REVIEW
CARDIOVASCULAR DISEASE IN RENAL PATIENTS:
THE CARDIO-RENAL LINK
Norman Lepor, MD, FACC, FAHA*
ABSTRACT
The risk of cardiovascular disease (CVD) and
poor cardiovascular outcomes increases as renal
function decreases. The increasing prevalence of
CVD and chronic kidney disease (CKD) is fueled
by the current obesity epidemic that is resulting in
an increased incidence of hypertension and dia-
betes mellitus. Hypertension and diabetes mellitus
are the 2 leading causes of CKD. It is anticipated
that the recent downward trend of decreasing
cardiovascular mortality will reverse directly as a
result of the increased prevalence of diabetes and
CKD. Observational evidence suggests that CKD
is largely driven by novel risk factors that under-
lie traditional risk factors. The presence of global
markers for acute inflammation and the
increased risk of atherosclerosis and thrombosis
in patients with CKD suggest that kidney disease
is associated with a state of chronic inflammation
similar to coronary artery disease. Anemia and
depressed erythropoietin levels are important
components of the renal dysmetabolic syn-
drome. Patients with reduced creatinine clear-
ance develop significant anemia, which is
associated with increased cardiac output and
detrimental vascular remodeling, such as left ven-
tricular hypertrophy and thickened vessel walls.
Anemia is an independent predictor of mortality
in patients with CVD and is associated with an
increased incidence of in-hospital mortality, 30-
day mortality, 1-year mortality, and disabling
strokes. Erythropoietin treatment for anemia has
*Associate Clinical Professor of Medicine, David Geffen
School of Medicine at UCLA; Attending Cardiologist,
Cedars-Sinai Medical Center, Los Angeles, California.
Address correspondence to: Norman Lepor, MD, FACC,
FAHA, David Geffen School of Medicine at UCLA, 99 N. La
Cienega Blvd, Ste 203, Beverly Hills, CA 90211.
E-mail: Norman.Lepor@cshs.org.
Advanced Studies in Medicine n S705
been shown to improve cardiac function and to
reduce diuretic use and rehospitalizations.
Treating anemia has clear benefit for patient
quality of life. Although the association between
anemia and the increased risk of cardiovascular
events is strong, it is unclear whether treating
T
anemia reduces cardiovascular risk in patients
with CKD.
(Adv Stud Med. 2005;5(7A):S705-S709)
he risk of cardiovascular disease (CVD) and
its associated adverse events increases with
decreasing renal function in an almost per-
fect dose-response curve. For patients with
end-stage renal disease (ESRD), the risk of having a
cardiovascular event is much greater than in the gener-
al population. The cardio-renal problem is quite large
considering the number of people with CVD and kid-
ney disease. Currently, in the United States, more than
430 000 people have ESRD,1 20 million have chronic
kidney disease (CKD),2 and 6 million have chronic
forms of both cardiovascular and kidney disease.3
Prevalence of these diseases is being driven to epidem-
ic numbers, in part by the increased incidence of dis-
orders associated with obesity, such as hypertension
and diabetes mellitus. The increased prevalence of
these high-risk factors will undoubtedly increase car-
diovascular mortality by engendering CKD in a sub-
stantial percentage of the population.3 Given the
current trend toward earlier age of onset, the increased
prevalence of these diseases could ultimately decrease
life expectancy in the United States.
In a community-based study of patients free of kid-
ney disease at baseline (mean age, 43 years), follow-up
after 18.5 years showed that, in addition to traditional
risk factors, such as age, diabetes mellitus, smoking, and
high body mass index, mildly reduced glomerular filtra-
tion rate (GFR) was a primary predictor of new onset
 REVIEW

