The document discusses the cardio-renal syndrome, which refers to the bidirectional relationship between heart and kidney dysfunction. It provides several key points: 1) The cardio-renal axis is an important but often underestimated player in cardiovascular disease, as the heart and kidneys regulate many of the same processes and their dysfunction can exacerbate each other. 2) There are different types and definitions of cardio-renal syndrome depending on whether heart or kidney disease initiated or occurred secondarily. 3) Worsening renal function in heart failure is associated with higher mortality and morbidity, though it may simply indicate more severe heart failure rather than having a direct causal relationship. 4) Several studies demonstrate the link

1. Understanding the Cardio-Renal
Syndromes
Alberto Palazzuoli
Department of Internal Medicine Cardiology Unit
S. Maria alle Scotte Hospital, University of Siena Italy
The Cardio-Renal axis: an underestimated player in cardiovascular diseases
ESC Congress Munich 27/08/2012

2. Regulation of volume and BP (Na+ and H2O)
Electrolyte and acid-base balance
Hormonal function (Erythropoiesis – Vascular tone)
Blood purification from metabolic waste products
Regulation of perfusion pressure and flow to periphery
Electrical activity depend on electrolytes and acid-base
Contractility depend on O2, volume, electrolytes, toxin
Hormonal function (ANP - BNP)
ADQI Acute Dialysis Quality Initiative Consensus Group ADQI
Heart and Kidney: Dangerous liaison

3. The Cardio-Renal Syndrome (CRS)
• How can we define it?
• Is an early diagnosis of AKI important?
• What is the exact significance of WRF?
• What is the link between heart and kidney?
• What is the prevalent pathophysiological mechanism??
ADQI Acute Dialysis Quality Initiative Consensus Group ADQI

4. Common Characteristics of the Cardiorenal Syndrome
Palazzuoli, Ronco Heart Fail Rev 2011
Reduced
renal
blood
flow and
GFR
Increased
vascular
resistance
Increased
venous
congestio
n
RAAS
activity
Tubular
and
glomerula
r damage
Diuretic
resistance
Inflammato
ry
activation,
endothelial
dysfunction
Albuminuri
a
Increased
BUN
Anemia
Heart
KidneyFluid
overload

5. Cardio Renal Syndromes
acute
chronic
Cardio-Renal Reno-Cardiac
Secondary
Cardio-Renal
Ronco, C. et al. J Am Coll Cardiol 2008

7. The cardiorenal syndrome in heart failure
Damman K et al. Prog Cardiovas Dis. 2011

8. When the Creatinine Rises…
• Patient can’t go home
• Diuretic doses are often decreased
• RAAS inhibitors are often discontinued
• Other medications are renally dosed
• Inotropes may be initiated
• PA catheter may be placed
• Foley catheter may be placed
• Renal advise may be ordered (and is rarely helpful)

9. 0
10
20
30
40
50
60
70
80 Primary outcome
0
10
20
30
40
50
60
Myocardial infarction
0
10
20
30
40
Cardiovascular death
0
10
20
30
40
50
60
All death
All patients
Placebo
Ramipril
Primary Outcome Myocardial Infarct Cardiovascular Death in
pz. with creatinine <1.4 mg/dl or  1.4 mg/dl
Creatinine
< 1.4 mg/dl
Creatinine
<1.4 mg/dl
Creatinine
<1.4 mg/dl
Creatinine
<1.4 mg/dl
Creatinine
 1.4 mg/dl
Creatinine
 1.4 mg/dl
Creatinine
 1.4 mg/dl
Creatinine
 1.4 mg/dl
HOPE Trial,
Ann Intern Med, 2001
Eventi/1000persone/anno
Eventi/1000persone/annoEventi/1000persone/anno
Eventi/1000persone/anno

