CRAS – Definition, Epidemiology and Pathophysiology

1
CRAS Definition, Epidemiology and
Pathophysiology

• Gerasimos Filippatos

2
Learning Objectives

• Discuss the definition of CRAS
• Review the prevalence of cardio-renal anemia
  syndrome (CRAS)
• Understand the consequences of CRAS for patients
• Discuss the pathophysiology of CRAS

3
Definitions of CRAS
4
Recommendations for NHLBI in Cardio-Renal
Interactions Related to Heart Failure
The result of interactions between the kidneys
and other circulatory compartments that increase
circulating volume and symptoms of heart failure
and disease progression are exacerbated. At its
extreme, cardio-renal dysregulation leads to what
is termed cardio-renal syndrome in which
therapy to relieve congestive symptoms of heart
failure is limited by further decline in renal
function
NHLBI Working Group. Cardio-renal connections in
heart failure and cardiovascular disease
executive summaryAvailable at
http//www.nhlbi.nih.gov/meetings/workshops/cardio
renal-hf-hd.htm.
5
Features of the Cardio-Renal Syndrome

• Cardiorenal failure
• Mild HF eGFR 3059 mL/min/1.73 m2
• Moderate HF eGFR 1529 mL/min/1.73 m2
• Severe HF eGFR lt15 mL/min/1.73 m2 or dialysis
• Worsening renal function during treatment of ADHF
• Change in creatine gt0.3 mg/dL or gt25 baseline
• Diuretic resistance
• Persistent congestion despite
• gt80 mg furosemide/day
• gt240 mg furosemide/day
• Continuous furosemide infusion
• Combination diuretic therapy (loop diuretic
  thiazide aldosterone antagonist)

Liang KV et al. Crit Care Med 200836
(Suppl)S7588
6
Cardio-Renal Syndrome (CRS)

• General CRS definition
• Pathophysiologic disorder of the heart and
  kidneys whereby acute or chronic dysfunction in
  one organ induces acute or chronic dysfunction in
  the other1

1. Ronco C et al. Eur Heart J 2009Dec 25 epub
ahead of print
7
There are Numerous Definitions of CRAS

• We propose that there is a vicious circle
  established whereby CHF (congestive heart
  failure) and CRF (chronic renal failure) both
  cause anemia and the anemia then worsens both the
  CHF and the CRF, causing more anemia and so
  on1
• The cardio-renal anemia syndrome is a set of
  complex and interrelated phenomena that are
  poorly understood2
• This combination of anemia, CKD and CHF has been
  called the cardio-renal anemia syndrome. The
  three seem to interact, each causing or worsening
  of the other two3

Anemia
CHF
CKD
CKD, chronic kidney disease CHF, chronic heart
failure
1. Silverberg D et al. Clin Nephrol 200258(suppl
1)37245 2. Jurkovitz C et al. Curr Opin
Nephrol Hypertens 2006151171223. Silverberg
D et al. Clin Exp Nephrol 200913101106
8
The Definition of CRAS Differs Depending on your
Viewpoint (1)

• Nephrologists

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
9
The Definition of CRAS Differs Depending on your
Viewpoint (2)

• Cardiologists

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
10
The Definition of CRAS for 2010

• CRAS is a pathophysiologic 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
• CRAS is a combination of heart failure, kidney
  failure and anemia

• What defines the above factors?
• See presentations by Piotr Ponikowski, Angel de
  Francisco and Bernard Canaud

11
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 patients are diagnosed and
  treated early so that CRAS does not progress

12
Prevalence of CRAS
13
The Prevalence of CRAS is Dependant upon your
Definition of CKD, CHF and Anemia
CHF CKD
CRAS
Anemia
Anemia CHF
Anemia CKD
14
The EuroHeart Failure survey programme a survey
on the quality of care among patients with heart
failure in Europe
500
N5249 men
400
300
Number of patients
200
100
0
44.4
55.4
66.4
88.4
99.4
77.4
1010.4
1111.4
1212.4
1313.4
2020.4
1414.4
1515.4
1616.4
1717.4
1818.4
1919.4
Hb (g/dL)
A total of 9971 patients had a value for Hb
reported, which was 11 g/dL in 18 of men and
23 of women
Cleland JG et al. Eur Heart J 200324442463
15
CRAS in US and European HF Surveys
60
50
40
Patients ()
30
20
10
0
ADHERE 105,000 patients
EuroHF Survey II
Renal failure
Anemia
Galvao M et al. J Card Fail 200612100107
Nieminen MS et al. Eur J Heart Fail
200810140148
16
Prevalence Data for CRAS are Varied

