Download The Kidney in Heart Failure

The Kidney in Heart Failure
Natale G. De Santo,* Massimo Cirillo,* Alessandra Perna,* Rosa Maria Pollastro,*
Annamaria Frangiosa,* Enzo Di Stazio,* Luigi Iorio,† Vito Andrea Di Leo,* and
Pietro Anastasio*
Renal dysfunction is a constant feature of congestive heart failure and is a stronger
predictor of mortality than left ventricular ejection fraction or New York Heart Association
classification. In heart failure, a reduction of glomerular filtration rate and renal plasma flow
occurs, although the filtration fraction increases. There are many reason for this pattern. A
reduction in effective circulating volume stimulates sympathetic activity and the reninangiotensin-aldosterone system, and it is associated with increased concentrations of
atrial natriuretic peptide, brain natriuretic peptide, and tumor necrosis factor ␣. Because in
chronic kidney disease heart dysfunction commonly is present, an efficient cardiologistnephrologist interaction should be promoted.
Semin Nephrol 25:404-407 © 2005 Elsevier Inc. All rights reserved.
KEYWORDS kidney disease, congestive heart failure, renal resistance, GFR, RPF, FF, survival
rate, creatinine clearance, cardiologist-nephrologist interaction
T
he problem of heart failure is an old one. It is even discussed in the Corpus Hippocraticum, in which patients
with shortness of breath, edema, anasarca, and cardiac cachexia are described.1 Edema was thought to be caused by a
shift of phlegm—a cold humor—from the brain into the
chest. This theory persisted for a long time and finally came
to an end with Andrea Cesalpino (1571, 1593) and William
Harvey (1628).
Katz2 provided a nice synopsis of the evolution of pathophysiology of heart failure over the past 2500 years. However, we disagree with him in his attribution to Harvey alone
of the theory of hemodynamics. In fact, in Quaestionum peripateticarum (1571) and in Quaestionum medicarum (1593),
Andrea Cesalpino of Arezzo (1524-1603) gave an exact demonstration of the general scheme of circulation.3,4
The crucial step in understanding the cardiorenal axis is
represented by the studies of Starling,5 who in the lectures to
the Royal College of Surgeon in February 1896, stated that
“ as effect of heart failure sodium retention occurs along with
reduced sodium excretion. Continuous increase in circulating fluid occurs till capillary pressure is restored.” However,
in 1931 Wollheim gave the first demonstration that blood
*First Division of Nephrology Second University of Naples, Naples, Italy.
†Division of Nephrology, “De Bosis” Hospital, Cassino, Italy.
Supported by Regione Campania.
Address reprint requests to Natale G. De Santo, MD, 5 Via Pansini, Pad 17,
First Division of Nephrology, Second University of Naples, 80131 Naples, Italy. E-mail: [email protected]
404
0270-9295/05/$-see front matter © 2005 Elsevier Inc. All rights reserved.
doi:10.1016/j.semnephrol.2005.05.010
volume increases with heart failure and edema, and in 1935
Peters6 noted that “the kidneys react to changes of circulating
blood but are indifferent to changes in the volume of body
fluids.” Shortly thereafter, it also became clear that in “heart
disease there is inadequate translocation of fluid from venous
to arterial side,”7 and that the link between inadequate filling
of the systemic arterial tree and edema formation is brought
up by the kidneys.8
However, as pointed out by Anand,9 “the effective blood
volume is a poorly defined entity because there are no known
mechanisms by which the body can directly monitor its inadequacy and it cannot be measured. Until we can measure
effective blood volume this concept must remain hypothetic.”
We now know that a reduction of effective circulating
volume stimulates catecholamines, angiotensin II, endothelin, and anti diuretic hormone (ADH), which cause reduction
of renal blood flow (RBF), glomerular filtration rate (GFR),
and an increase of filtration fraction (FF). An increase in
proximal reabsorption occurs, followed by reduced distal
sodium delivery and activation of the juxtaglomerular apparatus.10
In 1946, Merrill11 was the first to measure GFR and renal
plasma flow (RPF) in heart failure (Fig 1) and it was evident
that RPF was more affected than GFR. The information was
confirmed by Aas and Blegen.12 However, it took many more
years and the advent of micropuncture techniques to understand the underlying tubular and glomerular mechanisms.13,14
Kidney disease in CHF
405
Andreoli15 has shown nicely that in conditions of underfilling, similar to those occurring in systolic pump failure, a
suicidal arterial filling takes place. In fact, because of the
hemodynamic changes, there is an increase in afterload that
leads to an increased end-diastolic volume. However, underfilling affects sodium avidity, thus increasing preload and
causing an increase in end-diastolic volume, which reduces
the ejection fraction.
The second suicide occurs via tumor necrosis factor ␣,
which triggers apoptosis, increases nitric oxide, and enhances expression of proto-oncogenes. The synthesis of a
locally active cytokine induces the heart to commit suicide at
the molecular level.16 In fact, tumor necrosis factor ␣ causes
cachexia, anorexia, and inflammation.
and reduced sodium excretion. ANP and BNP are considered
markers of heart failure. BNP has a greater specificity and
may be used for diagnostic purposes. It has been shown that
in patients undergoing a 40% reduction of BNP concentration during treatment, this feature is associated with 1 class
decrease in New York Heart Association (NYHA) classification of heart failure.17
Aldosterone is sodium retaining and potassium wasting,
by acting on Nedd4, which causes sodium reabsorption. In
CHF an aldosterone escape failure occurs, and aldosterone
antagonists have many beneficial effects on sodium balance
and heart fibrosis.18
ANP and BNP increase GFR by increasing glomerular hydrostatic pressure and Kf, decrease proximal and distal sodium reabsorption, increase blood flow in vasa recta, and
decrease renin release. ANP and BNP blood concentrations
are increased significantly in CHF. A decreased response to
ANP has been shown in human beings with CHF. Hyporesponsiveness is of multifactorial origin, and includes a reduction of renal perfusion pressure and an increase in renal sympathetic activity. Finally, it should be stressed that in CHF the
kidneys are normal, and, when transplanted in healthy individuals, they operate normally.
