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Hypertension and Diabetic Kidney Disease Progression

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Hypertension and Diabetic Kidney Disease Progression Powered By Docstoc
					   Hypertension and Diabetic Kidney
   Disease Progression


   George L. Bakris, MD
   Professor and Vice-Chairman Dept. of Preventive Medicine
   Director, Hypertension/Clinical Research Center
   Rush University Medical Center
   Chicago, IL 60612


©2006. American College of Physicians. All Rights Reserved.
Disclosure of Relationships with Commercial Companies:



 George L. Bakris, MD, FACP
 Research Grants/Contracts: NIH (NIDDK/NHLBI),
   AstraZeneca, Abbott, Alteon, Boehringer-Ingelheim,
   GlaxoSmithKline, Merck, Novartis, Lilly, Sankyo
 Consultantship: Astra-Zeneca, AusAm, Abbott, Alteon,
  Biovail, Boehringer-Ingelheim, BMS/Sanofi,
  GlaxoSmithKline, Merck, Novartis, Lilly
 Speakers Bureau: Boehringer-Ingelheim, BMS/Sanofi,
   GlaxoSmithKline, Merck, Novartis, Lilly




          ©2006. American College of Physicians. All Rights Reserved.
Increasing Prevalence of
Diagnosed Diabetes in US Adults
1994                                                   2002




       <4%         4–4.9%          5–5.9%           6%


        Centers for Disease Control and Prevention Web site. Available at:
   http://www.cdc.gov/diabetes/statistics/prev/state/fig61994and2002.htm.
                                               Accessed August 30, 2004.

  ©2006. American College of Physicians. All Rights Reserved.
             Increasing Prevalence of
             Obesity* Among US Adults
            1994                                                        2002




               10%–14%               15%–19%           20%–24%            ≥ 25%


*BMI ≥ 30 kg/m2.         Centers for Disease Control and Prevention Web site. Available at:
                          http://www.cdc.gov/nccdphp/dnpa/obesity/trend/maps/index.htm.
                                                               Accessed August 30, 2004.

                   ©2006. American College of Physicians. All Rights Reserved.
Walking the dog




©2006. American College of Physicians. All Rights Reserved.
Incidence of Kidney Failure
per million population, 1990, by HSA, unadjusted




©2006. American College of Physicians. All Rights Reserved.
 Incidence of Kidney Failure
per million population, 2000, by HSA, unadjusted




©2006. American College of Physicians. All Rights Reserved.
             Diabetes:
  The Most Common Cause of ESRD
                     Primary Diagnosis for Patients Who Start Dialysis
                                                          Other      Glomerulonephritis
                                                              10%        13%                           No. of patients
                              700                                                                      Projection
                                                 Diabetes                     Hypertension             95% CI
        No. of dialysis patients




                              600                 50.1%                           27%

                              500
             (thousands)




                              400

                              300                                                                520,240
                                                                                   281,355
                              200
                                                                    243,524
                              100                                                               r2=99.8%
                                   0
                                       1984      1988       1992     1996       2000     2004        2008
United States Renal Data System. Annual data report. 2000.

                                       ©2006. American College of Physicians. All Rights Reserved.
           Cardiovascular Comorbidities,
5% Medicare sample, by Diabetes and CKD status, 1999-2000

     60                                          60
                %Stroke/TIA                                 %Heart Failure
     45                                          45

     30
                                                 30

     15
                                      CKD        15
      0                                                                            CKD
                                    Non-CKD
                                                   0                             Non-CKD
              Non-
            diabetes    Diabetes
                                                             Non-
                                                           diabetes   Diabetes

60                                                60
                %ASHD                                         %Amputation/PVD
45                                                45

30                                                30

15                                                15
                                     CKD                                           CKD
 0                                                     0                         Non-CKD
                                   Non-CKD
            Non-                                             Non-
                       Diabetes                            diabetes   Diabetes
          diabetes
              ©2006. American College of Physicians. All Rights Reserved.
   Level of Kidney Function Is an
Independent Risk Factor For CV Risk
N=15,350
Mean follow-up=6.2 years
Age -45-64

