Nephrol Dial Transplant (2002) 17: Editorial Comments 359

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Nephrol Dial Transplant (2002) 17: 359–362

Epoetin treatment: what are the arguments to expect

a beneficial effect on renal disease progression?

Jerome Rossert1, William M. McClellan2, Simon D. Roger3 and Dierik L. Verbeelen4

1
AP-HP, The University of Paris VI and INSERM U489, Paris, France, 2Department of Medicine, Emory University,
Atlanta, GA, USA, 3Department of Renal Medicine, Gosford Hospital, Gosford, Australia and 4Renal Unit,
University Hospital, Vrije Universiteit Brussel, Brussels, Belgium

Keywords: anaemia; chronic kidney disease; epoetin;
fibrosis; hypoxia; oxidative stress
Introduction
Progression of chronic kidney disease is usually a
relentless process. It is initially induced by the under-
lying kidney disease and its consequences. But, when
nephron numbers decrease beyond a certain threshold,
it is also caused by deleterious effects of this reduction
in nephron number, which creates a vicious circle.
Besides treatment of the underlying renal disease when-
ever possible, the main therapeutic tools that are
available to slow the progression of renal failure are
optimal control of blood pressure, use of angiotensin-
converting enzyme inhibitors, and to a lesser extent
dietary protein restriction (reviewed in w1x). The
Correspondence and offprint requests to: Jerome Rossert, Department
of Nephrology, Tenon Hospital, 4 rue de la Chine, F-75020 Paris,
France. Email: jerome.rossert@tnn.ap-hop-paris.fr
efficacy of these therapies is, however, limited, and
the need for other treatments is highlighted by the
observation that, for the past decade, the incidence
of end-stage renal disease has been increasing at an
annual rate of about 6–8% in most European coun-
tries. Among the other therapeutic interventions that
could slow the progression of renal failure is correction
of anaemia through administration of epoetin. Its
potential usefulness is suggested by analysis of the
pathophysiological mechanisms underlying progression
of renal failure and by a few clinical studies.
The roles of epoetin go beyond correction
of hypoxia
It is unanimously recognized that correcting anaemia
with epoetin increases oxygen delivery to tissues and
thus reduces hypoxia, even if epoetin may have some
vasoconstrictor properties w2x. Nevertheless, this treat-
ment may have other beneficial effects, including
protection against oxidative stress and apoptosis
(Figure 1).

# 2002 European Renal Association–European Dialysis and Transplant Association

360 Nephrol Dial Transplant (2002) 17: Editorial Comments

The links between oxidative stress and anaemia
come from the fact that erythrocytes represent a major
antioxidant component of the blood (reviewed in w3x).
Their antioxidant effects are mediated through the
glutathione system, enzymes such as superoxide dis-
mutase or catalase, and cellular proteins that are
devoid of enzymatic activity but can react with react-
ive oxygen species, such as low-molecular weight
proteins of the erythrocyte membrane, vitamin E or
coenzyme Q. Furthermore, erythrocytes can regenerate
consumed redox equivalents through the pentose
phosphate pathway, and through reduction of oxidized
glutathione by glutathione reductase.
The ability of erythropoietin to promote survival of
red blood cells via binding to its receptor has been
clearly established, and it appears to be mediated by
an inhibition of caspase activation, and by an induc-
tion of the expression of antiapoptotic proteins such as
Bcl-xL and Bcl-2 w4,5x. Recent in vivo data have shown
that anti-apoptotic effects can also be observed with
other cell types expressing the erythropoietin receptor,
such as neuronal cells w6,7x. In vitro, epoetin has also
been shown to protect endothelial cells or vascular
smooth muscle cells against apoptosis w8,9x. One can
speculate that this effect also exists for other cells that

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express the erythropoietin receptor, such as proximal
tubular cells and medullary collecting duct cells w10x.

Interstitial fibrosis and tubular damage play

a key role in the progression of renal failure

While for a long time nephrologists focused on glom-

Fig. 1. Schematic representation of the mechanisms by which
treatment with epoetin may modulate the progression of chronic
kidney diseases. See text for details.
eruli to try to decipher the mechanisms of progression
of renal failure, a few years ago attention switched
toward the tubulo-interstitial compartment of the
kidney, and interstitial fibrosis is now recognized as
one of the key factors of progression (Figure 2). The
main reason for such a shift of paradigm was probably
the observation that, in many cases, there is a striking
correlation between renal function and severity of
interstitial fibrosis, and that interstitial fibrosis is the
best prognostic marker of progression (reviewed in
w11x). The major mechanism by which interstitial fib-
rosis affects renal function seems to be the induction of

