U.O. di Nefrologia, Dialisi ed Ipertensione
Policlinico S.Orsola-Malpighi
Azienda Ospedaliero-Universitaria
Bologna
La fisiopatologia del
coinvolgimento renale nello
scompenso cardiaco refrattario
Antonio Santoro
Sintesi clinica
 donna, 75 anni
 scompenso cardiaco destro refrattario associato
a valvulopatia mitro-aortica reumatica
tricuspidalizzata
 insufficienza renale cronica stadio III
(sCr 1.3-1.5 mg/dl, CKD EPI 40 ml/min)
Anamnesi cardiologica
• 1986 fibrillazione atriale permanente
• 1991 intervento di sostituzione valvolare mitralica ed aortica
con protesi meccanica e anuloplastica della tricuspide
• 2003 impianto di protesi meccanica tricuspidale per insufficienza
grave
• 2008 impianto di PM monocamerale per FA bloccata con pause
patologiche (BAV 3° grado); classe NYHA I-II
• 2008-2009 frequenti ricoveri in Cardiologia per scompenso
cardio-circolatorio acuto con buona risposta alla terapia diuretica
massimale
• Gennaio 2010 nuovo ricovero per scompenso cardio-circolatorio
grave prevalentemente destro
• Aprile 2010 ricovero per recidiva di scompenso cardiocircolatorio
destro; classe NYHA III-IV; epatomegalia da stasi, ascite,
splenomegalia e pancitopenia (da sequestro splenico)
Dati ecocardiografici
Data
2001
2003
2008
2009
2010
FE
(%)
55
56
52
40-45
Volume
TS VS
(ml)
51
39
56
82
AD
Dilatazione
+++
Dilatazione
++
Dilatazione
++
Dilatazione
+++
AS
Dilatazione
+++
Dilatazione
+++
Dilatazione
++
Dilatazione
+++
VD
Dilatazione
+
VS
Normale
Dilatazione
++
Ipertrofico,
non dilatato
Dilatazione +
Ipertrofia
Ipocinesia
diffusa
Dimensioni e
funzione sistolica
normali
Dilatazione +++
Ipocinesia
diffusa
Dilatazione
++
Ipocinesia diffusa
Note
Post-protesi aortica
e mitralica;
anuloplastica
tricuspidalica
Post-protesi
tricuspidalica
CNG indenne da
lesioni significative
Post-PM monocamerale
Terapia cardiologica
1986
amiodarone -> digitale e antiaggregante
1991
idroclorotiazide + amiloride , digitale, TAO
2003
furosemide, canrenoato di potassio, digitale, TAO
(no beta-bloccante per bradicardia)
2008
furosemide, losartan, digitale, TAO
01-04/2010
furosemide, spironolattone, losartan, digitale, TAO
(tentativo infruttuoso introduzione beta bloccante)
05/2010
furosemide, spironolattone, metolazone,losartan
digitale, TAO
Durante il ricovero
• Furosemide in infusione continua e.v. (250
mg/24 ore)
• Diuresi 1005 ml/die
• sCr 2.8-3.5 mg/dl,BUN 150 mg/dl,Na134
mEq/l,K 5.6 mEq/l
Terapia cardiologica
1986
amiodarone-> digitale e antiaggregante
1991
idroclorotiazide + amiloride, digitale, TAO
2003
furosemide, canrenoato di potassio, digitale, TAO
(no beta-bloccante per bradicardia)
2008
furosemide, ace-inibitore, digitale, TAO
01-04/2010 furosemide, spironolattone, sartano, digitale, TAO
(tentativo infruttuoso introduzione beta bloccante)
05/2010
furosemide, metolazone, digitale, TAO; sospeso sartano
per ipotensione, sospeso sprironolattone per
iperpotassiemia
Sintesi clinica
• Nel corso del ricovero la paziente perde 2 Kg
di peso corporeo e viene dimessa con terapia
a base di furosemide per os ( 250 mg due
volte al giorno, metolazone, antialdosteronico,
sartano, TAO, atorvastatina ).
