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Giuseppe Remuzzi

Giuseppe Remuzzi Prevention of progression and remission/regression strategies of chronic renal diseases: can we do better now than 5 years ago? Bellagio, March 16, 2004. There are 1,065,000 people on dialysis worldwide

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Giuseppe Remuzzi

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  1. Giuseppe Remuzzi Prevention of progression and remission/regression strategies of chronic renal diseases: can we do better now than 5 years ago? Bellagio, March 16, 2004

  2. There are 1,065,000 people on dialysis worldwide 90 % of them live in North America, Japan, and Europe, whose population is less than 20 % of world population

  3. $ $ $ PREDICTED DIALYSIS COST OF APPROXIMATELY $ 1.1 TRILLION FOR THE COMING DECADE 1200 1000 800 Ten year medical costs of dialysis population $ ( billions) 600 400 200 0 1981-1990 1991-2000 2001-2010 Lysaght et al., J Am Soc Nephrol, 2002

  4. 1,000,000 deaths

  5. 80 60 40 1/Cr x 10 3(µmol/l) 20 0 0 10 20 30 40 50 Time(months) PROGRESSION OF RENAL FAILURE IN 9 DIABETICS Jones et al., Lancet, 1979

  6. ACE INHIBITION PREVENTS RENAL FAILURE AND DEATH IN UNINEPHRECTOMIZED MWF/ZTM RATS * 700 600 500 Urinary Protein Excretion (mg/24 hrs) 400 300 200 100 ** 0 Control UNx UNx + Lis * 100 Control 100 80 UNx + Lis Percentage of glomeruli affected by sclerosis 80 (%) 60 60 40 Survival 40 20 20 ** UNx 0 0 0 3 6 9 1 2 1 5 Control UNx UNx + Time (months after UNx) Lis * p < 0.05, **p < 0.01 vs control Remuzzi et al., Kidney Int, 1995

  7. EFFECT OF ACE-I THERAPY ON RISK OF DEATH IN NON-DIABETIC CHRONIC RENAL DISEASE Risk of death Author, year Patients Risk Ratio & C.I. - Zucchelli et al., 1992 121 60 - Kamper et al., 1992 70 - Brenner et al., 1993 112 50 % - Toto et al., 1993 124 - van Essen et al.,1994 103 - Hannedouche et al., 1994 100 35 % - Bannister et al., 1994 51 Patients with proteinuria (%) 30 - Hansson et al., 1995 260 - Ihle et al., 1996 70 15 % - Maschio et al., 1996 583 Pooled Risk Ratio (95% CI) - OVERALL 1594 1.24 (0.55 - 2.83) 0 ACE-I better ACE-I worse < 0.5 0.5 - 3 ≥ 3 Proteinuria (g/24 h) 1 0.01 0.05 0.2 5 20 100 Giatras et al, J Am Soc Nephrol, 1997

  8. REIN CORE Rate of GFR decline according to base-line proteinuria - Interim analysis on 177 patients p=0.001 0.89±0.11 1.0 p=0.001 Rate of GFR decline (ml/min/month) 1.0 0.39±0.10 Rate of GFR decline (ml/min/month) 0.5 0.67±0.08 0.5 0.25±0.08 0 Conventional Ramipril 0 STRATUM - 1 U. Prot. < 3 g/24 h STRATUM - 2 U. Prot. ≥ 3 g/24 h Ramipril 77 % Kidney survival: Conventional 54 % GISEN Group, Lancet, 1997

  9. REIN CORE Conventional Ramipril 1.6 70 1.4 60 1.2 50 Mean rate of GFR decline (ml/min/month) % patients with doubling of base-line creatinine or ESRF 1.0 40 0.8 30 0.6 20 0.4 10 0.2 0 0 3 - 4.5 4.5 - 7 ≥ 7 3 - 4.5 4.5 - 7 ≥ 7 Baseline proteinuria (g/24 h) Baseline proteinuria (g/24 h) GISEN Group, Lancet, 1997

