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

Disordered Mineral Metabolism and Vascular Calcification in Nondialyzed Chronic Kidney Disease Patients Rajnish Mehrotra, MD 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. © 2006 by the National Kidney Foundation, Inc.

H

YPERPHOSPHATEMIA, vitamin D deficiency, and secondary hyperparathyroidism are predictable consequences of progressive decreases in glomerular filtration rate (GFR) among patients with chronic kidney disease (CKD).1,2 Until recently, renal osteodystrophy and extraskeletal calcifications were considered to be the principal complications associated with Division of Nephrology and Hypertension, Los Angeles Biomedical Research Institute at Harbor-UCLA, Torrance, CA, and David Geffen School of Medicine at UCLA, Los Angels, CA. 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. Address reprint requests to Rajnish Mehrotra, MD, 1124 West Carson Street, Torrance, CA 90502. E-mail: rmehrotra@ labiomed.org © 2006 by the National Kidney Foundation, Inc. 1051-2276/06/1602-0002$32.00/0 doi:10.1053/j.jrn.2006.01.006

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disordered mineral metabolism of CKD. Several studies over the last 15 years have drawn attention to the possibility that disordered mineral metabolism may contribute to the high mortality seen among end-stage renal disease (ESRD) patients. In an analysis of data from over 12,000 patients, Lowrie and Lew were the first to report that hyperphosphatemia (⬎7 mg/dL) is associated with a progressive increase in the risk for death among patients undergoing maintenance hemodialysis.3 Several studies have now confirmed these initial observations,4-9 and epidemiologic studies suggest that even mildly elevated serum phosphorus (P) concentrations (⬎4.5 to 5.0 mg/dL) confer an increased risk for nonfatal cardiovascular events, cardiovascular mortality, and all-cause mortality.6,9 Similar associations of hyperphosphatemia with all-cause mortality have been shown among patients undergoing chronic peritoneal dialysis.10 Furthermore, although early studies did not show any associations between elevated serum calcium (Ca) or parathyroid hormone (PTH) and mortality,3,4 recent studies are consistent in showing that both hypercalcemia and severe hyperparaJournal of Renal Nutrition, Vol 16, No 2 (April), 2006: pp 100-118

VASCULAR CALCIFICATION IN EARLY CKD

thyroidism (intact PTH levels ⬎480 to 600 pg/ mL) are also independent predictors of nonfatal and fatal cardiovascular events in patients undergoing maintenance hemodialysis.5-9 Thus, disordered mineral metabolism (hyperphosphatemia, hypercalcemia, and hyperparathyroidism) seems to be an independent and unique risk factor for cardiovascular disease among individuals with ESRD. It is important to recognize that the existing body of literature seems to suggest that of all the variables of disordered mineral metabolism that are measured in clinical practice, the greatest increase in cardiovascular risk is conferred by an elevated serum P; increases in serum Ca and PTH seem to amplify this risk.6,7 Like abnormalities in mineral metabolism, vascular calcification (VC) was first reported in CKD patients about 150 years ago.11 Since then, it has been recognized as a ubiquitous complication of CKD, particularly in the presence of ESRD.12-16 It seems that disordered mineral metabolism, especially hyperphosphatemia, is important in the pathogenesis of the accelerated VC in the presence of ESRD.13,16-20 Studies investigating the molecular mechanisms of VC have established it to be an active process in virtually all settings in which it occurs (intimal calcification as in atherosclerosis or medial calcification in the presence of diabetes mellitus and renal failure).21-28 In vitro studies have also shown the potential pathogenetic roles of Ca, P, and other components of the uremic plasma in inducing this active process of VC.28-31 Finally, the extent and/or severity of VC in ESRD patients is associated with increased mortality.32,33 Thus, it seems reasonable to conclude that the accelerated VC may be one of the mechanism by which disordered mineral metabolism contributes to the high nonfatal and fatal cardiovascular event rates experienced by CKD patients. Notwithstanding the evidence showing that the use of sevelamer hydrochloride is associated with the stabilization of VC,34,35 there are no studies that have shown that achieving certain target levels for serum Ca, P, and/or PTH levels will either attenuate or halt the progression of VC or reduce the risk for nonfatal or fatal cardiovascular events in ESRD patients. Like most abnormalities associated with uremia, the processes of disordered mineral metabolism and VC begin early in CKD and are already established in many patients at the time of commencement of maintenance dialysis therapy.1,2,36-38 In this review,

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the current state of knowledge about disordered mineral metabolism and VC in nondialyzed CKD patients is presented and whether the pathogenesis of VC differs in earlier stages of CKD is explored.

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 consistently shown disordered mineral metabolism to be an independent risk factor for cardiovascular disease.3-10,39 It follows, then, that the serum levels of Ca, P, and PTH are important in and of themselves, and it is possible that this may be independent of their effect on bone health. Thus, over the past 1 to 2 years, the debate on defining the acceptable ranges for serum levels of Ca, P, and PTH has expanded its focus from bone health to understanding the levels expected to be associated with maximum cardiovascular risk reduction. These considerations should be borne in mind when interpreting the existing body of literature regarding disordered mineral metabolism in stages 1 through 4 CKD.

Relationship of Disordered Mineral Metabolism to Renal Function Over the years, a large number of investigators have evaluated the relationship between measures of renal function (most often, glomerular filtration rate) with various measures of disordered mineral metabolism. Some of the representative studies are summarized in Table 1.37,39-64 As is evident, the preponderance of evidence suggests that with progressive renal insufficiency, there occurs a decrease in serum levels of Ca and 1,25 dihydroxy vitamin D levels and an increase in serum P and PTH. However, 2 areas have been extensively debated over the last several decades

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RAJNISH MEHROTRA

Table 1. Summary of Published Studies Evaluating the Relationship of Serum Markers for Disordered Mineral Metabolism to Glomerular Filtration Rate in Nondialyzed, Nontransplanted Adult Patients With Chronic Kidney Disease Relationship Between Declining GFR and Serum Levels

Author, year [ref] Measure of renal function: radionuclide GFR Madsen, 197640 Tougaard, 197741 Tessitore, 198742 St John, 199243 Messa, 199544 Measure of renal function: MDRD eGFR De Boer, 200245 Mehrotra, 200437 Measure of renal function: CrCl Coburn, 196946 Massry, 197347 Malluche, 197648 Christensen, 197749 von Lilienfeld-Toal, 198250 Pitts, 198851 Reichel, 199152 Saha, 199453 Fajtova, 199554 Martinez, 199755 Rix, 199956 Measure of renal function: CGF Ishimura, 199957 Hsu, 200258 Kestenbaum, 200539 Measure of renal function: SCr Coburn, 197359 Cheung, 198360 McGonigle, 198461 Coen, 198962 Yumita, 199663 Kates, 199764

