The role of calcium supplementation in healthy musculoskeletal ageing - An expert consensus meeting of the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis ans Musculoskeletal Diseases (ESCEO) and the International Foundation for Osteoporosis (IOF)
Harvey, N.C.; Biver, E.; Kaufman, J.-M.et al.
2017 • In Osteoporosis International, 28 (2), p. 447-62
[en] Abstract The place of calcium supplementation, with or
without concomitant vitamin D supplementation, has been
much debated in terms of both efficacy and safety. There have
been numerous trials and meta-analyses of supplementation
for fracture reduction, and associations with risk of myocardial
infarction have been suggested in recent years. In this report, the product of an expert consensus meeting of the
European Society for Clinical and Economic Aspects of
Osteoporosis, Osteoarthritis and Musculoskeletal Diseases
(ESCEO) and the International Foundation for Osteoporosis
(IOF), we review the evidence for the value of calcium supplementation,
with or without vitamin D supplementation, for
healthy musculoskeletal ageing.We conclude that (1) calcium
and vitamin D supplementation leads to a modest reduction in
fracture risk, although population-level intervention has not
been shown to be an effective public health strategy; (2) supplementation
with calcium alone for fracture reduction is not
supported by the literature; (3) side effects of calcium supplementation
include renal stones and gastrointestinal symptoms;
(4) vitamin D supplementation, rather than calcium supplementation,
may reduce falls risk; and (5) assertions of increased
cardiovascular risk consequent to calciumsupplementation
are not convincingly supported by current evidence. In
conclusion, we recommend, on the basis of the current evidence,
that calcium supplementation, with concomitant vitamin
D supplementation, is supported for patients at high risk
of calcium and vitamin D insufficiency, and in those who are
receiving treatment for osteoporosis.
Disciplines :
Rheumatology Public health, health care sciences & services
Author, co-author :
Harvey, N.C. ✱
Biver, E. ✱
Kaufman, J.-M.
Bauer, J.
Branco, J.
Brandi, M. L.
Bruyère, Olivier ; Université de Liège > Département des sciences de la santé publique > Santé publique, Epidémiologie et Economie de la santé
Coxam, V.
Cruz-Jentoft, A.
Czerwinski, E.
Dimai, H.
Fardellone, P.
Landi, F.
Reginster, Jean-Yves ; Université de Liège > Département des sciences de la santé publique > Santé publique, Epidémiologie et Economie de la santé
✱ These authors have contributed equally to this work.
Language :
English
Title :
The role of calcium supplementation in healthy musculoskeletal ageing - An expert consensus meeting of the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis ans Musculoskeletal Diseases (ESCEO) and the International Foundation for Osteoporosis (IOF)
Publication date :
2017
Journal title :
Osteoporosis International
ISSN :
0937-941X
eISSN :
1433-2965
Publisher :
Springer Science & Business Media B.V., Godalming, United Kingdom
Volume :
28
Issue :
2
Pages :
447-62
Peer reviewed :
Peer Reviewed verified by ORBi
Funders :
The meeting was funded by the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO), a Belgian not-for-profit organisation.
