Does calcium kill ESRD patients—the skeptic's perspective

Joseph A. Coladonato1, Lynda A. Szczech1, Eli A. Friedman2 and William F. Owen, Jr1,

1 Duke Institute of Renal Outcomes Research and Health Policy, Duke University Medical Center, Durham, NC and 2 Downstate Medical Center, Brooklyn, NY, USA

Keywords: calcium-containing phosphate binders; end-stage renal disease; vascular calcification

Recently, there has been intense interest in vascular calcification and the use of calcium-containing phosphate binders for patients with end-stage renal disease (ESRD). A multi-centre trial evaluating the role of calcium-containing phosphate binders vs non-calcium, non-aluminum-containing binders and the progression of coronary calcification by electron beam computerized tomography (EBCT) has been underway for approximately 1 year. The interim results support observational data that the administration of calcium salts is associated with progressive coronary calcification, in contrast to non-calcium containing binders [1].

Vascular calcification occurs at two pathologic sites: in the intima, where it is invariably associated with atherosclerosis, and in the tunica media, where it is relevant to loss of vascular elasticity and compliance [2]. Medial calcification, also known as Mönckeberg's sclerosis, is common and so may occur independently of atherosclerosis, thus implying different aetiological mechanisms from intimal calcification [2]. It has been posited that accelerated vascular calcification of the intima is provoked in ESRD patients by the putative systemic calcium load arising from the use of calcium-containing phosphate binders, and thus contributes to patients' increased cardiovascular morbidity and mortality. While there is some clinical evidence to support this contention, these associations are circumstantial and fraught with considerable confounding on critical examination.

Coronary artery calcification may be a highly reliable predictor of atherosclerotic coronary artery disease among the general population [3,4] and can be measured by non-invasive techniques such as conventional computed tomography [57], spiral computed tomography [8], ultra-fast, EBCT [912], and fluoroscopy [1318]. ESRD patients have an exaggerated risk of cardiac events and mortality [1925], and some patients are observed to have a 2.5–5-fold increase in coronary artery calcium scores compared with non-dialysis patients [26]. For example, in a relatively small, observational cohort study, it was reported that coronary artery calcification was common and progressive among young ESRD patients [27]. In this cohort, increased coronary artery calcification was directly associated with reported oral calcium intake; patients with progressive calcifications were prescribed almost 2-fold greater amounts of calcium in phosphate binders compared with patients with calcium scores within the normal range. Interestingly, parathyroid hormone (PTH) levels did not correlate with coronary calcifications. Similarly, in another small observational study, it was observed that carotid artery compliance and vascular calcifications were positively associated with reported calcium ingestion among ESRD patients [28]. PTH levels, however, were negatively correlated with calcium scores. Based on these studies, and an unproven chain of logic, calcium salts have been incriminated as provocateurs for vascular calcification. Moreover, some clinical thought leaders have advocated for the virtual abandonment of calcium-containing phosphate binders in exchange for newer, more costly, non-calcium, non-aluminum, non-magnesium containing agents.

Although the pathobiologic chain of logic appears sound, we urge that the renal community be circumspect of the putative, isolated role of calcium salts in the pathobiology of coronary artery calcification. Several troubling issues impugn the interpretation of the associations, such as: (i) a flawed causal pathway linking calcium ingestion to intimal calcifications; (ii) the occurrence of coronary artery calcifications in patients not exposed to calcium salts as phosphate binders; (iii) the absence of uniformity of the associations between changes in divalent ion concentrations, PTH level, and extent of intimal calcifications; (iv) limitations of study design in those cases in which an association with reported calcium intake is reported; and (v) the assumption that coronary artery calcification is a suitable surrogate outcome for clinically relevant atherosclerotic cardiovascular disease. We will examine each of these issues.

