Cardiorenal Syndrome: A Difficult Balancing Act

ABVP 2017
Margie Scherk, DVM, DABVP (Feline)
Vancouver, Canada

Renal dysfunction is extremely common in elderly cats and when cardiac disease occurs concurrently, the
practitioner is faced with a complex therapeutic challenge. The actual prevalence of this combination in cats
has not been studied extensively; however, one paper reported a 59% prevalence of azotemia in cats with
hypertrophic cardiomyopathy (HCM), compared to that in 25% of age-matched cohorts.1 In humans, the term
"cardiorenal syndrome" (CRS) is used, and up until 2008, it merely described the worsening of renal function
as a result of myocardial disease. This simplistic view has been revised as the complex nature of the
pathophysiologic bidirectional interactions between heart and kidneys has been studied. Outcomes for human
patients with both conditions are worse than for patients with either condition alone. There are five types of
CRS in human medicine defined by the chronology (which came first) and the type of insult or pathology
present (Table 1).2,3 Early recognition may allow for appropriate intervention to improve clinical signs and
patient wellbeing. Knowing what initiated the process and how it is being maintained may help with monitoring
as well as treatment planning. In an ideal world, a patient with CRS can call on the multidisciplinary expertise
of a cardiologist and nephrologist, as well as that of a criticalist and radiologist. In veterinary patients,
terminology and classification have been redesignated by a group of veterinary cardiologists and
nephrologists as cardiovascular-renal disorders (CvRD) to include the effects systemic hypertension (Table
1).4

Table 1. Classification scheme for human cardiorenal syndrome and canine/feline cardiovascular-
renal axis disorders

Human Dog/Cat

Type 1 (acute Acute cardiac CvRDH (CV driven - Kidney disease/dysfunction secondary to cardiovascular
CRS) decompensation => acute formerly CRS 1 and 2) disease
renal injury

Type 2 (chronic Chronic cardiac

CRS) abnormalities =>
progressive decline in renal
function

Type 3 (acute Acute decompensation in CvRDK (kidney driven - Cardiovascular disease/dysfunction secondary to kidney
renocardiac renal function => acute formerly CRS 3 and 4) disease
syndrome) cardiac pathology

Type 4 (chronic Chronic renal disease =>

renocardiac progressive decline in
syndrome) cardiac function

Type 5 Systemic disease => decline CvRDO (secondary - Kidney and cardiovascular injury/dysfunction as a result of:
(secondary CRS) in both cardiac and renal formerly CRS 5) a primary disease process from outside of, but affecting both,
function cardiovascular or renal systems; or drugs, toxins that affect
both systems

From: Ronco C, Haapio M, House AA, et al. Cardiorenal syndrome. J Am Coll Cardiol. 2008;52:1527–1539 combined with
Pouchelon JL, Atkins CE, Bussardori C, et al. Cardiovascular-renal axis disorders in the domestic dog and cat: a veterinary
consensus statement. J Sm Anim Pract. 2015;56:537–552.
WHICH COMES FIRST? PATHOPHYSIOLOGY
The diseased heart affects renal function in numerous ways. Similarly, acute or chronic renal impairment can
also affect cardiac function negatively. And once either begins, a cycle of cause and effect becomes self-
perpetuating and progressive through neurohormonal feedback/communication mechanisms.

In humans, CRS type 1 ("acute CRS") is characterized by an acute worsening of cardiac function; for
example, due to acute cardiogenic shock, exogenous agents (including contrast media, diuretics, ACE
inhibitors), or acute decompensation of chronic heart failure, resulting in kidney injury. Mechanisms by which
this may occur are shown in Figure 1 (from Pouchelon et al.).4 CRS type 2 ("chronic CRS") is characterized by
chronic changes in cardiac function, such as in chronic heart failure causing progressive chronic kidney
disease (CKD). CRS types 1 and 2 are reflected in veterinary patients as CvRDH. CRS type 3 ("acute
renocardiac syndrome") is characterized by abrupt worsening of renal function (for example, due to acute
kidney failure) causing acute cardiac disorder (e.g., heart failure, arrhythmia, pulmonary edema). CRS type 4
("chronic renocardiac syndrome") is characterized by sequelae of CKD; e.g., hypertension, chronic glomerular
disease (rarely in cats) contributing to decreased cardiac function, cardiac hypertrophy, or increased risk of
adverse cardiovascular events. In cats, types 3 and 4 (renal-sourced cardiac problems) are probably mostly
seen resulting from systemic hypertension and are termed CvRDK. CRS type 5 ("secondary CRS")/CvRDO is
characterized as a systemic condition, such as diabetes mellitus, or sepsis, causing both cardiac and renal
dysfunction (Table 1). Understanding of animal CvRD is still preliminary, and categorization and
understanding regarding mechanisms will undoubtedly evolve.

Figure 1. Schema suggesting mechanisms relating cardiovascular disease and renal disease

Pathways showing renal dysfunction resulting from cardiac dysfunction are shown in blue; pathways by which renal
dysfunction results in cardiac dysfunction are shown in red. Credited to Pouchelon et al. J Sm Anim Pract. 2015.
GFR, glomerular filtration rate; RAAS, renin-angiotensin-aldosterone system; SNS, sympathetic nervous system
Regardless of species or origin, these disorders entail more than "merely" the difficulties encountered in
balancing cardiac output with renal perfusion and glomerular filtration rate (GFR). The problem goes well
beyond a decreasing ability of the kidneys to deal with volume overload, even in the face of increasing diuretic
therapy. The reader is strongly encouraged to review the papers by Ronco 2,3 with elegant images depicting
suggested neurohormonal, hemodynamic, immune-mediated, inflammatory mediators and metabolic
components. These include:

Inadequate cardiac output (CO)

Activation of the renin-angiotensin-aldosterone system (RAAS)

Stimulation of the sympathetic system

B-type natriuretic peptide (BNP) effects

Electrolyte (e.g., hypo- or hyperkalemia, Na, Ca, Phos), acid-base and coagulation imbalances

Hypoperfusion, ischemia, reperfusion

Endothelial dysfunction, thromboembolism

Hypertension

Systemic inflammation (possibly subclinical), monocyte stimulation, and cytokine production