10. Kidney Function Stage
Parameter I
(n=10,660)
II
(n=32,433)
III
(n=51,533)
IV
(n=15,553)
V (n=82769) p†
Age, mesn (SD), y 61.7 815.9) 70.1 (14.7) 75.7 (12.0) 76.3 (11.6) 67.4 (14.7) <.0001
Atrial fibrillation 19.3 28.6 35.0 34.7 19.8 <.0001
Diabetes 38.0 37.4 45.0 53.6 55.1 <.0001
Hypertension 68.2 70.3 73.0 76.7 85.0 <.0001
Peripheral vascular disease 10.7 13.6 19.1 24.3 24.7 <.0001
Renal insufficiency 2.9 5.8 28.7 70.9 94.6 <.0001
BNP, pg/mL, n 3845 13,243 22,449 6800 2623 ns
Hb, means (SD), g/dL 13.0 (2.6) 13.0 (2.5) 12.3 (2.5) 11.4 (2.3) 11.5 (2.5) <.0001
† Accross stage using chi-square tests for categoric variables and analysis of variance for continuos variables
Heywood JT et al, J Card Fail, 2007
Demographic and Baseline Characteristics by
Kidney Function Stage in ADHERE Database

11. Quartile 1
(n=234)
Quartile 2
(n=235)
Quartile 3
(n=234)
Quartile 4
(n=234) P
eGFR, mL•min -1·1.73 m-2 82 (75-94) 60 (55-65) 45 (42-48) 29 (25-33) <0.01‡
Primary end point, d 5 (4-10) 6 (4-13) 7 (4-14) 8 (5-17) <0.01
Deaths, n(%)
In hospital * 1 (0.44) 3 (1.3) 8(3.4) 16 (6.8) <0.01
At 60 days † 10 (4.3) 9 (3.9) 25 (10.8) 44 (19) <0.01
Hazards ratio (95% CI) Referent 0.9 (0.37-2.22) 2.63 (1.26-5.48) 4.73 (2.38-9.39)
Readmissions/death within 60 days, n (%) † 53 (22.9) 71 (31) 93 (40.1) 106 (45.3) <0.01
Odds ratio (95% CI) Referent 1.51 (1-2.29) 2.25 (1.5-3.37) 2.8 (1.86-4.15)
Main Clinical Outcomes by eGFR Quartiles: OPTIME-HF
*Odds ratios for in-hospital death are questionable because of the small numbers of events and thus are not presented
†Raw percentages of patients followed up to the 60-day visit. Cox proportional-hazards regression using indicator variables was used to analyze 60-
day death rate. Categorical variables were analyzed with logistic regression. Probability values represent overall relationship with eGFR as a
continuous variable for regression models.
‡All individual quartiles vs lowest quartile, p<0.05
Klein M et al, Circ Heart Fail, 2008

12. Nohria et al ESCAPE Trial JACC 2008
Relationship Between Renal Parameters and 6-Months Outcomes
Time to Death Time to Death or Rehospitalization
HR* 95% CI P Value HR* 95% CI p Value
Baseline SCr 1.20 1.11–1.29 < 0.0001 1.14 1.08–1.21 <0.0001
Baseline eGFR 1.25 1.13–1.38 <0.0001 1.10 1.05–1.15 <0.0001
Discharge SCr 1.30 1.20–1.41 <0.0001 1.14 1.08–1.21 <0.0001
Discharge eGFR 1.28 1.14–1.43 <0.0001 1.09 1.03–1.15 0.002
> 0.3 mg/dl ↑ SCr† 1.31 0.81–2.10 0.27 1.26 0.96–1.64 0.09
> 25% 2 eGFR‡ 1.49 0.91–2.44 0.12 1.06 0.79–1.43 0.69
*Hazard ratio (HR) calculated per 0.3-mg/dl increments in serum creatinine (SCr) and per 10-ml/min decrements in estimated
glomerular filtration rate (eGFR). Worsening renal function, defined as:
1) †an increase in SCr 0.3 mg/dl; and 2) ‡a decrease in eGFR 25% from baseline to discharge, is treated as a dichotomous variable.
CI confidence interval.