First, calcium-containing phosphate binders are purported to be a dietary source of excessive amounts of the elemental calcium contributing to the development and progression of coronary artery calcification. This physiologic scenario is plausible if calcium-containing salts are ingested in excess or incorrectly timed with meals. The pathobiologic model predicts that the serum calcium concentration will be positively associated with coronary calcification in ESRD patients. However, when ingested properly, calcium salts dissociate and form a relatively insoluble complex with dietary phosphorus in the gastrointestinal tract [29,30]. The calcium is thereby sequestered, so that substantial amounts are unavailable for absorption. We suggest that if systemic hypercalcaemia is a major provocateur for arterial calcification, an alternative exogenous source of calcium should be considered, such as the dialysate. Current data suggests that dialysis patients with normal pre-dialysis serum calcium concentrations are in negative calcium balance with a 1.25 mmol/l dialysate calcium concentration and in balance when treated with 1.5 mmol/l dialysate calcium concentration, respectively [31]. Therefore, it is likely that positive calcium balances develops when patients are routinely exposed to the more conventional dialysate calcium concentrations of >=2 mmol/l. Thus, if a pathobiologic link exists between calcium loads and arterial calcification in standard contemporary clinical practice, the dialysate should be scrutinized, as well. It is noteworthy that the serum calcium concentration does not correlate with death risk, nor are serum calcium concentrations elevated in studies quantifying coronary calcification in ESRD patients [26,27,32].

An alternative mechanism(s) for accelerating coronary artery calcification, unrelated to calcium-containing phosphate binders is suggested by the observation that patients with more coronary calcification had reduced skeletal mass [26]. It is suggested that the pathobiology may involve calcium mobilization from bone, rather than external loading, or that bone buffering of a calcium load may be limiting. The skeletal system has extensive buffering capacity for serum calcium levels, which may be attenuated, during states of low-bone turnover [33]. An increased exogenous calcium load may contribute to increased vascular calcification in the setting of such low-bone turnover states. It is noteworthy that adynamic bone disease is common in surveys of bone pathology among ESRD patients and that patients with this abnormality were found to have abnormal calcium homeostasis [34] and higher morbidity and mortality rates than patients exhibiting other histological abnormalities [35].

Other processes associated with ESRD may account for accelerated atherosclerotic calcification and define its extent. Alternative and more likely provocateurs include other prevalent and severe atherogenic abnormalities in ESRD, such as oxidative damage to the endothelium, quantitative and qualitative abnormalities of lipoproteins, and/or hyperhomocysteinaemia [36]. This is further supported by the fact that intimal calcification occurs exclusively in atherosclerotic arteries present soon after fatty streak formation [37] and is absent in normal vessel wall [38,39].

Limiting the interpretation of the relationship between atherosclerotic plaque calcification and clinical outcomes is the uncertainty of its prognostic meaning. For example, some studies suggest that plaque calcification may be protective, despite its statistical association with increased morbidity [40]. This hypothesis has been supported by studies of human atherosclerotic plaques which have revealed that calcification does not decrease the mechanical stability of the coronary atheroma as does lipid inclusion [41]. Moreover, there was an inverse relationship between the per cent area of calcification and maximum principal stress. Alternatively, there was a significant positive correlation between stress and per cent area of lipid. These findings are consistent with the success of lipid-lowering therapies in the prevention of coronary events [42] and may challenge the utility of therapies targeted against calcified lesions as opposed to those treating the systemic manifestations of atherosclerosis, specifically inflammation, intimal injury, and dyslipidaemia.

In view of the atherogenic milieu associated with ESRD, it is unsurprising that cardiac calcifications and an excessive cardiovascular mortality were observed in dialysis patients decades before the prevalent use of calcium-containing phosphate binders [43]. Many of these historic patients received aluminum-based phosphate binders and had hyperphosphataemia and secondary hyperparathyroidism with hypocalcaemia [4345]. Therefore, it is predictable that the degree of coronary artery calcification does not correlate with serum calcium, phosphorus, or PTH levels in a recent study [27]. In contrast, several data sets have demonstrated a significant increase in mortality risk associated with elevated serum phosphate concentrations, especially for values >6.5 mg/dl and [calcium]x[phosphate] >72 mg2/dl2 [32,46]. The inconstancy of the statistical associations between divalent ions and coronary calcifications may be affected by differences among patient cohorts across studies, associations due to co-linearity in disease processes rather than causality, and/or limitations of study designs.