Oxidative stress, hypoxia

Endogenous and exogenous toxins

Some examples of the interactive, cumulative, spiraling, detrimental progressive effects may include:

Decreased CO => hypotension => vasoconstriction of afferent arterioles => decreased renal perfusion
and decreased GFR => retention of uremic toxins; alterations in blood flow => increased chance for
thromboembolism; Na retention

Chronic kidney disease-associated hypertension => increased afterload on heart => left-ventricular
hypertrophy (LVH) => left-atrial (LA) enlargement, which may => heart failure

Activation of sympathetic and RAA systems to support cardiac output augments renal vasoconstriction
as well as Na retention

RAAS activation causes hyperkalemia, negatively affecting cardiac conduction

As alluded to, a notable difference between the human and feline species is that the former is predisposed to
vascular and glomerular lesions, whereas the latter suffers mostly from inflammatory tubulointerstitial renal
lesions. These differences affect pathogenic progression, diagnostics, and therapeutics.

CvRDK with chronic kidney disease is probably the most common pathogenic sequence in cats. Primary
CKD, especially in later IRIS stages, can contribute to decreased cardiac function, LVH, and diastolic
dysfunction. Humans with CKD are at extremely high risk for cardiovascular disease and "more than 50% of
deaths in CKD stage 5 cohorts are attributed to cardiovascular disease. The 2-year mortality rate after
myocardial infarction in patients with CKD stage 5 is estimated to be 50%. In comparison, the 10-year
mortality rate post-infarct for the general population is 25%. Patients with CKD have between a 10-
and 20-fold increased risk of cardiac death compared with age-/gender-matched control subjects
without CKD. Part of this problem may be related to the fact that such individuals are also less likely
to receive risk-modifying interventions compared to their non-CKD counterparts."2 (Excerpted from
Ronco, p. 1533.) As already mentioned, it must be remembered that the common types of renal disease in
people are vascular in nature and commonly glomerular in location - very different than those found in cats,
which are inflammatory and interstitial. A concern in the human CKD population is the lack of CKD population-
specific data with respect to treatment effect. This limits the ability to make treatment-planning decisions.2

Perhaps acute renocardiac syndrome (like type 3 in humans) is the second most likely CvRD K scenario in
cats. Acute kidney injury (e.g., from ischemia, toxin, or infection), especially if superimposed on preexisting
chronic kidney disease, can affect the heart via several pathways.

1. Fluid overload may => pulmonary edema

2. Hyperkalemia can => arrhythmias (humans, especially in academia)

3. Uremia causes increased myocardial depressant factors which impair myocardial contractility

4. Acidemia => pulmonary vasoconstriction and has a negative inotropic effect

5. Renal ischemia can precipitate inflammation and apoptosis in the heart2

GOALS
At this time in feline medicine, even as understanding changes regarding possible pathophysiologic pathways
in CvRD, we have only a few questions that we might expect to answer. 5

1. How do we identify a patient with both cardiac and renal disease?

a. Are there clinical signs or tests that might be of value for early diagnosis?

2. How do we treat or change our treatment plan for a cat with both diseases?

a. If renal disease preceded cardiac failure?

b. If cardiac disease preceded renal failure?

One scenario in feline medicine is the cat with CKD who may develop concurrent (usually secondary) heart
disease in the later, decompensating stages of CKD. It is prudent to assess the cardiovascular status closely
to determine whether CvRD is occurring vs. a linear progression of the renal disease. Similarly, a cat in acute
kidney injury (AKI) may have primary, previously subclinical heart failure (e.g., thromboembolism resulting in
renal infarction) or have developed it secondary to the AKI. Anticipating this possibility requires making an
accurate diagnosis of the type of renal disease affecting the patient. To this end, the International Renal
Interest Society (IRIS) staging scheme is very helpful. Staging hinges on the urine specific gravity (USG);
serum creatinine (Cr); quantifying the degree of proteinuria using urine protein:creatinine ratio (UPC) if
proteinuria is present; and evaluating the presence and degree of hypertension.

DIAGNOSIS
Azotemia may be misleading if a cat is dehydrated and it is not possible to properly stage to prognosticate or
plan appropriate therapies until the individual has been rehydrated. Using the IRIS staging system, stage 1
cats are not azotemic but are classified based on having inadequate renal concentrating ability (a urine
specific gravity ≤1.040) in a dehydrated state. The diuretic effect of diet (e.g., high NaCl, canned vs. dry) or
drugs will make assessment of USG difficult. Collecting urine after a period of sleep may help counter this
effect somewhat.

Stages 2–4 are based on elevation of Cr levels. Again, as with specific gravity, numerous nonrenal factors
may affect this parameter. When inadequate protein is available for their ongoing needs, cats (being obligate
carnivores) catabolize protein stores (muscle) to fuel metabolic pathways, resulting in an artificially low serum
creatinine value. Prerenal azotemia associated with dehydration will have the opposite effect on Cr and will
also result in misleading increases in serum symmetrical dimethylarginine (SDMA).

Blood urea nitrogen (BUN) can be especially difficult to interpret as it reflects ammonia intake, production, and
excretion. Urea is a byproduct of ammonia metabolism that is excreted in bile (so there is enterohepatic
recirculation) as well as eliminated by the kidney. The majority of the ammonia produced in the body is by
bacterial fermentation in the gut with lesser amounts produced by breakdown (catabolism) of endogenous
protein and other molecules such as heme and some of the cytochromes that are rich in nitrogen. Dietary
factors can be important - there have been cases of animals being fed organ meats as treats that resulted in
producing spuriously high urea, so you have to look at everything the patient is ingesting. Bleeding into the
gastrointestinal (GI) tract is one of the most common "pathological" causes due to the large amount of
nitrogen in blood, which is broken down by the bacteria. Other potential causes would include factors that
could change the amount of ammonia being produced by the bacteria in the gut, such as shifts in bacterial
populations and changes in motility/GI transit of food. Any metabolic derangement that causes excess
catabolism of protein in the body as an energy substrate has the potential to increase urea levels. Increases
in urea (independent of creatinine) are common in diabetes mellitus and hyperthyroidism. (Interestingly, urea
can be elevated in renal disease when creatinine is normal, especially in neonates or animals with muscle
wasting since these individuals have decreased muscle mass compared to the population "normal," so their
creatinine levels are correspondingly lower. In this situation, urea may be more sensitive than creatinine for
predicting renal disease.)

