Editorial
Cardiovascular Disease Prevention in CKD
Related Article, p. 375
C ardiovascular disease risk is increased in patients
with chronic kidney disease (CKD), with doubling
of the risk for most events (heart failure, myocardial
infarction, stroke, atrial fibrillation, and peripheral
artery disease).1 Cardiovascular disease accounts for
58% of deaths in this group, and patients aged 30 and
55 years with estimated glomerular filtration rates
(eGFRs) of 15-29 mL/min/1.73 m2 will have a loss in
life expectancy of 12.5 and 6.2 years, respectively,
due to cardiovascular disease. Despite this, patients
with CKD for several reasons have received subop-
timal preventive care. Recently, KDIGO (Kidney
Disease: Improving Global Outcomes) published a
new clinical practice guideline on lipid management
in CKD. 2 One of the main recommendations was
statin treatment in non–dialysis-dependent patients 50
years or older with eGFRs , 60 mL/min/1.73 m 2.
Treatment cutoff values were based on 10-year risk
for hard coronary events found in a large, but at that
time unpublished, Canadian cohort. Cardiovascular
disease prevention has been a “problem child” in
nephrology for decades, with many aspects unresolved,
so the new guideline recommendations were eagerly
awaited.
In this issue of AJKD, Tonelli et al3 present evidence
from the Canadian cohort, which constituted important
data for the rationale of the guideline recommendations.
They describe the relationships among age, kidney
function, and absolute coronary risk in 1.2 million pa-
tients having serum creatinine measured for any reason
and followed up for a median of 4 years. For patients
older than 50 years with CKD, the risk for myocardial
infarction or coronary death was more than 10 per 1,000
patient-years for all combinations of sex, eGFR, and
albuminuria. This is a commonly used risk cutoff value
for deciding whether to start cardiovascular preventive
intervention. In contrast, patients younger than 50 years
with CKD had coronary risk below this level (except for
men aged 40-49 years with eGFRs , 60 mL/min/
1.73 m2 and increased albuminuria). Clinically, the risk
estimates represent highly significant differences with
narrow 95% confidence intervals (CIs). Sensitivity
analysis including sudden cardiac death or other
Address correspondence to Stein Ivar Hallan, MD, PhD,
Department of Renal Medicine, St. Olav University Hospital,
N-7006 Trondheim, Norway. E-mail: stein.hallan@ntnu.no
Ó 2014 by the National Kidney Foundation, Inc.
0272-6386/$36.00
http://dx.doi.org/10.1053/j.ajkd.2014.06.005
326
cardiovascular outcomes did not change the main re-
sults, neither did subgroup analysis of patients with
diabetes or prior cardiovascular disease.
Cardiovascular pathophysiology in CKD has distinc-
tive characteristics, including intensive calcification.
However, there has been an increasing misconception
that patients with CKD are affected mainly by Möncke-
berg sclerosis and not a traditional lipid-driven athero-
sclerosis. There is very little evidence that Mönckeberg
sclerosis is an independent nonatherogenic process.4
Most likely Mönckeberg sclerosis and typical CKD
vascular pathology should be described as type Vb
atherosclerotic lesions, that is, a very advanced lipid-
depleted heavy calcified lesion affecting both media
and intima layers. Clearly, CKD-specific bone mineral
disturbances strongly contribute to calcification of pla-
ques and substantially accelerate the atherosclerotic
process. However, cholesterol crystallization seems to be
an important trigger for cardiovascular disease pathology
in CKD also, thereby creating a strong theoretical ratio-
nale for lipid intervention in patients with non–dialysis-
dependent CKD.
What is the clinical evidence that lipid intervention
is effective in patients with CKD? Nephrology
regrettably is the medical subspecialty with fewest
randomized controlled trials, and patients with CKD
have been systematically excluded from such studies.
Currently, there are only 4 randomized trials on lipid
treatment primarily targeting patients with CKD. One
included kidney transplant recipients only (ALERT
[Assessment of Lescol in Renal Transplantation]),5 2
included dialysis patients only (4D [Die Deutsche
Diabetes Dialyse Studie] and AURORA [A Study to
Evaluate the Use of Rosuvastatin in Subjects on Reg-
ular Hemodialysis: An Assessment of Survival and
Cardiovascular Events]),6,7 and only one studied un-
selected patients with CKD (SHARP [Study of Heart
and Renal Protection]: 36%, 42%, 20% and 32% of
participants with eGFRs of 30-59, 15-29, ,15 mL/
min/1.73 m2, and on dialysis therapy, respectively).8 In
SHARP, patients with CKD with higher traditional risk
levels (systolic blood pressure, total cholesterol level,
and body mass index) had higher relative risk (RR)
reductions, whereas patients with more advanced kid-
ney disease (ie, lower eGFRs) had less effect of the
intervention with simvastatin, 20 mg, plus ezetimibe,
10 mg, daily. The overall effect (nonfatal myocardial
infarction, coronary death, nonhemorrhagic stroke,
or arterial revascularization) was a 22% RR reduction
(RR, 0.78; 95% CI, 0.67-0.91) in patients not on
dialysis therapy, whereas there was no significant
effect in dialysis patients (RR, 0.90; 95% CI,
Am J Kidney Dis. 2014;64(3):326-328
Editorial
0.75-1.08).8 This risk reduction probably is somewhat
less than in primary prevention of patients without
CKD, as summarized in a Cochrane database meta-
analysis (RR, 0.70; 95% CI, 0.61-0.79).9 In addition,
2 meta-analyses of post hoc studies reporting results in
subgroups of participants with reduced eGFRs
(respectively comprising 9 and 20 studies and 20,000
and 45,000 patients) reported very similar treatment
effects on major cardiovascular events despite using
different methods, with RRs of 0.76 (95% CI, 0.73-
0.80) and 0.78 (95% CI, 0.71-0.86), respectively.10,11
Although such post hoc analysis could be biased, the
2 analyses give consistent results, supporting the view
that lipid lowering in patients with non–dialysis-
dependent CKD is effective.
