1. THOROUGH CRITICAL APPRAISAL JNEPHROL 2011; 24 ( 03 ) : 274-281
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 Re- 1
Mario Negri Institute for Pharmacological Research and
search Center “Aldo e Cele Daccò” 1 Unit of Nephrology, Bergamo - Italy
2
Azienda Ospedaliera «Ospedali Riuniti di Bergamo»,
* See “Appendix” Bergamo - Italy
AbstrAct approach might be safely applied in day-by-day hos-
pital practice. Effective prevention of ESRD would re-
Randomized multicenter studies in diabetic and nondi- duce costs of renal replacement therapy by dialysis or
abetic patients with chronic proteinuric nephropathies transplantation and would be life-saving where these
have clearly demonstrated that renin-angiotensin sys- are not available for all patients in need.
tem (RAS) inhibitors, such as angiotensin-converting
enzyme (ACE) inhibitors and angiotensin II receptor Key words: ACE inhibitor, Angiotensin II receptor
blockers (ARBs) used alone or in combination, effec- blocker, Blood pressure, Chronic kidney disease, Pro-
tively retard renal disease progression. Proteinuria re- teinuria, Remission Clinic
duction, 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) prog- IntroductIon
ress to end-stage renal disease (ESRD). This high-
lights the importance of innovative therapies to halt
End-stage renal disease (ESRD) is a major public health
or revert CKD progression in those at risk. Along this
problem. A forecast analysis based on data from the US
line, a multimodal strategy (Remission Clinic) target-
ing urinary proteins by dual RAS inhibition with ACE Renal Data System and Medicare predicts that by the year
inhibitors and ARBs up-titrated to maximum tolerated 2020, the total number of patients on renal replacement
doses, by intensified blood pressure control, amelio- therapy will almost double, approximating 785,000, which
ration of dyslipidemia by statins, smoking cessation is expected to significantly increase public expenditure for
and healthy lifestyle implementation was safely and dialysis (1). Since most of the current ESRD patients pro-
effectively applied at our outpatient clinic to normalize gressively lost their kidney function over years, retarding or
urinary proteins and prevent renal function loss in pa- even halting the progression of chronic nephropathies is in-
tients otherwise predicted to rapidly progress to ESRD strumental in substantially decreasing the need and costs
because of nephrotic-range proteinuria refractory to for renal replacement therapy.
standard antihypertensive dosages of an ACE inhibi- Many studies in animals and humans suggest that progres-
tor. This approach achieved remission or regression of
sion of renal damage is independent from the initial disease
proteinuria and stabilized kidney function in most cas-
and follows pathogenic mechanisms that are common
es, and almost fully prevented progression to ESRD.
among different nephropathies (2, 3). After an initial renal
Provided patients are closely monitored and treatment
is cautiously up-titrated according to tolerability, this
injury, remnant intact nephrons undergo hypertrophy with
concomitant lowering of arteriolar resistance and increased
274 © 2011 Società Italiana di Nefrologia - ISSN 1121-8428

2. JNEPHROL 2011; 24 ( 03 ) : 274-281
glomerular plasma flow (4). Since the tone of afferent arteri- an ARB may inhibit the activity of angiotensin II produced
oles drops more than that of efferent ones, hydraulic pres- via ACE-independent pathways.
sure of glomerular capillaries rises, increasing the filtrate per Animal (10, 11) and human (12, 13) studies have consis-
nephron. These changes enhance the filtration capacity of tently found that ACE inhibitors and ARBs in combination
remaining nephrons to minimize the functional consequenc- reduce proteinuria more effectively than the 2 agents alone
es of their reduced number, but they are ultimately detri- (14). Of note, a meta-analysis of 425 patients with chronic
mental. Indeed, the high intraglomerular capillary pressure proteinuric nephropathies found that the reduction achieved
enlarges the radii of glomerular pores and, along with podo- by dual RAS inhibition exceeded the reduction achieved by
cyte cytoskeleton rearrangement secondary to increased ACE inhibitors or ARB therapy alone, by 60% and 54%, re-
angiotensin II levels, impairs the size selectivity of the mem- spectively (15).