Seeman E (2008) Structural basis of growth-related gain and age-related loss of bone strength. Rheumatology (Oxford) 47(Suppl 4):iv2–iv8
Rozenberg S, Body JJ, Bruyere O et al (2016) Effects of dairy products consumption on health: benefits and beliefs—a commentary from the Belgian Bone Club and the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases. Calcif Tissue Int 98:1–17
Bruyere O, Cavalier E, Souberbielle JC, Bischoff-Ferrari HA, Beaudart C, Buckinx F, Reginster JY, Rizzoli R (2014) Effects of vitamin D in the elderly population: current status and perspectives. Archives of public health = Archives belges de sante publique 72:32
Rizzoli R, Boonen S, Brandi ML, Bruyere O, Cooper C, Kanis JA, Kaufman JM, Ringe JD, Weryha G, Reginster JY (2013) Vitamin D supplementation in elderly or postmenopausal women: a 2013 update of the 2008 recommendations from the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO). Curr Med Res Opin 29:305–313
Ethgen O, Hiligsmann M, Burlet N, Reginster JY (2016) Cost-effectiveness of personalized supplementation with vitamin D-rich dairy products in the prevention of osteoporotic fractures. Osteoporos Int 27:301–308
Cianferotti L, Parri S, Gronchi G, Rizzuti C, Fossi C, Black DM, Brandi ML (2015) Changing patterns of prescription in vitamin D supplementation in adults: analysis of a regional dataset. Osteoporos Int 26:2695–2702
Kuo IY, Ehrlich BE (2015) Signaling in muscle contraction. Cold Spring Harb Perspect Biol 7:a006023
Gehlert S, Bloch W, Suhr F (2015) Ca2+-dependent regulations and signaling in skeletal muscle: from electro-mechanical coupling to adaptation. Int J Mol Sci 16:1066–1095
Rizzoli R, Stevenson JC, Bauer JM, van Loon LJ, Walrand S, Kanis JA, Cooper C, Brandi ML, Diez-Perez A, Reginster JY (2014) The role of dietary protein and vitamin D in maintaining musculoskeletal health in postmenopausal women: a consensus statement from the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO. Maturitas 79:122–132)
Harvey N, Dennison E, Cooper C (2010) Osteoporosis: impact on health and economics. Nat Rev Rheumatol 6:99–105
Fielding RA, Vellas B, Evans WJ et al (2011) Sarcopenia: an undiagnosed condition in older adults. Current consensus definition: prevalence, etiology, and consequences. International working group on sarcopenia. J Am Med Dir Assoc 12:249–256
Hernlund E, Svedbom A, Ivergard M, Compston J, Cooper C, Stenmark J, McCloskey EV, Jonsson B, Kanis JA (2013) Osteoporosis in the European Union: medical management, epidemiology and economic burden: a report prepared in collaboration with the International Osteoporosis Foundation (IOF) and the European Federation of Pharmaceutical Industry Associations (EFPIA). Arch Osteoporos 8:136
Silk LN, Greene DA, Baker MK (2015) The effect of calcium or calcium and vitamin D supplementation on bone mineral density in healthy males: a systematic review and meta-analysis. International journal of sport nutrition and exercise metabolism 25:510–524
Lips P, Bouillon R, van Schoor NM, Vanderschueren D, Verschueren S, Kuchuk N, Milisen K, Boonen S (2010) Reducing fracture risk with calcium and vitamin D. Clin Endocrinol 73:277–285
Boonen S, Bischoff-Ferrari HA, Cooper C, Lips P, Ljunggren O, Meunier PJ, Reginster JY (2006) Addressing the musculoskeletal components of fracture risk with calcium and vitamin D: a review of the evidence. Calcif Tissue Int 78:257–270
Tai V, Leung W, Grey A, Reid IR, Bolland MJ (2015) Calcium intake and bone mineral density: systematic review and meta-analysis. BMJ 351:h4183
Tang BM, Eslick GD, Nowson C, Smith C, Bensoussan A (2007) Use of calcium or calcium in combination with vitamin D supplementation to prevent fractures and bone loss in people aged 50 years and older: a meta-analysis. Lancet 370:657–666