No. of Subjects

8 24 41 51 43

Renal Function, Range

2 to 27 5 to 25 20 to ⬎90 ⬍30 to 158

% Diabetic

Calcium

Phosphorus

PTH

25 (OH) D

1,25 di (OH) D

0 0 0 6% 0

↔ 2 – 2 ↔

↔ 1 – 1 ↔

↔ 1 1 1 1

– – – ↔ ↔

– – 2 2 2

218 90

34 (mean) 7 to normal

41% 100%

– 2

– 1

1 1

– –

– 2

103 74 72 89

⬍5 to 100 ⬍20 to normal ⬍5 to ⬎110 UKn

UKn 0 1% UKn

2 2 – –

1 1 1 –

– – – 1

– – – –

– – – –

61 72 85 50 39 157 202

⬍20 to ⬎80 ⬍20 to ⬎95 20 to ⬎90 71 ⫾ 36 3 to 120 10 to ⬎100 6 to ⬎150

UKn 13% 4% 24% 41% UKn 23%

2 2 ↔ ↔ 2 ↔ 2

1 1 1 1 1 ↔ 1

1 1 1 1 1 1 1

– ↔ ↔ ↔ – ↔ –

– 2 2 ↔ 2 2 2

76 14,722 3,295

ⵑ21.5 (mean) ⬍20 to ⬎80 47.2 (mean)

49% UKn 45%

– ↔ –

– 1 1

– – –

↔ – –

2 – –

159 39 60 32 195 84

⬍1.0 to ⬎13.0 3.4 ⫾ 0.3 1.0 to 12.0 6.5 ⫾ 2.9 ⬍1.0 to ⬎8.0 1.2 to ⬎7.0

UKn 8% 15% 0 – 18%

2 ↔ – 2 2 2

1 1 – 1 1 1

– 1 1 1 1 1

– – – ↔ – –

– 2 – 2 2 2

Abbreviations: PTH, parathyroid hormone; 25 (OH) D, 25 hydroxy vitamin D; 1,25 di (OH) vitamin D, 1,25 dihydroxy vitamin D; GFR, glomerular filtration rate; eGFR, estimated glomerular filtration rate; CrCl, creatinine clearance, mL/min; UKn, unknown; CGF, Cockcroft-Gault formula; SCr, serum creatinine, mg/dL.

and a third has regained prominence since the recent publication of the Kidney Disease Outcomes Quality Initiative (K/DOQI) guidelines.2 First, there has been controversy with regard to the level of GFR at which the abnormalities in the serum levels of each of the markers of disordered mineral metabolism first become apparent. Second, the precise interrelationships between

each of 4 measures of disordered mineral metabolism and more specifically, the pathogenesis of secondary hyperparathyroidism that is apparent so early in renal failure, has been hotly debated. Finally, the prevalence and clinical significance of 25 hydroxy vitamin D insufficiency in early CKD has been receiving increased attention since the publication of the K/DOQI guidelines.

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Although a large number of investigators have evaluated the relationship between GFR and disordered mineral metabolism in early CKD, it is important to make a few observations. First, virtually all of these studies have been cross-sectional in nature—such studies, although helpful, do not take into account interindividual and intraindividual variability. The need for longitudinal assessment of these variables would be particularly relevant, for example, in light of emerging knowledge that genetic factors may be important determinants of the relationship between 1,25 dihydroxy vitamin D and GFR as well.65 Second, many of these studies have enrolled individuals already receiving treatment with oral Ca, phosphate binders, and/or vitamin D.39,45,50,51,54,60-62 This, in turn, would result in significant confounding of the relationship between disordered mineral metabolism and GFR. Moreover, several other groups of medications often used for patients with CKD (for example, diuretics) can independently affect the serum levels of some variables. Most of the studies either do not report the data on the use of these medications or the analyses are not controlled for the use of these medications. Finally, most of these studies have enrolled a very small proportion of diabetic patients, now the most common cause of ESRD in many parts of the world. Data from ESRD populations suggest that the presence of diabetes mellitus has an independent effect on disordered

mineral metabolism (with greater tendency toward hypoparathyroidism).66,67 Some although not all studies suggest that diabetes mellitus may also have an independent effect on vitamin D metabolism in early CKD.57,68 On the other hand, some investigators have been unable to show any relationship between diabetic status and serum PTH levels in stages 1 through 4 CKD.45,68 Thus, it is important to systematically evaluate the effect of diabetic status on all aspects of disordered mineral metabolism in early CKD. With the limitations of the currently available studies in mind, the data suggest that among the earliest abnormalities to become apparent with a decrease in GFR are a decrease in serum 1,25 dihydroxy vitamin D and an increase in PTH levels. The serum 1,25 dihydroxy vitamin D levels remain within the normal range in most patients until stage 4 or 5 CKD.37,43,55 However, when compared with individuals with normal renal function, the serum levels of 1,25 dihydroxy vitamin D levels are reduced as early as in stage 2 CKD,37,43,51 and the serum levels decline progressively (albeit remaining within the normal range) with a decrease in GFR (Table 1).37,42-44,51,52,54-57,60,62-64 Moreover, normal serum levels of 1,25 dihydroxy vitamin D in the face of increased PTH levels are abnormal. The preponderance of evidence also suggests that levels of serum PTH begin to increase when the GFR declines to about 60 mL/min.43,45,54 How-

Table 2. Summary of Variables Related to Disordered Mineral Metabolism Among Nondialyzed Patients With Diabetic Nephropathy

Serum phosphorus n K/DOQI goal range, mg/dL Mean (95% CI), mg/dL % above range Serum parathyroid hormone n K/DOQI range, pg/mL Geometric mean (95% CI), pg/mL % above range Serum 25 hydroxy vitamin D n K/DOQI range, ng/mL Insufficiency (16-30 ng/mL), % Mild deficiency (7-15 ng/mL), % Undetectable (⬍7 ng/mL), %

Stage 2

Stage 3

Stage 4

25 – 4.0 (3.7-4.4) 24

38 2.7-4.6 4.4 (4.2-4.6) 32

24 2.7-4.6 4.6 (4.3-4.8) 46

25 – 50 (40-63) 24

38 35-70 60 (48-74) 39

24 70-110 174 (132-229) 71

23 – 48 30 9

37 ⬎30 41 35 16

11 ⬎30 18 54 18

Note. The K/DOQI guidelines have not made any recommendations regarding the desirable range for various measures of disordered mineral metabolism. In this table, the percentages of patients outside the range are based on the recommendations for patients with stage 3 CKD.