brane and induces protein ultrafiltration (4, 5). An excess of In these studies, however, dual RAS blockade had a more
proteins in the lumen of the tubules eventually results in a consistent antihypertensive effect than single ACE inhibitor
nephritogenic effect, through a direct tubular toxicity and a or ARB therapy, which did not allow the studies to address
secondary process of tubular epithelial endocytosis (2, 6). the issue of whether the superior antiproteinuric effect of
On the basis of this background, reduction of protein traffic, combined therapy really reflected more effective RAS block-
along with strict blood pressure (BP) control, should play a ade or, rather, was just a function of more BP reduction.
central role in intervention strategies aimed to prevent or re- To address this issue, the antiproteinuric effect of fixed dos-
vert renal disease progression. In animals, renin-angiotensin es of the ACE inhibitor benazepril and of the ARB valsar-
system (RAS) blockers reduce intraglomerular hydraulic tan given alone were compared with that of halved doses
pressure and improve the selectivity of the glomerular bar- of the 2 drugs used in combination in a cross-over study in
rier, an effect that translates into a reduction of proteinuria patients with nondiabetic chronic kidney disease (16). With
and prevention of glomerulosclerosis and kidney scarring this approach, BP reduction was similar in the 3 treatment
(3). Prospective randomized placebo-controlled trials found groups, but proteinuria reduction was more consistent with
that, at comparable BP control, angiotensin-converting en- dual therapy. This provided evidence that the superior an-
zyme (ACE) inhibitors (7) are more effective than non-ACE tiproteinuric effect of dual compared with single-drug RAS
inhibitor therapy in limiting progression to ESRD in diabetic blockade was not explained by a higher antihypertensive ef-
and nondiabetic patients with chronic proteinuric neph- fect, but by a more effective inhibition of the RAS (16). On
ropathies (8). Notably, the Ramipril Efficacy In Nephropathy the basis of these results, patients were maintained on dual
(REIN) trial found that reduction in urinary protein excretion RAS inhibitor therapy (benazepril 10 mg/day plus valsartan
rate with the ACE inhibitor ramipril was the only time-de- 80 mg/day) and prospectively followed up. Their outcome
pendent covariate that predicted a lower rate of glomerular at 6 years was compared with that of matched reference
filtration rate (GFR) decline and progression to ESRD in pa- patients maintained on single-drug RAS blockade with a full
tients with nondiabetic chronic nephropathies, clearly indi- dose of an ACE inhibitor (ramipril 5 mg/day).
cating that reduction of protein traffic is renoprotective (9). Decline of estimated GFR (eGFR) was significantly lower in
Hence, minimizing urinary protein excretion should repre- patients compared with reference patients (Fig. 1), and pro-
sent the primary goal to retard/stabilize renal progression of teinuria reduction independently predicted the rate of eGFR
chronic renal disease. decline. In patients, GFR (measured by iohexol clearance),
filtration fraction, renal vascular resistances and urinary pro-
duAl rAs InhIbItIon: A strAtegy to tein to creatinine ratio decreased at 1 year, were stable up
mAxImIze AntIproteInurIc effect of Ace to 6 years and recovered to baseline after treatment with-
InhIbItors And AngIotensIn II receptor drawal. No patient versus 6 reference patients (log-rank
blockers test: p=0.01) had a renal or cardiovascular event (2 refer-
ence patients suffered a myocardial infarction, 1 stroke, 1
The combination of an ACE inhibitor and angiotensin II re- heart failure, 1 ESRD and 1 a doubling of serum creatinine
ceptor blockers (ARBs) has been suggested as a way to plus ESRD). Notably, there were no drug-related adverse
maximize RAS inhibition by affecting both the bioavailability events.
of angiotensin II through ACE inhibition and also its activity These data confirm and extend evidence that in patients
at the receptor level. Moreover, an ACE inhibitor may pre- with proteinuric nephropathies, dual RAS blockade is the
vent the compensatory increase in angiotensin II synthesis most efficient way to reduce proteinuria and therefore slow
frequently observed during ARB therapy. On the other hand, or even halt the progression of chronic kidney disease (3,
© 2011 Società Italiana di Nefrologia - ISSN 1121-8428 275

3. Ruggenenti et al: The Remission Clinic
Fig. 1 - Change in esti-
mated glomerular filtration
rate (ΔeGFR) over 6 years
of follow-up in 20 nondia-
betic 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 in-
terquartile range.
