Oral calcium carbonate affects calcium but not phosphorus balance in stage 3–4 chronic kidney disease
2012; Elsevier BV; Volume: 83; Issue: 5 Linguagem: Inglês
10.1038/ki.2012.403
ISSN1523-1755
AutoresKathleen M. Hill Gallant, Berdine R. Martin, Meryl E. Wastney, George P. McCabe, Sharon M. Moe, Connie M. Weaver, Munro Peacock,
Tópico(s)Folate and B Vitamins Research
ResumoPatients with chronic kidney disease (CKD) are given calcium carbonate to bind dietary phosphorus, reduce phosphorus retention, and prevent negative calcium balance; however, data are limited on calcium and phosphorus balance during CKD to support this. Here, we studied eight patients with stage 3 or 4 CKD (mean estimated glomerular filtration rate 36ml/min) who received a controlled diet with or without a calcium carbonate supplement (1500mg/day calcium) during two 3-week balance periods in a randomized placebo-controlled cross-over design. All feces and urine were collected during weeks 2 and 3 of each balance period and fasting blood, and urine was collected at baseline and at the end of each week. Calcium kinetics were determined using oral and intravenous 45calcium. Patients were found to be in neutral calcium and phosphorus balance while on the placebo. Calcium carbonate supplementation produced positive calcium balance, did not affect phosphorus balance, and produced only a modest reduction in urine phosphorus excretion compared with placebo. Calcium kinetics demonstrated positive net bone balance but less than overall calcium balance, suggesting soft-tissue deposition. Fasting blood and urine biochemistries of calcium and phosphate homeostasis were unaffected by calcium carbonate. Thus, the positive calcium balance produced by calcium carbonate treatment within 3 weeks cautions against its use as a phosphate binder in patients with stage 3 or 4 CKD, if these findings can be extrapolated to long-term therapy. Patients with chronic kidney disease (CKD) are given calcium carbonate to bind dietary phosphorus, reduce phosphorus retention, and prevent negative calcium balance; however, data are limited on calcium and phosphorus balance during CKD to support this. Here, we studied eight patients with stage 3 or 4 CKD (mean estimated glomerular filtration rate 36ml/min) who received a controlled diet with or without a calcium carbonate supplement (1500mg/day calcium) during two 3-week balance periods in a randomized placebo-controlled cross-over design. All feces and urine were collected during weeks 2 and 3 of each balance period and fasting blood, and urine was collected at baseline and at the end of each week. Calcium kinetics were determined using oral and intravenous 45calcium. Patients were found to be in neutral calcium and phosphorus balance while on the placebo. Calcium carbonate supplementation produced positive calcium balance, did not affect phosphorus balance, and produced only a modest reduction in urine phosphorus excretion compared with placebo. Calcium kinetics demonstrated positive net bone balance but less than overall calcium balance, suggesting soft-tissue deposition. Fasting blood and urine biochemistries of calcium and phosphate homeostasis were unaffected by calcium carbonate. Thus, the positive calcium balance produced by calcium carbonate treatment within 3 weeks cautions against its use as a phosphate binder in patients with stage 3 or 4 CKD, if these findings can be extrapolated to long-term therapy. Patients with chronic kidney disease (CKD)-mineral bone disorder have altered mineral metabolism because of disruptions in homeostasis of serum phosphate, calcium, and the mineral-regulating hormones, parathyroid hormone (PTH), 1,25-dihydroxyvitamin D (1,25D), and fibroblast growth factor-23 (FGF-23).1.Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD Work Group. KDIGO clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD).Kidney Int Suppl. 