13 : 2

Cardio-Renal Syndrome

Abstract:
The term Cardiorenal syndrome has gained wide attention
of physicians in recent times specially due to the increasing
presentations of patients with dual organ dysfunction resulting from
a web of pathophysiological causation , the proper understanding
of which might have important bearings on management and
outcome of these patients. This web of causation, though poorly
understood has been termed the cardio-renal connection and
in nutshell includes the Renin- Angiotensin- Aldosterone System
(RAAS), Sympathetic Nervous system (SNS), Nitric Oxide ,
inflammatory cytokines etc1.Recently in the World Congress of
Nephrology the bi-directional nature of the Cardiorenal syndrome
was emphasized and a classification based on pathophysiology was
proposed. Till now the management of the syndrome has met
with little success and no specific treatment strategy has been
established definitively. Diuretics, inotropes, vasodilators, renal
replacement therapy and others have all been tried with variable

CARDIO-RENAL SYNDROME

Inflammatory
Mediators

success. More research and definitive clinical trials are required

to further understand the pathophysiology and devise effective
management strategies for the syndrome.
Key Words: Cardiorenal syndrome, RAAS, heart failure
Concomitant cardiac and renal dysfunction is the most simplistic
view of cardio-renal syndrome. However the definition is
ambiguous as it lacks a direction of pathogenesis of the disease
process. In fact the general view holds that renal injury occurs
secondary to a diseased heart and in the presence of a normal
cardiac function the same kidneys would perform normally (c.f
Hepato-renal syndrome) 2. However it is a known fact that primary
disorder of one of these two organs often causes secondary
dysfunction of the other.3Hence a more comprehensive definition
that encompasses the complete patho-physiology linking the two
organs is required.

CARDIO-RENAL SYNDROME: DEFINITION

CARDIAC
FAILURE

RAAS, SNS,
NO-ROS,

Khan SA, Gupta V, Haque SF, Aligarh

KIDNEY
INJURY

The cardio-renal syndrome includes a variety of acute or chronic

disorders where the primary failing organ can be either the heart
or the kidney leading to the secondary dysfunction of the other.4
(Fig.1)Thus according to the chronology of events the cardiorenal syndrome can be subdivided into 5 sub-types, namely4:
1. CRS type 1:Acute cardio-renal syndrome
2. CRS type 2:Chronic cardio-renal syndrome
3. CRS type 3: Acute reno-cardiac syndrome
4. CRS type 4: Chronic reno-cardiac syndrome
5. CRS type 5: Secondary cardio-renal syndrome
CRS type 1: Acute cardio-renal syndrome is defined as acute
cardiac failure leading to worsening of renal function.Within this is
a spectrum of disorders involving the heart and the blood vessels
leading to acute heart failure which further causes Acute kidney
injury through multiple mechanisms5. These mechanisms include:
1. Acute hypo perfusion leading to decreased G.F.R
2. Decreased Oxygen delivery

Fig. 1 : Cardiorenal syndrome Pathophysiology

Medicine Update 2010 Vol. 20

Table 1 : Lists important biomarkers for the early detection of AKI.

excretion12.
Patients who have diuretic resistant volume overload may still
respond to ultrafiltration13.

Biomarker
Associated Injury
Cystatin C
Proximal tubule injury
KIM-1
Ischemia and nephrotoxins
NGAL
Ischemia and nephrotoxins
NHE3
Ischemia, pre-renal, post-renal AKI
Proximal Tubular injury, Acute rejection
-GST
-GST
Distal Tubular injury, Acute rejection
L-FABP
Ischemia and nephrotoxins
Cyr61
Ischemic ATN
Netrin-1
Ischemia and nephrotoxins,sepsis
GST = glutathione S-transferase; IL = interleukin; KIM = kidney injury molecule; L-FABP = L-type fatty acid binding protein; NGAL =
neutrophil gelatinase-associated lipocalin; NHE = sodium-hydrogen
exchanger;Cyr61=Cysteine rich protein 61.

3.

