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Approccio clinico per prevenire la progressione della patologia renale

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Approccio clinico per prevenire la progressione della patologia renale

  1. 1. THOROUGH CRITICAL APPRAISAL JNEPHROL 2011; 24 ( 03 ) : 274-281 DOI:10.5301/JN.2011.7763The Remission Clinic approach to halt theprogression of kidney diseaseThe Remission Clinic Task Force* 1, 2, Clinical Re- 1 Mario Negri Institute for Pharmacological Research andsearch 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 increased274 © 2011 Società Italiana di Nefrologia - ISSN 1121-8428
  2. 2. JNEPHROL 2011; 24 ( 03 ) : 274-281glomerular plasma flow (4). Since the tone of afferent arteri- an ARB may inhibit the activity of angiotensin II producedoles 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 combinationremaining nephrons to minimize the functional consequenc- reduce proteinuria more effectively than the 2 agents alonees of their reduced number, but they are ultimately detri- (14). Of note, a meta-analysis of 425 patients with chronicmental. Indeed, the high intraglomerular capillary pressure proteinuric nephropathies found that the reduction achievedenlarges the radii of glomerular pores and, along with podo- by dual RAS inhibition exceeded the reduction achieved bycyte 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 moreproteins in the lumen of the tubules eventually results in a consistent antihypertensive effect than single ACE inhibitornephritogenic effect, through a direct tubular toxicity and a or ARB therapy, which did not allow the studies to addresssecondary process of tubular epithelial endocytosis (2, 6). the issue of whether the superior antiproteinuric effect ofOn 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 dosespressure and improve the selectivity of the glomerular bar- of the 2 drugs used in combination in a cross-over study inrier, an effect that translates into a reduction of proteinuria patients with nondiabetic chronic kidney disease (16). Withand 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 withthat, 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 RASinhibitor 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). Onropathies (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 valsartanrate with the ACE inhibitor ramipril was the only time-de- 80 mg/day) and prospectively followed up. Their outcomependent covariate that predicted a lower rate of glomerular at 6 years was compared with that of matched referencefiltration rate (GFR) decline and progression to ESRD in pa- patients maintained on single-drug RAS blockade with a fulltients 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 inHence, 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 eGFRchronic 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, 1The combination of an ACE inhibitor and angiotensin II re- heart failure, 1 ESRD and 1 a doubling of serum creatinineceptor blockers (ARBs) has been suggested as a way to plus ESRD). Notably, there were no drug-related adversemaximize 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 patientsat the receptor level. Moreover, an ACE inhibitor may pre- with proteinuric nephropathies, dual RAS blockade is thevent the compensatory increase in angiotensin II synthesis most efficient way to reduce proteinuria and therefore slowfrequently 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. 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 byfer 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 patientsnuria (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 56proteinuria to start with (19). It progressively wanes at de- months, the incidence of cardiovascular events was similarcreasing levels of proteinuria and tends to vanish when 24- in the 3 treatment groups, as well as the incidence of ESRDhour proteinuria ranges between 1 and 2 g (Fig. 2). At lower or doubling of serum creatinine. Indeed, renal events werelevels of proteinuria, no specific protective effect of RAS in- extremely rare in all groups, which reflected the remarkablyhibitor 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 generalpatients with chronic kidney disease, but cases with a 24- population as an effect of aging (24). This can be largelyhour urinary protein excretion rate lower than 1 g showed explained by the fact that only 4% of patients had overtno 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 thispected to have no specific advantages in term of nephro- population. Conversely, the need for acute dialysis to treatprotection from ACE inhibitor or ARB therapy and, at the acute renal function deterioration and/or hyperkalemia wassame time, are exposed to the risks of RAS inhibition such more frequent in patients on dual RAS blockade than inas 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 patientsand in patients with type 2 diabetes and concomitant kid- with excessive BP reduction, hypovolemia or ischemicney 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 facilitated276 © 2011 Società Italiana di Nefrologia - ISSN 1121-8428