2009; 113: S1-130PubMed Google Scholar Progressive hypocalcemia and hyperphosphatemia as kidney function decreased were the original biochemical hallmarks of mineral bone disorder.2.Nortman D.F. Coburn J.W. Renal osteodystrophy in end-stage renal failure.Postgrad Med. 1978; 64: 123-130PubMed Google Scholar Calcium and phosphorus absorption studies dating back to the 1970s–80s3.Coburn J.W. Koppel M.H. Brickman A.S. et al.Study of intestinal absorption of calcium in patients with renal failure.Kidney Int. 1973; 3: 264-272Abstract Full Text PDF PubMed Scopus (152) Google Scholar, 4.Coburn J.W. Hartenbower D.L. Massry S.G. Intestinal absorption of calcium and the effect of renal insufficiency.Kidney Int. 1973; 4: 96-104Abstract Full Text PDF PubMed Scopus (55) Google Scholar, 5.Clarkson E.M. Eastwood J.B. Koutsaimanis K.G. et al.Net intestinal absorption of calcium in patients with chronic renal failure.Kidney Int. 1973; 3: 258-263Abstract Full Text PDF PubMed Scopus (38) Google Scholar, 6.Francis R.M. Peacock M. Barkworth S.A. Renal impairment and its effects on calcium metabolism in elderly women.Age Ageing. 1984; 13: 14-20Crossref PubMed Scopus (61) Google Scholar, 7.Peacock M. Aaron J.E. Walker G.S. et al.Bone disease and hyperparathyroidism in chronic renal failure: the effect of 1alpha-hydroxyvitamin D3.in: Clin Endocrinol. 1977: 73s-81sGoogle Scholar showed that intestinal calcium and phosphorus absorption were low in CKD and reversible with calcitriol and vitamin D analogs.7.Peacock M. Aaron J.E. Walker G.S. et al.Bone disease and hyperparathyroidism in chronic renal failure: the effect of 1alpha-hydroxyvitamin D3.in: Clin Endocrinol. 1977: 73s-81sGoogle Scholar Hypocalcemia from calcium malabsorption and hyperphosphatemia from phosphorus retention were considered to be responsible for the progression of secondary hyperparathyroidism, a common feature of CKD.8.Slatopolsky E. Brown A. Dusso A. Role of phosphorus in the pathogenesis of secondary hyperparathyroidism.Am J Kidney Dis. 2001; 37: S54-S57Abstract Full Text Full Text PDF PubMed Scopus (153) Google Scholar More recently, it has been established that the reduced 1,25D is more likely because of the elevation of the phosphate-regulating hormone, FGF-23, which suppresses kidney 1-alpha hydroxylation of 25-hydroxyvitamin D (25D), and that PTH, FGF-23, and 1,25D form a sophisticated hormonal axis that regulate mineral homeostasis and skeletal mineralization.9.Gutierrez O. Isakova T. Rhee E. et al.Fibroblast growth factor-23 mitigates hyperphosphatemia but accentuates calcitriol deficiency in chronic kidney disease.J Am Soc Nephrol. 2005; 16: 2205-2215Crossref PubMed Scopus (746) Google Scholar There has been increasing awareness that abnormalities in the mineral-regulating hormones occur early in kidney failure (CKD stage 2) before serum calcium and phosphorus move from their fasting reference ranges.10.Isakova T. Wahl P. Vargas G.S. et al.Fibroblast growth factor 23 is elevated before parathyroid hormone and phosphate in chronic kidney disease.Kidney Int. 2011; 79: 1370-1378Abstract Full Text Full Text PDF PubMed Scopus (922) Google Scholar,11.Levin A. Bakris G.L. Molitch M. et al.Prevalence of abnormal serum vitamin D, PTH, calcium, and phosphorus in patients with chronic kidney disease: results of the study to evaluate early kidney disease.Kidney Int. 2007; 71: 31-38Abstract Full Text Full Text PDF PubMed Scopus (1153) Google Scholar Increase in serum phosphate and phosphorus retention in CKD-mineral bone disorder are considered to be the main culprits in exacerbating vascular and other soft tissue complications of CKD, and even within the normal reference range, serum phosphate is independently associated with increased mortality in pre-dialysis CKD patients.12.Kestenbaum B. Sampson J.N. Rudser K.D. et al.Serum phosphate levels and mortality risk among people with chronic kidney disease.J Am Soc Nephrol. 