JNEPHROL 2011; 24 ( 03 ) : 274-281
THOROUGH CRITICAL APPRAISAL
DOI:10.5301/JN.2011.7763
The Remission Clinic approach to halt the
progression of kidney disease
The Remission Clinic Task Force* 1, 2, Clinical Research Center “Aldo e Cele Daccò” 1
* See “Appendix”
Abstract
Randomized multicenter studies in diabetic and nondiabetic patients with chronic proteinuric nephropathies
have clearly demonstrated that renin-angiotensin system (RAS) inhibitors, such as angiotensin-converting
enzyme (ACE) inhibitors and angiotensin II receptor
blockers (ARBs) used alone or in combination, effectively retard renal disease progression. Proteinuria reduction, in addition to arterial blood pressure control,
largely mediates the nephroprotective effect of RAS
inhibitor therapy. Despite RAS inhibition, however,
most patients with chronic kidney disease (CKD) progress to end-stage renal disease (ESRD). This highlights the importance of innovative therapies to halt
or revert CKD progression in those at risk. Along this
line, a multimodal strategy (Remission Clinic) targeting urinary proteins by dual RAS inhibition with ACE
inhibitors and ARBs up-titrated to maximum tolerated
doses, by intensified blood pressure control, amelioration of dyslipidemia by statins, smoking cessation
and healthy lifestyle implementation was safely and
effectively applied at our outpatient clinic to normalize
urinary proteins and prevent renal function loss in patients otherwise predicted to rapidly progress to ESRD
because of nephrotic-range proteinuria refractory to
standard antihypertensive dosages of an ACE inhibitor. This approach achieved remission or regression of
proteinuria and stabilized kidney function in most cases, and almost fully prevented progression to ESRD.
Provided patients are closely monitored and treatment
is cautiously up-titrated according to tolerability, this
274
Mario Negri Institute for Pharmacological Research and
Unit of Nephrology, Bergamo - Italy
2
Azienda Ospedaliera «Ospedali Riuniti di Bergamo»,
Bergamo - Italy
1
approach might be safely applied in day-by-day hospital practice. Effective prevention of ESRD would reduce costs of renal replacement therapy by dialysis or
transplantation and would be life-saving where these
are not available for all patients in need.
Key words: ACE inhibitor, Angiotensin II receptor
blocker, Blood pressure, Chronic kidney disease, Proteinuria, Remission Clinic
Introduction
End-stage renal disease (ESRD) is a major public health
problem. A forecast analysis based on data from the US
Renal Data System and Medicare predicts that by the year
2020, the total number of patients on renal replacement
therapy will almost double, approximating 785,000, which
is expected to significantly increase public expenditure for
dialysis (1). Since most of the current ESRD patients progressively lost their kidney function over years, retarding or
even halting the progression of chronic nephropathies is instrumental in substantially decreasing the need and costs
for renal replacement therapy.
Many studies in animals and humans suggest that progression of renal damage is independent from the initial disease
and follows pathogenic mechanisms that are common
among different nephropathies (2, 3). After an initial renal
injury, remnant intact nephrons undergo hypertrophy with
concomitant lowering of arteriolar resistance and increased
© 2011 Società Italiana di Nefrologia - ISSN 1121-8428
JNEPHROL 2011; 24 ( 03 ) : 274-281
glomerular plasma flow (4). Since the tone of afferent arterioles drops more than that of efferent ones, hydraulic pressure of glomerular capillaries rises, increasing the filtrate per
nephron. These changes enhance the filtration capacity of
remaining nephrons to minimize the functional consequences of their reduced number, but they are ultimately detrimental. Indeed, the high intraglomerular capillary pressure
enlarges the radii of glomerular pores and, along with podocyte cytoskeleton rearrangement secondary to increased
angiotensin II levels, impairs the size selectivity of the membrane and induces protein ultrafiltration (4, 5). An excess of
proteins in the lumen of the tubules eventually results in a
nephritogenic effect, through a direct tubular toxicity and a
secondary process of tubular epithelial endocytosis (2, 6).