Regardless of creatinine, evaluation of blood pressure and urinary protein is required for complete IRIS
staging. A persistent urine protein:creatinine ratio (UPC) of >0.4 has been shown to be associated with
increased mortality as well as progression of renal insufficiency. Hypertension increases risk of vascular
damage to target organs (brain, kidneys, eyes).6

Standard diagnostics for renal disease include the minimum database of complete blood count and
differential, serum biochemistries, blood pressure, urinalysis, and (if significant urinary protein is present) a
UPC. Hypotension is detrimental to renal perfusion; hypertension, to cardiac output and renal function. In
stages 1 and 2, we have the best chance to identify treatable causes of renal disease. Hence, in addition to
the aforementioned, basic measures, urine culture, abdominal ultrasound, and possibly renal biopsy should
ideally be pursued. Urine cultures are worth performing when a USG is ≤1.030 regardless of sediment and, in
more concentrated samples, if significant numbers of white blood cells and/or bacteria are seen. If a
hematogenous source of infection is suspected, blood culture may be considered. Abdominal ultrasound is
useful to assess gross renal pathology, to guide in collection of intrapelvic urine samples, and for renal
biopsies if indicated. Determination of the cause should be encouraged in stable patients, as this knowledge
provides the only chance for accurate treatment of potentially reversible renal disease. When there is concern
for primary or secondary cardiac pathology, an echocardiogram and thoracic radiographs should be
evaluated. Contributing systemic disease (including electrolyte imbalances) should be identified and stabilized
if possible.

These standard tests show existing change. Earlier diagnosis could help to blunt pathologic processes and
stop progression of CRS or CvRD. In human medicine, numerous biomarkers have been evaluated to identify
early ischemic or nephrotoxic kidney injury. In veterinary medicine, SDMA and urinary neutrophil gelatinase-
associated lipocalin (uNGAL) may be of use. In cats with CKD, uNGAL is higher than in healthy cats and may
be helpful in predicting progression.7 SDMA detects a decrease in renal function when approximately 40% of
GFR is lost compared to ∼75% loss before Cr levels increase. Additionally, it is unaffected by muscle mass.
Both SDMA and Cr are, however, affected (as mentioned) by prerenal factors (i.e., dehydration). By
monitoring serial increases in Cr, significant decreases in GFR can be recognized before the analyte exceeds
normal reference level (e.g., an increase in Cr from 0.7 to 1.4 mg/dl over time, without evidence of
dehydration or an increase in muscle mass, would indicate at least a 50% reduction in GFR). In addition,
using a cutoff of >1.6 mg/dL (144 µmol/L) detects renal azotemia at the same time as does SDMA.8

Diagnosing CKD in patients already being treated for heart failure is challenging. Urine specific gravity is
lowered due to diuretic therapy; increases in BUN and Cr may also be present. As with CKD, however,
monitoring for serial increases in Cr in a hydrated patient is indicative of a decline in renal function and
development of CvRD.

In veterinary medicine, two biomarkers are available to detect heart failure. Cardiac troponin 1 is a myofibrillar
protein that is released with cardiac myocyte injury, cell death, and necrosis. It has not been shown to be able
to distinguish between respiratory distress from pulmonary vs. cardiac causes. B-type (brain) natriuretic
peptide (BNP) is a neurohormone that is secreted in response to volume expansion or pressure overload of
the atria or ventricles. It reflects myocyte stress. NT-proBNP is sensitive for diagnosing cats with moderate to
severe HCM, but poor in detection of cats with subclinical, mild HCM and may even miss cats with severe
HCM.9 Another limitation is that because it is renally excreted, NT-proBNP concentrations increase in both
AKI as well as CKD.10 The sensitivity of a bedside point-of-care NT-proBNP ELISA assay to differentiate cats
with cardiac disease from apparently healthy cats was 65.4% with a 100% specificity, thereby performing
moderately well.11 It appears to be useful to detect cardiac from noncardiac pleural effusions when used on
plasma, but not pleural fluid.12 Ultrasound remains necessary to identify cardiac disease in subclinically
affected cats. Longitudinal changes may be monitored on thoracic radiographs and on echocardiograms.

Both heart and kidneys are organs at risk for damage by systemic hypertension; it is important to measure
and monitor blood pressure in cats, especially those known to have CKD.6 Studies report between 19.4–65%
of cats with CKD being hypertensive, with this range reflecting a different definition of hypertension (>160 vs.
>175 mm Hg) as well as different patient populations (referral vs. tertiary care settings).13-16

Diagnosis of coexisting cardiac and renal disease requires vigilance and an index of suspicion. As is
suggested by Marie Claire Belanger17 in her elegant table summarizing the therapeutic approach to the cat
with CvRD syndrome (Table 2), the first step is recognizing and anticipating the development of CvRD. This
requires having a baseline BUN, serum creatinine, urine specific gravity, protein:creatinine ratio, and systemic
blood pressure and then monitoring creatinine over time to detect increases in this biochemical parameter.

Table 2. Therapeutic approach to the cat with CvRD

1. Recognize and anticipate CvRD - Record baseline BUN/Cr/USG/UPC ratio/SBP

- Monitor for serial Cr increases over time

2. Optimize heart failure therapy - Use lowest effective dose of furosemide

- Consider dual-diuretic therapy
- Consider torsemide if diuretic resistance
- Use ACE inhibitors
- Use other cardiac drugs directed at primary disease
- Perform thoracocentesis/abdominocentesis as needed

3. Evaluate and monitor renal function - CBC/serum chemistry profile/urinalysis ± UPC ratio
- Repeat every 1–3 months or when changing treatment plan
- Culture urine if indicated
- Ultrasound abdomen
4. Control hypertension - Assess systolic blood pressure (SBP)
- Treat when SBP ≥160 mm Hg
- Use amlodipine and/or telmisartan

