Kidney International, Vol. 61, Supplement 80 (2002), pp.
S18S22
Slowing the progression of renal failure
MANUEL PRAGA
Nephrology Department, Hospital 12 de Octubre, Madrid, Spain
Slowing the progression of renal failure. In recent years several
multicentric prospective studies have demonstrated the efficacy
of some therapeutic measures to slow the progression of renal
diseases. Inhibition of renin-angiotensin system (RAS) both
by ACE inhibitors (ACEI) and angiotensin II receptor antago-
nists (ARA) is probably the strongest therapeutic alternative:
The antiproteinuric effect of these drugs is an excellent surro-
gate marker and a predictor of the beneficial influences on
the progression of renal failure. The type of renal disease,
an inadequate control of blood pressure, and the presence
of obesity may counteract the beneficial influences of RAS
inhibition, whereas early treatment of all patients with signifi-
cant proteinuria before the appearance of renal insufficiency
and combined therapy with an ACEI and an ARA may aug-
ment it. Dietary protein restriction is a classic treatment of
chronic renal insufficiency whose effectiveness has been vali-
dated by multicentric studies. However, a poor compliance of
the patient and the risk of malnutrition with very strict protein
restriction could limit the benefits of this treatment. Treatment
of hyperlipidemia, prevention of obesity, avoidance of smok-
ing, and regular physical exercise are interventions whose ther-
apeutic potential is progressively recognized, particularly in
type 2 diabetic nephropathy. Early correction of anemia may
contribute to the slowing of renal disease progression. Al-
though further studies are required, the accumulated evidence
and the likelihood of additive beneficial effect of these thera-
peutic measures advise their combined implementation in pa-
tients with chronic renal diseases.
A large number of experimental studies have demon-
strated that renal diseases share pathogenic mechanisms
that play a fundamental role in the progression toward
end-stage renal failure, independently of the original
etiology. In recent years a number of therapeutic mea-
sures that can halt or slow these common, harmful patho-
genic ways have emerged. In this article, we review some
of the most relevant new insights in the field of general
renoprotective measures.
INHIBITION OF THE RENIN-ANGIOTENSIN
SYSTEM (RAS)
There is compelling clinical evidence that the pharma-
cologic inhibition of RAS with angiotensin-converting
Key words: ACE inhibitors, proteinuria, angiotensin II receptor antag-
onists, obesity, hyperlipidemia.
2002 by the International Society of Nephrology
S-18
enzyme inhibitors (ACEI) or with angiotensin II subtype
1 receptor antagonists (ARA) slow the progression of
renal failure in many chronic nephropathies. Several
large, multicentric, and prospective studies have shown
a significant reduction in the risk of doubling baseline
serum creatinine or progression toward end-stage renal
failure in patients with type 1 and type 2 diabetic ne-
phropathy treated with ACEI or ARA, in comparison
with control patients [14]. Similarly, these drugs have
shown a clear renoprotective effect in proteinuric non-
diabetic chronic nephropathies [5, 6]. The accumulating
evidence of the beneficial effects offered by ACEI and
AT1RA has led to the generalized use of these drugs
in both diabetic and non-diabetic nephropathies. Some
patients may exhibit a clear beneficial response, with
dramatic proteinuria decrease and stabilization of GFR
over the years. However, a review of the referred multi-
centric trials [16] shows that the number of patients that
reach the most commonly analyzed primary outcome
(doubling of baseline SCr) is still considerably high. Thus,
in the AIPRI and REIN studies, which included prefera-
bly non-diabetic nephropathies, 1030% of the patients
treated with ACEI had doubled the baseline serum creat-
inine (SCr) after 23 years of follow up [5, 6]. In the studies
performed with diabetic patients [14], the number of
patients doubling baseline SCr reached 2040% among
those treated with ACEI and ARA, after 2.53.5 years
of follow up. Although the number of patients reaching
primary outcomes was significantly higher in control
groups, these results indicate that RAS inhibition with
ACEI or ARA should not be considered, unfortunately,
as the definitive defeat of renal failure progression.