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Serum iPTH, pg/ml

1000

500 400 300 200

100

50 40 30 20 10 0

20

40

60

80

100

120

140

Estimated GFR, ml/min/1.73 m2

Figure 1. Relationship of serum parathyroid hormone (pg/mL) to estimated glomerular filtration rate (mL/min/1.73 m2) in 101 nondialyzed, untreated patients with diabetic nephropathy. Serum parathyroid hormone was measured using the chemiluminescent immunometric assay (Nichols Institute, San Juan Capastrino, CA), and the normal range for this assay is 10 to 65 pg/mL. The shaded boxes represent the range for serum phosphorus levels recommended by the Kidney Disease Outcome Quality Initiative for the level of glomerular filtration rate (stage 3: 35 to 70 pg/mL; stage 4: 70 to 110 pg/mL; and stage 5: 150 to 300 pg/mL).

ever, although some studies suggest that serum PTH levels do not increase until the GFR decreases to 20 to 40 mL/min, our studies suggest that elevated serum levels of PTH may be apparent in some individuals with diabetic nephropathy as early as in stage 2 CKD (Table 2, Fig 1).37,55,69 As with 1,25 dihydroxy vitamin D, when compared with non-CKD individuals, the serum levels of P are higher as early as stage 2 or 3 CKD; however, most (although not all) patients are able to maintain serum P levels within the normal range until the GFR decreases to 30 to 40 mL/min (Table 2, Fig 2).37,39,51,54,58 Finally, a decrease in the serum levels of Ca is the last abnormality to appear during the course of progressive CKD, and most patients are able to maintain serum Ca levels within the normal range until the GFR decreases to below 15 to 20 mL/min.37,43,50,51,54,58 The precise temporal relationship between the various parameters of disordered mineral metabolism has been vigorously debated, and a discussion of these issues is beyond the scope of this article.2 The debate has focused largely on how the disordered mineral metabolism associated with CKD leads to secondary hyperparathyroid-

ism.2 The following mechanisms have been considered as potentially important in this regard: (1) phosphate retention (trade-off hypothesis); (2) decreased circulating levels of 1,25 dihydroxy vitamin D, reduced number of vitamin D receptors, and vitamin D resistance associated with uremia; and (3) skeletal resistance to the calcemic action of PTH and reduced number of calcium sensing receptors. It is clear now that each of these mechanisms is not mutually exclusive. For example, recent evidence suggests that subclinical phosphate retention may lead to increased levels of fibroblast growth factor 23—its phosphaturic action may maintain serum phosphorus in the normal range, but as a result of inhibition of 1-␣ hydroxylase action, may contribute to vitamin D deficiency.70,71 It is also highly likely that the relative importance of each of these pathways changes during the course of CKD. Furthermore, the interrelationships may be substantially modified by race/ethnicity and genetic polymorphisms (for example, of the vitamin D receptor)—thus, the relative importance of each of these pathways may vary across individuals with the same severity of renal failure.45,65 Finally, as discussed previously, in addition to affecting bone health, disordered mineral metabolism is an independent risk factor for cardiovascular disease in patients with 8

7

Serum Phosphorus, mg/dl

2000

6

5

4

3

2 0

20

40

60

80

100

120

140

Glomerular Filtration Rate, ml.min/1.73 m2

Figure 2. Relationship of serum phosphorus levels (mg/dL) to estimated glomerular filtration rate (mL/ min/1.73 m2) in 101 nondialyzed, untreated patients with diabetic nephropathy. The shaded boxes represent the range for serum phosphorus levels recommended by the Kidney Disease Outcome Quality Initiative for the level of glomerular filtration rate (stage 3 and 4 chronic kidney disease: 2.7 to 4.6 mg/dL, and stage 5 chronic kidney disease: 3.5 to 5.5 mg/dL).

VASCULAR CALCIFICATION IN EARLY CKD

CKD.3-10 In this regard, the greatest increase in cardiovascular risk is conferred by hyperphosphatemia with hypercalcemia (and not hypocalcemia, as seen associated with a decrease in GFR), and moderate to severe hyperparathyroidism amplifies this risk. It follows then that rather than considering secondary hyperparathyroidism as central to the management of disordered mineral metabolism in CKD, understanding the pathogenesis and aggressive management of each of the 3 abnormalities is probably important to improving the overall health and outcome of CKD patients. Finally, the recently published National Kidney Foundation K/DOQI guidelines (Bone Metabolism and Chronic Kidney Disease) as well as the Renal Physician Associations’ Guidelines on preparing patients for renal replacement therapy recommend the monitoring and correction of 25 hydroxy vitamin D deficiency in patients with stage 3 and 4 CKD and hyperparathyroidism.2,72 When compared with the general population, the serum levels of circulating 25 hydroxy vitamin D levels are reduced in the majority of patients with CKD, particularly in those with nephrotic syndrome.73-76 Using a conservative definition, 80% to 90% of patients with stage 2 through 4 CKD have demonstrable vitamin D insufficiency (serum 25 hydroxy vitamin D levels ⬍ 30 ng/mL)77 (Table 2). Unlike serum 1,25 dihydroxy vitamin D, the severity of vitamin D insufficiency does not seem to depend on the GFR.43,44,51,52,55,57,62 Indeed, 25 hydroxy vitamin D and vitamin D binding proteins are lost in the urine of individuals with proteinuric renal diseases, and severity of vitamin D insufficiency is dependent on the magnitude of proteinuria.53,74,78-80 Consistent with these observations, in our studies of individuals with diabetic CKD, both GFR and urine albumin-creatinine ratio were significantly correlated with the serum 25 hydroxy vitamin D levels on univariate analyses. However, on multivariate analyses, urine albumin-creatinine ratio was the only significant predictor of circulating 25 hydroxy vitamin D levels. It follows then that although vitamin D insufficiency is near-universal in CKD stages 1 through 4, it is particularly pronounced in individuals with proteinuric renal diseases such as diabetic nephropathy and glomerular diseases. Although it seems intuitive to make CKD patients replete with 25 hydroxy vitamin D before embarking on therapy with 1,25 hydroxy

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Table 3. Potential Consequences of Disordered Mineral Metabolism in Stages 1 Through 4 of Chronic Kidney Disease Morbidity and mortality All-cause mortality39 Acute myocardial infarction39 Renal osteodystrophy Osteitis fibrosa42,48,73,82-85,93 Osteomalacia48,73,81,82,85,86,93 Adynamic bone disease84,85,87-89 Reduced bone mineral density41,56,90-95 Calcific uremic arteriolopathy* (calciphylaxis)98-102 *Although calcific uremic arteriolopathy is described in nondialyzed CKD patients, the relationship of this complication to disordered mineral metabolism has not been consistently shown.

vitamin D or its analogs, this approach should be systematically validated in future studies.

