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Orhid June 21- 23, 2012

This conference presentation discusses various strategies to slow down the progression of Chronic Kidney Disease (CKD), including blood pressure reduction, RAS inhibition, low protein diet, statins, anemia correction, smoking cessation, and vitamin D. It also explores the role of baseline hypertension and other risk factors in CKD progression.

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Orhid June 21- 23, 2012

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  1. Orhid June 21- 23, 2012 How to slow down the progression of CKD? Francesco Locatelli Department of Nephrology, Dialysis and Renal Transplant Alessandro Manzoni Hospital Lecco, Italy

  2. Chronic Kidney Disease DIALYSIS and TRANSPLANTATION UNKNOWN CKD The Burden of CKD is increasing • Ageing population • Diabetes • Cardiovascular disease

  3. Kidney Int 2006; 69: 2118-2120

  4. Slowing down CKD progression: where are we now? Blood pressure reduction RAS inhibition Low protein diet Statins Anemia correction Smoking cessation Vitamin D?

  5. CKD Progression Role of baseline hypertension 1.00 0.95 Mean BP 0.90 < 107 mmHg 0.85 N = 122 Cumulative renal survival 0.80  107 mmHg 0.75 N = 229 0.70 0.65 0 6 12 18 24 30 Months Locatelli F et al. Nephrol Dial Transplant 1996;11:461-7

  6. 29% less for low PA P = 0.006 P = 0.01 CKD progression and blood pressure The MDRD Study A D GFR ( ml/min ) MAP 92 mmHg P = NS MAP 107 mmHg Time ( months ) Klahr S et al. N Engl J Med 1994; 330: 877 - 84

  7. The AASK Trial Blood pressure goal intervention 3 1094 African-Americans randomized to BP goal and drug intervention 0 No effect - 3 D GFR from baseline P = ns - 6 - 9 Usual BP goal (MAP 102-107mmHg) Lower BP goal (MAP ≤ 92 mmHg) - 12 0 6 12 18 42 48 24 30 36 Follow up ( months ) Wright JT et al. JAMA  2002; 288: 2421-2431.

  8. The REIN-2 Study Proportion of patients with ESRD in each study arm 45 Intensified control (n =167) Median follow-up:19 months 40 Mean GFR: ~35 ml/min Conventional control (n =168) 35 30 No effect N =338 25 Proportion with ESRD ( % ) 20 15 10 5 HR: 1·00, 95% CI 0·61–1·64; p=0.99) 0 0 6 12 18 24 30 36 42 48 54 Follow up ( months ) Ruggenenti P et al. Lancet 2005; 365 (9463): 939 - 46

  9. Blood pressure and time to ESRD MDRD Study A 60 Target blood pressure D Time 1.24 years 50 MAP 92 mmHg 40 MAP 107 mmHg Baseline GFR ( ml / min ) 30 20 - 3.5 ml / min / year 10 - 4.1 ml / min / year 0 0 2 14 16 4 6 8 10 12 Time ( years ) Locatelli F and Del Vecchio L Nephrol Dial Transplant 1999; 14: 1360-4

  10. A critical look to single and dual RAS block Blood pressure reduction RAS inhibition Single Blockade with ACE-i Low protein diet Statins Anemia correction Ca-P metabolism Smoking cessation

  11. Time to ESRD in the AIPRI Study Benazepril n = 281 60 D time: 3.85 years Placebo n = 252 50 40 Baseline GFR ( ml / min ) 30 - 3.38 ml / min / year 20 - 4.95 ml / min / year 10 0 0 2 14 16 4 6 8 10 12 Time ( years ) Locatelli F and Del Vecchio L Nephrol Dial Transplant 1999; 14: 1360-4

  12. SBP and proteinuria interaction in the AIPRI Study 12 10 8 Follow – up proteinuria (g/day) 6 Control Group 4 ACE-in. Group 2 0 80 100 120 140 160 180 200 220 Follow - up SBP Locatelli F et al J Am Soc Nephrol. 2002 Nov; 13 Suppl 3: S196-201

  13. Renal insufficiency as a predictor of cardiovascular outcome in the HOPE trial Endpoint: cardiovascular death, myocardial infarction or stroke 80 Adjusted HR 1.40 (1.16-1.69) All Taking placebo 60 Taking ramipril Events per 1000 person-years 40 20 0 Serum creatinine <1.4 mg/dL Serum creatinine 1.4 mg/dL Mann JF et al. Ann Intern Med 2001; 134: 629-636

  14. A meta-analysis of ACE inhibitors in non-diabetic renal disease Survival without ESRD 1.0 ACE inhibitors 0.8 Controls 0.6 End points: ACEI: 7.4 % Controls: 11.6 % Survival without ESRD RR = 0.69 (CI, 0.51 to 0.94) 0.4 N = 1860 11 randomised trials 0.2 P < 0.003 0.0 0 12 24 36 48 Follow - up ( months ) Jafar TH et al. Ann Int Med2001; 135: 73 - 87