PROTEINURIA AS A SURROGATE MARKER
OF THE EFFECTIVENESS OF RAS INHIBITION
The antiproteinuric effect of ACEI is well known after
numerous studies performed in the past 15 years [7].
More recently, ARA have demonstrated a similar effect.
A review of the mechanisms implicated in this beneficial
effect, shared so far by all classes of ACEI and ARA
so far, is beyond the scope of this article. In 1992 we
reported, for the first time, that in those captopril-treated
 Praga: Progression of renal failure
patients showing a substantial proteinuria decrease, a
clear slowing in the progression of renal insufficiency
was observed. On the contrary, those patients also
treated with captopril but in whom no significant protein-
uria decrease was observed, continued to show a progres-
sive loss of renal function [8]. Interestingly, the protein-
uria decrease was unrelated to blood pressure changes
in our study, and several studies have confirmed our
results later. Very importantly, in all the above-cited
multicentric landmark studies [16], the slowing in the
progression of renal insufficiency has always strongly
been related to proteinuria decrease induced by ACEI
or ARA, whereas it appears to be largely independent
of the blood-pressure lowering effects induced by these
drugs. Because the proteinuria decrease is already ob-
served within the fist weeks or months of treatment, it
should be considered as an excellent clinical predictor of
the long-term renoprotective effects of RAS inhibition.
Therefore, there is mounting evidence that the level of
proteinuria is of paramount importance in order to moni-
tor the effectiveness of ACEI and/or ARA in proteinuric
nephropathies. Some authors have suggested that the
definitions of partial or complete remissions (proteinuria
decreases to 2.5 g/24 h and 0.5 g/24 h, respectively),
commonly used to define the responses to immunosup-
pressive drugs in many glomerular diseases, should also
be applied to evaluate the response of chronic protein-
uric nephropathies when ACEI/ARA are introduced.
On the other hand, the absence of a significant antipro-
teinuric response should be considered as a resistance
to the beneficial effects of these drugs. In this case, an
analysis of those factors that may contribute to the resis-
tance should be performed.
FACTORS THAT CONTRIBUTE TO
THE FAILURE OF ACEI/ARA
ANTIPROTEINURIC EFFECT
A significant number of patients treated with ACEI/
ARA did not show a clear antiproteinuric response, and
this failure heralds a progressive loss of renal function
in most cases [18]. The factors that may contribute to
this resistance are largely unknown, but their identifica-
tion and correction should have an obvious clinical im-
portance to slow the progression of renal insufficiency
more effectively in proteinuric renal diseases. Some clini-
cal studies have brought forward interesting data in this
field.
Clinical diagnosis
Although the number of clinical studies concerning
this issue is relatively scarce, the antiproteinuric response
to RAS inhibition appears to be influenced by the type
of renal disease. Thus, we have reported that those renal
diseases defined as hyperfiltration disorders (reflux ne-
S-19
phropathy, significant reductions of functioning renal
mass whatever the cause, healed crescentic glomerulone-
phritis) show a striking proteinuria decrease after the
introduction of an ACEI, with reductions of 5565% of
the baseline values [8]. In the same study, we observed
an also satisfactory response among patients with IgA
nephropathy (43%) and benign nephroangiosclerosis
(58%). On the contrary, patients with idiopathic focal
and segmental glomerulosclerosis (FSG) and membra-
nous glomerulonephritis showed a less evident response,
with proteinuria decreases oscillating between 24% and
27% [8]. However, it is important to remark that a strik-
ing variability in the response was also observed within
each specific diagnosis group. Thus, some patients with
membranous GN or idiopathic FSG showed proteinuria
decreases higher than 50%.
Adequate blood pressure control
Given the results obtained in the Modification of Diet
in Renal Disease Study (MDRD), blood pressure control
should be targeted to values 130/80 mm Hg in patients
with proteinuric nephropathies [9]. The basis of antihy-
pertensive therapy should be the inhibition of RAS sys-
tem, either with an ACEI or an ARA, because of their
demonstrated renoprotective and antiproteinuric effects.