This fourth issue of study design limitations substantially compromises putative pathobiologic links to calcium-containing phosphate binders. The preponderance of studies examining the relationship between calcium-containing phosphate binders and coronary artery calcifications are cross-sectional and observational. Although hypothesis generating based on the security of the described statistical associations, the burden of proof for causality is not met by this analytic design. In addition, because of their uniform small size, they may not be adequately powered to detect other possible relationships in the pathobiology of coronary artery calcification and to exclude statistical confounders. For example, reported calcium intake may be a surrogate for the severity of hyperparathyroidism. Because the latter is a time-dependent, continuous measure, whose risk may be non-linear and persist even after levels have been normalized, small cross-sectional or short longitudinal trials may not be adequately powered.

A particularly troubling limitation of these previous analyses is their uniform reliance on reported or prescribed calcium intake, rather than measured amounts. Repeated voluntary non-adherence with ingestion of calcium-containing phosphate binders has been reported in 65–80% of dialysis patients [47]. Let us assume that many patients in a trial overstate their compliance with their calcium-containing phosphate binder. Because a benchmark reduction in the serum phosphorus concentration is not achieved, the prescribed dose of calcium salt is increased. Using a similar chain of logic, such patients may have accelerated calcification related to poor phosphorus control and/or its consequences. However, an analysis that fails to account for a disparity between the prescribed and the ingested dose of calcium may detect a misleading statistical association with higher doses of calcium.

A final concern is the uncertainty about the clinical consequences of coronary calcifications among patients with ESRD. EBCT has a high sensitivity for detecting the presence of calcified coronary artery lesions. However, its specificity, clinical application, and reproducibility remains unclear [48]. Hence, it is unsurprising that the American Heart Association has not reached a consensus on the application of EBCT as a screening tool for patients with normal renal function. If its ability to predict future cardiovascular events in healthy patients is unknown, even less is understood among patients with ESRD.

Warnings of putative dangers associated with calcium-containing phosphate binders seem premature and perhaps even misplaced in context of the trade-off of risks documented with some, alternative non-calcium containing binders. Prior to the use of calcium salts for controlling phosphorus, ESRD patients were at risk from aluminum intoxication syndromes such as osteomalacia, anemia, and encephalopathy. As advocated by some nephrology thought leaders, the wholesale abandonment of calcium salts may result in hypocalcaemia and the increased emergence of osteopenic bone disease. Moreover, it is important to recognize that differences exist in the efficacy of calcium-containing phosphate binders, which results in differences in the systemic calcium load. Phosphate binders such as calcium acetate have a greater affinity for dietary phosphorus with half the elemental calcium concentration of calcium carbonate [29]. Therefore, with a reduced systemic calcium load, calcium acetate is relatively more effective at lowering the serum phosphorus and PTH concentration, and [calcium]x[phosphorus] [4951].

Clearly, there is a need for prospective, randomized control trials of three types in this area. First, trials need to be conducted to examine the pathobiology of coronary calcification in chronic kidney disease and ESRD. Such studies should examine the difference in rates of calcification as a function of calcium containing vs calcium-free phosphate binders, while controlling for hyperphosphataemia, hypercalcaemia, hyperlipidaemia, and hyperparathyroidism. Secondly, trials need to be conducted to examine the effects of interventions directed toward altering processes associated with ESRD known to induce intimal injury and propagate atherosclerosis such as dyslipidaemia, inflammation, and hyperhomocysteinaemia. Finally, there is a need for outcome-based trials using clinical cardiac events as primary outcomes, rather than intermediate measures like coronary calcification as study endpoints. Until such scientific research is completed, the wholesale abandonment of calcium-containing phosphate binders may be unwarranted given the current level of understanding and scientific evidence.