kidney disease.4 Patients with a GFR of below 90 tein A, C-reactive protein, fibrinogen, and Factor VII.7
mL/min/1.73 m2 at baseline were 3 times more likely Individually, many of these markers are surrogate mark-
to develop CKD than patients with a normal GFR ers for increased risk of CVD. The presence of elevated
(120 mL/min/1.73 m2). The odds of developing levels of C-reactive protein and fibrinogen with CKD
CKD steadily increased as the number of risk factors suggests that kidney disease is associated with a state of
increased. The compounding nature of these risk fac- chronic inflammation.
torsin particular, those linked with obesitysuggest
that CKD has an associated dysmetabolic syndrome
similar to that of diabetes mellitus. CKD appears to be
driven, in large part, by novel risk factors, such as
inflammation, thrombosis, and calcium-phosphate Figure 1. Cardiovascular Risk Increases in the Presence
imbalances that underlie more traditional risk factors.3 of Kidney Disease
Depressed erythropoietin levels and the resulting ane-
mia that are prevalent in patients with CKD may have
a major role in this dysmetabolic process. The outcome
of what appears to be a largely obesity-driven increase
in CKD will be increased cardiovascular mortality Cardiac Renal
disease disease
(Figure 1).3 The next generation of patients with CKD
will likely have more severe kidney disease at an earlier
age and will likely present with an increased number of
confounding risk factors. This combination of factors Acute renal failure
and death in the
Nonfatal myocardial infarction
Heart failure
will increase the difficulty of assessing and treating this cardiac patient Valvular disease
Arrhythmias
population. Cardiac death in the renal patient

RECOGNIZING THE CARDIO-RENAL LINK

Reprinted with permission from McCollough PA. Cardiorenal risk: an important clin-
ical intersection. Rev Cardiovasc Med. 2002;3(2):71-76.3
Serum creatinine level is an important indicator of
kidney disease, and it has been shown to correspond
with a given GFR for different age groups.5 In a 70-
year-old man, a relatively low serum creatinine of 1.26
mg/dL may not be perceived as an indicator of
impaired renal function. Nevertheless, that serum crea- Figure 2. The Rate of Cardiovascular Events Increases
tinine level has been shown to correspond with a GFR with Kidney Disease Severity
of 60 mL/min/1.73 m2, the threshold of kidney disease.
As GFR falls below 60 mL/min/1.73 m2, the risk of car-
diovascular events increases in a consistent, graded fash- 40
CV Events (per 100 person-years)

ion (Figure 2).6 This correlation suggests that physicians 35

Age-Standardized Rate of

should use the calculation of estimated GFR to identify 30

patients with early renal impairment who are often con- 25
sidered normal because of a normal serum creatinine 20
and intervene aggressively before these patients reach 15
middle- or late-stage CKD. 10
A study comparing patients with either normal or 5
elevated serum creatinine (1.5 mg/dL for men and
0
1.3 mg/dL for women) found a higher incidence of 60 4559 3044 1529 <15

the metabolic syndrome in those patients with elevated Estimated GFR (mL/min/1.73m )2

creatinine. Patients with kidney disease had an

CV = cardiovascular; GFR = glomerular filtration rate.
increased incidence of diabetes mellitus, lower levels of Reprinted with permission from Go et al. Chronic kidney disease and the risks of death,
high-density lipoprotein, and higher levels of lipopro- cardiovascular events, and hospitalization. N Engl J Med. 2004;351(13):1296-1305.6

S706 Vol. 5 (7A) n July 2005

 REVIEW

Another study found that for patients presenting
with acute coronary syndromes, the in-hospital mor-
tality rates for those patients who also had renal insuf-
ficiency (creatinine clearance <60 mL/min) were 3
times higher than for patients without renal insuffi-
ciency.8 For patients presenting with acute myocardial
infarction (AMI), in-hospital mortality rates have
shown to be sharply increased for those patients whose
creatinine clearance was below 60 mL/min at baseline
(Figure 3).9 Data from the Heart and Estrogen/
Progestin Replacement Study, which enrolled women
with coronary artery disease (CAD) and congestive
heart failure (CHF), showed that patients with creati-
nine clearance between 50 mL/min and 60 mL/min
had sharply increased mortality risk.10 These studies
show that kidney disease increases mortality risk from
are less well defined. However, it is reasonable to specu-
late that anemia could contribute to arterial hypertro-
phy and eventually lead to increased systemic vascular
resistance.
Although the precise effects of anemia and anemia
treatment need to be determined through prospective
clinical trials, anemia remains a significant mortality
multiplier for patients with CKD, CVD, or both. A
Figure 3. In-hospital Mortality Increases as in Creatine
Clearance Declines in Patients with AMI
25