Bischoff-Ferrari HA, Dawson-Hughes B, Baron JA et al (2007) Calcium intake and hip fracture risk in men and women: a meta-analysis of prospective cohort studies and randomized controlled trials. Am J Clin Nutr 86:1780–1790
DIPART Group (2010) Patient level pooled analysis of 68 500 patients from seven major vitamin D fracture trials in US and Europe. BMJ 340:b5463
Bolland MJ, Leung W, Tai V, Bastin S, Gamble GD, Grey A, Reid IR (2015) Calcium intake and risk of fracture: systematic review. BMJ 351:h4580
Weaver CM, Alexander DD, Boushey CJ, Dawson-Hughes B, Lappe JM, LeBoff MS, Liu S, Looker AC, Wallace TC, Wang DD (2016) Calcium plus vitamin D supplementation and risk of fractures: an updated meta-analysis from the National Osteoporosis Foundation. Osteoporos Int 27:367–376
Prentice RL, Pettinger MB, Jackson RD et al (2013) Health risks and benefits from calcium and vitamin D supplementation: Women’s Health Initiative clinical trial and cohort study. Osteoporos Int 24:567–580
Chapuy MC, Arlot ME, Duboeuf F, Brun J, Crouzet B, Arnaud S, Delmas PD, Meunier PJ (1992) Vitamin D3 and calcium to prevent hip fractures in the elderly women. N Engl J Med 327:1637–1642
Grant AM, Avenell A, Campbell MK et al (2005) Oral vitamin D3 and calcium for secondary prevention of low-trauma fractures in elderly people (Randomised Evaluation of Calcium Or vitamin D, RECORD): a randomised placebo-controlled trial. Lancet 365:1621–1628
Institute of Medicine of the National Academies, National Academy of Sciences, Washington, DC (2011). Dietary Reference Intakes for Calcium and Vitamin D (report)
Curtis EM, Moon RJ, Dennison EM, Harvey NC, Cooper C (2015) Recent advances in the pathogenesis and treatment of osteoporosis. Clinical medicine (London, England) 15(Suppl 6):s92–s96
McCloskey EV, Beneton M, Charlesworth D et al (2007) Clodronate reduces the incidence of fractures in community-dwelling elderly women unselected for osteoporosis: results of a double-blind, placebo-controlled randomized study. J Bone Miner Res 22:135–141
Bonnick S, Broy S, Kaiser F, Teutsch C, Rosenberg E, DeLucca P, Melton M (2007) Treatment with alendronate plus calcium, alendronate alone, or calcium alone for postmenopausal low bone mineral density. Curr Med Res Opin 23:1341–1349
Hirata D, Nagashima T, Saito S, Okazaki H, Kano S, Minota S (2002) Elevated muscle enzymes in a patient with severe hypocalcemia mimicking polymyositis. Modern rheumatology / the Japan Rheumatism Association 12:186–189
Thabit H, Barry M, Sreenan S, Smith D (2011) Proximal myopathy in lacto-vegetarian Asian patients responding to vitamin D and calcium supplement therapy - two case reports and review of the literature. J Med Case Rep 5:178
Beaudart C, Buckinx F, Rabenda V, Gillain S, Cavalier E, Slomian J, Petermans J, Reginster JY, Bruyere O (2014) The effects of vitamin D on skeletal muscle strength, muscle mass, and muscle power: a systematic review and meta-analysis of randomized controlled trials. J Clin Endocrinol Metab 99:4336–4345
Bischoff-Ferrari HA, Dawson-Hughes B, Staehelin HB, Orav JE, Stuck AE, Theiler R, Wong JB, Egli A, Kiel DP, Henschkowski J (2009) Fall prevention with supplemental and active forms of vitamin D: a meta-analysis of randomised controlled trials. BMJ (Clinical research ed) 339:b3692
Bischoff-Ferrari HA, Dawson-Hughes B, Willett WC, Staehelin HB, Bazemore MG, Zee RY, Wong JB (2004) Effect of vitamin D on falls: a meta-analysis. JAMA 291:1999–2006
Jackson C, Gaugris S, Sen SS, Hosking D (2007) The effect of cholecalciferol (vitamin D3) on the risk of fall and fracture: a meta-analysis. QJM: monthly journal of the Association of Physicians 100:185–192
Kalyani RR, Stein B, Valiyil R, Manno R, Maynard JW, Crews DC (2010) Vitamin D treatment for the prevention of falls in older adults: systematic review and meta-analysis. J Am Geriatr Soc 58:1299–1310
