Chronic kidney disease and risk of major cardiovascular disease and non-vascular mortality: prospective population based cohort studyBMJ 2010; 341 doi: https://doi.org/10.1136/bmj.c4986 (Published 30 September 2010) Cite this as: BMJ 2010;341:c4986
All rapid responses
We read with interest the manuscript by Di Angelantonio et al about
the influence of renal disease on outcomes in the general adult population
. Authors found that in people without manifest vascular disease, even
the earliest stages of chronic kidney disease were associated with excess
risk of subsequent coronary heart disease. However, assessment of chronic
kidney disease in addition to conventional risk factors modestly improved
prediction of risk for coronary heart disease in this population. Even
more, the incremental gain provided by chronic kidney disease was lower
than that provided by diabetes or smoking.
This does occur not only in general population, but even more importantly
in patients with cardiovascular disease. For example, in the SYNERGY
trial, in which 9978 patients with non-ST-segment elevation acute coronary
syndrome were randomly assigned and treated with either enoxaparin or
unfractionated heparin and an intended early angiography strategy in a
multicenter, open-label study, patients with chronic kidney disease showed
higher rates of 30-day death or myocardial infarction and bleeding than
those without chronic kidney disease, regardless of randomized
antithrombin therapy . In the CINHTIA study, in which 2024 hypertensive
patients with chronic ischemic heart disease were included, the subset of
patients with renal dysfunction was older, more frequently women, with
more atrial fibrillation, diabetes, organ damage, associated clinical
conditions and a worse blood pressure control [3,4].
All these data suggest that renal dysfunction is an independent
predictor for cardiovascular morbidity and mortality, but in the context
of a global assessment of patients, it adds only small information, as
other risk factors and comorbidities exhibit the overall risk of subjects.
Nevertheless, this does not mean that renal function determination may be
useless for risk stratification. As renal failure is associated with a
worse clinical profile, small deterioration of glomerular filtration rate
should warn about the possible presence of concomitant risk factors, even
before their clinical diagnosis. As a result, renal disease, at all
stages, is not only a predictor of cardiovascular disease, but also an
early marker, particularly when decline of glomerular function is
incipient, for the development of other cardiovascular risk factors and
organ damage. Therefore, renal function should be assessed in all
subjects, with the aim not only to assess kidney disease, but also to
highlight the presence of risk factors or cardiovascular disease.
1. Di Angelantonio, Chowdhury R, Sarwar N et al. Chronic kidney
disease and risk of major cardiovascular disease and non-vascular
mortality: prospective population based cohort study. BMJ 2010; 341:
2. Spinler SA, Mahaffey KW, Gallup D et al. Relationship between
renal function and outcomes in high-risk patients with non-ST-segment
elevation acute coronary syndromes: results from SYNERGY. Int J Cardiol
3. Barrios V, Escobar C, Murga N et al. Clinical profile and
management of hypertensive patients with chronic ischemic heart disease
and renal dysfunction attended by cardiologists in daily clinical
practice. J Hypertens 2008;26:2230-5.
4. Escobar C, Echarri R, Barrios V. Renal Function and coronary
disease: Not only in clinical trials. Int J Cardiol 2010; 145: 91-2.
Competing interests: No competing interests
In his rapid response William Moody wrote, "a more appropriate
primary endpoint would have been the wider composite of cardiovascular
deaths and adverse events including all strokes, non-fatal myocardial
infarction, sudden cardiac death (SCD) and heart failure". I submit this
too is too narrow.
In a review that Professor Ken Taylor, cardiac surgeon at the
Hammersmith, once asked me to write I reported the results of a logistic
regression analysis I performed in some 85 patients having open heart
surgery and 50 having abdominal aortic suirgery at the University of
Massachusetts(1). Those having cardiac surgery had there gastric
intramucosal pH measured and those haviong aortic surgery their signoid
intramucosal pH measured. Yet, whilst intramucosal pH proved to be the
best predictor of perioperative mortlaity the location in which the
intramucosal pH had been meausred was of not stand-alone predictive value.
