Series

Global Kidney Disease 5

Chronic kidney disease and cardiovascular risk:
epidemiology, mechanisms, and prevention
Ron T Gansevoort, Ricardo Correa-Rotter, Brenda R Hemmelgarn, Tazeen H Jafar, Hiddo J Lambers Heerspink, Johannes F Mann,
Kunihiro Matsushita, Chi Pang Wen

Since the first description of the association between chronic kidney disease and heart disease, many epidemiological Lancet 2013; 382: 339–52
studies have confirmed and extended this finding. As chronic kidney disease progresses, kidney-specific risk factors Published Online
for cardiovascular events and disease come into play. As a result, the risk for cardiovascular disease is notably May 31, 2013
http://dx.doi.org/10.1016/
increased in individuals with chronic kidney disease. When adjusted for traditional cardiovascular risk factors,
S0140-6736(13)60595-4
impaired kidney function and raised concentrations of albumin in urine increase the risk of cardiovascular disease by
This online publication has
two to four times. Yet, cardiovascular disease is frequently underdiagnosed and undertreated in patients with chronic been corrected. The corrected
kidney disease. This group of patients should, therefore, be acknowledged as having high cardiovascular risk that version first appeared at
needs particular medical attention at an individual level. This view should be incorporated in the development of thelancet.com on July 26, 2013
guidelines and when defining research priorities. Here, we discuss the epidemiology and pathophysiological This is the fifth in a Series of
mechanisms of cardiovascular risk in patients with chronic kidney disease, and discuss methods of prevention. six papers about global
kidney disease
Department of Nephrology,
Introduction disease. Many studies have since confirmed and extended University Medical Centre
Bright wrote in 1836, “The obvious structural changes in
1
this association, and explanations have been sought. As Groningen, University Hospital
the heart have consisted chiefly of hypertrophy...and what part of this Series on global kidney disease, we discuss the Groningen, Groningen,
is most striking, out of fifty-two cases…no valvular disease relation between chronic kidney disease and cardiovascular Netherlands
(R T Gansevoort MD);
could be detected in thirty-four…This naturally leads us to risk. We present available information on the epidemi- Department of Nephrology
look for some less local cause”, and “It is observable, that ology, pathophysiological mechanisms, and prevention of and Mineral Metabolism,
the hypertrophy of the heart seems, in some degree, to chronic kidney disease and aim to provide guidance for National Medical Science and
have kept pace with the advance of disease in the kidneys; future research. Nutrition Institute Salvador
Zubiran, Mexico City, Mexico
for in by far the majority of cases, when the heart was (Prof R Correa-Rotter MD);
increased, the hardness and contraction of the kidney Epidemiology Department of Medicine,
bespoke the probability of long continuance of the disease.” Cardiovascular risk University of Calgary,
Bright was the first to report the association between As discussed by Eckardt and colleagues3 in this Series, Calgary, Canada
(Prof B R Hemmelgarn MD);
chronic kidney disease and cardiovascular abnormalities. chronic kidney disease is defined as impaired kidney Programme in Health Services
He suggested that the altered quality of the blood in function or raised proteinuria that are confirmed on two and Systems Research,
patients with renal disease affected the peripheral or more occasions at least 3 months apart. The estimated Duke-NUS Graduate Medical
School, Singapore, Singapore
vasculature, particularly the capillaries, in a way that glomerular filtration rate is the recommended method
required increased force to propel the blood around the
body.2 By taking the view that renal disease is the primary
disorder and cardiovascular changes are secondary, Bright Key messages
established the concept of the renal origin of cardiovascular • In patients with chronic kidney disease, compared with the general population,
cardiovascular disease is more frequent and severe, is often not recognised, and is
often undertreated
Search strategy and selection criteria
• Patients with chronic kidney disease should be viewed among the highest-risk groups
We searched PubMed and Medline in April, 2012, with search for cardiovascular events and disease, and require special clinical attention at an
terms that included but were not restricted to “chronic individual patient level, in the development of guidelines, and in the defining of
kidney disease”, “chronic kidney failure”, “glomerular research priorities
filtration rate”, or “albuminuria”, in combination with • The strong causal association between chronic kidney disease and cardiovascular risk
“cardiovascular morbidity”, “cardiovascular mortality”, implies that to prevent progression of chronic kidney disease is, by definition, to
“cardiovascular risk”, “myocardial infarction”, or “heart prevent cardiovascular disease
failure”. Further publications were identified from references • In patients with chronic kidney disease, the increased cardiovascular risk is
cited in relevant articles. We also relied on our own familiarity multifactorial and is due partly to pathophysiological processes specific to chronic
with the scientific literature. We reviewed only papers kidney disease that make prevention of cardiovascular disease by standard
published in English. No date restrictions were placed on interventions directed at single traditional risk factors difficult; therefore, innovative
searches. Our reference list was modified on the basis of strategies need to be investigated (eg, the targeting of non-traditional cardiovascular
comments from peer reviewers. risk factors, early prevention, and multifactorial intervention strategies)