Consequences of Disordered Mineral Metabolism in Nondialyzed Patients With CKD The key consequences of disordered mineral metabolism apparent in CKD stages 1 through 4 are summarized in Table 3. As has been consistently shown among patients with ESRD, a recent study has highlighted the potential relationship of hyperphosphatemia to the high mortality rates experienced by patients with stage 3 or 4 CKD.39 In an analysis of data from 3,490 US veterans in the Pacific Northwest with nondialyzed CKD, followed up for a median of 2.1 years, Kestenbaum et al showed the independent association of serum P levels and all-cause mortality as well as with nonfatal myocardial infarction.39 This increase in risk was apparent at serum P levels of 3.5 to 4.0 mg/dL, and the risk increased linearly with higher serum P levels. There is a clear need to confirm these findings and for studies that evaluate the relationship of other parameters of disordered mineral metabolism—Ca, PTH, and 1,25 dihydroxy vitamin D, or their interactions—to the outcome of patients with stage 1 to 4 CKD. Several investigators have evaluated bone biopsies of patients with stage 3 or 4 CKD and have shown that most patients have histologic abnormalities consistent with renal osteodystrophy (Table 3).42,48,73,81-85 Despite the high prevalence of bone disease, most patients are clinically asymptomatic. The early data regarding the frequency of various subtypes of bone disease (low-

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or high-turnover bone disease or mixed renal osteodystrophy) were rather inconsistent. The reasons for the discrepancy may, in part, be related to the sophistication of the methods of analyses of bone histology as well as the use (or lack thereof) of tetracycline labeling in some of the early studies. Some investigators have also suggested that mineralization defect seen early in CKD may be a manifestation of hyperparathyroidism.48 Thus, although earlier studies suggested a preponderance of osteomalacia in early CKD, recent studies suggest that mixed renal osteodystrophy may be the most frequent lesion.81,82,85,86 Finally, adynamic bone disease has also been reported to occur in the predialysis phase of CKD, often (although not always) in association with treatment with calcium-containing phosphate binders and vitamin D therapy.84,85,87-89 Data seem to suggest that the spectrum of renal osteodystrophy in stage 1 through 4 CKD is probably a direct result of vitamin D deficiency and/or resistance, hyperparathyroidism, skeletal resistance to PTH, and metabolic acidosis; disordered calcium and phosphorus metabolism may exert their effects through one or more of these mechanisms. However, a direct effect of hypocalcemia and hyperphosphatemia on bone health cannot be excluded and needs to be explored. In concert with the pathologic changes of renal osteodystrophy, the bone mineral content of patients with nondialyzed CKD is reduced as well.41,56,90-95 Several studies have shown that the reduction in bone mineral content is apparent in patients with stage 2 or 3 CKD that occurs both in the axial and appendicular skeleton and worsens with progressive loss of GFR.56 On the other hand, multivariate analyses of data from the Third National Health and Nutrition Survey in the United States (adjusting for age, gender, and body weight) suggested that there was no independent association between GFR and bone mineral density in patients with stage 2 or 3 CKD.96 Furthermore, the pathophysiologic basis of this decline in bone mineral content is unclear. Hyperparathyroidism and metabolic acidosis have been considered as potential factors, but no consistent associations have been shown in crosssectional studies.41,56,91,93,97 The interpretation of the data may, in part, be confounded by the differential effect of severe secondary hyperparathyroidism—it may lead to a paradoxical increase

in the bone mineral density in the axial skeleton and a reduction in the appendicular skeleton. Finally, calcific uremic arteriolopathy (or calciphylaxis) is one of the most serious complications in ESRD patients and is believed to be a consequence of disordered mineral metabolism. Although extremely rare, this syndrome has been described in nondialyzed CKD patients.98-102 The primary abnormality in patients with calciphylaxis involves arteriolar calcification in the skin leading to ischemic necrosis. However, the relationship of this complication as well as of vascular calcification at other sites (as discussed later) to disordered mineral metabolism is unclear.

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 osteoblastic phenotype. These osteoblastic cells then synthesize and deposit hydroxyapatite in the vessel wall, the same mineral found in bone.27 Intimal calcification almost exclusively occurs in the setting of atherosclerosis, and this forms the basis for the use of electron beam computed tomography (EBCT) for the noninvasive diagnosis of coronary artery disease.104 The magnitude of intimal calcification correlates best with the atherosclerotic plaque burden, but the correlation with obstructive coronary artery disease is at best modest.104,105 However, many episodes of acute myocardial infarction occur in patients with noncritical lesions, and the atherosclerotic plaque burden is a strong determinant of patient outcome. It is not surprising, therefore, that in the general population the coronary artery calcification score has consistently been shown to be predictive of nonfatal and fatal cardiovascular outcomes.106,107 Medial calcification is significantly less common than intimal calcification and is often associated with the presence of diabetes mellitus or

VASCULAR CALCIFICATION IN EARLY CKD

CKD. Most of the tests used to make an antemortem diagnosis of VC (for example, plain radiographs or EBCT scanning) establish the presence or absence and the severity of the total calcification burden. However, the antemortem distinction of intimal from medial calcification is difficult. Some investigators have attempted to diagnose medial calcification based on radiologic patterns. The reliability of these techniques to distinguish intimal from medial calcification has not been systematically evaluated. Nevertheless, using these techniques, the purported presence of medial calcification (as for intimal calcification) has been associated with an increased risk of death in individuals with diabetes mellitus as well as among those with ESRD.108-111 Given the increased risk of death associated with the presence of either intimal or medial calcification, the total calcification burden should be expected to correlate with outcome. This is best illustrated by a study of patients with ESRD—these patients often have heavily calcified atherosclerotic plaques (and thus, an increased intimal calcification burden), and medial calcification develops.27,112 The total calcification burden in ESRD patients, ascertained either ultrasonographically by the number of calcified blood vessels or using EBCT scan by the total coronary artery calcification score, is directly associated with mortality.32,33 It follows then that given the inability of currently available technologies to differentiate intimal from medial calcification, the total calcification burden is an appropriate surrogate for population-based investigations to study the prevalence, pathophysiology, and prognostic value of VC in CKD patients. Finally, an inverse association between VC and bone mineral density has been shown in the general population.113,114 Thus, it has been proposed that bone resorption (leading to osteoporosis) and vascular calcification share common pathogenetic mechanisms, and a similar relationship between bone mineral density and coronary artery calcification score has been shown in patients with end-stage renal disease.115