2005; 16: 520-528Crossref PubMed Scopus (949) Google Scholar To prevent phosphate retention and hyperphosphatemia, use of phosphate binders in the management of end-stage renal disease began in the mid-1970s.13.Slatopolsky E. Rutherford W.E. Rosenbaum R. et al.Hyperphosphatemia.Clin Nephrol. 1977; 7: 138-146PubMed Google Scholar Calcium carbonate as a phosphate binder was introduced in the mid 1980s as an alternative to aluminum-based phosphate binders that carried the risk of aluminum toxicity.14.Slatopolsky E. Weerts C. Lopez-Hilker S. et al.Calcium carbonate as a phosphate binder in patients with chronic renal failure undergoing dialysis.N Engl J Med. 1986; 315: 157-161Crossref PubMed Scopus (311) Google Scholar Calcium carbonate is a popular phosphate binder because of both its availability over the counter and its low cost relative to other phosphate binders. Not only does it bind dietary phosphate when given with meals, but some believe it has the added advantage of preventing or reversing negative skeletal calcium balance, thought to contribute to the increased fracture risk in CKD.15.Alem A.M. Sherrard D.J. Gillen D.L. et al.Increased risk of hip fracture among patients with end-stage renal disease.Kidney Int. 2000; 58: 396-399Abstract Full Text Full Text PDF PubMed Scopus (661) Google Scholar,16.Ensrud K.E. Lui L.Y. Taylor B.C. et al.Renal function and risk of hip and vertebral fractures in older women.Arch Intern Med. 2007; 167: 133-139Crossref PubMed Scopus (231) Google Scholar However, there is increasing concern over the risk of vascular calcification and cardiovascular events with use of calcium-based phosphate binders.17.Moe S.M. Chertow G.M. The case against calcium-based phosphate binders.Clin J Am Soc Nephrol. 2006; 1: 697-703Crossref PubMed Scopus (91) Google Scholar There are only limited and inconsistent data regarding the safety of calcium-based and non-calcium-based binders.18.Moorthi R.N. Moe S.M. CKD-mineral and bone disorder: core curriculum 2011.Am J Kidney Dis. 2011; 58: 1022-1036Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar Until recently,19.Spiegel D.M. Brady K. Calcium balance in normal individuals and in patients with chronic kidney disease on low- and high-calcium diets.Kidney Int. 2012; 81: 1116-1122Abstract Full Text Full Text PDF PubMed Scopus (140) Google Scholar no data on calcium balance in either early- or late-stage CKD patients were available, and there are no studies utilizing calcium kinetics. One study19.Spiegel D.M. Brady K. Calcium balance in normal individuals and in patients with chronic kidney disease on low- and high-calcium diets.Kidney Int. 2012; 81: 1116-1122Abstract Full Text Full Text PDF PubMed Scopus (140) Google Scholar showed that stage 3 and 4 CKD patients were in neutral calcium balance while consuming an 800mg/d calcium diet, and in positive calcium balance while consuming a diet of 2000, mg/d calcium. No equivalent data are available on phosphorus balance in CKD patients. The purpose of this study was to determine whether calcium carbonate, used as a phosphate binder, altered calcium and phosphorus balance and calcium kinetics in patients with stage 3/4 CKD while on a controlled diet. Further, the effects of calcium carbonate on fasting serum mineral and mineral-regulating hormone biochemistry were also determined. Seventeen volunteers were screened for the study. Five did not qualify on the basis of the inclusion/exclusion criteria. Four enrolled patients were withdrawn from the study in the first week that was used to assess dietary compliance and to equilibrate patients to the calcium and phosphorus content of the diet. Three patients were withdrawn owing to difficulties complying with the controlled diet, and one patient owing to starting kayexalate for high serum potassium. One patient who completed the study inadvertently remained on paricalcitol (2mcg/d) during the study; despite this, this patient had the lowest calcium absorption out of all the study participants (6–7% on both placebo and calcium carbonate). Therefore, the data from this patient were retained in the analysis. Eight