SLOWING PROGRESSION Mark SLOWING PROGRESSION OF KIDNEY DISEASE

Mark Rosenberg MD

University of MinnesotaOF KIDNEY DISEASE Minnesota

OUTLINEOUTLINE

1. Epidemiology of progression

2. Therapy to slow progressionBl d P t la. Blood Pressure control

b. Renin-angiotensin-aldosterone blockade

c. Dietary protein restriction

d. Bicarbonate

e. Delivery of care

f Future therapiesf. Future therapiesI. Endothelin receptor antagonism

II. Therapy directed at inflammation/oxidant stress

III Anti fibrotic therapyIII. Anti-fibrotic therapy

3. Conclusions

EPIDEMIOLOGY OF PROGRESSIONEPIDEMIOLOGY OF PROGRESSION

WHY IDENTIFY PATIENTS WITH EARLY CKD ?

Manage complications

AnemiaAnemia

Mineral and bone disorders

Hypertension

C di l **Cardiovascular **

Slow progressionp g

Plan for renal replacement therapy

PATHOPHYSIOLOGY OF PROGRESSIONPATHOPHYSIOLOGY OF PROGRESSION

Hyperfiltration

R i i i ldRenin-angiotensin-aldosterone

Inflammation/oxidant stressInflammation/oxidant stress

Genetic susceptibility

BP CONTROLBP CONTROL

INVEST (136 mmHg)

Trial SBP achieved

CONVINCE (137 mmHg)ALLHAT (138 mmHg)IDNT (138 mmHg)IDNT (138 mmHg)RENAAL (141 mmHg)UKPDS (144 mmHg)ABCD (132 mmHg)MDRD (132 mmHg)HOT (138 mmHg)HOT (138 mmHg)AASK (128 mmHg)

Number of BP Meds1 2 3 4

Bakris GL. Am J Kidney Dis. 2000;36(3):646-616

Number of BP Meds

Bakris

• 2272 subjects, non-diabetic kidney disease, trials comparing 2 different BP levels• MDRD• AASK• AASK• REIN-2

• BP target 125/75-130/80 not better than <140/90BP target 125/75 130/80 not better than <140/90• Low target may be beneficial in subgroups with

proteinuria >300-1000 mg/dproteinuria >300 1000 mg/d• Low BP needed more medications and had more

adverse eventsadverse events• SPRINT Study underway

MDRD STUDY(MAP 107 VS 92 MMHG)

d GFR 13-24GFR 25-55

n = 32n = 63n = 136n = 54n = 104n = 420

Usual 140/90 (mean 102 107)JAMA. 2002;288(19):2421-2431. doi:10.1001/jama.288.19.2421

Usual 140/90 (mean 102-107)Lower 125/75 (mean 92)

ADVERSE EFFECTS OF ANGIOTENSIN II

Efferent arteriole glomerular capillary hypertension

proteinuria

Loss of podocytes

⇑ mesangial matrix⇑ mesangial matrix and proliferation

Afferent arteriole

Pro-fibrotic

proinflammatory

The renin-angiotensin-aldosterone system

Angiotensinogen Slide from Parving

Angiotensin I

Renin Renin Inhibitor

Angiotensin I

ACE-IACE

Angiotensin II

Angiotensin II receptor

ARB

Aldosterone antagonistAngiotensin II receptor Aldosterone antagonist

Aldosterone Aldosterone receptor

BENEFICIAL EFFECT OF RAS INHIBITION

Diabetic patientsNormoalbuminuric normotensive Microalbuminuric normotensiveDiabetic nephropathyDiabetic nephropathy

Non-diabetic kidney disease

Angiotensin II receptor blockade = Angiotensin converting enzyme inhibition

20% risk reduction

Group 1: Cr 1.5-3.0Group 2: Cr 3.1-5.0P i iPrimary outcome: time to doubling of Cr, ESRD, death

Hyperkalemia not a problem

EXPERIMENTAL MODELS IMPLICATINGALDOSTERONE AS A PATHOGENIC FACTOR

Remnant kidneyDOCA saltDOCA saltRadiation nephritisCyclosporine toxicityDi b tDiabetesObstructionOther models of hypertension

Efficacy of Eplerenone in Type 2 diabetic Patients with Albuminuria treated with Enalapril 20 mg dailyAlbuminuria treated with Enalapril 20 mg daily

Antiproteinuric effects after 12 weeks treatmentPlacebo Eplerenone Eplerenone

50 mg 100 mg

Antiproteinuric effects after 12 weeks treatment

10

0

g g(n=80) (n=83) (n=77)

e (%

)