Vascular Calcification: Is It a Problem in Nondialyzed Patients With CKD? Most of the investigators working in the field of VC have focused their efforts on the problem in

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patients with ESRD, and only a handful of studies have systematically examined the problem in nondialyzed patients with CKD.14,15,36-38,116-120 (Table 4, Fig 3). It has been known for over 150 years that soft-tissue and vascular calcification are often present in patients with stage 4 or 5 CKD11,14,15,116,121 (Table 4). However, the availability of sensitive, noninvasive tools such as EBCT has allowed a systematic evaluation of VC in larger and more representative populations of patients with CKD.36-38,117,119,120 (Table 4, and Fig 3). These studies over the last 2 years permit us to begin to understand the relationship between the 2 broad groups of patients with CKD—those with albuminuria (and preserved GFR) and those with reduced GFR (with and without albuminuria). In this section, the available evidence for diabetic and nondiabetic patients is discussed separately, using sensitive tools such as computed tomography, to detect VC. Several studies have shown a significant relationship between the degree of albuminuria and the severity of coronary artery calcification among individuals with type 1 or 2 diabetes.122-128 On the other hand, secondary analyses of the data from either the Dallas Heart Study or Multi-Ethnic Study on Atherosclerosis was unable to show any relationship between urinary albumin excretion (stage 1 or 2 CKD) in diabetic patients and coronary artery calcification scores.118,120 However, these studies did not control for the duration of diabetes mellitus, and the stage 1 and 2 diabetic CKD individuals in these two studies had low levels of urinary albumin excretion, with most in the microalbuminuric range. Over the last few years, our group has systematically studied the problem of coronary artery calcification in individuals with type 2 diabetes.36,37,129 When diabetic renal disease is defined as the presence of urine protein excretion ⱖ1 g/day in an individual with diabetes duration ⱖ10 years (or ⱖ5 years in the presence of retinopathy), individuals with diabetic nephropathy have an 8-fold greater probability for the presence of coronary artery calcification when compared with diabetes-duration-matched normoalbuminuric subjects.37 Furthermore, the median coronary artery calcification score was 15-fold higher among diabetic patients with versus without diabetic nephropathy.37 As expected, the calcification burden in diabetic patients was significantly greater than among age- and gender-matched subjects from

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Table 4. Summary of Some of the Studies That Have Evaluated Vascular Calcification in Nondialyzed CKD Patients

Author, year [ref]

Calcification Assessed By

Meema, 197614

Skeletal survey

Kuzela, 197715

Autopsy

Ejerblad, 1979116

Histology†

Merjanian, 200336

Total Patient No.*

CKD Patient No.*

% CKD Diabetic

CKD Stage

52

52

None

4 or 5

18

18

None

8

8

25

EBCT

145

32

100

Mehrotra, 200437

EBCT

90

60

100

Fox, 200438

EBCT

319

32

Unk

Russo, 2004117

Spiral CT

140

85

None

Kramer, 2005118 EBCT

Qunibi, 2005119

Skeletal survey and spiral CT

Kramer, 2005120 EBCT

2,660 211 (GFR⬍60,41)

58

6,775

27

58

100

954 (albuminuria)

38

Key Findings

38% had arterial calcifications; 36% with increase in calcification over 11.6 months Unk 5/18 (28%) had vascular calcification; 44% had soft-tissue calcification 5 4/8 (50%) had medial calcification, 2/8 (25%) had intimal calcification of radial artery 1-4 Diabetic renal disease significantly associated with severity of CAC; age, male sex, and hypertension were additional predictors; diabetic renal disease significantly associated with vascular calcification 1-5 CAC significantly more prevalent and severe among diabetic patients with nephropathy compared with normoalbuminemic, duration-matched diabetic patients; number of antihypertensive drugs accounted for difference in CAC score seen in 2 groups 3 Higher median CAC scores in lower quartiles of GFR; relationship significant even after adjustment for traditional CVD risk factors 2-5 40% of patients and 13% of controls with CAC score ⬎0; only age significant predictor of score 1-5 No association between stage 1 and 2 diabetic or nondiabetic CKD with CAC; significant association of stage 3 to 5 CKD with CAC score, particularly robust in diabetics 1, 2, 4, 5 Prevalence and severity of abnormal coronary and peripheral arterial calcification significantly greater in stage 4 or 5 CKD; CAC score related to creatinine clearance and smoking Unk Increased urine albumin excretion associated with higher frequency and greater severity of CAC; association significantly attenuated on adjusting data for diabetes and hypertension

*Refers to the number of patients without ESRD in study. †Histology of sample of radial artery obtained at time of fistula surgery.

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Figure 3. Summary of the published data on the prevalence of coronary artery calcification among nondialyzed patients with chronic kidney disease.37,117-119,130 In the study by Spiegel et al, all of the patients had been undergoing maintenance dialysis for ⱕ3 months at the time of scanning.130 The data on only 60 of the 130 patients from our center (Mehrotra), presented in this figure, have been previously published.37

the general population—this was significantly more likely to occur in diabetic patients with nephropathy when compared with those without (Fig 4A and 4B). These observations have been extended to 123 subjects with diabetic nephropathy and an overall prevalence of coronary artery calcification of ⬎90% has been noted; 28% have coronary artery calcification scores ⬎400 (Figs 3 and 5). Furthermore, when using a higher threshold of proteinuria for the diagnosis of diabetic nephropathy, the prevalence and severity of vascular calcification does not seem to be influenced by the stage of CKD (Figs 5 and 6). Indeed, it is possible that the relationship of creatinine clearance to coronary artery calcification score in the recent report by Qunibi et al119 was confounded by the differences in the degree of proteinuria (stage 1 and 2 CKD: 334 mg/day, and stage 4 and 5 CKD: 5172 mg/day) and the duration of diabetes mellitus (stage 1 and 2 CKD: 11.6 years, and stage 4 and 5 CKD: 18.0 years) in their study population. Our group has recently reported on follow-up EBCT scans in the initial cohort. After a median follow-up of 19 months, individuals with diabetic nephropathy were more likely to have a significant increase in coronary artery calcification scores when compared with diabetes-duration-matched individuals with normoalbuminuria.129 Putting these sets of data

together, it does seem that increasing urine protein excretion is associated with an increased prevalence and severity of vascular calcification among individuals with type 2 diabetes. Moreover, proteinuria may be a stronger predictor of coronary artery calcification score than GFR, at least among individuals with stage 1 through 3 CKD, and probably even early in stage 4 CKD. Finally, “calcium begets calcium”, such that the baseline calcification burden is an important predictor of progression of calcification, even after progression to ESRD. The data on nondiabetic patients with CKD are substantially more limited. With regard to albuminuria, Kramer et al were unable to show any relationship between urine albumin excretion and severity of coronary artery calcification among individuals without diabetes mellitus.120 However, the vast majority of albuminuric individuals were in the microalbuminuric range, and only 38 nondiabetic participants had overt proteinuria. With regard to the relationship between reduced GFR and VC among nondiabetic patients, Russo et al recently reported a prevalence of 40% in a cohort of 85 nondiabetic patients with CKD—significantly lower than the 90% or more prevalence noted in our cohort of diabetic patients36,37,117 (Fig 3). Similarly, Spiegel et al recently undertook EBCT scanning of 62 non-