Fig. 2. Schematic representation of the mechanisms of progression of glomerular diseases. An initial glomerular insult is responsible for
glomerulosclerosis, leading to reduction in nephron number (black colour). Reduced nephron number induces an increase in glomerular
capillary pressure anduor in glomerular volume, leading to further glomerular damage (blue colour). Reduced nephron number is also
associated with tubular dysfunction responsible for interstitial fibrosis, that, in turn, leads to destruction of peritubular capillaries and to
tubular destruction (red colour). Destruction of interstitial capillaries may also increase glomerular capillary pressure, and thus enhance
glomerular damage (dotted red line). Proteinuria enhances tubular dysfunction and, thus, interstitial fibrosis (dotted black line).
Nephrol Dial Transplant (2002) 17: Editorial Comments
tubular lesions that ultimately lead to tubular destruc-
tion, with formation of atubular glomeruli w12x. This
has been nicely exemplified by study of a remnant
kidney model. Histological examination 25 weeks
after surgery showed that almost half of the remain-
ing glomeruli were atubular and one fourth were
connected to atrophic tubules while only 14% were
globally sclerotic, suggesting that progression toward
end-stage renal failure was mostly secondary to tubular
destruction w13x.
Hypoxia appears to link interstitial fibrosis
and tubular damage
As suggested by Fine et al. w14x, hypoxia of tubular
cells may be the main link between interstitial fibrosis
and tubular damage. Tubular hypoxia appears to be
secondary not only to increased oxygen consumption
by the remaining nephrons or to interposition of extra-
cellular matrix between capillaries and tubules, but
also to destruction of peritubular capillaries, since
histological analyses have shown a strong inverse
correlation between the number of peritubular capil-
laries and either the extent of interstitial fibrosis or the
severity of renal failure. For example, in a rat model
of glomerulonephritis, interstitial volume was tightly
correlated with the number of interstitial capillaries,
and in patients with diabetic glomerulosclerosis renal
function was very strongly correlated with the relative
area of postglomerular capillaries w15,16x. The concept
that interstitial fibrosis is associated with hypoxia of
tubular cells is also supported by a recent study of
renal biopsies with various tubulo-interstitial diseases
w17x. It showed not only a loss of peritubular capillaries
but also an overexpression of vascular endothelial
growth factor by tubular cells, suggesting that these
cells are deprived of oxygen.
Hypoxia could play a role not only in inducing
tubular damage, but also in favoring the development
of interstitial fibrosis. In vitro, hypoxia has been shown
to increase collagen production by different fibro-
blastic cells, including human renal fibroblasts w18,19x.
Furthermore, the production of TGF-b, which is a
potent profibrotic cytokine, is stimulated by oxygen
deprivation w18x. Finally, in some in vitro experi-
ments, hypoxia also decreased the production of
metalloproteases and increased the expression of one
of their inhibitors, TIMP-1, suggesting that it may
slow the degradation of extracellular matrix w19x.
Oxidative stress and apoptosis may enhance
the effects of hypoxia
Associated with chronic reduction in nephron number,
is an increased oxygen consumption by the remaining
nephrons, which leads to an increased production of
reactive oxygen species (reviewed in w20x). This oxid-
ative stress may enhance both tubular damage and
361
interstitial fibrosis. Experimental data have shown that
oxidative stress stimulates interstitial production of
extracellular matrix, and for example, in vitro, non-
cytolytic doses of hydrogen peroxide stimulate col-
lagen synthesis by renal fibroblastic cells, as well as
TGF-b production w21x. Similarly, lipid peroxidation
products, which are produced in increased amounts
in response to oxidative stress, up-regulate collagen
production by fibroblasts w22,23x. In vivo, treatment of
rats with antioxidants can protect against the devel-
opment of interstitial fibrosis, while deprivation of
antioxidants seems to have opposite effects w21,24x.
Recently, apoptosis has also been implicated in the
progressive loss of tubular cells observed during chronic
kidney diseases. For example, apoptosis appears to
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play an important role in the progression of tubular
atrophy in kidneys of rats submitted to subtotal
nephrectomy or to experimental anti-glomerular base-
ment membrane nephritis w25,26x. The mechanisms
underlying this increased apoptosis of tubular cells are
still poorly understood, but reactive oxygen species
have also been shown to have proapoptotic effects w27x.
Clinical studies suggest that epoetin may slow
the progression of renal failure
Since progressive destruction of tubules appears to
play a key role in the progression of chronic kidney
diseases, and to depend on hypoxia, oxidative stress,
and apoptosis, it is easy to envisage a beneficial effect
of correcting anaemia with epoetin. The possibility of
such a protective effect is actually supported by a few
clinical studies. The effects of correcting anaemia with
epoetin on the progression of renal failure have been
tested in two prospective studies including a relat-
ively large number of patients w28,29x. The first study
included 83 patients with severely impaired renal
function w28x. No beneficial effect of epoetin could be
demonstrated by simply comparing the two groups of
patients. Nevertheless, when the patients were analysed
only after their haemoglobin levels had reached the
target values, the rate of glomerular filtration rate
decline was three times slower in the treated group
than in the control group. In the second study, which
included patients with less severe renal failure, partial
correction of anaemia with epoetin significantly slowed
the rate of progression of renal failure w29x. During
the follow-up period, creatinine doubled in about
50% of the patients in the treated group, and in more
than 90% of the patients in the control group.
In conclusion, different experimental data support
the hypothesis that correction of anaemia with epoetin
may slow the rate of progression of renal failure, and
a few small clinical studies also suggest that this
hypothesis is worthy of testing. The definitive answer
should come from the ECAP study (Effect of early
Correction of Anaemia on the Progression of chronic
kidney disease). In this trial, 630 patients from Europe,
North America and Australia will be randomly
362
assigned to partial or complete correction of anaemia
and followed-up using iohexol-based measurements of
glomerular filtration rate to assess disease progression.
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