  10. AN ARTIFICIAL NEURAL NETWORK TO MODEL INDIVIDUAL OUTCOME OF PATIENTS WITH CHRONIC NEPHROPATHIES ON THE BASIS OF DATA FROM THE REIN STUDY Besides serum creatinine, the model identified proteinuria and Ca*P product as the strongest predictors of ESRD

  11. RISK OF PROGRESSION TO ESRD OVER 20 MONTHS FOLLOW-UP IN PROTEINURIC CHRONIC NEPHROPATHIES Predicted risk in 3 explicative cases 80 % 60 40 1.2 1.9 24.3 2.1 3.9 35.1 3.5 5.2 37.2 Serum creat mg /dl Proteinuriag /24 h CaxP mg2/dl2 20 0

  12. 3 MONTHS PROTEINURIA REDUCTION PREDICTS LONG-TERM GFR DECLINE The REIN study Ramipril Overall Conventional - 0.9 > 3 gr/24 h - 0.8 - 0.7 • GFR (ml/min/month) 3 years - 0.6 -0.5 - 0.4 -0.3 -0.2 - 20 0 20 40 D proteinuria * ( percent change vs .baseline) 3 months * Corrected for GFR Perna et al., J Am Soc Nephrol, 2000

  13. CORRELATION BETWEEN CHANGES IN PROTEINURIA AND GFR DECLINE 1 - 3 gr/24 h 40 Ramipril Overall Placebo 20 D proteinuria * (percent change vs. baseline) 3 months 0 - 20 - 0.2 -0.3 - 0.4 > 3 gr/24 h 40 D proteinuria * ( percent change vs .baseline) 3 months 20 0 - 20 -0.2 -0.3 - 0.4 -0.5 - 0.6 - 0.7 - 0.8 0.9 • GFR (ml/min/month) 3 years * Corrected for GFR Perna et al., J Am Soc Nephrol, 2000

  14. 6 MONTHS PROTEIN/CREATININE RATIO REDUCTION PREDICTS RENAL AND CARDIOVASCULAR EVENTS The RENAAL study Hazard ratio (95 % C.I.) ESRD CV events Heart failure Increased risk Decreased risk 1 0.8 1.2 0.4 0.6 0.2 RENAAL Study group, 2002

  15. PROTEINURIA AND RISK OF DEVELOPING ESRD Community-based screening in 106,177 general population Follow-up: 17 years 16 14 12 10 Cumulative incidence of ESRD (%) 8 6 4 2 0 Proteinuria Number of screened Number of ESRD - 86,253 185 + 10,000 38 + 4,007 55 2+ 1,072 76 >3+ 357 55 Iseki et al., Kidney Int, 2003

  16. RISK OF ESRD: PREDICTIVE VALUE OF BASELINE GFR AND PROTEINURIA 1993 mass screening conducted by the Okinawa General Health Maintenance Association (OGHMA) Subjects Inclusion criteria Baseline parameters Follow-up End point 95,255 > 20 years of age GFR > 15 ml/min Dipstick proteinuria Calculated GFR (Cockcroft-Gault method) 7 years ESRD Iseki et al., J Am Soc Nephrol, 2003

  17. Fig3 80 Proteinuria (+) Proteinuria (-) 60 Cumulative Incidence of ESRD per 1,000 screened in 7 years 40 20 0 15.0-57.1 57.2-77.6 77.7-102.6 ≥102.7 Total GFR, ml/min/1.73m2 Proteinuria (+) 1,125 811 717 800 3,453 Number of screened 84 11 7 6 108 Number of ESRD Proteinuria (-) 21,872 22,254 22,312 22,229 88,667 Number of screened 22 18 1 3 44 Number of ESRD

  18. EFFECTS OF LOSARTAN ACCORDING TO RACE: Post-hoc analyses of the RENAAL study Region n° Primary end point (Doubling s. creat, ESRD or death) p Hazard ratio (95 % C.I.) 252 230 734 277 19 1,261 0.024 0.94 0.07 0.99 0.76 0.18 Asian Black White Hispanic Other Overall Losartan worse Losartan better 1.25 1.0 1.5 0.5 0.75 0.25 The whole effect of Losartan was fully driver by Asian patients

