CHRISTIAN W. MENDE, MD FACP,FACN,FASN,FASH

Clinical Professor of Medicine, University of California, San Diego

La Jolla, Calif.

Hypertension and Kidney Disease( CKD ) in Diabetes

Hypertension and Kidney Disease( CKD ) in Diabetes

FACULTY DISCLOSURE

Company Nature of AffiliationUnlabeled Product

Usage

NONE Boehringer

Ingelheim Lilly Janssen ( J&J ) Forest AstraZenica

Speakers Bureau

Hypertension Incidence ( USA )

33 % US Population > age 21 50 % > age 60 75 % > age 75 90% > age 90

70 – 80% Hypertension in Diabetes mellitus

Awareness of Hypertension 81 % On Therapy 75 % CDC ( 2014 ) 64%* at Goal !

Go AS. et al 2013 AHA Update ,Circulation 127: 143-52 * Morbidity and Mortality Weekly Report , 2/14/ 2014

DIABETES Incidence 2015 ( USA )

13 % Diabetes FBS >125 , 2 hr PP > 199 A1C 6.5 % and above

38 % Prediabetes FBS 100 -125 or 2hr PP 140-199 mg A1C 5.6 - 6.4% 51 % PREDIABETES and DIABETES !!

Menke,A. et.al. JAMA 2015;314 (10),1021

CKD Incidence in Diabetes

Stage CKD 3a ( eGFR 45 – 59 ml /min )

> age 21 = 22 % > age 65 = 43 %

Stage CKD 3b ( eGFR 30 – 44 ml / min )

> age 21 = 9 % > age 65 = 18 %

Bailey RA et.al BMC Research Note ,2014 ;7:421

OBESITY in HYPERTENSION / DIABETES

1) 68 % of US adults are Overweight ( BMI > 25 ) 33 % Obesity ( BMI > 30 ) 33 to 38 % Metabolic Syndrome

2) ~ 75 % of Obese Patients have Hypertension

3) 70 -80 % of Type 2 Diabetes are Overweight or Obese

4) 1/3 of US Adults ( 18 and older ) have Hypertension

5) 50% of all Hypertensive have BMI > 30

Linear Relationship between Weight and SBP ( BMI 25- 35 )

1 kg (2.2 lbs ) Weight Gain or Loss = 1 mmHg Systolic BP CHANGE

DefinitionsDefinitions

Hypertention ( HTN )Hypertention ( HTN ) JNC 8 , ASH , ADA , ASN JNC 8 , ASH , ADA , ASN

BP > 140 / 90 mmHgBP > 140 / 90 mmHg

Chronic Kidney Disease Chronic Kidney Disease ( KDIGO 2013 ) ( KDIGO 2013 )present ≥ 3 months :present ≥ 3 months :

a) a) eGFR < 60 ml/min eGFR < 60 ml/min / 1.73 m² or/ 1.73 m² orb) b) Albuminuria ≥ 300 mgAlbuminuria ≥ 300 mg or orc) Abnormal Histology ( Biopsy ) or c) Abnormal Histology ( Biopsy ) or

TransplantationTransplantation

Definitions Definitions

Progression of CKDProgression of CKDa) Loss of ≥ 5 ml eGFR / Yeara) Loss of ≥ 5 ml eGFR / Yearb) Change of Category ( i.e. CKD b) Change of Category ( i.e. CKD

3 to 4 )3 to 4 )c) Loss of ≥ 25 % from Baselinec) Loss of ≥ 25 % from Baseline

Resistant HypertensionResistant HypertensionUse of Use of 33 antihypertensive antihypertensive DrugsDrugs in full in full Doses including a Doses including a Diuretic Diuretic and and BP BP NOT at GoalNOT at Goal. .

How to Obtain a Correct Blood Pressure

• Sitting with Back Support , both Legs on Floor• Rest for at least 3 min• Ascertain correct Cuff Size• Obtain 3 Readings about 2 min apart• Discard 1st Reading and average 2nd and 3rd

• Obtain HOME BP Readings , if possible

JNC 7, JAMA 2003

Office BP Details

How many BP Readings are ideal ?

