Delaying Progression. Paul Drawz, MD, MHS, MS Assistant Professor of Medicine University of MN Minneapolis, MN

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1 Delaying Prgressin Paul Drawz, MD, MHS, MS Assistant Prfessr f Medicine University f MN Minneaplis, MN

2 Disclsure Paul Drawz, MD, MHS, MS has n financial relatinships with cmmercial interest(s).

3 Learning Objective Identify strategies fr delaying the prgressin f CKD in at-risk patients.

4 Sessin Outline Recgnize evidence-based management strategies that will help delay CKD prgressin in at-risk patients and imprve utcmes. ACEI/ARBs DM cntrl Recgnize that BP lwering des nt slw prgressin f CKD Recgnize uncnventinal treatment strategies t slw prgressin f CKD

5 Self Assessment Questins 1. Target bld pressure in nn-dialysis diabetic CKD with a albumin-tcreatinine rati f <30mg/g shuld be: <120/80mmHg <140/90mmHg <150/90mmHg <130/80mmHg 2. A 55 year-ld Caucasian-American man, with a histry f type 2 diabetes (15 years), hypertensin (3 years) dyslipidemia (5 years) and cardivascular disease (mycardial infarctin 3 years ag). He was recently diagnsed with CKD. His mst recent labs reveal an egfr f 45 ml/min/1.73m 2 and an ACR f 38 mg/g. Which f the fllwing shuld be avided? ACE and ARB in cmbinatin Daily lw-dse aspirin NSAIDs Statins A and C

6 Steps t CKD Patient Care 1. Des the patient have CKD? 2. Assess GFR, albuminuria 3. Determine etilgy 4. Assess fr evidence f prgressin 5. Assess fr assciated cmplicatins 6. Patient educatin 7. Assess life expectancy and patient wishes fr dialysis/transplantatin

7 Delaying Prgressin f CKD

8 GFR 100 CKD- Prgressin f Kidney Failure Cncept Variable depending n several factrs including (1) type f disease and (2) hw well it is treated Stage Stage 3 Stage 4 Stage 5 (Dialysis) Years

9 ACEI/ARBs t Slw CKD Prgressin Study Baseline Prteinuria ACEI/ARB Reductin in Renal Events Diabetic RENAAL UACR ~1250mg/g lsartan 21 (5 t 34) A IDNT Uprt 2.9g/24hr irbesartan 33 (13 t 48) D Lewis, et al. Uprt 2.7g/24hr captpril 48 (16 t 69) D HOPE 32% micralbuminuria ramipril 24 (3 t 40) B Nn-diabetic REIN 2 Uprt 5.3g/24hr ramipril 48 (9 t 70) A AIPRI Uprt 1.8g/24hr benazepril 53 (27 t 70) A REIN 1 Uprt 1.7g/24hr ramipril 63 (18 t 84) C AASK Uprt/Cr 0.5g/24hr ramipril 38 (10 t 58) E Hu, et al. Uprt 1.7g/24hr Benazepril 40 (P=0.02) C Outcmes: A: dubling f serum creatinine r ESRD; B: vert nephrpathy defined by 24 h urine albumin 300mg, 24 h urine prtein 500mg, r urine albumin/creatinine rati >36mg/mml; C: ESRD; D: dubling f serum creatinine; E: 50% decline in GFR r ESRD

10 ACEI/ARBs t Slw CKD Prgressin With prteinuria ACEi r ARB +/- diuretic N prteinuria ACEi r ARB preferred Fujisaki K, et al. Impact f cmbined lsartan/hydrchlrthiazide n prteinuria in patients with CKD and hypertensin. Hypertens Res. 2014;37:

11 Delaying CKD Prgressin: ACEi/ARB Check labs after initiatin If less than 25% SCr increase, cntinue and mnitr If mre than 25% SCr increase, stp ACEi and evaluate fr RAS Cntinue until cntraindicatin arises, n abslute egfr cutff Better prteinuria suppressin with lw Na diet (<2 g f sdium; r <5 g sdium chlride per day) and diuretics Avid vlume depletin and NSAIDs QUESTION- TRUE OR FALSE- ACEI-ARBs have been shwn t slw prgressin f CKD in patients with prteinuria?