13. Tokmakova et al SAVE Study Circulation 2008
Kaplan-Meier curves for CV mortality/morbidity
stratified by eGFR: SAVE study
60%
50%
40%
30%
20%
10%
0%
1 year 2 year 3 year 4 year
eGFR <60, placebo
eGFR <60, captopril
eGFR >60, placebo
eGFR >60, captopril
Years post-MI
%Events

14. 0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0 1 2 3 4
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0 1 2 3 4
Kaplan-Meier plot of cumulative incidence of cardiovascular death or unplanned
admission to hospital for the management of worsening CHF in patients with
reduced LVEF and preserved LV systolic function
<45.0
45.0 – 60.0
> 60.0
<45.0
45.0 – 60.0
> 60.0
years
years
cumulativeincidence
cumulativeincidence
Hillege et al CHARM Circulation 2006

15. 38
51
24
0
10
20
30
40
50
60
Any impairment Moderate/severe
impairment
No impairment
%
Smith GL et al, J Am Coll Cardiol 2006
Mortality:
15% for every 0.5 mg/dl increase in creatinine
7% for every 10 ml/min decrease in eGFR
What is the “real” Risk when IR is
associated to CHF
HR 1.56
(p= 0.001)
HR 2.31
(p= 0.001)

16. WRF outcome during hispitalization and at early and post discharge:
COACH study
1.0
0.9
0.6
0.7
0.8
0.0
0 18012060 300240 420 480 540360
Follow-up time (days)
Cumulativesurvival(deathorHFadmission)
WRF in-hospital WRF 0-6 months WRF 6-12 months
Damman K et al. Eur J Heart Fail 2009
No WRF
WRF

17. Clinical Characteristics and Outcomes of Patients With
Improvement in Renal Function During the Treatment of
Decompensated Heart Failure
Testani JM et al. Journal of Cardiac Fail 2011

18. Potential mechanisms of increased mortality in
WRF
Marker of more
decompensated HF
Greater prevalence of
coexistent diseases
Discontinuation of common
treatments
Relationship due to
cardio-renal
interaction

20. The “traditional” concept of WRF in acute HF
Decrease in
cardiac output
Arterial
underfilling
Decreased
perfusion
pressure
Increased
neuro-hormonal
activity
Systemic and
Renal
vasocostriction
Glomerular and
interstitial
damage

21. Acute CRS Type 1
Renal hypoperfusion
Reduced oxygen delivery
Necrosis / apoptosis
Decreased GFR
Resistance to ANP/BNP
BIOMARKERS
KIM-1
Cystatin-C
N-GAL
Creatinine
Hemodynamically mediated damage
Immune mediated damage
Humorally mediated damage
Humoral
signalling
Cytokine
secretion
Exogenous factors
Contrast media
ACE inhibitors
Diuretics
Acute
Kidney
Injury
Caspase
activation
Apoptosis
Caspase
activation
Apoptosis
Decreased
perfusion
Acute decompensation
Ischemic insult
Coronary angiography
Cardiac surgery
Decreased CO
Increased
venous
pressure
Toxicity
Vascocostriction.
RAA activation, Na + H2O
retention, vasoconstriction
BNP
Sympathetic Activation
Hormonal factors
Monocyte
Activation Endothelial
activation
Natriuresis
Acute
Heart
Disease
or
Procedures
ADQI Acute Dialysis Quality Initiative Consensus Group ADQI

22. Characteristics overall cohort no SBP-reduction yes SBP-reduction P
Demographics
Age (years) 56.4±13.9 57.1±13.3 55.7±14.5 0.309
Males 74,1% 74,1% 74,1%
Functional status/
ejection fraction
NYHA class (mean class) 3.9±0.4 3.9±0.3 3.9±0.4 0.773
Six minut walk (feet) 422±420 460±445 384±392 0.092
MVO2 (mL/kg/min) 10.1±3.5 10.4±3.9 9.7±2.8 0.324
Ejection fraction 19.5±6.5 19.6±6.7 19.3±6.4 0.684
Systolic blood pressure 101.5±14.7 107.6±15.0 95.5±11.7 <0.001*
Admission to discharge
change in blood pressure
Absolute 4.3±16.8 8.6±10.0 -17.2±11.5 <0.001*
Relative 2.8±15.3 9.1±10.8 -14.7±8.2 <0.001*
Laboratory findings
GFR(mL/min/1.73 m2) 56.9±25.2 53.7±25.6 60.1±24.5 0.012*
*Significant P- value.
Impact of changes in blood pressure during the treatment of
acute decompensated heart failure on renal and clinical outcomes
Testani et al. Eur J of Heart Fail 2011