Notes

Correspondence and offprint requests to: Dr Joseph A. Coladonato, Duke Institute of Renal Outcomes Research and Health Policy, Box 3646, Duke University Medical Center, Durham, NC 27710, USA. Email: joe.coladonato{at}duke.edu Back

References

  1. Press Releases Genzyme General (Nasdaq:GENZ), June 26, 2001: Genzyme study demonstrates significant impact of Renagel® on cardiac calcification. www.genzyme.com/ir/genz/press/20010626.html
  2. Stehbens WE. Atherosclerosis and degenerative diseases of blood vessels. In: Stehbens WE, Lie JT, &!lpar;eds&!rpar;. Vascular Pathology. Chapman & Hall Medical, London, UK, 1995; 177–269
  3. Blankenhorn DH. Coronary arterial calcification: a review. Am J Med Sci1961; 242: 41–49
  4. Frink RJ, Achor RW, Brown AL, Kincaid OW, Brandenburgh RO. Significance of calcification of the coronary arteries. Am J Cardiol1970; 26: 241–247[ISI][Medline]
  5. Timmins ME, Pinsk R, Sider L, Bear G. The functional significance of calcification of coronary arteries as detected on CT. J Thorac Imaging1991; 7: 79–82[ISI][Medline]
  6. Rienmuller R, Lipton MJ. Detection of coronary artery calcification by computed tomography. Dynam Cardiovasc Imaging1987; 1: 139–145
  7. Masuda Y, Naito S, Aoyagi Y et al. Coronary artery calcification detected by CT: clinical significance and angiographic correlates. Angiology1990; 41: 1037–1047[ISI][Medline]
  8. Shemesh J, Apter S, Rozenman J et al. Calcification of coronary arteries: detection and quantification with double-helix CT. Radiology1995; 197: 779–783[Abstract]
  9. Achenbach S, Moshage W, Ropers D, Nossen J, Daniel WG. Value of electron-beam computed tomography for the noninvasive detection of high-grade coronary-artery stenoses and occlusions. N Engl J Med1998, 339: 1964–1971[Abstract/Free Full Text]
  10. Mautner SL, Mautner GC, Froehlich J. Coronary artery disease: prediction with in vitro electron beam CT. Radiology1994; 192: 625–630[Abstract]
  11. Rumberger JA, Sheedy PM III, Breen JF, Schwartz RS. Coronary calcium as determined by electron beam computed tomography and coronary disease on arteriogram: effect of patient's sex on diagnosis. Circulation1995; 91: 1363–1367[Abstract/Free Full Text]
  12. Rumberger JA, Schwartz RS, Simons DB, Sheedy PF III, Edwards WD, Pitzpatrick LA. Relation of coronary calcium determined by computed tomography and lumen narrowing determined by autopsy. Am J Cardiol1994; 73: 1169–1173[ISI][Medline]
  13. Bartel AG, Chen JT, Peter RH, Behar VS, Kong Y, Lester RG. The significance of coronary calcification detected by fluoroscopy: a report of 360 patients. Circulation1974; 49: 1247–1253[ISI][Medline]
  14. Hamby RI, Tabrah F, Wisoff BG, Hartstein ML. Coronary artery calcification: clinical implications and angiographic correlates. Am Heart J1974; 87: 565–570[ISI][Medline]
  15. Aldrich RF, Brensike JF, Battaglini JW et al. Coronary calcifications in the detection of coronary artery disease and comparison with electrocardiographic exercise testing: results from the National Heart, Lung and Blood Institute's type II coronary intervention study. Circulation1979; 59: 1113–1124[ISI][Medline]
  16. Margolis JR, Chen JT, Kong Y, Peter RH, Behar VS, Kisslo JA. The diagnostic and prognostic significance of coronary artery calcification: a report of 800 cases. Radiology1980; 137: 609–616[Abstract]
