IJC Metabolic & Endocrine 9 (2015) 1–4

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IJC Metabolic & Endocrine

journal homepage: http://www.journals.elsevier.com/ijc-metabolic-and-endocrine

The Cardio-renal Syndrome (CRS)

Enrico V. Scabbia, Luca Scabbia
U.O.C. Nefrology, Hospital “S. Andrea” (University La Sapienza), Rome, Italy

a r t i c l e i n f o a b s t r a c t

Article history: The presence of impaired kidney function during heart failure and vice versa is a frequent occurrence. This situ-
Received 6 October 2014 ation is defined “Cardio-renal Syndrome”.
Accepted 21 October 2014 In the Cardio-renal Syndrome (CRS) are included 5 different sub-syndromes defined on the basis of the organ
Available online 17 April 2015
primitively responsible: Acute Cardio-renal Syndrome (Type 1), Chronic Cardio-renal Syndrome (Type 2),
Acute Reno-cardiac Syndrome (Type 3), Chronic Renal-cardiac Syndrome (Type 4) and Secondary Cardio-renal
Keywords:
Cardio-renal Syndrome
Syndrome (Type 5).
Reno-cardiac syndrome The physiopathologic mechanisms underlying CRS are still partially obscure, but, a key role seems to be played by
Acute decompensated heart failure the renin-angiotensin-aldosterone axis.
Acute heart failure Therapeutic strategies involved in CRS treatment include the use of diuretics, ACE inhibitors, Angiotensin Recep-
Chronic heart failure tor Blockers and β-Blockers, emphasizing the role of a proper use of medication indicated for the treatment of car-
Acute kidney injury diac decompensation.
Acute renal failure © 2014 Published by Elsevier Ireland Ltd. This is an open access article under the CC BY-NC-ND license
Chronic renal failure
(http://creativecommons.org/licenses/by-nc-nd/3.0/).

1 . Introduction – Type 3 Acute Reno-cardiac Syndrome: acute worsening of renal func-

The presence of a new-onset of renal failure, or the aggravation of a
pre-existing one within the ambit of an acute or chronic heart failure ex-
acerbation is frequently found in daily cardiologic clinical practice. It
also frequently occurs as a contemporary and progressive cardiac in-
volvement in the development of cadres of renal failure [1].
Existing relationships between the two diseases had not been fully
elucidated for a long time, although it soon became evident that the si-
multaneous involvement of the two apparatuses conditioned the prog-
nosis in a pejorative sense [2].
Frequent detailed evidence in literature found a definite classifica-
tion to this effect in the specific ‘consensus’ conference held in Venice
in 2008 [3], which enabled the definition of clinical pictures and physio-
pathological shared areas within the ambit of the Cardio-renal Syn-
drome (CRS).
2. Classification of the CRS
General definition: The Cardio-renal Syndrome is a physiopatholog-
ical disorder of the heart and kidneys in which the acute or chronic dys-
function of one organ induces acute or chronic dysfunction in the other
[2,3].
In the sense defined above 5 subtypes can be identified:
– Type 1 Acute Cardio-renal Syndrome: acute worsening of cardiac
function that determines renal dysfunction;
– Type 2 Chronic Cardio-renal Syndrome: chronic abnormalities in car-
diac function that determines renal dysfunction;
tion that determines cardiac dysfunction;
– Type 4 Chronic Reno-cardiac Syndrome: chronic abnormalities of
renal function that determine a cardiac dysfunction;
– Type 5 Secondary Cardio-Renal Syndrome: simultaneous cardiac and
renal dysfunction caused by an acute systemic condition.
3. Acute Cardio-renal Syndrome (CRS Type 1)
This condition occurs when an acute deterioration of cardiac func-
tion determines an “Acute kidney injury (AKI)” and/or Acute renal fail-
ure (ARF).
The spectrum of acute cardiac conditions that may contribute to a
worsening of renal function in the sense of the development of
Cardio-renal Acute Syndrome (CRS Type 1) includes:
– acutely decompensated heart failure (ADHF),
– acute coronary syndrome (ACS),
– cardiogenic shock, and
– low-flow syndrome following cardiac surgery.
Also attributable to this type of renal impairment is the nephrotoxic
effect due to contrast medium, widely used in diagnostic tests indicated
in acute cardiac conditions that give rise to CRS Type 1.
Acute impairment of renal function, as evidenced by an increase
greater than 0.3 mg/dl of baseline serum creatinine, occurring in a

