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Clinical Epidemiological of
Cardiovascular Disease in Chronic
Renal Disease
Claudio Rigatto
AMERICAN JOURNAL OF KIDNEY DISEASES

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CARDIOVASCULAR DISEASE IN CHRONIC RENAL DISEASE
Clinical Epidemiology of Cardiovascular Disease
in Chronic Renal Disease
Robert N. Foley, MB, Patrick S. Parfrey, MD, and Mark J. Sarnak, MD
INDEX WORDS: Epidemiology; kidney failure; myocardial ischemia; heart hypertrophy; heart failure.
CLINICAL RECOMMENDATIONS
● The risk of cardiovascular disease (CVD) in
patients with chronic renal disease (CRD) ap-
pears to be far greater than in the general popula-
tion. For example, among patients treated by
hemodialysis (HD) or peritoneal dialysis (PD),
the prevalence of coronary artery disease (CAD)
is approximately 40% and the prevalence of left
ventricular hypertrophy (LVH) is approximately
75%. Among HD and PD patients, total deaths
caused by CVD in 1995 were approximately
16,000. CVD mortality in HD and PD patients
has been estimated to be approximately 9% per
year. Even after stratification by age, gender,
race, and presence of diabetes, CVD mortality in
HD and PD patients is 10 to 20 times higher than
in the general population.
● Patients with CRD should be considered in
the highest risk group for subsequent CVD events.
Treatment recommendations based on CVD risk
stratification should take into account this ‘‘high-
est risk’’ status of patients with CRD.
● Congestive heart failure (CHF) is more com-
mon in CRD than in the general population and is
an independent predictor of death in CRD. Among
HD and PD patients, the prevalence of CHF is
approximately 40%. Both CAD and LVH are risk
factors for the development of CHF.
● In practice, it is difficult to determine
whether CHF reflects left ventricular (LV) dys-
function or extracellular fluid (ECF) volume over-
load. Patients who develop clinical manifesta-
tions of CHF should be evaluated for CVD.
From the Divisions of Nephrology and Clinical Epidemi-
ology, Memorial University of Newfoundland, St John’s,
Newfoundland, Canada, and the Division of Nephrology,
New England Medical Center, Boston, MA.
Address reprint requests to Robert Foley, MB, The Patient
Research Centre, Memorial University of Newfoundland,
300 Prince Philip Dr, St John’s, Newfoundland, Canada A1B
3V6. E-mail: r n_foley@hotmail.com
娀 1998 by the National Kidney Foundation, Inc.
0272-6386/98/3205-0308$3.00/0
S112 American Journal of Kidney Diseases, Vol 32, No 5, Suppl 3 (November), 1998: pp S112-S119
● The excess risk of CVD in CRD is caused,
in part, by a higher prevalence in these patients
of conditions that are recognized as risk factors
for CVD in the general population. The predomi-
nant factors include older age, hypertension, hy-
perlipidemia, diabetes, and physical inactivity.
● In addition, the excess risk may also be due,
in part, to hemodynamic and metabolic factors
characteristic of CRD, including proteinuria, in-
creased ECF volume, electrolyte imbalance, ane-
mia, and higher levels of thrombogenic factors
and homocysteine than in the general population.
Whether other factors unique to CRD also con-
tribute to the excess risk is unknown.
TARGET POPULATION: CHRONIC
RENAL INSUFFICIENCY
Prevalence
The epidemiology of CVD in patients with
chronic renal insufficiency (CRI) has received
scant attention to date. This is a major gap in our
knowledge. The lack of basic information partly
reflects the fact patients are not ‘‘captive’’ in their
treatment setting as are their HD, PD, and renal
transplant recipient (RTR) counterparts. The clini-
cal impression is that the burden of CVD is very
large. We know that patients at the far end of the
CRI spectrum, those starting renal replacement
therapy, have a very high prevalence of CVD. If
CVD and CRI are a lethal combination, it is quite
possible that many CRI patients die before ever
reaching ESRD. One could easily speculate that
the burden of CVD in CRI actually exceeds that
seen among patients starting renal replacement
therapy. Extrapolating from the large burden of
disease at onset of ESRD, and its strong associa-
tion with subsequent morbidity and mortality, it
seems reasonable to assume that the overall
prevalence of CAD and CHF is similar to that in
ESRD, still increasing and approaching approxi-
mately 40% for each condition (Table 1).1 If one
assumes that CRI is a risk factor for CVD and
vice versa, it seems reasonable to suggest that:
CARDIOVASCULAR DISEASE EPIDEMIOLOGY IN RENAL DISEASE
Table 1. Approximate Prevalence (%)
of CVD by Target Population
CAD CHF
(Clinical) LVH (Echo) (Clinical)
GP 5-12* 20† 5‡
CRI NA 25-50 (varies with NA
renal function)§
HD 40㛳 75¶ 40㛳
PD 40㛳 75¶ 40㛳
RTR 15# 50** NA
Abbreviation: NA, not available.