patients completed the entire study and were included in the analysis and results. Patients participated in a randomized cross-over study of calcium carbonate (daily elemental calcium 2457mg) and placebo (daily elemental calcium 957mg) (Figure 1). All eight patients were overweight based on the body mass index and had hypertension, and six patients had type 2 diabetes mellitus. At baseline, serum calcium and serum phosphate were within normal ranges (8.8–10.2 and 2.3–4.5mg/dl for calcium and phosphate, respectively)20.National Kidney Foundation. K/DOQI clinical practice guidelines for bone metabolism and disease in chronic kidney disease.Am J Kidney Dis. 2003; 42: S1-201PubMed Google Scholar for all but one patient with serum calcium of 10.3mg/dl and one patient with serum phosphate of 4.9mg/dl. Six patients had serum PTH above the upper normal limit of the assay (54pg/ml) and five patients had serum intact FGF-23 above the upper normal limit of the assay (54.3pg/ml). Bone mineral density z-scores for total body, lumbar spine (L1–L4), and femoral neck were normal for age, race, and sex (Table 1). Usual dietary intake of calcium by 1-day dietary recall was 533mg/d (range: 141–1211mg/d) and phosphorus was 981mg/d (range: 351–1778mg/d).Table 1Patient demographics and baseline characteristicsaValues are means±s.d. (min, max) unless otherwise noted. N=8. BMD z-scores are matched for age, race, and sex.Male/female, n2/6Black/white, n5/3Diabetes present, n6Hypertension present, n8Age, years58.5±6.9(47.2, 68.7)BMI, kg/m238.7±8.7(27.9, 52.2)eGFR, ml/min per 1.73m236±8.8(26, 53)Serum Ca, mg/dl9.6±0.3(9.3, 10.3)Serum Pi, mg/dl3.8±0.6(3.2, 4.9)Serum PTH, pg/ml84.5±58.7(36.6, 214.0)Serum intact FGF-23, pg/ml79.4±39.7(33.7, 149.6)Total body BMD, g/cm21.26±0.10(1.11, 1.38)Z-score0.4±1.0(-0.8, 1.9)Lumbar spine BMD, g/cm21.29±0.21(0.98, 1.51)Z-score0.5±1.5(-1.3, 2.6)Femoral neck BMD, g/cm20.98±0.12(0.80, 1.11)Z-score-0.5±0.5(-1.3, 0.3)Abbreviations: BMD, bone mineral density; BMI, body mass index; eGFR, estimated glomerular filtration rate; FGF, fibroblast growth factor; PTH, parathyroid hormone.a Values are means±s.d. (min, max) unless otherwise noted. N=8. BMD z-scores are matched for age, race, and sex. Open table in a new tab Abbreviations: BMD, bone mineral density; BMI, body mass index; eGFR, estimated glomerular filtration rate; FGF, fibroblast growth factor; PTH, parathyroid hormone. As assessed by analysis of food leftovers, patients consumed >90% of the prescribed dietary calcium and phosphorus. Calcium and phosphorus balance calculations were adjusted for calcium and phosphorus in leftover foods. Fecal calcium-to-polyethylene glycol ratios showed that patients were in steady state by the end of the 1-week equilibration period. Creatinine-corrected urine calcium and phosphate values differed minimally from uncorrected values (by 0.0–6.6 and 0.0–27mg/d, respectively). Compliance for calcium carbonate and placebo was 100% for all participants as assessed by pill count. On placebo (daily elemental calcium 957mg), calcium balance was neutral (not significantly different from zero). With calcium carbonate (daily elemental calcium 2457mg), calcium balance was positive and significantly higher than placebo (508 vs. 61mg/d, respectively, P=0.002) (Figure 2). Fecal calcium was greater with calcium carbonate (1902 vs. 843mg/d, P 0.05). Data are presented as least squares mean±pooled s.e.m.View Large Image Figure ViewerDownload (PPT) CKD patients who had not received calcium carbonate had lower urine calcium (46 vs. 121mg/d, P=0.01) and fecal calcium (842 vs. 1092mg/d, P=0.03) compared with healthy adult women (historical data21.Spence L.A. Lipscomb E.R. Cadogan J. et al.The effect of soy protein and soy isoflavones on calcium metabolism in postmenopausal women: a randomized crossover study.Am J Clin Nutr. 2005; 81: 916-922PubMed Google Scholar). Calcium balance was higher in CKD patients compared with healthy adults (60 vs. -159mg/d, P=0.03) (Supplementary