Perit Dial Int
29(Supplement_2):
9-14
2009
© 2009 International Society for Peritoneal Dialysis
Part 1: Calcium and Phosphorus Metabolism in Peritoneal
Dialysis |
VASCULAR AND OTHER TISSUE CALCIFICATION IN PERITONEAL DIALYSIS PATIENTS
Angela Yee-Moon Wang
University Department of Medicine, Queen Mary Hospital, University of
Hong Kong, Hong Kong SAR, PR China
Correspondence to: A.Y.M. Wang, University Department of Medicine, Queen Mary
Hospital, University of Hong Kong, 102 Pok Fu Lam Road, Hong Kong SAR, PR
China.
aymwang{at}hku.hk
 |
ABSTRACT
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Cardiovascular disease is the leading cause of mortality in patients
with end-stage renal disease (ESRD) and is attributed to a combination of
traditional and non-traditional cardiovascular risk factors. In recent years,
there has also been an increasing recognition of a very high prevalence of
cardiovascular calcification in the ESRD population, including in patients
receiving long-term peritoneal dialysis (PD). Numerous observational cohort
studies have demonstrated the prognostic importance of cardiovascular
calcifications in these patients. The mechanisms are not completely
understood, but are likely multifactorial. The present article reviews the
prevalence, clinical course, prognostic significance, and some contributing
factors for vascular and valvular calcification in ESRD patients, including
patients receiving PD therapy.
KEY WORDS: Vascular calcification; valvular calcification; fetuin-A; C-reactive protein; matrix Gla protein; osteoprotegerin.
Vascular and valvular calcifications are frequent and important
complications in end-stage renal disease (ESRD) patients. The prevalence of
coronary artery calcification has been reported to range from 40% to nearly
100% in dialysis patients. All except two of the relevant studies examined
hemodialysis (HD) populations
(1–9).
The two studies in patients on peritoneal dialysis (PD) were relatively small
and reported a calcification prevalence of about 60%
(1,8).
In the general population, the Agatston score for the coronary arteries, as
determined using electron-beam computed tomography (EBCT) or multislice
computed tomography, reflects the plaque burden and has important implications
for future cardiovascular risk
(10). In HD patients, the
degree of coronary artery calcification was directly proportional to the
prevalence of atherosclerotic vascular disease
(7). However, in contrast to
the general population, where calcification occurs mainly in the intimal
layer, vascular calcification in ESRD patients typically develops in both the
intimal and the medial layers. A recent autopsy study
(11) showed that the coronary
plaques in patients with advanced renal failure were strikingly different from
those in non–renal failure subjects in terms of morphology,
calcification, and inflammation characteristics. The intimal and medial layers
both contained more calcium in renal patients than in non-renal patients.
Furthermore, the proportion of the media that was occupied by calcified
plaques was significantly higher in renal failure patients.
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PROGNOSTIC IMPORTANCE OF VASCULAR AND VALVULAR CALCIFICATION
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The intimal and the medial types of vascular calcification as determined by
plain radiographs both predict long-term mortality and cardiovascular death in
HD patients, those having intimal calcification also having the worst clinical
outcomes (12). Valvular
calcification detected using echocardiography has also been shown to be a
powerful predictor of mortality and cardiovascular death in chronic PD
patients (13). The presence of
valvular calcification reflects the presence of generalized atherosclerosis
and calcification in PD patients
(14). More recently, abdominal
aortic calcification detected using plain lateral abdominal radiographs has
been shown to predict coronary artery calcification
(15) and is significantly
associated with all-cause and cardiovascular mortality in HD patients
(16). However, calcification
detected using echocardiography and plain radiography was non-quantitative.
Using EBCT, Block et al. recently demonstrated a significant
association between coronary artery calcification and mortality among incident
HD patient (17).
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PROGRESSION OF CORONARY ARTERY CALCIFICATION IN ESRD
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Coronary artery calcification in ESRD patients is progressive in nature. In
the landmark paper by Goodman et al.