On the basis of this background, reduction of protein traffic,
along with strict blood pressure (BP) control, should play a
central role in intervention strategies aimed to prevent or revert renal disease progression. In animals, renin-angiotensin
system (RAS) blockers reduce intraglomerular hydraulic
pressure and improve the selectivity of the glomerular barrier, an effect that translates into a reduction of proteinuria
and prevention of glomerulosclerosis and kidney scarring
(3). Prospective randomized placebo-controlled trials found
that, at comparable BP control, angiotensin-converting enzyme (ACE) inhibitors (7) are more effective than non-ACE
inhibitor therapy in limiting progression to ESRD in diabetic
and nondiabetic patients with chronic proteinuric nephropathies (8). Notably, the Ramipril Efficacy In Nephropathy
(REIN) trial found that reduction in urinary protein excretion
rate with the ACE inhibitor ramipril was the only time-dependent covariate that predicted a lower rate of glomerular
filtration rate (GFR) decline and progression to ESRD in patients with nondiabetic chronic nephropathies, clearly indicating that reduction of protein traffic is renoprotective (9).
Hence, minimizing urinary protein excretion should represent the primary goal to retard/stabilize renal progression of
chronic renal disease.
Dual RAS inhibition: a strategy to
maximize antiproteinuric effect of ACE
inhibitors and angiotensin II receptor
blockers
The combination of an ACE inhibitor and angiotensin II receptor blockers (ARBs) has been suggested as a way to
maximize RAS inhibition by affecting both the bioavailability
of angiotensin II through ACE inhibition and also its activity
at the receptor level. Moreover, an ACE inhibitor may prevent the compensatory increase in angiotensin II synthesis
frequently observed during ARB therapy. On the other hand,
an ARB may inhibit the activity of angiotensin II produced
via ACE-independent pathways.
Animal (10, 11) and human (12, 13) studies have consistently found that ACE inhibitors and ARBs in combination
reduce proteinuria more effectively than the 2 agents alone
(14). Of note, a meta-analysis of 425 patients with chronic
proteinuric nephropathies found that the reduction achieved
by dual RAS inhibition exceeded the reduction achieved by
ACE inhibitors or ARB therapy alone, by 60% and 54%, respectively (15).
In these studies, however, dual RAS blockade had a more
consistent antihypertensive effect than single ACE inhibitor
or ARB therapy, which did not allow the studies to address
the issue of whether the superior antiproteinuric effect of
combined therapy really reflected more effective RAS blockade or, rather, was just a function of more BP reduction.
To address this issue, the antiproteinuric effect of fixed doses of the ACE inhibitor benazepril and of the ARB valsartan given alone were compared with that of halved doses
of the 2 drugs used in combination in a cross-over study in
patients with nondiabetic chronic kidney disease (16). With
this approach, BP reduction was similar in the 3 treatment
groups, but proteinuria reduction was more consistent with
dual therapy. This provided evidence that the superior antiproteinuric effect of dual compared with single-drug RAS
blockade was not explained by a higher antihypertensive effect, but by a more effective inhibition of the RAS (16). On
the basis of these results, patients were maintained on dual
RAS inhibitor therapy (benazepril 10 mg/day plus valsartan
80 mg/day) and prospectively followed up. Their outcome
at 6 years was compared with that of matched reference
patients maintained on single-drug RAS blockade with a full
dose of an ACE inhibitor (ramipril 5 mg/day).
Decline of estimated GFR (eGFR) was significantly lower in
patients compared with reference patients (Fig. 1), and proteinuria reduction independently predicted the rate of eGFR
decline. In patients, GFR (measured by iohexol clearance),
filtration fraction, renal vascular resistances and urinary protein to creatinine ratio decreased at 1 year, were stable up
to 6 years and recovered to baseline after treatment withdrawal. No patient versus 6 reference patients (log-rank
test: p=0.01) had a renal or cardiovascular event (2 reference patients suffered a myocardial infarction, 1 stroke, 1
heart failure, 1 ESRD and 1 a doubling of serum creatinine
plus ESRD). Notably, there were no drug-related adverse
events.