LeBlanc ES, Chou R (2015) VItamin d and falls—fitting new data with current guidelines. JAMA Intern Med 175:712–713
Michael YL, Whitlock EP, Lin JS, Fu R, O’Connor EA, Gold R (2010) Primary care-relevant interventions to prevent falling in older adults: a systematic evidence review for the U.S. Preventive Services Task Force. Ann Intern Med 153:815–825
Murad MH, Elamin KB, Abu Elnour NO et al (2011) Clinical review: the effect of vitamin D on falls: a systematic review and meta-analysis. J Clin Endocrinol Metab 96:2997–3006
O’Donnell S, Moher D, Thomas K, Hanley DA, Cranney A (2008) Systematic review of the benefits and harms of calcitriol and alfacalcidol for fractures and falls. J Bone Miner Metab 26:531–542
Richy F, Dukas L, Schacht E (2008) Differential effects of D-hormone analogs and native vitamin D on the risk of falls: a comparative meta-analysis. Calcif Tissue Int 82:102–107
Cameron ID, Gillespie LD, Robertson MC, Murray GR, Hill KD, Cumming RG, Kerse N (2012) Interventions for preventing falls in older people in care facilities and hospitals. Cochrane Database Syst Rev 12:CD005465
Cameron ID, Murray GR, Gillespie LD, Robertson MC, Hill KD, Cumming RG, Kerse N (2010) Interventions for preventing falls in older people in nursing care facilities and hospitals. Cochrane Database Syst Rev Cd005465
Bolland MJ, Grey A, Gamble GD, Reid IR (2014) Vitamin D supplementation and falls: a trial sequential meta-analysis. The lancet Diabetes & endocrinology 2:573–580
Dukas L, Bischoff HA, Lindpaintner LS, Schacht E, Birkner-Binder D, Damm TN, Thalmann B, Stahelin HB (2004) Alfacalcidol reduces the number of fallers in a community-dwelling elderly population with a minimum calcium intake of more than 500 mg daily. J Am Geriatr Soc 52:230–236
Gillespie LD, Robertson MC, Gillespie WJ, Lamb SE, Gates S, Cumming RG, Rowe BH (2009) Interventions for preventing falls in older people living in the community. Cochrane Database Syst Rev Cd007146
Gillespie LD, Robertson MC, Gillespie WJ, Sherrington C, Gates S, Clemson LM, Lamb SE (2012) Interventions for preventing falls in older people living in the community. Cochrane Database Syst Rev 9:CD007146
Uusi-Rasi K, Patil R, Karinkanta S, Kannus P, Tokola K, Lamberg-Allardt C, Sievanen H (2015) Exercise and vitamin D in fall prevention among older women: a randomized clinical trial. JAMA Intern Med 175:703–711
Sanders KM, Stuart AL, Williamson EJ, Simpson JA, Kotowicz MA, Young D, Nicholson GC (2010) Annual high-dose oral vitamin D and falls and fractures in older women: a randomized controlled trial. JAMA 303:1815–1822
Bischoff-Ferrari HA, Dawson-Hughes B, Orav EJ, Staehelin HB, Meyer OW, Theiler R, Dick W, Willett WC, Egli A (2016) Monthly high-dose vitamin D treatment for the prevention of functional decline: a randomized clinical trial. JAMA Intern Med 176:175–183
Gallagher JC (2016) Vitamin D and falls—the dosage conundrum. Nat Rev Endocrinol
Bolland MJ, Barber PA, Doughty RN, Mason B, Horne A, Ames R, Gamble GD, Grey A, Reid IR (2008) Vascular events in healthy older women receiving calcium supplementation: randomised controlled trial. BMJ 336:262–266
Bjelakovic G, Gluud LL, Nikolova D, Whitfield K, Wetterslev J, Simonetti RG, Bjelakovic M, Gluud C (2014) Vitamin D supplementation for prevention of mortality in adults. Cochrane Database Syst Rev 1:CD007470
Lewis JR, Zhu K, Prince RL (2012) Adverse events from calcium supplementation: relationship to errors in myocardial infarction self-reporting in randomized controlled trials of calcium supplementation. J Bone Miner Res 27:719–722
Bolland MJ, Avenell A, Baron JA, Grey A, MacLennan GS, Gamble GD, Reid IR (2010) Effect of calcium supplements on risk of myocardial infarction and cardiovascular events: meta-analysis. BMJ 341:c3691
Prince RL, Devine A, Dhaliwal SS, Dick IM (2006) Effects of calcium supplementation on clinical fracture and bone structure: results of a 5-year, double-blind, placebo-controlled trial in elderly women. Arch Intern Med 166:869–875