• Anemia is common in patients with heart failure
  (HF) prevalence ranges from 4551
• In patients with CHF NYHA functional class IV,
  the prevalence of anemia when defined as lt12g/dL
  and 11g/dL was 79.13 and 14.4, respectively4
• The prevalence of renal impairment plus anemia
  (11g/dL) in New York heart association (NYHA)
  functional class IV HF patients is 6.34
• The prevalence of chronic renal insufficiency
  (CRI) in new onset HF patients is 8.82 and the
  prevalence of renal insufficiency in acutely
  decompensated HF patients is 305
• The prevalence of CHF in endstage renal disease
  is 63.76

1. Lang C Mancini D. Heart 200793665671 2.
Ezekowitz J et al. Circulation 2003107223225
3. Silverberg D et al. J Am Coll Cardiol
20003517371744 4. Cromie N et al. Heart
200287377378 5. Fonarow G et al. JAMA
2005293572580 6. Avorn J et al. Arch Intern
Med 200216220022006
17
New-onset HF Patients with both CKD and Anemia

• Population-based cohort of 12,065 patients with
  new-onset CHF
• Database analysis from 138 acute-care Canadian
  hospitals
• April 1993March 2001
• Analysis of prevalence and cause of anemia

Adapted from Ezekowitz J et al. Circulation
2003107223225
18
Fourteen Per Cent of NYHA Class IIIV HF Patients
have both CKD and Anemia

• Multivariable analysis of data from the
  Candesartan in Heart Failure Assessment of
  Reduction in Mortality and Morbidity (CHARM)
  Program
• 2653 patients with NYHA class IIIV

Adapted from OMeara E et al. Circulation
2006113986994
Hb lt12 g/dL in women, lt13 g/dL in men eGFR
lt60 mL/min/1.73 m2
19
Twenty-two Per Cent of HF Patients with LVEF lt45
have both CKD and Anemia

• Prospective, single-center, observational study
• 955 consecutive patients with HF (LVEF lt45)
• Median follow-up 531 days
• Investigation of the presence of anemia and its
  cause

LVEF, left ventricular ejection fraction Hb lt12
g/dL in women, lt13 g/dL in men eGFR lt60
mL/min/1.73 m2
Adapted from de Silva R et al. Am J Cardiol
200698391398
20
Prevalence of CRAS may be Greater than Current
Estimates

• about half the patients admitted to hospital
  with a primary diagnosis of CHFhave anemiaand
  the great majority will also have CKI (chronic
  kidney insufficiency)1
• Silverberg et al. noted the majority of CKI
  patients with anemia also had CHF2

1. Silverberg DS et al. Semin Nephrol
200626296 2. Silverberg D et al. Nephrol Dial
Transplant 200318(suppl 8)viii7viii12
21
Prevalence Data for CRAS are Limited

• Very few studies have specifically assessed the
  prevalence of CRAS within the CKD and CHF
  populations
• Exclusion criteria for clinical trials often
  remove patients with CRAS and so a true
  prevalence of the disorder is unknown

22
Consequences of CRAS
23
Anemia, CHF and CKD have an Additive Effect on
Mortality

• Anemia is responsible for increased disease
  progression, hospitalization, morbidity and
  mortality in patients with CHF13 and CKD48
• There is an additive effect of anemia, CKD and
  CHF affecting mortality risk6,9,10 and
  progression to ESRD9,10