These data confirm and extend evidence that in patients
with proteinuric nephropathies, dual RAS blockade is the
most efficient way to reduce proteinuria and therefore slow
or even halt the progression of chronic kidney disease (3,
© 2011 Società Italiana di Nefrologia - ISSN 1121-8428
275
Ruggenenti et al: The Remission Clinic
Fig. 1 - Change in estimated glomerular filtration
rate (ΔeGFR) over 6 years
of follow-up in 20 nondiabetic patients with chronic
proteinuric nephropathies
on angiotensin-converting
enzyme (ACE) inhibitor
(benazepril, 10 mg/day)
plus angiotensin II receptor
blocker (ARB) (valsartan,
80 mg/day) therapy and
in 20 reference patients
on ACE inhibitor therapy
alone (ramipril, 10 mg/day).
Physiological decline of
eGFR for patients over 40
years of age is -0.1 ml/min
per 1.73 m2 per month (17).
Data are medians with interquartile range.
17). Conversely, dual RAS blockade is not expected to confer any additional renoprotective effect as compared with
ACE inhibitors or ARB therapy alone and even compared
with non-RAS inhibitor therapy in patients without proteinuria (18). Analyses of the REIN study results found that
most of the protective effect of RAS inhibition against progressive renal function loss is seen in patients with heavy
proteinuria to start with (19). It progressively wanes at decreasing levels of proteinuria and tends to vanish when 24hour proteinuria ranges between 1 and 2 g (Fig. 2). At lower
levels of proteinuria, no specific protective effect of RAS inhibitor therapy against renal disease progression is expected. This is consistent with trials of ACE inhibitor therapy in
patients with chronic kidney disease, but cases with a 24hour urinary protein excretion rate lower than 1 g showed
no appreciable treatment effect in this population (20, 21).
Actually, patients with nonproteinuric renal disease are expected to have no specific advantages in term of nephroprotection from ACE inhibitor or ARB therapy and, at the
same time, are exposed to the risks of RAS inhibition such
as hyperkalemia and acute renal function deterioration (22),
events that may be particularly frequent in elderly subjects
and in patients with type 2 diabetes and concomitant kidney vascular disease (23). These risks are even increased
when RAS inhibition is maximized by ACE inhibition and
276
ARB combination therapy. Thus, safety concerns raised by
the results of the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET) (18)
were largely expected. This study assigned 25,620 patients
with established atherosclerotic vascular disease or diabetes with end-organ damage to the ACE inhibitor ramipril,
the ARB telmisartan, or a combination of the 2. Over 56
months, the incidence of cardiovascular events was similar
in the 3 treatment groups, as well as the incidence of ESRD
or doubling of serum creatinine. Indeed, renal events were
extremely rare in all groups, which reflected the remarkably
slow rate of renal function loss that, independent of treatment allocation, was close to that observed in the general
population as an effect of aging (24). This can be largely
explained by the fact that only 4% of patients had overt
proteinuria and, in turn, may also explain why RAS inhibitor therapy did not appear to affect renal outcomes in this
population. Conversely, the need for acute dialysis to treat
acute renal function deterioration and/or hyperkalemia was
more frequent in patients on dual RAS blockade than in
those on ACE inhibitor or ARB therapy alone. This conceivably reflected transient kidney hypoperfusion in patients
with excessive BP reduction, hypovolemia or ischemic
kidney disease that improved with treatment withdrawal.
Thus, it was a treatment-related adverse effect facilitated
© 2011 Società Italiana di Nefrologia - ISSN 1121-8428
JNEPHROL 2011; 24 ( 03 ) : 274-281
Fig. 2 - Rate of glomerular filtration rate (GFR)
decline in 352 patients
with nondiabetic proteinuric nephropathies included in the REIN trial
according to treatment
and range of 24-hour
proteinuria at baseline. The 2 equations
describe the curves interpolating the points
showing GFR decline
within each treatment
group
(solid
circles
for ramipril and empty
circles for non-RASinhibiting antihypertensive therapy) at different
ranges of proteinuria.
Dashed circles show the
estimated GFR declines
for patients with proteinuria <1 g per 24 hours.
RAS = renin-angiotensin
system.
by maximized RAS inhibition and could not be considered
as a renal outcome related to proteinuria or renal disease
progression (19).