Bolland MJ, Grey A, Avenell A, Gamble GD, Reid IR (2011) Calcium supplements with or without vitamin D and risk of cardiovascular events: reanalysis of the Women’s Health Initiative limited access dataset and meta-analysis. BMJ 342:d2040
Lewis JR, Radavelli-Bagatini S, Rejnmark L, Chen JS, Simpson JM, Lappe JM, Mosekilde L, Prentice RL, Prince RL (2015) The effects of calcium supplementation on verified coronary heart disease hospitalization and death in postmenopausal women: a collaborative meta-analysis of randomized controlled trials. J Bone Miner Res 30:165–175
Rosamond WD, Sprafka JM, McGovern PG, Nelson M, Luepker RV (1995) Validation of self-reported history of acute myocardial infarction: experience of the Minnesota Heart Survey Registry. Epidemiology 6:67–69
Colditz GA, Martin P, Stampfer MJ, Willett WC, Sampson L, Rosner B, Hennekens CH, Speizer FE (1986) Validation of questionnaire information on risk factors and disease outcomes in a prospective cohort study of women. Am J Epidemiol 123:894–900
Bolland MJ, Grey A, Reid IR (2013) Calcium supplements and cardiovascular risk: 5 years on. Therapeutic advances in drug safety 4:199–210
Larsen ER, Mosekilde L, Foldspang A (2004) Vitamin D and calcium supplementation prevents osteoporotic fractures in elderly community dwelling residents: a pragmatic population-based 3-year intervention study. J Bone Miner Res 19:370–378
Mao PJ, Zhang C, Tang L, Xian YQ, Li YS, Wang WD, Zhu XH, Qiu HL, He J, Zhou YH (2013) Effect of calcium or vitamin D supplementation on vascular outcomes: a meta-analysis of randomized controlled trials. Int J Cardiol 169:106–111
Hsia J, Heiss G, Ren H et al (2007) Calcium/vitamin D supplementation and cardiovascular events. Circulation 115:846–854
Cauley JA, Chlebowski RT, Wactawski-Wende J, Robbins JA, Rodabough RJ, Chen Z, Johnson KC, O’Sullivan MJ, Jackson RD, Manson JE (2013) Calcium plus vitamin D supplementation and health outcomes five years after active intervention ended: the Women’s Health Initiative. J Women’s Health 22:915–929
Manson JE, Allison MA, Carr JJ et al (2010) Calcium/vitamin D supplementation and coronary artery calcification in the Women’s Health Initiative. Menopause 17:683–691
Rejnmark L, Avenell A, Masud T, et al. (2012) Vitamin D with calcium reduces mortality: patient level pooled analysis of 70,528 patients from eight major vitamin D trials. J Clin Endocrinol Metab 97:2670–2681
Avenell A, MacLennan GS, Jenkinson DJ et al (2012) Long-term follow-up for mortality and cancer in a randomized placebo-controlled trial of vitamin D(3) and/or calcium (RECORD trial. J Clin Endocrinol Metab 97:614–622)
Reid IR, Bolland MJ (2008) Calcium supplementation and vascular disease. Climacteric: the journal of the International Menopause Society 11:280–286
Heaney RP, Kopecky S, Maki KC, Hathcock J, Mackay D, Wallace TC (2012) A review of calcium supplements and cardiovascular disease risk. Adv Nutr (Bethesda, Md) 3:763–771
Lind L, Skarfors E, Berglund L, Lithell H, Ljunghall S (1997) Serum calcium: a new, independent, prospective risk factor for myocardial infarction in middle-aged men followed for 18 years. J Clin Epidemiol 50:967–973
Jorde R, Sundsfjord J, Fitzgerald P, Bonaa KH (1999) Serum calcium and cardiovascular risk factors and diseases: the Tromso study. Hypertension 34:484–490
Tonelli M, Sacks F, Pfeffer M, Gao Z, Curhan G (2005) Relation between serum phosphate level and cardiovascular event rate in people with coronary disease. Circulation 112:2627–2633
Dhingra R, Sullivan LM, Fox CS, Wang TJ, D’Agostino RB Sr, Gaziano JM, Vasan RS (2007) Relations of serum phosphorus and calcium levels to the incidence of cardiovascular disease in the community. Arch Intern Med 167:879–885