  15. Adjusted Relative Risk for Kidney Disease Progression by Systolic Blood Pressure during Follow-up 9 3.5 8 3.0 7 2.5 6 2.0 5 Events ( % ) Relative Risk 4 1.5 3 1.0 2 0.5 1 0 0.0 SBP mmHg < 110 110-119 120-129 130-139 140-159 ≥ 160 Modified from Jafar TH et al. Ann Int Med 2003; 139: 244-252

  16. A critical look to single and dual RAS block Blood pressure reduction RAS inhibition Single Blockade with ARBs Low protein diet Statins Anemia correction Ca-P metabolism Smoking cessation

  17. 14.9 9.7 5.2 Onset of diabetic nephropathy is delayed, but not prevented by ARB therapy Patients reaching onset of overt proteinuria after 24 months % 15 10 5 0 Placebo Irbesartan150 mg Irbesartan 300 mg Parving H-H, et al. N Engl J Med. 2001; 345: 870–8

  18. Renoprotection of Optimal Antiproteinuric Doses (ROAD) Study Renal survival: primary composite end point of a doubling of SCr, ESRD, or death 40 Benazepril, conventional dose (10 mg) Benazepril, titrated dose (10-40 mg) Losartan, conventional dose (50 mg) Losartan, titrated dose (50-200 mg) 30 N = 360 Median follow-up: 3.7 years Primary Composite end-point (%) 20 10 0 0 12 24 36 Months Hou FF et al. J Am Soc Nephrol 2007; 18(6): 1889-98

  19. The RENAAL Study The IDNT Study Time to Doubling of Serum Creatinine, ESRD, or Death Primary Composite End Point The IDNT Study 50 Placebo Placebo 40 0.6 Amlodipine 30 0.5 Losartan End Point % Proportion with primary end point 0.4 Irbesartan 20 0.3 RR 23% P=0.006 Risk reduction 16% P = 0.02 0.2 10 RR 20% P = 0.02 P = NS 0.1 0 0.0 0 12 48 24 36 0 6 12 18 24 30 36 42 48 54 Months Months Brenner BM et al. N Engl J Med 2001; 345 (12): 861-9 Lewis EJ et al. N Engl J Med 2001; 345 (12): 851-60

  20. Renin system suppression with an ARB Despite treatment with ARBs, the decline in renal function is still greater than expected due to ageing RENAAL IDNT 0 Normal rate of decline due to ageing −2 −4 −6 −8 Mean rate of decline in GFR (mL/min/1.73 m2/yr) Placebo (no renin system suppression) Weber MA & Giles TD. Rev Cardiovasc Med 2006; 7: 45–54

  21. Many clinical studies ( HOPE, CHARM, SAVE, LIFE and IDNT ) have demonstrated that ACEIs and ARBs provide organ protective benefits across a wide spectrum of patient types However, the cardiorenal protection afforded by ACEI and ARB therapy is limited. A substantial proportion of patients still experience cardiovascular and renal morbidity and mortality ACEIs and ARBs provide organ protection,but their benefits are limited

  22. A critical look to single and dual RAS block Blood pressure reduction RAS inhibition Dual Blockade with ACE-i & ARBs Low protein diet Statins Anemia correction Ca-P metabolism Smoking cessation

  23. THE LANCET The Lancet October 10-16, 2009 Comment Retraction – Combination treatment of angiotensin-II receptor blocker and angiotensin-converting-enzyme inhibitor in non-diabetic renal disease (COOPERATE): a randomized controlled trial An investigation committee concluded that it was not possible to prove the authenticity of the data — The conlusions mean that the paper must be retracted from the published record —

  24. 0.539 (0.050) 0.584 (0.054) 120 adjusted geometric mean ratio (±s.e.) 100 80 60 40 20 0 Ramipril + irbesartan Ramipril + placebo Baseline Week 20 IMPROVE microalbuminuria in hypertensive subjects with elevated cardiovascular risk Geometric mean AER (mcg/min) Bakris Gl, Ruilope L, Locatelli F et al. Kidney Int. 2007; 72(7): 879-85

  25. 24% eGFR < 60 mL/min/1·73 m²: n = 6157 eGFR below 30 mL/min/1·73 m²: n = 263 Microalbuminuria: n = 2781 1% 13% • 25 620 participants aged 55 years or older with established atherosclerotic vascular disease or with diabetes with end-organ damage wererandomly assigned to: • Ramipril 10 mg • Telmisartan 80 mg • A combination of both drugs • Median follow-up of 56 months