The Remission Clinic approach
Experimental and clinical data converge to indicate that
optimal BP control and maximized RAS inhibition are
key components of nephroprotective strategy in patients
with proteinuric chronic nephropathies. Other tools are,
however, available to further decrease proteinuria and
improve renal outcomes in those patients with persistent
urinary protein loss. Indeed, evidence has been provided that hydroxymethylglutaryl-CoA reductase inhibitors
(statins) may reduce proteinuria regardless of their effect
on serum lipids (25), though their antiproteinuric effect
has been recently questioned (26, 27). Low salt intake,
smoking cessation and optimal metabolic control in diabetics represent other crucial tools to retard progression
of chronic nephropathies.
Analogous to cancer and AIDS therapy, where the integrated use of different treatments against the same
target, such as uncontrolled cell or viral replication, has
dramatically improved patients’ outcomes, experimental data suggest that combined therapies targeted to
proteinuria reduction may further retard renal disease
progression as compared with single treatments (10).
This formed the rationale for the establishment of a
multimodal intervention strategy, the “Remission Clinic”
program, using all available pharmacological tools and
lifestyle rules to reduce urinary proteins in patients with
chronic renal disease and heavy proteinuria despite ACE
inhibitor therapy (28).
Each step of the Remission Clinic protocol is implemented
according to a predefined sequence until 24-hour proteinuria is consistently lower than 0.3 g or the protocol has
to be stopped because of safety/tolerability reasons. The
first step consists in the administration of a fixed dosage
(5 mg/day) of ramipril or of an equivalent dosage of any
other ACE inhibitor. When tolerated, the dosage is uptitrated to full antihypertensive dosage, and thereafter a
fixed dosage (50 mg/day) of losartan or an equivalent
dosage of another ARB is added on and progressively
up-titrated to full antihypertensive dosage. Then patients
© 2011 Società Italiana di Nefrologia - ISSN 1121-8428
277
Ruggenenti et al: The Remission Clinic
are maintained on dual RAS blockade, with ramipril and
losartan doses progressively up-titrated to maximum tolerated dosages or with full remission of proteinuria (24hour urinary protein excretion <0.3 g) is achieved.
A statin is also prescribed independently from cholesterol
levels, to further reduce proteinuria (29) and limit the excess cardiovascular risk in this population. Patients are
recommended a low-sodium diet (30) with a controlled
(0.8 g/kg body weight per day) protein content and are
invited to refrain from smoking. Strict metabolic control
is recommended to patients with diabetes.
Adjustments of antihypertensive agents are allowed to
target BP ≤120/80 mm Hg without inducing symptomatic hypotension. Diastolic BP should not be reduced to
less than 60 mm Hg, to avoid an excess cardiovascular
risk possibly associated with target organ hypoperfusion. Thiazide (if serum creatinine ≤1.4 mg/dL) or loop
(if serum creatinine >1.4 mg/dL) diuretics are first-line
therapy to target BP, prevent hyperkalemia and/or control edema. Aldosterone antagonists may help to further
reduce urinary proteins (31, 32), but are associated with
an increased risk of life-threatening hyperkalemia, in particular in elderly patients and in those with diabetes and
more severe renal insufficiency (24), and thus these must
be used with caution and under close patient monitoring.
Alpha or beta-blockers (in case of an heart rate >60 bpm),
along with nondihydropyridine calcium channel blockers
(CCB) are second-line therapy (33). Dihydropyridine CCB
are used for safety reasons in those with BP >140/90 mm
Hg despite the other treatments, as evidence exists that
they may increase proteinuria and accelerate loss of renal
function. Minoxidil is considered as rescue therapy.
The Remission Clinic program has been applied since 1999
to all consecutive patients who were referred to the Bergamo Nephrological Outpatient Clinic because of chronic
renal disease and heavy proteinuria despite ACE inhibitor
therapy (28).