AHA and JNC 7: Minimum of 2 sitting BP and average out both NHANES ( 1999 - 2008 )

Using 3 Readings and discarding # 1 and average # 2 and 3

RECLASSIFIES ~ 1/3 ( 35 % ) of Stage I Hypertension as

NORMOTENSIVE = NO THERAPY Needed

Handler J.et.al J.Clinical Hypertension , 2012 ;11: 751

HOME BP FACTS

1) 2 : 1 better Correlation of CV events HOME vs. OFFICE BP 2) Diagnoses MASKED Hypertension

3) Home BP taken x 2 / week for 48 weeks leads to

4 x More Likely Reaching BP GOAL ( Kim J.et.al. JCH , 2010; 12: 253-260 )

4) Diagnoses WHITE COAT Hypertension

Hypertension and Dementia

Hypertension is associated with Vascular Dementia ( Micro-Infarcts , CVA and Alzheimer;s Disease ) Systolic BP 110 -139 vs. > 160 mmHg Odds Ratio = 4.3 for Dementia ( Honolulu Heart )

Antihypertensive Therapy Lowers Risk of Alzheimer’s Disease Hazard Ratios : HCTZ 0.51 , ACEI 0.5, ARB 0.31 CCB 0.62 , BB 0.58 Gingko Evaluation / Memory study :1900 pat.= 6.1 year F/U

Proteinuria ( > 300 mg/d ) is associated with Cognitive Decline ( even without CKD )

ADA Blood Pressure Guidelines (2014)

GOAL < 140 / 90 mmHg

• Lower target : < 130 / 80 for young Patients ( if no side effects ) • ACE inhibitor or ARB : including ONE or more BP Drugs at Bedtime • Lifestyle : DASH style diet Weight Loss ( if BMI > 25 ) Salt < 6 gm ( 2300 mg Na ) Increase Potassium ( Fruit ,Vegetables ) 150 min exercise / week No Smoking ( Doubles CVD Mortality )

Standards of Medical Care in Diabetes – 2014 Diabetes Care 37,Suppl.1

Bedtime Dosing in Diabetes or CKD( at least 1 BP drug at HS )

DIABETES ABPM 48hrs: HTN present, if BP > 135 / 85 or Nocturnal BP > 120 / 70

448 patients on 3 drugs : using ONE Drug HS F/U 5.4 years

Each 5 mmHg Nocturnal SBP Decline = 12 % Decline of CV Events ( CVA, MI, CV death )

CKD * 695 patients with eGFR < 60 , 7 years F/U ( ABPM 48hrs as above)

Each 5 mmHg Nocturnal SBP Decline = 14 % Decline of CV Events

Hermida, RC, et.al. Diabetes Care 2011 ; 134: 1270-1276 *J Am Soc Nephrol. 2011 ; 22: 2313-2321

IDEAL Blood Pressure ? ( > 40,000 Hypertensives )

1 ) PROVE – IT- TIMI 4,162 patients

2 ) INVEST 6,400 patients with DM + CAD

3 ) ON TARGET 15,981 w/o and 9,603 with Diabetes

4) ACCORD 4,733 with Diabetes

LOWEST EVENT RATE ~ 135 /85 mmHg

Blood Pressure Lowering in Type II Diabetes

Systematic Review and Meta-analysis

Effect of 10 mmHg Systolic BP Reduction

Macro -vascular Risk Reduction ( ONLY if SBP > 140 at Baseline )

Mortality 13 % CVD , CHD 12 % CVA 27 %

Micro -vascular Risk Reduction ( Regardless of Baseline SBP )

Retinopathy 13 % Albuminuria 17 %

Emden CA et.al. ,JAMA 2015 ;313 (6) :603

SPRINT Trial

9300 hypertensive Patients with CKD or high Risk for CVD divided into 2 Groups : Systolic BP < 120 vs. < 140 mmHg ( Trial stopped > 2 Years early )

~ 23 % Reduction of Mortality ~ 31 % Reduction of MI , CVA , CHF

( Analysis of Adverse Events and Subgroups to follow ) Exclusions : Diabetes , prior CVA , PCK

( NIH press release 9/11/15 )

1) Average 1) Average MONO TherapyMONO Therapy ( Placebo corrected ) ( Placebo corrected )

9.1 / 5.5 mm Hg BP Reduction9.1 / 5.5 mm Hg BP Reduction

( in Stage I Hypertension , Law BMJ , 2003 ) ( in Stage I Hypertension , Law BMJ , 2003 )

2) NHANES ( 2007- 2010 ) Combination Therapy to Goal2) NHANES ( 2007- 2010 ) Combination Therapy to Goal

75 % needed 2 drugs75 % needed 2 drugs

25 % needed 3 drugs25 % needed 3 drugs

Mono /Combo - TherapyMono /Combo - Therapy

Metanalysis of 11,000 patients in 42 TrialsMetanalysis of 11,000 patients in 42 Trials

( ( Wald DS, et.al. Am. J. Med. 2009; 122 :290 )Wald DS, et.al. Am. J. Med. 2009; 122 :290 )

COMBO - THERAPY = 5 X more likely toCOMBO - THERAPY = 5 X more likely to ACHIEVE BP GOAL ACHIEVE BP GOAL ( in 6 month )( in 6 month )