In-hospital Mortaility Rate (%)

a variety of cardiovascular events, supporting the con- 20
cept of a cardio-renal link.
15
The presence of these global markers for acute
inflammation and increased risk of atherosclerosis and 10
thrombosis suggests that CKD is associated with a 5
chronic inflammatory state. Future research should be
0
focused on the ill effects of this syndrome as well as
20 30 40 50 60 70 80 90 100 110 120 130
conditions such as anemia that may contribute to
Creatinine Clearance at Admission (mL/min)
and/or exacerbate the metabolic effects of CKD.
AMI = acute myocardial infarction.
THE ROLE OF ANEMIA IN THE CARDIO-RENAL LINK Reprinted with permission from Wright et al. Acute myocardial infarction and renal
dysfunction: a high-risk combination. Ann Intern Med. 2002;137(7):563-570.9

Significant anemia begins to appear in patients who

have reduced creatinine clearance. CKD-related anemia
is generally defined as hemoglobin (Hb) below 11 g/dL
in association with reduced renal function. The anemia
associated with CKD has effects on cardiac and vascular
structures, leading to increases in cardiac output, as well Table. Effect of CKD, CHF, and Anemia as Combined
as detrimental adaptations, including left ventricular Risk Factors for Mortality
hypertrophy (LVH) and thickening of the blood vessel
walls. LVH is associated with chronic anemia and has Patient Group 2-Year Mortality (%)
been shown to increase mortality, perhaps because it
predisposes patients to diastolic dysfunction and aggra- Control 7.7
vation of coronary ischemia, thereby lowering the Anemia 16.6
threshold for life-threatening arrhythmias. Clinical CKD 16.4
database analysis showed that patients with an increased CHF 26.1
Hb concentration had a reduced left ventricular mass CKD, anemia 27.3
index compared with patients whose Hb was reduced or CHF, anemia 34.6
unchanged.11 This indirect evidence suggests that CHF, CKD 38.4
improving anemia may have a beneficial effect on LVH. CHF, CKD, anemia 45.6
Likewise, patients with CHF have been shown to have
CKD = chronic kidney disease; CHF = congestive heart failure.
a 13% increase in annual mortality risk per 1-g/dL Reprinted with permission from Collins A. The hemoglobin link to adverse out-
decrease in Hb. Anemias effects on the arterial system comes. Adv Stud Med. 2003;3(3C):S194-S197.12

Advanced Studies in Medicine n S707

 REVIEW

database analysis of Medicare patients, for example,
showed that patients with anemia had twice the mortal-
ity rate of the control patients. Medicare patients with
heart failure, CKD, and anemia had more than 5 times
the mortality risk of the control patients (Table).12
In a study of women presenting with symptoms of
CAD, those patients with an Hb below 12 g/dL had an
increased risk of cardiovascular events compared with
those patients with an Hb of 12 g/dL or higher.13 In the
Controlled Abciximab and Device Investigation to
Lower Late Angioplasty Complications (CADILLAC)
tional risk factors, and novel risk factors such as anemia,
can reduce the cardiovascular risk associated with CKD.
DISCUSSION
Dr Agarwal: Dr Lepor mentioned that athero-
sclerosis in renal disease is more malignant. That is
because it is medial sclerosis as opposed to the inti-
mal process, isnt it? Do you think that correlates
very well with the coronary disease?
Dr Lepor: I think the observation that you have

trial, which studied the impact of anemia on event rates made is correct; it is a different form of atherosclerosis.
in patients with AMI undergoing primary percutaneous As interventional cardiologists, we are much more anx-
coronary intervention, anemia was an independent pre- ious about the care of patients with CKD in the
dictor of in-hospital mortality.14,15 In this study, anemic catheterization lab. We know that complication rates,
patients were 3 times more likely to have a fatal in-hos- including bleeding and the development of contrast-
pital event, and anemia was induced nephropathy, are
associated with a higher inci- higher in these patients but
dence of 30-day mortality, Anemia is an independent predictor of increased the benefits are also much
1-year mortality, and disabling mortality in patients with a variety of greater with revasculariza-
strokes. cardiovascular presentations, and anemia tion. The dysmetabolic syn-
Anemia is an independent drome associated with CKD
predictor of increased mortali- may confer additional risk for many reasons, is analogous to the metabol-
ty in patients with a variety of including tissue hypoxia, the induction of ic syndrome associated with
cardiovascular presentations, arrhythmia or myocardial ischemia, or the insulin resistance in that

