2018. 10. 25. Cardiorenal Syndrome: Cardiologist vs.

Nephrologist - ACVIM 2014 - VIN

Cardiorenal Syndrome: Cardiologist vs. Nephrologist

ACVIM 2014
Joao S. Orvalho, DVM, DACVIM (Cardiology); Larry D. Cowgill, DVM, PhD, DACVIM
(SAIM)
San Diego, CA, USA

Introduction
It has become increasingly recognized by cardiologists and nephrologists that there are
important bidirectional functional and pathological interactions between the heart and the
kidney, wherein dysfunction of either organ promotes clinical worsening of the other.1
Cardiovascular disease constitutes a significant threat for patients with renal disease, and
renal dysfunction is also often present in patients with cardiac disease. The clinical
consequences of these interactions have gained increasing focus and have prompted
further definition, classification, and understanding. These interactions are the
pathophysiological basis for the clinical entity termed cardiorenal syndrome (CRS) in
human medicine.1-4 Cardiorenal syndrome per se has not been well characterized in
veterinary medicine.
A Definition
The definition of CRS includes a variety of acute or chronic conditions, in which the
primary failing organ: the heart, the kidney, or both (due to a systemic condition),
promotes dysfunction and/or failure of the other organ system.4
Classification
Five subtypes of CRS have been suggested in order to simplify the identification and the
clinical approach.3-5
Type 1 CRS - Acute cardiorenal syndrome is characterized by a rapid impairment of
cardiac function leading to acute kidney injury. There are multiple and complex
mechanisms by which acute heart failure or an acute onset of chronic heart failure leads to
acute kidney injury (AKI).6 In humans, the onset of AKI is more pronounced in patients with
decreased left systolic function, which may imply reduced renal perfusion.7 The congestive
state may also induce decreased diuretic responsiveness, which may lead to excessive
use of diuretics and further kidney injury.8,9 In CRS type 1, the early recognition of AKI
remains a challenge due to the lack of early stage biomarkers. Serum creatinine (sCr) and
blood urea nitrogen (BUN) have been the classic markers for AKI, but when the
concentrations of these markers are detectably elevated the injury process is well
established, and it is often too late to protect the kidney or prevent further damage. The
discovery of novel urinary biomarkers such as neutrophil gelatinase-associated lipocalin
(NGAL), cystatin c, symmetrical dimethylarginine (SDMA), may allow an earlier recognition
of AKI and CRS.10,11
Type 2 CRS - Chronic cardiorenal syndrome consists of chronic cardiovascular
disease causing progressive chronic kidney disease (CKD).3-5 Chronic heart failure (CHF)
is likely to cause persistently reduced renal perfusion, chronic renal congestion
("congestive kidney failure"), and neurohormonal changes associated with chronic
sympathetic stimulation (production of epinephrine, angiotensin, endothelin, and release of
natriuretic peptides and nitric oxide).13,14 CHF therapy using diuretics and renin-
angiotensin aldosterone system (RAAS) blockers can cause drug-induced hypovolemia,
decreased renal perfusion, and hypotension.6 In humans, the prevalence of renal
dysfunction in CHF patients is high and constitutes an independent predictor of outcomes
and mortality, therefore it is of the upmost importance to preserve the renal function in
these patients.15

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Type 3 CRS - Acute renocardiac syndrome is characterized by an acute primary
worsening of kidney function that leads to acute cardiac dysfunction. AKI can affect the
cardiac function through multiple mechanisms, such as fluid overload, electrolyte
disturbances, neurohormonal activation, and myocardial depressant factors, potentially
contributing to the development of arrhythmias, pericarditis and acute heart failure.16,17
Diagnosis of AKI in patients concurrently treated for heart failure may force clinicians to
reduce the dose or discontinue heart failure medications, further decompensating the
cardiovascular system in detriment of preventing additional kidney injury.
Type 4 CRS - Chronic renocardiac syndrome consists of primary chronic kidney
disease that contributes to cardiac dysfunction. Decreased systolic function, left ventricular
hypertrophy, systemic hypertension, and a high output state (secondary to anemia) are
some of the potential long-term cardiac sequelae of CKD.5,12 The medical management of
CKD and concurrent CHF is not as problematic as the acute forms of these conditions, but
most CHF patients are likely undertreated, due to concerns of further worsening renal
function and creating a vicious cycle of bidirectional damage secondary to the specific
pathophysiology and pharmacotherapy of both conditions.
Type 5 CRS - Secondary cardiorenal syndrome is characterized by cardiac and renal
dysfunction secondary to an acute or chronic systemic condition. Sepsis is the most
common acute condition that affects both the heart and the kidney.5,18,19 Diabetes mellitus
and hyperadrenocorticism are typical chronic diseases in dogs that have a similar effect on
the urinary and cardiovascular systems.20-22
Table 1. Cardiorenal syndrome classification