  17. Hung J, Chaitman BR, Lam J et al. Noninvasive diagnostic test choices for the evaluation of coronary artery disease in women: a multivariate comparison of cardiac fluoroscopy, exercise electrocardiography, and exercise thallium myocardial perfusion scintigraphy. J Am Coll Cardiol1984; 4: 8–16[ISI][Medline]
  18. Detrano R, Salcedo EE, Hobbs RE, Yiannikas J. Cardiac cinefluoroscopy as an inexpensive aid in the diagnosis of coronary artery disease. Am J Cardiol1986; 57: 1041–1046[ISI][Medline]
  19. Patient mortality and survival. In: Renal Data System. USRDS 1998 Annual Data Report. National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, 1999; 63–78
  20. Causes of death. In: Renal Data System. USRDS 1998 Annual Data Report. National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, 1999; 79–90
  21. Silverberg JS, Barre PE, Prichard SS, Sniderman AD. Impact of LVH on survival in end-stage renal disease. Kidney Int1989; 36: 286–290[ISI][Medline]
  22. Foley RN, Parfrey PS, Harnett JD. Clinical and echocardiographic disease in patients starting end-stage renal disease therapy. Kidney Int1995; 47: 186–192[ISI][Medline]
  23. Foley RN, Parfrey PS, Harnett JD, Kent GM, Murray DC, Barre PE. The prognostic importance of left ventricular geometry in uremic cardiomyopathy. J Am Soc Nephrol1995; 5: 2024–2031[Abstract]
  24. Harnett JD, Foley RN, Kent GM, Barre PE, Murray D, Parfrey PS. Congestive heart failure in dialysis patients: prevalence, incidence, prognosis, and risk factors. Kidney Int1995; 47: 884–890[ISI][Medline]
  25. Parfrey PS, Foley RN, Harnett JD, Kent GM, Murray D, Barre P. Outcome and risk factors of ischemic heart disease in chronic uremia. Kidney Int1996; 49: 1428–1434[ISI][Medline]
  26. Braun J, Oldendorf M, Moshage W, Heidler R, Zeitler E, Luft FC. Electron beam computed tomography in the evaluation of cardiac calcifications in chronic dialysis patients. Am J Kidney Dis1996; 27: 394–401[ISI][Medline]
  27. Goodman WG, Goldin J, Kuizon BD et al. Coronary-artery calcification in young adults with end-stage renal disease who are undergoing dialysis. N Engl J Med2000; 342: 1478–1483[Abstract/Free Full Text]
  28. Guerin AP, London GM, Marchais SJ, Metivier F. Arterial stiffening and vascular calcifications in end-stage renal disease. Nephrol Dial Transplant2000; 15: 1014–1021[Abstract/Free Full Text]
  29. Emmett M, Sirmon MD, Kirkpatrick WG, Nolan CR, Schmitt GW, Cleveland MvB. Calcium acetate control of serum phosphorus in hemodialysis patients. Am J Kidney Dis1991; 17: 544–550[ISI][Medline]
  30. Mai ML, Emmett M, Sheikh MS, Santa Ana CA, Schiller L, Fordtran JS. Calcium acetate, an effective phosphorus binder in patients with renal failure. Kidney Int1989; 36: 690–695[ISI][Medline]
  31. Argiles A, Mion CM. Calcium balance and intact parathormone variations during hemodiafiltration. Nephrol Dial Transplant1995; 10: 2083–2089[Abstract]
  32. Block GA, Hulbert-Shearon TE, Levin NW, Port FK. Association of serum phosphorus and calciumxphosphate product with mortality risk in chronic hemodialysis patients: a national study. Am J Kidney Dis1998; 31: 607–617[ISI][Medline]
  33. Meric F, Yap P, Bia MJ. Etiology of hypercalcemia in hemodialysis patients on calcium carbonate therapy. Am J Kidney Dis1990; 16: 459–464[ISI][Medline]
  34. Kurz P, Monier-Faugere M-C, Bognar B et al. Evidence for abnormal calcium homeostasis in patients with adynamic bone disease. Kidney Int1994; 46: 855–861[ISI][Medline]