(3), a doubling in coronary
artery calcium score was observed in young dialysis patients over a mean
follow-up period of 20 months. Block et al. showed that nearly one
third of incident HD patients show no evidence of coronary calcification at
baseline. Importantly, no subjects with zero coronary artery calcium score
(CACS) at baseline progressed to a CACS above 30 during 18 months of follow-up
(18). Those data raise the
possibility that some patients may be protected against the development of
vascular calcification. The exact mechanism requires further elucidation.
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MECHANISMS OF VASCULAR AND VALVULAR CALCIFICATION
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The mechanisms of vascular and valvular calcification are not completely
understood, but are likely multifactorial, involving not only traditional
Framingham risk factors, but also nontraditional risk factors. Disturbances in
mineral metabolism with resulting hyperphosphatemia have been suggested to
play a major contributory role to vascular and valvular calcification in ESRD
patients. Cross-sectional clinical studies have consistently reported
associations between hyperphosphatemia and vascular and valvular calcification
in ESRD patients
(2,3,7,8,19–23).
A recent longitudinal study also demonstrated a significant association for
serum phosphorus and CaxP product with change in CACS over 1 year in PD
patients (24). Jono et
al. showed that inorganic phosphate was able to induce an osteoblastic
phenotype change in vascular smooth muscle cells that led to deposition of
calcium- and phosphate-containing apatite crystals, providing in
vitro evidence to support the involvement of phosphate in vascular
calcification (25).
Hyperphosphatemia is a frequent complication in PD patients as it is in HD
patients. According to a previous cross-sectional survey by our group, about
40% of prevalent PD patients had hyperphosphatemia as defined by the Kidney
Disease Outcomes Quality Initiative (K/DOQI) target of 1.78 mmol/L
(26). That prevalence was the
same as the prevalence reported in the Netherlands Cooperative Study on the
Adequacy of Dialysis (NECOSAD)
(27). Hyperphosphatemia has
also been shown to be a significant predictor of mortality in PD patients
(28). In the NECOSAD study, a
serum phosphorus above the target of 1.78 mmol/L was associated with
time-dependent adjusted hazard ratios of 1.6 and 1.4 for all-cause mortality
in PD and in HD patients respectively. These data clearly indicate that
optimizing phosphorus control is equally important in PD and in HD
patients.
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IMPORTANCE OF RESIDUAL RENAL FUNCTION IN PHOSPHORUS CONTROL IN PD PATIENTS
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Residual renal function is one of the key determinants of phosphorus
control in PD patients. Among PD patients with residual renal function, serum
phosphorus showed the strongest correlation with normalized protein intake
(r = 0.440, p < 0.001), followed by residual glomerular
filtration rate (r = –0.393, p < 0.001) and PD
creatinine clearance (r = –0.255, p = 0.004). Among
anuric PD patients, the correlation between serum phosphorus and PD creatinine
clearance (r = –0.474, p < 0.001) out-weighed that
between serum phosphorus and normalized protein intake (r = 0.425,
p < 0.001) (26).
Based on our data, we propose that total weekly urea and creatinine clearances
of at least 2.0 and 60 L/1.73m2 respectively may be optimal
clearance targets to maintain serum phosphorus below 5 mg/dL in continuous
ambulatory PD patients. However, the data also suggest a limitation of PD
alone to achieve adequate phosphorus control in anuric PD patients.
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INFLAMMATION IN VASCULAR AND VALVULAR CALCIFICATION: IS IT A RISK MARKER OR RISK FACTOR?
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There is increasing evidence to suggest that vascular and valvular
calcification is not a passive process involving the precipitation of calcium
and phosphorus, but rather an active cellular-mediated process involving
calcification inducers and inhibitors. Our group's previous study reported an
important link between inflammation and valvular calcification in PD patients
(23). Among patients with high
CaxP (
5 mmol2/L2), the prevalence of valvular
calcification was about 85% for patients with both inflammation and
malnutrition as compared with 25% for patients with no evidence of
inflammation and malnutrition. Notably, even among patients with CaxP
below 5 mmol2/L2, the presence of inflammation and
malnutrition (as compared with no evidence of inflammation or malnutrition)
was associated with at least a doubling in the prevalence of valvular
calcification. In HD patients, a similar association was observed between
C-reactive protein and annualized change in CACS
(29). C-Reactive protein was
also associated with progression of the abdominal calcification index in HD
patients (30). All these data
support a possible causal link between inflammation and calcification.