23. Influence of renal dysfunction phenotype on mortality in the setting of
cardiac dysfunction: analysis of three randomized controlled trials
Testani JM et al. Eur J Heart Fail 2011
*
LBC Low BUN creatinine
HBC High BUN creatinine

24. Blood urea nitrogen as biomarker of neurohormonal activation
Kazory A Am J Cardiol 2010

25. Relationship Between Neurohormones and LVEF and GFRc
GFRc LVEF
Univariate r Multivariate Univariate Multivariate
Norepinephrine −0.28 <0.001 0.001 −0.15 0.004 NS
Epinephrine −0.05 0.036 NS −0.15 0.004 0.007
Dopamine −0.23 <0.001 0.001 −0.08 0.143 NS
Renin −0.13 0.013 0.005 −0.22 <0.001 NS
Aldosterone −0.15 0.005 0.006 −0.04 0.501 NS
ANP −0.35 <0.001 <0.001 −0.27 <0.001 0.002
N-terminal ANP−0.53 <0.001 <0.001 −0.33 <0.001 <0.001
Endothelin −0.10 0.069 NS −0.18 0.001 0.046
Epinine −0.07 0.201 NS −0.01 0.899 NS
Hillege HL et al. Circulation 2000

26. Adaptive response to renal hypoperfusion in HF
Ruggenenti P et al. Eur H J 2011

27. VENOUS CONGESTION AND WORSENING RENAL
FUNCTION
Mullens et al, JACC, 2009

28. Relation among renal dysfunction and Congestion in CHF
Damman K et al Eur J Heart Fail 2010

29. Variable Death, Transplant, or HF Rehospitalization
Univariable HR (95% CI)* Univariable P Value Multivariable HR (95% CI)*
Multivariable P Value
Previous HF 1.73 0.005 1,79 0.01
0.01
CKD 1.69 <0.0021 1.87 0.008
Laboratory characteristics
Plasma hemoglobin, 0.59 <0.0035
Serum sodium, admission 0.6 <0.0001
Serum sodium, discharge 0.48 0.001
Congestion and WRF .
1: Yes WRF and yes congestion 5.35 <0.0001 2.44 0.009
1.39 (0.88, 2.2) 0.1597
2: No WRF and yes congestion 1.95 0.136 1.35 0.53
0.2247
3: Yes WRF and no congestion 1.24 0.42 1.04 0.88
Reference: No WRF and no congestion Ref Ref
Metra et al Circ Heart Fail 2012
Is WRF as ominous prognostic sign in AHF patients? The
role of congestion

30. Changes in renal parameters and Intra abdominal pressure
Mullens W et al J Am Coll Cardiol 2008

31. Changes in IAP and serum creatinine in patients underwent
to paracentesis or ultrafiltration
Mullens W et al J Cardiac Fail 2008

32. Fluid
overload re-
distribution
Increased
vascular
resistance
Increased
venous return
and preload
Reduced
capacitance in
veins
Increased
arterial
stiffness leads
to hightened
afterload
Cotter G et al Eur J Heart Fail 2008
Fluid overload: redistribution and accumulation mechanisms

33. Interaction among fluid overload cardiac output and mean blood pressure
Haemodinamic control (Guyton)
Volume expansion
Increased cardiac output
Total body autoregolation
Increased peripheral resistance
Increased blood pressure
Pressure natriuresis
Cardiorenal connection
NO-ROS Dysbalance
Sympathetic Nervous Systolic Activation
Renin Angiotensin System Activation
Inflammation
Cardiovascular damage
Renal
failure
Heart
failure
Bongartz L G et al. Eur Heart J 2005