Figure S1 online). Calcium kinetics data indicate that fractional calcium absorption tended to be lower in CKD patients compared with healthy adults (20 vs. 26%, P=0.09), but this difference was not statistically significant. Total calcium absorption (Va), endogenous calcium secretion (Vf), bone formation rate (Vo+), and bone resorption rate (Vo-) were not different between CKD patients and healthy adults. Bone balance (VBal) was greater in CKD patients compared with healthy adults (57 vs. -108mg/d, P=0.03) (Figure 6). No equivalent data on phosphorus balance are available on these controls. Download .jpg (.03 MB) Help with files Supplementary Figure S1 Fasting serum calcium and phosphate were within normal reference ranges and did not differ between calcium carbonate and placebo (Table 2). Fasting serum 25D was within normal range but was slightly lower with calcium carbonate (25.1 vs. 26.7ng/ml, P=0.03). Fasting serum PTH and FGF-23 were higher than the normal ranges for the assays, whereas fasting serum 1,25D was within but in the lower end of the normal range for the assay. Serum osteocalcin was higher than the normal range, and serum bone alkaline phosphatase and urine N-telopeptides of type I collagen were normal. None of these measures differed between calcium carbonate and placebo.Table 2Fasting serum and urine biochemistries on placebo and calcium carbonateaValues are least squares means and pooled±s.e.m. (Min, Max), n=8. For each patient, the values during placebo and calcium carbonate are the average of three fasting measurements.PlaceboCalciumP-value Placebo vs. calciumReference rangeSourcesCa, mg/dl9.5±0.19.7±0.10.158.8–10.2KDOQI(9.0, 9.9)(8.8,10.2)sPi, mg/dl3.8±0.14.0±0.10.292.3–4.5KDOQI(3.3, 4.2)(3.7, 5.2)s25D, ng/ml26.7±0.425.1±0.40.0315–80Merck manual(20.1, 39.7)(18.5, 37.6)s1,25D, pg/ml33.1±2.330.6±2.30.4925–65Merck manual(15.7, 57.9)(15.6, 62.9)sPTH, pg/ml63.1±3.058.9±3.00.3713–54Diasorin assay(38.2, 111.5)(26.7, 113.1)sFGF23, pg/ml75.6±14.589.9±14.50.518.2–54.3Kianos assay(52.4, 142.5)(38.7, 286.1)sOC, ng/ml20.8±1.220.1±1.20.713.7–10.0MicroVue assay(14.0, 41.3)(14.7, 34.5)sBAP, U/l31.9±1.032.4±1.00.73Men: 15.0–41.3MicroVue assay(21.2, 47.4)(19.7, 51.7)Women: 14.2–2.7PostmenopausaluNTX/Cr, nM/mM38.8±4.134.9±4.10.53Men: 3-63Osteomark assay(19.8, 66.1)(12.1, 96.4)Women: 5–65PremenopausaluCa/Cr0.03±0.010.03±0.010.82(0.003, 0.12)(0.002, 0.14)uPi/Cr0.4±0.040.4±0.040.24(0.2, 0.7)(0.05, 0.52)TmP, mg/100ml GF2.8±0.13.1±0.10.11(2.5, 3.3)(2.7, 3.8)CPi/CCr0.23±0.010.19±0.010.10(0.11, 0.30)(0.02, 0.24)TmCa, mg/100ml GF5.2±0.045.3±0.040.22(4.7, 5.5)(4.5, 5.7)CCa/CCr0.01±0.0030.01±0.0030.94(0.001, 0.05)(0.001, 0.06)Abbreviations: s25D, serum 25-hydroxyvitamin D; s1,25D, serum 1,25-dihydroxyvitamin D; sBAP, serum bone alkaline phosphatase; sOC, serum osteocalcin; sFGF, serum fibroblast growth factor; TmCa, tubular maximal reabsorption of calcium; TmP, tubular maximal reabsorption of phosphate.a Values are least squares means and pooled±s.e.m. (Min, Max), n=8. For each patient, the values during placebo and calcium carbonate are the average of three fasting measurements. Open table in a new tab Abbreviations: s25D, serum 25-hydroxyvitamin D; s1,25D, serum 1,25-dihydroxyvitamin D; sBAP, serum bone alkaline phosphatase; sOC, serum osteocalcin; sFGF, serum fibroblast growth factor; TmCa, tubular maximal reabsorption of calcium; TmP, tubular maximal reabsorption of phosphate. Kidney function measurements (estimated glomerular filtration rate, serum creatinine, and creatinine clearance) were not different between calcium carbonate and placebo (data not shown). Urine Ca/Cr, tubular maximal reabsorption of calcium (TmCa), and fractional calcium excretion (CCa/CCr) were not different between calcium carbonate and placebo (Table 2). Urine Pi/Cr and fractional phosphate excretion (CPi/CCr) tended to be lower and tubular maximal reabsorption of phosphate (TmP) tended to be higher with calcium carbonate compared with