Furthermore Bjrck and Hedberg, vascular siegeons in Sweden, found gastric
and signoid intramucosal pH to be equally predictive of outcome from
abdominal aortic surgery (2).
The difference between patients having cardiac and aortic surgery in
our analysis was in the way they died, those having cardiac surgery mostly
having cardiac deaths and those having aortic surgery mostly dying from
sepsis and multiple organ failure. In intensive care, however, patients
with surgical and medical diseases die from ther same conditions (3). In
this patient population "the putative consequences of intramucosal
acidosis and associated mucosal injury include nosocomial pneumonia,
myocardial depression, sepsis from enteric organisms, multiple system
organ failure, and death" (4). These findings are consistent with the
hypothesis first formulated some 10 years ago, that chronic diseases
might also be associated with the antecedent development of acute and/or
chronic intramucosal acidosis. The inference is that all these end-points
should be considered in the evaluation of patients with single organ
disease be it acute or chronic, including chronic renal disease.
1. Fiddian-Green RG. Gut mucosal ischemia during cardiac surgery.
Semin Thorac Cardiovasc Surg. 1990 Oct;2(4):389-99.
2. Dr. M. Bj?rck, B. Hedberg. Early detection of major complications
after abdominal aortic surgery: Predictive value of sigmoid colon and
gastric intramucosal ph monitoring. British Journal of Surgery
Volume 81, Issue 1, pages 25-30, January 1994.
3. Jean-Louis Vincent, Prof Mervyn Singer. Critical care: advances
and future perspectives. The Lancet, Volume 376, Issue 9749, Pages 1354 -
1361, 16 October 2010 doi:10.1016/S0140-6736(10)60575-2.
4. Fiddian-Green RG. Associations between intramucosal acidosis in
the gut and organ failure. Crit Care Med 1993; 21:S103-S107.
Competing interests: Tonometric patents
Di Angelantonio and colleagues have reported on the incremental value
of assessment of chronic kidney disease (CKD) for prediction of risk for
coronary heart disease (CHD), yet they clearly state in their abstract
their aim was to quantify associations of CKD stages with "major
cardiovascular disease". We agree with their written objective but
suggest they were wrong to restrict their principal outcome measure to CHD
related events. A more appropriate primary endpoint would have been the
wider composite of cardiovascular deaths and adverse events including all
strokes, non-fatal myocardial infarction, sudden cardiac death (SCD) and
Whilst the association of CKD with CHD is well established, only
about one quarter of cardiovascular mortality in patients with end-stage
renal disease (ESRD) is attributable to acute myocardial infarction.
There is increasing evidence that the major driver of cardiovascular
mortality is non-atherosclerotic change affecting the arterial system and
left ventricle rather than occlusive coronary atheroma. Increased arterial
stiffness is a potent predictor of mortality in patients with advanced
CKD. Similarly, left ventricular hypertrophy (LVH) is a major risk factor
for cardiovascular mortality  and particularly prevalent in CKD
affecting more than 80% of patients with ESRD. We have recently shown
that even in patients with stage 2 and 3 CKD, when serum creatinine is
often considered "normal", both aortic and left ventricular stiffness are
increased producing a pattern resembling heart failure with preserved
ejection fraction. In the same population, we have demonstrated
evidence of significant left ventricular systolic dysfunction using
echocardiographic measurement of strain and strain rate. In addition,
we and others  have observed diffuse myocardial fibrosis in advanced
CKD patients using contrast enhanced magnetic resonance imaging (Figure
1). These pathophysiological features serve as the substrate for stroke,
heart failure, lethal arrhythmia and SCD.