17). Conversely, dual RAS blockade is not expected to con- ARB combination therapy. Thus, safety concerns raised by
fer any additional renoprotective effect as compared with the results of the Ongoing Telmisartan Alone and in Combi-
ACE inhibitors or ARB therapy alone and even compared nation with Ramipril Global Endpoint Trial (ONTARGET) (18)
with non-RAS inhibitor therapy in patients without protei- were largely expected. This study assigned 25,620 patients
nuria (18). Analyses of the REIN study results found that with established atherosclerotic vascular disease or diabe-
most of the protective effect of RAS inhibition against pro- tes with end-organ damage to the ACE inhibitor ramipril,
gressive renal function loss is seen in patients with heavy the ARB telmisartan, or a combination of the 2. Over 56
proteinuria to start with (19). It progressively wanes at de- months, the incidence of cardiovascular events was similar
creasing levels of proteinuria and tends to vanish when 24- in the 3 treatment groups, as well as the incidence of ESRD
hour proteinuria ranges between 1 and 2 g (Fig. 2). At lower or doubling of serum creatinine. Indeed, renal events were
levels of proteinuria, no specific protective effect of RAS in- extremely rare in all groups, which reflected the remarkably
hibitor therapy against renal disease progression is expect- slow rate of renal function loss that, independent of treat-
ed. This is consistent with trials of ACE inhibitor therapy in ment allocation, was close to that observed in the general
patients with chronic kidney disease, but cases with a 24- population as an effect of aging (24). This can be largely
hour urinary protein excretion rate lower than 1 g showed explained by the fact that only 4% of patients had overt
no appreciable treatment effect in this population (20, 21). proteinuria and, in turn, may also explain why RAS inhibi-
Actually, patients with nonproteinuric renal disease are ex- tor therapy did not appear to affect renal outcomes in this
pected to have no specific advantages in term of nephro- population. Conversely, the need for acute dialysis to treat
protection from ACE inhibitor or ARB therapy and, at the acute renal function deterioration and/or hyperkalemia was
same time, are exposed to the risks of RAS inhibition such more frequent in patients on dual RAS blockade than in
as hyperkalemia and acute renal function deterioration (22), those on ACE inhibitor or ARB therapy alone. This conceiv-
events that may be particularly frequent in elderly subjects ably reflected transient kidney hypoperfusion in patients
and in patients with type 2 diabetes and concomitant kid- with excessive BP reduction, hypovolemia or ischemic
ney vascular disease (23). These risks are even increased kidney disease that improved with treatment withdrawal.
when RAS inhibition is maximized by ACE inhibition and Thus, it was a treatment-related adverse effect facilitated
276 © 2011 Società Italiana di Nefrologia - ISSN 1121-8428

4. JNEPHROL 2011; 24 ( 03 ) : 274-281
Fig. 2 - Rate of glomeru-
lar filtration rate (GFR)
decline in 352 patients
with nondiabetic protei-
nuric nephropathies in-
cluded in the REIN trial
according to treatment
and range of 24-hour
proteinuria at base-
line. The 2 equations
describe the curves in-
terpolating the points
showing GFR decline
within each treatment
group (solid circles
for ramipril and empty
circles for non-RAS-
inhibiting antihyperten-
sive therapy) at different
ranges of proteinuria.
Dashed circles show the
estimated GFR declines
for patients with protei-
nuria <1 g per 24 hours.
RAS = renin-angiotensin
system.
by maximized RAS inhibition and could not be considered target, such as uncontrolled cell or viral replication, has
as a renal outcome related to proteinuria or renal disease dramatically improved patients’ outcomes, experimen-
progression (19). tal data suggest that combined therapies targeted to
proteinuria reduction may further retard renal disease
the remIssIon clInIc ApproAch progression as compared with single treatments (10).