and anemia may confer addi- activation of the sympathetic nervous system. there are a constellation of
tional risk for many reasons,
including tissue hypoxia, the
induction of arrhythmia or
myocardial ischemia, or the
activation of the sympathetic nervous system. In
patients whose anemia results from erythropoietin
deficiency, adverse vascular remodeling may result
from a reduced number of vascular progenitor cells,
limiting the potential for vascular repair and thereby
increasing the risk of a cardiovascular event. For
patients with heart failure, survival is clearly related to
Hb levels. Treating anemia with erythropoietin can
have a positive impact on a patients quality of life.
Erythropoietin treatment has been shown to improve
cardiac function according to the New York Heart
Association functional classification and reduce diuret-
ic use and the rate of rehospitalizations.16,17
Anemia is certainly a key link between CKD and
CVD. It plays a major role in a destructive process in
which these diseases appear to be propagating one anoth-
er; the impact can be measured in increased cardiovascu-
lar event rates and increased cardiovascular mortality.
What remains to be seen is whether eliminating tradi-
abnormalities, including
anemia, lipid abnormalities,
elevations of homocysteine
levels, insulin resistance, and
abnormalities of calcium-phosphate homeostasis, that
are probably responsible for the heightened platelet
activation and endothelial dysfunction associated with
CKD. In particular, the vascular abnormalities, includ-
ing endothelial dysfunction, may be related to the reduc-
tion in erythropoietin and vascular progenitor cells
responsible for optimal vascular health. Dr Brinker, do
you have any comments on that?
Dr Brinker: One message I took from your presen-
tation was that we really know very little about the
association between CKD and nonrenal death. There
are a wide variety of possible influences, but it is a
jump to assume a cause-and-effect relationship for any
of them at this time. There are mechanisms at that we
do not yet fully understand. This relationship, howev-
er, provides fuel for those who are interested in design-
ing prospective trials because there are several
straightforward ways of approaching the individual
questions. For now, I am uncertain as to the clinical