  19. 1-YEAR PROTEINURIA REDUCTION IN TYPE 2 DIABETICS ENROLLED IN THE RENAAL STUDY ACCORDING TO RACE ASIA n = 252 Non-ASIA n = 1,261 0 -5 -10 Median (I.Q. range) proteinuria reduction vs baseline (%) -9 (-51 to 40) -15 -20 -19 (-56 to 36) p = 0.03 (ANCOVA)

  20. p Reduced proteinuria Outcome improved Baseline proteinuria (alb/creat g/g) Risk reduction (95 % C.I.) 0.016 0.27 0.59 0.35 Asian Non Asian YES NO YES NO 1.535 YES NO NO NO 1.167 Increased risk Decreased risk -50 -25 1 25 50 75 -75

  21. BASELINE CHARACTERISTICS OF ASIAN AND NON-ASIAN PATIENTS OF RENAAL STUDY p 0.72 <0.005 <0.0001 Asian (257) 60+7 102+11 25+4 Non-Asian (1256) 60+7 106+11 31+5 Age (yrs) MAP (mmHg) BMI (Kg/m2)

  22. Ramipril Ramipril 4 5 D GFR = -0.44 ± 0.54 4 0 D GFR = -0.10 ± 0.50 GFR (ml/min/month) 3 5 3 0 D GFR = -0.81 ± 1.12 D GFR = -0.14 ± 0.87 2 5 Conventional Ramipril FOLLOW-UP CORE Ruggenenti et al., Lancet, 1998

  23. 0,10 ml/min/month

  24. Regression Remission 16 patients with stableD GFR 10 patients with increasing D GFR 90 90 GFR (ml/min/month) 80 80 70 70 60 60 50 50 GFR (ml/min/month) 40 40 30 30 20 20 10 10 0 0 0 10 20 30 40 50 60 0 10 20 30 40 50 60 months months Slopes refer to 26 patients on continuated Ramipril treatment since randomization who had at least 6 GFR measurements (≥ 3 on Core and ≤ 3 on Follow-up study)

  25. 0 - 20 -31 % - 40 -52 % - 60 RELATIONSHIP BETWEEN REMISSION/REGRESSION AND POST-BREAKPOINT CHANGES IN PROTEINURIA Post hoc analyses of the REIN study Remission n = 16 Regression n = 10 Proteinuria reduction vs pre-breakpoint values (%) The further improvement in DGFR during continued ramipril therapy was always associated with further proteinuria reduction The extent of DGFR amelioration was associated with the extent of proteinuria reduction Ruggenenti et al., J Am Soc Nephrol, 1999

  26. REGRESSION OF THE DISEASE IN PATIENTS ON CONTINUED RAMIPRIL 50 40 30 * GFR (ml/1.73 sqm) 20 Y1 = - 0.3291x + 44.794 Y2 =0.387x + 19.677 10 p (y1 vs y2 ): < 0.01 (F-test) * Y= 0.0092x - 0.6033x2 + 45.586 0 0 6 12 18 24 30 36 42 48 54 months

  27. 100 MWF 60 w 80 60 100 40 MWF 50 w 80 20 Number of Glomeruli (%) 60 0 0% <25% 25-50% 50-75% >75% 40 20 0 0% <25% 25-50% 50-75% >75% EVIDENCE FOR GLOMERULAR CAPILLARY REGENERATION AND REABSORPTION OF SCLEROSIS AREAS 100 MWF 60 w + LIS 80 60 40 20 0 0% <25% 25-50% 50-75% >75% Remuzzi et al., J Am Soc Nephrol, 2003

  28. CAN WE DO BETTER? protein traffic Intensify blood pressure control Up-titrate ACE inhibitor dose Combine with other antiproteinuric agents Vasopeptidase inhibitors • - Non-dihydropyridinic Ca-channel blockers • Ang II receptor blockers • Aldosterone antagonists consequences of protein traffic Drugs targeted to inflammatory or vasoactive genes which are up-regulated by protein reabsorption • - ET-1 receptor antagonists • TGFb inhibitors • Lipid lowering agents