This formed the rationale for the establishment of a
Experimental and clinical data converge to indicate that multimodal intervention strategy, the “Remission Clinic”
optimal BP control and maximized RAS inhibition are program, using all available pharmacological tools and
key components of nephroprotective strategy in patients lifestyle rules to reduce urinary proteins in patients with
with proteinuric chronic nephropathies. Other tools are, chronic renal disease and heavy proteinuria despite ACE
however, available to further decrease proteinuria and inhibitor therapy (28).
improve renal outcomes in those patients with persistent Each step of the Remission Clinic protocol is implemented
urinary protein loss. Indeed, evidence has been provid- according to a predefined sequence until 24-hour protei-
ed that hydroxymethylglutaryl-CoA reductase inhibitors nuria is consistently lower than 0.3 g or the protocol has
(statins) may reduce proteinuria regardless of their effect to be stopped because of safety/tolerability reasons. The
on serum lipids (25), though their antiproteinuric effect first step consists in the administration of a fixed dosage
has been recently questioned (26, 27). Low salt intake, (5 mg/day) of ramipril or of an equivalent dosage of any
smoking cessation and optimal metabolic control in dia- other ACE inhibitor. When tolerated, the dosage is up-
betics represent other crucial tools to retard progression titrated to full antihypertensive dosage, and thereafter a
of chronic nephropathies. fixed dosage (50 mg/day) of losartan or an equivalent
Analogous to cancer and AIDS therapy, where the in- dosage of another ARB is added on and progressively
tegrated use of different treatments against the same up-titrated to full antihypertensive dosage. Then patients
© 2011 Società Italiana di Nefrologia - ISSN 1121-8428 277

5. Ruggenenti et al: The Remission Clinic
are maintained on dual RAS blockade, with ramipril and cohort (−0.17 vs. −0.56 ml/min per 1.73 m2; p<0.0001),
losartan doses progressively up-titrated to maximum tol- and ESRD events were significantly reduced (Fig. 3)
erated dosages or with full remission of proteinuria (24- compared with the reference cohort. Follow-up BP, cho-
hour urinary protein excretion <0.3 g) is achieved. lesterol and proteinuria were lower in Remission Clinic
A statin is also prescribed independently from cholesterol patients than in reference subjects, and disease remis-
levels, to further reduce proteinuria (29) and limit the ex- sion or regression was achieved in up to 50% of patients
cess cardiovascular risk in this population. Patients are who would have been otherwise expected to progress
recommended a low-sodium diet (30) with a controlled rapidly to ESRD on conventional therapy. Proteinuria re-
(0.8 g/kg body weight per day) protein content and are duction independently predicted a lower rate of eGFR
invited to refrain from smoking. Strict metabolic control decline and ESRD incidence, further highlighting its cru-
is recommended to patients with diabetes. cial pathogenic role in renal disease progression. Impor-
Adjustments of antihypertensive agents are allowed to tantly, therapy was well tolerated, and no patient was
target BP ≤120/80 mm Hg without inducing symptom- withdrawn because of hyperkalemia (28).
atic hypotension. Diastolic BP should not be reduced to This was the first evidence that a multidrug treatment
less than 60 mm Hg, to avoid an excess cardiovascular titrated to urinary protein level can be safely and effec-
risk possibly associated with target organ hypoperfu- tively applied to normalize proteinuria and to slow the
sion. Thiazide (if serum creatinine ≤1.4 mg/dL) or loop loss of renal function in day-by-day clinical practice.
