Download Figure 1

Journal of the American College of Cardiology
© 2003 by the American College of Cardiology Foundation
Published by Elsevier Science Inc.
EDITORIAL COMMENT
Why Is Chronic Kidney
Disease the “Spoiler” for
Cardiovascular Outcomes?*
Peter A. McCullough, MD, MPH, FACC,
FACP, FCCP, FAHA
Kansas City, Missouri
The modern-day, first-world epidemics of obesity and
hypertension are central drivers of an epidemic of combined
chronic kidney disease (CKD) and cardiovascular disease
(CVD) (1). Among those with diabetes for 25 years or
more, the prevalence of diabetic nephropathy in type 1 and
type 2 diabetes is 57% and 48%, respectively (2). Approximately half of all cases of end-stage renal disease (ESRD)
are due to diabetic nephropathy, with most of these cases
driven by obesity-related type 2 diabetes and hypertension.
With the graying of America, and cardiovascular care
shifting towards the elderly, there is an imperative to
understand why decreasing levels of renal dysfunction act as
a major adverse prognostic factor after cardiovascular events.
See page 718
CKD AND RISK
Chronic kidney disease is defined through a range of
estimated glomerular filtration rate (eGFR) values by the
National Kidney Foundation Kidney Disease Outcomes
Quality Initiative, as depicted in Figure 1 (3). Most studies
of cardiovascular outcomes have found that a breakpoint for
increased risk of restenosis, recurrent myocardial infarction
(MI), congestive heart failure, and cardiovascular death
occurs below an eGFR of 60 ml/min/1.73 m2, which
roughly corresponds to a serum creatinine (Cr) of ⬎1.5
mg/dl in the general population (4 –7). Because Cr is a
crude indicator of renal function, and often underestimates
renal dysfunction in women and the elderly, calculated
measures of eGFR by the Cockroft-Gault equation or by
the Modification of Diet in Renal Disease equations, now
available on personal digital assistants, are the preferred
methods of estimating and reporting renal dysfunction (3).
In addition, microalbuminuria at any level of eGFR is
considered to represent CKD, and has been thought to
occur as the result of hyperfiltration in the kidneys due to
diabetes and hypertension-related changes in the glomeruli
(8). There have been several definitions developed for
*Editorials published in the Journal of the American College of Cardiology reflect the
views of the authors and do not necessarily represent the views of JACC or the
American College of Cardiology.
From the Departments of Basic Science and Internal Medicine, Cardiology
Section, University of Missouri-Kansas City School of Medicine, Truman Medical
Center, Kansas City, Missouri.
Vol. 41, No. 5, 2003
ISSN 0735-1097/03/$30.00
doi:10.1016/S0735-1097(02)02955-8
microalbuminuria (8). A simple definition for microalbuminuria is 30 to 300 mg/l on a single voided casual
specimen; ⬎300 mg/l is usually considered gross proteinuria. In this issue of the Journal, Freeman et al. (9) describe
the influence of baseline renal dysfunction on the outcomes
of 889 patients with acute coronary syndromes (ACS). This
article highlights several of the leading explanations for why
CKD is such a potent risk factor for adverse outcomes after
cardiovascular events: 1) excess comorbidities in patients
with CKD; 2) lesser use of beneficial therapies in patients
with CKD, or therapeutic nihilism; 3) excess toxicities from
conventional therapies used; and 4) the unique pathobiology
of the CKD state, which leads to accelerated and more
severe cardiovascular disease.
EXCESS COMORBIDITIES
Population-based studies have demonstrated that there are
higher rates of diabetes, poorly controlled hypertension,
elevated triglycerides, lower high-density lipoprotein cholesterol, and elevated lipoprotein(a) levels in patients with
CKD and ESRD (10). However, there are lower rates of
smoking in the same groups compared to the general
population. There are insufficient data regarding CVD
family history or exercise to make conclusions regarding
these contributory CVD risks to the CKD and ESRD
populations. It is clear that age is a contributing factor to the
elevated risk of CKD. In the study by Freeman et al. (9),
there was a 14-year difference between those above and
below the cutpoint of 60 m/min/1.73 m2. However, for
those with ESRD, where the mean age is 56 years in U.S.
dialysis patients, age alone cannot be an explanatory factor
for adverse outcomes. Multivariate analyses used in almost
every retrospective study reported, when controlling for all
known confounders including age, have demonstrated an
independent association between CKD and cardiovascular
outcomes. The paper by Freeman et al. (9) is no exception.
Of particular interest is the observation that when diabetes
and renal function are taken into consideration together,
CKD is the dominant risk factor. In the study by Freeman
et al. (9), the adjusted odds ratio for in-hospital mortality for
diabetes was 2.17, whereas the calculated odds ratio for
those with eGFR ⬍30 ml/min would be 5.27 when using
eGFR ⬎90 ml/min as the referent. In the Bypass Angioplasty Revascularization Investigation Trial, again CKD
(defined as baseline Cr ⬎1.5 mg/dl) was found to be a more
important factor related to survival than diabetes, with
relative risks of 2.31 and 1.80, respectively (Fig. 2) (7).