Doubling of Mono – vs. Combo TherapyDoubling of Mono – vs. Combo Therapy

Combos Combos to to AVOIDAVOID in Hypertension in Hypertension

1) Beta Blocker + Verapamil or Diltiazem1) Beta Blocker + Verapamil or Diltiazem

2) Beta Blocker + Centrally acting antihypertensives2) Beta Blocker + Centrally acting antihypertensives ( Clonidine)( Clonidine)

DUAL RAAS BLOCKADEDUAL RAAS BLOCKADE : : 1) ACE Inhibitors + Angiotensin Receptor Blockers 1) ACE Inhibitors + Angiotensin Receptor Blockers ( ONTARGET trial )( ONTARGET trial ) 2) Aliskiren + ACE inhibotors ( ALTITUDE trial )2) Aliskiren + ACE inhibotors ( ALTITUDE trial ) 3) Aliskiren + ARB 3) Aliskiren + ARB

Aldactone and ACE inhibitors or ARB’s are excluded !Aldactone and ACE inhibitors or ARB’s are excluded !

Resistent and Refractory Hypertension Definitions :

Resistant Uncontrolled on 3 or more drugs incl. Diuretic and BP still > 140 / 90 or Controlled on 4 or more drugs with BP < 140 / 90 Refractory Uncontrolled on 5 or more classes of drugs ( Chlorthalidone , Aldactone ) and BP still > 140 / 90

Incidence :

Resistant Hypertension 10-15% of all treated Hypertensive Patients Refractory Hypertension 10 % of all Resistent Hypertension

Concern : High Risk for CV Events ( CVA, CAD, CHF ) Target Organ Damage ( LVH , Albuminuria, CKD ) Framingham CAD Score 2x compared with “ essential Hypertension “

Issues in Resistent Hypertension

1) 1/3 controlled by ABPM and therefore NOT “ Resistent “ (*)

2) Adherence German study using urine and blood drug analysis ONLY 53% Compliance (#)

3) Low Use Mineralocorticoid Antagonists ALDACTONE NHANES 3%

REGARDS 18 %

(#) Jung O et.al. J.Hypertens 2013 ;31: 766-774 REGARDS Study :Calhoun DA. Hypertension 2014; 63 :451

Guidelines to Resistent Hypertension

Exclude White Coat Effect ( 24 hr AMBP , Home BP )Assure Compliance ( MEMS or Urine screen for drugs )Use correct 3 Drug Regimen RAAS blocker , CCB and Diuretic ( Chlorthalidone ) Use Full Dosing of above Listed DrugsEvaluate for ALDO excess ( 20% !) Aldo / Renin ratio , CKD , PHEO OSA ( 96% of Males ! )Check for Excessive Salt Intake ( > 6 gm ) = 24 hr Urine NSAID Use ( may raise BP by 10 / 5 mmHg ) Drug Abuse ( Cocaine, Amphetamine, ETOH excess ) Use Beta Blockers ( Nebivolol / Carvedilol ) for Heart Rate > 80 /min Add ALDACTONE 12.5 – 25 mg / day !!

CKD Blood Pressure Guidelines

( With or Without DIABETES - KDIGO 2013 )

NO Albuminuria BP < 140 / 90 mmHg

Albuminuria > 30 mg / day BP < 130 / 80 mmHg Use ACEI or ARB’S if > 30mg /d Albuminuria Lifestyle : BMI > 20 – 25 , Salt < 6 gm ( 2400 mg Na ) Exercise 30 min 5 X / week

Cardiovascular Risks in Diabetes and CKD

1) Cardiovascular Risk in Diabetes ( MI, CVA ,CHF ) greater than CKD Progression: 70 % CVD Mortality 4 % reach ESRD ( Dialysis , Transplantation )

2) eGFR < 45 ml /min major = Risk Factor for CVD ( +/- Diabetes )

3) Obesity independent Risk Factor for = CVD , CKD , Diabetes Hypertension

4) Sleep disordered Breathing ( Sleep Apnoe ) Risk Factor for Diabetes, Hypertension , CKD

5) Combination of Diabetes + CKD = 4- fold Risk of CVD and Mortality

BP Level and CVD Risk in T2DM and CKD

Swedish National Diabetes Registry

33,350 patients , aged 75 (+/-9 ) , diabetes duration 10 ( +/- 8 ) years, follow up 5.3 years

BP 135 –139 / 72-74 mmHg best Outcome for CV Events and Mortality .