*Lower value, age 45-64; higher value, age ⬎65. Data
from NHLBI Morbidity and Mortality Chartbook 1996.
†Data from Levy.39
‡Age 60. Data from NHLBI Morbidity and Mortality Chart-
book 1996.40
§Data from Levin.4
㛳Data from USRDS Case-Mix Adequacy Study.17
¶Data from Foley.11
#Data from Kasiske.31
**Data from Parfrey.32
(1) the burden of CVD varies inversely with the
level of renal function, and (2) our approach to
risk factors like hypertension, lipids, and smok-
ing should be guided by the principle that CRI
patients are at high risk for CVD. If we accept
that these patients are in the ‘‘highest risk group’’
for CVD, it is reasonable to suggest that our
thresholds for risk factor intervention should be
lower than in the general population.
More is known about the prevalence of LVH
in CRI (Table 1). Greaves and coworkers2 did
echocardiograms in 38 undialyzed patients with
CRI (serum creatinine ⬎ 3.4 mg/dL), 54 patients
receiving continuous ambulatory peritoneal dialy-
sis (CAPD), 30 patients receiving HD, and 59
healthy age- and sex-matched volunteers. LV
mass index was 78.7 g/m2 in controls, 120.5 g/m2
in CRI patients, and 136 g/m2 in dialysis patients
(P ⬍ 0.0001). Echocardiography was normal in
only 37% of CRI patients and 29% of dialysis
patients, with LVH being the major discriminat-
ing feature of CRI patients. Tucker and cowork-
ers3 studied 118 nondiabetic CRI patients and
found LVH in 16% of patients with creatinine
clearance greater than 30 mL/min, and 38% of
patients with creatinine clearance less than 30
mL/min. A similar inverse relationship between
the level of renal function and prevalence of
LVH was reported by Levin et al.4 As part of a
prospective study, 175 consecutive CRI patients
S113
underwent echocardiography. The prevalence of
LVH was 26.7% in patients with creatinine clear-
ance greater than 50 mL/min, 30.8% in those
with clearances between 25 and 49 mL/min, and
45.2% in those with clearance less than 25 mL/
min (P ⫽ 0.05). A similar association between
increasing LV mass index and falling renal func-
tion has been shown in the prospective arm of the
study.5
CVD Outcomes
Little is known about CVD morbidity in CRI.
Hospitalization for CVD is probably higher than
in the general population. In the Modification of
Diet in Renal Disease Study of nondiabetic CRI
patients,6 25% of first hospitalizations, about 3
per 100 patient years, were due to CVD. In the
study by Maschio and coworkers,7 patients with
serum creatinine between 1.5 and 4.0 mg/dL
were randomly assigned to receive either pla-
cebo or the angiotensin-converting enzyme
(ACE)-inhibitor, benazepril. Overall, the com-
bined end-point of sudden death, fatal and nonfa-
tal myocardial infarction occurred at a rate of
approximately 1% per year. Similar findings were
observed in nondiabetic patients with proteinuria
levels greater than 3 g/d in the Ramipril Efficacy
in Nephropathy Study.8
Relationship of CAD and LVH
to CVD Outcomes
The extent, severity, and distribution of coro-
nary artery lesions in CRI are unknown. As in the
general population, two major patterns of in-
creased LV mass are seen in CRI: concentric
LVH (in which excessive wall thickening leads
to LVH) and LV dilatation plus hypertrophy,
more commonly known by the confusing term
‘‘eccentric hypertrophy’’ (LV dilatation is the
primary abnormality; wall thickening is a second-
order adaptation that minimizes the increased
wall tension caused by LV dilatation). Concen-
tric hypertrophy is associated with pressure over-
load, as in aortic stenosis or hypertension. LV
dilatation plus hypertrophy is associated with
volume overload, as in aortic regurgitation or
severe anemia. Both patterns are more common
in CRI than in the general population.3-5 The
relationships of CAD and LVH to subsequent
CVD outcomes have yet to be systematically
evaluated in CRI. There is little reason to believe
S114
that they are different than those seen in the
general population.