12 Sessin Outline Recgnize evidence-based management strategies that will help delay CKD prgressin in at-risk patients and imprve utcmes. ACEI/ARBs DM cntrl Recgnize that BP lwering des nt slw prgressin f CKD Recgnize uncnventinal treatment strategies t slw prgressin f CKD

13 Managing Hyperglycemia Hyperglycemia is a fundamental cause f vascular cmplicatins, including CKD Pr glycemic cntrl has been assciated with albuminuria in type 2 diabetes. Risk f hypglycemia increases as kidney functin becmes impaired. Declining kidney functin may necessitate changes t diabetes medicatins and renally-cleared drugs. Target HbA1c ~7.0% Can be extended abve 7.0% with cmrbidities r limited life expectancy, and risk f hypglycemia. NKF KDOQI. Diabetes and CKD: 2012 Update. Am J Kidney Dis :

14 7 studies 28,065 participants Cnventinal cntrl versus intensive cntrl A1c 7.3 t 9.1 versus 6.4 t 7.4

15 Micralbuminuria 0.86 ( ) Macralbuminuria 0.74 ( )

16 Dubling f Serum Creatinine 1.06 ( ) ESRD 0.69 ( )

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18 Sessin Outline Recgnize evidence-based management strategies that will help delay CKD prgressin in at-risk patients and imprve utcmes. ACEI/ARBs DM cntrl Recgnize that BP lwering des nt slw prgressin f CKD Recgnize uncnventinal treatment strategies t slw prgressin f CKD

19 Lw BP targets and renal utcmes Tt et al. Lewis cllabrative study grup REIN-2 MDRD AASK

20 Tt et al CKD patients (GFR < 70), nrmal urine sediment, Uprt < 2g/d Randmized Strict (DBP 65 t 80, n = 42) Cnventinal (DBP 85 t 95, n = 35) Fllw up ~40m, mean DBP 81.1 and 87.1 GFR decline vs (P > 0.25) Secndary utcme 50% decline GFR, dubling Cr, ESRD r death 12 vs 7 (P > 0.25) Tt RD, KI, 1995, pg 851.

21 Type 1 DM with nephrpathy 129 subjects Cr <4 Randmized Lw MAP f 92 t 100 mmhg High MAP f 100 t 107 mmhg Fllw up >2yrs, avg MAP difference 6 mmhg All treated with ramipril Primary utcme abslute change in igfr Lw MAP 62 t 54 High MAP 64 t 58 Secndary utcme 24hr Uprt lwer in lw MAP grup Lewis JB, AJKD, 1999, pg 809.

22 REIN nn-dm patients receiving ramipril 1-3gm/24hr with CrCl <45 3gm/24hr with CrCl <70 Randmized DBP <90 Intensified BP cntrl (< 130/80) Median f/u 19m; difference in BP: 4.1/2.8 mmhg ESRD 20% in cnventinal arm 23% in intensified arm (P = 0.99) N difference in rate f GFR decline r Uprt Ruggenenti P, Lancet, 2005, pg 939.

23 MDRD Usual BP MAP 107 mmhg (140/90) Lw BP MAP 92 mmhg (125/75) Study subjects GFR 25 t 55 Mean decline in GFR (ml/min/3yrs) 12.3 in usual vs 10.8 in lw BP target (P = 0.18) Study subjects GFR 13 t 24 Mean decline in GFR (ml/min/yr) 4.2 in usual vs 3.7 in lw BP target (P = 0.28) Klahr S, NEJM, 1994, pg 877.

