Editorial
Renal Function and Heart Failure Treatment
When Is a Loss Really a Gain?
Marvin A. Konstam, MD
A number of studies have demonstrated a linkage between
renal dysfunction and adverse clinical outcomes in both
acute and chronic heart failure.1–3 Heart failure treatments can
affect renal function in a variety of ways, with decreased
glomerular filtration rate (GFR) during treatment often de-
noting a poorer prognosis.4 – 6 Angiotensin-converting en-
zyme inhibitors (ACEIs) and angiotensin receptor blockers
(ARBs) reduce GFR through intrarenal mechanisms yet
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convey reduced rates of morbidity and mortality, presenting
the hypothesis that the association between change in GFR
and clinical outcomes depends on the factors that drive that
change more than on GFR itself. In this issue of Circulation:
Heart Failure, Testani et al7 present evidence that supports
this hypothesis, showing that within the SOLVD (Studies of
Left Ventricular Dysfunction) study, early reduction in GFR
was associated with increased mortality within the placebo
group but not in the enalapril group. It is reasonable to
conclude that inhibiting the renin-angiotensin system (RAS)
reduces GFR through a mechanism that does not convey an
adverse prognosis. In evaluating new therapies, focus should
be placed on clarifying the pathways through which agents
influence renal function.
Article see p 685
Within the SOLVD study, despite exclusion of patients
with serum creatinine of ⬎2.0 mg/dL, baseline renal impair-
ment was associated with reduced survival.2,3 Patients ran-
domized to enalapril showed slight, but statistically signifi-
cant mean increases in serum creatinine during treatment
relative to those receiving placebo.8,9 There exist a number of
putative mechanisms whereby heart failure therapies may
influence renal function. Diuretics may predispose to prerenal
azotemia through intravascular volume depletion, excessive
cardiac preload reduction, and a resulting reduction in cardiac
output. Loop diuretics also induce intrarenal mechanisms for
reducing GFR, principally through adenosine release and
diminished glomerular blood flow and filtration pressure,
through A1-receptor stimulation.10 On the other hand, diuret-
ics may augment cardiac output by reducing functional
valvular regurgitation and diminishing ventricular interde-
The opinions expressed in this article are not necessarily those of the
editors or of the American Heart Association.
From the Tufts Medical Center and Tufts University School of
Medicine, Boston, MA.
Correspondence to Marvin A. Konstam, MD, The CardioVascular
Center, Tufts Medical Center, Box 108, 800 Washington St, Boston, MA
02111. E-mail mkonstam@tuftsmedicalcenter.org
(Circ Heart Fail. 2011;4:677-679.)
© 2011 American Heart Association, Inc.
Circ Heart Fail is available at http://circheartfailure.ahajournals.org
DOI: 10.1161/CIRCHEARTFAILURE.111.964874
677
pendent effects and may increase GFR by reducing central
and renal venous pressures.11 So, although reduced GFR
during diuretic treatment is associated with increased mortal-
ity among hospitalized patients,4 – 6 more work is needed to
tease out the various mechanisms by which diuretics influ-
ence GFR within patient subgroups and the manner in which
these mechanisms drive clinical outcomes.
The intrarenal RAS finely regulates volume and electrolyte
homeostasis by modulating both glomerular filtration and
sodium reabsorption or excretion. RAS inhibition diminishes
GFR largely through withdrawal or blockade of angiotensin
II-mediated efferent glomerular arteriolar constriction,
thereby reducing glomerular filtration pressure. On the other
hand, RAS inhibitors have been well shown to reduce the
progression of renal impairment and the need for dialysis,
particularly among patients with diabetes.12,13 It appears
clear, then, that the short-term effects of ACEIs and ARBs on
serum creatinine and GFR generally do not constitute renal
injury but, rather, reflect intrarenal hemodynamic effects,
which in fact may be associated with long-term renal
preservation.
SOLVD represented the first demonstration of the benefit
of RAS inhibition on cardiovascular outcomes in asymptom-
atic patients and those with mild to moderate clinical heart
failure and reduced left ventricular ejection fraction. Since
that time, numerous studies have substantiated this finding
with both ACEIs and ARBs.14 –16 In these studies, worsening
renal function along with hypotension and hyperkalemia
represents one of the principal sources of adverse events,
including those resulting in drug discontinuation. The first
ELITE (Evaluation of Losartan in the Elderly) study17 dem-
onstrated comparability of renal effects with the ACEI
captopril and the ARB losartan. However, the absolute rate of
study drug discontinuation due to these events has been small,
perhaps speaking to the recognition among clinicians and
investigators that modest increases in serum creatinine are
well tolerated in this setting. We demonstrated dose depen-
dency for both the outcome benefit and the adverse event rate
with the ARB losartan, comparing daily doses of 150 and 50
mg.18 However, drug discontinuation because of renal impair-
ment occurred at rates of only 0.65 and 0.49 events per 100
person-years, with the 2 doses, resulting in a favorable
risk-benefit profile for the higher dose. In a multivariable
analysis, we identified increased age, concomitant aldoste-
rone receptor blockade, and higher baseline serum creatinine
as independent predictors of adverse renal events.