However, if the recommended target is not reached after
an appropriate and progressive increase of doses, other
antihypertensive drugs should be added, according to
the individual patients characteristics.
Genetic basis
Efforts to characterize genetic peculiarities that can
contribute to a better or poorer response to the renopro-
tection offered by ACEI and ARA have been mainly
concentrated on polymorphisms of genes coding the con-
stituents of RAS. Some studies have reported a greater
antiproteinuric effect of ACEI in patients with the II
genotype of the ACE [10]. On the contrary, a greater
renoprotective efficacy of these drugs in patients with
the DD genotype has been found in non-diabetic ne-
phropathies [11]. These contradictory results should be
resolved with more extensive studies and the analysis of
other RAS genes.
Obesity
We have described that both weight loss and ACEI
can induce a dramatic proteinuria decrease in patients
with obesity related proteinuria [12]. However, when we
analyzed the long-term evolution of patients with FSG
associated with obesity, we found that most patients es-
caped from the antiproteinuric effect of ACEI after the
612 months of treatment [13]. In many cases, this later
failure of the ACEI-induced proteinuria decrease was
correlated to further weight gains that many patients
exhibited. These findings are of interest, taking into ac-
S-20 Praga: Progression of renal failure
count that, in our experience, the long-term prognosis
of obesity associated FSG is poorer than previously con-
sidered, with almost 50% of patients developing end-
stage renal failure [13]. In addition, the prevalence of
obesity related glomerulopathies has dramatically in-
creased in the past years, as has been pointed out recently
[14], and a great majority of type 2 diabetics are obese.
We have observed obese patients with different ne-
phropathies and resistance to the antiproteinuric effect
of ACEI or ARA that showed a marked proteinuria
reduction coinciding with weight loss. All these data
suggest that obesity could be considered a condition of
increased resistance to the beneficial renal effects of
RAS inhibition.
FACTORS THAT CAN IMPROVE THE
EFFECTIVENESS OF RAS INHIBITION
Early treatment
ACEI and ARA have confirmed their efficacy to slow
the progression of renal failure in several multicentric
and prospective studies [16]. The majority of patients
included in these studies had different degrees of chronic
renal insufficiency. Nevertheless, some data strongly in-
dicate that the introduction of RAS inhibitors in chronic
proteinuric nephropathies before the appearance of re-
nal insufficiency should be the preferable option. Thus,
studies in type 1 and type 2 diabetes mellitus have dem-
onstrated that treatment with ACEI or ARA in patients
with microalbuminuria significantly decrease the risk of
developing overt diabetic nephropathy [4, 15]. At pres-
ent, data about early treatment of non-diabetic protein-
uric nephropathies are scarce. Since 1987 we have fol-
lowed a prospective therapeutic protocol with ACEI or
ARA in patients with IgA nephropathy and proteinuria
1 g/24 h, regardless of blood pressure and renal func-
tion status. We have analyzed recently the evolution of
those patients that started treatment when SCr was 1.5
mg/dL: After 5 years of follow up renal survival (defined
as the absence of a SCr increase higher than 50% of
baseline values) was 100% (Kaplan-Meier analysis). By
contrast, renal survival at 5 years was only 65% in pa-
tients with the same characteristics that were not treated
with ACEI or ARA (abstract; Gonzalez et al, J Am
Soc Nephrol 12:102A, 2001). In our experience, it is not
uncommon to observe similar satisfactory responses to
RAS inhibition in other nephropathies when the treat-
ment is started early in the course of the disease. We
believe that ACEI or ARA should be administered to all
patients with chronic renal diseases showing significant
proteinuria values (0.51 g/24 h) regardless of blood
pressure and preferably before the appearance of renal
insufficiency.
