Sevelamer and Secondary Hyperparathyroidism in Chronic Kidney Disease
Condition: Hyperparathyroidism; Chronic Kidney Disease
MeSH terms: Kidney Diseases; Renal Insufficiency, Chronic; Hyperparathyroidism; Hyperparathyroidism, Secondary
Study type: Interventional
Phase: Phase 3

Summary: 
      The hypothesis underlying this study is that phosphate interferes with PTH-mediated calcium
      reabsorption in the distal nephron and thereby necessitates supranormal [PTH]to maintain
      normocalcemia in chronic kidney disease. This study will examine the hypothesis with measures
      of phosphate homeostasis and calcium reabsorption. A double-blind trial of the intestinal
      phosphate binder sevelamer carbonate will be employed to examine whether reductions in
      phosphate influx alter distal nephron phosphate concentration and the [PTH] required for
      calcium reabsorption in the expected manner.
    

Detailed description: 
      The parathyroid hormone concentration ([PTH)] rises as glomerular filtration rate (GFR)
      falls. This almost universal phenomenon is called secondary hyperparathyroidism (SHPT). [PTH]
      rises with dietary phosphate in chronic kidney disease. [PTH] also rises with stable dietary
      phosphate as GFR falls. The mechanism underlying these phenomena is unknown.

      We hypothesize that phosphate exerts its effect on [PTH] in the cortical distal nephron
      (CDN). Ordinarily, intestinal phosphate absorption does not fall in proportion to GFR as
      chronic kidney disease (CKD) progresses. Consequently, the concentration of phosphate
      increases in the cortical distal nephron (CDN), where PTH regulates tubular calcium
      reabsorption. We speculate that increased [P]cdn reduces the concentration of free calcium
      through complexation, and thereby necessitates high [PTH] for achievement of calcium
      reabsorption sufficient to maintain normocalcemia. We can show algebraically that [P]cdn is
      proportional to the ratio EP/Ccr, where EP is the urinary excretion rate of phosphate and Ccr
      is creatinine clearance, a surrogate for GFR. EP/Ccr can be calculated from measurements in
      aliquots of serum and urine as [P]u[cr]s/[cr]u. If our hypothesis is correct, we anticipate
      that [PTH] will be proportional to EP/Ccr in CKD, and that delta [PTH] will be proportional
      to delta EP/Ccr obtained with sequential determinations.

      We will study 30 patients with CKD and a comparable number of controls. All subjects will
      have normocalcemia. Controls will be seen once for informed consent, and once in the fasting
      state between 8:00 a.m. and 10:00 a.m. for collection of urine and blood specimens.

      Patients with CKD will be seen at five visits at intervals of four weeks. At the first visit,
      we will obtain informed consent and obtain a specimen for measurement of 25-hydroxyvitamin D
      (25OHD). At visits 2-5, we will obtain necessary specimens to measure concentrations of PTH,
      fibroblast growth factor 23 (FGF23), 25OHD, and 1,25-dihyroxyvitamin D (1,25(OH)2D). We will
      also measure ionized and ultrafilterable calcium, creatinine, and phosphorus in serum and
      calcium, phosphorus, and creatinine in urine. These measurements will enable us to follow the
      effects of interventions on hormone concentrations and parameters of calcium and phosphorus
      homeostasis.

      At visit 2 we will prescribe vitamin D in accordance with [25OHD] obtained at visit 1. For
      [25OHD] < 32 ng/mL, doses will be 50,000 units/d of D2 for one week, followed by 2000 mg/d of
      D2 for 3 weeks. For [25OHD] > 32 ng/mL, the dose will be D3 2000 mg/d for four weeks. The
      purpose of this intervention is to minimize the likelihood that vitamin D insufficiency or
      deficiency contributes to SHPT.

      At visit 3, we will instruct patients in a phosphate-restricted diet. At visit 4 we will
      quantify the metabolic effects of the diet, and will randomly assign patients to receive
      either placebo or sevelamer carbonate 800 mg tablets, 3 with each meal. At visit 5, we will
      quantify the effects of the two interventions on parameters of calcium and phosphate
      homeostasis and on hormone concentrations. We will view positive regressions of [PTH] on
      EP/Ccr and of ∆[PTH] on ∆EP/Ccr as evidence for our hypothesis.
    

Intervention name(s): sevelamer carbonate; placebo
Intervention type(s): Drug; Drug
Intervention description(s): 2400 mg with each meal for 4 weeks; 3 tablets with each meal
Other intervention name(s): Renvela (Genzyme)
Intervention MeSH terms: Sevelamer
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: secondary hyperparathyroidism; phosphate; calcium; chronic kidney disease