• Dopo 7 giorni la paziente si reca in PS per
dispnea ingravescente e stato confusionale
All’ingresso in ospedale
• La paziente è dispnoica , oligurica , ha un
incremento del peso corporeo di 4 Kg, edemi
colonnari agli arti inferiori, polmone congesto,
PA 104/70 mmHg, frequenza cardiaca 58/min
• Na plasmatico 129 mEq/l, sCreat 2,5 mg/dl,
azotemia 169mg/dl, S02 87, pO2 75, CO2 42,
HCO3 18 mEq/l.
Despite the use of diuretics,
a significant percentage of patients admitted for acute
decompensated CHF
are discharged with a little or no weight loss and persistent
symptomatology1
and
in 90% of patients, 20% gain weight on discharge2,
44% are readmitted within 6 months3
1 ADHERE® Registry. 3rd Quarter. 2003 National Benchmark Report.
http://www.adhereregistry.com/national_BMR/index.html
2 Adams et al. Am Heart J. 2005;149:209-216
3 Costanzo MR, J ACC 2007
Kidney Function in CHF
• 70% of patients experience some
increase in Cr during hospitalization for
CHF
• Worsening of kidney function usually
occurs during the first 2-3 days after
admission
• It is as common in diastolic as it is in
systolic CHF
Predictors of Mortality in
Hospitalized HF Patients
EFFECT Study
30-Day Mortality
Serum concentration
OR (95% CI)
1-Year Mortality
P
Value
P
OR (95% CI) Value
Hemoglobin <10.0 g/dL
1.73 (1.25-2.36) <.001
2.07 (1.65-2.60) <.001
Sodium <136 mEq/L
1.69 (1.30-2.20) <.001
1.61 (1.34-1.94) <.001
Potassium <3.5 mEq/L
0.66 (0.38-1.08)
0.68 (0.49-0.93)
Creatinine >2 mg/dL
(>177 µmol/L)
2.47 (1.84-3.29) <.001
2.90 (2.33-3.63) <.001
Urea nitrogen, mg/dL
(per 10-unit increase)
1.32 (1.26-1.39) <.001
1.37 (1.30-1.44) <.001
0
1
2
3
4
n=2624.
Lee et al. JAMA. 2003;290:2581-2587.
.12
0
1
2
3
4
.02
ADHF with Renal Dysfunction
The Acute DecompensatedHeart Failure National Registry (ADHERE)
2001-2005:175.000 hospital admissions;280 participating hospitals
Heywood JT et al. J Card Fail 2007 Aug;13(6):422:30
Sottogruppo (972 pz) del PRIME II
LEVF
NYHA
How Can the Heart Negatively Affect
the Kidney
Basic Concepts to Understand Kidney
Function in CHF
1. Effective blood volume
2. The Starling curve
3. The relationship between SVR and
Stroke Volume
4. Neuro-hormones (RAAS, SNS,
Vasopressin)
The Basis for the Concept of Effective
Blood Volume
• Normally:
– Volume expansion increases BP and urine
Na+ excretion (2° to: ↓ SNS, ↓ AII, ↓ Aldo
and ↑ ANP).
– Volume contraction decreases BP and
urine Na+ (2° to: ↑ SNS, ↑ AII, ↑ Aldo and
↓ ANP).
• In congestive heart failure (CHF) or
hepatic cirrhosis
– ECF and urine Na+ excretion become
uncoupled.