CRD Outcomes
The relationship of CAD and LVH to CRD
outcomes is not known in this target population.
TARGET POPULATION: END-STAGE RENAL
DISEASE TREATED BY HEMODIALYSIS
Prevalence of CVD
The prevalence of CVD is much higher in HD
than in the general population. The USRDS
Dialysis Morbidity and Mortality Study (Wave
2) is studying patients starting HD and began
collecting data in 1996. The average age of HD
patients was 61 years, and 50% had a history of
diabetes mellitus. Forty-two percent of patients
had a history of myocardial infarction or coro-
nary artery revascularization procedure, while
40% had a previous episode of cardiac failure.9
The prevalence of LVH, using echocardiogra-
phy, is approximately 75%.10-13 In our study, 433
patients had echocardiograms at initiation of
renal replacement therapy. Only 20% had normal
cardiac function and dimensions. Fifteen percent
had systolic dysfunction, 30% had LV dilatation
with preserved systolic function, and 40% had
concentric LVH.11,14
CVD Outcomes
Reporting on cause of death is very often a
subjective affair and has inherent limitations.
Interobserver agreement in assigning cause of
death in end-stage renal disease (ESRD) has
been reported to be very low.15
In the USRDS study, the mean age of incident
ESRD appeared to plateau at approximately 59.6
years from 1992 to 1994. The proportion of
diabetic patients appears to be rising, from 30.1%
in 1987 to 37.3 in 1994. Death rates, adjusted for
race, age, sex, and diabetes, have declined pro-
gressively for patients who started renal replace-
ment therapy in the years 1983 through 1994.
The adjusted death rates have fallen by 25%
from 30 per 100 patient years at risk for the 1987
cohort, to 24 per 100 for the 1994 cohort. The fall
in death rates has been seen in HD and PD
patients as well as RTR. The proportion of deaths
attributed to CVD has remained relatively con-
stant. If practices on death reporting have not
changed over time, these very promising trends
FOLEY, PARFREY, AND SARNAK
suggest progress is being made in the manage-
ment of CVD in ESRD. The improvements in
death rates have been most marked within the
first year of ESRD; likewise, the year-to-year
trends have not been as encouraging in prevalent
patients. Thus, it is not yet clear whether better
patient management in CRI prior to ESRD is
responsible for the improved mortality rates.9
After stratification for age, race, and gender,
current CVD mortality rates are approximately
10 to 20 times those of the general population
(Table 2 and Fig 1). Figure 2 shows a comparsion
between diabetic and nondiabetic HD and PD
patients. Diabetes has a dramatic impact on CVD
mortality rates. However, nondiabetic dialysis
patients also have higher rates than the general
population. This observation, that CVD mortal-
ity rates are an order of magnitude higher in
dialysis patients, suggests that HD patients should
be considered in the ‘‘highest risk group’’ when
considering CVD risk factor intervention.
CHF has been consistently shown to be a very
strong, independent mortality risk factor in hemo-
dialysis patients.16-18 One of the earliest studies
to demonstrate this was a retrospective cohort
study by Huthchinson and coworkers. In this
Table 2. Cardiovascular Mortality by Gender, Race,
and Target Population (Annual Mortality, %)*
All Men Women White Black Diabetic Nondiabetic
GP 0.28 0.28 0.27 0.29 0.23 0.80 0.26
HD 9.12 9.38 8.83 11.18 6.68 11.09 7.78
PD 9.24 10.27 8.14 10.76 6.07 13.22 7.09
RTR 0.54 0.59 0.43 0.53 0.56 1.11 0.39
NOTE. Data from Sarnak MJ, Levey AS: J Am Soc
Nephrol 9:160A, 1998. CVD mortality is defined as death
from arrhythmias, cardiomyopathy, cardiac arrest, MI, ath-
erosclerotic heart disease, and pulmonary edema.
