Phosphate Lowering to Treat Vascular Dysfunction in Chronic Kidney Disease

Condition(s) targeted: Chronic Kidney Disease; Cardiovascular Disease

Intervention: Lanthanum carbonate (Drug); placebo (Drug); Ascorbic Acid (Drug); Nitroglycerin (Drug); Flow-mediated dilation measurement (Procedure); Aortic pulse-wave velocity (Procedure); Endothelial cell collection (Procedure)

Phase: Phase 4

Status: Recruiting

Sponsored by: Department of Veterans Affairs

Official(s) and/or principal investigator(s):
Anna Jovanovich, MD, Principal Investigator, Affiliation: VA Eastern Colorado Health Care System, Denver, CO

Overall contact:
Anna Jovanovich, MD, Email: Anna.Jovanovich@va.gov

The proposed research is a randomized-controlled trial to determine the effectiveness of reducing serum phosphorus using a phosphate binder, lanthanum carbonate, for improving the function of arteries in adults with moderate to severe chronic kidney disease (CKD).

Official title: Phosphate Lowering to Treat Vascular Dysfunction in Chronic Kidney Disease

Study design: Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Primary outcome:

Brachial Artery Flow-mediated Dilation

Aortic Pulse-wave Velocity

Secondary outcome:

Oxidative stress-associated suppression of EDD and large elastic artery stiffness

Vascular Endothelial Cell Protein Expression

Interleukin-6 and C-reactive protein to measure systemic inflammation

Oxidized low-density lipoprotein to measure systemic oxidized stress

Detailed description: Chronic kidney disease (CKD) is a major health concern both in the general and Veteran populations. Indeed, the prevalence of CKD in a large Veteran population is 20%. Cardiovascular disease (CVD) is significantly increased in CKD and is an important cause of morbidity and mortality. As much as 80% of all CVD is associated with vascular dysfunction, particularly impaired endothelium-dependent dilation (EDD), measured by brachial artery flow-mediate dilation (FMD), and stiffening of the large elastic arteries, measured by aortic pulse-wave velocity (aPWV). Not surprisingly, patients with CKD demonstrate these dysfunctional vascular phenotypes. Even in early stages of CKD, there is an increase in oxidative stress resulting in structural and functional vascular changes, which, in turn, contributes to vascular dysfunction (impaired EDD and large elastic artery stiffening). In CKD, phosphorus remains within the normal range (2. 5-4. 5 mg/dL) until late in the disease. However, elevated serum phosphorus, even within the normal range, is associated with impaired EDD and with indirect measures of arterial stiffness. Whether lowering serum phosphorus in patients with CKD will improve EDD and arterial stiffness is unknown. This study is a randomized-controlled trial of lanthanum carbonate, a non-calcium based phosphate binder, to treat vascular dysfunction. The efficacy of phosphate binding with lanthanum carbonate for treating vascular endothelial dysfunction and large elastic artery stiffness in patients with stage IIIb and IV CKD (estimated glomerular filtration rate 15-45 mL/min/1. 73m2) with baseline serum phosphorus of 3. 5-5. 5 mg/dL will be assessed. The study will also determine if lowering serum phosphorus with lanthanum carbonate also reduces circulating and endothelial cell markers of oxidative stress. This study could shift clinical practice guidelines by establishing a novel therapy for reducing CVD risk in CKD patients not requiring chronic hemodialysis.

Minimum age: 40 Years. Maximum age: 79 Years. Gender(s): Both.

Criteria:

Inclusion Criteria:

- Age 40-79, women must be post-menopausal

- CKD stage IIIb or IV (estimated glomerular filtration rate by MDRD 15-45

mL/min/1. 73m2), stable for 3 months

- Serum phosphorus 3. 0-5. 5 mg/dL, stable for 3 months

- Not using phosphate binders

- Albumin > 3. 0 g/dL

- If using antioxidants and/or omega-3 fatty acids, must discontinue 4 weeks prior to

participation

- Free from alcohol dependence or abuse

- Ability to provide informed consent

- BMI < 40 kg/m2

- Not taking medications that interact with agents administered during experimental

sessions (e. g., sildenafil interacts with nitroglycerin) Exclusion Criteria:

- Life expectancy <1 year

- Uncontrolled hypertension

- History of severe liver disease

- History of congestive heart failure (EF < 35%)

- History of hospitalizations within the last 3 months

- History of ileus or bowel obstruction

- Active infection or antibiotic therapy

- Expected kidney transplant in the next 6 months

- Active vitamin D analogue use (i. e. calcitriol, paricalcitol, doxercalciferol)

- Vasculitis requiring immunosuppressive therapy within the last year

- Current tobacco abuse

Anna Jovanovich, MD, Email: Anna.Jovanovich@va.gov

University of Colorado Denver, Aurora, Colorado 80045, United States; Recruiting
Anna Jovanovich, MD, Phone: 303-724-7797, Email: anna.jovanovich@ucdenver.edu

VA Eastern Colorado Health Care System, Denver, CO, Denver, Colorado 80220, United States; Recruiting
Anna Jovanovich, MD, Email: Anna.Jovanovich@va.gov
Anna Jovanovich, MD, Principal Investigator

Starting date: September 2014
Last updated: March 23, 2015