5. Avoid hypotension - If SBP <100 mm Hg

- Reassess potentially hypotensive drugs
- Consider positive inotropes

6. Improve renal function/optimize renal therapy - Supplement with omega-3 PUFA

- Feed renal diet if ≥ IRIS stage 2
- Ensure adequate calories are being ingested to optimize BCS and MCS
- Consider phosphate binders
- Supplement with potassium
- Control gastrointestinal signs (e.g., proton-pump inhibitor)
- Consider long-term SC fluids
- Consider renal replacement therapy

7. Improve cardiac output - Consider positive inotropes

- Treat hypertension if present

8. Correct anemia of CKD - When HT <18–20%

- EPO or darbepoetin administration
- Supplement iron if indicated

9. Review and modify drug dosages - Extend dosage interval of renally excreted drugs
- Check for drug interactions

Modified from: Belanger MC. Heart failure and chronic kidney disease. In: Little S, ed. The Cat: Clinical Medicine and
Management. Elsevier; 2nd edition in press.
ACE, angiotensin-converting enzyme; BUN, blood urea nitrogen; CBC, complete blood count; PUFAs, polyunsaturated fatty
acids; BCS, body condition score; MCS, muscle condition score; SC, subcutaneous; SBP, systemic blood pressure; UPC,
urine protein/creatinine ratio; USG, urine specific gravity.

THERAPY AND MONITORING

While challenging, these patients may be cared for best when the practitioner recognizes that they will require
a commitment on the part of not only the client, but also the veterinary team to close, ongoing assessment
and that many changes in therapy may be required. With heart failure, the most obvious imminent and
ongoing challenge is balancing opposing fluid volume requirements regardless of instigating mechanism.
Renal perfusion and GFR demand adequate volume, which a compromised cardiac capacity may be unable
to handle. While it is therefore tempting to favor the heart, in the long term this strategy may backfire due to
the effect on the aforementioned neurohormonal, hemodynamic, immune-mediated, inflammatory mediators
and metabolic components communicating with the other organ.

The goal is to optimize both cardiac and renal function. If a patient presents in heart failure, draining the
accumulated fluid (pleural or, less commonly, peritoneal) provides immediate reduction of cardiac overload.
Simultaneous initiation of diuretic therapy will help reduce the load further. Thereafter, diuretics play a critical
role in maintaining a compensated state as well as urine production. Using respiratory rate and effort, the
dose of the diuretic can be adjusted on a daily basis at home. If or when the patient becomes resistant to the
diuretic being used and decompensates, a constant-rate infusion of furosemide may be more effective than
oral administration. Sometimes a different/additional mechanism of action is preferable; torsemide has been
shown to be ten times more potent in cats with experimentally induced LV hypertrophy. The clinically
appropriate dose needs to be determined for the individual patient. 18 Adding or switching to other loop
diuretics, such as hydrochlorothiazide, can be considered. Spironolactone is an alternative with its potassium-
sparing and aldosterone-blocking effects. Reports of facial dermatitis exist, but this reversible complication is
idiosyncratic. In a patient at risk for hyperkalemia, this agent would not be advisable. Vasodilation can be
used cautiously to decrease cardiac load through diuresis; use of vasodilatory agents requires careful
monitoring of blood pressure to avoid hypotension. Hemodialysis may be considered in some patients to
correct azotemia.

Additional support for cardiac output may be necessary. Because cats generally suffer from diastolic
dysfunction rather than output disorders, a positive inotrope may only be needed in later stages to support
renal perfusion. Along with traditional treatment of CHF, pimobendan has been shown to increase survival in
cats with HCM.19 It increases cardiac output, thereby improving renal blood flow. It may allow a reduction in
diuretic dose.

Hypertension is detrimental to both the progression of renal disease as well as heart failure and should be
aggressively corrected. Vasodilation may be part of the therapeutic approach to this problem, but amlodipine
will probably be needed as well. Telmisartan is an angiotensin receptor blocker that is effective in decreasing
proteinuria20 as well as having antihypertensive effect21. Angiotensin-converting enzyme inhibitors (ACE I) will
have a marginal effect in reduction of blood pressure (BP); however, this is unlikely to be adequate on its
own. Sequential BP measurements should be taken to evaluate effect and to titrate the dose in order to avoid
hypotension. A reasonable regimen would be at 3–5 days after initiation of therapy and after any dose
adjustment; thereafter every 1–2 months of therapy. The goal is to achieve a systolic pressure between 120–
150 mm Hg.

By blocking the effects of ongoing RAAS activation, ACE inhibitors provide benefits to both organs, especially
if glomerular hypertension and proteinuria are present. While ACE inhibition as well as angiotensin receptor
blockade may decrease GFR, the drop has been shown to be mild and not progressive with benazepril 22 or
telmisartan. Thus, contrary to common fears, cats with cardiac disease who develop CKD or who have pre-
existing renal disease and then develop cardiac disease can stay on ACE I. The dose of the drug may need
to be reduced especially in CvRDK in a patient with advanced CKD, in order to prevent renal function
deteriorating further.2

Ensuring careful hydration to reduce the risk for renal ischemia and significant GFR reduction is key for renal
health and reduction of azotemia. Intravenous fluids must be given with great care in the clinic; ideally central
venous pressure (CVP) should be monitored but so, a cat with CvRD may become overloaded. Monitoring
bodyweight, assessing urine production (palpating bladder size, weighing clean and used litter boxes or
towels), monitoring heart and respiratory rates, and ausculting for murmurs or gallop sounds will help detect
overhydration. The presence of chemosis is an easy way to detect fluid overload. Echocardiography can be
used to follow left atrial size (progressive dilation), another means to monitor response to therapy.

One should not avoid rehydration; the goal is to achieve a state of normal hydration and euvolemia safely.
Replacement formula fluids such as lactated Ringer's solution (LRS), Plasmalyte 148, or Normosol-R may be
appropriate in the short term. Once the dehydration has been corrected, either NaCl 0.45% with 2.5%
dextrose or Plasmalyte 56 with 5% dextrose is more appropriate from a cardiac standpoint while still providing
fluid to attempt to reduce the azotemic state. Fluids should be given in small volumes slowly and frequently.
Serum Na levels must be taken into consideration.