A recent autopsy study showed markedly increased expression of C-reactive
protein messenger RNA in the vessel walls of renal patients as compared with
non-renal patients in both calcified and non-calcified parts of arteries
(11), suggesting that uremia
is associated with increased vascular inflammation that may mediate the
development of vascular calcification. The presence of inflammation was also
recently shown to be predictive of a worse prognosis among patients with
valvular calcification (31).
However, this evidence that supports a link between inflammation and
calcification is all circumstantial. Whether inflammation is a risk factor or
instead a risk marker of vascular and valvular calcification in ESRD patients
remains unknown.
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FETUIN-A AND VASCULAR CALCIFICATION
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Several extracellular calcification inhibitory proteins were recently
identified by genetic manipulation in mice; one of these was fetuin-A or
alpha-Heremans–Schmid glycoprotein (AHSG). Mice deficient in AHSG or
fetuin-A being fed a mineral- and vitamin D–rich diet showed extensive
calcification in various organs, including kidneys, lungs, myocardium, skin,
and blood vessels (32),
providing novel evidence to support a critical role of fetuin-A in inhibiting
ectopic calcification. Serum fetuin-A co-localized with calcified vascular
smooth muscle cells culture in vitro and in calcified arteries in
vivo (33), and there is
in vitro evidence that fetuin-A inhibited mineralization of vascular
smooth muscle cells in a concentration-dependent manner
(33). As compared with healthy
control subjects, dialysis patients had significantly reduced serum fetuin-A
concentrations (34). Sera from
dialysis patients with low fetuin-A had impaired ex vivo capacity to
inhibit CaxP precipitation
(34). In HD patients, serum
fetuin-A was linked to inflammation and cardiovascular mortality
(34). In prevalent PD
patients, serum fetuin-A has also been shown to be associated with valvular
calcification and malnutrition, inflammation, and atherosclerosis syndrome and
to predict mortality and cardiovascular death
(34,35).
There is also additional evidence that serum fetuin-A is inversely related to
aortic pulse wave velocity and calcification in pediatric dialysis patients
(36). All these data lend
supporting evidence to the hypothesis that fetuin-A is involved in inhibiting
vascular and valvular calcification.
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OSTEOPROTEGERIN AND VASCULAR CALCIFICATION
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Osteoprotegerin (OPG) is a secreted protein that belongs to a member of the
tumor necrosis factor receptor gene superfamily. It serves as a soluble decoy
receptor for the receptor activator of nuclear factor 
B ligand, and it
inhibits osteoclast activation and promotes osteoclast apoptosis in
vitro. In genetic knockout animal models, OPG deficiency not only leads
to early onset osteoporosis, but also to medial calcification of the aorta and
the renal arteries (37). These
data suggest the involvement of OPG in postnatal bone-mass formation and also
the medial type of arterial calcification. It also clearly indicates that the
regulation of OPG and its signaling pathway plays a role in the long-observed
association between osteoporosis and vascular calcification, although the
exact mechanism requires further elucidation.
Clinical data regarding OPG in humans is inconsistent with the data in
animals, however. In the general population, serum OPG was found to be
positively associated with the extent and severity of coronary artery disease
(38). Serum OPG has also been
shown to be independently associated with the severity of abdominal aortic
calcification in HD patients
(39). Furthermore, both serum
C-reactive protein and OPG were higher among patients showing rapid
progression of abdominal calcification as compared with those showing slow
progression (40). Recent data
also suggest that serum OPG is higher in dialysis patients than healthy
controls and that OPG is positively associated with aortic pulse wave velocity
and calcification (36). These
data are somewhat in contrast with a recent study relating OPG to mortality in
ESRD patients. In this study by Morena et al.