  26. ONTARGET study – Renal Outcomes Secondary Renal Outcome: dialysis and doubling of serum creatinine 0.004 Telmisartan Ramipril 0.003 Telmisartan and Ramipril 0.002 Cumulative incidence rates T vs R p=0.420 0.001 R+T vs R p=0.038 0 0 1 2 3 4 5 Number at risk Year of follow-up Telmisartan 8542 8362 8123 7895 7643 4999 4968 8406 8194 7933 7670 Ramipril 8576 8301 8074 7797 4850 7526 Telmisartan and Ramipril 8502 The ONTARGET Investigators Lancet 2008; 372: 547-53

  27. ONTARGET study – Renal Outcomes Secondary Renal Outcomes: progression of proteinuria Changes in log urine albumin to creatinine ratio P = 0.033 P = 0.0028 1.4 1.2 1.0 Ramipril 0.8 Telmisartan 0.6 0.4 Ramipril plus Telmisartan 0.2 0 UACR baseline Final ratio to baseline UACR: urine albumin to creatinine ratio (mg/mmol) The ONTARGET Investigators Lancet 2008; 372: 547-53

  28. ONTARGET Causes of Acute Renal Failure • Transient kidney hypoperfusion in patients with excessive blood pressure reduction, hypovolemia or ischemic kidney disease that improved with treatment withdrawal • It was a treatment related adverse effect facilitated by RAAS inhibitors

  29. ACEIs and ARBs cause compensatory rises in PRA Kidney • Glomerularvasoconstriction • Inflammation • Fibrosis Angiotensinogen Renin Heart Ang I • Hypertrophy • Fibrosis • Vasoconstriction PRA Non ACE pathways ACE ACEIs Feedback Loop Vessels • Hyperplasia hypertrophy • Inflammation • Oxidation • Fibrosis Ang II ARBs AT1 Receptor Brain • Vasoconstriction Biological effects Adapted from Müller DN & Luft FC. 2006

  30. Direct renin inhibition neutralizes the PRA rise Direct renin inhibitor Kidney • Glomerularvasoconstriction • Inflammation • Fibrosis Angiotensinogen Renin Heart Ang I • Hypertrophy • Fibrosis • Vasoconstriction Non ACE pathways PRA ACE Feedback Loop Vessels • Hyperplasia hypertrophy • Inflammation • Oxidation • Fibrosis Ang II AT1 Receptor Brain • Vasoconstriction Biological effects Adapted from Müller DN & Luft FC. 2006

  31. All patients continue to receive open-label losartan 100 mg and optimal antihypertensive therapy during the double-blind period Patients force-titrated after 12 weeks All treatments administered once daily AVOID – Design overview Randomization Aliskiren 150 mg Aliskiren 300 mg Placebo Placebo + Losartan 100 mg + optimal antihypertensive therapy Open-label Double-blind 12–14 weeks 12 weeks 12 weeks Parving H-H et al. N Engl J Med 2008; 358: 2433-46

  32. Aliskiren significantly reduced UACR from baseline to week 24 compared with placebo Mean change from baseline in UACR (%) 5 2% 0 –5 20% reduction in UACR vs placebo –10 –15 *p = 0.0009 –18% * –20 Aliskiren (n = 287) Placebo (n = 289) Data shown as percentage change in geometric mean UACR, urinary albumin:creatinine ratio Parving H-H et al. N Engl J Med 2008; 358: 2433-46

  33. ALTITUDE – Design overview Randomization Aliskiren 150 mg Aliskiren 300 mg once daily Placebo Conventional treatment (according to national guidelines; must include an ACEI or ARB, but not both) 4–12 weeks 4 weeks ~4 years* *ALTITUDE is an event driven study and will conclude when ~1628 patients meet the primary endpoint

  34. Locatelli et al, Nephron Clin Pract. 2009 Sep; 113(4):c286-c293

  35. Inhibition of the Renin-Angiotensin System in Chronic Kidney Disease: A Critical Look to Single and Dual Blockade Editorial Comment M. El Nahas, Sheffield This review by Locatelli offers the readers a critical appraisal of the literature relating to the inhibition of the renin-angiotensin-aldosterone system (RAAS) in CKD. It gives a balanced well-informed view of the literature on the subject It is not always easy to jump off a bandwagon such as ‘ACE inhibition for all’, but some have the courage and knowledge to ask pertinent questions. The Authors of this minireview certainly do — — Locatelli et al, Nephron Clin Pract. 2009 Sep; 113(4):c286-c293