  29. THE COURSE OF THE EFFECT OF ANG II ANTAGONISM ON BLOOD PRESSURE AND URINARY PROTEIN EXCRETION Blood pressure Urinary protein excretion Gansevoort et al., Kidney Int, 1994

  30. EFFECTS OF UP-TITRATING LISINOPRIL IN MEMBRANOUS NEPHROPATHY + 40 + 30 + 20 Serum Albumin Changes vs. basal (%) + 10 0 - 10 - 20 - 30 LDL Cholesterol 0 10 20 30 40 10 0 Lisinopril dose (mg/day) Ruggenenti et al., Circulation, 2003

  31. DUAL RENIN-ANGIOTENSIN SYSTEM BLOCKADE IS HIGHLY EFFECTIVE TO IN NON-DIABETIC PROTEINURICS 9 non-diabetic renal patients (6 weeks treatment per dose) 0 -25 Change of proteinuria(%) Losartan -50 -75 Lisinopril Combined -100 0 50 100 150 50 - 150 10 - 40 0 10 20 40 Laverman et al., Kidney Int, 2002

  32. VALSARTAN (160 mg/day) BENAZEPRIL (20 mg/day) EFFECTS ON PROTEINURIA OF 8 WEEKS COMPARABLE BLOOD PRESSURE CONTROL ACHIEVED BY COMBINED THERAPY IN 23 PATIENTS WITH CHRONIC NON-DIABETIC NEPHROPATHIES BENAZEPRIL + VALSARTAN (10 + 80 mg/day) 10 0 -10 -20 Percent change from baseline -30 24 hrs Uprot excretion -40 MAP -50 p = 0.022 -60 p = 0.024 -70 p = 0.002 Campbell et al., 2002

  33. * * * * ** ** ** ** ** ** * ** ** Baseline Baseline * ** * Valsartan Benazepril ** * 22 30 38 46 54 62 70 1.0 0.1 * * * Dextran Fractional Clearance * ** ** ** ** 0.01 ** ** Basaline ** Benazepril + Valsartan ** * 30 38 46 54 62 70 22 30 38 46 54 62 70 22 Molecular radius (Å) Dextran clearance studies found no differences in size selective properties of the membrane but more reduction in renal vascular resistance (p = 0.046) in combination therapy compared to each drug alone Campbell et al., 2002

  34. COOPERATE study: results 100 Combination Losartan 80 Trandolapril Patients without events * (%) 60 40 20 0 0 6 12 18 24 30 36 Months after randomisation * ESRD and doubling of serum creatinine Nakao et al., Lancet, 2003

  35. SEVERE PASSIVE HEYMANN NEPHRITIS (UNINEPHRECTOMY) 800 Treatment for 10 months (start treatment at 2 months) 600 Urinary protein excretion (mg/day) * 400 200 * 0 80 60 Glomerulosclerosis (%) 40 * * 20 * Lisinopril Lis + AII-RA Lis + AII-RA +Cerivastatin Control Vehicle Zoja et al., J Am Soc Nephrol, 2002

  36. EDITORIALJ Am Soc Nephrol 13:3024 - 3026, 2002 The Next Treatments of Chronic Kidney Disease: If We Find Them, can We Test Them? THOMAS H. HOSTETTER National Institute of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland

  37. REMISSION CLINIC Start low-dose sodium diet Add low-dose ACE i or AII RA Up-titrate ACE i or AII RA to max tolerated dose Add a diuretic Add a low dose of another antiproteinuric agent Add AII RA or ACE i Up-titrate AII RA or ACE i to maximum dose K > 5.5 mEq/l K < 5.5 mEq/l Add non-dihydropyridine CCBs (Verapamil/Diltiazem) Up-titrate non-dihydropiridine CCBs to max tolerated dose Up titrate concomitant antihypertensive agents to achieve the maximum tolerated blood pressure reduction Add a lipid lowering agent Ruggenenti et al., Lancet, 2001