The Remission Clinic approach in day-by-day
clinical practice
To assess the safety/efficacy profile of the Remission
Clinic strategy, the rate of eGFR decline and the incidence of ESRD in a cohort of 56 patients with chronic
proteinuric nephropathies treated according to this approach were compared with outcomes of 56 matched
historical reference patients who had received ACE inhibitor therapy titrated to target BP (28). Over a median
follow-up of 4 years, the median monthly rate of eGFR
decline was significantly lower in the Remission Clinic
278
cohort (−0.17 vs. −0.56 ml/min per 1.73 m2; p<0.0001),
and ESRD events were significantly reduced (Fig. 3)
compared with the reference cohort. Follow-up BP, cholesterol and proteinuria were lower in Remission Clinic
patients than in reference subjects, and disease remission or regression was achieved in up to 50% of patients
who would have been otherwise expected to progress
rapidly to ESRD on conventional therapy. Proteinuria reduction independently predicted a lower rate of eGFR
decline and ESRD incidence, further highlighting its crucial pathogenic role in renal disease progression. Importantly, therapy was well tolerated, and no patient was
withdrawn because of hyperkalemia (28).
This was the first evidence that a multidrug treatment
titrated to urinary protein level can be safely and effectively applied to normalize proteinuria and to slow the
loss of renal function in day-by-day clinical practice.
Importantly, this study also pointed out the importance
of the early beginning of nephroprotective strategies.
Indeed, in patients with overt diabetic nephropathy, response to Remission Clinic therapy was incomplete, in
line with experimental evidence that ACE inhibitor treatment has limited efficacy in advanced phases of diabetic
nephropathy (34). A potential explanation is that renal
structural changes in these patients are so advanced
and diffuse that they prevent pharmacological treatments from achieving the desired effect on proteinuria
and disease progression. Experimental data show that
RAS inhibitor therapy may fully prevent renal lesions of
diabetes when treatment is started early, at induction
of diabetes, but is marginally affected when RAS inhibition is started when structural changes are already severe (34). The findings that in the Bergamo Nephrologic
Diabetes Complications Trial (BENEDICT), ACE inhibitor
therapy with trandolapril delayed the onset of microalbuminuria – taken as an early marker of renal disease and
a major risk factor for cardiovascular events – in patients
with type 2 diabetes, arterial hypertension and normoalbuminuria can be taken to suggest that early intervention, before overt nephropathy is established, is needed
in people with diabetes to maximize renoprotection (35).
The potential large-scale impact of the
Remission Clinic approach
Hopefully, extension of the Remission Clinic approach to
clinical practice will translate into a reduced incidence of
new patients requiring renal replacement therapy, with
an obvious economical benefit for health care systems
(http://clinicalweb.marionegri.it/remission/index.php).
© 2011 Società Italiana di Nefrologia - ISSN 1121-8428
JNEPHROL 2011; 24 ( 03 ) : 274-281
Fig. 3 - Cumulative incidence of end-stage renal
disease (ESRD) in 56 patients with chronic proteinuric
nephropathies
treated according to a multidrug treatment titrated to
urinary proteins (the Remission Clinic approach)
and 56 matched reference
patients receiving a conventional
angiotensinconverting enzyme (ACE)
inhibitor treatment titrated
to blood pressure. HR =
hazard ratio.
This would be of utmost importance especially for developing countries, where dialysis and kidney transplantation are available only for a small minority of patients in
need. In these countries, 10% to 20% of subjects are
estimated to be at risk of ESRD (36), and effective renoprotection could be life-saving in a large fraction of this
population. Availability of out-of-patent drugs in a fixed
combination (polypill) (37), in addition to enhancing patient compliance, would dramatically reduce treatment
costs, allowing implementation of cost-effective programs of prevention and treatment of renal disease, in
particular in limited resource settings.
Appendix
Financial support: None.
Conflict of interest statement: None.
Address for correspondence:
Piero Ruggenenti, MD
“Mario Negri” Institute for Pharmacological Research
Centro Anna Maria Astori
Science and Technology Park Kilometro Rosso
Via Stezzano, 87
IT-24126 Bergamo, Italy
[email protected]
References
1.
The remission clinic task force
2.
Coordination: Piero Ruggenenti, Andrea Remuzzi, Giuseppe
Remuzzi. Patient selection and care: Elena Perticucci, Roberto Trevisan, Alessandro Dodesini. Data handling and
monitoring: Vincenzo Gambara, Bogdan Ene-Iordache, Sergio Carminati, Nadia Rubis, Giulia Gherardi. Data analysis:
Annalisa Perna, Paolo Cravedi.
3.
4.
United States Renal Data System (USRDS), Annual Data Report 2007:92.
Abbate M, Zoja C, Remuzzi G. How does proteinuria
cause progressive renal damage? J Am Soc Nephrol.
