Phophate Lowering Trial
Phophate Lowering Trial
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). [COMIRB
 13-0328] Additionally, it will determine phosphorus balance among adults with CKD and whether
 there is a difference in phosphorus balance after three months of treatment with lanthanum
 carbonate. [COMIRB 15-0384]
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]

 To ensure adequate enrollment in the Phosphorus Balance Study (COMIRB 15-0384), an amendment
 was approved to recruit patients with stage IIIb and IV CKD with normal or modestly elevated
 serum phosphorus (2.8-5.5 mg/dL) who are not currently participating in the parent Phosphorus
 Lowering RCT (COMIRB 13-0328). Similar to the Phosphorus Lowering RCT, these patients will
 follow a low phosphorus diet and will be randomized to lanthanum carbonate or placebo for 12
 weeks (run-in period) prior to beginning the current Phosphorus Balance protocol.
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

 -  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) or completion of 12-week run-in phase

 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