European Heart Journal (2005) 26, 11–17

doi:10.1093/eurheartj/ehi020

Review

The severe cardiorenal syndrome:

‘Guyton revisited’
Lennart G. Bongartz1, Maarten Jan Cramer1, Pieter A. Doevendans1,
Jaap A. Joles2, and Branko Braam2*
1
Department of Cardiology, Heart-Lung Centre Utrecht, Utrecht, The Netherlands
2
Department of Nephrology and Hypertension F03.226, University Medical Centre Utrecht, PO Box 85500, 3508 GA
Utrecht, The Netherlands
Received 5 July 2004; revised 20 September 2004; accepted 23 September 2004; online publish-ahead-of-print 30 November 2004

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KEYWORDS The incidence of cardiac failure and chronic renal failure is increasing and it has now
Renal function; become clear that the co-existence of the two problems has an extremely bad
Heart failure; prognosis. We propose the severe cardiorenal syndrome (SCRS), a pathophysiological
Cardiorenal connection; condition in which combined cardiac and renal dysfunction amplifies progression of
Severe cardiorenal
failure of the individual organ, so that cardiovascular morbidity and mortality in
syndrome
this patient group is at least an order of magnitude higher than in the general popu-
lation. Guyton has provided an excellent framework describing the physiological
relationships between cardiac output, extracellular fluid volume control, and blood
pressure. While this model is also sufficient to understand systemic haemodynamics
in combined cardiac and renal failure, not all aspects of the observed accelerated
atherosclerosis, structural myocardial changes, and further decline of renal function
can be explained. Since increased activity of the renin–angiotensin system, oxidative
stress, inflammation, and increased activity of the sympathetic nervous system seem
to be cornerstones of the pathophysiology in combined chronic renal disease and heart
failure, we have explored the potential interactions between these cardiorenal con-
nectors. As such, the cardiorenal connection is an interactive network with positive
feedback loops, which, in our view, forms the basis for the SCRS.

Introduction (MI) within 2 years after initiating dialysis therapy, and

mortality in these patients is high.4 Even a slightly
Cardiovascular disease is a profound problem in chronic decreased kidney function correlates with a substantial
renal failure (CRF), with 43.6% of all deaths in patients increase in cardiovascular disease risk and higher mor-
with end-stage renal disease (ESRD) due to cardiac tality, independently of other known risk factors.5–10
causes.1 Death from cardiac causes is 10–20 times more A recent statement from the American Heart
common in patients with CRF than in matched segments Association11 determined that both proteinuria and a
of the general population.2 In ESRD, the prevalence of decline in glomerular filtration rate (GFR) are indepen-
left ventricular hypertrophy (LVH) and coronary artery dent risk factors for the development of cardiovascular
disease are 75 and 40%, respectively.3 About half of disease, and highlighted our lack of knowledge on the
ESRD-patients will suffer from myocardial infarction pathophysiology of this syndrome. Impaired renal func-
tion is also associated with adverse outcomes after
* Corresponding author. Tel: þ31 30 250 7329; fax: þ31 30 254 3492. acute coronary syndromes,12 percutaneous coronary
E-mail address: [email protected] intervention,13 coronary artery bypass surgery,14 or

European Heart Journal vol. 26 no. 1 & The European Society of Cardiology 2004; all rights reserved.
12 L.G. Bongartz et al.

fibrinolytic therapy.15 The incidence of heart failure as Guytonian rules to explain and treat cardiovascular
cause of death was inversely related to GFR.16,17 disease.24 Nevertheless, pathophysiological mechanisms
Another major concern is the incipient epidemic of underlying this reciprocal relationship between the
CRF.18 Not only the prevalence of ESRD increases, but heart and kidneys are still enigmatic. We propose the
also the number of patients with moderate renal severe cardiorenal syndrome (SCRS), a pathophysiologi-
dysfunction.19 An epidemic of heart failure is also in pro- cal condition in which combined cardiac and renal
gress, due to increasing age and better survival after dysfunction amplifies progression of failure of the individ-
MI.20 The risk for developing CRF in heart failure has ual organ to lead to astounding morbidity and mortality
not been defined clearly, but renal dysfunction is often in this patient group.25 SCRS is a syndrome with acceler-
observed in heart failure patients,21 and is associated ated and extensive cardiovascular disease that has dis-
with adverse prognosis.22 The frequency of the combi- tinct properties not occurring in conditions that affect
nation of heart failure and CRF will thus increase and either organ alone.
inescapably come with high morbidity and mortality. In the heart, the consequence of the SCRS is in part due
The mechanisms that cause decline of kidney function to the described accelerated atherosclerosis in the form of
and its repercussions are, however, still poorly under- coronary artery stenosis.26–28 Similarly, LVH is an almost
stood. In this review, we would like to explore potential invariable finding, in both clinical and experimental
pathophysiological interactions that lead to strong inter- uraemia, in the absence of significant haemodynamic
actions between cardiovascular and renal disease. stimuli.29,30 Rather, the interplay between renal failure
and cardiovascular disease reflects an inappropriate remo-
delling process. The SCRS also involves myocardial
The severe cardiorenal syndrome micro-angiopathy, manifested in the intramyocardial
arterioles by wall thickening and reduced lumen diameter
The strong connection between renal and cardiovascular as a consequence of hypertrophy of smooth muscle cells.31
disease has revived interest in the complex interactions Clinically, the narrowed lumen diameter may interfere
between heart and kidneys. The late Arthur Guyton with the already reduced coronary perfusion reserve.
extensively described normal physiological interactions The intramyocardial capillaries of uraemic rats exhibit