Taken together, the neurohormonal response activated in
CHF is identical to that which occurs after physical exercise
or hemorrhage.19,20 A response evolved over the millennia to
resist those life-threatening conditions such as hemorrhage
and physical exercise. Under these conditions there is an
increased sympathetic activity with venoconstriction, tachycardia, myocardial stimulation, and regional vasoconstriction.9 Additionally, in CHF the threat to blood pressure is
long lasting, therefore the effector mechanism is operating
continuously, thus the unloading of high-pressure baroreceptors stimulate sympathetic activity, as well as the RAAS
and Arginine Vasopressin (AVP).
Neurohormonal Activation
GFR and Starling Forces
Although kidney dysfunction at the present time is considered a general feature of congestive heart failure (CHF) it still
is undecided17 if it should be considered as a comorbidity or
a maladaptation that induces changes of fluid regulation and
the renin-angiotensin-aldosterone system (RAAS).
In CHF, significant changes occur in the cardiorenal axis,
which operates under the control of the RAAS (sodium retaining, antidiuretic, vasoconstricting, and profibrotic), and
of a group of peptides (atrial natriuretic peptide [ANP], brain
natriuretic peptide [BNP], and C-type natriuretic peptide
[CNP]). ANP and BNP, released by myocardial cells of the
heart, and CNP, released by the endothelium, are natriuretic,
diuretic, vasodilating, inhibitory for renin and aldosterone,
and antifibrotic. In this context, ANP and BNP are seen as
diuretic hormones secreted in response to stretch. ANP and
BNP operate through guanylated cyclase A receptors,
whereas CNP operates through a guanylate cyclase B receptor. All of them are bound to a clearance receptor that metabolizes them through the neutral endopeptidase. Blockade
of neutral endopeptidase–receptor results in reduced GFR
The transcapillary hydrostatic pressure (⌬P) slowly decreases
along the capillary length both in health and heart failure.
However, in CHF it is much higher than in normal patients
because of efferent arterial vasoconstriction. The transmural
oncotic pressure (⌬␲) increases over the capillary length
both in normal patients and patients with CHF. However, in
CHF it also is higher because of the increase in FF. This
situation is brought about by a disproportionate increase in
efferent vasoconstriction that protects GFR.
Along the peritubular capillary, ⌬P is reduced more than
in normal subjects. However, ⌬␲ is higher, thus the driving
force (⌬P ⫺ ⌬␲) enhances proximal reabsorption of sodium
and water. However, in CHF the changes in intrarenal hemodynamics, the sympathetic stimulation, and the stimulation
of angiotensin II also may promote sodium reabsorption in
Henle’s loop.21
The afferent to efferent balance is shown in Figure 2, which
gives a synopsis of RBF and GFR in treated and untreated
heart failure patients.22 It should be added that patients with
end-stage heart failure treated with angiotensin-converting
700
600
control
CHF
500
400
40
300
30
200
20
100
10
0
inulin,
PAH,
mL/min mL/min
FF %
Figure 1 GFR, RPF, and FF. , control; □, CHF. Data from Merrill.11
Two Suicides
N.G. De Santo et al.
406
enzyme (ACE) inhibitors have a normal renal reserve23 even
in the presence of a reduction in GFR and RPF associated
with enhanced FF (Fig 3). This also happens in mild CHF
(grade I NYHA) in which ACE inhibitors reinstate a renal
reserve after infusion of amino acids.24
Renal Function
and Survival in CHF
It is a common notion that in CHF survival depends on
plasma sodium potassium and magnesium levels.25,26 Even
blood urea, considered an unreliable index of renal function,
can predict survival. Renal function is the most powerful
predictor of mortality.27 A study in 1,906 patients with a
creatinine clearance level less than 44 mL/min (calculated by
means of the Cockroft and Gault equation) had a mortality
risk of 2.85 in comparison with those patients with a creatinine clearance of more than 76 mL/min (P ⬍ .001). The
study also showed that creatinine clearance is a stronger predictor of mortality than left ventricular ejection fraction or
NYHA class and strongly correlated with N-terminal ANP.27
NephrologistCardiologist Interaction
There is a general quest from patients with heart disease and
from patients with kidney disease for a nephrologist-cardiologist interaction. This also is stressed nicely by Packer28:
As medicine is practiced in the 1990s the patients with
heart disease and renal disease (whether these disorders are
seen in the same patient or in different patients) are frequently managed by physicians who are interested in only
one of the two organ systems. Under the rare circumstances,
when the patient is visited by both types of specialists, the
physicians take frequently opposite point of view and make
therapeutic recommendations that are principally designed
to preserve the function as a single organ system (that is the
Figure 2 Afferent to efferent in different groups of patients with end
stage heart failure (HF), also given ACE inhibitors (ACEI). Modified
from Leier and Boudoulas.22
40 %
40
control
CHF
35
30 %
30
25
20 %
20
15
10 %
10
5
0
Renal reserve (ml/min)
Renal reserve (%)
Figure 3 Renal reserve in patients with end stage heart failure waiting
for heart transplantation. , control; □, CHF. Data from Frangiosa
et al.23
focus of the physician’s specialty). Since kidneys play an important role in heart disease and the heart plays a role in all
patients with renal disease, cardiorenal interactions are becoming more and more important.21
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