24 Mean Rate f GFR Decline (ml/min/yr) Effect f lw BP target depends n baseline level f prteinuria 0 Study 1 Study 2 0 Lw BP target Usual BP target n = 420 n = 104 n = 54 n = 136 n = 63 n = 32 <1 1 <3 3 <1 1 <3 3 Base-Line Urinary Prtein (g/day) 12 Klahr S et al. N Engl J Med 1994;330:

25 MDRD lng term utcmes Kidney failure Kidney failure r all-cause mrtality Usual BP Usual BP Lw BP Lw BP Fllw-up, m Fllw-up, m Sarnak MJ, Ann Int Med, 2005, pg 342.

26 AASK African American, nn-dm, GFR Randmized Usual MAP (102 t 107 mmhg) Lw MAP (92 mmhg) Achieved BP 141/85 vs 128/78 GFR decline (ml/min/1.73m 2 /yr) Usual: 1.95 Lw: 2.21 (P = 0.24) N difference in 50% decline GFR, death, ESRD r cmpsite Wright JT Jr, JAMA, 2002, pg 2421.

27 AASK Dubling f Cr, ESRD r Death Accrding t Baseline Prteinuria Status Appel LJ, NEJM, 2010, pg 918.

28 Renal Outcmes Placeb Active treatment P value DBP 115 t 129 mmhg 2/70 0/ DBP 90 t 114 mmhg 3/191 0/

29 UKPDS subjects type 2 DM, median fu 8.4yrs At 9 years N difference in Cr r prprtin f patients with a dubling f Cr Outcme Tight cntrl Less tight cntrl RR Ualb > 50mg/l 28.8% 33.1% 0.87 (0.60 t 1.26) Ualb > 300mg/l 7.0% 6.6% 1.06 (0.42 t 2.67) UK Prspective Diabetes Study Grup, BMJ, 1998, pg 703.

30 Systlic Hypertensin in the Elderly Study (SHEP) 4736 men and wmen Randmized Active tx target SBP < 160 mmhg (r decrease 20 mmhg if baseline < 180 mmhg) Placeb Outcme Grup Active Placeb Cr 2mg/dl 1+ UPrt DM 4.5% 4.1% Nn-DM 2.6% 2.1% DM 32.3% 34.6% Nn-DM 17.2% 19.8% Curb JD et al, JAMA, 1996, pg 1886.

31 4,733 participants with type 2 DM SBP target <120mmHg vs. <140mmHg Achieved SBP 119mmHg vs mmHg Outcme Intense Standard HR P value Primary* 1.87 %/yr 2.09 %/yr 0.88 ( ) 0.20 Strke 0.32 %/yr 0.53 %/yr 0.59 ( ) 0.01 Death 1.28 %/yr 1.19 %/yr 1.07 ( ) 0.55 egfr < % 2.2 % <0.001 Macralbuminuria 6.6 % 8.7 % * Nnfatal MI, nnfatal strke, r death frm CV causes. ACCORD, NEJM, 2010, p1575.

32 BP targets in CKD CV risk reductin Target bld pressure in nn-dialysis CKD: 1 ACR <30 mg/g: 140/90 mm Hg ACR mg/g: 140/90 mm Hg* ACR >300 mg/g: 140/90 mm Hg* Individualize targets and agents accrding t age, cexistent CVD, and ther cmrbidities Avid ACEi and ARB in cmbinatin 3,4 Risk f adverse events (impaired kidney functin, hyperkalemia) QUESTION True r False Intense BP lwering slws prgressin f CKD? *Reasnable t select a gal f 140/90 mm Hg, especially fr mderate albuminuria (ACR mg/g.) 2 1) 2014 Evidence-Based Guideline fr the Management f High Bld Pressure in Adults - Reprt Frm the Panel Members Appinted t the Eighth Jint Natinal Cmmittee (JNC 8), JAMA. 2014;311(5): ) Kidney Disease: Imprving Glbal Outcmes (KDIGO) Bld Pressure Wrk Grup. Kidney Int Suppl. (2012);2: ) KDOQI Cmmentary n KDIGO Bld Pressure Guidelines. Am J Kidney Dis. 2013;62: ) Kunz R, et al. Ann Intern Med. 2008;148:30-48.