Highest Risk for CV Events / Mortality

1) SBP < 120 mmHg = HR 2.3 / 2.4 2) SBP > 160 mmHg = HR 3.0 / 2.0

Afghahi H. et.al. Diabetologia , March 2015 ( online)

OBESITY and Renal Disease

Obesity is an independent Risk Factor for :

CKD RR 1.83 , ( female > male )

Progression of CKD

ESRD

Renal Calculi

Renal cell carcinoma

Renal Effects of Obesity

1) Hormonal

Activation of RAAS ,SNS, Leptin , ROS

2) Physical

Compression of Renal Parenchyma

3) Structural

Glomerulopathy ( FGS )

Albuminuria

4) Hyperfiltration ( elevated eGFR )

Afferent Vasodilation and efferent Vasocon-

constriction

BMI and CKD

Association of Age and BMI on Renal Function and Mortality 3.376,000 US Veterans with a eGFR > 60 ml /min mean age of 60 and BMI ~ 29 , 7 Year follow up Results :

1) 8.1 % ( 274.746 ) > age 40 with BMI > 30 Progressive eGFR loss of > 5 ml / year

2) BMI > 25 to < 30 best Clinical Outcome 3) Age 40 and younger had no BMI Risk for eGFR Loss 4) Mortality Risk paralleled eGFR Risk Lu,JL. et.al Lancet Diabetes Endocrinology, 2015:3 :704-714

Risk Factors for CKD

• Hypertension ( Uncontrolled )• Age eGFR loss 0.7 – 1.0 ml /year > age 40• Diabetes eGFR loss ~ 2.0 ml /year (good care)• Obesity ( BMI > 30 )

• Albuminuria > 300 mg ( ACR )• Microalbuminuria < 300 mg No Risk ( per se)

Risk Factors , cont’d

AKI Recovery from AKI even within 10% of Baseline Value leads

to increased Risk and Progression of CKD

( AKI definition : SCr increase by 0.3mg in 48hrs, or < 0.5ml /kg urine in 6hrs )

Nephrotoxic agents Dye studies , Antibiotics , NSAID

Smoking Albuminuria increased , Nephrosclerosis Diabetes = Doubles Risk of CV Mortality !!

Ethnicity Afro-Americans ( 3.5x ESRD risk ) and Native Americans , Hispanics Positive Family History of CKD or ESRD

NSAID use in Hypertension and CKD Lower Efficacy of ALL Antihypertensive Drugs ,

incl. Diuretics by 10 -15 % ( except CCB’ s ) Cause Salt Sensitivity ( > 3-4 day use )

In CKD 3 (< 60 ml GFR )

Reduce GFR by 10-15 % Risk of Hyperkalemia , AKI and CHF

Measures to Slow CKD in Diabetes

Note : All studies to slow CKD are in Non –Diabetes Subjects ( MDRD , REIN-2 , AASK )

eGFR Loss ( after age 40 ) NO Disease = 0.7 – 1.0 ml / year Diabetes = 2.0 ml / year

HYPERTENSION ( most important ! )

BP goal < 140 / 90 mmHg ( may attain < 130 / 80 for Albuminuria and / or Young ) ACE inhibitors or ARB’s slow CKD progression by 20%

ALBUMINURIA ( > 300 mg ACR )

ACE inhibitors or ARB’s lower Albuminuria 30% Reduction of Albumin will decrease ESRD Risk by 24 %

( Lambers-Heerspink ,et.al JASN 2015; 26: 206 )

CKD Slowing Measures ( cont’d ) HYPERGLYCEMIA Reducing A1C to < 7% will lower Micro – and Macro albuminuria No data on CKD progression

HYPERLIPIDEMIA

Reducing LDL will lower Cardiovascular Events No Data on CKD slowing

Other Measures a) No smoking b) Salt restriction to < 2400 mg Na ( 6 gm Salt ) c) Weight Loss for BMI > 25 d) Hyperuricemia > 7.0 mg% consider Allopurinol ( No outcome data ) Salt reduction by 6 gm ( Na 2400 mg ) will reduce Albuminuria by 33%

Specialist Referral for CKD

AKI ( Acute Kidney Injury ) CKD 4 ( eGFR < 30 ml ) Albuminuria > 300mg ACR CKD Progression > 5 ml Loss / year or change in Stage

Red cell cast ( Glomerular Disease ) or > 20 RBC w/o cause

CKD and Resistent Hypertension Not at Goal on 3 Drugs ( CCB, RAAS ,Diuretic)

Recurrent Nephrolithiasis ( 2 or more episodes )Hyperkalemia ( persistent )Hereditary Kidney Disease ( i.e. PCK )

ASH Hypertension Guidelines 2013

BP Goals :

Age 80 and older < 150 / 90 mmHg Age 60 - 79 < 140 / 90 mmHg Age 50 and younger < 140 / 90 mmHg < 130 / 80 ( if tolerated )

CKD or DIABETES:

w /o Proteinuria < 140 / 90 mmHg with Proteinuria < 130 / 80 mmHg ( no consensus ) ASH Guidelines for Hypertension : J.Clinical Hypertension , 2013