SEVERE PASSIVE HEYMANN NEPHRITIS (UNINEPHRECTOMY) 800 Urinary protein excretion Treatment for 10 months (start treatment at 2 months) 600 (mg/day) * 400 200 0 80 Glomerulosclerosis 60 (%) 40 * * 20 0 Lisinopril Lis + AII-RA Control Vehicle 38 Zoja et al., J Am Soc Nephrol, 2002
A MATCHED-COHORT STUDY OF SINGLE OR DUAL RAS INHIBITION IN PATIENTS WITH NON-DIABETIC CHRONIC NEPHROPATHIES Ramipril ( n = 20) Benazepril + Valsartan ( n = 20) Proteinuria 3 g/24 hours 2 * p < 0.01 1 * * * * 0 0 6 12 18 24 months Ruggenenti et al, J Nephrol , in press 39
A CASE-CONTROL STUDY OF SINGLE OR DUAL RAS INHIBITION IN PATIENTS WITH NON-DIABETIC CHRONIC NEPHROPATHIES Ramipril ( n = 20) Benazepril + Valsartan ( n = 20) Proteinuria GFR 3 70 g/24 hours 2 60 ml/min * p < 0.01 1 50 * * * * 40 0 0 6 12 18 24 0 6 12 18 24 months months 40 Ruggenenti et al, J Nephrol , in press
> 20,000 patients (16,000 non diabetics) for 56 months Although combination therapy reduces proteinuria to a greater extent than monotherapy, overall it worsens major renal outcomes 41
The ONTARGET study Renal outcomes analysis - 83 % of patients with normoalbuminuria Dilution effect - 4% with macroalbuminuria - More BP reduction on combined therapy Functional GFR - No pre-screening for ischemic kidney diseases - Secondary outcome analysis Competitive risk Mann et al., Lancet, 2008 42
REIN 1.2 1.0 Non-RAS inhibiting therapy y=-0.059+0.224*X-0.010*X 2 Mean rate of GFR decline 0.8 (ml/min/month) 0.6 0.4 Ramipril 0.2 y=0.0142+0.162*X 2 -0.012*X 2 0 -0.2 0-<1 1-2 2-3 3-4.5 > 4.5 Base-line urinary protein excretion (g/24 hours) 43
44 44
ONTARGET: components of the composite renal outcome P Ramipril Telmisartan Combined (combined vs (n = 8,576) (n = 8,542) (n = 8,502) ramipril) All deaths 1,014 993 1,065 0.14 Doubling s.creat. 140 155 166 0.11 ESKD 33 31 34 0.85 Acute dialysis 13 20 28 0.02 * Duration < 2 months 45
EFFECT OF ONE-MONTH ADD-ON VALSARTAN THERAPY IN 196 PATIENTS WITH CHRONIC PROTEINURIC NEPHROPATHY ON BACKGROUND BENAZEPRIL THERAPY: THE ESPLANADE TRIAL Run-In Phase 24h Total LDL Proteinuria Cholesterol Cholesterol 0 Patient Characteristics 0 -10 -4 (mg/dl) - CKD Changes vs Inclusion -8 -20 - Proteinuria >1 g/24h - BP >140/90 mmHg -12 -30 (percent) (or less with antihypertensive therapy -16 p=0.022 p=0.002 - LDL Cholesterol < 190 mg/dl -40 - CrCl > 20 ml/min/1.73m 2 -50 -60 -70 p<0.001 -80 Benazepril (20 mg/day) Benazepril+Valsartan (20 + 160 mg/d) 46 Ruggenenti P et al, CJASN 2010
SEVERE PASSIVE HEYMANN NEPHRITIS (UNINEPHRECTOMY) 800 Treatment for 10 months (start treatment at 2 months) Urinary protein excretion 600 (mg/day) * 400 200 * 0 80 Glomerulosclerosis 60 40 (%) * * 20 * 0 Lisinopril Lis + AII-RA Lis + AII-RA Vehicle Control +Cerivastatin 47 Zoja et al., J Am Soc Nephrol, 2002