Combined treatment with ACEI and ARA
From a theoretical point of view, the combined use
of an ACEI and an ARA would augment the beneficial
influences of both classes of agents: ARA would provide
a complete blocking of AT1 receptors of angiotensin II,
not guaranteed by ACEI, whereas the later would contrib-
ute with an increased synthesis of bradykinin. In clinical
practice, a greater antiproteinuric effect of the combina-
tion ACEIARA in comparison with single therapy with
an ACEI or an ARA has been reported in patients with
IgAnephropathy [16]. In the last two meetings of the ASN,
more than 20 studies have analyzed the antiproteinuric
effect of the combination ACEIARA, and nearly all
have found it significantly greater than the one observed
with just ACEI or ARA, although the doses of these
drugs were increased when used alone. Interestingly,
no differences in blood pressure that could explain the
greater antiproteinuric effect of the combination were
observed. Although other published studies have not
confirmed the superiority of the combination [17], pro-
spective multicentric studies including a larger number
of patients should be performed in order to evaluate
definitely the indication of the ACEIARA combina-
tion in proteinuric diseases.
PROTEIN RESTRICTION
An in-depth review of the beneficial effects of low
protein diets on the progression of renal failure is beyond
the scope of this article, but several meta-analyses and
secondary analyses of randomized trials have demon-
strated that protein restriction slows the progression of
renal diseases [18, 19]. Protein intakes of 0.60.7 g/kg/
day are the most commonly recommended in patients
with GFR5055 mL/min/1.73 m2. In addition, low pro-
tein diets induce a significant proteinuria decrease, i.e.,
additive to that achieved by ACEI [20]. However, some
potential limitations of low protein diets have been
pointed out by several studies. Thus, the patients com-
pliance has been rather low in some studies; a risk of
malnutrition should be considered, particularly when
very strict protein restriction is prescribed to patients
with advanced renal failure; and the benefits obtained
by protein restriction, although evident, are rather mod-
est in terms of the delay in the start of chronic dialysis
that we obtain with this dietary intervention [21].
TREATMENT OF HYPERLIPIDEMIA
The pathogenic role of hyperlipidemia has been dem-
onstrated in several experimental models of progressive
renal diseases: Mesangial cells posses receptors for LDL-
cholesterol, and LDL-cholesterol stimulates the prolifer-
ation of mesangial cells and their extracellular matrix.
Conversely, treatment of hyperlipidemia with clofibrates
 Praga: Progression of renal failure
or statins induces a clear improvement of renal lesions in
these experimental models. In spite of the accumulating
experimental evidence, clinical trials aimed at demon-
strating the role of hyperlipidemia in human renal dis-
eases have been disappointing so far because, with some
exceptions, no differences in the level of proteinuria or
in the progression of renal failure were found between
patients treated with lipid-lowering drugs and controls.
However, a very interesting meta-analysis of the previ-
ous trial has been recently published [22]. Increasing the
statistical power by the sum of these studies, a significant
beneficial effect of antilipemic agents could be demon-
strated, with proteinuria decrease and slowing of renal
failure progression in comparison with non-treated pa-
tients. Taking into account the high prevalence of hyper-
lipidemia and cardiovascular events among patients with
renal diseases and the demonstrated preventive effects
of antilipemic agents (particularly statins) on the appear-
ance of new cardiovascular events, it may be unethical (as
the authors of the meta-analysis stated) to design long-
term prospective clinical trials with a group of hyperlipid-
emic patients with renal diseases serving as controls with-
out lipid-lowering treatment.
