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Phosphate Lowering to Treat Vascular Dysfunction in Chronic Kidney Disease

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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-mediated dilation (FMDBA), 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 adverse CVD outcomes in CKD. Elevations in serum phosphorus have been 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. Furthermore, little is known about phosphorus balance in CKD. There are no studies evaluating the effect of non-calcium based phosphate binders on phosphorus balance in subjects with CKD nor other studies examining the effects of changing phosphorus balance on vascular function. For this Career Development Award-2 (CDA-2), a randomized-controlled trial of lanthanum carbonate, a non-calcium based phosphate binder, to treat vascular dysfunction and examine phosphorus balance in CKD is proposed. Aim 1 will assess the efficacy of phosphate binding with lanthanum carbonate for treating vascular endothelial dysfunction and large elastic artery stiffness in patients with stage IIIb or IV CKD (estimated glomerular filtration rate 15-45 mL/min/1.73 m2) with baseline serum phosphorus of 3.5-5.5 mg/dL. Aim 2 will determine if lowering serum phosphorus with lanthanum carbonate also reduces circulating and endothelial cell markers of oxidative stress. Aim 3 will determine phosphorus balance in subjects with stage IIIb and IV CKD after 12 weeks of treatment with lanthanum carbonate or placebo and its effects on changes in FMDBA. These studies could shift clinical practice guidelines by establishing a novel therapy for reducing CVD risk in CKD patients not requiring chronic hemodialysis. With a long-term career goal of becoming an independent VA clinical investigator, this mentored CDA-2 will provide the principal investigator, Dr. Anna Jovanovich, with the opportunity to build on her knowledge of and skills in epidemiology, biostatistics, and study design. She will also gain important experience in all aspects of conducting a randomized-controlled trial, including patient recruitment, carrying out an intervention, and data collection and analysis. Additionally, she will learn and develop techniques to measure vascular function, an important CVD intermediate end-point. Along with the guidance of her multidisciplinary mentoring team, this CDA-2 will allow her to successfully transition to an independent VA investigator.
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