EFFECT OF SIX-MONTH ADD-ON FLUVASTATIN THERAPY IN 196 PATIENTS WITH CHRONIC PROTEINURIC NEPHROPATHY ON BACKGROUND DUAL RAS BLOCKADE: THE ESPLANADE TRIAL Treatment Phase 24h Total LDL Proteinuria Cholesterol Cholesterol 0 0 Changes vs Randomization -10 Patient Characteristics -8 -20 - CKD (percent) -30 -16 - Residual proteinuria >0.25 g/24h -40 (despite dual RAS blockade) -50 -24 (mg/dL) -60 -32 -70 -80 -40 -48 Fluvastatin NO Fluvastatin YES (80 mg/day) -56 p<0.001 p<0.001 48 Ruggenenti P et al, CJASN 2010
REMISSION CLINIC Low sodium diet with or without diuretics * Dual RAS Blockade with maximum tolerated doses of ACEi and ARB Start and up-titrate an ACEi (or an ARB) * Add and up-titrate an ARB (or an ACEi) * Add and up titrate other antihypertensive agents to achieve the maximum tolerated blood pressure reduction (consider dCCBs as last choice) Add a lipid lowering agent Vitamin D ? * Before moving to the following step check serum potassium and optimize the control of metabolic acidiosis and hyperglycemia to minimize the risk of hyperkalemia 49 Ruggenenti et al., JASN 2008
REMISSION CLINIC Targets: Blood pressure < 120/80 mmHg Proteinuria < 0.3 g/24 h LDL < 100 mg/dl LDL + VLDL < 130 mg/dl HbA1c < 7.5 % (diabetics) Ruggenenti et al., Lancet, 2001 50
The Remission Clinic A matched-cohort study - 56 patients CKD Proteinuria > 3 g/24 h ACEi or ARB therapy for > 6 months - 56 reference patients CKD from REIN or REIN2 Proteinuria > 3 g/24 h On Ramipril (5 mg/d) for > 6 months - Matching 1:1 Age Gender Creatinine clearance (+ 5 ml/min) Proteinuria (+ 1 g/24 h) ESRD, ∆ GFR (CrCl), 24 h proteinuria - Outcomes Ruggenenti et al., J Am Soc Nephrol, 2008 51
The Remission Clinic 60 Ramipril (reference-patients) Cumulative incidence of patients with ESRD (%) 50 40 30 P < 0.0015 20 10 Remission Clinic (patients) 0 0 6 12 18 24 30 36 42 48 54 60 66 72 78 months Ruggenenti et al., J Am Soc Nephrol, 2008 52
Placebo (REIN1) 80 (historical controls)* 60 Cumulative incidence of patients with ESRD (%) 50 Ramipril (reference-patients) 40 30 P < 0.0015 20 10 Remission Clinic (patients) 0 0 6 12 18 24 30 36 42 48 54 60 66 72 78 months * Patients from REIN with CKD and proteinuria > 3 g /24 h 53
54
Non - Diabetics Diabetics Pre Post Pre Post 0 Post ∆ GFR (ml/min/months) 0.20 0.40 0.60 0.80 p < 0.0001 Ruggenenti et al., J Am Soc Nephrol, 2008 55
180 160 Arterial blood pressure 140 120 (mmHg) 100 80 60 40 Patients with diabetes Patients without diabetes 20 0 0 6 12 18 24 30 36 42 48 54 60 66 72 Months 5 4.5 Urinary protein excretion 4 3.5 3 (g/24h) 2.5 2 1.5 1 0.5 0 0 6 12 18 24 30 36 42 48 54 60 66 72 Months 56
RENAAL R.R.: 0.72 (0.58-0.89) p=0.002 30 Patients with ESRD (%) Placebo 20 Losartan 10 0 Months 0 12 24 36 48 Brenner et al., N Engl J Med, 2001 57
RENAAL R.R.: 0.72 (0.58-0.89) p=0.002 30 Patients with ESRD (%) Placebo 20 ? Losartan 10 0 Months 0 12 24 36 48 Brenner et al., N Engl J Med, 2001 58
SIX MONTHS PROTEIN/CREATININE RATIO REDUCTION PREDICTS LESS RENAL AND CARDIOVASCULAR EVENTS The RENAAL study Hazard ratio (95 % C.I.) ESRD CV events Heart failure Decreased risk Increased risk 1 0.8 1.2 0.2 0.4 0.6 RENAAL Study group, 2002 59 59