Effective Circulating Blood Volume
(ECV)
• Is the volume of arterial blood (vascular
extracellular fluid) that effectively
perfuses vital organs
• It is also defined as the circulating
arterial volume perceived by
baroreceptors in the arteries and kidney
• ECV is a dynamic quantity and not a
measurable, distinct compartment
The Starling Curve
The Relationship Between SVR and
Stroke Volume
The low-flow-state Hypothesis
Reduced Cardiac Output
RBF,
GFR
FF
Net proximal absorption
Distal sodium delivery
Activation of JGA baroreceptors
Renin & aldosterone
Pathophysiology of acute decompensated heart failure
Low-output cardiac
failure
High output cardiac
failure
↓ Cardiac output
Systemic arterial
vasodilation
Arterial
underfilling
↑ Nonosmotic
AVPrelease
↑ Sympathetic
nervous system
↑ Renin-angiotensin
-aldosterone system
Diminished renal hemodynamics and
renal sodium and water excretion
Mechanisms of Cardio-renal
involvement
Neurohumoral-hormonal imbalance
Hemodynamic-impaired renal perfusion
Metabolic-hypoxic inflammatory
nephropathy
renal
injury
+
sympathetic activity
vasoconstriction
sodium retention
Pazienti in end stage renal failure
Normotesi
Ipertesi
Controlli
n = 38
n = 97
n = 30
MBP clinostatismo, mmHg
96±2
123±3**
87±2
FC, batt/min
73±6
79±5*
63±3
HcT, %
31±2
31±3
45±3
Sodio plasmatico, mEq/L
139±4
140±3
140±1
PRA, ng/ml/h
1.03±0.4
2.08±0.5*
0.5±0.2
NE, ng/L
198±24
285±30*
146±32
28±3
49±5*
21±7
3650±322
4060±347*
3013±293
50±2
56±1**
57±1
23.01±2.3
25.7±3.41**
24±1.57
E, ng/L
Volume, plasmatico ml
NaE, mEq/kg/LBM
ECV, %
Santoro A.Zuccalà A. et al. Nephron 1985
* = p <0.05; ** = p< 0.01
Heart failure
Sympathetic nervous system
Negative cardiac effects
a) 1 Receptorial Down Regulation
b) Alteration of the transduction signs (1/2)
c) Myocytic toxicity (necrosis/fibrosis)
d) Increase of the arhytmic potential
e) Deterioration of the systolic function
f) Deterioration of the dyastolic function
Heart failure
Sympathetic nervous system
Negative renal effects
a) Renal vasoconstriction
b) Activation of renal sympathetic nerves
c) Release of cathecholamines hormones
d) Renal vascular resistance increase
e) Increase in Na absorption
f) Activation of the RAA system
g) Renal vascular resistence increase
h) Decreased response to the natriuretic factors
Effects of sympathetic stimulation on
renal autoregulation
3
Renal blood flow (ml/min/g)
Normal
2
sympathetic
Stimulation
1
0
0
20
40
60
80
100
120
Renal perfusion pressure (mmHg)
(mean arterial pressure - renal venous pressure)
Moore K. Clinical Science, 1997
THE CHANGE IN BLOOD PRESSURE AFTER RADIOFREQUENCY
ABLATION OF RENAL SYMPATHETIC NERVES
Changes in blood pressure (mmHg)
Significant improvements in GFR in 24% of
pts.undergoing the procedure
Block JS et al. Circulation. 2010;121:2592-2600
Sympathetic Activation
ROS
production
Proliferation
Apoptosis
Renin Release
by Renal
Sympathetic Neurons
NA/NPY-Mediated
Macrophage
Activation
By Citokine
Release
Renin-Angiotensin System
SNS
Activation
by
Failing
Kidneys
ROS
Production
via
NADPH
Oxidase
NF-KB
Mediated
Inflammation
Heart
failure
Angiotensin II
Central and
Vascular
Peripheral
Smooth
Muscle Nervous System
Arteriolar
Constrinction
Adrenal
Cortex
Direct Effects
On Kidneys
(Tubules)
Facilitation of
Sympatetic
Activity
Aldosterone
Secretion
(Arterioles)
Filtration
Fraction
Na
Reabsorption
Brain
 GFR
 ADH
Secretion
 Thirst
H2O
H2O
Reabsorption Ingestion
Angiotensin II effect:
Reduced Filtration Surface Area
Deleterious Effects of Aldosterone
Renin-Angiotensin Activation
Potassium
Aldosterone
K+
loss
Na+
retention
Mg++
loss
PAI-1
Proinflammatory
effects of COX-2
and osteopontin
Norepinephrine
release
Endothelial
dysfunction
Vascular
compliance
Stroke
Renal Failure
Coronary Artery Disease
Myocardial Infarction
Progression of renal disease, heart failure, and endothelial dysfunction
Epstein M. Nephrol Dial Transplant. 2003; 18:1984
Vasopressin stimulation of V2 and V1a receptors can contribute to events
that worsen cardiac function
Cardiac failure
↑ Nonosmotic
vasopressin release
V2 receptor
stimulation
Water retention
V1a receptor stimulation
↑ Protein
synthesis of
cardiac
myocytes
Coronary
constriction
Systemic arteriolar
vasoconstriction
Myocardial
ischemia
Venoconstriction
↑ Cardiac
afterload
↑Wall stress
Left ventricular dilatation
and hypertrophy
↑ Cardiac
preload
ANGIOTENSIN II
HYPEROSMOLARITY
ACTIVITY of ATRIAL
RECEPTORS
Hypovolemia
RECEPTORS V1
Aortic smooth muscle cells
Mesangial cells
Adrenal glomerulosa cells
Synaptosomal membranes
from hyppocampus
Liver membranes
HYPOPHYSIS
AVP
RECEPTORS V2
Collecting duct
ADENYLATE CYCLASE
ACTIVATION
PHOSPHOLIPASE C
ACTIVATION
VASOCONSTRICTION
ANTIDIURETIC ACTION
Prevalence of Hyponatremia in HF Patients
28%
30
25
20
15
10
Percent
21%
5
0
N=254
N=319
5%
N=58,919
ACTIV
[Na+] <136 mEq/L
ADHF
Gheorghiade 2003
[Na+] <136 mEq/L
ADHF
ADHERE
[Na+] <130 mEq/L
Stable HF
ADHF=acute decompensated heart failure.