Although controversial, the subcutaneous route may be less dangerous because unabsorbed fluid pockets
are not harmful to the heart and indicate that a reduction in dose is warranted. 23 A counter-argument is that
the fluid pockets may interfere with oxygen transfer in the tissues. For homecare fluids, NaCl 0.45% or
Normosol-M may be suitable depending on serum Na concentration. Warming the fluids to body temperature
appears to make them better tolerated. A dedicated client can be taught to pay close attention to the
development of pulmonary edema/effusion, respiratory rate, and energy/appetite. They can also monitor the
volume of urine produced by keeping track of (and diarizing) the number and size of litter clumps. Stool
character (hard pellets vs. moist logs) is another indication of adequate cellular hydration. Fluids may also be
given enterically; a feeding tube is especially well suited for this need as long as caloric needs are being met
concurrently. Nutritional requirements mustn't fail due to limitations of stomach volume. Blood pressure should
be monitored regularly in a stable cardiorenal patient. In the hypokalemic cat, KCl may be given IV with fluids
while hospitalized or given orally at home. In cats needing more potassium than they tolerate orally, up to 40
mEq can be added to a liter of lactated Ringer's or other balanced electrolyte solution and be administered in
the subcutaneous fluids. B vitamins may, of course, also be added to fluids, but the client must be made
aware that they are susceptible to degradation if the fluids are not kept in a dark place. Serum electrolytes
(including sodium and potassium), creatinine, urine protein should be included in ongoing care in order to
titrate doses and adjust therapies as needed for the individual patient. The needs and status of the
patient will change, and the veterinary team should anticipate and be prepared (and willing to) reevaluate and
adjust treatment plans regularly.

Dietary therapy for both renal and cardiac dysfunction includes use of lower sodium diets, treats, and possibly
even water. Examples include Hill's k/d with a modest Na restriction, Purina's PVD CV or NF and Royal Canin
Renal LP for more strict restriction. Purina's Whisker Lickin' and Stewart Fiber Formula treats are suitable.
Distilled or low-sodium bottled water can be considered. While recommended in the IRIS schema for cats in
stages 2 onward, protein restriction must be tailored to the individual. Protein:calorie malnutrition not only
results in muscle wasting, but also in anemia and an immunocompromised state. Practically speaking, it may
also cause inappetence, as animal protein is very palatable to cats. Phosphorus reduction may be achieved
through other means, including intestinal phosphate binders and daily subcutaneous fluid therapy.
Supplementation with B vitamins and omega-3 fatty acids may be incorporated into the commercial or
homemade diet or added separately as needed. Omega-3 polyunsaturated fatty acids have been shown in
dogs to be beneficial in cardiac disease and in both dogs and cats with renal disease. 24 Ensuring that the cat
is eating enough of a balanced diet is more important than the diet they eat. Changing diets in the clinic to a
prescription diet often results in development of a food aversion, so diet changes should be done gradually,
over several weeks, in the safe, home environment.

Anemia is commonly seen in patients with chronic disease as well as in cats with CKD through reduction in
erythropoietin production. Inappetence may reduce dietary iron intake, and restriction of dietary protein may
result in less substrate for hemoglobin production. Azotemia shortens red cell lifespan. While the anemia may,
therefore, be multifactorial, when the hematocrit drops below 18%, erythropoietin or darbepoetin therapy
should be considered. Concurrent use of iron, as oral ferrous gluconate or as injectable iron dextran, is
advisable at least until the patient is eating well.

Hypergastrinemia may negatively impact appetite. Proton-pump inhibitors are appropriate to decrease gastric
acid secretion and are superior to H2 antagonists.25 In a patient with extreme or acute anemia, for whom a
transfusion is being considered, the effects of the increased vascular load must be weighed.

Drug Drug class Dose range, frequency, and route Indications

Furosemide Loop diuretic 2–4 mg/kg IV, IM, PO q 6–12 h Diuresis

CRI: 0.3–0.6 mg/kg/h IV

Torsemide, torasemide Loop diuretic 0.3 mg/kg PO q 24 h Diuretic resistance

Hydrochlorothiazide Thiazide diuretic, acts on 1–4 mg/kg PO q 12 h Diuretic resistance

distal tubule

Spironolactone K-sparing diuretic, 1–2 mg/kg PO q 12 h Diuretic resistance

aldosterone antagonist

Pimobendan Calcium sensitizer and 1.25–1.5 mg/cat PO q 12 h Increase cardiac contractility

 selective inhibitor of PDE3

Amlodipine Calcium channel blocker 0.625–1.25 mg/cat PO q 24 h Hypertension

(dihydropyridine class)

Telmisartan Angiotensin-receptor 1 mg/kg PO q 24 h Decrease glomerular capillary

blocker pressure and increase renal blood
flow; hypertension

Benazepril ACE I 0.25 mg/kg PO q 24 h to 0.5 mg/kg PO q 12 h Decrease glomerular capillary

pressure and increase renal blood
flow

Erythropoietin Hormone 100 IU/kg SQ three times/week until PCV is Anemia

35%, then decrease to twice a week, long
term. Monitor PCV for 60–90 days

Darbepoetin Hormone 0.45 mg/kg/week SC Anemia

Ferrous gluconate, Iron 50–100 mg PO q 24 h Anemia

ferrous sulfate

Iron dextran Iron 50 mg IM q 3–4 weeks Anemia

Omeprazole Proton-pump inhibitor 0.7–1.5 mg/kg PO q 12–24 h Uremic gastritis

Expect to titrate doses frequently, depending on patient response.

What About Dietary Sodium?

