CARDIO-RENAL ANEMIA SYNDROME (CRAS)

Recommendations for NHLBI in Cardio-Renal Interaction Related to Heart

Failure
Rekomendasi NHLBI pada interaksi cardio-Renal dihubungkan pada gagal jantung
Akibat interaksi antara ginjal dan kompartemen sirkulasi lain yang meningkatkan volume sirkulasi
dan gejala gagal jantung dan progresi penyakit yang eksaserbasi. Ketika itu ekstrim, disregulasi
cardio-renal mengakibatkan apa yang dinamakan ‘cardio-renal syndrome’ yang mana terapinya
untuk mengurangi gejala kongesif dari gagal jantung terbatas yang lebih lanjut menurunkan fungsi
renal.

Feature of the cardio-renal syndrome

 Cardiorenal failure
- Mild: HF + eGFR 30-59 mL/min/1,73 m2
- Moderate: HF + eGFR 15-29 mL/min/1,73 m2
- Severe: HF + eGFR < 15mL/min/1,73 m2 or dialysis
 Worsening renal function during treatment od ADHF
- Change in creatine >0,3 mg/dL or >25% baseline
 Diuretic resistance
Persistent congestion despite
- >80 mg furosemide/day
- >240 mg furosemide/day
- Continous furosemid infusion
- Combination diuretic therapy
(loop diuretic + thiazid + aldosterone antagonist)

Cardio-Renal Syndrome (CRS)

General CRS definition:
Pathophysiologic disorder of the heart and kidney whereby acute or chronic dysfunction in one
organ induces acute o chronic dysfunction in the other.

CRS Type I
(Acute Cardiorenal Syndrome)
Abrupt worsening of cardiac function leading acute kidney injury
CRS type II
(Chronic Cardiorenal Syndrome)
Chronic abnormalities in cardiac function (e.g. chronic congestive heart failure) causing progressive
and permanent chronic kidney disease.
CRS type III
(Acute Renocardiac syndrome)
Abrupt worsening of renal function (e.g. acute kidney ischemia or glomerulonephritis) causing acute
cardiac disorder (e.g. heart failure, arrhythmia, ischemia)
CRS type IV
(Chronic Renocardiac syndrome)
Chronic kidney disease (e.g. chronic glomerular disease) contributing to decreased cardiac
disfunction, cardiac hypertrophy and/or increased risk of adverse cardiovascular events.
CRS type V
(Sekunder Renocardiac syndrome)
Systemic condition (e.g. DM, sepsis) causing both cardiac and renal dysfunction.
The definition of CRAS differs depending on your viewpoint (1)
Nephrologist

1 Cardio-Renal Anemia Syndrome

 CKD Anemia CHF
CKD Any degree of anemia Any degree of heart failure
CKD Severe anemia Severe heart failure
Renal failure Severe anemia Cardiovascular events
Renal failure Anemia Cardiovascular disease

Cardiologist
CHF Anemia CKD
CHF Any degree of anemia Any degree of renal insufficiency
CHF Severe anemia Renal failure
Cardiovascular disease Severe anemia Renal failure
Cardiovascular disease Anemia renal insufficiency

The definition of CRAS for 2010

1. CRAS is a pathophysiology process involving the progressive deterioration of heart and
kidney function linked with worsening anemia.
- CRAS is a vicious cycle where worsening of one factor negatively impacts on the
other two conditions and itself, resulting in progressive deterioration
2. CRAS is a combination of heart failure, kidney failure and anemia
Any degree of heart failure Any degree of kidney failure Any degree of Anemia

Multidisciplinary teams should aim to prevent CRAS development

 Any patient diagnosed with CHF should be monitored for renal failure and anemia
 Any patient diagnosed with CKD should be monitored for heart failure and anemia
 Multidisciplinary management strategies are needed to ensure patient are diagnosed and
treated early so that CRAS does not progress

Prevalence of CRAS is dependent upon your definition of CKD, CHF and

anemia

2 Cardio-Renal Anemia Syndrome

CRAS is a vicious cycle
 Deteriorating kidney function worsens anemia and heart function, which further impacts
on kidney function
- The same is true of worsening anemia and deteriorating heart function

Patofisiologi CRAS

Heart and kidney failure are linked through the sympathetic nervous system

The heart and kidney can directly interact through:

- The sympathetic nervous system
- The rennin-angiotensin system
- Inflammation
- Reactive oxygen species
- Nitric oxide balance

Pathophysiology of CRAS

3 Cardio-Renal Anemia Syndrome

EPO and Iron deficiency can cause anemia in patient with CKD
 Causes of anemia in CKD
- Erythropoietin (EPO) deficiency resistance
- Iron deficiency
 Anemia can worsen kidney function through:
- Renal ischemia
- Vasoconstriction

Pathophysiology of CRAS

Mechanism of anemia in CHF

 Hemodilution
- Plasma volume 
 Forward failure
- BM dysfunction
 Iron deficiency
- Fe2+ uptake 
- Malabsorbtion
- Chronic bleeding (aspirin)
 Chronic immune activation
- TNFα
Production of EPO 
EPO activity in BM 
 Drugs
- ACEI: EPO synthesis 
- EPO activity in BM 
 Chronic kidney failure
- Production of EPO 
- Loss in urine 

4 Cardio-Renal Anemia Syndrome

Increased levels of inflammatory cytokines and iron deficiency can cause
anemia in patient with CHF
 Causes of anemia in CHF
- Increased cytokine levels
- Iron deficiency
 Anemia can worsen heart function through:
- Ischemia
- Hemodilution

Pathophysiology of CRAS

CRAS: The cardiologist’s view

5 Cardio-Renal Anemia Syndrome

The Cardio-Renal Anemia Syndrome
A vicious circle

Reciprocal Relationship: Diabetes, CKD, CVD and Anemia

Renal anemia and cardiovascular complication

6 Cardio-Renal Anemia Syndrome

Clinical characteristics associated with increased risk of anemia in HF
 Advance age
 Female gender
 Chronic renal disease
 Severity of HF
 Acute (vs chronic) settings
 Other comorbidities (e.g. diabetes mellitus)
 Decreased BMI
 Use of ACEI/ARB/BB

Potential causes of anemia in HF

The first definition of CRAS

We proposed the term Cardio-Renal Anemia syndrome (CRAS) 10 years ago to suggest that there is
an interaction between renal failure, heart failure and anemia.

CRAS is a vicious cycle

7 Cardio-Renal Anemia Syndrome

Risk factors for CKD include age and family history
 Low birth weight
 Family history
 Obesity
 Ethnicity
 Diabetes mellitus
 Hypertension
 Systemic infection
 Age

Anemia is defined by a reduction in hemoglobin levels

There are numerous groups that have defined anemia patient with CKD
EBPG 2004 KDOQITM 2006/2007 ERBP 2008
Hb < 11,5 g/dL (F) Hb < 12 g/dL (F) Hb < 12 g/dL (F)
Hb < 13,5 g/dL (M≤70 years) Hb < 13,5 g/dL (M) Hb < 13,5 g/dL
Hb < 12 g/dL (M>70 years)

Pathophysiology of CRAS

Stages of HF

Defenition of Anemia and Hb targets

Numerous group have defined anemia in patient with CKD

8 Cardio-Renal Anemia Syndrome

Monitoring
 Hb monitoring
- Hb levels should be monitored on a monthly basis at least in patients treated with
ESAs
 Iron status monitoring
- Iron status should be regularly assessed for optimal management of anemia of CKD
- Iron status should be monitored monthly during initial ESA therapy
- Iron status at least should be monitored every 3 months during stable ESA therapy

Conclusions
 Iron first
- Early treatment of anemia in patient with CKD should include effective iron
supplementation
- Most studies demonstrate the superiority of IV vs Oral iron
 Low Hb levels are associated with poor prognosis and increased mortality
- However, interventional ESA trials have not shown a beneficial effect of anemia
correction on survival
 ESA treatment to a low target (10-12 g/dL) is associated with positive effects on QoL and
physical function
 A restrictive transfusion policy is recommended

Possible etiologies of anemia in hearth failure

Iron syscle in human and erythropoiesis

9 Cardio-Renal Anemia Syndrome

Hepcidin and Iron Regulation

10 Cardio-Renal Anemia Syndrome

Prevalence of iron deficiency in patients with CHF and CKD

11 Cardio-Renal Anemia Syndrome