2006;17:2974-2984.
Remuzzi G, Benigni A, Remuzzi A. Mechanisms of progression and regression of renal lesions of chronic nephropathies
and diabetes. J Clin Invest. 2006;116:288-296.
Ruggenenti P, Perna A, Mosconi L, Pisoni R, Remuzzi G;
Gruppo Italiano di Studi Epidemiol. Urinary protein excre-
© 2011 Società Italiana di Nefrologia - ISSN 1121-8428
279
Ruggenenti et al: The Remission Clinic
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
280
tion rate is the best independent predictor of ESRF in nondiabetic proteinuric chronic nephropathies. Gruppo Italiano
di Studi Epidemiologici in Nefrologia (GISEN). Kidney Int.
1998;53:1209-1216.
Macconi D, Abbate M, Morigi M, et al. Permselective dysfunction of podocyte-podocyte contact upon angiotensin II
unravels the molecular target for renoprotective intervention.
Am J Pathol. 2006;168:1073-1085.
Remuzzi G, Bertani T. Pathophysiology of progressive nephropathies. N Engl J Med. 1998;339:1448-1456.
Cravedi P, Ruggenenti P, Remuzzi G. Intensified inhibition of
renin-angiotensin system: a way to improve renal protection?
Curr Hypertens Rep. 2007;9:430-436.
Campbell RC, Ruggenenti P, Remuzzi G. Halting the progression of chronic nephropathy. J Am Soc Nephrol. 2002;13(Suppl 3):S190-S195.
The GISEN Group (Gruppo Italiano di Studi Epidemiologici in
Nefrologia). Randomised placebo-controlled trial of effect of
ramipril on decline in glomerular filtration rate and risk of terminal renal failure in proteinuric, non-diabetic nephropathy.
Lancet. 1997;349:1857-1863.
Zoja C, Corna D, Camozzi D, et al. How to fully protect the
kidney in a severe model of progressive nephropathy: a multidrug approach. J Am Soc Nephrol. 2002;13:2898-2908.
Cao Z, Bonnet F, Davis B, Allen TJ, Cooper ME. Additive hypotensive and anti-albuminuric effects of angiotensin-converting enzyme inhibition and angiotensin receptor antagonism in diabetic spontaneously hypertensive rats. Clin Sci
(Lond). 2001;100:591-599.
Russo D, Minutolo R, Pisani A, et al. Coadministration of
losartan and enalapril exerts additive antiproteinuric effect in
IgA nephropathy. Am J Kidney Dis. 2001;38:18-25.
Mogensen CE, Neldam S, Tikkanen I, et al. Randomised controlled trial of dual blockade of renin-angiotensin system in
patients with hypertension, microalbuminuria, and non-insulin
dependent diabetes: the candesartan and lisinopril microalbuminuria (CALM) study. BMJ. 2000;321:1440-1444.
Taal MW, Brenner BM. Combination ACEI and ARB therapy:
additional benefit in renoprotection? Curr Opin Nephrol Hypertens. 2002;11:377-381.
Catapano F, Chiodini P, De Nicola L, et al. Antiproteinuric response to dual blockade of the renin-angiotensin system in
primary glomerulonephritis: meta-analysis and metaregression. Am J Kidney Dis. 2008;52:475-485.
Campbell R, Sangalli F, Perticucci E, et al. Effects of combined ACE inhibitor and angiotensin II antagonist treatment
in human chronic nephropathies. Kidney Int. 2003;63:10941103.
Ruggenenti P, Schieppati A, Remuzzi G. Progression, remission, regression of chronic renal diseases. Lancet.
2001;357:1601-1608.
Mann JF, Schmieder RE, McQueen M, et al; ONTARGET
investigators. Renal outcomes with telmisartan, ramipril, or
both, in people at high vascular risk (the ONTARGET study):
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
a multicentre, randomised, double-blind, controlled trial.
Lancet. 2008;372:547-553.
Ruggenenti P, Remuzzi G. Proteinuria: Is the ONTARGET renal
substudy actually off target? Nat Rev Nephrol. 2009;5:436437.