Newer promisimg approaches in the management include the

Arginine Vassopressin Receptor antagonists like Tolvaptan
(EVEREST trial) 14 15and Adenosine A1 receptor antagonists.
CRS type 2: Chronic cardio-renal syndrome involves Chronic
Congestive cardiac failure causing progressive kidney dysfunction
set on a background of chronically reduced renal perfusion
and chronic renal venous congestion. The prevalence of renal
dysfunction in chronic HF has been reported to be approximately
25% 16. In fact the pathophysiology of renal dysfunction in this
syndrome is poorly understood. The ESCAPE study found no
link between pulmonary artery catheter measured hemodynamic
variables and serum creatinine17.The different putative mechanisms
include low cardiac output causing activation of RAAS and
sympathetic nervous system, subclinical inflammation, endothelial
dysfunction, increased renal vascular resistance and accelerated
atherosclerosis. Recently it has been found that these patients
have relative/absolute erythropoietin deficiency causing more
severe anaemia than can be accounted for by renal failure alone18.
In fact erythropoietin receptor activation in the heart may reduce
the risk of apoptosis, inflammation and fibrosis19 20.

Resistance to ANP/BNP

4. Cell Necrosis/ apoptosis

In fact AKI tends to be more severe in patients with impaired
Left Ventricular ejection fraction, being >70% in patients with
cardiogenic shock6.
Early diagnosis of kidney injury in CRS 1 and also CRS 3 (discussed
later) is important , but still remains difficult as serum creatinine
rises when the AKI is already established. Recently, novel
biomarkers which rise within first few hours of onset of AKI
have been discovered. Of these Neutrophil Gelatinase Associated
Lipocalin (NGAL) is one of the earliest and highly sensitive marker
of ischemic/nephrotoxic kidney injury detected in the blood/
urine. Similarly Kidney Injury Molecule is a highly specific marker
for ischemic AKI.Table 1 lists important biomarkers for the early
detection of AKI.

Management: Although diuretics are helpful in managing a

volume expanded state, the key drugs in treating left ventricular
systolic dysfunction are the Angiotensin-Converting Enzyme
Inhibitors and Angiotensin Receptor Blockers. They by blocking
the RAAS not only affect cardiac remodeling and cause regression
of LVH but also retard proteinuria and progression of CKD.
Due to the presence of excessive vasoconstrictor mediators in
chronic heart failure, vasodilators might be of use in reducing the
congestion and improving renal perfusion.

Thus by using a combination of assay of these biomarkers Type 1

CRS can be diagnosed early with timely intervention to prevent
ongoing renal damage.
Management:While diuretics, both loop and thiazides have been
useful in volume overloaded non-hypotensive patients, there
overzealous use is associated with worsening of renal function7.
Also diuretic therapy exacerbates neurohormonal activity,activates
the RAAS, increases systemic vascular resistance and worsens
left ventricular function8 9. Besides, inotropes like dobutamine,
dopamine, milrinone may be judiciously used in patients with
impaired cardiac output although their role is still controversial
as they have been associated with increased mortality and cardiac
events10.Vasodilators like Nesiritide have been used favourably in
the treatment of Acute Decompensated Heart Failure where a
non hypotensive, low cardiac output state is combined with cold
extremities and increased peripheral vascular resistance due to
excessive vasoconstriction. In fact Nesiritide has been shown to
reduce both systemic and pulmonary pressures and increase the
cardiac and stroke volume indices11. However in the context of
cardiorenal dysfunction Wang and colleagues found that nesiritide
had no effect on GFR, renal plasma flow, urine output, or sodium

686

CRS type 3: Acute renocardiac syndrome is Acute Kidney

injury leading to acute cardiac dysfunction through different
pathophysiological mechanisms involving three main systems: the
RAAS, Nitric Oxide-Reactive oxygen species and the sympathetic
nervous system. Fluid overload and accelerated hypertension
can lead to acute pulmonary edema. Hyperkalemia can lead to
life threatening cardiac arrhythmias and sudden cardiac arrest.
Metabolic acidosis can affect cardiac inotropy21 and cause
pulmonary vaso-constriction leading to right sided heart failure22.
Acute uremia may cause depression of myocardial contractility
while uremic pericarditis may act as a mechanical hindrance
for the same. Myocardial ischemia frequently complicates AKI
which is due to a reduced coronary reserve which fails to meet
increases in myocardial oxygen demand. Renal ischemia also
induces a Systemic inflammatory response syndrome producing
a number of pro-inflammatory cytokines leading to a delayed
cardiodepressant response23.
A variety of markers of cardiac dysfunction/injury including
Cardiac Troponins, NT-Pro BNP, cytokines like TNF , IL-6 and
myeloperoxidase may be utilized for early detection of this