http://dx.doi.org/10.1016/j.ijcme.2014.10.013
2214-7624/© 2014 Published by Elsevier Ireland Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).
2 E.V. Scabbia, L. Scabbia / IJC Metabolic & Endocrine 9 (2015) 1–4
variable percentage of 27–40% of patients with acute heart failure and/
or acute coronary syndrome [2].
The development of a CRS Type 1 causes a significant deterioration
in morbidity and mortality as well as prolonged hospitalization [4].
4. Chronic Cardio-renal Syndrome (CRS Type 2)
It is a very common situation, which occurs when chronic renal fail-
ure develops during cardiac impairment (CRF). Approximately 63% of
patients with chronic congestive heart failure presents a picture of
chronic renal failure (Stages 3–5), with values of glomerular filtrate
(GF) inferior to 60 ml/min/m2 [2].
The definition of “chronic cardiac impairment” includes many differ-
ent heart conditions:
– chronic heart failure,
– atrial fibrillation,
– congenital cyanotic heart disease,
– constrictive pericarditis, and
– chronic ischemic heart disease.
Since the coexistence of chronic cardiac impairment in chronic kid-
ney disease is not uncommon, it can be difficult to define which condi-
tion is pre-existing and, in this sense, an accurate anamnestic
reconstruction is extremely valuable.
In this subtype (CRS Type 2), the coexistence of two pathological
conditions, renal and cardiac, also worsens prognosis, both in terms of
increased morbidity and in the sense of an increased mortality risk
[5–7], therefore renal failure can be considered a negative prognostic
factor in the independent assessment of the evolution of a framework
of heart failure.
5. Acute Reno-cardiac Syndrome (CRS Type 3)
CRS Type 3 is identifiable in the situation where an acute deteriora-
tion of renal function (ARF) results in damage and/or acute cardiac
dysfunction.
The boundaries of this condition are still partially undefined, since it
is only possible to rely on occasional and unsystematic reports. Typical
clinical conditions consist in:
– drug-induced acute renal disease,
– acute renal failure after major surgery (cardiac and non),
– acute nephritic syndromes, and
– Rhabdomyolysis.
This type of CRS also refers to acute renal failure from medium con-
trast (CI-AKI), especially if not determined by diagnostic tests aimed at
evaluating a preexistent heart disease, which otherwise would identify
a Type 1 CRS. These conditions of AKI are frequently accompanied by the
development of acute coronary syndrome, arrhythmias, acute decom-
pensation and EPA [3].
6. Chronic Reno-cardiac Syndrome (CRS Type 4)
Type 4 CRS consists of the condition in which primitive chronic renal
failure (CRF) contributes to the deterioration of cardiac function (e.g.
cardiac remodeling, left ventricular diastolic dysfunction, left ventricu-
lar hypertrophy) with an increased risk of acute cardiovascular events
(myocardial infarction, stroke, acute heart failure).
The presence of chronic renal failure in this group of patients deter-
mines a mortality rate 10–20 times higher than in a comparable popu-
lation by age and sex, but without IRC [3,4].
Observational and population studies have largely documented a
rising trend in morbidity and mortality from cardiovascular disease
with the passage to worsening stages of renal dysfunction (from stage
1 to stage 3) [8–12].
An inverse relationship emerges between renal function and nega-
tive cardiovascular outcome for high-risk cohorts, the creatinine clear-
ance is a short-term predictor of poor outcome (cardiovascular death
or myocardial infarction) [8].
This negative correlation, if basically pre-existent, could be further
compounded by a kind of fear, or “therapeutic nihilism” attitude to-
wards persons with renal insufficiency, in which less attention is devot-
ed to modifying traditional cardiovascular risk factors [13,14], as a result
of a less aggressive therapeutic approach for fear of a further deteriora-
tion of renal function associated with the use of drugs [8,15,16].
7. Secondary Cardio-renal Syndrome (CRS Type 5)
Type 5 CRS is characterized by an acute or chronic systemic disease
that causes simultaneous cardiac and renal dysfunction.
Examples of this can be found in sepsis, SLE, amyloidosis, diabetes
mellitus, and sarcoidosis. The co-existence of aggravating conditions,
such as diabetes and/or hypertension, may increase the severity of the
impairment of the two organs.
The physiopathological characteristics of condition have not yet
been well defined, but it has its own current epidemiological logic.
8. Physiopathology of CRS
Physiopathological mechanisms supporting the simultaneous in-
volvement of cardiovascular and renal functions in the manifestation
of CRS are complex and have not yet been fully elucidated. In heart fail-
ure, the impairment of systolic and/or diastolic blood pressure leads to a
series of adjustments that are configured in the decrease of cardiac out-
put, stroke volume, and finally in reduced circulating volume [17]
(Fig. 1).
The decrease in arterial circulating blood volume is taken up by arte-
rial baroreceptors and causes neurohormonal activation that produces
compensatory mechanisms aimed at correcting the state of relative hy-
povolemia and restoring proper tissue perfusion. In this sense, activa-
tion of the reninaangiotensina-aldosterone system (RAAS), the
sympathetic nervous system (SNS), endothelin system and arginine–
vasopressin causes water retention, mediated by sodium–retentive va-
soconstriction, and counterbalanced by the activation of vasodilatory
natriuretic hormone (natriuretic peptide) systems and cytokines (pros-
taglandins, bradykinin, NO) [18,19].
Under normal conditions, these mechanisms act unanimously in
maintaining vascular tone and normalize cardiac output and tissue
perfusion.
However, in terms of heart failure, the same mechanisms act by per-
petuating vicious circles that waver, finally, in a state of chronic renal
hypoxia, inflammation and oxidative stress which alone can alter cardi-
ac and renal structure and function [20].
The activation of SRAA determines renal hypoxia, vasoconstriction,
intraglomerular hypertension, glomerulosclerosis, tubulointerstitial fi-
brosis and proteinuria [21], and proteinuria [21,22]. Similarly the activa-
tion of the SNS involves proliferation of smooth muscle cells and
adventitial fibroblasts in the intrarenal vascular walls [23].
An attempt to attribute the responsibility of renal impairment to ini-
tial hemodynamic components, or modify the therapy in the course of
acute heart failure has produced controversial and ultimately inade-
quate explanations, both because responsibility for the changes in cardi-
ac output has not been identified, inasmuch as kidneys are able to
tolerate decreases in cardiac index up to 1.5 l/min/m2 [24,25], and also
because renal failure can occur under conditions of both low as well as
preserved tissue perfusion [20,25]. The only hemodynamic variable in-
volved is the right atrial pressure (or central venous) [26].
Transrenal perfusion pressure is calculated from the mean arterial
pressure minus the central venous pressure: therefore even a modest
 E.V. Scabbia, L. Scabbia / IJC Metabolic & Endocrine 9 (2015) 1–4 3

