Sevelamer and Secondary Hyperparathyroidism in Chronic Kidney Disease

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.