ESRD, end-stage renal disease
1. Vasu S et al. Clin Cardiol 200528454458 2.
He WS Wang LX. Congest Heart Fail
200915123130 3. Lindenfeld J. Am Heart J
2005149391401 4. Xia H et al. J Am Soc
Nephrol 19991013091316 5. Levin A et al.
Nephrol Dial Transplant 200318(suppl
4)358393394 6. Herzog CA et al. J Card Fail
200410467472 7. Ma JZ et al. J Am Soc Nephrol
1999,10610619 8. Thorp M et al. Nephrology
200914240246 9. Efstratiadis G et al.
Hippokratia 2008121116 10. Silverberg D et
al. Nephrol Dial Transplant 200318(suppl
8)viii7viii12
24
Relationship Between Anemia and Mortality in HF
A Systematic Review and Meta-analysis
.4
.5
1
2
4
8
10
Lower risk of anemia
Higher risk of anemia
Groenveld HF et al. J Am Coll Cardiol
20085281827
25
Relationship Between Baseline Hemoglobin and
Annual Mortality in HF. A Systematic Review and
Meta-analysis
40
35
30
25
20
Mortality per year ()
15
10
5
R -0.396, P 0.025
0
11.5
12.0
12.5
13.0
13.5
14.0
14.5
Baseline Hb levels (g/dL)
Groenveld HF et al. J Am Coll Cardiol
20085281827
26
Relation of Low Hemoglobin and Anemia to
Morbidity and Mortality in Patients Hospitalized
With Heart Failure (Insight from the OPTIMIZE-HF
Registry)
0.11
0.10
0.09
0.08
0.07
Predicted probability of in-hospital death
0.06
0.05
0.04
0.03
0.02
0.01
0.10
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
Admission Hb (520 g/dL)
Young JB et al. Am J Cardiol 2008101223230
27
Patients with CRAS have a 2-year Mortality Rate
of 46

• 1,136,201 patients in the 5 Medicare database
• Anemia, CKD and CHF contribute significantly to
  mortality rates

50
45
40
35
30
2-year mortality ()
25
20
15
10
5
0
Silverberg D et al. Nephrol Dial Transplant
200318(suppl 8)viii7viii12
28
Patients with CRAS have a 2-year ESRD Incidence
Rate of 6

• 1,136,201 patients in the 5 Medicare database
• Anemia, CKD and CHF contribute significantly to
  the incidence of ESRD

6
4
2-year incidence of ESRD ()
2
0
Silverberg D et al. Nephrol Dial Transplant
200318(suppl 8)viii7viii12
29
The Prognostic Value of Anemiain Patients with
Diastolic Heart Failure
1.0
0.8
No Anemia (n132)
0.6
Survival distribution function ()
Anemia (n162)
0.4
0.2
0
0
10
20
30
40
50
60
70
Survival time (months)
Tehrani F et al. Texas Heart J 200936220225
30
Anemia in Diastolic HF
1
No anemia/PSF
0.9
No anemia/ISF
0.8
0.7
0.6
Survival probability
0.5
0.4
Anemia/ISF
Anemia/PSF
0.3
0.2
0.1
0
0
1
2
3
4
5
6
7
Years
Felker GM et al. Am Heart J 2006151457462
31
Pathophysiology of CRAS
32
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

33
The Pathophysiology of CRAS
Mak G et al. Curr Treat Options Cardiovasc Med
200810455464 Murphy CL McMurray JJV. Heart
Fail Rev 200813431438 Felker GM et al. J Am
Coll Cardiol 200444959966 van der Meer P et
al. Eur Heart J 200425285291 Malyszko J
Mysliwiec M. Kidney Blood Press Res 2007301530
34
Heart and Kidney Failure are Linked through the
Sympathetic Nervous System
Sympathetic nervous system Renin-angiotensin
system
CKD
CHF

• The heart and kidney can directly interact
  through13
• The sympathetic nervous system
• The renin-angiotensin system
• Inflammation
• Reactive oxygen species
• Nitric oxide balance

1. Efstratiadis G et al. Hippokratia
2008121116 2. Jie KE et al. Am J Physiol
Renal Physiol 2006291F932F944 3. Ronco C et
al. Blood Purif 200927114126
35
Pathophysiology of CRAS
Sympathetic nervous system Renin-angiotensin
system
CKD
CHF
Reduced erythropoiesis
Anemia
Mak G et al. Curr Treat Options Cardiovasc Med
200810455464 Murphy CL McMurray JJV. Heart
Fail Rev 200813431438 Felker GM et al. J Am
Coll Cardiol 200444959966 van der Meer P et
al. Eur Heart J 200425285291 Malyszko J
Mysliwiec M. Kidney Blood Press Res 2007301530
36
EPO and Iron Deficiency can Cause Anemia in
Patients with CKD