Figure 1. Contrast enhanced image obtained by MRI in a short axis
view. Late gadolinium enhancement is present (arrows) in the inferior sub-epicardium in keeping with myocardial fibrosis
As the Study of Heart and Renal Protection (SHARP) investigators will
testify, selecting the right endpoint is not always easy. In a trial of
over 9000 CKD patients randomised to lipid-lowering therapy or placebo,
they changed the focus of their statistical analysis from major vascular
events to major atherosclerotic events. This decision followed the release
of results from 4D  and AURORA  which reinforced the theory that a
significant proportion of major vascular events in CKD patients are non-
atherosclerotic. With CHD a much less frequent cause of death than
originally anticipated, the investigators sought to reduce the possibility
of a "false-negative" trial, where the potential benefit of
simvastatin/ezetimibe on atherosclerotic outcomes in CKD patients might be
diluted by non-atherosclerotic events.
In contrast, for Di Angelantonio et al to have made a true assessment
of cardiovascular risk, a much wider endpoint including non-
atherosclerotic events was warranted. In omitting heart failure, stroke
and SCD from their primary analysis, we suggest the risk of "major
cardiovascular disease" associated with CKD may have been underestimated.
William Moody, Clinical Research Fello; Colin Chue, Clinical Research Fellow; Richard Steeds, Cardiac Consultant; Charles Ferro, Consultant Nephrologist and Senior Clinical Lecturer; Jonathan Townend, Cardiac Consultant and Reader
University of Birmingham
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and risk of major cardiovascular disease and non-vascular mortality:
prospective population based cohort study. BMJ 2010; 341: c4986.
2. U S Renal Data System, USRDS 2010 Annual Data Report: Atlas of Chronic
Kidney Disease and End-Stage Renal Disease in the United States, National
Institutes of Health, National Institute of Diabetes and Digestive and
Kidney Diseases, Bethesda, MD, October 2010.
3. Foley RN, Parfrey PS, Kent GM, Harnett JD, Murray DC, Barre PE. Serial
change in echocardiographic parameters and cardiac failure in end-stage
renal disease. J Am Soc Nephrol 2000; 11: 912-6.
4. Stewart GA, Gansevoort RT, Mark PB et al. Electrocardiographic
abnormalities and uremic cardiomyopathy. Kidney Int 2005; 67: 217-26.
5. National Kidney Foundation. K/DOQI clinical practice guidelines for
chronic kidney disease: evaluation, classification, and stratification. Am
J Kidney Dis 2002; 39(Suppl 1): S1-S266.
6. Edwards NC, Ferro CJ, Townend JN, Steeds RP. Aortic Distensibility and
Arterial-Ventricular Coupling in Early Chronic Kidney Disease: a Pattern
Resembling Heart Failure with Preserved Ejection Fraction. Heart 2008;
7. Edwards NC, Hirth A, Ferro CJ, Townend JN, Steeds RP. Subclinical
abnormalities of left ventricular myocardial deformation in early-stage
chronic kidney disease: the precursor of uremic cardiomyopathy? J Am Soc
Echocardiogr 2008; 21: 1293-8.
8. Mark PB, Johnston N, Groenning BA et al. Redefinition of uremic
cardiomyopathy by contrast-enhanced cardiac magnetic resonance imaging.
Kidney Int 2006; 69: 1839-45.
9. SHARP Collaborative Group. Study of Heart and Renal Protection (SHARP):
Randomized trial to assess the effects of lowering low-density lipoprotein
cholesterol among 9438 patients with chronic kidney disease. Am Heart J
10. Wanner C, Krane V, M?rz W et al, for the German Diabetes and Dialysis
Study Group. Atorvastatin in patients with type 2 diabetes mellitus
undergoing hemodialysis. N Engl J Med 2005; 353: 238-48.
11. Fellstrom BC, Jardine AG, Schmieder RE, et al. Rosuvastatin and
cardiovascular events in patients undergoing hemodialysis. N Engl J Med
2009; 360: 1395-1407.
Competing interests: No competing interests