placebo, but these differences were not statistically significant. This 3-week placebo-controlled balance and kinetic study demonstrated that stage 3/4 CKD patients were in neutral calcium balance while consuming a diet adequate22.Ross A.C. Taylor C.L. Yaktine A.L. Institute of Medicine. Dietary Reference Intakes for Calcium and Vitamin D. National Academy Press, 2011Google Scholar in calcium containing 957mg per day. Increasing calcium intake with 500mg calcium from calcium carbonate taken with three daily meals produced positive calcium balance. The ability of CKD patients to maintain neutral calcium balance on an adequate calcium diet was largely because of low urine calcium excretion, and to achieve positive calcium balance with calcium carbonate was largely because of increased calcium absorption and net retention, and failure to increased urine calcium excretion. The study demonstrated that phosphorus balance was also neutral on an average23.Calvo M.S. Park Y.K. Changing phosphorus content of the U.S. diet: potential for adverse effects on bone.J Nutr. 1996; 126: 1168S-1180SPubMed Google Scholar US intake of phosphorus of 1564mg per day. Further, phosphorus balance was unaffected by calcium carbonate, even though there was a reduction in urine phosphate excretion of about 148mg/d. Thus, the overall effect of a 500mg calcium supplement with three meals per day in CKD stage 3/4 patients was to produce a large positive calcium balance without affecting neutral phosphorus balance and only a modest effect on reducing urine phosphate. The decrease in urine phosphate was about 1mg for every 10mg elemental calcium supplement, which is close to that found by others.24.Russo D. Miranda I. Ruocco C. et al.The progression of coronary artery calcification in predialysis patients on calcium carbonate or sevelamer.Kidney Int. 2007; 72: 1255-1261Abstract Full Text Full Text PDF PubMed Scopus (287) Google Scholar The reduction in urine phosphate was likely because of a reduction in phosphate absorption, although the increase in fecal phosphorus with the calcium supplement was not significant, probably reflecting greater imprecision in the fecal phosphorus measurement. Calcium kinetics demonstrated that calcium carbonate increased bone formation, decreased bone resorption, and improved bone balance by about 200mg/day. Calcium kinetic modeling is currently unable to estimate the rate of calcium deposition into extraskeletal tissues. However, overall calcium balance measured by chemical methods, after subtracting 79mg calcium/day in sweat,25.Martin B.R. Davis S. Campbell W.W. et al.Exercise and calcium supplementation: effects on calcium homeostasis in sportswomen.Med Sci Sport Exer. 2007; 39: 1481-1486Crossref PubMed Scopus (17) Google Scholar showed an increase in calcium balance of over 300mg/day, suggesting that an appreciable proportion of the retained calcium from calcium carbonate was deposited in extraskeletal tissue and/or in the skeleton independent of bone formation and resorption mechanisms. It is generally assumed that CKD patients have phosphorus retention due to the need to excrete normal dietary phosphorus by increasing serum phosphate to accommodate for decreased glomercular filtration rate. However, this study demonstrated that despite phosphate retention in serum, CKD patients stage 3/4 remain in overall neutral phosphate balance. Phosphorus balance studies have not been conducted previously in CKD patients partly because of concern over the accuracy of measuring fecal phosphorus.26.Dormaar J.F. Webster G.R. Determination of total organic phosphorus in soil by extraction methods.Can J Soil Sci. 1964; 43: 35-43Crossref Google Scholar,27.Yokota T. Ito T. Saigusa M. Measurement of total phosphorus and organic phosphorus contents of animal manure composts by the dry combustion method.Soil Sci Plant Nutr. 2003; 49: 267-272Crossref Scopus (12) Google Scholar Analysis of phosphorus-spiked fecal samples showed that the method used