SLOWING PROGRESSION OF KIDNEY DISEASE. Mark Rosenberg MD University of Minnesota

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1 SLOWING PROGRESSION OF KIDNEY DISEASE Mark Rosenberg MD University of Minnesota

2 OUTLINE 1. Epidemiology of progression 2. Therapy to slow progression a. Blood Pressure control b. Renin-angiotensin-aldosterone blockade c. Dietary protein restriction d. Bicarbonate e. Delivery of care f. Future therapies I. Endothelin receptor antagonism II. III. 3. Conclusions Therapy directed at inflammation/oxidant stress Anti-fibrotic therapy

3 EPIDEMIOLOGY OF PROGRESSION

6 WHY IDENTIFY PATIENTS WITH EARLY CKD? Manage complications Anemia Mineral and bone disorders Hypertension Cardiovascular C l ** Slow progression Plan for renal replacement therapy

8 PATHOPHYSIOLOGY OF PROGRESSION Hyperfiltration Renin-angiotensin-aldosterone Inflammation/oxidant stress Genetic susceptibility

9 BP CONTROL

10 Trial SBP achieved INVEST (136 mmhg) CONVINCE (137 mmhg) ALLHAT (138 mmhg) IDNT (138 mmhg) RENAAL (141 mmhg) UKPDS (144 mmhg) ABCD (132 mmhg) MDRD (132 mmhg) HOT (138 mmhg) AASK (128 mmhg) Bakris Number of BP Meds Bakris GL. Am J Kidney Dis. 2000;36(3):

11 2272 subjects, non-diabetic kidney disease, trials comparing 2 different BP levels MDRD AASK REIN-2 BP target 125/75-130/80130/80 not better than <140/90 Low target may be beneficial in subgroups with proteinuria > mg/d Low BP needed more medications and had more adverse events SPRINT Study underway

12 MDRD STUDY (MAP 107 VS 92 MMHG) d GFR GFR n = 420 n = 104 n = 54 n = 136 n = 63 n = 32

13 Usual 140/90 (mean ) 107) Lower 125/75 (mean 92) JAMA. 2002;288(19): doi: /jama

16 ADVERSE EFFECTS OF ANGIOTENSIN II Efferent arteriole glomerular capillary hypertension proteinuria Loss of podocytes mesangial matrix and proliferation Pro-fibrotic Afferent arteriole proinflammatory

17 The renin-angiotensin-aldosterone system Angiotensinogen Slide from Parving Renin Renin Inhibitor Angiotensin I ACE ACE-I Angiotensin II ARB Angiotensin II receptor Aldosterone antagonist Aldosterone Aldosterone receptor

18 BENEFICIAL EFFECT OF RAS INHIBITION Diabetic patients Normoalbuminuric normotensive Microalbuminuric normotensive Diabetic nephropathy Non-diabetic kidney disease Angiotensin II receptor blockade = Angiotensin converting enzyme inhibition 20% risk reduction

19 Group 1: Cr Group 2: Cr Pi Primary outcome: time to doubling of Cr, ESRD, death Hyperkalemia not a problem

21 EXPERIMENTAL MODELS IMPLICATING ALDOSTERONE AS A PATHOGENIC FACTOR Remnant kidney DOCA salt Radiation nephritis Cyclosporine toxicity Diabetesb t Obstruction Other models of hypertension

22 Efficacy of Eplerenone in Type 2 diabetic Patients with Albuminuria treated with Enalapril 20 mg daily Antiproteinuric effects after 12 weeks treatment UAC CR Ch hange (%) Placebo Eplerenone Eplerenone 50 mg 100 mg (n=80) (n=83) (n=77) - 7 *p< vs. placebo - 41* - 44 * Epstein M et al., Clin J Am Soc Nephrol 1: , 2006

24 The renin-angiotensin-aldosterone system Angiotensinogen Slide from Parving Renin Renin Inhibitor Angiotensin I ACE ACE-I Angiotensin II ARB Angiotensin II receptor Aldosterone antagonist Aldosterone Aldosterone receptor