(if serum creatinine >1.4 mg/dL) diuretics are first-line Importantly, this study also pointed out the importance
therapy to target BP, prevent hyperkalemia and/or con- of the early beginning of nephroprotective strategies.
trol edema. Aldosterone antagonists may help to further Indeed, in patients with overt diabetic nephropathy, re-
reduce urinary proteins (31, 32), but are associated with sponse to Remission Clinic therapy was incomplete, in
an increased risk of life-threatening hyperkalemia, in par- line with experimental evidence that ACE inhibitor treat-
ticular in elderly patients and in those with diabetes and ment has limited efficacy in advanced phases of diabetic
more severe renal insufficiency (24), and thus these must nephropathy (34). A potential explanation is that renal
be used with caution and under close patient monitoring. structural changes in these patients are so advanced
Alpha or beta-blockers (in case of an heart rate >60 bpm), and diffuse that they prevent pharmacological treat-
along with nondihydropyridine calcium channel blockers ments from achieving the desired effect on proteinuria
(CCB) are second-line therapy (33). Dihydropyridine CCB and disease progression. Experimental data show that
are used for safety reasons in those with BP >140/90 mm RAS inhibitor therapy may fully prevent renal lesions of
Hg despite the other treatments, as evidence exists that diabetes when treatment is started early, at induction
they may increase proteinuria and accelerate loss of renal of diabetes, but is marginally affected when RAS inhibi-
function. Minoxidil is considered as rescue therapy. tion is started when structural changes are already se-
The Remission Clinic program has been applied since 1999 vere (34). The findings that in the Bergamo Nephrologic
to all consecutive patients who were referred to the Ber- Diabetes Complications Trial (BENEDICT), ACE inhibitor
gamo Nephrological Outpatient Clinic because of chronic therapy with trandolapril delayed the onset of microalbu-
renal disease and heavy proteinuria despite ACE inhibitor minuria – taken as an early marker of renal disease and
therapy (28). a major risk factor for cardiovascular events – in patients
with type 2 diabetes, arterial hypertension and normoal-
The Remission Clinic approach in day-by-day buminuria can be taken to suggest that early interven-
clinical practice tion, before overt nephropathy is established, is needed
in people with diabetes to maximize renoprotection (35).
To assess the safety/efficacy profile of the Remission
Clinic strategy, the rate of eGFR decline and the inci- The potential large-scale impact of the
dence of ESRD in a cohort of 56 patients with chronic Remission Clinic approach
proteinuric nephropathies treated according to this ap-
proach were compared with outcomes of 56 matched Hopefully, extension of the Remission Clinic approach to
historical reference patients who had received ACE in- clinical practice will translate into a reduced incidence of
hibitor therapy titrated to target BP (28). Over a median new patients requiring renal replacement therapy, with
follow-up of 4 years, the median monthly rate of eGFR an obvious economical benefit for health care systems
decline was significantly lower in the Remission Clinic (http://clinicalweb.marionegri.it/remission/index.php).
278 © 2011 Società Italiana di Nefrologia - ISSN 1121-8428

6. JNEPHROL 2011; 24 ( 03 ) : 274-281
Fig. 3 - Cumulative inci-
dence of end-stage renal
disease (ESRD) in 56 pa-
tients with chronic pro-
teinuric nephropathies
treated according to a mul-
tidrug treatment titrated to
urinary proteins (the Re-
mission Clinic approach)
and 56 matched reference
patients receiving a con-
ventional angiotensin-
converting enzyme (ACE)
inhibitor treatment titrated
to blood pressure. HR =
hazard ratio.
This would be of utmost importance especially for devel- Financial support: None.
oping countries, where dialysis and kidney transplanta- Conflict of interest statement: None.
tion 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 reno-
protection could be life-saving in a large fraction of this Address for correspondence:
population. Availability of out-of-patent drugs in a fixed Piero Ruggenenti, MD
combination (polypill) (37), in addition to enhancing pa- “Mario Negri” Institute for Pharmacological Research
Centro Anna Maria Astori
tient compliance, would dramatically reduce treatment
Science and Technology Park Kilometro Rosso
costs, allowing implementation of cost-effective pro- Via Stezzano, 87
grams of prevention and treatment of renal disease, in IT-24126 Bergamo, Italy
particular in limited resource settings. manuelap@marionegri.it
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Annalisa Perna, Paolo Cravedi. Gruppo Italiano di Studi Epidemiol. Urinary protein excre-
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© 2011 Società Italiana di Nefrologia - ISSN 1121-8428 281