Stage of Kidney Disease                             N
                                                                        1.16

   Stage 2 (GFR-60-89)                            7,665
                                                                             1.38
   Stage 3 &4 (GFR-15-59)                           444



                                                            0.75 1.0     1.25 1.5 1.75 2.0

      Manjunath G et.al JACC 2003;41:47-55
               ©2006. American College of Physicians. All Rights Reserved.
Go, A. S. et al. N Engl J Med 2004;351:1296-1305

                       ©2006. American College of Physicians. All Rights Reserved.
CKD Hospitalization Rates for Cardiovascular Disease



• CHF admission rates are 5 times higher in
  patients with a diagnosis of CKD vs non-
  CKD
• Ischemic heart disease admissions at 2-2.5
  times higher in the CKD population
• Cardiac arrhythmia admission rates are
  twice as common in CKD populations




        ©2006. American College of Physicians. All Rights Reserved.
USRDS

          CKD Prevalence in US (AJKD 2002)
        8,000,000                               7,600,000
        7,000,000
                                                                          5,900,000
        6,000,000                                            5,300,000
        5,000,000
        4,000,000
        3,000,000
        2,000,000
        1,000,000      300,000      400,000
               0
                    Stage 5          Stage 4      Stage 3      Stage 2      Stage 1
        GFR (ml/min) <15             15-29        30-59         60-89        > 90

                    ©2006. American College of Physicians. All Rights Reserved.
                    CVD Risk Factors
 Hypertension*
 Cigarette smoking
 Obesity* (BMI >30 kg/m2)
 Physical inactivity
 Dyslipidemia*
 Diabetes mellitus*
 Microalbuminuria
 Estimated GFR <60 ml/min
 Age (older than 55 for men, 65 for women)
 Family history of premature CVD
  (men under age 55 or women under age 65)
*Components of the metabolic syndrome.           Chobanian A et.al Hypertension, Dec. 2003
                ©2006. American College of Physicians. All Rights Reserved.
         1000

          900
                                   CV Risk and Presence of Renal
          800                      Dysfunction and Vascular Dysfunction
          700

          600
mg/day




          500

          400

          300
                 CV Risk and
          200   Vascular
                Dysfunction
          100

            0
                Microalbuminuria
    Normal
                                            Albuminuria
                                                       (Proteinuria)
                  ©2006. American College of Physicians. All Rights Reserved.
     Proteinuria Predicts Stroke and
     CHD Events in Type 2 Diabetes
                        A: U-Prot <150 mg/L          B: U-Prot 150–300 mg/L C: U-Prot >300 mg/L

                       1                                                        40
                                                                                     P<0.001
                      0.9
Survival Curves For




                                                                                30
                                                            A
   CV Mortality




                      0.8




                                                                    Incidence
                                                            B




                                                                       (%)
                      0.7                                                       20

                      0.6
                                                            C                   10
                      0.5       Overall: P<0.001

                       0                                                         0
                            0     20    40      60    80    100                        Stroke    CHD
                                                                                                Events
                                       Months
   U-Prot = Urinary protein concentration.
   Miettinen H et al. Stroke. 1996;27:2033-2039.

                                 ©2006. American College of Physicians. All Rights Reserved.
Kaplan-Meier curves of 3-year all-cause mortality in the AMI patients stratified
by DM status and ACR >30µg/mg or <30µg/mg on the 3rd day after admission




                                                   Berton G et.al. Diabetologia, Aug. 2004

                ©2006. American College of Physicians. All Rights Reserved.
      Use of MAU, CRP, and BNP as Predictors of Mortality and CV
      Events
                                                                                                                        P=.008
                                    MAU
                                                                                                                P=014
 Mortality                         CRP
                                                                                                                            P=.007
                              NT-proBNP


                                                                                                                                      P=.003
                                    MAU
First Major CV                                                                                     P=.96
                                   CRP
     Event
                                                                                                                                               P=<.001
                              NT-proBNP