Cardio-Renal Syndrome
Table 2 : Chronic Kidney Disease and CV Risk
Stage CKD
1
2
3
4
5

GFR(ml/min)
>90
60-89
30-59
15-29
<15

thase, Myeloperoxidase are capable of oxidizing LDL Besides there are increased levels of inflammatory biomarkers
like CRP,IL-6, fibrinogen which along with Oxidised LDL are
proatherogenic and also lead to endothelial dysfunction.
The situation is further worsened by coexisting hypoalbuminemia which is a scavenger for these oxidants29.Oxidative
stress also increases the production of Advanced Glycation
End Products Pentosidine and N CarboxyMethyl Lysine
which may contribute to accelerated atherosclerosis.

CV Risk (OR)
??(proteinuria)
1.5
2-4
4-10
>20

syndrome.
Management:Adequate treatment of accelerated hypertension,
hyperkalemia and metabolic acidosis reduces the risk of cardiac
injury. At the same time hemodialysis can be used in removing
the uremic toxins as well as treating the pericarditis effectively.
In patients with hemodynamic instability Continuous renal
replacement therapies may offer better outcomes.
CRS type 4: Chronic Renocardiac syndrome is characterized by
primary chronic kidney disease contributing to the development
of cardiac dysfunction resulting in increased cardiovascular
morbidity and mortality. While microalbuminuria is known to
increase the Cardiovascular risk 2-4 times, declining GFR per se
is associated with increasing CV risk as shown in Table 224.

6. Proteinuria: Urinary ACR is independently associated with

the presence and severity of cardiovascular disease in nondiabetic population.
7. Hyperhomocysteinemia: The prevalence of hyperhomocysteinemia in ESRD patients exceeds 90%.However their
exact relationship with Cardiovascular disease is still not
clear31.
8. ADMA: A competitive inhibitor of NO synthase, causes decreased NO bioavailability. ADMA is degraded by dimethyl
arginine aminohydrolase an enzyme found in renal tissue.
With advancing CKD, ADMA accumulates and leads to endothelial dysfunction and is strongly associated with CV
mortality32.

Besides the traditional risk factors, uremia and related novel risk
factors are responsible for the development of cardiovascular
disease, especially in CKD stages IV and V.25These include (1)
Anemia (2) Hypervolemia and hypertension (3)Abnormal Calcium
and phosphate metabolism (4) Oxidative stress and inflammation
(5) Endothelial dysfunction (6) ADMA (7) Hyperhomocystenemia
(8) Proteinuria
1.

5. Endothelial Dysfunction: In CKD various factors including

inflammation ,ADMA , oxidative stress, hypertension result
in endothelial dysfunction leading to accelerated atherosclerosis and increased cardiovascular mortality30

Management: The primary prevention of CRS type 4 consists

of cessation of smoking, adequate control of Diabetes and
hypertension,.

Anemia: For every 1g/dl decrease in mean haemoglobin the

risk of cardiac failure increases by 25% 26 .Anemia further
causes reduced viscosity, increased venous return and aggravation of sympathetic activity leading to Left ventricular
hypertrophy.

2. Hypervolemia and hypertension: Fluid overload as well as

hypertension increases the risk of cardiac failure. It is further associated with Left Ventricular hypertrophy, development of Ischemic Heart Disease and cardiomyopathy.
3. Abnormal Calcium and phosphate metabolism: CKD patients have increased disturbances of calcium and phosphate
metabolism as early as stage 3 and are associated with accelerated calcifying atherosclerosis and arteriosclerosis. In
ESRD patients , extensive vascular, in particular coronary
artery calcification can be observed in young age group
and they are strong predictors of Cardiovascular Disease
and all cause mortality27. The secondary hyperparathyroidism along with hyperphosphatemia and increased Calcium
Phosphate ionic product are independent risk factors for
Cardiovascular disease28.
4. Oxidative stress and inflammation: CKD is a state of chronic inflammation and increased oxidative stress. Various enzymes involved in production of reactive oxygen species :
NADPH Oxidase, Superoxide Dismutase, Nitric Oxide Syn-

687

Correction of anemia using iron supplements and Erythropoietin to maintain a Haemoglobin between 11-12g% and a
packed cell volume >36%33.