HAZARD RATIO FOR CARDIOVASCULAR EVENTS ACCORDING TO TREATMENT AND RESIDUAL (6 MONTHS) PROTEINURIA CV Endpoint 1.05 Hazard ratio relative to 1.04 lowest proteinuria Losartan Placebo 1.03 1.02 1.01 1 <0.4 2.0 3.0 4.1 > 5.2 Protein/creatinine ratio at 6 months (g/g) 60 60 RENAAL study group, 2002
RENAAL Secondary Composite Endpoint and Components Losartan n=751 Placebo n=762 % Risk p n Change n Heart Failure 89 0.005 127 - 32 MI 50 0.079 68 - 28 Stroke 47 0.787 50 - 5 CV Death 90 0.455 79 + 12 61
ANNUAL MORTALITY AND ESRD IN SUBJECTS WITH TYPE 2 DIABETES AND NEPHROPATHY 25 ° 20 RENAAL UKPDS (percent) 15 ? 10 * 5 0 Mortality ESRD Estimate from the ° UKPDS and the *RENAAL studies Adler et al., Kidney Int, 2003 62
Can we do better ? 63
SALT INTAKE AND RENOPROTECTION BY ACE INHIBITOR THERAPY IN PROTEINURC NEPHROPATHY: A post-hoc analysis of REIN and REIN 2 studies - 500 patients CrCl: 20-70 ml/min 1.73sqm U.P. > 1 g/day Ramipril therapy (5 mg/day) - Urinary Na+/creat ratio * Low: < 100 n = 108 (mEq/g/day) Middle: 100 - 200 n = 336 High: > 200 n = 56 * As a marker of daily sodium intake adjusted for body weight Vegter et al., 2009 64 64
100 Sodium intake 80 Low Patients without ESRD (%) Middle 60 40 High * 20 * P < 0.05 vs middle and low 0 0 12 24 36 48 Follow-up (months) Vegter et al., 2009 65 65
110 MAP (mmHg)* 100 90 80 70 Low Middle High Sodium intake 66 * On follow-up Vegter et al., 2009 66
P<0.01 110 4 P<0.01 creatinine excretion (g/g)* MAP (mmHg)* 100 3 Urianry protein/ 90 2 80 1 70 0 Low Middle High Low Middle High Sodium intake Vegter et al., 2009 67 * On follow-up 67
SODIUM INTAKE AND RISK OF ESRD HR (95 % C.I.) for ESRD for each 100 mEq/g increase in Na+ intake Unadjusted Adjusted for proteinuria High sodium better High sodium worse - 25 - 0.5 1 2 4 Vegter et al., 2009 68 68
SPIRONOLACTONE (25 mg/day) IN ADDITION TO ACE INHIBITION TO REDUCE PROTEINURIA IN 8 PATIENTS WITH CHRONIC RENAL DISEASE* Proteinuria SBP p < 0.02 5 138 + 9 150 3.8 + 0.8 131 + 7 4 140 (g/24 hours) (mmHg) 3 130 1.7 + 0.3 2 120 1 110 0 100 Pre Post Post Pre * Antiproteinuric effect driven by 5 patients with type 2 diabetes Chrysostomou et al., N Egl J Med , 2001 69
81 DIABETIC PATIENTS WITH MACROALBUMINURIA Lisinopril (80 mg day) 160 20 UACR (% change vs baseline) 48 weeks 140 24-hour SBP (mmHg) 0 Placebo Losartan (100 mg/day) Spironolactone (25 mg/day ) 120 - 20 100 80 - 40 60 40 - 60 Creatinine clearance decreased with placebo or losartan, whereas did not change appreciably in the spironolactone group Mehdi et al., J Am Soc Nephrol , 2009 70 70
AN OBSERVATIONAL STUDY OF 25 PATIENTS ADMITTED IN AN INTENSIVE CARE UNIT SINCE 1994 TO 1998 FOR LIFE-THREATING HYPERKALEMIA DURING ACEi AND SPIRONOLACTONE COMBINED THERAPY Serum Potassium S. creatinine Risk factors p < 0.05 p < 0.0001 6 3.8 + 1.8 10 Renal insufficiency (n=22) 7.7 + 0.7 Age > 70 yrs (n=21) 5 8 Dehydration (n=12) 4 Worsening heart failure (n=9) (mEqL) 3.8 + 1.8 (mg/dl) 6 1.9 + 1.2 Diabetes (n=5) 3 Dose >25 mg/d 4 2 2 1 0 0 Pre Post Pre Post Schepkens et al., Am J Med , 2001 71