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Framingham Heart Study.38 This association was independent of the traditional risk factors for cardiovascular disease. In contrast to these findings, Kramer et al were unable to show any association between reduced GFR and coronary artery calcification scores among nondiabetic patients with stage 3 to 5 CKD.118 However, among the 2,400 nondiabetic participants in their study, only 28 had GFR ⬍ 60 mL/min, and so their results should be interpreted with caution.118 The existing body of evidence does suggest that the VC burden is increased in many nondiabetic patients with advanced CKD, but as would be expected, the magnitude of the problem is significantly lower than is observed among diabetic patients with a similar degree of renal impairment. It follows then that most patients already have established VC by the time they present for maintenance dialysis, and among diabetic patients, the calcification burden is not infrequently quite severe.

Age (Years)

Figure 4. Scatter plots comparing the coronary artery calcification (CAC) scores among individuals with diabetic nephropathy and control patients to the 25th, 50th, 75th and 90th percentile scores from 8,673 nondiabetic individuals (5,945 men and 2,728 women) between the ages of 40 and 65 years, without evidence of manifest coronary artery disease and who have undergone electron beam computed tomography scanning at Harbor-UCLA Medical Center. The closed circles represent the individuals with DN, and the open circles represent the diabetic controls. Individuals with DN were significantly more likely to have scores greater than the 50th percentile (82% versus 57%, P ⫽ .01) or the 90th percentile (32% versus 7%, P ⫽ .008) for age and gender when compared with diabetic controls. Reprinted with permission from Blackwell Publishing.37

diabetic patients within the first 3 months of commencement of dialysis therapy and reported a prevalence of coronary artery calcification of 54%130 (Fig 3); 20% of these subjects had coronary artery calcification scores that exceeded the 90th percentile for age and gender.130 Consistent with these observations of increased calcification burden among the nondiabetic CKD population, Fox et al reported a significant and inverse relationship between coronary artery calcification scores and GFR among the participants in the

Figure 5. Prevalence of coronary artery calcification at various stages of chronic kidney disease among 123 nondialyzed patients with diabetic nephropathy. The bars represent the proportion of patients with coronary artery calcification scores ⬎0, ⬎20, ⬎100, and ⬎400 for each stage of chronic kidney disease, respectively. Diabetic nephropathy was deemed to be present in an individual with diabetes duration ⱖ10 years (or ⱖ5 years in the presence of retinopathy) and ⱖ1.0 g/day of proteinuria. There was no significant difference in the prevalence of coronary artery calcification using any of the 4 cut-offs (score ⬎0, ⬎20, ⬎100, or ⬎400) between the 5 stages of CKD (␹2 P ⫽ .64, .61, .65, and .69 respectively).

VASCULAR CALCIFICATION IN EARLY CKD

creatinine and progression to ESRD.129 Thus, for the same baseline serum creatinine level, individuals who progressed to ESRD on follow-up had a significantly greater progression of coronary artery calcification when compared with those who did not require maintenance dialysis.129 All of these observations, however, should be considered preliminary and hypothesis-generating, and there is a compelling need to conduct large, prospective cohort studies to identify the determinants of VC in nondialyzed patients with CKD.

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Figure 6. Box plots showing the coronary artery calcification scores among 123 nondialyzed subjects with different stages of diabetic chronic kidney disease. There was no significant difference in the coronary artery calcification scores (median and 25th and 75th percentiles) across the different stages of chronic kidney disease: stage 1, 217 (86,814); stage 2, 97 (10,384); stage 3, 182 (8,529); stage 4, 147 (23,419); and stage 5, 117 (5,564).

Determinants of Vascular Calcification in Nondialyzed Patients With CKD The information on the determinants of VC in nondialyzed patients with CKD is even more limited. The studies to date have been small and have shown that the severity of coronary artery calcification in these patients is related to traditional cardiovascular risk factors such as age,36,117,130 gender,36 smoking,119 hypertension,36,37 and duration of diabetes mellitus.37 Similarly, in the study by Kramer et al, the relationship between urine albumin excretion and coronary artery calcification scores was significantly attenuated after adjusting the data for diabetes mellitus and hypertension.120 These data suggest that in the early stages of CKD, the determinants of VC may be similar to those seen in the general population (atherosclerosis) rather than those observed among individuals with ESRD. However, with progression of the severity of renal failure, the magnitude of reduction in GFR may play an increasingly important role in the pathogenesis of VC. In our recent study of the progression of coronary artery calcification among diabetic patients with and without CKD, we observed a significant interaction between serum

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.131-133 On the other hand, there is a large body of evidence showing that hyperphosphatemia contributes to the high calcification burden seen in the setting of ESRD, and the risk with hyperphosphatemia is amplified by the presence of hypercalcemia.134 As is clear from the foregoing discussion, both disordered mineral metabolism and VC are present and seem to be clinically significant in nondialyzed patients with CKD. Thus, it is relevant to examine the available evidence to determine whether these abnormalities are causally linked in patients with stage 1 through 4 CKD.