(41), OPG had no prognostic
value for mortality among HD patients who showed no evidence of inflammation.
However, among HD patients with elevated C-reactive protein, both a high OPG
and a low OPG were predictive of increased mortality. These data were
difficult to interpret because the study had a relatively small sample size.
Further study will be needed to confirm the relationship between OPG and
clinical outcome in dialysis patients and the biologic importance of OPG in
the development of vascular and valvular calcification.
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MATRIX Gla PROTEIN AND VASCULAR CALCIFICATION
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Matrix Gla protein (MGP) belongs to a family of the N-terminal
-carboxylated proteins that require a vitamin K–dependent
-carboxylation for their biologic activation. A study by Luo et
al. showed that MGP gene knockout mice developed spontaneous medial
calcification in arteries and cartilage alike, leading to lethal rupture of
the bone-like aorta within weeks after birth
(42). This novel evidence
supports the importance of MGP in inhibiting vascular and cartilage
calcification. High levels of local MGP expression have been demonstrated
adjacent to atherosclerotic plaques, especially near the calcified areas
(43). Using antibodies that
differentiated total MGP, activated -carboxylated MGP (Gla–MGP),
and inactivated -carboxylated MGP (Glu–MGP), immunohistochemical
localization studies demonstrated a very high level of Glu–MGP
expression in calcified areas of the arteries—that is, the intima in
atherosclerosis and the media in Mönckeberg sclerosis. On the other hand,
an abundance of Gla–MGP expression was present in arteries that showed
no calcification (44). Because
a reduced form of vitamin K is required as a cofactor for
-carboxylation of the glutamic acid residues or activation of MGP,
these data not only demonstrated the importance of -carboxylation of
MGP in inhibiting the intimal and medial types of vascular calcification, but
also the pivotal role of vitamin K in the activation of MGP as a potent
inhibitor of vascular calcification.
Blood MGP levels were found to correlate inversely with coronary artery
calcification in the general population in that the more severe the coronary
artery calcification, the lower the blood MGP level
(45). In patients undergoing
percutaneous coronary intervention, blood MGP levels remained low for some
months after the intervention
(44), suggesting low
constitutive expression of MGP in patients with coronary artery disease.
However, it is important to note that these measurements accounted for total
blood levels of MGP without differentiating between undercarboxylated and
-carboxylated MGP and without taking into account tissue deposition.
More recently, measurement of serum undercarboxylated MGP was shown to be
significantly lower in HD patients than in the non–renal failure
population; it was also found to be markedly reduced in patients with
calciphylaxis (46). Notably,
serum undercarboxylated MPG levels were negatively correlated with serum
phosphate and positively associated with serum fetuin-A
(47).
There are increasing experimental and clinical data linking vitamin K
deficiency to vascular and valvular calcification. High-dose warfarin has been
shown to induce rapid calcification of the elastic lamellae in rat arteries
and heart valves (48). In
patients undergoing valvular replacement, preceding warfarin treatment was
associated with greater valvular calcification
(49). In HD patients, recent
data suggest that the use of warfarin for more than 18 months is independently
associated with an increased risk of aortic valve calcification
(50). In experimental models
of warfarin-treated rats, menaquinone-4 (vitamin K2) but not
vitamin K1 prevented the development of arterial calcification
(51). This finding is in
keeping with a study in the general population showing that higher dietary
intake of menaquinone was indeed associated with a reduced risk of coronary
artery disease (52). Taken
together, these data suggest that treatment with menaquinone may be useful in
preventing vascular calcification in the ESRD population—a hypothesis
that will require further evaluation.
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CONCLUSIONS
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Vascular and valvular calcifications represent markers of atherosclerotic
vascular disease and are powerful predictors of adverse cardiovascular
outcomes in ESRD patients, including patients receiving PD treatment. The
mechanisms of vascular and valvular calcification are multifactorial,
involving not only hyperphosphatemia, inflammation, and lipids as inducers,
but also loss of various calcification inhibitory proteins.
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ABSTRACT
PROGNOSTIC IMPORTANCE OF...