MANAGING CARDIOVASCULAR AND RENAL RISK: The potential of direct renin inhibition The reactive rise in renin activity may limit the effectiveness of ACE inhibitors and ARBs Sever et al., JRAAS, 2009 72
ALISKIREN COMBINED WITH LOSARTAN IN 599 TYPE 2 DIABETICS WITH OVERT NEPHROPATHY Placebo Aliskiren (150-300 mg/d) Comparable BP control in the two groups Similar incidence of hyperkalemia on Aliskiren (5.0%) or placebo (5.7%) Parving et al., N Engl J Med, 2008 73
ANY ADDITIONAL BENEFIT FROM RENIN- INHIBITION? More proteinuria reduction/nephroprotection as compared to dual RAS blockade with ACEi and ARBs? Less hyperkalemia or other side effects? Lower costs? 74
SELECTIVE VITAMIN D RECEPTOR ACTIVATOR (PARICALCITOL) FOR ALBUMINURIA LOWERING (VITAL) IN 281 TYPE 2 DIABETIC PATIENTS WITH NEPHROPATHY ON STABLE RAS THERAPY Placebo Paricalcitol Paricalcitol (n = 93) 1 µg/d 2 µg/d (n = 93) (n = 95) 0 (% change at 24 weeks vs baseline) 24-h urinary albumin excretion - 10 - 20 - 30 - 40 P = 0.015 De Zeeuw et al, Lancet 2010 75
OPPOSITE EFFECTS OF SALT INTAKE ON THE ANTIPROTEINURIC RESPONSE TO PARICALCITOL AND RAS INHIBITORS 60 Change in UACR (%) * Paricalcitol 1 Losartan 2 30 Sodium Excretion Sodium Excretion Low High Low High 0 30 60 P=0.005 P<0.05 1. VITAL study group , Lancet, 2010 76 2. Vogt L, et al., J Am Soc Nephrol , 2008
EVIDENCE THAT ACE-I HAS A DIFFERENT EFFECT ON GLOMERULAR INJURY ACCORDING TO THE DIFFERENT PHASE OF THE DISEASE AT WHICH THE TREATMENT IS STARTED Diabetes 200 300 * Proteinuria (mg/24h) Proteinuria (mg/24h) Diabetes 160 ACEi 200 120 * ACEi Diabetes + 80 100 ACEi Diabetes + ACEi 40 0 0 0 20-24 24-28 28-32 0 31-33 35-37 39-41 Time (weeks) Time (weeks) Perico et al., J Am Soc Nephrol, 1994 77
IRMA 2 RENAAL BENEDICT B IDNT ESRD Normoalbuminuria Micro Macro UAE µg/min < 20 20 - 200 > 200 Duration of diabetes (years) 0 18 25 13 78
PROTECTIVE EFFECT OF IRBESARTAN AGAINST PROGRESSION TO MACROALBUMINURIA IN 590 PATIENTS WITH TYPE 2 DIABETES AND MICROALBUMINURIA The IRMA-2 Trial 20 Placebo macroalbuminuria (%) 15 Patients with 10 5 Irbesartan (300 mg/d) 0 0 3 6 12 18 22 24 Follow-up (months) 79 Parving H-H, et al. N Engl J Med 2001
EFFECTS ON URINARY ALBUMIN EXCRETION OF TRANDOLAPRIL ALONE OR IN COMBINATION WITH VERAPAMIL IN 281 HYPERTENSIVE TYPE 2 DIABETIC PATIENTS WITH MICROALBUMINURIA The BENEDICT B Trial Patients with Regression to Patients with Progression to Normoalbuminuria Macroalbuminuria 50 Trandolapril plus 40 Verapamil (n=138) Percent 30 20 10 10 Percent Trandolapril (n=143) 0 0 0 6 12 18 24 30 36 42 48 0 6 12 18 24 30 36 42 48 Months Months 80 Ruggenenti P. J Hypertension, 2010
Patients with fatal or non fatal major cardiovascular events according to regression to Normoalbuminuria 25 Follow-Up SBP ( mmHg) Patients with event (percent) No Regression (n=148) 140 20 120 15 100 No Yes 10 5 Regression (n=133) HR (95% CI): 0.37 (0.19-0.71), p<0.01 0 48 Months 0 6 12 18 24 30 36 42 81 Ruggenenti et al, Personal Communication, 2010