*Data from the National Center for Health Statistics
(NCHS) 1993 Multiple Cause of Mortality data files, ICD 9
codes 402, 404, 410-414, and 425-429. Diabetes mellitus
in the general population was calculated using multiple
cause of mortality data files, population statistics files and
national health interview surveys, all from NCHS in 1993.
CVD mortality is underestimated in individuals with diabe-
tes and overestimated in those without diabetes because
of the incomplete listing of diabetes on death certificates.
†Data from USRDS 1994-1996 (special data request).
HCFA form 2746 no. 23, 26-29, and 31. Death rates per
1000 patient-years at risk were converted to annual per-
cent mortality. CVD mortality is underestimated in RTR
because of the incomplete ascertainment of the cause of
death.
CARDIOVASCULAR DISEASE EPIDEMIOLOGY IN RENAL DISEASE
—䉬—, GP male; —䊏—, GP female; —䉱—, GP black; —䊉—,
GP white; —䉫—, dialysis male; —䊐—, dialysis female; —䉭—,
dialysis black; —䊊—, dialysis white.
Age (years)
Fig 1. CVD mortality defined by death due to ar-
rhythmias, cardiomyopathy, cardiac arrest, myocar-
dial infarction, atherosclerotic heart disease, and pul-
monary edema in the general population (GP) (Data
from NCHS multiple cause of morality data files ICD 9
codes 402, 404, 410-414, and 425-429, 1993) compared
to ESRD treated by dialysis (Data from USRDS special
data request HCFA form 2746, #s 23, 26-29, and 31,
1994-1996). Data is stratified by age, race, and gender.
study, age, diabetes and CHF, by a factor of 2,
were the only independent predictors of mortal-
ity.16 Clinical ischemic heart disease has not been
shown to consistently predict mortality indepen-
dently of CHF. The USRDS found that both
CAD (relative risk [RR] ⫽ 1.22) and CHF (RR ⫽
1.26) independently predicted mortality in an
inception cohort study of 3,399 patients starting
hemodialysis therapy.16 A large-scale study, by
Silberberg and coworkers, showed an indepen-
dent association between LVH and mortality in
HD patients.10 In our study, a long-duration,
prospective inception cohort study, CHF at incep-
tion of dialysis therapy was associated with very
poor survival rates.18 Both CAD19 and LVH20
were associated with higher mortality rates. Most
of their adverse effects, however, seemed to
occur via the development of CHF.
In addition to LVH and CAD, other factors,
such as anemia,21 hypertension,22 and perhaps
chronic fluid overload23 contribute to CHF. Also,
the clinical manifestations of CHF may be differ-
ent in dialysis patients. For example, ultrafiltra-
tion may prevent fluid overload, and intradialytic
hypotension may be the only manifestation of
LV dysfunction in some patients.
S115
Morbidity due to CVD in HD patients also
appears to be very high. In the most recent
USRDS report, using data from 1995, a typical
dialysis patient was hospitalized 1.3 times per
annum.9 The precise reason for hospitalization is
not given in this report. However, preliminary
and as yet unpublished data from the Hemodialy-
sis (HEMO) study suggest that about one third of
first hospitalizations are for CVD. Rocco and
coworkers24 examined a cohort of 1,572 patients
starting dialysis in 1989 and showed that isch-
emic heart disease and CHF were both indepen-
dent predictors of future hospitalization. Hospi-
talization is likely to be an inaccurate surrogate
for counting CV events and can be strongly
influenced by ‘‘nonmedical’’ factors. In addition,
these data cannot determine whether a CVD
hospitalization was a result of a new CV event or
a recurrence in a patient with pre-existent CVD.
In our prospective study, we found that the inci-
dence of new onset CHF was 7% per year,18
whereas the incidence of new onset clinically
defined ischemic heart disease was lower, at 3%
per year.19 These incidence rates are high, but
consistent with those seen in the prospective
Canadian Hemodialysis Morbidity Study.25 It is
likely, though unproven, that these incidence
rates are higher than in the general population
—䉬—, male DM; —䉫—, male no DM; —䊏—, female DM;
—䊐—, female no DM; —䊉—, white DM; —䊊—, white no DM;
—䉱—, black DM; —䉭—, black no DM.