Type of cardiorenal
syndrome Brief definition Conditions

Type 1 - Acute Acute impairment of the cardiac function - Acute heart

cardiorenal syndrome leading to acute kidney injury (AKI) failure
- Cardiogenic
shock

Type 2 - Chronic Chronic cardiovascular disease causing - Chronic heart

cardiorenal syndrome progressive chronic kidney disease (CKD) failure
- "Congestive
kidney failure"

Type 3 - Acute Acute primary worsening of kidney function - Acute kidney

renocardiac syndrome that leads to cardiac dysfunction injury
- Hyperkalemia,
uremia

Type 4 - Chronic Primary chronic kidney disease that - Chronic

renocardiac syndrome contributes to cardiac dysfunction glomerular
disease
- Anemia,
systemic
hypertension

Type 5 - Secondary Cardiac and renal dysfunction secondary to - Diabetes

cardiorenal syndrome and acute or chronic systemic condition mellitus
- Sepsis

Hypothesis
In dogs and cats, like in people, intrinsic dysfunction of the cardiovascular system and/or
its management promotes secondary injury and dysfunction of the kidney. In addition,
intrinsic dysfunction of the kidney and/or its management promotes secondary injury and
dysfunction of the cardiovascular system.
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Cardiovascular Disease Contributes to Kidney Dysfunction
In patients with cardiovascular disease the renal hemodynamics is affected and
considered the main contributor to secondary kidney disease.13,23 A low output stage
triggers neurohormonal activation through the sympathetic nervous system (SNS) and the
RAAS. This process leads to initial preservation of the glomerular filtration rate (GFR), but
decreased renal perfusion and secondary tubular hypoxic injury and loss of nephrons.
These systems also promote water and sodium retention, elevating central venous
pressure and causing organ congestion ('congestive kidney failure'). Renal congestion in
turn also stimulates the SNS and RAAS contributing to progressive reduction of
GFR.13,23-25
Cardiac biomarkers such as N-terminal pro-B-type natriuretic peptide (NT-proBNP) and
cardiac troponin-I (cTnI) are well established indicators of cardiac disease or injury.26-30
Identification of tubular biomarkers of early kidney injury, such as NGAL, clusterin and
cystatin c, are crucial to the recognition of CRS and management of both conditions.5,10,11
Classification of the heart disease, AKI and CKD is an important step to characterize the
type of CRS. The recommended cardiac disease classification is the American College of
Veterinary Internal Medicine (ACVIM) cardiac disease severity classification, which was
adapted from the American College of Cardiology/American Heart Association
classification system that uses an A through D categorization (Table 2).31 The International
Renal Interest Society (IRIS) proposed AKI and CKD classifications, which are the most
widely accepted in veterinary medicine (Tables 3 and 4, respectively).11,32,33
Table 2. ACVIM cardiac disease classification

ACVIM Class
classification Class A Class B1 Class B2 Class C1 C2 Class D1 Class

Brief Patient Asymptomati Asymptomati Heart Heart Refractory Refra

definition s at risk c c failure failur HF y HF
No Cardiomegaly Hospitalize e Hospitalize At ho
cardiomegaly d At d
home

Table 3. IRIS acute kidney injury (AKI) grading criteria

AKI Serum
Grade creatinine Clinical description

Grade < 1.6 Non azotemic AKI:

I (mg/dL) - Documented AKI: (Historical, clinical, laboratory, or imaging
(< 140 evidence of acute kidney injury, clinical oliguria/anuria, volume
µmol/l) responsiveness) and/or
- Progressive non azotemic increase in serum creatinine; ≥ 0.3 mg/dL
(≥ 26.4 μmol/l) within 48 hours
- Measured oliguria (< 1 ml/kg/h) or anuria over 6 h

Grade 1.7–2.5 Mild AKI:

II mg/dL Documented AKI and static or progressive azotemia
(141–220 Progressive azotemic increase in serum creatinine; ≥ 0.3 mg/dL (≥
µmol/l) 26.4 μmol/l) within 48 hours), or volume responsiveness
- Measured oliguria (< 1 ml/kg/h) or anuria over 6 h

Grade 2.6–5.0 Moderate to severe AKI:

III mg/dL Documented AKI and increasing severities of azotemia and
(221–439 functional renal failure
µmol/l)

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Grade 5.1–10.0
IV mg/dL
(440–880
µmol/l)

Grade > 10.0

V mg/dL
(> 880
µmol/l)
Courtesy IRIS Board
Kidney Disease Contributes to Cardiovascular Dysfunction
Abnormal kidney function may lead to metabolic and functional disturbances in multiple
organs, which include the cardiovascular system. These processes may directly affect the
heart, such as systemic hypertension causing decreased systolic function, left ventricular
hypertrophy and diastolic dysfunction; or indirectly by reducing the production of
erythropoietin leading to anemia.34-36
Management of the Cardiorenal Syndrome Patient
A significant number of patients with AKI and CKD are treated by cardiologists, but there
is no established protocol for the treatment or monitoring of cardiovascular disorders in
these patients. Patients with kidney dysfunction may receive a suboptimal treatment for
concurrent cardiovascular conditions, even though they may benefit from the standard
therapies. This may account for part of the worse prognosis attributed to patients with
renal disease. In human medicine, early referral to a nephrologist is associated with a
delayed progression of CKD. CRS patients may benefit from co-management by
cardiologists and nephrologists.37
Angiotensin converting enzyme inhibitors and angiotensin receptor blockers (ARBs) are
beneficial in cardiovascular and renal diseases, but patients with renal dysfunction are less
likely to receive this type of drugs due to the concern of worsening renal function.38-41 A
better understanding of the relative risk of using these and other drugs may be very
important in CRS patients.
Mineralocorticoid receptor antagonists (aldosterone blockers) have the potential for renal
and cardiac protection; therefore the use of spironolactone in this subset of patients may
be beneficial if the patients tolerate the drug.31
Loop diuretics may have conflicting effects on the renal function. By reducing renal
congestion they may improve GFR and delay the progression of CKD, but on the other
hand, excessive doses of diuretics may also decrease renal perfusion and consequently
GFR. The combination of loop diuretics and thiazide diuretics has a synergistic effect that
may cause excessive volume depletion and electrolyte disturbances, therefore they should
be used with caution in the CRS patient.
Pimobendan improves the systolic function, which may increase GFR. Pimobendan does
not enhance or suppress furosemide-induced RAAS activation.39,42
Digoxin and other drugs with predominant renal excretion may require closer monitoring
and potential reduction of the dose.
Omega-3 fatty acids are a recommended oral supplement that has been used as an
antioxidant and appetite stimulant in patients with heart and kidney disease.22-35
Table 4. IRIS chronic kidney disease (CKD) classification

Serum
CKD creatinine
Stage (mg/dl) Comments

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Stage < 1.4 Non-azotemic

I Dogs Some other renal abnormality present, e.g., inadequate urinary
< 1.6 concentrating ability without identifiable nonrenal cause; abnormal
Cats renal palpation and/or abnormal renal imaging findings; proteinuria of
renal origin; abnormal renal biopsy results; increasing blood
creatinine concentrations in samples collected serially

Stage 1.4–2.0 Mild renal azotemia (lower end of the range lies within reference
II Dogs ranges for many laboratories but the insensitivity of creatinine as a
1.6–2.8 screening test means that animals with creatinine values close to the
Cats upper reference limit often have excretory failure)
Clinical signs usually mild or absent

Stage 2.1–5.0 Moderate renal azotemia

III Dogs Many extrarenal clinical signs may be present
2.9–5.0
Cats

Stage > 5.0 Severe renal azotemia

IV Dogs and Many extrarenal clinical signs are usually present
Cats
Courtesy J. Elliott and A.D.J. Watson, and the IRIS Board
Conclusions and Future Directions
An accurate appreciation of the kidney and the cardiovascular system and their
interactions may have practical clinical implications. A multidisciplinary evaluation
including the expertise of cardiologists and nephrologists may be the most appropriate
approach for the patient at risk for CRS.43 The outcome of CRS patients is likely to
improve with the increasing awareness and ability to identify and understand the
pathophysiological characteristics of cardiorenal syndrome.
References
VIN editor: References 2 and 4 are the same
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