  35. Hercz G, Sherrard DJ, Chan W, Pei Y. Aplastic osteodystrophy: follow-up after 5 years [abstract]. J Am Soc Nephrol1994; 5: 851
  36. London G, Drüeke TB. Atherosclerosis and arteriosclerosis in chronic renal failure. Kidney Int1997; 51: 1678–1695[ISI][Medline]
  37. Stary HC. The sequence of cell and matrix changes in atherosclerotic lesions of coronary arteries in the first forty years of life. Eur Heart J1990; 11 [Suppl E]: 3–19[ISI][Medline]
  38. Schwartz U, Buzello M, Ritz E et al. Morphology of coronary atherosclerotic lesions in patients with end-stage renal disease. Nephrol Dial Transplant2000; 15: 218–223[Abstract/Free Full Text]
  39. Wexler L, Brundage B, Crouse J et al. Coronary artery calcification: pathophysiology, epidemiology, imaging methods, and clinical implications. A statement for health professionals from the American Heart Association Writing Group. Circulation1996; 94: 1175–1192[Free Full Text]
  40. Fitzgerald PJ, Ports TA, Yock PG. Contribution of localized calcium deposits to dissection after angioplasty: an observational study using intravascular ultrasound. Circulation1992; 86: 64–70[Abstract]
  41. Huang H, Virmani R, Younis H, Burke AP, Kamm RD, Lee RT. The impact of calcification on the biomechanical stability of atherosclerotic plaques. Circulation2001; 103: 1051–1056[Abstract/Free Full Text]
  42. Vaughan CJ, Gotto AM Jr, Basson CT. The evolving role of statins in the management of atherosclerosis. J Am Coll Cardiol2000; 35: 1–10[ISI][Medline]
  43. Kuzela DC, Huffer WE, Conger JD, Winter SD, Hammond WS. Soft tissue calcification in chronic dialysis patients. Am J Pathol1977; 86: 403–417[Abstract]
  44. Anderson DC, Stewart WK, Piercy DM. Calcifying panniculitis with fat and skin necrosis in a case of uremia with autonomous hyperparathyroidism. Lancet1968; 2: 323–325[Medline]
  45. Terman DS, Alfrey AC, Hammond WS, Donndelinger T, Ogden DA, Holmes JH. Cardiac calcification in uremia: a clinical, biochemical and pathologic study. Am J Med1971; 50: 744–755[ISI][Medline]
  46. Owen WF, Lowrie EG. C-reactive protein as an outcome predictor for maintenance hemodialysis patients. Kidney Int1998; 54: 627–636[ISI][Medline]
  47. Curtin RB, Svarstad BL, Andress D, Keller T, Sacksteder P. Geriatr Nephrol Urol1997; 7: 35–44[Medline]
  48. O'Rourke RA, Brundage BM, Froelicher VF et al. American College of Cardiology/American Heart Association expert consensus document on electron-beam computed tomography for the diagnosis and prognosis of coronary artery disease. Circulation2000; 101: 126–140
  49. Pflanz S, Henderson IS, McElduff N, Jones MC. Calcium acetate versus calcium carbonate as phosphate-binding agents in chronic hemodialysis. Nephrol Dial Transplant1994; 9: 1121–1124[Abstract]
  50. Ring T, Nielsen C, Andersen SP, Behrens JK, Sodemann B, Kornerup HJ. Calcium acetate versus calcium carbonate as phosphorus binders in patients on chronic hemodialysis: a controlled study. Nephrol Dial Transplant1993; 8: 341–346[Abstract]
  51. Schaefer K, Scheer J, Asmus G, Umlauf E, Hagemann J, von Herrath D. The treatment of uremic hyperphosphatemia with calcium acetate and calcium carbonate: a comparative study. Nephrol Dial Transplant1991; 6: 170–175[Abstract]
  52. Antonsen JE, Sherrard DJ, Andress DL. A calcimimetic agent acutely suppresses parathyroid hormone levels in patients with chronic renal failure. Kidney Int1998; 53: 223–227[ISI][Medline]