Phophate Lowering Trial

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 2.8-5.5 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. [COMIRB 13-0328]

Little is known about phosphorus balance in CKD. It is assumed that CKD patients remain in
neutral phosphorus balance despite decreases in kidney function. Serum phosphorus remains in
the normal range until late in CKD thus making it difficult to recognize perturbations in
phosphorus balance. Indeed, among CKD patients treated with the non-calcium containing
phosphate binder, sevelamer, serum phosphorus did not change after six weeks of treatment but
urinary phosphate excretion, parathyroid hormone, and fibroblast growth factor-23 changed
significantly, suggesting a shift in phosphorus homeostasis. However, two other studies found
that patients with CKD III-IV treated with calcium-containing phosphate binders remained in
neutral phosphorus balance. There are no studies evaluating the effects of non-calcium based
phosphate binders on phosphorus balance among patients with CKD nor other studies examining
the effect of changing phosphorus balance on vascular function.

An extension of the above-described 12-week prospective randomized, placebo-controlled
double-blind trial (COMIRB 13-0328) will be conducted in a subset of subjects. A total of 24
subjects from COMIRB 13-0328 will be recruited to participate in the Phosphorus Balance
sub-investigation (12 subjects treated with lanthanum carbonate and 12 subjects treated with
placebo). [15-0384] They will consume a diet with a fixed phosphorus content (1000 +/- 50 mg)
for seven days. They will then be admitted to the inpatient Center for Translational Clinical
Research at the University of Colorado Denver for 48 hours to accurately collect urine and
stool samples. The goal of the Phosphorus Balance sub-investigation (COMIRB 15-0384) is to
determine whether lowering serum phosphorus, accomplished during the parent phosphorus
lowering randomized-controlled trial (COMIRB 13-0328), affects phosphorus balance compared to
those subjects treated with placebo. A key secondary goal is to determine if differences in
phosphorus balance affect vascular function as measured by FMD. [15-0384]

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 2.8-5.5 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)

- For COMIRB 15-0384, completion of the prospective, randomized, placebo-controlled
double-blind trial, Phosphorus Lowering to Treat Vascular Dysfunction in Chronic
Kidney Disease (COMIRB 13-0328)

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