Control of volume overload and hypertension by using loop

diuretics as well as blocking the overactive RAAS by using
ACE inhibitors and ARBs. ACE inhibitors and ARBs should
be used even if the patient is not hypertensive because they
are antiproteinuric and retard the progression of kidney
disease34.Since CKD is a state of sympathetic overactivity
blockers as well as central sympatholytics are useful not
only in controlling the blood pressure but also reducing the
sympathetic drive.

Hyperphosphatemia and secondary hyperparathyroidism

have to be controlled and the Calcium * Phosphate ionic
product should be kept below 50mg2/m2 by dietary phosphate restriction and use of phosphate binders. Moreover
newer non-calcium containing phosphate binders like
Sevelamer are known to reduce the progression of coronary and aortic calcification better than the calcium containing phosphate binders35.

CKD patients are high risk cardiovascular individuals, hence

Medicine Update 2010 Vol. 20

Statins should be used to achieve a LDL cholesterol level

of less than 100 mg/dl (K/DOQI guidelines).Besides Statins
also have modest antiproteinuric effect36.However there
use should be judicious in view of recent reports that they
may favour development of renal fibrosis37

with chronic congestive heart failure. Activation of the neurohumoral

axis. Ann Intern Med. 1985;103:1-6.
10 Felker GM, OConnor CM. Inotropic therapy for heart failure: an evidence-based approach. Am Heart J.2001;142:393 401.
11 [No authors listed]. Intravenous nesiritide vs nitroglycerin for treatment of decompensated congestive heart failure: a randomized controlled trial. JAMA. 2002;287:1531-40

Antioxidants like Vitamin E and acetylcysteine have been

shown to have a beneficial effect on cardiovascular events
in recent small studies and require further authentication.

12 Wang DJ, Dowling TC, Meadows D, et al. Nesiritide does not improve
renal function in patients with chronic heart failure and worsening serum creatinine. Circulation. 2004;110:1620-5.

CRS type 5: It is characterized by cardiac and renal dysfunction

due to acute or chronic systemic cause.While in the acute setting
sepsis is the most important cause, chronic conditions consist of
diabetes, amyloidosis, SLE etc.The acute or chronic inflammatory
states acting through various cytokines like TNF ,IL-1,IL-6 etc.
may affect the functioning of both these organs38 39.Thereafter
the pathophysiological mechanisms of both Type 1 and Type 3
CRS apply in sepsis while those of Type 2 and Type 4 CRS for
chronic conditions.
Management:Treatment is directed at the prompt identification
and treatment of the underlying cause while supporting organ
function , both cardiac and renal by judicious use of vasopressors
, inotropes and diuretics. In septic patients, preliminary studies
suggest that intensive renal replacement therapy may have a role
in improving myocardial performance while providing optimal
small solute clearance 40.

Bongartz L.G., Cramer M.J., Doevendans P.A., Joles J.A. , Braam B., The
severe cardiorenal syndrome: guyton revisited., Eur Heart J 26 (2005),
pp. 1117.

15

Konstam MA, Gheorghiade M, Burnett JC, Jr, et al. Effects of oral tolvaptan in patients hospitalized for worsening heart failure: The EVEREST
Outcome Trial. JAMA. 2007;297:131931

16 Hillege H.L., Nitsch D. ,Pfeffer M.A et al., Renal function as a predictor

of outcome in a broad spectrum of patients with heart failure, Circulation 113 (2006), pp. 671678.

18 Jie K.E, Verhaar M.C. and Cramer M.J. et al., Erythropoietin and the
cardiorenal syndrome: Cellular mechanisms on the cardiorenal connectors, Am J Physiol Renal Physiol 291 (2006), pp. F932F944
19 Fu P. ,Arcasoy M.O., Erythropoietin protects cardiac myocytes against
anthracycline -induced apoptosis, Biochem Biophys Res Commun 354
(2007), pp. 372378
20 Riksen N.P., Hausenloy D.J., Yellon D.M., Erythropoietin: ready for
prime-time cardioprotection,Trends Pharmacol Sci 29 (2008), pp. 258
267.
21 Brady J.P. and Hasbargen J.A., A review of the effects of correction of
acidosis on nutrition in dialysis patients, Semin Dial 13 (2000), pp. 252
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