Calcium Carbonate versus Sevelamer Hydrochloride as Phosphate Binders after Long-Term Disease Progression in 5/6 Nephrectomized Rats

Abstract

Our aim was to compare the effects of calcium carbonate and sevelamer-HCl treatments on calcium-phosphate metabolism and renal function in 5/6 nephrectomized (NX) rats so that long-term disease progression preceded the treatment. After 15-week progression, calcium carbonate (3.0%), sevelamer-HCl (3.0%), or control diets (0.3% calcium) were given for 9 weeks. Subtotal nephrectomy reduced creatinine clearance (−40%), plasma calcidiol (−25%), and calcitriol (−70%) and increased phosphate (+37%), parathyroid hormone (PTH) (11-fold), and fibroblast growth factor-23 (FGF-23) (4-fold). In NX rats, calcium carbonate diet increased plasma (+20%) and urinary calcium (6-fold), reduced plasma phosphate (−50%) and calcidiol (−30%), decreased creatinine clearance (−35%) and FGF 23 (−85%), and suppressed PTH without influencing blood pH. In NX rats, sevelamer-HCl increased urinary calcium (4-fold) and decreased creatinine clearance (−45%), PTH (−75%), blood pH (by 0.20 units), plasma calcidiol (−40%), and calcitriol (−65%). Plasma phosphate and FGF-23 were unchanged. In conclusion, when initiated after long-term progression of experimental renal insufficiency, calcium carbonate diet reduced plasma phosphate and FGF-23 while sevelamer-HCl did not. The former induced hypercalcemia, the latter induced acidosis, while both treatments reduced vitamin D metabolites and deteriorated renal function. Thus, delayed initiation influences the effects of these phosphate binders in remnant kidney rats.

Phosphate Binding with Sevelamer Preserves Mechanical Competence of Bone Despite Acidosis in Advanced Experimental Renal Insufficiency

“…This influence was not due to selection bias, as the CRI groups were well matched: equal kidney tissue removal, and equal initial plasma creatinine, body weight, and urine output before the treatment. Sevelamer-HCl administration has been previously shown to increase dietary acid load and reduce serum bicarbonate levels [ 14 , 15 , 26 ]. Metabolic acidosis, in turn, enhances renal phosphate and calcium excretion probably due to net efflux of phosphate and calcium from bones [ 14 , 47 ].…”

“…Forty-eight 8-week old male Sprague-Dawley rats were subjected to surgical 5/6 nephrectomy (n = 30) or sham-operation (renal decapsulation, n = 18) [ 23 – 26 ]. Postoperative pain was relieved with 0.2 mg/kg buprenorphine (subcutaneously; Reckitt & Colman, Hull, UK) 3 times a day during the first 3 postoperative days.…”

“…During 9 weeks of treatment, all groups continued on 0.3% calcium and 0.8% phosphate chow (AnalyCen), and 3% sevelamer-HCl (RenaGel, Genzyme, MA, USA) was added to the chow of CRI+Sev and Sham+Sev rats ( Fig 1 ) [ 12 , 27 ]. All rats were housed 3–4 per cage in an animal laboratory (illuminated 06:00-18:00 h, temperature + 22°C) with free access to water and food [ 26 ].…”

“…During the last study week 24-hour urine was collected. At close, the rats were anaesthetized by intraperitoneal urethane (1.3 g/kg), carotid artery was cannulated, and blood samples were drawn [ 23 – 26 ]. Both femora were excised, cleaned and stored at -20°C in sealed freezer bags [ 23 , 24 ], using a procedure that preserves their mechanical properties [ 28 , 29 ].…”

“…Hemoglobin was measured photometrically (Technicon H*2, Technicon Instruments Corporation, Tarrytown, NY, USA), plasma pH using an ion selective electrode (634 pH Analyzer, Ciba Corning Diagnostics, Sudbury, UK), rat intact PTH levels using immunoradiometric assay (Immutopics Inc. San Clemente, CA, USA), and 25OH-D 2 and 1,25(OH) 2 D 3 using radioimmunological assays (IDS Inc., Arizona, USA). Plasma fibroblast growth factor-23 (FGF-23) was determined using ELISA (Kinos Inc., Tokyo, Japan) [ 26 , 27 , 30 ].…”