  38. FULL RESPONDERS (n=19) - Full remission of nephrotic syndrome (U.prot. <1g/24 h) - Stable s. creatinine over 4 years 5 8 Remission clinic 4 6 3 Serum creatinine (mg/dl) Urinary protein excretion (g/24 hours) 4 2 2 1 0 0 50 0 10 20 30 40 - 10 months

  39. Remission clinic 8 5 4 6 3 4 2 2 1 0 0 40 -10 0 20 30 10 months PARTIAL RESPONDERS (n=7) - Partial remission of nephrotic syndrome - s. creat increase < 0.2 mg/dl/year Serum creatinine (mg/dl) Urinary protein excretion (g/24 hours)

  40. REMISSION CLINIC Targets of the multidrug approach: 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

  41. OUTCOMES OF 160 TYPE 2 DIABETICS WITH MICROALBUMINURIA ACCORDING TO MULTIFACTORIAL OR CONVENTIONAL THERAPY Relative risk (95 % C.I.) Fatal and non-fatal CV events Nephropathy Retinopathy Multifactorial therapy better Multifactorial therapy worse 0.0 0.5 1.0 1.5 2.0 Gaede et al., N Engl J Med, 2003

  42. When to start, why never stop

  43. INCIDENCE OF ESRD IN 352 PATIENTS WITH PROTEINURIC, CHRONIC NEPHROPATHIES ACCORDING TO TREATMENT AND TERTILES OF BASAL GFR p < 0.05 70 60.0 % 60 50 40.4 % Incidence of ESRD(%) 40 30 21.4 % p < 0.01 20 Conventional 13.4 % 10.9 % Ramipril 10 0.0 % 0 Middle (32.6 - 50.8 ml/min) Lowest (10.5 - 32.6 ml/min) Highest (50.8 - 101.0 ml/min) Ruggenenti et al., J Am Soc Nephrol, 2002

  44. 1998 - 2010 PREDICTED ESRD PREVALENCE AND CUMULATIVE SAVINGS FOR DIFFERENT DEGREES OF DGFR REDUCTIONS ESRD Prevalence projections Predicted DGFR (ml/min/yrs) DGFR reduction* - 10 % - 30 % 0 661,330 7.56 65,000 10 615,767 Prevalence 60,000 20 18,56 55,000 30 -10 % Costs saved ($ billion) 50,000 40 466,438 50 45,000 -30 % 60 40,000 60,61 70 35,000 2000 2005 2010 * Predicted for patients with basal GFR ≤ 60ml/min Hariprasad et al., Am J Kidney Dis, 2002

  45. GFR DECLINE ACCORDING TO DIFFERENT UNDERLYING RENAL DISEASE Conventional 1.2 Ramipril 1.0 0.8 D GFR (ml/min/month) 0.55±0.13 0.53±0.09 0.49±0.11 0.6 0.36±0.09 0.31±0.09 0.4 0.31±0.07 0.2 0 Primary Glomerular Disease IgA Nephropathy Nephrosclerosis -42 -35 -37 • % DGFR • reduction vs control Ruggenenti et al., Am J Kidney Dis, 2000

  46. DEVELOPMENT OF A LOW COST “POLYPILL” TO PREVENT RENAL PROGRESSION AND CARDIOVASCULAR EVENTS • A single combination low cost pill containing six active components, including aspirin, a statin, three antihypertensive agents (a thiazide, a b-blocker, an ACE inhibitor) at half standard dose, and folic acid has been proposed for the prevention of cardiovascular disease Wald and Law, British Med J, 2003

  47. Statin Aspirin ACE inhinitors The superpill could be valuable also for patients with chronic nephropathies to limit both renal and cardiovascular events

  48. A LOW COST POLYPILL COULD USE GENERIC COMPONENTS Generic drugs are not subject to patent protection This formulation may not have the lowest rate of adverse effects, but even if about 10% of people were intolerant of the formulation it would still have considerable public health merit

  49. So far, treatment of renal patients has been aimed to limit or prevent progression to ESRD

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