been ascribed to dysregulation of pro- and anticoagulant clotting factors due to urinary protein losses and reflected by the low serum albumin. However, the direct evidence for this mechanism is inconsistent and relatively poor. Another feature of NS is that of severe hyperlipidemia which also correlates with hypoalbuminemia. In other severely hyperlipidemic states (e.g. Familial Hypercholesterolemia), the level of oxidized low-density lipoprotein (oxLDL) is markedly elevated. Forms of oxidized LDL interact with monocytes and macrophages leading to expression of Tissue Factor (TF), a procoagulant molecule. Furthermore, monocytes and macrophages activated in this fashion also release microparticles, small cell-membrane derived vesicles, that also express TF and participate in initiating intravascular clot formation. the investigator hypothesizes that the hyperlipidemia of the nephrotic syndrome leads to elevations in oxidized LDL and in turn, elevations in microparticle Tissue Factor (MP-TF) and its activity. The investigator also hypothesizes that serum albumin levels will inversely correlate with hyperlipidemia as well as oxLDL levels and MP-TF activity. Here, the investigator will study the effect of treatment with HMGCoA reductase inhibitors (statins) on ox LDL and MP-TF activity patients with NS.

Study Design

Study Type:

Interventional

Actual Enrollment :

7 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Prevention

Official Title:

Assessment of the Efficacy of Lipid-lowering Agents to Limit Lipid Oxidation and Activation of the Clotting System in Patients With the Nephrotic Syndrome: a Pilot Study.

Actual Study Start Date :

May 1, 2012

Actual Primary Completion Date :

Jan 1, 2017

Actual Study Completion Date :

Jan 1, 2017

Arms and Interventions

Arm	Intervention/Treatment
Other: pravastatin All participants will receive pravastatin 20mg daily	Drug: Pravastatin After collecting baseline plasma samples, participants will receive pravastatin 20mg daily. After 6 weeks, we will collect samples and safety data. Subsequent statin therapy will be at the discretion of the treating physician. Other Names: Pravachol

Arm

Intervention/Treatment

Other: pravastatin

All participants will receive pravastatin 20mg daily

Drug: Pravastatin

After collecting baseline plasma samples, participants will receive pravastatin 20mg daily. After 6 weeks, we will collect samples and safety data. Subsequent statin therapy will be at the discretion of the treating physician.

Other Names:

Pravachol

Outcome Measures

Primary Outcome Measures

Changes in Microparticle tissue factor (MP-TF) activity [tested at baseline and week 6]
The investigator will measure MP-TF activity . Microparticles will be isolated from platelet-free plasma (PFP) in a two-step sequential ultracentrifugation (20,000xg) process. Following the addition of Factor VIIa, Factor X and CaCl2, FXa generation is measured. Recombinant human relipidated TF will be used as a standard. TF-dependent plasma coagulation activity (PCA)generation is calculated by subtracting PCA generated in the presence of blocking antibodies from the amount of total PCA generated in the presence of an IgG control. The use of MP-TF activity as an outcome measure is unique in that it reflects both the pathophysiology and is a measure of PCA that correlates with VTE events

Secondary Outcome Measures

Changes in plasma coagulation activation [baseline and week6]
the investigator will also perform other more routine measures of plasma coagulation activation to determine the overall effect of hyperlipidemia in NS that may include TF-independent mechanisms. Thrombin-antithrombin complexes (TAT) also provide information regarding the downstream effect of Tissue Factor in the coagulation cascade. D-Dimer measurement - human D-Dimer ELISA Thrombin-antithrombin complexes (TAT) - Other covariates: Fasting lipid profile (including direct LDL measurement), serum albumin, proteinuria (by urine protein/creatinine ratio), estimated Glomerular Filtration Rate (eGFR), immunosuppressive therapy, age, sex, race.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 70 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:• Prevalent or incident patients of either sex, ages 18-70, with Membranous Nephropathy (MN) , Focal Segmental GlomeruloSclerosis (FSGS), or Minimal Change Disease (MCD).