Review
Disordered Mineral Metabolism and Vascular Calcification in Nondialyzed Chronic Kidney Disease Patients

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It is well established that abnormalities in mineral metabolism are apparent early in the course of chronic kidney disease (CKD) and result in clinically relevant consequences such as renal osteodystrophy. Furthermore, there is emerging evidence linking some of these abnormalities (hyperphosphatemia) to the high cardiovascular morbidity and mortality experienced by nondialyzed patients with CKD. Most studies have evaluated vascular calcification in patients with stage 5 CKD. Reports published over the last 2 years show that the process begins rather early in CKD and is particularly severe among elderly and type 2 diabetic patients. Furthermore, “calcium begets calcium”, such that the calcification burden in early CKD is an important predictor of subsequent progression, including the rapid increase seen in stage 5 CKD. There is an increasing body of evidence that supports the thesis that elevated serum levels of phosphorus and calcium and deficiency of inhibitors of calcification (for example, fetuin-A) are important in the progression of vascular calcification in patients with end-stage renal disease. However, the concentrations of calcium and phosphorus shown to induce mineralization in cell culture studies are not observed in most patients until late in stage 4 or stage 5 CKD. Cross-sectional and longitudinal studies have also been unable to show a correlation between serum levels of markers of disordered mineral metabolism and severity of vascular calcification. Future studies should evaluate the pathogenetic role of phosphorus retention, which occurs early in the course of CKD, in the induction and/or progression of vascular calcification. Finally, there is a need to identify alternative pathogenetic mechanisms that may be important causes of the high calcification burden observed early in CKD.

Section snippets

Is There Disordered Mineral Metabolism in Nondialyzed Patients With CKD

In the care of patients with CKD, disordered mineral metabolism is monitored by the measurement of serum levels of divalent ions such as Ca and P and hormones like PTH.1, 2 Not too long ago, the serum levels of markers of disordered mineral metabolism were viewed largely as surrogates for bone turnover and health, and the acceptable range for each of these parameters was defined as one that was expected to result in the normalization of bone metabolism.1 However, recent studies have

Vascular Calcification in Nondialyzed Patients With CKD

Under normal circumstances, there is usually no detectable calcification in the blood vessel walls. In pathologic states, calcification can occur in either the intima or the media of the vessel walls, and the term VC is used to refer to either of the 2 clinical entities. The process of vascular calcification, whether intimal or medial, is an active process akin to ossification of the bones.22, 24, 103 Under a variety of stimuli, calcifying vascular cells change from a mesenchymal to an

Is the Vascular Calcification in Nondialyzed Patients With CKD a Consequence of Disordered Mineral Metabolism?

A relationship between mineral metabolism and VC has long been sought in many populations, including but not limited to CKD. In the general population, investigators have been unable to show any relationship between serum Ca, P, and PTH with the severity of VC.122, 131 Some studies, although not all, have shown an inverse relationship between circulating serum 1,25 dihydroxy vitamin D levels and the severity of coronary artery calcification.131, 132, 133 On the other hand, there is a large body

Conclusions

The process of VC begins in early CKD, particularly among the elderly and those with type 2 diabetes. Although the calcification burden is less severe than among patients with ESRD, it is significantly more severe than in age- and gender-matched controls. Furthermore, calcium begets calcium, and among individuals with diabetic nephropathy, the coronary artery calcification burden is an important predictor of future progression, including after the appearance of ESRD. Thus, this early

References (148)

  • S.M. Moe et al.

    Uremia induces the osteoblast differentiation factor Cbfa1 in human blood vessels

    Kidney Int

    (2003)
  • H. Yang et al.

    Elevated extracellular calcium levels induce smooth muscle cell matrix mineralization in vitro

    Kidney Int

    (2004)
  • G.M. Chertow et al.

    Sevelamer attenuates the progression of coronary and aortic calcification in hemodialysis patients

    Kidney Int

    (2002)
  • R. Merjanian et al.

    Coronary Artery, Aortic Wall and Valvular Calcification in Nondialyzed Patients With Type 2 Diabetes and Renal Disease

    Kidney Int

    (2003)
  • R. Mehrotra et al.

    Determinants of coronary artery calcification in diabetic patients with and without nephropathy

    Kidney Int

    (2004)
  • C.S. Fox et al.

    Kidney function is inversely associated with coronary artery calcification in men and women free of cardiovascular diseaseThe Framingham Heart Study

    Kidney Int

    (2004)
  • H.H. Malluche et al.

    Bone histology in incipient and advanced renal failure

    Kidney Int

    (1976)
  • I. Martinez et al.

    The importance of dietary calcium and phosphorus in the secondary hyperparathyroidism of patients with early renal failure

    Am J Kidney Dis

    (1997)
  • M. Rix et al.

    Bone mineral density and biochemical markers of bone turnover in patients with predialysis chronic renal failure

    Kidney Int

    (1999)
  • E. Ishimura et al.

    Serum levels of 1,25-dihydroxyvitamin D, 24,25-dihydroxyvitamin D, and 25-hydroxyvitamin D in nondialyzed patients with chronic renal failure

    Kidney Int

    (1999)
  • J.W. Coburn et al.