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 Series
(Prof T H Jafar MD); Department
of Clinical Pharmacology,
University Medical Centre
Groningen, Groningen,
Netherlands
(H J Lambers Heerspink PharmSc);
Department of Nephrology,
Munich General Hospitals,
Munich, Germany
(Prof J F Mann MD); Department
of Medicine, Clinic IV,
University of Erlangen-
Nurnberg, Germany
(Prof J F Mann); Department of
Epidemiology, Bloomberg
School of Public Health, Johns
Hopkins University, Baltimore,
MD, USA (K Matsushita MD);
and China Medical University
Hospital, Taichung, Taiwan and
Institute of Population Health
Science, National Health
Research Institutes, Zhunan,
Taiwan (Prof C P Wen MD)
Correspondence to:
Dr R T Gansevoort, Department
of Nephrology, University
Medical Centre Groningen,
PO Box 30.001,
9700 RB Groningen, Netherlands
r.t.gansevoort@umcg.nl
340
of assessment. The preferred equation to calculate esti-
mated glomerular filtration rate is that of the Chronic
Kidney Disease Epidemiology Collaboration (commonly
known as the CKD-EPI), which takes into account sex,
age, ethnic origin, and serum creatinine concentration.4
Proteinuria should preferably be assessed by the urinary
albumin-to-creatinine ratio.4 On the basis of these
measurements, chronic kidney disease is classified into
six stages of estimated glomerular filtration rate (1, 2, 3A,
3B, 4, and 5) and three proteinuria stages (1, 2, and 3),
with stage 1 representing normal values and higher
stages reflecting more severe disease.3
Many studies in various populations have reported that
low estimated glomerular filtration rate and raised
albuminuria are associated with cardiovascular disease.
Only a handful of studies have, however, simultaneously
assessed these two measures of chronic kidney damage
in this context. Data from these and 30 other published
and unpublished cohort studies involving more than
1·4 million individuals were assessed in meta-analyses.5,6
After adjustment for traditional cardiovascular risk
factors and albuminuria, the risk gradient for cardio-
vascular mortality changed little when estimated
glomerular filtration rates were higher than 75 mL/min
per 1·73 m² and linearly increased with decreasing
A disease,9 coronary heart disease,10 and atrial fibrillation.11
4 Significant values
HR for CVD mortality (ACR studies)
Non-significant values
2
1
0·5
15 30 45 60 75
eGFR (mL/min per 1·73 m2)
B showed, however, that impaired kidney function and
4·0
HR for CVD mortality (ACR studies)
2·0
1·0
0·5
2·5 5 10 30
ACR (mg/g)
Figure 1: Independent associations of kidney function and proteinuria with
cardiovascular mortality
(A) Kidney function (eGFR); reference value of 95 mL/min per 1·73 m² is shown
with a diamond. (B) Albuminuria (ACR); the reference value of 5 mg/g is shown
with a diamond. Hazard ratios are adjusted for each other (eGFR or ACR), age,
sex, ethnic origin, and traditional cardiovascular risk factors. HR=hazard ratio.
CVD=cardiovascular disease. ACR=albumin-to-creatinine ratio. eGFR=estimated
glomerular filtration rate. Based on data in reference 5.
estimated glomerular filtration rates below this threshold
(figure 1).5,6 Cardiovascular mortality was about twice as
high in patients with stage 3 chronic kidney disease
(estimated glomerular filtration rate 30–59 mL/min per
1·73 m²) and three times higher at stage 4 (15–29 mL/min
per 1·73 m²) than that in individuals with normal kidney
function.5,6 In contrast to the non-linear risk relationship
for estimated glomerular filtration rate, the association of
albuminuria with cardiovascular risk has no threshold
effect, even after adjustment for traditional cardiovascular
risk factors and estimated glomerular filtration rate
(figure 1).5,6 The adjusted risk of cardiovascular mortality
is more than doubled at the upper end of the
microalbuminuria category (30–299 mg/g), compared
with the risk in individuals with normal albuminuria.5,6
This lack of threshold effect indicates that albuminuria
even at the upper end of the normal range (threshold
30 mg/g) confers cardiovascular risk. Thus, even slight
increases in albuminuria require clinical attention.
A wide variety of specific cardiovascular diseases have
been associated with estimated impaired kidney func-
tion. Risk of heart failure is roughly doubled in patients
with estimated glomerular filtration rates lower than
60 mL/min per 1·73 m² compared that in people with
preserved estimated glomerular filtration rates.7 The
risk is similarly increased for stroke,8 peripheral artery
Data for albuminuria in this context are sparse.12
The associations between chronic kidney disease and
cardiovascular disease are largely irrespective of age,13
sex,14 and ethnic origin: data have been reported for
US,15 European,16 Taiwanese,17 and South Korean17
general-population cohorts.
Chronic kidney disease is frequently the result of
hypertension and diabetes mellitus. The increased
cardiovascular risk in patients with chronic kidney
90 105 120 disease was, therefore, assumed for a long time to be the
result of these underlying diseases. Meta-analyses clearly
raised albuminuria are cardiovascular risk factors
independently of hypertension and diabetes mellitus
status.18,19 This assumption is strengthened by the obser-
vations that 40–50% of patients with low estimated
glomerular filtration rate and high albuminuria do not
have diabetes or hypertension, and that the associations
of estimated glomerular filtration rate and albuminuria
with cardiovascular mortality in these patients are similar
to those in individuals with chronic kidney disease who
300 1000 do have diabetes or hypertension.18,19 In one study, the
coronary risk conferred by chronic kidney disease even
surpassed that conferred by diabetes.20 Thus, individuals
with chronic kidney disease should be viewed as one of
the highest-risk groups for cardiovascular disease. How-
ever, so far only a few national and international guide-
lines on the management of cardiovascular risk have
paid specific attention to chronic kidney disease as a
notable risk factor.21
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Burden of cardiovascular disease A

The absolute cardiovascular risk in individuals with 45 eGFR stages 1–2,
chronic kidney disease was investigated in two large 40·9
normal or mildly decreased
(≥60 mL/min per 1·73 m²)
general population cohorts in Canada (n=949 119) and 40 eGFR stage 3A, mildly decreased
Taiwan (n=515 648; appendix pp 1–2).22,23 Life expectancy 36·9 (25–59 mL/min per 1·73 m²)
was substantially reduced for patients with impaired eGFR stage 3B, moderately decreased
35 (30–44 mL/min per 1·73 m²)
kidney function in the Canadian cohort (figure 2). eGFR stage 4, severely decreased
Patients aged 30 years with estimated glomerular (15–29 mL/min per 1·73 m²)
30 eGFR stage 5, severely decreased
filtration rate stage 3B (30–44 mL/min per 1·73 m²) or 4 (<15 mL/min per 1·73 m²) or RRT

Life expectancy (years)

(15–29 mL/min per 1·73 m²) had reductions in life
25 23·9
expectancy of around 17 or 25 years, respectively, com-
pared with individuals with normal kidney function 19·9
(figure 2). Reductions in life expectancy were also seen 20
among patients with raised albuminuria at age 30 years: 15·3 18·8
stage 2 and 3 albuminuria (30–299 mg/g and 300 mg/g 15
12·1 12·4
or higher, respectively) were associated with shortening
of life expectancy by around 10 and 18 years, respectively, 10
compared with that in individuals without albuminuria 7·2

(figure 2). Similar results were obtained by the same 5

5·6
methods in the Taiwan cohort (appendix p 3), which
supports the consistency of harmful effects from chronic 0
kidney disease across ethnic groups. Of note, reductions
in life expectancy reported for middle-aged patients with B
diabetes or hypertension are around 8 years26 and 45 Albuminuria stage 1, normal or
42·0 mildly increased (ACR <30 mg/g)
2–3 years,27,28 respectively. Albuminuria stage 2, moderately
The proportion of deaths from cardiovascular disease 40 increased (ACR 30–299 mg/g)
increases as estimated glomerular filtration rate declines Albuminuria stage 3, severely
increased (≥300 mg/g)
(figure 3). In the Canadian cohort, when adjusted for 35
age and sex, cardiovascular disease accounted for 27·5% 31·8
of deaths in individuals with normal kidney function 30
versus 58·0% in those with kidney failure. In the
Life expectancy (years)