25 RAS blockade Dual blockade RAS blockade

26 Randomized controlled trial Ramiprili il 10mg, telmisartan t 80 mg or both 25,620 subjects, age 55 with established ASCVD or diabetes with end organ damage FU 56 months

27 ONTARGET ENDPOINTS Primary outcome: dialysis, doubling of Cr, death Secondary outcome: dialysis or doubling of Cr Secondary outcome: dialysis Combination therapy: worse renal outcomes despite lower proteinuria

28 8561 with DM2 and CKD, CVD or both Aliskiren (300 mg/d) or placebo added to ARB Primary end point: time to CVD (cardiac arrest, MI, stroke, unplanned hospitalization for heart failure), ESRD, death to kidney failure, doubling of Cr, need for RRT Study stopped: no difference in end point, more K>6 and hypotension with combination >reduction in proteinuria with aliskiren

32 134 subjects CrCl Serum HCO year follow up

33 120 subjects Macroalbuminuric hypertensive nephropathy GFR year follow up

35 No effect of renal disease progression: ESRD, death, or doubling of creatinine i

36 FUTURE THERAPIES Endothelin antagonists Therapy directed at inflammation/oxidant stress Anti-fibrotic therapy Cellular therapy

37 ENDOTHELIN-1

39 Atrasentan treatment significantly reduces albuminuria. Kohan D E et al. JASN 2011;22: subjects with DN2, egfr >20, Ualb/Cr mg/g 2011 by American Society of Nephrology

40 Atrasentan treatment significantly increases the percentage of subjects achieving 40% reduction in UACR compared to placebo. Kohan D E et al. JASN 2011;22: by American Society of Nephrology

42 BEAM Study Antioxidant inflammation modulator - activates nrf 2 transcription factor that controls 250 cytoprotective proteins and inhibits NF-kB 227 DM2 egfr 20-45

44 BEACON: Bardoxolone Methyl Evaluation in Patients with CKD and Type 2 Diabetes: The Occurrence of Renal Events (Phase III) Study stopped - "for safety concerns due to excess serious adverse events and mortality in the bardoxolone methyl arm."

46 113 patients egfr <60 randomly assigned to allopurinol 100 mg/d or usual therapy; measurements at 6, 12 and 24 months Decrease in uric acid, GFR changes, decreased CV events

47 77 patients with DN egfr 20-75, albuminuria Primary outcome change in egfr at 1 year 2400 mg group high dropout rate (11/25) GI symptoms fatigue photosensitivity rash N=26 N=26 N=25

48 DELIVERY OF CARE Multidisciplinary CKD programs CKD Clinic Better adherence to guidelines Fistula first Outpatient dialysis starts Early nephrology referral Access to a nephrologist for >1 year before dialysis initiation decreases mortality

50 TELEHEALTH

52 CONCLUSIONS Lower BP exact target unclear but be more aggressive in those patients with >proteinuria Use RAAS blockade but only single agent Keep HCO 3 >22; consider low protein diets Early nephrology referral and coordinated CKD care The future: endothelin antagonists, antifibrotic agents, antioxidants, cellular therapy Future trial to watch for: SPRINT

53 Questions / Comments?

54 Courtesy of Jeff Connaire

56 OTHER THERAPY Glycemic control DCCT decreased transition from micro to macroalbuminuria ACCORD stringent diabetes control reduced the transition to micro and macro albuminuria ADVANCE no difference in ESRD Minimal data of progression Phosphate Associated with faster decline in GFR No trials Vitamin D No trials VITAL (paricalcitol) lowered albuminuria in DN Lipid Observational studies demonstrate association between high lipids and progression Meta analysis small but sig effect on decline in GFR with statins vs placebo SHARP no effect on progression (simvastatin 20 + ezetimibe 10 mg

57 RATES OF PROGRESSION Study Disease Rate of progression (ml/min/year) Normal aging None AASK Hypertensive kidney disease

Aggressive blood pressure reduction and renin angiotensin system blockade in chronic kidney disease: time for re-evaluation?

http://www.kidney-international.org & 2013 International Society of Nephrology Aggressive blood pressure reduction and renin angiotensin system blockade in chronic kidney disease: time for re-evaluation?