  4. 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, hasas 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 aExperimental 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 andkey components of nephroprotective strategy in patients lifestyle rules to reduce urinary proteins in patients withwith proteinuric chronic nephropathies. Other tools are, chronic renal disease and heavy proteinuria despite ACEhowever, 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 implementedurinary 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. Theon serum lipids (25), though their antiproteinuric effect first step consists in the administration of a fixed dosagehas been recently questioned (26, 27). Low salt intake, (5 mg/day) of ramipril or of an equivalent dosage of anysmoking 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 aof chronic nephropathies. fixed dosage (50 mg/day) of losartan or an equivalentAnalogous to cancer and AIDS therapy, where the in- dosage of another ARB is added on and progressivelytegrated 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. 5. Ruggenenti et al: The Remission Clinicare 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 ClinicA 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 patientscess cardiovascular risk in this population. Patients are who would have been otherwise expected to progressrecommended 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 eGFRinvited 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 wastarget 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 treatmentless 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 thesion. 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 importancetherapy 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, inan 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 diabeticmore severe renal insufficiency (24), and thus these must nephropathy (34). A potential explanation is that renalbe used with caution and under close patient monitoring. structural changes in these patients are so advancedAlpha 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 thatare used for safety reasons in those with BP >140/90 mm RAS inhibitor therapy may fully prevent renal lesions ofHg despite the other treatments, as evidence exists that diabetes when treatment is started early, at inductionthey 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 Nephrologicto all consecutive patients who were referred to the Ber- Diabetes Complications Trial (BENEDICT), ACE inhibitorgamo 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 andtherapy (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 RemissionClinic strategy, the rate of eGFR decline and the inci- The potential large-scale impact of thedence of ESRD in a cohort of 56 patients with chronic Remission Clinic approachproteinuric nephropathies treated according to this ap-proach were compared with outcomes of 56 matched Hopefully, extension of the Remission Clinic approach tohistorical reference patients who had received ACE in- clinical practice will translate into a reduced incidence ofhibitor therapy titrated to target BP (28). Over a median new patients requiring renal replacement therapy, withfollow-up of 4 years, the median monthly rate of eGFR an obvious economical benefit for health care systemsdecline was significantly lower in the Remission Clinic (http://clinicalweb.marionegri.it/remission/index.php).278 © 2011 Società Italiana di Nefrologia - ISSN 1121-8428
  6. 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 inneed. In these countries, 10% to 20% of subjects areestimated 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, MDcombination (polypill) (37), in addition to enhancing pa- “Mario Negri” Institute for Pharmacological Research Centro Anna Maria Astoritient compliance, would dramatically reduce treatment Science and Technology Park Kilometro Rossocosts, allowing implementation of cost-effective pro- Via Stezzano, 87grams of prevention and treatment of renal disease, in IT-24126 Bergamo, Italyparticular in limited resource settings. manuelap@marionegri.it AppendIx references 1. United States Renal Data System (USRDS), Annual Data Re-The remission clinic task force port 2007:92. 2. Abbate M, Zoja C, Remuzzi G. How does proteinuria cause progressive renal damage? J Am Soc Nephrol.Coordination: Piero Ruggenenti, Andrea Remuzzi, Giuseppe 2006;17:2974-2984.Remuzzi. Patient selection and care: Elena Perticucci, Ro- 3. Remuzzi G, Benigni A, Remuzzi A. Mechanisms of progres-berto Trevisan, Alessandro Dodesini. Data handling and sion and regression of renal lesions of chronic nephropathiesmonitoring: Vincenzo Gambara, Bogdan Ene-Iordache, Ser- and diabetes. J Clin Invest. 2006;116:288-296.gio Carminati, Nadia Rubis, Giulia Gherardi. Data analysis: 4. Ruggenenti P, Perna A, Mosconi L, Pisoni R, Remuzzi G;Annalisa Perna, Paolo Cravedi. Gruppo Italiano di Studi Epidemiol. Urinary protein excre- © 2011 Società Italiana di Nefrologia - ISSN 1121-8428 279