These data taken together suggest a considerable amount of
the risk conveyed by the diabetic state is really driven by the
degree of renal dysfunction present.
UNDERUSE OF CARDIOPROTECTIVE THERAPIES
Given the excess comorbidities in patients with CKD and
ESRD, it is not unexpected that reduced rates of proven
726
McCullough
Editorial Comment
JACC Vol. 41, No. 5, 2003
March 5, 2003:725–8
Figure 1. The classification of chronic kidney disease (CKD) according to the National Kidney Foundation Kidney Disease Outcomes Quality Initiative.
Increased rates of adverse effects are generally seen below an estimated glomerular filtration rate of 60 ml/min/1.73 m2. CHF ⫽ congestive heart failure;
CV ⫽ cardiovascular; ESRD ⫽ end-stage renal disease; GFR ⫽ glomerular filtration rate; MI ⫽ myocardial infarction. Adapted from reference 3.
therapies may explain, in part, the outcomes observed.
Although data to support this hypothesis are limited,
Beattie et al. (5) have recently reported that in the setting of
ST-segment myocardial infarction, there are graded decreases in the use of routine therapies as renal function
declines. The paper by Freeman et al. (9) also demonstrated
reduced rates of catheterization, angioplasty, and glycoprotein (GP) IIb/IIIa inhibitor usage in patients with more
advanced CKD. Of interest is the observation that with
lower rates of catheterization, the relative rates of bypass
surgery increased, suggesting that the burden of severe
coronary disease is far greater in those with CKD. It is
certainly conceivable that quality programs may target these
opportunities for improvement, especially with respect to
the use of aspirin, beta-blockers, agents that block the renin
angiotensin system (RAS), reperfusion therapy, and revascularization where possible. In a recent analysis, aspirin and
beta-blockers, although underused in CKD patients with
acute MI, demonstrated a consistent and large mortality
benefit across all strata of renal dysfunction (11).
EXCESS TOXICITIES OF THERAPIES
It is clear that patients with CKD and ESRD have
worsened outcomes after angioplasty and bypass surgery,
and this in part can be considered a “toxicity” of the therapy
offered. However, data on the drug toxicities and drug
interactions that result in poor outcomes in CKD and
ESRD patients are difficult to find. One of the reasons for
this is that CKD and ESRD are routinely excluded from
randomized trials. The study by Freeman et al. (9) demonstrated both risks and benefits with the use of GP IIb/IIIa
inhibitors. In fact, the majority of major bleeding events in
those patients with eGFR ⬍60 ml/min occurred on GP
IIb/IIIa inhibitors. However, it is unknown whether it was
the GP IIb/IIIa inhibitor or concomitant unfractionated
Figure 2. Freedom from cardiovascular death after angioplasty or bypass surgery in the Bypass Angioplasty Revascularization Investigation (BARI) Trial
and Registry, n ⫽ 3,608. CKD ⫽ chronic kidney disease; DM ⫽ diabetes mellitus. Adapted from reference 7.
McCullough
Editorial Comment
JACC Vol. 41, No. 5, 2003
March 5, 2003:725–8
727
Figure 3. The unique pathobiology of the chronic kidney disease (CKD) state and its effects on the cardiovascular system. Ca ⫽ calcium; HDL ⫽
high-density lipoprotein cholesterol; LDL-C ⫽ low-density lipoprotein cholesterol; Lp(a) ⫽ lipoprotein (a); LPL ⫽ lipoprotein lipase; LV ⫽ left ventricle;
PO4 ⫽ phosphorus; PTH ⫽ parathyroid hormone; RAS ⫽ renin angiotensin system; SNS ⫽ sympathetic nervous system; TG ⫽ triglycerides.
heparin that was the culprit, given that both have renaldependent clearance mechanisms and both have graded
increased bleeding risks in those with low eGFR (12).
Cardiologists need to understand how to use conventional
antithrombotics, including unfractionated heparin, lowmolecular-weight heparin, GP IIb/IIIa inhibitors, and bivalirudin in the settings of acute coronary syndromes and
percutaneous coronary intervention. These sources of data
will be best derived from future, prospective randomized
trials in the CKD population. A substantial number of other
drugs require dose adjustment or special precautions in
CKD, including antiarrhythmics, intravenous inodilators
(milrinone), and digoxin. From the reported outcomes
studies, it is unknown how often these CKD-related drug
adverse events contribute to hard outcomes. Lastly, despite
their proven benefit in CKD and congestive heart failure,
agents that block the RAS may hasten the progression to
ESRD and cause problems with hyperkalemia; hence, their
underuse in the most advanced CKD patients results in a
lack of cardioprotection.
ABNORMAL VASCULAR BIOLOGY IN CKD
As renal function declines, there are a host of abnormalities
that develop, including changes in coagulation, fibrinolysis,
lipids, endothelial dysfunction, homocysteine, anemia, calcium/phosphorus balance, and many other factors that have
been related to CVD (Fig. 3) (13). The leading hypotheses
include hyperactivation of the RAS leading to adverse
cardiac remodeling, accelerated atherosclerosis, and symptomatic events (13). There is a growing body of evidence
that erythropoietin deficiency and anemia are related to
adverse ventricular remodeling and cardiac failure (14).