Role of Serum Ca, P, PTH, and Vitamin D Laboratory Evidence As indicated earlier, VC is an active, cellmediated process and does not arise from the passive precipitation of Ca and P. Thus, to implicate disordered mineral metabolism in inducing VC in patients with CKD, it is necessary to determine whether circulating Ca, P, PTH, and

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vitamin D can participate in this active cellmediated process. With regard to phosphorus, incubation of vascular smooth muscle cells either with a phosphate donor such as ␤-glycerophosphate or inorganic phosphate in the culture medium leads to mineralization in the culture medium.29,31,135,136 This calcification is associated with the increased expression Cbfa1, a transcription factor that plays a key role in the differentiation of osteoblasts, and osteopontin and osteocalcin, bone-matrix-related proteins.28,29,135,136 The induction of osteoblastrelated proteins seems to depend on the activity of Pit-1, a type III sodium-phosphate co-transporter.29,136 Put differently, it seems that phosphorus can enter the vascular smooth muscle cells via Pit-1 transporter and can induce a change in the phenotype of a smooth muscle cell to that of an osteoblast. This, in turn, leads to mineralization. These data provide a compelling role for serum phosphorus in inducing VC as seen in CKD. However, a phosphorus concentration of 1.4 mM (⬃4.3 mg/dL) does not lead to mineralization of the culture medium, concentration of 1.6 mM (⬃5.0 mg/dL) is associated with a trend (statistically insignificant) toward increased mineral content, and only when the concentration reaches or exceeds 2.0 mM (ⱖ6.2 mg/dL) does there occur a significant increase in mineralization in the culture medium.29,31,135,136 Thus, the P concentrations associated with induction of calcification in vitro are rarely seen in nondialyzed stage 2 or 3 CKD and only in some patients with stage 4 CKD. Increased concentrations of Ca in the culture medium have also been associated with increased mineralization seen in vascular smooth muscle cell cultures, and there seems to be a synergistic effect of increased calcium and phosphorus concentrations in the culture medium.31 However, treatment-naive nondialyzed patients with CKD have low rather than high serum calcium concentrations. The author is not aware of any laboratory evidence linking low vitamin D levels, as seen in CKD patients, with VC. With regard to the role of PTH, the addition of PTH-related peptide to a vascular smooth cell culture is associated with a significant attenuation of mineralization in the medium and the induction of the activity of alkaline phosphatase.137,138 Furthermore, in an animal model of arterial calcification (low-density

lipoprotein receptor knockout mice), treatment with human PTH (1-34) was associated with inhibition of VC and aortic osteogenic differentiation.139 Finally, in a study of patients undergoing maintenance dialysis, there was an inverse relationship between serum PTH levels and the number of calcified arteries.140 Thus, the cell culture, animal, and human data suggest that an oversuppression of PTH may contribute to the progression of VC in CKD. At this time, there is no laboratory evidence that suggests a role for elevated PTH levels in the process of VC.

Clinical Evidence A total of 4 studies—3 cross-sectional and 1 longitudinal— have evaluated the relationship of serum levels of Ca, P, PTH, and vitamin D levels to VC in nondialyzed patients with CKD stages 1 through 5, and have been unable to show any such relationship.37,117,119,129 The lack of correlation between serum levels of markers of disordered mineral metabolism and the prevalence, severity, or progression of VC in nondialyzed CKD is consistent with the range of concentrations of Ca and P that result in mineralization in cell culture studies— concentrations that are rarely observed in early stages of CKD. In light of the in vitro and clinical observational data that do not seem to support a role for a range of serum abnormalities to the VC burden observed in nondialyzed patients with CKD, can one still posit a role for disordered mineral metabolism in the initiation and/or progression of VC in stage 1 through 4 CKD? Two different, but not necessarily mutually exclusive, lines of argument are proposed in this regard. First, studies over the last 30 years have led to the development of the paradigm that phosphate retention with progressive loss of GFR is a key mechanism for the development of secondary hyperparathyroidism in early CKD (the trade-off hypothesis). Despite the phosphate retention, most patients maintain serum phosphorus levels within the normal range. It is conceivable then that this early phosphate retention may similarly either induce or contribute to the progression of VC even in early CKD. A similar argument could be developed for calcium, given the early appearance of hypocalciuria in CKD patients. Second, it is conceivable that the processes that lead to the initiation of calcification (either in intima or media)

VASCULAR CALCIFICATION IN EARLY CKD

differ from those that lead to progression of vascular calcification. Thus, the initiation of calcification in early CKD may not be related to disordered mineral metabolism, but after an initial nidus of calcification is present, calcium and phosphorus contribute to the progression of calcification. Disordered mineral metabolism would then assume a progressively important role with progressive loss of GFR and an increasing degree of phosphate retention that eventually leads to the appearance of hyperphosphatemia. At this time, there is no evidence to accept or dismiss the plausibility of either of these mechanisms, each of which posits an important role for disordered mineral metabolism in early CKD. However, it would be reasonable to explore alternative pathophysiologic mechanisms that may be equally or more important in initiation or progression of VC seen in early CKD.

Role of Deficiency of Inhibitors of Calcification Laboratory Evidence A large number of inhibitors of calcification have been identified and studied in context of vascular calcification. Some of these inhibitors, such as matrix Gla protein, are synthesized in the vessel wall, whereas others, such as fetuin-A, are circulating inhibitors.141 A lot of attention has recently been focused on the role of fetuin-A. The addition of fetuin-A to a cell culture of vascular smooth muscle cells inhibits the mineralization induced by ␤-glycerophosphate.142 Fetuin-A knockout mice develop extensive vascular and soft-tissue calcification when fed a high mineral-vitamin D diet.143 There is increasing evidence showing that this inhibition of calcification by fetuin-A occurs via multiple cell-dependent mechanisms—it inhibits the precipitation of basic calcium phosphate inside the matrix vesicles, reduces apoptosis, and increases phagocytosis of calcium-laden apoptotic bodies.31,144 Fetuin-A is also a negative acute phase reactant, and thus the presence of inflammation may induce a state of fetuin deficiency. It has been hypothesized that inflammation, commonly present in CKD patients, induces fetuin deficiency. This, in turn, may result in accelerated VC, particularly in the presence of abnormal serum levels of Ca and P, and contribute to the high cardiovascular mortality seen in patients with renal diseases. Thus, fe-

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tuin-A deficiency may provide a link between inflammation and cardiovascular mortality in ESRD patients.