Taiwanese cohort the proportions were 22·0% and

25 23·5
71·0%, respectively (appendix p 4). A similar increase in
20·7
the proportion of deaths due to cardiovascular disease is
20
observed among people with with raised albuminuria
(figure 3, appendix p 4).
15 14·0
In view of the increasing mortality and contribution
of cardiovascular disease as an underlying cause when
9·4
chronic kidney disease progresses, the substantial reduc- 10
tion in life expectancy due to cardiovascular disease in
these patients is unsurprising. When adjusted for sex, life 5
expectancy due to cardiovascular disease is shortened by
1·3, 7·0, 12·5, and 16·7 years, respectively, in patients aged 0
30 years with estimated glomerular filtration rate stages 30 35 40 45 50 55 60 65 70 75 80
Index age (years)
3A, 3B, 4, and 5 (45–59, 30–44, 15–29, and less than
15 mL/min per 1·73 m², respectively), compared with that Figure 2: Life expectancy, according to chronic kidney disease stages (Canadian data)
in individuals with normal kidney function (figure 4). In (A) eGFR stages and (B) albuminuria stages. Data are adjusted per eGFR and albuminuria stage for sex
to the WHO world average in 2000–05. eGFR=estimated glomerular filtration rate. RRT=renal replacement therapy.
Taiwan life expectancy was shortened by 2·1, 8·8, 17·8, Based on data in references 24 and 25 (appendix pp 1–2).
and 21·3 years, respectively (appendix p 5). Life expectancy
was also shortened in individuals with stage 2 or 3
albuminuria, as compared with no albuminuria: in Canada that the true burden of disease in patients with chronic See Online for appendix
by 2·3 and 10·2 years, respectively (figure 4), and in Taiwan kidney disease is related to the increased risk of
by 2·9 and 11·0 years, respectively (appendix p 5). cardiovascular disease rather than the risk of reaching
Importantly, in patients with mild to moderate kidney failure requiring renal-replacement therapy.
chronic kidney disease (stages 3A and 3B), the inci- Only in patients with severely impaired kidney function
dence of cardiovascular mortality is much higher than (stage 4) does the risk of kidney failure surpass that of
the incidence of kidney failure.5,6,29 These data indicate cardiovascular events.30,31

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A B
filtration rate is lower than 30 mL/min per 1·73 m²,
100 around 50% of patients develop left-ventricular hyper-
90
trophy,35 of which most is concentric hypertrophy.36 Apart
26·8
37·9 39·0
33·0 34·5 37·3 35·4 32·8 from hypertension, renal anaemia and increased vascular
80
stiffness might have pivotal roles in development of left-
Proportion of patients (%)

70 ventricular hypertrophy that leads to reduced coronary

24·4 7·5
60
25·9
50 28·1 32·5 31·6
34·6
40
30 58·0
48·8
20 41·1
27·5
32·9 30·1 32·9
10
0 ventricular hypertrophy in chronic kidney disease is
Stage 1–2 Stage 3A Stage 3B Stage 4 Stage 5 Stage 1–2 Stage 2
or RRT
eGFR stages Albuminuria stages
Others Cancer CVD
Figure 3: Causes of death per chronic kidney disease stage (Canadian data)
(A) eGFR stages and (B) albuminuria stages. Data are adjusted per eGFR and albuminuria stage for age and sex to
the WHO world averages in 2000–05. RRT=renal replacement therapy. Based on data in references 24 and 25
(appendix pp 1–2).
Pathophysiological mechanisms
Increased cardiovascular risk in individuals with chronic
kidney disease is due partly to the high prevalence of
traditional risk factors, such as hypertension and diabetes.
The associations of kidney function and albuminuria
with cardiovascular risk are, however, independent of
these traditional cardiovascular risk factors. Thus, non-
traditional kidney-specific mechanisms make notable
contributions to cardiovascular risk. Elucidation of these
mechanisms could reveal ways to lessen the cardiovascular
risk in individuals with chronic kidney disease.32 Research
has taken many avenues, but the main therapeutic routes,
especially those leading to specific therapies for chronic
kidney disease, have yet to be discovered.
Hypertension is a well known and strong risk factor for
development of chronic kidney disease. Nevertheless, the
cause-effect association can also be in the opposite
direction. Even in the early phases chronic kidney disease
can cause hypertension, which is likely to increase
cardiovascular risk in affected patients. In a Japanese
study hypertension increased cardiovascular risk more
evidently in people with chronic kidney disease than in
those without.33 These data suggest that antihypertensive
therapy would more effectively reduce cardiovascular
risk in patients with chronic kidney disease than in those
without this disorder. Few studies, however, support
this assumption. A target blood pressure of less than
140/90 mm Hg is deemed appropriate to prevent cardio-
vascular events in patients with chronic kidney disease; a
lower target blood pressure of less than 130/80 mm Hg is
recommended only in patients with increased album-
inuria (higher than 30 mg/g).34
In patients with early or advancing chronic kidney
disease, the prevalence of left-ventricular hypertrophy
is strikingly increased. When estimated glomerular
22·6 reserve.37 The latter could be aggravated by reduced
cardiac capillary density in chronic kidney disease and
impaired coronary dilatory responses, as has been shown
in animal studies. Expression of endothelial nitric-oxide
44·6 synthase is downregulated, which suggests a possible
mechanism for coronary endothelial dysfunction in early
stages of chronic kidney disease.32 Histologically, left-
Stage 3
characterised by myocardial fibrosis that is thought to
impair contractility. The high prevalence of left-ven-
tricular hypertrophy, with its associated risk of cardiac-
rhythm disturbances, could at least partly explain why
the prevalence of sudden cardiac death is increased in
people with chronic kidney disease.38 In the general
population, sudden cardiac death accounts for roughly
one death per 1000 person-years and for 6–13% of all
deaths, whereas among individuals with kidney failure,
the rates are 59 deaths per 1000 person-years and 26% of
total mortality.39 Besides the high prevalence of left-
ventricular hypertrophy, abnormal electrolyte concen-
trations and increased prevalence of coronary artery
disease are predisposing factors for sudden cardiac death
in patients with chronic kidney disease.39
Dyslipidaemia and low-grade inflammation are also
caused by chronic kidney disease.40 In patients with
impaired kidney function and high albuminuria, lipid
profiles become atherogenic, owing partly to defective
HDL cholesterol function and excessive oxidation of
LDL cholesterol.41 Mechanisms of increased systemic
inflammation in chronic kidney disease are unclear, but
increased production of inflammatory mediators has
been attributed to raised oxidative stress and accumu-
lation of postsynthetically modified proteins and toxins
that are cleared with normal renal function.32,40
Other factors that raise cardiovascular risk in patients
with chronic kidney disease include increased activity of
the renin–angiotensin system and sympathetic nerve
activity in chronic kidney disease. Angiotensin stimu-
lates production of superoxide, interleukin 6, and other
cytokines. Bioavailability of nitric oxide, which is involved
with vascular smooth-muscle contraction and growth,
platelet aggregation, and leucocyte adhesion to the
endothelium, becomes decreased. Activity of renalase is
lowered in individuals with chronic kidney disease. This
enzyme is produced by the kidney and inactivates
catecholamines.32 All these vasoactive factors impinge on
endothelial function. Albuminuria can be interpreted as
a sign of, but also as a contributor to, impaired endo-
thelial function.32,42 Another key factor for endothelial
function seems to be asymmetric dimethylarginine.
Concentrations increase with decreasing kidney function