OBESITY, SEDENTARY LIFESTYLE, AND
OTHER SOCIOECONOMIC FACTORS IN THE
PROGRESSION OF RENAL DISEASES
As commented above, obesity may counteract the ben-
eficial antiproteinuric effects of ACEI and ARA. In addi-
tion, obesity plays a facilitating role in the progresion
of some renal diseases, particularly those mediated by
hyperfiltration [23]. Nevertheless, the possible influence
of overweight on the general progression of renal dis-
eases, independent of their origin, has been scarcely in-
vestigated. We have recently performed a prospective
randomized study in overweight patients (body mass in-
dex 27 kg/m2) with proteinuric renal diseases of several
etiologies. One half of the cases had type 2 diabetic
nephropathy. We have found that a moderate weight
loss (4.1 3% of the baseline values) by hypocaloric
normoproteic diet induced a significant proteinuria de-
crease higher than 30% of baseline together with stable
GFR. On the contrary, a tendency to body weight and
proteinuria increases together with significant GFR de-
crease was observed in control group patients, who main-
tained their dietary habits (abstract; Morales et al, J Am
Soc Nephrol 12:231, 2001). These results indicate that
treatment of obesity should be an important target in
chronic proteinuric nephropathies. Taking into account
the increasing prevalence of obesity in the general popu-
lation and the fact that a great majority of patients with
type 2 diabetic nephropathy (the leading cause of end-
stage renal disease) are obese, further studies are re-
quired to confirm these results.
S-21
The influence of obesity on the progression of renal
diseases could be related to the emerging hypothesis that
emphasizes the importance of intrauterine/congenital
factors in the predisposition to suffer some diseases in
adulthood. Experimental studies have demonstrated that
an inadequate protein intake in pregnant experimental
animals leads to the birth of animals with a reduced
number of nephrons and endocrine pancreatic tissue
[24, 25]. Some autopsy studies performed in dead neo-
nates support the validity of these findings for the human
being, because the number of glomeruli was significantly
lower among neonates with a birth weight 2500 g com-
pared with neonates with normal birth weight [26]. Epi-
demiologic studies coming from Britain, US, China, and
other countries have confirmed an inverse relationship
between weight at birth and the risk to develop hyperten-
sion, type 2 diabetes mellitus and renal insufficiency in
adulthood [27]. In addition, a disproportionate tendency
to the development of hypertension, type 2 diabetes, and
end-stage renal disease has been repeatedly reported in
social groups such as Native Americans or Australian
aborigines [28]. The prevalence of prematurity and low
birth weight is high among these groups, as well as the
prevalence of obesity in adulthood. Therefore, it could
be hypothesized that the presence of a reduced number
of nephrons and pancreatic islets, determined by intra-
uterine factors mainly related to maternal nutrition, facil-
itates the development of hypertension, type 2 diabetes
and renal insufficiency. The development of obesity and
a sedentary lifestyle in adulthood could be the crucial
factors to precipitate the appearance of these diseases.
According to this hypothesis, an adequate maternal nu-
trition during pregnancy, and regular physical exercise
and avoidance of obesity in adulthood, should decrease
the risk of progressive renal failure in the general popula-
tion.
SMOKING
Several recently published retrospective studies have
stressed the role of smoking in the progression of both
diabetic and non-diabetic nephropathies [29]. Direct
harmful effects of smoking on kidney vascular beds have
been demonstrated by other studies. Therefore, avoid-
ance of smoking should be strongly recommended to all
patients with renal diseases.
EARLY CORRECTION OF ANEMIA
Although some experimental studies had suggested
that anemia correction could hasten the progression of
renal failure, clinical studies have shown that erythropoi-
etin improves anemia in predialysis patients and does
not accelerate the rate of renal failure progression [30].
Furthermore, recent studies have suggested that early
S-22 Praga: Progression of renal failure
correction of anemia may induce a beneficial influence
retarding the progression of renal failure [31]. Hypoxia
stimulates the progression of renal interstitial fibrosis
[32], and erythropoietin could counteract these harmful
pathways. Prospective studies are warranted in order
to assess these important implications of erythropoietin
therapy.
CONCLUSION
Several therapeutic interventions, briefly reviewed in
this article, have demonstrated a beneficial effect slowing
the progression of renal diseases, and they are likely to
have additive beneficial influences. Therefore, as it has
been recently proposed [33], a multiple-risk-factor inter-
vention including all these possibilities appears to be
the most plausible approach in patients with chronic
nephropathies.
Reprint requests to Prof. Manuel Praga, Servicio de Nefrologa, Hospi-
tal 12 de Octubre, Carretera de Andaluca Km 5,400 28041 Madrid, Spain.
E-mail: mpragat@senefro.org
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