• Causes of anemia in CKD14
• Erythropoietin (EPO) deficiency/resistance
• Iron deficiency
• Anemia can worsen kidney function through
• Renal ischemia
• Vasoconstriction

CKD
Reduced erythropoiesis
? EPO
? Hct
Renal ischemiaVasoconstriction
Anemia
Hct, hematocrit
1. Kazory A Ross EA. J Am Coll Cardiol
200953639647 2. Akram K Pearlman BL. Int J
Cardiol 2007117296305 3. Elliot J et al. Adv
Chronic Kidney Dis 20091694100 4. Fishbane S
et al. Clin J Am Soc Nephrol 200945761
37
Pathophysiology of CRAS
Sympathetic nervous system Renin-angiotensin
system
CKD
CHF
? EPO
Reduced erythropoiesis
? Hct
Renal ischemia Vasoconstriction
Anemia
Mak G et al. Curr Treat Options Cardiovasc Med
200810455464 Murphy CL McMurray JJV. Heart
Fail Rev 200813431438 Felker GM et al. J Am
Coll Cardiol 200444959966 van der Meer P et
al. Eur Heart J 200425285291 Malyszko J
Mysliwiec M. Kidney Blood Press Res 2007301530
38
Mechanisms of Anemia in CHF

• Hemodilution
• Plasma Volume ?
• Forward failure
• BM dysfunction
• Iron deficiency
• Fe2 uptake ?
• Malabsorption
• Chronic bleeding (Aspirin)

• Chronic immune activation
• TNF?
• Production of EPO ?
• EPO activity in BM ?
• Drugs
• ACEi EPO synthesis ?
• EPO activity in BM ?
• Chronic kidney failure
• Production of EPO ?
• Loss in urine ?

BM, bone marrow EPO, erythropoietin ACEi,
angiotensin-converting enzyme inhibitor
Silverberg DS et al. J Am Coll Cardiol
20003517371744
39
Distribution of Various Etiologies of Anemia
among Patients with Advanced Congestive Heart
Failure
100
Iron deficiency
Anemia of chronic disease
Hemodilution
80
73.0
Drug induced
60
Patients ()
40
18.9
20
5.4
2.7
0
Nanas JN et al. J Am Coll Cardiol
20064824852489
40
Increased Levels of Inflammatory Cytokines and
Iron deficiency can Cause Anemia in Patients with
CHF

• Causes of anemia in CHF15
• Increased cytokine levels
• Iron deficiency
• Anemia can worsen heart function through
• Ischemia
• Hemodilution

CHF
? Cytokines etc
Reduced erythropoiesis
? Hct
Ischemia Hemodilution
Anemia
1. Akram K Pearlman BL. Int J Cardiol
2007117296305 2. Morelli S et al. Acta
Cardiol 200863565570 3. Kazory A Ross EA. J
Am Coll Cardiol 200953639647 4. Anand IS. J
Am Coll Cardiol 200852501511 5. Caramelo C et
al. Rev Esp Cardiol 200760848860
41
Pathophysiology of CRAS
Sympathetic nervous system Renin-angiotensin
system
CKD
CHF
? EPO
Reduced erythropoiesis
? Cytokines etc
? Hct
Renal ischemia Vasoconstriction
Ischemia Hemodilution
Anemia
Mak G et al. Curr Treat Options Cardiovasc Med
200810455464 Murphy CL McMurray JJV. Heart
Fail Rev 200813431438 Felker GM et al. J Am
Coll Cardiol 200444959966 van der Meer P et
al. Eur Heart J 200425285291 Malyszko J
Mysliwiec M. Kidney Blood Press Res 2007301530
42
Conclusions

• CRAS is a vicious cycle involving the progressive
  deterioration of heart and kidney function linked
  with worsening anemia
• The prevalence of CRAS has not been adequately
  investigated, but it is likely to be greater than
  most current estimates
• Anemia, CHF and CKD have an Additive Effect on
  Mortality