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and predict mortality and cardiovascular complications

A
in patients with chronic kidney disease.43 Asymmetric 0
dimethylarginine inhibits generation of nitric oxide, –0·3
reduces cardiac output, and raises systemic vascular –2 –1·3
resistance and blood pressure. Increased concentrations
–3·1
of asymmetric dimethylarginine and sympathetic over- –4
activity are strongly associated with concentric left-
ventricular hypertrophy, which fits well with the –6
–6·2

Loss in life expectancy (years)

hypothesis that these factors are causally related with –7·0
cardiac abnormalities in chronic kidney disease.44 –8
–8·3
Atherosclerosis and valvular heart disease are fre-
quently seen in patients with kidney failure,45 but also –10

occur in those with early chronic kidney disease. The key

–12
modulators in this field have not been elucidated in
–12·5
intervention trials, but might include calcification
–14 eGFR stage 3A, mildly decreased
inhibitors (eg, fetuin-A and matrix Gla protein), pro-
(25–59 mL/min per 1·73 m²)
motors (eg, hyperphosphataemia), and calcium-phos- eGFR stage 3B, moderately decreased
–16
phate product, parathyroid hormone, and leptin.32,45 (30–44 mL/min per 1·73 m²)
–16·7 eGFR stage 4, severely decreased
Patients with impaired kidney function frequently –18 (15–29 mL/min per 1·73 m²)
develop deficiency of active vitamin D because of a lack eGFR stage 5, severely decreased
of its precursor, impaired activity of the kidney enzyme (<15 mL/min per 1·73 m²) or RRT
–20
1 α-hydroxylase, which converts this precursor to the
active hormone, or both.46 Observational studies in B
patients with chronic kidney disease have shown asso- 0
ciations between vitamin D deficiency and increased
risk of cardiovascular events, and experimental data –2 –1·5
–2·3
suggest that the vitamin D pathway is involved in
modifying cardiac structure and function.47 –4

The aforementioned list of pathophysiological mechan-

–6
isms linking chronic kidney disease to increased cardio- –6·2
Loss in life expectancy (years)

vascular risk is far from complete. Many other

–8
mechanisms have been suggested, but in-depth
discussion of each is beyond the scope of this report. The
–10
complex interaction between the kidneys and the heart –10·2
has been termed the cardiorenal syndrome, in which five –12
types have been defined.48 Type 4 is classified as chronic
kidney disease contributing to decreased cardiac –14
function, cardiac hypertrophy, and increased risk of
adverse cardiovascular events, and is referred to as –16
chronic renocardiac syndrome. The risk of cardiovascular Albuminuria stage 2, moderately
disease in individuals with chronic kidney disease is –18 increased (ACR 30–299 mg/g)
Albuminuria stage 3, severely
driven by kidney-specific risk factors in addition to increased (≥300 mg/g)
traditional risk factors (figure 5). As chronic kidney –20
30 35 40 45 50 55 60 65 70 75 80
disease progresses and kidney-specific risk factors
Index age (years)
become more and more relevant, the risk of
cardiovascular disease is amplified. Intervention trials Figure 4: Loss of life expectancy due to cardiovascular disease, by chronic kidney disease stage (Canadian data)
(A) eGFR stages, (B) albuminuria stages. Loss is compared with life expectancy in people with normal or mildly
that test hypotheses emerging from these mechanisms
impaired kidney function (stage 1–2, eGFR 60 mL/min per 1·73 m² or higher) and normal or mildly increased
are needed. Unfortunately, only a few have been albuminuria (stage 1, albumin-to-creatinine ratio less than 30 mg/g). Data are adjusted for sex. eGFR=estimated
investigated. glomerular filtration rate. RRT=renal replacement therapy. Based on data in references 24 and 25 (appendix pp 1–2).

Prevention of cardiovascular disease

Cardiovascular disease can be prevented by lifestyle and
pharmacological interventions. In low-income countries
lifestyle modifications might be particularly useful. The
prevention of cardiovascular disease in patients with
chronic kidney disease is generally focused on achieving
the best possible control of traditional cardiovascular risk
factors (tables 1, 2). In view of the progressive increase in
cardiovascular risk as kidney function declines, however,
prevention of loss of kidney function should be viewed as
a target by itself. Treatment strategies that slow or even
halt the progressive loss of kidney function might not only
postpone the need for dialysis or kidney transplantation,

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 Series

but also attenuate cardiovascular risk. Thus, the assign- Lifestyle interventions
ment of strength and grade to recommendations balances The evidence of a causal association between smoking
cardiovascular and renal protective effects. and chronic kidney disease is growing. In epidemio-

Acute kidney injury

Primary kidney diseases

Hypertension
Obesity
Diabetes mellitus
Early CKD Dyslipidaemia
eGFR >60 mL/min per 1·73m2, Smoking
urinary protein loss present Chronic inflammation
Atherosclerosis
Genetic risk factors
Coronary artery disease
Valvular disease
Left-ventricular hypertrophy
Decreased coronary perfusion
Arrhythmias

Glomerular/interstitial
damage

Hypertension
Dyslipidaemia
Mild to moderate CKD
Ca⁺ and PO₄² abnormalities
eGFR 30–60 mL/min per 1·73m2
NA⁺ overload
Chronic inflammation

Sclerosis–fibrosis

Hormonal inbalances
Anaemia and malnutrition
Severe Ca⁺ and PO₄² abnormalities
Soft-tissue calcification
NA⁺+H2O overload Chronic
Severe CKD EPO resistance inflammation
eGFR <30 mL/min per 1·73m2 Uraemic toxins
or requirement for RRT Parathyroid hormone
Sympathetic nerve overactivity

RRT-related: Monocyte stimulation

artificial surfaces,
contaminated fluids

Figure 5: Pathophysiological interactions between kidney and heart in chronic kidney disease
Chronic kidney disease contributes to decreased cardiac function, cardiac hypertrophy and increased risk of adverse cardiovascular events. eGFR=estimated
glomerular filtration rate. CKD=chronic kidney disease. EPO=erythropoietin. RRT=renal-replacement therapy. Adapted from reference 48 by permission of Elsevier.