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between the control of extracellular fluid volume by decreased capillary density,32 which increases the oxygen
the kidney and the systemic circulation by the heart diffusion distance and may further impair the ability of the
(Figure 1 ). The framework of reasoning about the myocardium to withstand episodes of hypoxia.
control of extracellular fluid volume (ECFV) and systemic Pulse wave velocity (PWV) is a reflection of the elastic
haemodynamics, the concept of total body autoregula- properties of ‘windkessel’ arteries and a high PWV has
tion, as well as the renal control mechanisms for been recognized as a prognostic factor for cardiovascular
sodium excretion with their ‘infinite gain’,23 are of events. Uraemia affects PWV by functional (angiotensin,
invaluable importance. A recent monograph on volume volume expansion)33 and structural (vascular calcifica-
control in haemodialysis treatment has applied the tion) derangements. The aggressiveness of the calcifica-
tion process is almost exclusively observed in severe
CRF and ESRD,34 and is present not only in the large
arteries but also in coronary plaques of CRF patients.35–37
Finally, heart failure can lead to excessive and inap-
propriate activation of the renin–angiotensin system
(RAS),38 which has been implicated in many ways in the
progression of renal disease.39 Thus, combined renal and
cardiac disease invokes a number of forces that are
specific for this combination and synergistically aggravate
renal and cardiac disease.

Components of the cardiorenal connection

contributing to the SCRS
Central in Guyton’s model are the kidney, as regulator of
ECFV, and the RAS with its corresponding extensions
(aldosterone, endothelin) and its antagonists [natriuretic
peptides, nitric oxide (NO)]. The model is sufficient to
explain the changes in ECFV, blood pressure, and
Figure 1 Pathophysiological basis of the severe cardiorenal syndrome. cardiac output in combined heart and renal failure.
The model of Guyton explains heart–kidney interaction with respect to However, can we also explain the accelerated athero-
extracellular fluid volume, cardiac output, and mean arterial pressure. sclerosis, cardiac remodelling and hypertrophy, and pro-
When one of these organs fails, a vicious circle develops in which the
renin–angiotensin system, the NO–ROS balance, the sympathetic nervous
gression of renal disease observed in the SCRS (Figure 1 )?
system, and inflammation interact and synergize, here called the cardio- In this respect, we have recently proposed an exten-
renal connection. sion to the Guytonian model of volume and blood
The cardiorenal connection 13

pressure control called the Cardiorenal Connection

(CRC).25 Over the past decades, actions have been
described by the regulators central in Guyton’s model
which do not directly control haemodynamics, but
affect other aspects of cardiac and renal function. In dis-
secting the pathophysiological events in the SCRS, we try
to couple actions of the regulators of Guyton’s model to
their extended actions on structure and function of
heart and kidney. We propose the RAS, the balance
between NO and reactive oxygen species (ROS), inflam-
mation, and the sympathetic nervous system (SNS) as
actual connectors in the CRC (Figure 1 ). We envisage
that derangement of one connector of the CRC leads to
a vicious circle in which the other connectors become dis-
turbed as well and synergize, ultimately resulting in
cardiac and renal functional derangement and structural
damage. Accordingly, renal failure and heart failure
would lead to the SCRS via common pathophysiological
mechanisms: the CRC. The following sections describe
evidence on the pathophysiological mechanisms and
interactions between connectors of the CRC.