7-20

-10

hang

e - 7

-40

-30

CR

Ch

60

-50

UA

C - 41*- 44 *

*p<0 01 vs placebo-60

Epstein M et al., Clin J Am Soc Nephrol 1: 940-951, 2006

p<0.01 vs. placebo

The renin-angiotensin-aldosterone system

Angiotensinogen Slide from Parving

Angiotensin I

Renin Renin Inhibitor

Angiotensin I

ACE-IACE

Angiotensin II

Angiotensin II receptor

ARB

Aldosterone antagonistAngiotensin II receptor Aldosterone antagonist

Aldosterone Aldosterone receptor

RAS blockade Dual blockade RAS blockade

1993 2003 2008 2012 2013

Randomized controlled trialR i il 10 t l i t 80 b thRamipril 10mg, telmisartan 80 mg or both25,620 subjects, age 55 with established ASCVD or diabetes with end organ damageFU 56 months

ONTARGET ENDPOINTSONTARGET ENDPOINTS

Primary outcome: dialysis, doubling of Cr, death

Secondary outcome: dialysis or doubling of Cr

Secondary outcome: dialysis

Combination therapy: worse l t d it lrenal outcomes despite lower

proteinuria

• 8561 with DM2 and CKD, CVD or both

• Aliskiren (300 mg/d) or placebo ( g ) padded to ARB

• Primary end point: time to CVD (cardiac arrest, MI, stroke, unplanned(cardiac arrest, MI, stroke, unplanned hospitalization for heart failure), ESRD, death to kidney failure, doubling of Cr need for RRTdoubling of Cr, need for RRT

• Study stopped: no difference in end point, more K>6 and hypotension

ith bi tiwith combination• >reduction in proteinuria with

aliskiren

• 134 subjects j• CrCl 15-30• Serum HCO3 16-20

2 f ll• 2 year follow up

• 120 subjects• MacroalbuminuricMacroalbuminuric

hypertensive nephropathy

• GFR 60 90• GFR 60-90• 5 year follow up

No effect of renal disease progression: ESRD, death, or d bli f ti idoubling of creatinine

FUTURE THERAPIESFUTURE THERAPIES

Endothelin antagonists

Therapy directed at inflammation/oxidant stressinflammation/oxidant stress

Anti-fibrotic therapy

Cellular therapy

ENDOTHELIN 1ENDOTHELIN-1

Atrasentan treatment significantly reduces albuminuria.

Kohan D E et al. JASN 2011;22:763-772

©2011 by American Society of Nephrology

89 subjects with DN2, eGFR >20, Ualb/Cr 100-3000 mg/g

Atrasentan treatment significantly increases the percentage of subjects achieving ≥ 40% reduction in UACR compared to placebo.

Kohan D E et al. JASN 2011;22:763-772

©2011 by American Society of Nephrology

• BEAM Study• Antioxidant inflammation modulator - activates nrf 2 –

transcription factor that controls 250 cytoprotective proteins and inhibits NF-kB227 DM2 GFR 20 45• 227 DM2 eGFR 20-45

BEACON: Bardoxolone Methyl Evaluation in Patients with CKD and Type 2 Diabetes: The Occurrence of Renal Events (Phase III)yp ( )

Study stopped - "for safety concerns due to excess serious adverse events and mortality in the bardoxolone methyl arm."

• 113 patients eGFR <60 randomly assigned to allopurinol 100 mg/d orassigned to allopurinol 100 mg/d or usual therapy; measurements at 6, 12 and 24 months

• Decrease in uric acid GFR changes• Decrease in uric acid, GFR changes, decreased CV events

• 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 rashN=26 N=26 N=25

p y

DELIVERY OF CAREDELIVERY OF CARE

Multidisciplinary CKD programs “CKD Clinic”Better adherence to guidelinesg

Fistula first

Outpatient dialysis startsOutpatient dialysis starts

Early nephrology referralEarly nephrology referralAccess to a nephrologist for >1 year before dialysis initiation decreases mortalityinitiation decreases mortality

TELEHEALTHTELEHEALTH

CONCLUSIONSCONCLUSIONS

Lower BP – exact target unclear but be more aggressive in those patients with >proteinuriagg p p

Use RAAS blockade but only single agent

Keep HCO >22; consider low protein dietsKeep HCO3 >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

Questions / Comments?

Courtesy of Jeff Connaire

OTHER THERAPYOTHER THERAPY

Glycemic controlDCCT – decreased transition from micro to macroalbuminuriaACCORD – stringent diabetes control reduced the transition to micro and macro albuminuriaalbuminuriaADVANCE – no difference in ESRDMinimal data of progression

PhosphatePhosphateAssociated with faster decline in GFRNo trials

Vitamin DNo trialsVITAL (paricalcitol) lowered albuminuria in DN

Lipid Observational studies demonstrate association between high lipids and progressionMeta analysis – small but sig effect on decline in GFR with statins vs placeboSHARP – no effect on progression (simvastatin 20 + ezetimibe 10 mgp g ( g

RATES OF PROGRESSIONRATES OF PROGRESSION

Study Disease Rate of progression(ml/min/year)

Normal aging None .5 – 1.0

AASK Hypertensive kidney disease 1.9 – 2.2