34. Peripheral vascular
resistance
Arterial Underfilling
Cardiac output
Renal hemodinamics and renal
salt/water excretion
Pulmonary
hypertension
RV failure
Venous congestion
Renal interstitial
pressure
Neurohormonal
Activation
↑ SNS activity
↑ RAAS activity
↑ AVP release
↑ Renal venous
pressure
↑ Intra-abdominal
pressure
? Myocardial
depressant factor
Tang WW et al. Heart 2010

35. The Perfect SormThe “Perfect Storm”

36. Risk
Injury
Failure
Loss
ESRD End Stage Renal Disease
Creatinine Criteria Urine Output Criteria
UO <0.3 mL/kg/h
x 24 hr or
anuria x 12 hrs
UO <0.5 mL/kg/h
x 12 hr
UO <0.5 mL/kg/h
x 6 hr
Creatinine increase
x 2
Creatinine increase
x 3
or creatinine 4 mg/dL
(Acute rise of 0.5 mg/dlL
High
Sensitivity
High
Specificity
Persistent ARF** = complete loss of renal
function > 4 weeks
ADQIADQI
Increased creatinine x1.5
or Creatinine increase > 0.3
mg/dl
ADQI Acute Dialysis Quality Initiative Consensus Group ADQI

37. Mortality by RIFLE Class
0
5
10
15
20
25
30
35
40
45
50
Non-AKI Risk Injury Failure
Mortality
13 studies, n >71,000 patients
ADQI Acute Dialysis Quality Initiative Consensus Group ADQI

38. Acute Reno-Cardiac syndome: epidemiology
Heterogeneity of AKI
different methods to define AKI
different risk profile in the enrolled population
few studies reporting cardiac events
clinical information about cardiac conditions at baseline
POOR CLINICAL CHARACTERIZATION AND DEFINITION
Cruz D et al Heart Fail Rev 2011

39. Glomerulonephritis
Preexisting renal
insufficiency
Red. extracellular
volume
Red. effective
arterial volume
Impaired renal
microcirculation
Drug toxicity
Rhabdomyolysis
Exogenous
toxins
SIRS / sepsisCardio-Renal
Causes of Acute Kidney Injury
ADQI Acute Dialysis Quality Initiative Consensus Group ADQI

40. Krämer et al. Am J Med. 1999;106:90.
Neurormonal increase leads to
Diuretic-Resistance
Proximal Tubul
Ang II increases Na
resorbtion
Glomerul
Norepinephrine
(and endothelin) reduce
blood flow and GRF
Collector Duct
Aldosteron increases Na
resorbtion

41. Acute RCS Type 3
Acute
Heart
Dysfunction
Glomerular diseases
Interstitial diseases
Acute tubular necrosis
Acute pyelonephritis
Acute urinary obstruction
Acute
Kidney
Injury
Acute decompensation
Acute heart failure
Ischemic insult
Arrythmias
Decreased CO
BIOMARKERS
Troponin
Myoglobin
MPO
BNP
Humoral
Signalling
Cytokine
secretion
Hypertension
Caspase
activation
Apoptosis
Caspase
activation
ApoptosisMonocyte
Activation
Electrolyte, acid-base
& coagulation imbalances
Volume
expansion
Decreased
GFR
Increased
pre-load
Na + H2O
retention
Sympathetic Activation
RAA activation,,
vasoconstriction
Endothelial
activation
ADQI Acute Dialysis Quality Initiative Consensus Group ADQI

42. Sarnak MJet al, Am J Kidney Dis, 2000
DEGREES OF RENAL AND CARDIOVASCULAR DISEASES
“At risk”
Starting
Progression
End
Stage
Renal terminal
insufficiency
Insuff. Renal
Chronic (FG)
Albuminuria
Proteinuria
Age, obesity
Diabetes
hypertension
Renal Disease Cardiovascular Disease
LV Insufficiency
Cardiovascular
Events
Refractory
heart failure
Age, obesity
Diabetes
hypertension

