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CHRISTIAN W. MENDE, MD FACP,FACN,FASN,FASH Clinical Professor of Medicine,

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. FACULTY DISCLOSURE. Hypertension Incidence ( USA ).

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CHRISTIAN W. MENDE, MD FACP,FACN,FASN,FASH Clinical Professor of Medicine,

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  1. 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

  2. FACULTY DISCLOSURE

  3. 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

  4. 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

  5. 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

  6. 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

  7. Definitions Hypertention ( HTN ) JNC 8 , ASH , ADA , ASN BP > 140 / 90 mmHg Chronic Kidney Disease ( KDIGO 2013 ) present ≥ 3 months : a) eGFR < 60 ml/min / 1.73 m² or b) Albuminuria ≥ 300 mg or c) Abnormal Histology ( Biopsy ) or Transplantation

  8. Definitions Progression of CKD a) Loss of ≥ 5 ml eGFR / Year b) Change of Category ( i.e. CKD 3 to 4 ) c) Loss of ≥ 25 % from Baseline Resistant Hypertension Use of 3 antihypertensive Drugs in full Doses including a Diuretic and BP NOT at Goal.

  9. 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

  10. 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

  11. HOME BP FACTS • 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

  12. 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 )

  13. 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

  14. 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

  15. 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

  16. Blood Pressure Lowering in Type II DiabetesSystematic 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

  17. 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 )

  18. 1) Average MONO Therapy ( Placebo corrected ) 9.1 / 5.5 mm Hg BP Reduction ( in Stage I Hypertension , Law BMJ , 2003 ) 2) NHANES ( 2007- 2010 ) Combination Therapy to Goal 75 % needed 2 drugs 25 % needed 3 drugs Mono /Combo - Therapy

  19. Metanalysis of 11,000 patients in 42 Trials ( Wald DS, et.al. Am. J. Med. 2009; 122 :290 ) COMBO - THERAPY = 5 X more likely toACHIEVE BP GOAL ( in 6 month ) Doubling of Mono – vs. Combo Therapy

  20. Combos to AVOID in Hypertension 1) Beta Blocker + Verapamil or Diltiazem 2) Beta Blocker + Centrally acting antihypertensives ( Clonidine) DUAL RAAS BLOCKADE : 1) ACE Inhibitors + Angiotensin Receptor Blockers ( ONTARGET trial ) 2) Aliskiren + ACE inhibotors ( ALTITUDE trial ) 3) Aliskiren + ARB Aldactone and ACE inhibitors or ARB’s are excluded !

  21. Resistent and Refractory Hypertension Definitions : ResistantUncontrolled on3 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 “

  22. 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 (#) • 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

  23. 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 Drugs Evaluate 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 AddALDACTONE 12.5 – 25 mg / day !!

  24. CKD Blood Pressure Guidelines (With or Without DIABETES - KDIGO 2013 ) NO AlbuminuriaBP < 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

  25. 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

  26. 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)

  27. 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

  28. 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

  29. 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

  30. 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)

  31. 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

  32. 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

  33. 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 )

  34. 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%

  35. 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 )

  36. 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

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