christian w. mende, md facp,facn,fasn,fash clinical professor of medicine, university of california,...

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