Fig 2. Cardiovascular mortality defined by death
due to arrhythmias, cardiomyopathy, cardiac arrest,
myocardial infarction, atherosclerotic heart disease,
and pulmonary edema in ESRD patients treated with
dialysis (Data from USRDS special data request HCFA
form #s 23, 26-29, and 31, 1994-96). Data is stratified by
age, race, gender, and the presence of diabetes (DM).
Shaded points describe diabetic individuals, whereas
nonshaded points describe nondiabetic individuals.
S116
when adjusted for comparative age, gender, race,
and diabetes.
Relationship of CAD to CVD Outcomes
The distribution of coronary artery lesions has
not been systematically studied in HD but is
likely to be similar to that of the general popula-
tion. In diabetic patients, the lesions appear to be
more extensive and diffuse than in nondiabetic
HD patients. For example, in the study of Man-
ske and coworkers,26 52 of 110 consecutive insu-
lin-dependent diabetic transplant candidates had
CAD on coronary arteriography. CAD preva-
lence increased significantly with age, with CAD
present in 13 of 16 patients older than 45 years.
Many dialysis patients, perhaps 30% or more of
HD patients, with clinical episodes typical of
myocardial ischemia have normal coronary arte-
riograms.27 Myocardial ischemia in these pa-
tients has been postulated to be caused by several
factors, such as small vessel disease, vascular
calcification, and LVH. As in the general popula-
tion, CAD is associated with subsequent CVD
outcomes, including CHF and death.17,19
Relationship of LVH to CVD Outcomes
LVH with normal cavity volume (concentric
LVH) and LVH secondary to LV dilatation (ec-
centric LVH) are very common in HD pa-
tients.10-13 The relationship of these abnormali-
ties to CVD outcomes is similar to that seen in
the general population.10,20 In our study, LV ab-
normalities were independently associated with
de novo ischemic heart disease, de novo cardiac
failure, and mortality in dialysis patients. For
each of these three outcomes, there was a graded
response as follows: normal LV ⬍ concentric
LVH ⬍ LV dilatation with normal systolic func-
tion ⬍ systolic dysfunction.11,14,18-20
TARGET POPULATION: END-STAGE
RENAL DISEASE TREATED
BY PERITONEAL DIALYSIS
Prevalence of CVD
The prevalence of CAD, LVH, and CHF ap-
pears to be similar in PD patients as in HD
patients (Table 1).
CVD Outcomes
As in HD, CVD accounts for approximately
40% of deaths in PD patients. CVD mortality is
FOLEY, PARFREY, AND SARNAK
about 9% per annum, similar to that of HD
patients (Table 2). Thus, age-controlled CVD
mortality rates are about 10 to 20 times those in
the general population (Table 2, Fig 1). As in
HD, death rates tend to be higher in patients who
are older, diabetic, and white.9 As in HD, CHF
appears to be a major predictor of mortality in
PD patients.18,28
The comparative mortality of PD versus HD is
a matter of considerable interest. The USRDS
has reported a higher death rate from CAD and
other cardiac causes.29 On the other hand, the
Canadian Organ Replacement Registry, compar-
ing at patients starting treatment between 1990
and 1994, reported lower mortality rates, at least
within the first 2 years of therapy.30 Very little
has been written on the comparative cardiovascu-
lar morbidity of HD and PD. In our study, we
found similar rates of de novo ischemic heart
disease and de novo CHF in HD and PD pa-
tients.28
Relationship of CAD and LVH
to CVD Outcomes
The distribution of coronary artery lesions in
unknown. The prevalence of LVH is similar to
that in HD patients, but the prevalence of LV
dilatation may be lower.28 As in HD, the presence
of CAD and LVH is associated with CVD out-
comes.28
TARGET POPULATION: RENAL
TRANSPLANT RECIPIENTS
Prevalence of CVD
The prevalence of CVD in RTR is higher than
in the general population. CAD prevalence has
been estimated at 15%.31 The prevalence of LVH
is high, between 50% and 70%.32-36
CVD Outcomes
In the most recent USRDS report, the annual
death rate from CVD was approximately 0.54%.9
While this is considerably better than for HD and
PD, it still approximately twice that of the gen-
eral population (Table 2). Overall, the proportion
of deaths due to CVD seems to be considerably
lower than in dialysis patients (17% v 40%-
50%).9 The CVD death rate of RTR is higher
than that of the general population, even after
stratifying for age, gender, and race. Figure 3
CARDIOVASCULAR DISEASE EPIDEMIOLOGY IN RENAL DISEASE
—䉬—, GP (all); —䊏—, RTR
Fig 3. Cardiovascular mortality defined by death
due to arrhythmias, cardiomyopathy, cardiac arrest,
myocardial infarction, atherosclerotic heart disease,
and pulmonary edema in ESRD patients treated with
transplantation (RTR) (Data from USRDS special data
request HCFA form #s 23, 26-29, and 31, 1994-96)
compared with the general population (GP) (Data from
NCHS multiple cause of morality data files ICD 9 codes
402, 404, 410-414, and 425-429, 1993). Data is stratified
by age. Cardiovascular mortality is underestimated in
RTRs due to incomplete ascertainment of cause of
death in these patients.