344 www.thelancet.com Vol 382 July 27, 2013

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logical studies smoking has repeatedly been asso- the already raised risk of cardiovascular disease in
ciated with high risk of chronic kidney disease and patients with chronic kidney disease.49 Whether this
kidney failure.69,70 Furthermore, smoking exaggerates risk is modified by smoking cessation remains to be

Treatment goal Comments

Smoking cessation Smoking cessation (1D)
Dietary sodium Lowering intake to <2 g (<90 mmol) sodium daily
reduction (corresponds to <5 g salt) (1C)
Dietary protein Lowering of protein intake to 0·8 g/kg of ideal
restriction bodyweight daily in adults with diabetes (2C) or
without diabetes (2B) and eGFR
<30 mL/min per 1·73m²
Weight Achievement of BMI 20–25 kg/m², according to
management country-specific demographics (1D)
Physical activity Encourage physical activity compatible with
cardiovascular health and tolerance, aiming for at
least 30 min five times per week (1D)
Ample level evidence is available of the benefits of smoking cessation for reduction in cardiovascular risk in the general
population. In CKD smoking is associated with disease progression,49 although no specific data support cessation of
smoking to delay CKD progression
Individuals with CKD should receive expert dietary advice and information in an educational programme tailored
to the severity of CKD and required interventions on salt, phosphate, potassium, and protein intake (1B). Dietary
sodium restriction might enhance the effects of ACE inhibitors and ARBs to lower albuminuria and prevent
CKD progression50–53
A high protein intake (>1·3 g/kg of ideal bodyweight daily) should be avoided in adults with CKD and at risk of progression
(2C). Individuals with CKD should receive expert dietary advice and information in an educational programme, tailored to
the severity of CKD and required interventions on salt, phosphate, potassium, and protein intake (1B)
··
A 13% reduction of all-cause mortality was found among patients with CKD who did the minimum amount of exercise
(average 15 min of moderate intensity) compared with those who did no exercise at all. The effect is expected to be
much greater when patients undertake 30 min of exercise five times per week54

Each recommendation is graded (1, recommended; 2 suggested; no number, not graded) and the quality of the supporting evidence is rated (A, high; B, moderate; C, low; D, very low), according to guidelines.4,55,56
CKD=chronic kidney disease. ACE=angiotensin-converting enzyme. ARBs=angiotensin-receptor blockers. eGFR=estimated glomerular filtration rate. BMI=body-mass index.

Table 1: Lifestyle interventions for patients with chronic kidney disease to prevent progression and cardiovascular disease

Treatment goal Comments

BP reduction In patients with CKD and ACR <30 mg/g, reduce BP
to <140/90 mm Hg (1B); if ACR ≥30 mg/g, reduce
BP to <130/80 mm Hg (2D)
Inhibition of RAAS Use ACE inhibitors or ARBs in patients with
diabetes and ACR ≥30 mg/g (2D) or in those with
or without diabetes and ACR ≥300 mg/g (1B)
Glycaemic control Haemoglobin A1c ~ 7·0% proportion of total
haemoglobin (1A)
Lipid control No specific lipid targets are established in CKD
patients, but treat in accordance with guidelines
for other high-risk populations60*
Antiplatelet Offer adults with CKD at risk of atherosclerotic events RCTs specifically in patients with CKD are lacking, but meta-analyses of subgroups in RCTs suggest benefits, albeit
therapy treatment with antiplatelet agents unless bleeding
risk outweighs cardiovascular benefits (2B).
Haemoglobin Consider erythropoietin-stimulating treatment
control to raise haemoglobin concentrations on
individual basis*
Phosphate Use phosphate binders and diet to maintain serum
reduction phosphate concentrations in the normal range (2C)
Vitamin D Counteract vitamin D deficiency
supplementation
Uric acid Lower uric acid concentrations in serum
BP targets and agents should be set individually according to risk of CKD progression, age, coexistent cardiovascular
disease other comorbidities, presence or absence of retinopathy, and tolerance
Post-hoc analyses of RCTs show that treatment-induced reduction in albuminuria was associated with improved
prognosis, which suggests that reductions in albuminuria might help to guide treatment.57–59* Dose adjustments are
generally not necessary unless warranted by side-effects (hyperkalaemia or acute renal dysfunction)*
In patients at high risk of hypoglycaemia, do not lower haemoglobin A1c to <7·0% (1B) and consider raising the target
value to 7·0% in individuals with comorbidities or limited life expectancy and risk of hypoglycaemia (1C)
Statins are the preferred agents. Fibrates require dose adjustment because they are metabolised by the kidney and
eliminated by renal excretion.* Relative risk reductions achievable with statins in patients with CKD depend on
baseline cholesterol concentrations (benefit increases with increasing cholesterol concentrations) and kidney function
(effects are lessened in advanced CKD).61,62* Few data support prevention of CKD progression with statins60*
possibly outweighed by bleeding risks63,64
Decisions about erythropoietin-stimulating treatment should be made on individual basis, dependent on falling
haemoglobin concentrations, response to iron therapy, comorbidities, and tolerability.* No preventive benefits
against CKD progression or cardiovascular disease was seen in patients with stage 3–4 CKD when haemoglobin
concentrations were raised to higher than 120 g/L.65,66 Iron replacement is often effective as an initial treatment for
anaemia related to CKD
Epidemiological data strongly suggest that serum phosphorus concentrations higher than the normal range are
associated with increased (cardiovascular) morbidity and mortality. There is, however, a lack of RCT data to show that
lowering phosphorus concentrations positively alters cardiovascular and CKD clinical outcomes. An individualised
treatment approach, therefore, seems reasonable
Insufficient evidence to support or refute the use of vitamin D supplementation to delay CKD progression or to prevent
cardiovascular disease in patients with CKD.67,68 Vitamin D analogues are used in CKD to maintain parathyroid hormone
and calcium concentrations in serum within target ranges, increase bone-mineral density and muscle strength, and
reduce the risk of fractures
Insufficient evidence to support or refute the use of agents to lower uric acid concentrations in serum in patients
with CKD and symptomatic or asymptomatic hyperuricaemia to delay CKD progression or prevention of
cardiovascular disease*

Each recommendation is graded (1, recommended; 2 suggested; no number, not graded) and the quality of the supporting evidence is rated (A, high; B, moderate; C, low; D, very low), according to guidelines.4,55,56
BP=blood pressure. CKD=chronic kidney disease. ACR=angiotensin-to-creatinine ratio. RAAS=renin–angiotensin–aldosterone system. ACE=angiotensin-converting enzyme. ARBs=angiotensin-receptor blockers.
RCTs=randomised, controlled trials. *Evidence not classifiable; advice is given at the discretion of the authors.