  36. How to reconcile all these findings and use them in Everyday Clinical Practice? ACE inhibitors and ARBs are effective therapeutic strategies to slow down CKD progression in diabetic and non-diabetic proteinuric nephropathies. Data about dual blockade are less strong, but suggest a significant antiproteinuric effect Bearing in mind the experience of the ONTARGET study, treatment success may be increased by starting with low doses and adding a second agent with caution only in selected patients (proteinuric patients are more likely to benefit from dual blockade) using an individualized approach — Data about dual blockade suggest a significant antiproteinuric effect — Treatment with low doses and adding a second agent with caution in proteinuric patients Locatelli et al, Nephron Clin Pract. 2009 Sep; 113(4):c286-c293

  37. Is Dual Blockade Really Harmful? Considering that those receiving the combination therapy had more frequently hypotensive symptoms than those receiving monotherapy, it is possible that some of them suffered from unappreciated chronic heart failure; excessive hypotension may have caused the acute worsening of renal function — Excessive hypotension may have caused the acute worsening of renal function Locatelli et al, Nephron Clin Pract. 2009 Sep; 113(4):c286-c293

  38. Is Dual Blockade Really Harmful? Ischemic nephropathy due to bilateral renovascular disease is increasingly recognised as a cause of CKD stage V in the elderly It is possible that in this high-risk population some of the patients had unknown stenosis of the renal artery or increased intra-renal vascular resistance. In this situation, dual blockade may have precipitated acute renal failure — Ischemic nephropathy due to bilateral renovascular disease — Unknown stenosis of the renal artery or increased intra-renal vascular resistance Locatelli et al, Nephron Clin Pract. 2009 Sep; 113(4):c286-c293

  39. 165 CKD patients already receiving ACEI/ARBs Percent reduction of proteinuria from baseline according to eGFR 83 patients spironolactone 25 mg/day for 1 yr ACEI/ARBs 82 patients ACEI/ARBs Long-term effects of spironolactone on proteinuria and kidney function in CKD patients A prospective, randomised, open-label study Bianchi et al. Kidney Int (2006) 70, 2116–2123

  40. Long-term effects of spironolactone on proteinuria and kidney function in patients with chronic kidney disease Percent decline in eGFR Bianchi et al. Kidney Int (2006) 70, 2116–2123

  41. Moderate dietary sodium restriction added to ACE inhibition compared with dual blockade in lowering proteinuria and blood pressure: randomised controlled trial 52 patients with non-diabetic nephropathy Trial design: cross-over, four 6-week periods ACE inhibition (lisinopril 40 mg/day) during the entire study • Valsartan 320 mg/day • Placebo • Low sodium diet (target 50 mmol Na+/day) • Regular sodium diet (target 200 mmol Na+/day) Slagman MC et al. BMJ. 2011; 343: d4366.

  42. Changes in proteinuria related to blood pressure in diabetics on different antihypertensive drugs 100 Conventional diuretic  b - blocker 50 0 Change in proteinuria ( % ) ACE inhibitor - 50 - 100 0 - 30 - 20 - 10 Change in mean blood pressure ( % ) Weidmann P et al Nephrol Dial Transplant 1995; 10: 39 - 45

  43. The sameblood pressure target for everybody? CKD and albuminuria PA < 130/80 CKD without albuminuria PA < 140/90 CKD and previous stroke PA < 130/80 ?? CKD and ischemic heart disease PA < 140/90 ??

  44. January 2008 | Volume 148 Issue 1 | Pages 30-48 Meta-analysis: Effect of Monotherapy and Combination Therapy with Inhibitors of the Renin-Angiotensin System on Proteinuria in Renal Disease Kunz R, Friedrich C, Wolbers M and Mann FE Combination ACE and ARB therapy

  45. The impact of stopping inhibitors of the RAS in patients with advanced CKD Changes in eGFR after stopping ACEi/ARB AK Ahmed… and AM El Nahas. Nephrol Dial Transplant 2010; 25: 3977–3982

  46. The impact of stopping inhibitors of the RAS in patients with advanced CKD Course of selected patients with sustained improvement in eGFR (>25%) up to 54 months after stopping ACEi/ARB AK Ahmed… and AM El Nahas. Nephrol Dial Transplant 2010; 25: 3977–3982

  47. Slowing down CKD progression: Blood pressure reduction RAS inhibition Low protein diet Statins Anemia correction Smoking cessation Vitamin D?

  48. 1.0 LPD 0.8 CPD 0.6 Renal survival N = 456 0.4 0.2 10 15 20 25 30 0 5 Time (months) Locatelli F et al. LANCET 1991; 337: 1299-04

  49. The Effects of Dietary Protein Restriction and Blood-Pressure Control on the Progression of Chronic Renal Disease Saulo Klahr, Andrew S. Levey, Gerald J. Beck, Arlene W. Caggiula, Lawrence Hunsicker, John W. Kusek, Gary Striker, for The Modification of Diet in Renal Disease Study Group

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