shows the CVD mortality of RTR stratified by
age and compared with members of the general
population. Overall, CVD mortality is much
higher in RTR. However, CVD mortality appears
similar to the general population in RTRs aged
65 years or older. This last statistic may reflect
the fact that older potential transplants are inten-
sively screened to exclude those with CVD. In
addition, CVD mortality may be underestimated
due to incomplete ascertainment of cause of
death. All these observations suggest that is rea-
sonable to treat RTR as being in the ‘‘highest risk
group’’ for CVD.
The incidence of CVD morbidity in RTR has
not been reported by many centers. The available
data suggest that incidence of myocardial infarc-
tion is at least 3 to 5 times that of the general
population.31,37
Relationship of CAD and LVH
to CVD Outcomes
The distribution of coronary artery lesions in
RTRs has not been well described. Type I dia-
betic transplant candidates have been exten-
sively studied by Manske and coworkers.38 They
S117
found a high prevalence of CAD, often diffuse.
The risk of vascular events, including myocar-
dial infarction was 4 times higher in those with
CAD compared to those without CAD. The types
of echocardiographic abnormalities are similar
to those seen in the general population. It is not
known whether these echocardiographic abnor-
malities are associated with increased CVD risk.
CRD Outcomes
The relationship of CAD and LVH to CRD
outcomes is not known in this target population.
RESEARCH RECOMMENDATIONS
Observational Studies
● Determine the prevalence, incidence, and
time-course of CVD in all CRD target popula-
tions and subgroups.
● Determine the relationship CVD risk fac-
tors in the general population to CVD outcomes
in CRD.
● Compare CVD prevalence, incidence, time-
course, and risk factors among different coun-
tries.
● Determine the prevalence of CVD and CVD
risk factors in children and adolescents.
● Identify risk factors unique to CRD, if any.
● Establish specimen banks for evaluation of
genetic and biochemical risk factors.
● Validate the cause of death as listed in
Health Care Financing Administration (HCFA)
death notification form, especially deaths due to
cardiac arrest and arrhythmia.
● Determine the causes of death and hospital-
izations in non-Medicare beneficiaries.
● Validate the cause of death as listed in
United Network for Organ Sharing reporting
forms.
● Validate cause of hospitalizations as listed
in HCFA claims forms (in Medicare beneficia-
ries)
● Improve coding related to CRD and CVD
in International Classification of Diseases (ICD).
● Define diagnostic criteria for causes of
ESRD on HCFA 2728 Form.
● Validate comorbid conditions as listed on
HCFA 2728 form.
● Develop one or more CRI registries to deter-
mine population-based estimates of prevalence
and incidence of CRI, risk factors, and complica-
S118
tions including CVD. Consider expanding the
scope of the USRDS to accomplish this task.
● Determine if CVD is a risk factor of CRD
outcomes in CRI and RTR target populations.
● In HD and PD patients, compare CVD
prevalence, incidence, and risk factors in patients
awaiting transplantation versus patients not on
the transplant waiting list.
● Compare CVD prevalence, incidence and
risk factors in RTR versus nontransplanted pa-
tients on the waiting list.
● In HD patients, determine the relationships
of abnormal cardiac structure and rhythms to
underlying CAD, and to the fluid and electrolyte
shifts associated with the HD procedure.
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