Recent papers have looked at the role of dietary sodium in lower urinary tract disease, renal disease, and
blood pressure in cats. Increasing dietary sodium has been evaluated as a way to increase urine output and
reduce specific gravity, thereby not only increasing frequency of voiding, but also reducing the relative
supersaturation of solutes to risk of urolith formation.26

As far as renal disease goes, there are many conflicting results. In one study, cats eating a higher sodium diet
had an increase in creatinine, BUN, and serum phosphorus compared to cats on a lower Na diet. 27 Another
study showed that a low Na diet resulted in a reduced glomerular filtration rate, increased urinary potassium
loss, activation of RAA.28 A third study showed that feeding higher levels of Na, along with Mg, protein, and
dietary fiber resulted in a lower risk for development of chronic renal failure.29 Finally, feeding a classic
restricted protein, phosphorus, and Na diet to cats in renal insufficiency resulted in fewer renal-related deaths
in a fourth study.30

There is no strong evidence that increased dietary sodium increases the risk of hypertension in dogs and
cats, and the current recommendation for hypertensive animals is to avoid high dietary salt intake without
making a specific effort to restrict it, as restriction may, in fact, activate the RAA system.26 Reduction of Na
has not been shown to have an effect on blood pressure (systolic, diastolic, mean) 27,28 and may, in fact, result
in hypotension in cats, especially if these cats are on an ACE inhibitor31.
It is important to recognize that these studies vary with respect to diet composition and what constituted high
vs. low Na levels. The studies reported in these six papers are designed differently, so drawing conclusions
relative to the other papers is not really possible.

PROGNOSIS
In general, the long-term prognosis is not good for these patients. Even in human medicine, patients with
CRS experience high rates of morbidity and mortality, and their care providers are frustrated by the many
challenges to improving their clinical status.32 Early detection and blunting of the effects and progression of
both cardiac and renal disease are necessary. With careful, frequent monitoring and prudent adjustments to
therapy, a dedicated veterinary team (specialists, general practitioner, and nursing staff) along with the
patient's family may have a gratifying and surprising effect on the longevity and quality of life for individual
cats.

References

1. Gouni V, Chetboul V, Pouchelon JL et al. Azotemia in cats with feline hypertrophic cardiomyopathy: prevalence and relationships
with echocardiographic variables. J Vet Cardiol. 2008;10:117.

2. Ronco C, Haapio M, House AA, et al. Cardiorenal syndrome. J Am Coll Cardiol. 2008;52:1527–1539.

3. Ronco C, Cruz DN, Ronco F. Cardiorenal syndromes. Curr Opin Crit Care. 2009;15:384–391.

4. Pouchelon JL, Atkins CE, Bussadori C, et al. Cardiovascular-renal axis disorders in the domestic dog and cat: a veterinary
consensus statement. J Sm Anim Pract. 2015;56:537–552.

5. Côté E. Seeking the perfect balance: management of concurrent cardiac and renal disease. Proceedings of Am College Vet Int
Med. 2008.

6. Brown S, Atkins C, Bagley R, et al. Guidelines for the identification, evaluation, and management of systemic hypertension in dogs
and cats. J Vet Intern Med. 2007;21:542–558.

7. Wang IC, Hsu WL, Wu PH. Neutrophil gelatinase-associated lipocalin in cats with naturally occurring chronic kidney disease. J Vet
Intern Med. 2017;31:102–108.

8. Hall JA, Yerramilli M, Obare E, et al. Comparison of serum concentrations of symmetric dimethylarginine and creatinine as kidney
function biomarkers in cats with chronic kidney disease. J Vet Intern Med. 2014;28(6):1676–1683.

9. Singh MK, Cocchiaro MF, Kittleson MD. NT-proBNP measurement fails to reliably identify subclinical hypertrophic cardiomyopathy
in Maine Coon cats. J Feline Med Surg. 2010;12(12):942–947.

10. Lalor SM, Connolly DJ, Elliott J, et al. Plasma concentrations of natriuretic peptides in normal cats and normotensive and
hypertensive cats with chronic kidney disease. J Vet Cardiol. 2009;11:S71–S79.

11. Harris AN, Beatty SS, Estrada AH, et al. Investigation of an n-terminal prohormone of brain natriuretic peptide point-of-care ELISA
in clinically normal cats and cats with cardiac disease. J Vet Intern Med. 2017.

12. Hezzell MJ, Rush JE, Humm K, et al. Differentiation of cardiac from noncardiac pleural effusions in cats using second-generation
quantitative and point-of-care NT-proBNP measurements. J Vet Intern Med. 2016;30(2):536–542.

13. Syme HM, Barber PJ, Markwell PJ, et al. Prevalence of systolic hypertension in cats with chronic renal failure at initial
evaluation. J Am Vet Med Assoc. 2002;220:1799–1804.

14. Stiles J, Polzin D, Bistner S. The prevalence of retinopathy in cats with systemic hypertension and chronic renal failure or
hyperthyroidism. J Am Anim Hosp Assoc. 1994;30:564–572.

15. Kobayashi DL, Peterson ME, Graves TK, et al. Hypertension in cats with chronic renal failure or hyperthyroidism. J Vet Intern
Med. 1990;4:58–62.
 16. Bijsmans ES, Jepson RE, Chang YM, Syme HM, Elliott J. Changes in systolic blood pressure over time in healthy cats and cats
with chronic kidney disease. J Vet Intern Med. 2015;29(3):855–861.

17. Belanger MC. Heart failure and chronic kidney disease. In: Little S, ed. The Cat: Clinical Medicine and Management. Elsevier; 2nd
edition in press.

18. Uechi M, Matsuoka M, Kuwajima E, et al. The effects of the loop diuretics furosemide and torasemide on diuresis in dogs and
cats. J Vet Med Sci. 2003;65:1057.

19. Reina-Doreste Y, Stern JA, Keene BW, et al. Case-control study of the effects of pimobendan on survival time in cats with
hypertrophic cardiomyopathy and congestive heart failure. J Am Vet Med Assoc. 2014;245:534–539.

20. Sent U, Gössl R, Elliott J, et al. Comparison of efficacy of long-term oral treatment with telmisartan and benazepril in cats with
chronic kidney disease. J Vet Intern Med. 2015;29(6):1479–1487.

21. Jenkins TL, Coleman AE, Schmiedt CW, et al. Attenuation of the pressor response to exogenous angiotensin by angiotensin
receptor blockers and benazepril hydrochloride in clinically normal cats. Am J Vet Res. 2015;76(9):807–813.

22. Mizuta H, Koyam H, Watanabe T, et al. Evaluation of the clinical efficacy of benazepril in the treatment of chronic renal
insufficiency in cats. J Vet Intern Med. 2006;20(5):1074–1079.

23. DeFrancesco TC. Maintaining fluid and electrolyte balance in heart failure. Vet Clin Small Anim Pract. 2008;38:727.

24. Plantinga EA, Everts H, Kastelein AM, et al. Retrospective study of the survival of cats with acquired chronic renal insufficiency
offered different commercial diets. Vet Rec. 2005;157:185.