Gheorghiade et al. JAMA. 2004;291:1963-1971; Gheorghiade et al. Circulation.
2003;107:2690-2696; ADHERE Registry. 3rd Quarter 2003 National Benchmark Report.
Neurohormones and CV Endpoints in
Post-MI Dysfunction
CV mortality or severe HF
or recurrent MI
Renin
Norepinephrine
SAVE Trial
P * Value
RR
(95% CI)
<.001 2.0 (1.4-2.7)
.004 1.6 (1.2-2.3)
ANP
<.001 1.9 (1.3-2.7)
AVP
<.001 1.9 (1.3-2.5)
Epinephrine
.077† 1.6 (1.0-2.6)
Aldosterone
<.001 1.9 (1.4-2.6)
Dopamine
NS
1.0 (0.7-1.5)
0
1
2
3
N=534. *P values were calculated on the basis of COX proportional hazard analysis. †Denotes
activation of neurohormone is borderline significant (.05<P<.1). ANP=atrial natriuretic peptide;
AVP=arginine vasopressin.
Rouleau et al. J Am Coll Cardiol. 1994;24:583-591.
↑ Atrial
Contractility
-
+
↑ Ventricular
Compliance
Right
Ventricular
Preload
+
-
+
-
↑ Venous
Pressure
Venous
Compliance
↑ Heart
Rate
+
↑ Inflow
Resistance
Venous Volume
• Venous Return
• Total Blood Volume
• Respiration
• Muscle Contraction
• Gravity
Factors determining right ventricular preload. A “+” sign indicates that an
increase in this particular variable increases right ventricular end-diastolic
volume, and therefore preload, while the “-” indicates that the variable
decreases preload.
147 NYHA class IV pts; congestion score to evaluate freedom from congestion at 4-6 weeks posthospitalization: - Orthopnea, - JVD, - 2 lbs ( 1 Kg) weight gain; -  diuretic dose, - edema
87%
67%
41%
Lucas C et al. Am Heart J 2000
CVP
CI
“…….common cardiovascular measures of disease severity (including systolic blood
pressure, serum sodium, plasma B-type natriuretic peptide, PCWP, systolic pulmonary
arterial pressure, and dosage of loop diuretics) were similar between those with versus
without WRF……”
SAP
PCWP
IMPORTANCE OF VENOUS CONGESTION FOR WORSENING
RENAL FUNCTION IN ADHF (Mullens, 2009)
ROC CURVES FOR CVP AND CI (ADMISSION)
FOR DEVELOPMENT OF WORSENING RENAL FAILURE
p< 0.0001
p 0.6
Increased Central Venous Pressure Is Associated With
Impaired Renal Function and Mortality in a Broad
Spectrum of Patients With Cardiovascular Disease
CI>3.2 l/min/m2
CI<2.5-3.2 l/min/m2
CI<2.5 l/min/m2
Damman K et al. JACC 2009
Role of venous congestion on
Kidney Function
Effect on increasing central venous pressure on GFR
in dogs with constant BP
Raised Venous
Pressure: A
direct cause of
renal sodium
retention
GFR (ml/min)
1.4
p<.05
1.1
p<.05
0.8
High CVP significantly
impairs GFR
0.5
0
6.25
12
18.75
25
0
Central Venous Pressure
mmHg
Firth et al Lancet 5/8/7/88
SNGFR = kS x (ΔP – Δp) = KfPUF
ΔP = PGC – PT = (50 – 14 mmHg)
Afferent and efferent pressures at a
glomerular capillary
Normal
Venous congestion
afferent efferent afferent efferent
FORCES,mmHg
Favoring filtration
PGC
Opposing filtration
PBC
pGC
Net filtration P