Table 2: Pharmacological interventions in patients with chronic kidney disease to prevent progression and cardiovascular disease

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 Series
formally assessed. The well documented benefits of
smoking cessation in the general population are,
however, likely to extend to patients with chronic kidney
disease. Thus, smoking cessation should be discussed
and encouraged in all individuals with and at risk of
chronic kidney disease.
High dietary sodium is a pivotal determinant of blood
pressure, and predisposes patients with established
chronic kidney disease to salt-sensitive hypertension
and fluid retention. A review of seven intervention
studies that included 6250 individuals without chronic
kidney disease showed that dietary-sodium restriction
was associated with a significant 20% reduction in
cardiovascular events during follow-up.71 In individuals
with chronic kidney disease, sodium restriction might
enhance the effects of blockers of the renin–
angiotensin–aldosterone system (RAAS) on albumin-
uria50,51 and renal function.52,53 Despite these encouraging
findings intensive reductions in dietary sodium can be
difficult to achieve owing to poor adherence. Thus, a
restriction to intake of 2 g (90 mmol) sodium daily
(which corresponds to 5 g salt) is advised in all patients
with chronic kidney disease. This change will primarily
control blood pressure, but will also improve the effect
of RAAS inhibition on albuminuria and progression of
chronic kidney disease, enable volume control in
individuals with advanced chronic kidney disease, and
possibly confer independent prevention of cardio-
vascular disease.72
Obesity is associated with the development of chronic
kidney disease and progression to kidney failure.73
Additionally, obesity is predictive of cardiovascular
disease and mortality in patients with chronic kidney
disease. Waist circumference has been suggested as a
better measure than body-mass index to assess obesity-
associated risks.74 A systematic review of 13 randomised,
controlled trials of weight loss in overweight or obese
patients with chronic kidney disease revealed that
intentional weight loss was associated with decreases in
albuminuria that were independent of decreases in blood
pressure.75 Further studies are needed to confirm bene-
ficial effects of weight loss on prevention of cardiovascular
disease and progression of chronic kidney disease in
morbidly obese individuals. In the meantime, however,
international guidelines recommend that people with
chronic kidney disease be encouraged to achieve a
healthy weight (body-mass index 20–25 kg/m²).4
Whether patients with chronic kidney disease should
be prescribed restricted dietary protein has been a matter
of much debate. A meta-analysis of seven randomised
trials that involved 1494 patients indicated a 39%
reduction in kidney failure or death in patients randomly
assigned to low dietary protein.76 From a nutritional
standpoint a low-protein diet in patients with advanced
chronic kidney disease is safe.77 Unfortunately, large-
scale studies on protein intake and cardiovascular disease
in patients with chronic kidney disease have not been
346
done. Observational data in the general population
suggest that high protein intake is associated with
increased risk of cardiovascular events.78 Thus, excessive
protein intake should be avoided by individuals with
chronic kidney disease, and moderate restriction on
dietary protein intake to 0·8 g/kg daily is recommended,
especially if estimated glomerular filtration rate is lower
than 30 mL/min per 1·73 m² or in the case of progressive
chronic kidney disease.4
Observational studies have shown that increased
physical activity is associated with the lowering of
albuminuria79 and all-cause and cardiovascular mortality
in patients with chronic kidney disease.54,80 Trial data show
that moderate-intensity physical activity is associated with
improvement in physical performance measures, cardio-
vascular risk factors, and quality of life in these patients.81
Thus, regular exercise should be encouraged in patients
with chronic kidney disease.4
Pharmacological interventions
Traditional cardiovascular risk factors
Treatment of high blood pressure in patients with
any stage of chronic kidney disease is of paramount
importance to slow or prevent disease progression, and
is the mainstay of cardiovascular protection. Any of the
various classes of antihypertensive agents can be effec-
tively used in patients with chronic kidney disease, but
RAAS inhibitors are the first-line agents. The benefits of
RAAS inhibitors go beyond those expected from the
lowering of blood pressure alone, and are largely
explained by their albuminuria-lowering effects.58,59 The
choice of additional blood-pressure-lowering drugs
should be tailored to the need and toleration of the
individual patient. Patients with chronic kidney disease
are generally volume overloaded and diuretic therapy is
often indicated. High-dose loop diuretics, rather than
thiazide diuretics, becomes necessary to control fluid
retention and accompanying hypertension if kidney
function declines. Diuretics increase the efficacy of
RAAS inhibitors to lower albuminuria,72,82 which can
result in additional renoprotection. To prevent cardio-
vascular disease, a target blood pressure of lower than
140/90 mm Hg is likely to be sufficient. Optimum
renoprotection is reached at blood-pressure levels lower
than 130/80 mm Hg, especially in patients with chronic
kidney disease and increased albuminuria58,83 or diabetic
nephropathy.84,85 In such patients drugs to control blood
pressure, especially RAAS inhibitors, should be titrated
until the target blood pressure is reached and baseline
albuminuria is reduced by at least 50%.58,59 These aims
are based on robust observational data, although no
formal interventional trial of specific proteinuria targets
has yet been done.
Lipid-lowering therapies have undoubtedly contribu-
ted to a reduced incidence of cardiovascular events in
the general population, but similar benefits are also seen
in patients with chronic kidney disease, especially those
www.thelancet.com Vol 382 July 27, 2013