43. Common factors for heart and kidney diseases
Ronco C et al JACC 2012 (in press)

44. Parenchimal
disease
Artery
disease
Congestion
and
hypoperfus.
Neuro-
endocrine and
cytokine
activation
Treatment
for HF
Renal
dysfunction
Cleland JG et al Heart Fail Rev 2012

45. RAAS Effects In Renal and Cardiac diseases
sodium and water reabsrobtion
Efferent arterioles constriction
proteinuria increase
glomerular sclerosis and tubular fibrosis
Reduced medullary blood flow
blood flow redistribution
idrostatic and oncotic pressure
Renal effects
Cardiovascular
effects
vascular muscle cell proliferation and thickness
Increase blood pressure
Left ventricular hypertrophy and fibrosis
Increase atherosclerosis activity
neuro hormonal overdrive
impairment endothelial function
Decrease fibrinolitic acitivity with plateled
aggregation

46. Inflammatory activation: cardiac and renal interaction
Arteries and
Veins
Endothelial dysf &
vascular stiffness
Kidney
Na retention & fluid
intake
Tubulo glomerular damage
Myocardium
Contractility
fibrosis & apoptosis
Inflammation
Congestion Colombo P et al Heart Fail Rev 2012

47. The role of Inflammation in Cardio-Renal syndrome
Endothelial cells activation
DAMP signaling
Complement activation
Leukocite infiltration
Platelet activation
increase prthrombotic and
Pro coagulative processes
Capillary obstruction
Peristent ischemia
Inflammation
Rosner MH et al. Semin Nephrol 2012

48. Relationship between CKD and urinary NAG, NGAL and KIM-1.
Damman K et al. Heart 2010
Tubular damage in chronic systolic heart failure is
associated with reduced survival independent of
glomerular filtration rate.

49. Adjusted for age, gender, eGFR, and UACR Multivariable adjusteda
Variable Multivariable HR P-value PCR Multivariable HR P-value PCR
logNAG (per SD) 0.20 0.28
Mortality
1.38 (1.18–
1.61)
0.001 1.30 (1.11–1.51) 0.001
HF
hospitalizations
1.22 (1.07–
1.40)
0.004 1.17 (1.02–1.33) 0.025
logKIM-1 (per
SD)
0.71 0.78
Mortality
1.17 (1.02–
1.34)
0.027 1.14 (0.99–1.31) 0.060
HF
hospitalizations
1.13 (1.00–
1.28)
0.054 1 11 (0.98–1.26) 0.094
logNGAL (per
SD)
0.017 0.023
Mortality
1.24 (1.08–
1.42)
0.021 1 23 (1.07–1.41) 0.003
HF
hospitalizations
1.01 (0.90–
1.13)
0.90 1 01 (0.90–1.13) 0.85
Clinical outcome of renal tubular damage in CHF
Damman K et al. Eur H J 2011

50. CONCLUSIONS
• The cardiorenal syndrome is heterogeneous group of pathophysiological entities
and the clinical course depends on the prevalent mechanism by which the renal
function is impaired
• There is priority to better understand the patophysiologic link between Heart
and Kidney, and to know the more sensitive and specific parameters able to
identify primitive organ damage their mechanism and significance
• WRF is a mirror of different clinical situation and it should be evaluated taking
into account previous cardio-renal damages as well as hemodynamic and non
hemodynamic conditions
• Pathophysiologic processes are different in CRS subtypes and involve several
actors (hemodynamic, neurohormones, inflammation, fluid overload)
• We need to focus on research agenda designed to recognize the vicious circle
of pathological heart-kidney interactions and mechanisms in every clinical
condition
• Better assessment of congestion, fluid redistribution, neuro-endocrine
overdrive, tubular and glomerular damage, could improve our understanding in
CRS