Foley RN, Collins AJ, Ishani A, Kalra PA (2008) Calcium-phosphate levels and cardiovascular disease in community-dwelling adults: the Atherosclerosis Risk in Communities (ARIC) Study. Am Heart J 156:556–563
Larsson TE, Olauson H, Hagstrom E, Ingelsson E, Arnlov J, Lind L, Sundstrom J (2010) Conjoint effects of serum calcium and phosphate on risk of total, cardiovascular, and noncardiovascular mortality in the community. Arterioscler Thromb Vasc Biol 30:333–339
Slinin Y, Blackwell T, Ishani A, Cummings SR, Ensrud KE (2011) Serum calcium, phosphorus and cardiovascular events in post-menopausal women. Int J Cardiol 149:335–340
Rohrmann S, Garmo H, Malmstrom H, Hammar N, Jungner I, Walldius G, Van Hemelrijck M (2016) Association between serum calcium concentration and risk of incident and fatal cardiovascular disease in the prospective AMORIS study. Atherosclerosis 251:85–93
Kim WS, Lee DH, Youn HJ (2013) Calcium-phosphorus product concentration is a risk factor of coronary artery disease in metabolic syndrome. Atherosclerosis 229:253–257
Gronhoj MH, Gerke O, Mickley H, Steffensen FH, Lambrechtsen J, Sand NP, Rasmussen LM, Olsen MH, Diederichsen A (2016) Associations between calcium-phosphate metabolism and coronary artery calcification; a cross sectional study of a middle-aged general population. Atherosclerosis 251:101–108
Foley RN, Collins AJ, Herzog CA, Ishani A, Kalra PA (2009) Serum phosphorus levels associate with coronary atherosclerosis in young adults. Journal of the American Society of Nephrology: JASN 20:397–404
Shiraki M, Sugimoto T, Nakamura T (2013) Effects of a single injection of teriparatide on bone turnover markers in postmenopausal women. Osteoporos Int 24:219–226
Neer RM, Arnaud CD, Zanchetta JR et al (2001) Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N Engl J Med 344:1434–1441
Nardi A, Ventura L, Cozzi L, Tonini G, Zennaro R, Celi M, Ramazzina E (2013) The bone anabolic therapy. Aging Clin Exp Res 25(Suppl 1):S121–S124
Reginster JY, Brandi ML, Cannata-Andia J, Cooper C, Cortet B, Feron JM, Genant H, Palacios S, Ringe JD, Rizzoli R (2015) The position of strontium ranelate in today’s management of osteoporosis. Osteoporos Int 26:1667–1671
Otsuka F, Yasuda S, Noguchi T, Ishibashi-Ueda H (2016) Pathology of coronary atherosclerosis and thrombosis. Cardiovascular diagnosis and therapy 6:396–408
Reid IR, Mason B, Horne A, Ames R, Clearwater J, Bava U, Orr-Walker B, Wu F, Evans MC, Gamble GD (2002) Effects of calcium supplementation on serum lipid concentrations in normal older women: a randomized controlled trial. Am J Med 112:343–347
Reid IR, Ames R, Mason B, Bolland MJ, Bacon CJ, Reid HE, Kyle C, Gamble GD, Grey A, Horne A (2010) Effects of calcium supplementation on lipids, blood pressure, and body composition in healthy older men: a randomized controlled trial. Am J Clin Nutr 91:131–139
Denke MA, Fox MM, Schulte MC (1993) Short-term dietary calcium fortification increases fecal saturated fat content and reduces serum lipids in men. J Nutr 123:1047–1053
Bell L, Halstenson CE, Halstenson CJ, Macres M, Keane WF (1992) Cholesterol-lowering effects of calcium carbonate in patients with mild to moderate hypercholesterolemia. Arch Intern Med 152:2441–2444
Griffith LE, Guyatt GH, Cook RJ, Bucher HC, Cook DJ (1999) The influence of dietary and nondietary calcium supplementation on blood pressure: an updated metaanalysis of randomized controlled trials. Am J Hypertens 12:84–92
Floege J (2016) Phosphate binders in chronic kidney disease: a systematic review of recent data. Journal of nephrology 29:329–340
Shroff RC, McNair R, Skepper JN, Figg N, Schurgers LJ, Deanfield J, Rees L, Shanahan CM (2010) Chronic mineral dysregulation promotes vascular smooth muscle cell adaptation and extracellular matrix calcification. Journal of the American Society of Nephrology: JASN 21:103–112