25. Šutalo S, Ruetten M, Hartnack S, et al. The effect of orally administered ranitidine and once-daily or twice-daily orally
administered omeprazole on intragastric pH in cats. J Vet Intern Med. 2015;29(3):840–846.

26. Chandler ML. Pet food safety: sodium in pet foods. Top Comp Anim Med. 2008;23(3):148–153.

27. Kirk CA, Jewell DE, Lowry SR. Effects of sodium chloride on selected parameters in cats. Vet Ther. 2006;7(4):333–346.

28. Buranakarl C, Mathur S, Brown SA. Effects of dietary sodium chloride intake on renal function and blood pressure in cats with
normal and reduced renal function. Am J Vet Res. 2004;65(5):620–627.

29. Hughes KL, Slater MR, Geller S. Diet and lifestyle variables as risk factors for chronic renal failure in pet cats. Prev Vet Med.
2002;55(1):1–15.

30. Ross SJ, Osborne CA, Kirk CA, et al. Clinical evaluation of dietary modification for treatment of spontaneous chronic kidney
disease in cats. J Am Vet Med Assoc. 2006;229(6):949–957.

31. Lefebvre HP, Toutain PL. Angiotensin-converting enzyme inhibitors in the therapy of renal diseases. J Vet Pharmacol Ther.
2004;27(5):265–281.

32. Shlipak MG, Massie BM. The clinical challenge of cardiorenal syndrome. Circulation. 2004;110:1514–1517.

_____________________________________________________________________________________

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

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 cardiorenal Acute impairment of the cardiac function leading to acute - Acute heart failure
syndrome kidney injury (AKI) - Cardiogenic shock

Type 2 - Chronic cardiorenal Chronic cardiovascular disease causing progressive chronic - Chronic heart failure
syndrome kidney disease (CKD) - "Congestive kidney
failure"

Type 3 - Acute renocardiac Acute primary worsening of kidney function that leads to - Acute kidney injury
syndrome cardiac dysfunction - Hyperkalemia, uremia

Type 4 - Chronic renocardiac Primary chronic kidney disease that contributes to cardiac - Chronic glomerular
syndrome dysfunction disease
- Anemia, systemic
hypertension

Type 5 - Secondary cardiorenal Cardiac and renal dysfunction secondary to and acute or - Diabetes mellitus
syndrome chronic systemic condition - 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.

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
classification Class A Class B1 Class B2 Class C1 Class C2 Class D1 Class D2

Brief definition Patients at Asymptomatic Asymptomatic Heart Heart Refractory Refractory

risk No Cardiomegaly failure failure HF HF
cardiomegaly Hospitalized At home Hospitalized At home

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

AKI Serum
Grade creatinine Clinical description

Grade I < 1.6 (mg/dL) Non azotemic AKI:

(< 140 - Documented AKI: (Historical, clinical, laboratory, or imaging evidence of acute kidney
µmol/l) injury, clinical oliguria/anuria, volume 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 II 1.7–2.5 Mild AKI:

mg/dL Documented AKI and static or progressive azotemia
(141–220 Progressive azotemic increase in serum creatinine; ≥ 0.3 mg/dL (≥ 26.4 μmol/l) within 48
µmol/l) 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 functional renal failure
(221–439
µmol/l)

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

CKD
Stage Serum Comments
creatinine
 (mg/dl)

Stage < 1.4 Dogs Non-azotemic

I < 1.6 Cats Some other renal abnormality present, e.g., inadequate urinary concentrating ability without
identifiable nonrenal cause; abnormal 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 Dogs Mild renal azotemia (lower end of the range lies within reference ranges for many laboratories
II 1.6–2.8 Cats but the insensitivity of creatinine as a screening test means that animals with creatinine values
close to the upper reference limit often have excretory failure)
Clinical signs usually mild or absent

Stage 2.1–5.0 Dogs Moderate renal azotemia

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

Stage > 5.0 Dogs Severe renal azotemia

IV and Cats Many extrarenal clinical signs are usually present

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

1. Schrier RW. Nat Clin Pract Nephrol. 2007;3:637.

2. Berl T, Henrich W. Clin J Am Soc Nephrol. 2006;1:8–18.

3. Ronco C. Int J Artif Organs. 2008;31:1–2.

4. Berl T, Henrich W. Clin J Am Soc Nephrol. 2006;1:8–18.

5. Ronco, C. et al. J Am Coll Cardiol. 2008; 52:1527–39.

6. Liang KV, Williams AW, et al. Crit Care Med. 2008;36:S75–88.

7. Jose P, Skali H, Anavekar N, et al. J Am Soc Nephrol. 2006;17:2886–91.

8. Ellison DH. Semin Nephrol. 1999;19:581–97.

9. Almeshari K, Ahlstrom NG, Capraro FE, Wilcox CS. J Am Soc Nephrol. 1993;3:1878–83.

10. De Loor, J. et al. J Vet Intern Med. 2013;27:998–1010.

11. Segev G, et al. J Vet Intern Med. 2013;27:1362–1367.

12. Graziani, G. et al. Heart Fail Rev. 2013.

13. Mullens W, et al. J Am Coll Cardiol. 2009;53:589–96.

14. Jessup M, Costanzo MR. J Am Coll Cardiol. 2009;53(7):597–9.

15. Hillege HL, Nitsch D, Pfeffer MA, et al. Circulation. 2006;113:671–8.

16. Blake P, et al. ASAIO J. 1996;42:M911–5.

17. Meyer TW, Hostetter TH. N Engl J Med. 2007;357:1316–25.

18. Langhorn, R. et al. J Vet Intern Med. 2013;27:895–903.

19. Cunningham PN, et al. J Immunol. 2002;168:5817–23.

20. Waldum B, Os I. Cardiology. 2013;126:175–186.

21. Atkins CE. Vet Clin North Am Small Anim Pract. 1991;21:1035–1080.

22. Polzin DJ. Vet Clin North Am Small Anim Pract. 2011;41:15–30.

23. Damman K, et al. Eur J Heart Fail. 2007;9:872–878.

24. Ruiz-Ortega M, et al. Kidney Int Suppl. 2002;S12–22.

25. Remuzzi G, Perico N, et al. Kidney Int Suppl. 2002;S57–65.

26. Sharkey LC, et al. J Am Vet Med Assoc. 2009; 234:767–770.

27. Häggström J, et al. J Vet Cardiol. 2000;2:7–16.

28. Serres F, et al. J Vet Cardiol. 2009;11:103–121.

29. Schmidt MK, et al. J Vet Cardiol. 2009;11(Suppl 1):S81–86.

30. Hezzell MJ, et al. J Vet Intern Med. 2012;26:302–311.

31. Atkins C, et al. J Vet Intern Med. 2009;23:1142–50.

32. Ross S. Vet Clin North Am Small Anim Pract. 2011;41:1–14.

33. www.iris-kidney.com.