with high cholesterol concentrations.61 A meta-analysis
of all statin trials in individuals with chronic kidney
disease showed that the cardiovascular protective effect
of these drugs is attenuated in those with low estimated
glomerular filtration rate values and limited in patients
undergoing dialysis.62 In the studies assessed, statins
were tested at fixed doses. A recommendation on treat-
ment goals, therefore, cannot be given, but treatment in
accordance with current targets in other high-risk
populations seems appropriate. Few data are available to
indicate that lipid-lowering treatment affects the rate of
kidney disease progression.60
Diabetes is an important cause of chronic kidney
disease and markedly increases cardiovascular risk in
these individuals. Optimum glycaemic control slows the
progression of microvascular complications,86 but the
evidence for cardiovascular or mortality outcomes is of
much lower quality.86,87 In later-stage chronic kidney
disease, with poor renal clearance, metformin and long-
acting hypoglycaemic agents are contraindicated because
of the risk of hypoglycaemia. New oral glucose-lowering
drugs have become available for clinical use (eg, GLP-1
analogues and dipeptidyl peptidase IV inhibitors), but
their long-term effects on cardiovascular and kidney
outcomes are not yet established.
Cardiovascular protection with antiplatelet and anti-
coagulant therapy has been documented in secondary
prevention trials. Because patients with chronic kidney
disease are at increased cardiovascular risk, they might
benefit from antiplatelet therapy, but they also have
abnormal platelet function that raises the risk of
haemorrhagic events when treated with anticoagulants,
including antiplatelet therapies.88 A meta-analysis found
that use of antiplatelet agents in patients with chronic
kidney disease and stable or no cardiovascular disease
prevented infarction, but had uncertain effects on
mortality and increased the risk of minor bleeding
episodes.63 Similarly, in patients with acute coronary
syndromes antiplatelet agents had little or no effect on all-
cause mortality and increased risk of bleeding.63 Another
surprising observation is that in patients with chronic
kidney disease and atrial fibrillation the anticoagulant
warfarin might increase, not decrease, the risk of stroke.64
Several potential explanations for this finding have been
provided, including that warfarin potentiates vascular and
valvular calcification to increase the risk of ischaemic
stroke.64 The benefits of antiplatelet and anticoagulant
therapy for primary and secondary prevention in chronic
kidney disease patients, therefore, remain uncertain while
these drugs increase the risk of bleeding events.
Kidney-related cardiovascular risk factors
Much attention has been paid to the targeted treatment
of specific kidney-related cardiovascular risk factors to
improve renal and cardiovascular health, but results
have been mixed. For instance, on basis of the obser-
vation that low haemoglobin concentrations were
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Series
associated with cardiovascular outcomes, erythropoiesis-
stimulating agents were assessed. Unfortunately, in
patients with stage 3 or 4 chronic kidney disease, no
benefit was seen with correction of haemoglobin con-
centrations to more than 120 g/L, and an increased risk
of stroke was suggested.65,66 A randomised controlled
trial reported beneficial effects of vitamin D therapy with
paricalcitol on albuminuria as a surrogate of renal and
cardiovascular outcomes.67 However, in another ran-
domised, controlled trial, paricalcitol did not alter left-
ventricular mass index or improve diastolic dysfunction
in patients with chronic kidney disease.68 Larger studies
with longer follow-up and hard outcomes, therefore, are
needed and, as yet, vitamin D supplementation to lower
cardiovascular risk is not indicated. The effects of the
lowering of parathyroid-hormone concentrations with
the calcimimetic agent cinacalcet in patients with hyper-
parathyroidism associated with renal failure and who
were undergoing haemodialysis have now been reported.
This drug was associated with reduced risk of cardio-
vascular events, but only after adjustment for differ-
ences in baseline characteristics between study groups
or study design, which makes interpretation of the
results difficult.89
Diagnosis and treatment of established
cardiovascular disease
Patients with recognised symptoms of acute coronary
syndromes are generally referred to hospital, where the
diagnostic work-up routinely consists of electrocardio-
graphy, measurement of cardiac damage biomarkers,
and, sometimes, coronary angiography. In cases of con-
firmed acute coronary syndrome, percutaneous throm-
bolysis or coronary artery bypass grafting are used,
followed by medical treatment and lifestyle advice to
prevent recurrence. Patients with chronic kidney disease
are disadvantaged at every step of this process.
The identification of clinical manifestations of cardio-
vascular disease is challenging in patients with chronic
kidney disease, especially identification of ischaemic
heart disease. Some patients with chronic kidney disease
present with classic symptoms, including angina,
oedema, shortness of breath, or syncopal events, but
many are asymptomatic, with no pain or adrenergic
manifestations, or develop atypical manifestations
despite a major acute ischaemic event.90,91 People with
diabetes might be particularly prone to asymptomatic
ischaemic heart disease because of visceral neuropathy.
Clinicians must be fully aware of the atypical presen-
tations of acute coronary syndromes in patients with
chronic kidney disease to avoid underdiagnosis of
potentially life-threatening cardiovascular events. This
consideration is particularly relevant because patients
with stage 3–5 chronic kidney disease have notably
higher rates of and worse prognoses from comorbidities,
conduction abnormalities, and anterior infarctions than
do individuals without chronic kidney disease.90,92
347
 Series

Electrocardiographic findings in acute coronary syn-
dromes may also be less specific and sensitive in patients
with chronic kidney disease than in those without.90,93
Unclear results should prompt a raised level of suspicion
of an acute coronary syndrome and the use of other
diagnostic procedures. Besides the traditional bio-
markers, such as creatinine phosphokinase-MB, some
newer molecules have been identified to detect acute
coronary events. These biomarkers are, however, poorly
assessed in patients with chronic kidney disease, particu-
larly troponins.94 Although cardiac troponins (I and T)
are more sensitive than creatinine phosphokinase-MB
A
100
95
90
85
Proportion of patients (%)
for detection of acute myocardial infarction in the general
population, sensitivity might be reduced in patients with
chronic kidney disease. Cardiac troponin concentrations
are frequently raised in patients with chronic kidney
disease, maybe because of reduced renal clearance,
which makes their use as biomarkers for acute coronary
syndromes problematic.95 In asymptomatic patients with
kidney failure, however, measurement of troponin T can
be used to predict long-term prognosis.96
Many physicians are reluctant to use coronary
angiography in patients with chronic kidney disease,
especially in those with estimated glomerular filtration
rate stage 3–5, owing to the risk of renal toxic effects
from the iodine contrast media. This low use has led to
underdiagnosis of atherosclerotic changes in patients
with chronic kidney disease.91 Whether reduced use of
coronary angiography in patients with chronic kidney
disease is justified is doubtful. Although the risk of
irreversible contrast-associated loss of kidney function
is poorly studied, it is likely to be low and might not
outweigh potential therapeutic benefits gained by a

80 correct diagnosis.97,98 As a consequence of withhold-

ing this test, percutaneous coronary intervention or
75
coronary artery bypass grafting are probably underused
70 in patients with chronic kidney disease, despite being
efficacious treatments.99–101 Thrombolysis in myocardial
65 infarction is also used less frequently in patients with
chronic kidney disease than in those without, despite
60
Aspirin having been proven effective.90,102
55
Clopidrogel The presence of chronic kidney disease often leads
β blocker
Statin
to therapeutic nihilism also in relation to secondary
50 prevention treatment. For instance, in one study indi-
viduals with chronic kidney disease and acute myocardial
B
100 infarction were less frequently prescribed statins,
β blockers, and antiplatelet agents than were patients
95 without chronic kidney disease (figure 6).103 Patients with
chronic kidney disease were even less likely to receive
90
advice for smoking cessation, weight loss, exercise,
85 and cardiac rehabilitation (figure 6). The reluctance to
use secondary prevention approaches increased with
Proportion of patients (%)

80 increasing severity of chronic kidney disease.