Potential pathways linking renal function to clinical out-
comes in heart failure are depicted in the Figure. As Testani
et al point out,7 2 principal possibilities are that (1) reduced
GFR directly contributes to worse outcomes and (2) reduced
 678 Circ Heart Fail November 2011
Figure. Schematic representation of possible interactions driv-
ing the association between renal functional impairment and
reduced survival in HF. A, Reduced survival may be a direct
consequence of reduction in GFR; alternatively, reduced GFR
and reduced survival may be a consequence of (1) worse heart
failure, (2) kidney injury, or (3) treatment effects. B, In the case
of RAS inhibition, reduction in GFR is principally a reversible,
pharmacological, intrarenal hemodynamic effect and is rarely an
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indicator of kidney injury. In fact, in other settings, such treat-
ment has been shown to offer long-term renal preservation. Any
modest direct adverse long-term clinical consequence of short-
term renal functional decline is likely off set by additional favor-
able cardiovascular and renal effects of these agents. GFR
indicates glomerular filtration rate; HF, heart failure; RAS, renin-
angiotensin system.
GFR is a marker of worse heart failure and, thereby, is
associated with worse outcomes. As depicted in Figure A,
heart failure may reduce GFR directly through hemodynamic
impairment (eg, reduced cardiac output or increased central
venous pressure) or through kidney injury. The former is
likely to be reversible with heart failure treatment, whereas
the latter is likely to be irreversible. Heart failure treatments
may similarly reduce GFR through reversible or irreversible
mechanisms. Although unproven, it is reasonable to hypoth-
esize that irreversible kidney injury is more likely to contrib-
ute directly to reduced survival than is reversible, hemody-
namically mediated reduction in GFR.
Figure B depicts ways in which RAS inhibition may affect
these interactions. In the absence of severe reduction in renal
perfusion, as may occur with bilateral renal artery stenosis,
RAS inhibition does not cause kidney injury. Rather, it
induces a dose-dependent, reversible, hemodynamically me-
diated reduction in GFR. This effect may contribute directly
to renal preservation as has been demonstrated in patients
with diabetic nephropathy. As Testani et al7 suggest, the lack
of association between early reduction in GFR during enal-
april administration and subsequent mortality may signify
that reduced GFR per se has no adverse impact on survival.
However, even if GFR does have a direct impact on survival,
when this effect occurs in the setting of ACEI initiation, any
adverse effect may be offset by the direct survival benefit of
this agent. It is striking that among patients continuing the
study drug in SOLVD, greater survival benefit of enalapril
versus placebo was observed in patients with early worsening
of renal function. This finding suggests that during ACEI
initiation, either reduced GFR is somehow directly linked
with improved survival or, more likely, GFR reduction is a
marker of greater RAS inhibitory effect with a resulting
greater survival benefit.
The presumption of a causal linkage between renal func-
tion and subsequent outcomes, or the categorization of renal
impairment as an important clinical outcome in its own right,
has led to the exploration of drugs that improve GFR or
preserve renal function in the setting of diuretic treatment. In
this regard, inhibitors of the adenosine A1-receptor have held
promise. Enthusiasm for this direction was dampened when
the phase III PROTECT (Placebo-Controlled Randomized
Study of the Selective A1 Adenosine Receptor Antagonist
Rolofylline for Patients Hospitalized With Acute Decompen-
sated Heart Failure and Volume Overload to Assess Treat-
ment Effect on Congestion and Renal Function) study19 failed
to confirm clinically relevant benefit with such an agent.
Nevertheless, the opportunity of pharmacological renal pro-
tection remains, partly because renal impairment limits the
use of other treatments, such as diuretics and RAS inhibitors,
including aldosterone receptor blockers. Additionally, agents
should be sought that prevent renal injury, as determined by
the impact on markers such as neutrophil gelatinase-
associated lipocalin,20 rather than on functional measures,
such as GFR, alone.
Clearly, modest reduction in GFR associated with initiation
of RAS inhibitors should not be viewed as carrying an
adverse prognosis and should not be cause for drug discon-
tinuation. On the contrary, it is a marker of pharmacological
effect associated with this salutary treatment modality. Future
research should be directed toward adding to the important
insights provided by Testani et al7 and further deciphering the
complex interdependencies among heart failure severity,
treatment effects, renal function, and survival. Such insights
will yield more cogent directions for drug discovery and
investigation in both acute and chronic heart failure.
Disclosures
Dr Konstam has received research support from and has been a
consultant for Merck.
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KEY WORDS: Editorials 䡲 angiotensins 䡲 heart failure 䡲 kidney 䡲 renal
insufficiency 䡲 renin-angiotensin system
 Renal Function and Heart Failure Treatment: When Is a Loss Really a Gain?
Marvin A. Konstam

Circ Heart Fail. 2011;4:677-679

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doi: 10.1161/CIRCHEARTFAILURE.111.964874
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