33 Sessin Outline Recgnize evidence-based management strategies that will help delay CKD prgressin in at-risk patients and imprve utcmes. ACEI/ARBs DM cntrl Recgnize that BP lwering des nt slw prgressin f CKD Recgnize uncnventinal treatment strategies t slw prgressin f CKD

34 Metablic Acidsis Often becmes apparent at GFR < ml/min Mre severe with higher prtein intake May cntribute t bne disease, prtein catablism, and prgressin f CKD Crrectin f metablic acidsis may slw CKD prgressin and imprve patients functinal status 1,2 Adults with CKD (egfr ml/min/1.73m 2 ) with bicarbnate mml/l; treated with sdium bicarbnate fr 2 years t nrmalize serum bicarbnate cncentratin 2 1) Mahajan, et al. Kidney Int. 2010;78: ) de Brit-Ashurst I, et al. J Am Sc Nephrl. 2009;20:

35 Metablic Acidsis Maintain serum bicarbnate > 22 mml/l Start with meq/kg per day Sdium bicarbnate tablets 325mg, 625 mg tablets; 1 g = 12 meq Sdium citrate slutin 1 meq/ml Avid if n aluminum phsphate binders Baking sda 54 mml/level tsp

36 Allpurinl? Randmized cntrlled trial 54 patients with either Uprt > 0.5g/24hr r Cr >1.35mg/dL (but <4.5) Uric acid >7.6mg/dL Allpurinl 100mg/d versus placeb Cr 1.64 t 1.99 versus 1.86 t 2.89 (P=0.08) Deteriratin in renal functin: 16% versus 46% (P=0.02) Siu et al, AJKD, 2006, p51.

37 Allpurinl RCT #2 113 patients egfr <60 ml/min/1.73m2 Allpurinl 100mg/day versus usual therapy After 24 mnths, treatment with allpurinl: Lwered uric acid: 6.0 vs 7.5 (P<0.001) Stabilized egfr: 42.2 vs (P<0.001) N effect n albuminuria N effect n bld pressure HR fr new CV events: 0.29 (0.09 t 0.86) Gicechea et al, cjasn, 2010, p1388.

38 Impact f primary care CKD detectin with a patient safety apprach Patient Safety Fllwing CKD detectin Imprved diagnsis creates pprtunity fr strategic preservatin f kidney functin Fink et al. Am J Kidney Dis. 2009,53:

39 Discuss Take Hme Pints

40 Self Assessment Questins 1. Target bld pressure in nn-dialysis diabetic CKD with a albumin-t-creatinine rati f <30mg/g shuld be: A. 120/80mmHg B. *140/90mmHg* C. 150/90mmHg D. 130/80mmHg B Ratinale: Cmparisn f Guideline Recmmendatins fr CKD Bld Pressure Targets amng reliable surces, including JAMA2014 and KDIGO2012, cntain similar recmmendatins as less than 140/90 mm Hg in CKD 2. A 55 year-ld Caucasian-American man, with a histry f type 2 diabetes (15 years), hypertensin (3 years) dyslipidemia (5 years) and cardivascular disease (mycardial infarctin 3 years ag). He was recently diagnsed with CKD. His mst recent labs reveal an egfr f 45 ml/min/1.73m 2 and an ACR f 38 mg/g. Which f the fllwing shuld be avided? A. ACE and ARB in cmbinatin B. Daily lw-dse aspirin C. NSAIDs D. Statins E. *A and C* E. Ratinale: ACE and ARBs used in cmbinatin have been shwn t increase adverse events, particularly impaired kidney functin and hyperkalemia. NSAIDs have been shwn t cause kidney damage and increase CKD prgressin. Statins are indicated based n KDIGO guidelines and a daily lw-dse aspirin is nt cntraindicated in CKD.

41 Questins and Answers

42 Additinal Resurces KDOQI Clinical Practice Guideline Fr Diabetes: Update ntaries Hypertensin and Antihypertensive Agents in Chrnic Kidney Disease (2004) Natinal Kidney Fundatin Tl: Self-Management, Diabetes and CKD ent.pdf