S708 Vol. 5 (7A) n July 2005

 REVIEW
application of information arising from recent
research; there appears to be myriad factors that we
were essentially unaware of just 4 to 5 years ago that
could be important mediators of cardiovascular dis-
ease. The question is, can weor should wescreen
for and treat any of them?
Dr Lepor: I think that is a very reasonable state-
ment, but I think you can also make the analogy that
CKDs association with heart disease is not dissimilar
to the association of diabetes with heart disease.
Diabetes really is an umbrella for a whole host of meta-
bolic abnormalities, very similar to what we see with
CKD, and the question is, what are the major drivers
in either one of those disease states that push athero-
sclerotic event rates?
Dr Brinker: Your last statement is very important.
Yes, diabetes might be similar to CKD; however, cardi-
ologists today view diabetes as a vascular disease. There
seems to be some debate about the connection between
blood sugar per se and cardiovascular outcomes. It seems
that glucose is not the only issue; we must look deeper to
insulin resistance, growth factors, and so forth. We do
not completely understand these issues, but we have
reached the point where we accept diabetes as a vascular
disease. I am not certain that we are ready to accept
CKD as a vascular disease quite yet, but I think we are
now beginning to see more and more connections.
Perhaps, like glucose in diabetes, the creatinine level is a
surrogate for those factors accompanying CKD that
adversely affect the cardiovascular system.
Dr Berns: Should cardiologists look at their use of
microalbuminuria and creatinine to a greater extent,
such as they do with lipid levels and blood pressure,
than they currently do in assessing and managing car-
diovascular risk in their patients? Do you see a move-
ment among cardiologists to look at these other
potential risk factors?
Dr Lepor: I think it is clear that the level of inter-
est has increased significantly so that renal dysfunction
is looked for as a risk factor. The paradigm is chang-
ing. Renal dysfunction is now looked at as a reason to
engage in more intense therapy. In some situations,
this is a catch-22. For instance, a patient has a GFR of
15 mL/min/1.73m2 and serum creatinine of 4 mg/dL.
How do I treat his or her hypertension? Do I stop or
push the ACE [angiotensin-converting enzyme]
inhibitors? What alternative therapies are better? How
do I begin, and how does this affect my use of statins
and antiplatelet therapy? We still need nephrologists to
Advanced Studies in Medicine n S709
help guide us with the more difficult-to-read patients,
but I also think we have made progress in looking at
the patients with mild-to-moderate CKDthose we
used to view as having normal kidney functionand
we have learned how to intervene in those patients. I
do not think we necessarily should deal with stage 4 or
stage 5 patients on our own without the assistance and
insights of nephrologists, but we have certainly
become more aggressive as cardiologists with stage 3
and stage 4+ patients in terms of identification and
treatment. This really represents an opportunity for
cardiologists and nephrologists to work closely togeth-
er and optimize care. Would you agree?
Dr Brinker: Yes. I think the studies showing that
ACE inhibitors improve the outcomes of patients who
have microalbuminuria have been extremely helpful in
focusing the internists interest towards a treatment
that might decrease the incidence and/or the progres-
sion of CKD. This in turn should improve the prog-
nosis for those with CVD. So we are now paying
attention to very early renal disease, although there is
little doubt that we can do better.
Dr Fishbane: Recently, in the Annals of Internal
Medicine, there was an article that showed that in peo-
ple without kidney disease, the MDRD [Modification
of Diet in Renal Disease] formula underestimated the
actual level of kidney function by about 30% to 40%.
It is therefore probably best to apply the MDRD for-
mula only to people with kidney disease.
Dr Brinker: I have been told for years that the
MDRD formula is better than the Cockcroft-Gault
formula because it is more sensitive.
Dr Fishbane: No, I believe the MDRD was vali-
dated in other populations. It was never applied to
normal populations, so we look at data bases like
NHANES [National Health and Nutrition
Examination Survey] to attempt to determine how
much kidney disease there is in the normal population.
The Mayo Clinic took a normal population and used
iothalamic clearance or some other real measure of
renal function to look at the MDRD equation in that
population. What they found was that in normal
patients, it grossly understates kidney function. This
answers the criticism of the NKF [National Kidney
Foundation] guidelines that many people with normal
kidney function have GFRs and MDRDs of 80 or 75.
Therefore, in cases of mild kidney disease, MDRD is
probably not a very good formula. But, if you are look-
ing at people who have more advanced levels of kidney
 REVIEW
disease, MDRD seems to be very well validated.
Dr Scheel: In our laboratory, GFR and MDRD
levels greater than 60 will be reported, and a numeric
value will be reported for levels less than 60 units.
Every time anemia and mortality are discussed, a
member of the audience will bring up the one prospec-
tive trial where we looked at anemia and higher hema-
tocrits in patients with CVD. The trial had to be
stopped early because of increased mortality. Dr
Fishbane, do you want to comment?
Dr Fishbane: The difficulty is, thus far, the 5 or 6
published interventional studies have not shown ben-
efit and, if anything, have shown a slight risk of harm.
There were not many randomized studies of anemia in
the days when patients were started at 15 to 20 hema-
tocrits and increased to higher levels. There was such a
great interest in showing that erythropoietin worked,
that these tended to be nonrandomized trials or very
small randomized trials looking at movements of
hematocrits from 24, 25, up to 30. This is such a
robust effect that you would think that if they had
done randomized controlled trials, they probably
would have been very effective. But I agree with you
that, unfortunately, going from observational studies
to interventional studies to look at the further correc-
tion of anemia has not shown us much of anything.
Dr Scheel: I wonder whether it is the diabetic model.
By the time the diabetics get to us for treatment, they
have such irreversible disease that no matter what inter-
vention is used, we are unable to correct the problem. It
would be interesting to see if we started to intervene at
stage 3 CKD and did not allow the LVH to occur, and
looked at the higher hematocrits in that population,
whether we would actually reduce mortality.
Dr Fishbane: That would require longer end
points; 2-, 3-, 4-, or 5-year end points.
Dr Agarwal: Looking at the slide that Dr Lepor
presented with anemia as a multiplier for cardiovascu-
lar risk, the patient with anemia, CKD, and CHF has
a 45% mortality. In putting these together in the inter-
vention trial, treating anemia to a higher target yields
higher mortality. But looking at the study just pre-
sented, the patient with anemia already has a higher
risk for mortality. Of greatest concern is that we do not
know what the optimal Hb target is in this population.
There currently are 3 trials under way to determine the
Hb target.
S710
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Advanced Studies in Medicine n S711