  7. 7. Ruggenenti et al: The Remission Clinic tion rate is the best independent predictor of ESRF in non- a multicentre, randomised, double-blind, controlled trial. diabetic proteinuric chronic nephropathies. Gruppo Italiano Lancet. 2008;372:547-553. di Studi Epidemiologici in Nefrologia (GISEN). Kidney Int. 19. Ruggenenti P, Remuzzi G. Proteinuria: Is the ONTARGET renal 1998;53:1209-1216. substudy actually off target? Nat Rev Nephrol. 2009;5:436-5. Macconi D, Abbate M, Morigi M, et al. Permselective dys- 437. function of podocyte-podocyte contact upon angiotensin II 20. Maschio G, Alberti D, Janin G, et al; The Angiotensin-Con- unravels the molecular target for renoprotective intervention. verting-Enzyme Inhibition in Progressive Renal Insufficiency Am J Pathol. 2006;168:1073-1085. Study Group. Effect of the angiotensin-converting-enzyme6. Remuzzi G, Bertani T. Pathophysiology of progressive neph- inhibitor benazepril on the progression of chronic renal insuf- ropathies. 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Takaichi K, Takemoto F, Ubara Y, Mori Y. Analysis of factors minal renal failure in proteinuric, non-diabetic nephropathy. causing hyperkalemia. Intern Med. 2007;46:823-829. Lancet. 1997;349:1857-1863. 24. Davies DF, Shock NW. Age changes in glomerular filtration10. Zoja C, Corna D, Camozzi D, et al. How to fully protect the rate, effective renal plasma flow, and tubular excretory ca- kidney in a severe model of progressive nephropathy: a mul- pacity in adult males. J Clin Invest. 1950;29:496-507. tidrug approach. J Am Soc Nephrol. 2002;13:2898-2908. 25. Sandhu S, Wiebe N, Fried LF, Tonelli M. Statins for improv-11. Cao Z, Bonnet F, Davis B, Allen TJ, Cooper ME. Additive hy- ing renal outcomes: a meta-analysis. J Am Soc Nephrol. potensive and anti-albuminuric effects of angiotensin-con- 2006;17:2006-2016. verting enzyme inhibition and angiotensin receptor antago- 26. Conley J, Olafsson A, Djamali A. Do statins delay the inci- nism in diabetic spontaneously hypertensive rats. 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Effects of com- spironolactone on proteinuria and kidney function in patients bined ACE inhibitor and angiotensin II antagonist treatment with chronic kidney disease. Kidney Int. 2006;70:2116- in human chronic nephropathies. Kidney Int. 2003;63:1094- 2123. 1103. 32. Perico N, Benigni A, Remuzzi G. Present and future drug17. Ruggenenti P, Schieppati A, Remuzzi G. Progression, re- treatments for chronic kidney diseases: evolving targets in mission, regression of chronic renal diseases. Lancet. renoprotection. Nat Rev Drug Discov. 2008;7:936-953. 2001;357:1601-1608. 33. Egan CG, Pontremoli R. Role of the fixed-dose combination18. Mann JF, Schmieder RE, McQueen M, et al; ONTARGET lercanidipine-enalapril in renal protection. J Nephrol. 2011 investigators. Renal outcomes with telmisartan, ramipril, or Jan 24 (Epub ahead of print). both, in people at high vascular risk (the ONTARGET study): 34. Perico N, Amuchastegui SC, Colosio V, Sonzogni G, Bertani280 © 2011 Società Italiana di Nefrologia - ISSN 1121-8428
  8. 8. JNEPHROL 2011; 24 ( 03 ) : 274-281 T, Remuzzi G. Evidence that an angiotensin-converting en- Prevention programmes of progressive renal disease in de- zyme inhibitor has a different effect on glomerular injury ac- veloping nations. Nephrology (Carlton). 2006;11:321-328. cording to the different phase of the disease at which the 37. Yusuf S, Pais P, Afzal R, et al; Indian Polycap Study (TIPS). treatment is started. J Am Soc Nephrol. 1994;5:1139-1146. Effects of a polypill (Polycap) on risk factors in middle-aged35. Ruggenenti P, Fassi A, Ilieva AP, et al; Bergamo Nephrologic individuals without cardiovascular disease (TIPS): a phase Diabetes Complications Trial (BENEDICT) Investigators. Pre- II, double-blind, randomised trial. Lancet. 2009;373:1341- venting microalbuminuria in type 2 diabetes. N Engl J Med. 1351. 2004;351:1941-1951.36. Codreanu I, Perico N, Sharma SK, Schieppati A, Remuzzi G. Accepted: March 18, 2011 © 2011 Società Italiana di Nefrologia - ISSN 1121-8428 281

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