75
Future challenges and goals
70 Recommendations for prevention and treatment in
patients with chronic kidney disease (tables 1, 2) are,
65 unfortunately, based on only a small number of trials
that have investigated cardiovascular disease specifically
60
Smoking cessation in populations of patients with chronic kidney disease.
55
Cardiac rehabilitation Most of these trials were underpowered to assess hard
Diet
Exercise
endpoints for clinical outcomes. Analyses of subpopu-
50 lations of patients with chronic kidney disease in large
No CKD 3A 3B 4 5
eGFR stages
cardiovascular randomised, controlled trials are sparse,
because individuals with obvious chronic kidney
Figure 6: Counselling at discharge on preventive treatments in patients disease are often excluded. The paucity of good-quality
admitted for non-ST-segment myocardial infarction, by estimated
to high-quality evidence, in combination with the
glomerular filtration stage
Based on data in reference 103 for 30 462 patients. eGFR=estimated glomerular assumed increased risk of renal and other complications
filtration rate. related to standard cardiovascular therapy, has led to an

348 www.thelancet.com Vol 382 July 27, 2013


underuse of such treatments in patients with chronic
kidney disease, without close assessment of the risks
and benefits.104–106 Evidence for treatment benefit can,
however, be found and is reflected in the 2012 European
guidelines on cardiovascular disease prevention.21 This
knowledge should be applied to the care of patients
with chronic kidney disease. Nevertheless, systematic
research is urgently needed to increase understanding
of the biology of the increased risk of cardiovascular
disease in patients with chronic kidney disease and of
their therapeutic responses to preventive treatment
strategies.
Although tempting, extrapolation of cardiovascular
prevention results in people without chronic kidney
disease to those with chronic kidney disease is not
necessarily straightforward. For example, in the very
late stages of chronic kidney disease, reductions in
cardiovascular risk by statins are blunted, and warfarin
might increase, not decrease, the risk of stroke in
patients with atrial fibrillation.61,64 The weakened effect of
statins might be explained by epidemiological evidence
that relative mortality risk from an individual cardio-
vascular risk factor lessens when absolute risk
increases.13,107 Additionally, when chronic kidney disease
progresses, increasing numbers of pathophysiological
mechanisms contribute to the overall process of
atherosclerosis. Moreover, non-atherosclerosis-related
mechanisms leading to cardiovascular disease come into
play. Consequently benefits from a specific intervention
directed at one particular risk factor will become more
difficult to show.
In our opinion there are at least two approaches to
prevent cardiovascular events in people with chronic
kidney disease. First, treatment should be started in
early stages of chronic kidney disease. The presence of
moderate to severe albuminuria predicts progression of
chronic kidney disease and is associated with a high
risk of cardiovascular disease even when kidney func-
tion is normal.108 Post-hoc analyses of randomised,
controlled trials suggest that the effects of cardiac and
kidney protective treatments increase with increasing
severity of albuminuria.83,84,109,110 Observational data
from randomised, controlled trials of RAAS inhibitors
suggest that changes in albuminuria induced by treat-
ment can help to optimise treatment.59 Thus, screening
for albuminuria and treatment with angiotensin-
converting-enzyme inhibitors in patients who have
increased albuminuria might be a cost-effective
approach to prevent cardiovascular events and kidney
failure, especially in people at high risk of developing
chronic kidney disease, such as those with diabetes,
hypertension, or old age.111 Such an approach should be
formally investigated.
Second, in late-stage chronic kidney disease intensified,
multifactorial interventions may be mandatory. Gaede
and colleagues112,113 showed benefits with multimodal
treatment that included strict glucose management,
www.thelancet.com Vol 382 July 27, 2013
Series
statins, angiotensin-converting-enzyme inhibitors, other
antihypertensive agents, aspirin, and lifestyle interven-
tions (smoking cessation, increased physical activity, and
dietary changes) compared with standard care according
to national guidelines. The rate of macrovascular com-
plications was halved after 8 years of follow-up, as was
cardiovascular mortality after 13 years.113 A similar
multimodal strategy was safely and effectively applied to
normalise albuminuria and prevent loss of kidney
function in patients otherwise predicted to rapidly
progress to kidney failure.114,115
Conclusions
Since Bright’s first description of the association be-
tween chronic kidney disease and cardiovascular
disease, we have come a long way. Many epidemiological
studies have confirmed this association and established
that it is not only due to the fact that these two diseases
share common risk factors, such as smoking, obesity,
hypertension, hypercholesterolaemia, and diabetes.
Mechanisms specific to chronic kidney disease promote
vascular disease and, therefore, substantially increase
the burden of cardiovascular disease in individuals with
chronic kidney disease. Yet cardiovascular disease is
often underdiagnosed and undertreated in this group of
patients, despite treatments of proven usefulness being
available. To that end, we call for action. Patients with
chronic kidney disease should be acknowledged as a
group at high risk of cardiovascular events and disease
that requires special attention. This view should be
taken into account when guidelines are developed and
research priorities are defined. Trials dedicated to
prevention of cardiovascular disease in patients with
chronic kidney disease are urgently needed. In view of
the degree of knowledge so far, we favour investigation
of preventive strategies in early-stage chronic kidney
disease and multifactorial interventions in late-stage
chronic kidney disease.
Contributors
RTG was responsible for the initial design of this report and final
supervision. All authors contributed to the writing of specific sections
and participated in critical revisions of the drafts.
Conflicts of interest
RTG has received grants or honoraria from Abbott, Amgen, Baxter,
Bayer, Novartis, and Otsuka, BRH from Hoffman La-Roche, HJLH from
Abbott, Astellas, Johnson & Johnson, REATA, and VITAE, and JFM
from Bayer, Novartis, Amgen, Roche, Actelion, Abbott, Relypsa, Takeda,
Vifor, and Fresenius). All other authors declare that they have no
conflicts of interest.
Acknowledgments
BRH is supported by the Roy and Vi Baay Chair in Kidney Research,
THJ by a grant from the Ministry of health, Singapore, JHLH by a VENI
grant from the Netherlands Organisation of Scientific Research, JFM by
the European commission (grant 241544, SysKid), KM by grants from
the US National Institutes of Health and grants to the CKD Prognosis
Consortium from the National Kidney Foundation and its sponsors, and
CPW by the Taiwan Department of Health Clinical Trial and Research
Centre of Excellence (DOH 102-TD-B-111-004). The quotation from
Bright at the start of the paper was retrieved with the help of G Eknoyan,
Baylor College of Medicine, Houston, TX, USA.
349
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