Risk prediction is an important part of preventive
medicine and can be performed in several ways.
Models incorporating multiple variables can use score
sheets or computers to prognosticate future risk for
adverse advents. The Framingham models have been
used extensively in general medicine, but they do not
perform very well in patients with CKD.12 Specific
models for patients with CKD therefore have been
developed, but discrimination has been modest.13
However, the average cardiovascular risk level in pa-
tients with CKD is so high that individual risk predic-
tion might not be necessary. Diabetes has been
recognized as a coronary heart disease risk equivalent
(or at least very high risk), implying that most patients
with diabetes mellitus should receive lipid-lowering
therapy.14 The current study by Tonelli et al3 shows
that all patients older than 50 years with CKD, even
those with eGFRs . 60 mL/min/1.73 m2 (CKD cate-
gories G1 A2-3 and G2 A2-3), have a rate of coronary
death or nonfatal myocardial infarction higher than 10
per 1,000 person-years. This is an important finding that
could simplify risk prediction in patients with CKD and
facilitate implementation of preventive interventions.
The study has several strengths, including its very
large and clinically relevant cohort, use of state-of-
the-art methods for serum creatinine analysis and
GFR estimation, and a validated algorithm to find
participants with myocardial infarction during follow-
up. However, as noted by the authors, generalizability
of this Canadian study could be limited, and of
course, broad applicability is critical for the new in-
ternational lipid guideline. Similar data have not been
published previously, but data from general popula-
tion cohorts in the worldwide CKD Prognosis Con-
sortium can give some information. European
cardiovascular prevention guidelines define cardio-
vascular mortality .5 per 1,000 person years as high
risk needing intervention.15 In the 2.1 million CKD
Prognosis Consortium cohort cardiovascular death
accounted for 36% of deaths, and a total mortality risk
of .15 per 1,000 could be used to illustrate an
Am J Kidney Dis. 2014;64(3):326-328
equivalent high risk.16 Most patients aged 18-54 years
with CKD (except G1 A2, G1 A3, G2 A2, and G3a
A1) and all older patients with CKD have total mor-
tality risk above this level and could therefore be
eligible for intervention.17 Although not completely
comparable, the CKD Prognosis Consortium data
support the idea advanced by Tonelli et al3 that pa-
tients older than 50 years with CKD are at high risk,
whereas only those younger than 50 years with more
advanced CKD have sufficiently high risk to justify
preventive treatment. Overall, the study by Tonelli
et al3 is solid and gives an important contribution to
cardiovascular prevention in CKD.
The KDIGO work group labeled their main state-
ment on statin treatment of patients older than 50
years with CKD with eGFRs , 60 mL/min/1.73 m2
“grade 1A”; that is, the highest level of evidence and
class of recommendation. They also make a “grade
1B” statement that patients older than 50 years with
CKD with eGFRs $ 60 mL/min/1.73 m2 should be
treated with statins. Grade 1A statements usually
imply evidence from multiple randomized trials and
grade 1B pertains to evidence from one randomized
trial or nonrandomized trials18; however, KDIGO has
chosen a less stringent definition. The former
recommendation is strong (based on SHARP and post
hoc analysis), but the latter is an extrapolation of the
good efficacy of statins in general population-based
studies to patients with CKD stages 1-2. Although
these patients are at increased risk, we should be
careful with such strong recommendations because
statins have not been tested in this population.
In summary, in the current article, Tonelli et al3
provide good evidence on how we easily can use
age, eGFR, and albuminuria to select patients with
CKD with very high cardiovascular risk. This evi-
dence is used in the recent KDIGO lipid guideline,
which advocates statin treatment in patients older than
50 years with CKD. However, the guidelines should
be used with some caution given the limited amount
of evidence for statins in kidney medicine.
Stein Ivar Hallan, MD, PhD
St. Olav University Hospital and Norwegian University
of Science and Technology
Trondheim, Norway
ACKNOWLEDGEMENTS
Support: None.
Financial Disclosure: The author declares that he has no rele-
vant financial interests.
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