Fig 1.

reduction in blood pressure if accompanied by a state of congestion, en- order to prevent the onset of a condition of hyponatremia, aggravating
tails a clear impairment of renal perfusion pressure [27,28]: this condi- the condition of failure.
tion can aggravate pre-existing renal impairment or determine acute Untrainfiltation techniques, although yet to be clearly defined both for
impairment of renal function which, in addition to neuro-hormonal distinct and niche populations, are not of secondary importance. Finally,
mechanisms triggered by the failure, aggravates conditions for compen- the most crucial health facilities consist of constant suspicion and care-
sation of cardiac and renal function in a vicious cycle. ful research of signs that lead to timely diagnosing renal impairment in
To the above listed conditions must be added the direct effect of ure- all conditions of acute or chronic heart failure and/or ischemic heart
mia in determining Uremic Heart Disease, a peculiar cardiomyopathy, disease.
which adds to and somewhat overlaps already compromised pre- Finally, a routine determination of FG value (with the formulas
existing cardiac conditions [31]. MDRD or Cockcroft–Gault is sufficient [29]. Convenient calculators are
easily available online: e.g. http://www.mdcalc.com) to provide en-
lightening information. To integrate a possible error of GFR estimate cal-
9. Therapy culated, under conditions of severe ARF, the assessment of the rate of
progression (slope) of creatinine values is revealing.
To date, no one has identified and defined a specific therapeutic di-
rection in the treatment of the Cardio-renal Syndrome.
Current evidence indicates that an optimal treatment of acute and
chronic SCC, with an appropriate use of drugs proven to be effective
(ACE-I, Angiotensin receptor inhibitors, beta-blockers, diuretics, …) is
the best therapy possible [30] (Tables 1–2). Table 1
In practical terms, a) the introduction of therapy with an ACEI or ARB, Da: ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2008
[30].
must not cause alarm because of an expected increase of up to 33% in the
initial values of serum creatinine. Further and more substantial increases Terapia dello scompenso: raccomandazioni di Classe I
should suggest careful monitoring of the state of the patient's hydration, ACE Inibitori Tutti i pazienti Classe I
an eventual concomitant use of drugs interfering with the SRAA Livello A
(NSAIDs), as well as recommending a thorough study of the renal ARB Intollerante ACEI/segni o sintomi persistenti Classe I
in ACEI/BB Livello A
vessels.
Beta-Bloccanti Tutti i Pazienti Classe I
b) When using diuretic therapy in the presence of CRS with advanced Livello A
renal impairment (FG _30 ml/min/m2), the class of drugs of choice con- Antagonisti Sintomi severi in ACEI Classe I
sists of loop diuretics (furosemide, torasemide) whose dosage should Aldosterone Livello A
be gradually increased to attain the expected result, with a careful Diuretici Tutti i pazienti con segni o sintomi di Classe I
congestione Livello B
check of the water balance between the introduction and diuresis, in
4 E.V. Scabbia, L. Scabbia / IJC Metabolic & Endocrine 9 (2015) 1–4

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