The RAS

Activation of the RAS by low renal perfusion pressure or

blood flow serves as a defence against under-perfusion

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of vital organs, such as in haemorrhage. In heart
failure, this response can take a devastating downhill Figure 2. (A ) Angiotensin II (Ang II) affects the other cardiorenal con-
course: volume retention due to the haemodynamic and nectors: SNS activation in kidney failure, generation of ROS, and NF-kB
reabsorptive actions of angiotensin II (Ang II) develops40 mediated pro-inflammatory gene expression. (B ) Imbalance between
NO and ROS is a central event in cardiovascular diseases. In the cardior-
with further congestive heart failure as a consequence. enal connection, this balance may influence sympathetic nervous activity,
Unfortunately, inappropriate activation of the RAS is release of renin and angiotensin, and promote inflammation by oxidative
also one of the characteristics of renal failure.41 modification of substances. (C ) Persistent inflammation has been found in
Besides the (dys)regulation of ECFV and vasoconstric- both renal and heart failure. By altering ROS functioning, and promoting
ROS and noradrenaline (NA) formation, inflammation contributes to the
tion, one of the most deleterious actions of the RAS in
positive feedback loops in the cardiorenal connection. (D ) Sympathetic
the CRC is activation of NADPH-oxidase by Ang II, result- nervous activity is increased in both renal and heart failure. By affecting
ing in formation of ROS.42 This has been documented in the other cardiorenal connectors it can play a significant role in the SCRS.
endothelial cells, vascular smooth muscle cells,43 renal It stimulates renin release from the kidneys, generates ROS, and induces
tubular cells,44 and cardiomyocytes.45 Interesting obser- inflammation. NPY: neuropeptide Y.
vations in this context are raised NADPH-oxidase activity
in hearts of patients with end-stage heart failure46 and
increased NADPH-oxidase-mediated ROS release in with the other cardiorenal connectors are shown in
glomeruli of Dahl salt-sensitive rats with heart failure, Figure 2A.
which could be attenuated by angiotensin-converting
enzyme (ACE) inhibition.47 Moreover, ACE inhibition has
been shown to increase NO bioavailability in patients The balance between NO and ROS
with coronary artery disease, possibly related to reduced
vascular oxidative stress or increased extracellular super- NO is important in renal control of ECFV and blood press-
oxide dismutase (SOD) activity.48 ure by causing vasodilation, natriuresis, and desensitiza-
Ang II, potentially acting via changes in the cellular redox tion of tubuloglomerular feedback.56 There are now
state, is implicated in vascular inflammation via the many indications that superoxide has the opposite
nuclear factor kappa B (NF-kB) pathway, which induces effect on ECFV control and can contribute to high blood
production of chemotactic and adhesion molecules.49,50 pressure.57–60 In the SCRS, the balance between NO and
The RAS interacts with the SNS by complex the ROS is skewed towards the latter by increased pro-
mechanisms.51 It has been found that the stimulus for duction of ROS, a low anti-oxidant status, and lower
the sympathetic hyperactivity observed in renal failure availability of NO. Increased levels of different oxidative
arises from the failing kidneys52 and that increased sym- stress markers, like F2-isoprostane61 and antibodies
pathetic outflow in CRF could be controlled with against oxidized LDL,62 have been found in dialysis
ACE-inhibition.53,54 Blocking Ang II signalling reduced patients. A low antioxidant status is caused by oxidative
SNS hyperactivity after MI in rats, attenuating ensuing inactivation, decreased availability of antioxidant
development of heart failure.55 Interactions of the RAS vitamins, and removal of water-soluble antioxidants
14 L.G. Bongartz et al.