Clinical Evidence Although there are several studies evaluating the associations of serum levels of fetuin-A in patients with ESRD, the author is aware of only one such study in nondialyzed patients with CKD.145 In contradistinction to the reports of fetuin deficiency in patients with ESRD, the serum levels of fetuin-A in nondialyzed diabetic patients with nephropathy (average GFR, 30 mL/min/1.73 m2) were significantly higher when compared with those of normoalbuminuric diabetic patients.145 Furthermore, there was a direct (rather than the expected inverse) relationship between serum fetuin-A levels and coronary artery calcification scores.145 Finally, there was no significant relationship between fetuin-A levels and rates of progression of coronary artery calcification ascertained in 68 of these 88 subjects (unpublished data). The mechanisms underlying the higher fetuin-A levels in diabetic CKD patients and for the direct relationship with coronary artery calcification scores remain speculative. Nevertheless, it does suggest that nondialyzed patients with CKD may not have a relative deficiency of fetuin-A, and thus, it is unlikely to play a pathogenetic role in the VC seen in these patients. Practice Guidelines for Monitoring Disordered Mineral Metabolism The foregoing discussion indicates that abnormalities in mineral metabolism are apparent at least as early as stage 3 CKD and in some patients with stage 2 CKD. Furthermore, numerous studies have shown the causal link between disordered mineral metabolism and clinically relevant consequences such as renal osteodystrophy. Emerging data also seem to suggest that disordered mineral metabolism may be a cardiovascular risk factor even in nondialyzed patients with CKD. It follows then monitoring for and management of mineral metabolism should begin early in the course of CKD. Consistent with the data presented above, the recently published K/DOQI guidelines recommend that monitoring for disordered mineral metabolism should begin in patients with stage 3

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CKD.2 In other words, in a 50-year old individual, monitoring should begin when the serum creatinine exceeds 1.3 mg/dL in a nonblack man and 1.0 mg/dL in a nonblack woman. Monitoring should begin with routine measurements of serum Ca, P, and PTH and should include the measurement of 25 hydroxy vitamin D levels if the serum PTH levels are elevated.2 Some of the recommended target ranges for stage 3 and 4 CKD are summarized in Table 2. Data from CKD populations suggest that routine monitoring of disordered mineral metabolism was rarely performed in the 1990s.146,147 It is important then to educate health care providers to begin monitoring and managing abnormalities in mineral metabolism early in the course of CKD. It is also clear from the foregoing discussion that vascular calcification begins and is often severe early in CKD. However, the data on the pathogenetic mechanisms and/or interventions that could attenuate the progression of calcification are currently not available. Thus, the value of routine screening for the presence of vascular calcification is not clear and cannot be routinely recommended. There are no data to suggest that strategies that have been shown to be effective in slowing progression of VC among patients with stage 5 CKD (for example, treatment with sevelamer hydrochloride or etidronate) will be effective in early CKD.34,148 It is also unclear whether aggressive management of abnormalities of mineral metabolism in early CKD, as recommended by K/DOQI guidelines, will attenuate or halt the process of VC. There is a clear need for additional studies to provide us with data for developing therapeutic guidelines for the future.

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 calcification burden identifies patients who are at the greatest risk for progression.

There is also an increasing body of evidence that supports the thesis that elevated serum levels of Ca and P, oversuppression of PTH, and deficiency of inhibitors of calcification are important in the pathogenesis of VC in patients with ESRD. However, the present body of evidence does not allow us to link disordered mineral metabolism to VC in early CKD. Future studies need to explore the role of phosphate retention (in the absence of hyperphosphatemia) that is implicated in the pathogenesis of hyperparathyroidism to the induction and/or progression of VC in early CKD. However, it is also important to explore alternative pathogenetic mechanisms to identify therapeutic targets to attenuate the process of VC early in the course of CKD.

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31. Reynolds JL, Joannides AJ, Skepper JN, et al: Human vascular smooth muscle cells undergo vesicle-mediated calcification in response to changes in extracellular calcium and phosphate concentrations: A potential mechanism for accelerated vascular calcification in ESRD. J Am Soc Nephrol 15:28572867, 2004 32. Blacher J, Guerin AP, Pannier B, et al: Arterial calcifications, arterial stiffness, and cardiovascular risk in end-stage renal disease. Hypertension 38:938-942, 2001 33. Matsuoka M, Iseki K, Tamashiro M, et al: Impact of high coronary artery calcification score (CACS) on survival in patients on chronic hemodialysis. Clin Exp Nephrol 8:54-58, 2004 34. Chertow GM, Burke SK, Raggi P: Sevelamer attenuates the progression of coronary and aortic calcification in hemodialysis patients. Kidney Int 62:245-252, 2002 35. Asmus HG, Braun J, Krause R, et al: Two year comparison of sevelamer and calcium carbonate effects on cardiovascular calcification and bone density. Nephrol Dial Transplant 20:16531661, 2005 36. Merjanian R, Budoff M, Adler S, et al: Coronary Artery, Aortic Wall and Valvular Calcification in Nondialyzed Patients With Type 2 Diabetes and Renal Disease. Kidney Int 64:263271, 2003 37. Mehrotra R, Budoff MJ, Christenson P, et al: Determinants of coronary artery calcification in diabetic patients with and without nephropathy. Kidney Int 66:2022-2031, 2004 38. Fox CS, Larson MG, Keyes MJ, et al: Kidney function is inversely associated with coronary artery calcification in men and women free of cardiovascular disease: The Framingham Heart Study. Kidney Int 66:2017-2021, 2004 39. Kestenbaum B, Sampson JN, Rudser KD, et al: Serum phosphate levels and mortality risk among people with chronic kidney disease. J Am Soc Nephrol 16:520-528, 2005 40. Madsen S, Olgaard K, Ladefoged J: Renal handling of phosphate in relation to serum parathyroid hormone levels. Acta Med Scand 200:7-10, 1976 41. Tougaard L, Sorensen E, Christensen MS, et al: Bone composition and parathyroid function in chronic renal failure. Acta Med Scand 202:33-38, 1977 42. Tessitore N, Venturi A, Adami S, et al: Relationship between serum vitamin D metabolites and dietary intake of phosphate in patients with early renal failure. Miner Electrolyte Metab 13:38-44, 1987 43. St John A, Thomas MB, Davies CP, et al: Determinants of intact parathyroid hormone and free 1,25-dihydroxyvitamin D levels in mild and moderate renal failure. Nephron 61:422-427, 1992 44. Messa P, Mioni G, Turrin D, Guerra UP: The calcitonincalcium relation curve and calcitonin secretory parameters in renal patients with variable degrees of renal function. Nephrol Dial Transplant 10:2259-2265, 1995 45. DeBoer IH, Gorodetskaya I, Young B, et al: The severity of secondary hyperparathyroidism in chronic renal insufficiency is GFR-dependent, race-dependent, and associated with cardiovascular disease. J Am Soc Nephrol 13:2762-2769, 2002 46. Coburn JW, Popovtzer MM, Massry SG, et al: The physicochemical state and renal handling of divalent ions in chronic renal failure. Arch Intern Med 124:302-311, 1969 47. Massry SG, Coburn JW, Lee DB, et al: Skeletal resistance to parathyroid hormone in renal failure. Studies in 105 human subjects. Ann Intern Med 78:357-364, 1973

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