in this study (Supplementary Methods online) gives 92.2% (82.5–100.5%) mean recovery. Small sample size may have limited our ability to detect significant differences of calcium and phosphorus balance from zero, as the study was only powered to detect mean differences in balance between calcium carbonate and placebo. However, normal bone mineral density of the patients corroborates that they were not in long-term negative calcium balance on their habitual calcium intakes of 533mg/d. In addition, the potential bias toward underestimating fecal phosphorus and thus overestimating phosphorus balance lends support to the conclusion that these patients are not retaining phosphorus while consuming a liberal amount of dietary phosphorus. Fasting serum phosphate was unaffected by calcium carbonate, despite a decrease in urine phosphate. In addition, the hormones regulating phosphorus homeostasis, PTH, 1,25D, and FGF-23, were not affected by calcium carbonate, indicating that the decrease in phosphate excretion with calcium carbonate was insufficient to elicit changes in phosphorus homeostasis. Perhaps longer treatment periods are needed to observe changes in serum phosphate and its regulating hormones, as studies with sevelamer showed a reduction in FGF-23 in dialysis patients28.Koiwa F. Kazama J.J. Tokumoto A. et al.Sevelamer hydrochloride and calcium bicarbonate reduce serum fibroblast growth factor 23 levels in dialysis patients.Ther Apher Dial. 2005; 9: 336-339Crossref PubMed Scopus (124) Google Scholar over 4 weeks and a reduction in FGF-23 and PTH in normophosphatemic CKD patients over 6 weeks.29.Oliveira R.B. Cancela A.L. Graciolli F.G. et al.Early control of PTH and FGF23 in normophosphatemic CKD patients: a new target in CKD-MBD therapy?.Clin J Am Soc Nephrol. 2010; 5: 286-291Crossref PubMed Scopus (306) Google Scholar To assess the abnormalities that occur in CKD patients, calcium balance and kinetics were compared with historical data21.Spence L.A. Lipscomb E.R. Cadogan J. et al.The effect of soy protein and soy isoflavones on calcium metabolism in postmenopausal women: a randomized crossover study.Am J Clin Nutr. 2005; 81: 916-922PubMed Google Scholar from healthy postmenopausal women on a similar calcium-controlled diet. CKD patients had lower urine calcium and lower fractional calcium absorption than postmenopausal women. Importantly, calcium balance was higher in CKD patients, providing further support that stage 3/4 CKD patients are not in negative calcium balance. The strength of these comparisons is that the historical data were generated by the same research group using the same methodologies in healthy postmenopausal women of similar age to the CKD patients. Calcium balance studies combined with calcium kinetics in subjects in mineral equilibrium are the gold standard for measuring rates of calcium transport at the gut, bone, and kidney. Using the standard 1 week of dietary and environmental equilibration followed by 2 weeks of balance, our patients were well equilibrated as corroborated by constant outputs of fecal and urinary markers. As in most balance studies, the dietary calcium and phosphorus intake was fixed by protocol to be close to the average intake in the United States, and not on each patient’s usual intake. Balance utilizing a randomized cross-over intervention represents a strong study design to test the effects of a treatment on mineral balance. On the other hand, balance studies are very exacting both for patient and investigator and they inevitably suffer from small sample size. Further, in this study, as is typical of stage 3/4 CKD, the patients were not a homogenous sample and included men and women, American blacks and whites, and a high incidence of obesity and type 2 diabetes—all factors known to affect mineral metabolism and bone mass. Thus, the results may not be directly generalizable to all stage 3/4 CKD patients or to all dietary l
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