BENEDICT Normoalbuminuria Micro Macro ESRD UAE µg/min < 20 20 - 200 > 200 Duration of diabetes (years) 0 18 25 13 Age � 40 yrs 1,200 type 2 diabetes Systolic/Diastolic BP > 130/85 mmHg and/or need for antihypertensive agents UAE < 20 µg/min* S. Creat < 1.5 mg/dl Treatment Trandolapril 2 mg/day Verapamil 240 mg/day Trandolapril 2 mg/day + Verapamil 180 mg/day Placebo 3 years Follow-up Persistent microalbuminuria > 200 µg/min* Outcome *by nephelometry in fresh urine 82
BENEDICT Study - 2004 120 Follow-up MAP Placebo 100 (mmHg) 15 80 Cumulative incidence of microalbuminuria (%) 60 P T 10 5 Trandolapril 0 0 6 12 18 24 30 36 42 48 Follow-up (months) 83 83 83 Ruggenenti et al., N Engl J Med, 2004
BENEDICT Follow-up blood pressure 25 ACEi NO microalbuminuria (%) 20 Subjects with 15 10 ACEi YES 20 Follow up SBP microalbuminuria (%) 5 >139.16 mmHg Subjects with HR: 0.36 (95%CI: 0.20-0.63), p=0.0004 15 0 0 1 2 3 4 5 6 years 10 5 Follow up SBP <139.16 mmHg 0 years 0 1 2 3 4 5 6 HR: 1.57 (95%CI: 1.03-2.41), p=0.0378 Adjusted for ACEi therapy Ruggenenti et al., J Am Soc Nephrol, 2006 84
ROADMAP Normoalbuminuria Micro Macro ESRD UAE µg/min < 20 20 - 200 > 200 Duration of diabetes (years) 0 18 25 13 Age � 18 yrs 4,449 type 2 diabetes A/C ratio < 35 mg/g female < 25 mg/g male One CV risk factor: - hypertension - dyslipidemia - central obesity - smoking eGFR > 60 ml/min/1.73 sqm Treatment Olmesartan 40 mg/day Placebo Follow-up 3,2 years Outcome Onset of microalbuminuria 85
Why a placebo arm? Why not an ACEi rather than an ARB? 86 86
Placebo BENEDICT Placebo ROADMAP 15 Cumulative incidence of microalbuminuria (%) 10 5 0 0 6 12 18 24 30 36 42 48 Follow-up (months) 87 87 87 Ritz et al., Diabetologia, 2010
ROADMAP Study - 2010 Placebo 15 Olmesartan Cumulative incidence of microalbuminuria (%) 10 5 0 0 6 12 18 24 30 36 42 48 Follow-up (months) 88 88 88 Ritz et al., Diabetologia, 2010
Placebo 15 Hazard reduction (95 % CI) Olmesartan Cumulative incidence of microalbuminuria (%) Olmesartan : 23 % (6 % - 37%) Trandolapril : 56 % (19 % - 76 %) 10 Trandolapril 5 0 0 6 12 18 24 30 36 42 48 Follow-up (months) 89 89 89
RAS INHIBITOR THERAPY Deaths (n) Placebo Study drug BENEDICT 4 / 603 2 / 601 Mean age: 63 3 / 2139 15 / 2380 ROADMAP Mean age: 58 Treatment effect in the two study cohorts was significantly different (opposite) by Mantel-Haenszel test of homogeneity (P = 0.04) 90 90
RAS INHIBITOR THERAPY Deaths (n) Placebo Study drug BENEDICT 4 / 603 2 / 601 Mean age: 63 Double mortality on olmesartan 3 / 2139 15 / 2380 ROADMAP Mean age: 58 Treatment effect in the two study cohorts was significantly different (opposite) by Mantel-Haenszel test of homogeneity (P = 0.04) 91 91
10-YEAR CARDIOVASCULAR OUTCOMES IN HYPERTENSIVE TYPE 2 DIABETES PATIENTS WITH NORMOALBUMINURIA An extension of the BENEDICT trial - 1,208 subjects Age > 40 yrs BP > 130/85 mmHg UAE < 20 µg/min S. Creat < 1.5 mg/dl 9.1 years - Median follow-up Baseline UAE - Independent variable - Dependent variable Major CV events Fractional Polynomial Algorithm - Statistical method 92 92