Hyperhomocystinemia is an obvious therapeutic target for
future trials in ACS given its predictable elevation in CKD,
known association with adverse outcomes, and its reduction
with high doses of folic acid (15). Lastly, advanced atherosclerosis related to abnormal vascular calcification driven by
an elevated calcium-phosphorous product (CPP) is an
attractive hypothesis in ESRD, where recent studies suggest
that not only is CPP related to coronary calcification, but
that lowering of the CPP may reduce or stabilize the
coronary calcification process (16).
CONCLUSIONS
Chronic kidney disease is the most important factor in
predicting adverse outcomes after virtually all cardiac events
including acute coronary syndromes. Hence, CKD is really
a “spoiler” for the expected benefit of many treatments in
cardiovascular medicine. A combination of excess comorbidities, therapeutic nihilism, therapy-related toxicity, and a
unique vascular pathobiology accounts for this observation.
Through intense and systematic study of these mechanisms,
new diagnostic and therapeutic targets will be discovered,
which will enhance the cardiac care of patients with CKD,
and perhaps attenuate the powerful risks we are seeing
today.
728
McCullough
Editorial Comment
Reprint requests and correspondence: Dr. Peter A. McCullough, Department of Internal Medicine, Cardiology Section,
Truman Medical Center, 2301 Holmes Street, Kansas City,
Missouri 64108. E-mail: [email protected].
REFERENCES
1. Lewis CE, Jacobs DR Jr., McCreath H, et al. Weight gain continues
in the 1990s: 10-year trends in weight and overweight from the
CARDIA study. Coronary Artery Risk Development in Young
Adults. Am J Epidemiol 2000;151:1172–81.
2. Bretzel RG. Effects of antihypertensive drugs on renal function in
patients with diabetic nephropathy. Am J Hypertens 1997;10:208S–
17S.
3. National Kidney Foundation. Clinical practice guidelines for chronic
kidney disease: evaluation, classification, and stratification. Am J Kid
Dis 2002;2 Suppl 1:S46 –75.
4. McCullough PA, Soman SS, Shah SS, et al. Risks associated with
renal dysfunction in patients in the coronary care unit. J Am Coll
Cardiol 2000;36:679 –84.
5. Beattie JN, Soman SS, Sandberg KR, Yee J, Borzak S, McCullough
PA. Determinants of mortality after myocardial infarction in patients
with advanced renal dysfunction. Am J Kidney Dis 2001;37:1191–200.
6. Chertow GM, Lazarus JM, Christiansen CL, et al. Preoperative renal
risk stratification. Circulation 1997;95:878 –84.
7. Szczech LA, Best PJ, Crowley E, et al. Bypass Angioplasty Revascularization Investigation (BARI) Investigators. Outcomes of patients
with chronic renal insufficiency in the Bypass Angioplasty Revascularization Investigation. Circulation 2002;105:2253–8.
JACC Vol. 41, No. 5, 2003
March 5, 2003:725–8
8. Keane WF, Eknoyan G. Proteinuria, albuminuria, risk, assessment,
detection, elimination (PARADE): a position paper of the National
Kidney Foundation. Am J Kidney Dis 1999;33:1004 –10.
9. Freeman RV, Mehta RH, Al Badr W, Cooper JV, Kline-Rogers E,
Eagle KA. Influence of concurrent renal dysfunction on outcomes of
patients with acute coronary syndromes and implications of the use of
glycoprotein IIb/IIIa inhibitors. J Am Coll Cardiol 2003;41:718 –24.
10. Levey AS, Beto JA, Coronado BE, et al. Controlling the epidemic of
cardiovascular disease in chronic renal disease: what do we know?
What do we need to learn? Where do we go from here? National
Kidney Foundation Task Force on Cardiovascular Disease. Am J
Kidney Dis 1998;32:853–906.
11. McCullough PA, Sandberg KR, Borzak S, Hudson MP, Garg M,
Manley HJ. Benefits of aspirin and beta-blockade after myocardial
infarction in patients with chronic kidney disease. Am Heart J
2002;144:226 –32.
12. Robson R. The use of bivalirudin in patients with renal impairment.
J Invas Cardiol 2000;12:F33–6.
13. McCullough PA. Cardiorenal risk: an important clinical intersection.
Rev Cardiovasc Med 2002;3:71–6.
14. Silverberg DS, Wexler D, Sheps D, et al. The effect of correction of
mild anemia in severe, resistant congestive heart failure using subcutaneous erythropoietin and intravenous iron: a randomized controlled
study. J Am Coll Cardiol 2001;37:1775–80.
15. Bostom AG, Kronenberg F, Jacques PF, et al. Proteinuria and plasma
total homocysteine levels in chronic renal disease patients with a
normal range serum creatinine: critical impact of true glomerular
filtration rate. Atherosclerosis 2001;159:219 –23.
16. Chertow GM, Burke SK, Raggi P, the Treat to Goal Working Group.
Sevelamer attenuates the progression of coronary and aortic calcification in hemodialysis patients. Kidney Int 2002;62:245–52.