through the dialysis membrane.63 Oxidative stress is has a more than additive effect on the incidence of MI
further increased by interplay between the uraemic and death.80 In CRF, circulating levels of CRP81 and
state and inflammatory reactions on the dialysis mem- several pro-inflammatory cytokines such as IL-1b, IL-6,
brane. A relative NO-deficiency in renal failure is and TNFa, are predictors of atherosclerosis.82,83
caused by reaction of NO with oxygen radicals, as well It has been suggested that inflammation will aggravate
as by high concentrations of circulating asymmetric heart failure. In patients with heart failure, elevated
di-methyl arginine (ADMA), an endogenous NOS levels of TNF-a and IL-6 have been found in both
inhibitor.64 In heart failure, increased oxidative stress plasma and myocardium, and are related to progression
has also been demonstrated46 and decreased antioxidant of the disease.84,85 Interleukin-18 has also been associ-
status was found in rat myocardium after MI, which was ated with cardiac dysfunction after MI.86 The exact role
associated with progression to heart failure.65 Interest- of the activation of inflammatory cells is as yet far
ingly, haemodynamic improvement by captopril and pra- from clear; however, in both CRF and heart failure a
zosin led to enhanced antioxidant status.66 Kielstein state of chronic inflammation is present.
et al. 67 also showed a relationship between reduced This low-grade inflammation can cause ROS production
renal perfusion, impaired NO-mediated endothelial vaso- by activating leukocytes to release their oxidative
dilation and high concentrations of ADMA in patients with contents.87 In cultured rat vascular smooth muscle cells,
normotensive heart failure, markedly resembling the IL-6 induced upregulation of the AT1 receptor and Ang-II
situation in CRF patients. mediated production of ROS, providing evidence for
Additional potential interactions between the NO–ROS a possible link between inflammation and RAS
imbalance and other cardiorenal connectors in the SCRS activation.88 Cytokines may stimulate renin secretion as
are depicted in Figure 2B. Oxidative stress by hydrogen a component of the systemic stress response, and tubu-
peroxide (H2O2) has been shown to increase activity of lointerstitial inflammation may have effects on adaptive
pre-ganglionic sympathetic neurons in vivo and in vitro responses of glomerular haemodynamics to impaired
in rats, raising mean arterial pressure and heart rate.68 renal function.89 After MI, IL-1b is produced,90,91 which
Also, renal sympathetic nervous activity in spontaneously has been shown to stimulate noradrenaline release from
hypertensive rats was found to be regulated by vascular sympathetic neurons.92 Interactions between inflamma-

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superoxide concentrations.69 tory factors and the other connectors are depicted in
In renal failure, oxidative stress imposes damage on Figure 2C.
DNA (8-oxo-OH-deoxyguanosine), proteins (carbonyl
compounds,70 advanced oxidation protein products71), SNS
carbohydrates (advanced glycation end-products72), and
lipids (oxidized LDL62). These substances have By stimulating renin release via renal sympathetic
pro-inflammatory effects by attracting and activating neurons, the SNS contributes to long-term regulation of
leukocytes,73,74 but they can also damage endothelial ECFV and blood pressure. Converse et al. 52 were the
cells.75 Oxidative stress is a major initiator of an inflam- first to report increased peripheral sympathetic nerve
matory response, resulting in a shift towards production activity in ESRD, which was corrected when the diseased
(and activation) of pro-inflammatory cytokines, in par- kidneys were removed. The SNS is initially activated in
ticular IL-1, IL-6, and tumour necrosis factor alpha (TNFa). heart failure by the baroreflex to provide inotropic
Although as yet not completely resolved, oxidative support and preserve cardiac output. However, excessive
damage to the renal tubular or interstitial cells may sympathetic activity can induce cardiomyocyte apopto-
interfere with feedback systems involved in renin sis, hypertrophy, and focal myocardial necrosis.93
secretion and angiotensin formation in the SCRS. Cardiac hypertrophy is partly due to direct actions of cat-
Chronic inhibition of NO synthesis causes upregulation echolamines, as several studies have shown that nor-
of cardiac ACE and Ang II receptors, possibly mediating adrenaline induces hypertrophy of cultured
inflammatory changes.76 cardiomyocytes.94,95 Interestingly, this action involves
Himmelfarb et al. 77 have termed oxidative stress the induction of superoxide.94,95 Chronically, sympathetic
‘elephant’, or key-point, in uraemia. Treatments that over activity causes beta-adrenoceptor insensitivity in
decrease superoxide production (such as NADPH-oxidase both renal failure96 and heart failure.97,98 This can lead
inhibitors), aid in scavenging ROS, or support the function to a disturbed baroreceptor reflex, reduction in heart
of NO, are intriguing clues that support our concept. One rate variability, and increased susceptibility to arrhyth-
relatively small trial has reported a positive effect of mia. Whether the atherosclerotic process is associated
antioxidant therapy on cardiovascular endpoints in with increased sympathetic activation is unclear.
patients with renal failure,78 but more evidence is However, sympathetic over-activity can affect lipid
needed. metabolism, and beta-blockers have been shown to have
anti-atherosclerotic properties.99,100 There are several
Inflammation indications that the SNS affects the other connectors of
the CRC, for instance RAS activation, production of ROS
Together with increased oxidative stress, inflammation by sympathetic neuroactive substances, and activation
has been designated the other common denominator in of the immune system (Figure 2D ).
uraemia.79 The combined occurrence of chronic renal Next to direct sympathetic innervation of the kidneys,
insufficiency and high C-reactive protein (CRP) levels renin release can be enhanced because prolonged SNS
The cardiorenal connection 15

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