Phosphate Lowering in CKD Trial
Condition: Chronic Kidney Disease; Cardiovascular Disease
MeSH terms: Kidney Diseases; Renal Insufficiency, Chronic; Cardiovascular Diseases
Study type: Interventional
Phase: Phase 4

Summary: 
      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]
    

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 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.
    

Intervention name(s): Lanthanum carbonate; placebo; Ascorbic Acid; Nitroglycerin; Flow-mediated dilation measurement; Aortic pulse-wave velocity; Endothelial cell collection
Intervention type(s): Drug; Drug; Drug; Drug; Procedure; Procedure; Procedure
Intervention description(s): Non-calcium containing phosphorus binder; Table identical to lanthanum carbonate but with no active ingredient; Intravenous administration during measurement of flow mediated dilation.; Drug that is administered under the tongue that relaxes blood vessels. To be administered during measurement of flow mediated dilation.; Measurement of the blood flow in the brachial artery, an artery in the upper arm, using ultrasound.; Measurement of the stiffness of the arteries using a transcutaneous tonometer, a small device placed over the skin over the carotid, brachial, radial and femoral arteries.; Collection of endothelial cells from vein in arm. A flexible wire is inserted through an IV into a forearm vein to collect endothelial cells for further study. This is performed at the baseline visit and and the final study visit.
Other intervention name(s): Fosrenol; Vitamin C
Intervention MeSH terms: Ascorbic Acid; Nitroglycerin
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: hyperphosphatemia; vascular dysfunction; chronic kidney disease; cardiovascular disease; endothelial dysfunction