Maschio G, Alberti D, Janin G, et al; The Angiotensin-Converting-Enzyme Inhibition in Progressive Renal Insufficiency
Study Group. Effect of the angiotensin-converting-enzyme
inhibitor benazepril on the progression of chronic renal insufficiency. N Engl J Med. 1996;334:939-945.
Locatelli F, Carbarns IR, Maschio G, et al; The AngiotensinConverting-Enzyme Inhibition in Progressive Renal Insufficiency Study Group. Long-term progression of chronic renal
insufficiency in the AIPRI Extension Study. Kidney Int Suppl.
1997;63:S63-S66.
Ruggenenti P, Cravedi P, Remuzzi G. Proteinuria: increased
angiotensin-receptor blocking is not the first option. Nat Rev
Nephrol. 2009;5:367-368.
Takaichi K, Takemoto F, Ubara Y, Mori Y. Analysis of factors
causing hyperkalemia. Intern Med. 2007;46:823-829.
Davies DF, Shock NW. Age changes in glomerular filtration
rate, effective renal plasma flow, and tubular excretory capacity in adult males. J Clin Invest. 1950;29:496-507.
Sandhu S, Wiebe N, Fried LF, Tonelli M. Statins for improving renal outcomes: a meta-analysis. J Am Soc Nephrol.
2006;17:2006-2016.
Conley J, Olafsson A, Djamali A. Do statins delay the incidence of ESRD in diabetic patients with moderate CKD? J
Nephrol. 2010;23:321-327.
Ruggenenti P, Perna A, Tonelli M, et al. Effects of add-on
fluvastatin therapy in patients with chronic proteinuric nephropathy on dual renin-angiotensin system blockade: The ESPLANADE Trial. Clin J Am Soc Nephrol. 2010;5:1928-1938.
Ruggenenti P, Perticucci E, Cravedi P, et al. Role of remission
clinics in the longitudinal treatment of CKD. J Am Soc Nephrol. 2008;19:1213-1224.
Bianchi S, Bigazzi R, Caiazza A, Campese VM. A controlled,
prospective study of the effects of atorvastatin on proteinuria and progression of kidney disease. Am J Kidney Dis.
2003;41:565-570.
Heeg JE, de Jong PE, van der Hem GK, de Zeeuw D. Efficacy and variability of the antiproteinuric effect of ACE inhibition by lisinopril. Kidney Int. 1989;36:272-279.
Bianchi S, Bigazzi R, Campese VM. Long-term effects of
spironolactone on proteinuria and kidney function in patients
with chronic kidney disease. Kidney Int. 2006;70:21162123.
Perico N, Benigni A, Remuzzi G. Present and future drug
treatments for chronic kidney diseases: evolving targets in
renoprotection. Nat Rev Drug Discov. 2008;7:936-953.
Egan CG, Pontremoli R. Role of the fixed-dose combination
lercanidipine-enalapril in renal protection. J Nephrol. 2011
Jan 24 (Epub ahead of print).
Perico N, Amuchastegui SC, Colosio V, Sonzogni G, Bertani
© 2011 Società Italiana di Nefrologia - ISSN 1121-8428
JNEPHROL 2011; 24 ( 03 ) : 274-281
T, Remuzzi G. Evidence that an angiotensin-converting enzyme inhibitor has a different effect on glomerular injury according to the different phase of the disease at which the
treatment is started. J Am Soc Nephrol. 1994;5:1139-1146.
35. Ruggenenti P, Fassi A, Ilieva AP, et al; Bergamo Nephrologic
Diabetes Complications Trial (BENEDICT) Investigators. Preventing microalbuminuria in type 2 diabetes. N Engl J Med.
2004;351:1941-1951.
36. Codreanu I, Perico N, Sharma SK, Schieppati A, Remuzzi G.
Prevention programmes of progressive renal disease in developing nations. Nephrology (Carlton). 2006;11:321-328.
37. Yusuf S, Pais P, Afzal R, et al; Indian Polycap Study (TIPS).
Effects of a polypill (Polycap) on risk factors in middle-aged
individuals without cardiovascular disease (TIPS): a phase
II, double-blind, randomised trial. Lancet. 2009;373:13411351.
Accepted: March 18, 2011
© 2011 Società Italiana di Nefrologia - ISSN 1121-8428
281