34. Brown S, et al. J Vet Intern Med. 2007;21:542–558.

35. Polzin DJ. J Vet Emerg Crit Care (San Antonio). 2013;23:205–215.

36. Harison E, Langston C, Palma D, et al. J Vet Intern Med. 2012;26:1093–1098.

37. Campbell GA, Bolton WK. Adv Chronic Kidney Dis. 2011;18:420–427.

38. BENCH Study Group. J Vet Cardiol. 1999;1:7–18.

39. Häggström J, et al. The QUEST study. J Vet Intern Med. 2008;22:1124–1135.
 40. Ettinger SJ, et al. (LIVE) Study Group. J Am Vet Med Assoc. 1998;213:1573–1577.

41. The IMPROVE Study Group. J Vet Intern Med. 1995;9:234–242.

42. Lantis AC, Atkins CE, et al. Am J Vet Res. 2011;72:1646–1651.

43. Bock JS, Gottlieb SS. Circulation. 2010;121:2592–2600.

Cardiorenal Syndrome: The Cardiologist Perspective

WORLD SMALL ANIMAL VETERINARY ASSOCIATION CONGRESS PROCEEDINGS, 2016
Joao Orvalho, DVM, DACVIM (Cardiology)
University of California-Davis, Veterinary Medical Center San Diego, 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. 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 attention and have prompted further definition,
classification, and understanding of the relationship, and are the bases for the clinical entity termed
Cardiorenal Syndrome (CRS) in human medicine. Cardiorenal syndrome has not been well characterized in
veterinary medicine, but a recent attempt has been made to define a consensus for cardiovascular-renal
disorders (CvRD) of the dog and cat.

A DEFINITION
The definition of CRS includes a variety of acute or chronic conditions, where the primary failing organ can be
the heart or the kidney, or both due to a systemic condition, and how the dysfunction of one organ system
affects the function of the other organ system.

CLASSIFICATION
Five subtypes have been suggested in order to simplify the identification and the approach in the clinical
setting.

Type 1 CRS - Acute cardiorenal syndrome is characterized by a rapid impairment of the 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).

Type 2 CRS - Chronic cardiorenal syndrome consists of chronic cardiovascular disease causing progressive
chronic kidney disease (CKD). 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).

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.
Type 4 CRS - Chronic renocardiac syndrome consists of primary chronic kidney disease that contributes to
cardiac dysfunction. Decreased systolic function, left ventricular hypertrophy and a high output state
(secondary to anemia) are some of the potential long-term cardiac sequelae of CKD.

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. Diabetes mellitus and hyperadrenocorticism are typical chronic diseases in dogs that
have a similar effect on the urinary and cardiovascular systems.

Table 1. Human and veterinary classification of cardiorenal syndrome

Type of cardiorenal syndrome CvRD Brief definition Conditions

(human classification) Consensus

Type 1 - Acute cardiorenal CvRDH unstable Acute impairment of the cardiac function Acute heart failure
syndrome leading to acute kidney injury (AKI) Cardiogenic shock

Type 2 - Chronic cardiorenal CvRDH stable Chronic cardiovascular disease causing Chronic heart failure
syndrome progressive chronic kidney disease (CKD) "Congestive kidney failure"

Type 3 - Acute renocardiac CvRDK unstable Acute primary worsening of kidney function Acute kidney injury
syndrome that leads to cardiac dysfunction Hyperkalemia, uremia

Type 4 - Chronic renocardiac CvRDK stable Primary chronic kidney disease that contributes Chronic glomerular disease,
syndrome to cardiac dysfunction anemia, syst. hypertension

Type 5 - Secondary cardiorenal CvRDO Cardiac and renal dysfunction secondary to an Diabetes mellitus
syndrome acute or chronic systemic condition Sepsis

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).The International
Renal Interest Society (IRIS) proposed AKI and CKD classifications, which are the most widely accepted in
veterinary medicine.

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. 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.

Table 2. ACVIM cardiac disease classification

ACVIM Classification Class A Class B1 Class B2 Class C1 Class C2 Class D1 Class D2

Brief definition Patients at risk Asymptomatic Asymptomatic Heart failure Heart failure Refractory Refractory
No cardiomegaly Cardiomegaly Hospitalized At home Heart failure Heart Failure
Hospitalized At home

MANAGEMENT OF THE CARDIORENAL PATIENT

Cardiologists treat a significant number of patients with AKI and CKD, but there is no established protocol for
the treatment 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.
CRS patients may benefit from co-management by cardiologists and nephrologists.

Angiotensin converting enzyme-inhibitors and angiotension 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. 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.

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 also reduce GFR. The combination of loop diuretics and thiazide
diuretics has a synergistic effect that may cause excessive volume depletion and electrolyte disturbances,
therefore it 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.

Digoxin and other drugs with a 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.

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 cardiorenal patient. 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

1. Bock JS, Gottlieb SS. Cardiorenal syndrome: new perspectives. Circulation. 2010;121:2592–2600.

2. Ronco C, et al. Cardiorenal syndrome. J Am Coll Cardiol. 2008;52:1527–1539.

3. Waldum B, Os I. The cardiorenal syndrome: what the cardiologist needs to know. Cardiology. 2013;126:175–186.

4. Jessup M, Costanzo M. The cardiorenal syndrome: do we need a change of strategy or a change of tactics? J Am Coll Cardiol.
2009;53(7):597–599.

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