60
58
55
63
15
21
24
15
33
10
15
21
19
15
33
15
How Can the Kidney
Negatively Affect the Heart
Electrolytes and Acid Base
Disturbances in CHF
•
•
•
•
•
•
Hyponatremia (5-28%)
Hypokalemia or hyperkalemia
Hypomagnesemia (7-37%)
Hypocalcemia
Hypophosphatemia
Metabolic alkalosis
Inappropriately Elevated AVP Levels in
Hyponatremia Patients With HF
19.2
14.0
Plasma AVP
(pg/mL)
13.0
12.0
4.0
3.0
Normal Range
15.0
2.0
1.0
0.5
0.0
250
260
270
280 290
300
Plasma Osmolality, mOsm/kg of Water
Szatalowicz et al. N Engl J Med. 1981;305:263-266.
No diuretics
(n=14)
Taking diuretics
(n=23)
Importance of Hyponatremia
Most common electrolyte disorder
Acute severe hyponatremia results in
substantial morbidity and mortality
Mortality rates are higher in hyponatremic
patients with many different underlying
disorders
Excessively rapid correction can result in
neurologic deficits and death
Receptor-Mediated Effects of AVP
Receptor
Subtype
Site of Action
Vascular smooth muscle cells
V1a
Activation Effects
Vasoconstriction
Platelet aggregation
Platelets
Lymphocytes and monocytes
Glycogenolysis
Liver and adrenal cortex
V1b (V3)
V2
Anterior pituitary
Renal collecting duct
principal cells
Endothelial cells
ACTH and -endorphin
release
Free-water absorption
Coagulation factor release
AVP Receptor Antagonists in
Clinical Trials
Tolvaptan
Lixivaptan
SR-121463
Conivaptan
V2
V2
V2
V1a/V2
Route of
administration
Oral
Oral
Oral/IV
IV
Urine volume




Urine osmolality




Na+ excretion/
24 hours

 low dose
 high dose


Receptor
Lee et al. Am Heart J. 2003;146:9-18.
Effect of Conivaptan in Hyponatremia
Conivaptan 80 mg continuous infusion* (n=26)
Serum Sodium (mEq/L)
Conivaptan 40 mg continuous infusion* (n=29)
136
Placebo (n=29)
134
132
130
128
126
124
122
0
4
8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76 80 84 88 92 96
Measurement Time (Hours)
P<.001. 33.6% of patients were hypervolemic and 66.3% of patients were euvolemic.
Verbalis. Abstract presented at AHA. November 10, 2004; New Orleans, Louisiana.
From: Effects of Tolvaptan, a Vasopressin Antagonist, in Patients Hospitalized With Worsening Heart Failure: A
Randomized Controlled Trial
JAMA. 2004;291(16):1963-1971. doi:10.1001/jama.291.16.1963
Figure Legend:
P<.001 for all comparisons of tolvaptangroups vs placebo, except for 30 mg tolvaptan vs placebo, for which P = .02 for both day 1
and discharge. Error bars indicateSEM.
POSTULATED MECHANISMS UNDERLYING THE RELATIONSHIP
BETWEEN HF AND RENAL DYSFUNCTION.
Progressive Cardiac Dysfunction
↑ Sympathetic
Nervous System
Activity
↑ Renin-Angiotensin-Aldosterone System Activity
↑ Afterload
↓ Contractility
↓ Cardiac Output
↑ Volume
Anemia
↑ Renal
Oxidative Stress
Efferent
Pressure
↓ Renal Blow Flow/ ↓GFR
Apoptosis, Fibrosis
Progressive Renal Dysfunction