    Study of intestinal absorption of calcium in patients with renal failure

    Kidney Int

    (1973)
  • A.K. Cheung et al.

    Determinants of serum 1,25(OH)2D levels in renal disease

    Kidney Int

    (1983)
  • D.M. Kates et al.

    Evidence that serum phosphate is independently associated with serum PTH in patients with chronic renal failure

    Am J Kidney Dis

    (1997)
  • M.P. Marco et al.

    Vitamin D receptor genotype influences parathyroid hormone and calcitriol levels in predialysis patients

    Kidney Int

    (1999)
  • M. Inaba et al.

    Impaired secretion of parathyroid hormone, but not refractoriness of osteoblast, is a major mechanism of low bone turnover in hemodialyzed patients with diabetes mellitus

    Am J Kidney Dis

    (2002)
  • R. Mehrotra et al.

    Age-related decline in serum parathyroid hormone in maintenance hemodialysis patients is independent of inflammation and dietary nutrient intake

    J Ren Nutr

    (2004)
  • C.D. Arnaud

    Hyperparathyroidism and renal failure

    Kidney Int

    (1973)
  • P.W. Lambert et al.

    Urinary and plasma vitamin D3 metabolites in the nephrotic syndrome

    Metab Bone Dis Relat Res

    (1982)
  • J.M. Barragry et al.

    Vitamin-D metabolism in nephrotic syndrome

    Lancet

    (1977)
  • K.G. Koenig et al.

    Free and total 1,25-dihydroxyvitamin D levels in subjects with renal disease

    Kidney Int

    (1992)
  • M.E. Cohen-Solal et al.

    Nonaluminic adynamic bone disease in nondialyzed uremic patientsA new type of osteopathy due to overtreatment?

    Bone

    (1992)
  • A.J. Hutchison et al.

    Correlation of bone histology with parathyroid hormone, vitamin D3, and radiology in end-stage renal disease

    Kidney Int

    (1993)
  • M.L. Bianchi et al.

    Bone mass status in different degrees of chronic renal failure

    Bone

    (1992)
  • E.P. Boling et al.

    Noninvasive measurements of bone mass in adult renal osteodystrophy

    Bone

    (1993)
  • C.Y. Hsu et al.

    Bone mineral density is not diminished by mild to moderate chronic renal insufficiency

    Kidney Int

    (2002)
  • R. Mehrotra et al.

    Metabolic acidosis in maintenance dialysis patientsClinical considerations

    Kidney Int Suppl

    (2003)
  • A. Fine et al.

    Calciphylaxis presenting with calf pain and plaques in four continuous ambulatory peritoneal dialysis patients and in one predialysis patient

    Am J Kidney Dis

    (1995)
  • A.J. Bleyer et al.

    A case control study of proximal calciphylaxis

    Am J Kidney Dis

    (1998)
  • T. Coates et al.

    Cutaneous necrosis from calcific uremic arteriolopathy

    Am J Kidney Dis

    (1998)
  • K/DOQI Clinical practice guidelines for chronic kidney diseaseEvaluation, classification and stratification

    Am J Kidney Dis

    (2002)
  • K/DOQI clinical practice guidelines for bone metabolism and disease in chronic kidney disease

    Am J Kidney Dis

    (2003)
  • S.K. Ganesh et al.

    Association of elevated serum PO(4), Ca × PO(4) product, and parathyroid hormone with cardiac mortality risk in chronic hemodialysis patients

    J Am Soc Nephrol

    (2001)
  • G.A. Block et al.

    Mineral metabolism, mortality, and morbidity in maintenance hemodialysis

    Am Soc Nephrol

    (2004)
  • L.A. Stevens et al.

    Calcium, phosphate, and parathyroid hormone levels in combination and as a function of dialysis duration predict mortalityEvidence for the complexity of the association between mineral metabolism and outcomes

    J Am Soc Nephrol

    (2004)
  • Y. Slinin et al.

    Calcium, phosphorus, parathyroid hormone, and cardiovascular disease in hemodialysis patientsThe USRDS waves 1, 3, and 4 study

    J Am Soc Nephrol

    (2005)
  • R. Virchow

    Kall metastasen

    Virchow Arch

    (1855)
  • R.M. Mulligan

    Metastatic calcification

    Arch Pathol

    (1947)
  • H.E. Meema et al.

    Arterial calcifications in severe chronic renal disease and their relationship to dialysis treatment, renal transplant, and parathyroidectomy

    Radiology

    (1976)
  • D.C. Kuzela et al.

    Soft tissue calcification in chronic dialysis patients

    Am J Pathol

    (1977)
  • J. Oh et al.

    Advanced coronary and carotid arteriopathy in young adults with childhood-onset chronic renal failure

    Circulation

    (2002)
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    Supported by a grant from the National Center for Research Resources (NCRR, NIH), RR18298-01 A1 for Rajnish Mehrotra and grant M01-RR00425 from the NCRR, NIH, for the General Clinical Research Center (GCRC) located at the Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center. Additional support has been provided by Clinical Research Feasibility Funds from the GCRC at Harbor-UCLA and Genzyme Pharmaceuticals.

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