INCREMENTAL 10-YEAR RISK FOR MAJOR CV EVENTS FOR PROGRESSIVELY INCREASING ALBUMINURIA AT INCLUSION IN 1,208 TYPE 2 DIABETES PATIENTS WITH NORMOALBUMINURIA The BENEDICT extension study 3 Adjusted* Odds Ratio for 2.5 CV events 2 1.5 1 14 UAE (ug/min) 0 1 2 3 4 5 6 7 8 9 10 11 12 13 *A fractional polynomial algorithm adjusted for: Age � yr, Gender - female vs. Male, Duration of diabetes � yr, History of CV disease - n/y, Smoker status � n/y, Body Mass Index - kg/m 2 , Mean blood pressure � mmHg, logarithm of HbA1c - % , logarithm of LDL-c/HDL-c ratio, Triglycerides - mg/dL, , logarithm of Serum creatinine - mg/dL , Allocation to ACEI � n/y 93 93 Porrini et al., Personal Comm, 2010
The excess CV risk is already significant for an increase in UAE from 1 to 2 � g/min R.R. (95 % C.I.) UAE (µg/min) 0 - 1 1 - 2 3 1 1.05 1.10 Adjusted* Odds Ratio for 2.5 CV events 2 1.5 1 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 UAE , ug/min 94 94 Porrini et al., Personal Comm, 2010
review Kidney International (2006) Time to abandon microalbuminuria? P. Ruggenenti and G. Remuzzi Clinical Research Centre for Rare Diseases � Aldo e Cele Daccò � , Mario Negri Institute for Pharmacological Research, Villa Camozzi, Ranica, Bergamo, Italy and Unit of Nephrology, Azienda Ospedaliera, Ospedali Riuniti, Bergamo, Italy 95 95
INCREMENTAL CARDIOPROTECTIVE EFFECTS OF ACE INHIBITOR THERAPY FOR INCREASING ALBUMINURIA AT INCLUSION IN 1,208 TYPE 2 DIABETES PATIENTS WITH NORMOALBUMINURIA The BENEDICT extension study HR for CV events significantly lower on ACE Yes 4 ACE No 3.5 Adjusted* Odds Ratio for 3 CV events 2.5 2 ACE Yes 1.5 1 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 UAE , ug/min 96 Porrini et al., Personal Comm, 2010
Insulin resistance/endothelial dysfunction Unselective proteinuria Reduced - Obesity Albuminuria nephron Worsening metabolic syndrome - Hypertension Increasing cardiovascular risk number ? - Diabetes 150 ACEi (ml/min/1.73m 2 ) ? 100 Transient hyperglycemia, hypertension GFR 50 0 Normoalbuminuria Micro Macro ESRD UAE µg/min < 20 20 - 200 > 200 0 15 25 10 Duration of diabetes (years) 97
RESULTS OF A RENAL AND CARDIOVASCULAR TREATMENT PROGRAM IN AN AUSTRALIAN ABORIGINAL COMMUNITY The Tiwi Kidney Disease Study 1990-2000 Conventional Perindopril 20 20 Events per 100 persons/years Controls Events per 100 persons/years Treatment cohort 15 15 ESRD 10 10 5 5 Death 0 0 8 1 2 4 7 0 < 34 34-99 100-199 200+ 3 5 6 9 9 9 9 9 9 9 9 9 9 0 / 7 / / / / / / / / / 0 1 2 3 4 5 6 8 9 9 9 9 9 9 9 9 9 9 9 ACR category at baseline (g/mol) A cost effectiveness analysis estimated savings of $ 800,000 AUS to $ 4,1 million at 2 years in cost of dialysis avoided or delayed Hoy et al., J Am Soc Nephrol, 2003 98
1,000,000 deaths 99
These slides are belonging to Piero Ruggenenti, M.D. Mario Negri Institute for Pharmacological Research, Bergamo, Italy. Using these slides is only authorized by mentioning the source 100
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