                                                       0           0.5            1          1.5            2           3         4            5

                                                                   Hazard Ratio ( 95% CI ) for Values Above 80th Percentile
 Adjusted for age, sex, smoking, DM, HTN, Afib, LVEF<50%, LVH, total cholesterol, serum creatinine. Mortality analysis based on 91 deaths, and CV event
 data based on 63 events due to missing covariates. The 80 th percentile corresponds to values more than 5.85 pg/mL for NT-proBNP, 5.76 mg/L for CRP, and
 18.4 mg/g for MAU.
 Kistorp K, et al. JAMA. 2005;293:1609-1616.

                              ©2006. American College of Physicians. All Rights Reserved.
                         Predictive value of antiproteinuric effect on
                                       renal protection
                                                        Diabetes                                       Non-Diabetes
                                          15                                            15



                                          10
Rate of decline in GFR




                                                                                        10
                         (ml/min/ year)




                                          5                                               5



                                          0                                               0
                                                                   r=0.73                                                      r = 0.47
                                                                   p<.001.                                                     p < 0.011
                                          -5                                             -5
                                               -100   -50     0      50    100                 -100   -50            0      50      100
                                                            delta Proteinuria (% change from pretreatment)
               Rossing P et al. Diabetologia. 1994;37:511-516.                                Apperloo AJ et al; Kidney Int 1994; 45:S174-8.
                                                      ©2006. American College of Physicians. All Rights Reserved.
         Clinical Trials and Renal Outcomes
          Based on Proteinuria Reduction
Increased Time to Dialysis                         No Change in Time to Dialysis
(30-35% proteinuria reduction)                     (NO proteinuria reduction)
  Captopril Trial-N Engl J Med, 1993                   DHPCCB arm-IDNT
  AASK Trial-JAMA, 2001                                DHPCCB arm-AASK
  RENAAL-N Engl J Med, 2001
  IDNT-N Engl J Med, 2001
  COOPERATE-Lancet, 2003

  Hart P & Bakris GL Managing Hypertension in the Diabetic Patient.
  IN: Egan BM, Basile JN, and Lackland DT (eds.) Hot Topics in Hypertension
  Hanley and Belfus, Philadelphia, 2004, pp.249-252.

                  ©2006. American College of Physicians. All Rights Reserved.
  IDNT Proportion of Patients with the Primary
            Composite Endpoint*
                     0.7
                     0.6
  primary endpoint

                                   P=0.02 for irbesartan compared to
   Proportion with




                     0.5           placebo

                     0.4
                     0.3
                     0.2
                                                                    *Composite of a doubling of
                     0.1                                            serum creatinine, end stage
                                                                    renal disease, or death
                     0.0
                           0        6      12     18  24   30    36  42                  48   54
                                                   Months of Follow-up
Irbesartan (n)             579     555     528    496     400    304     216     146     65
Amlodipine (n) 565                 542     508    474     385    287     187     128     46
Placebo (n)                568     551     512    471     401    280     190     122     53
  Lewis EJ, et al. N Engl J Med. 2001;345(12):851-860.
  ©2001 Massachusetts Medical Society. All rights reserved.

                               ©2006. American College of Physicians. All Rights Reserved.
Relationship Between Rate of Decline in Renal
 Function and Change in Proteinuria in IDNT
                           Creatinine clearance (mL/min/1.73 m2)
                           Proteinuria (g/d)

                  Irbesartan                Placebo                Amlodipine
         0
         -1
         -2
         -3
      -4
         -5
         -6
         -7
         -8

Lewis EJ et al. N Engl J Med. 2001;345:851-860.
              ©2006. American College of Physicians. All Rights Reserved.
RENAAL; Baseline Proteinuria as a Determinant
    for Cardiac Events in Type 2 diabetes
         (adjusted for all conventional risk factors)
                           CV Endpoint                                                    Heart Failure
                   6                                                          6




                                                               Hazard ratio
    Hazard ratio




                   4                                                          4



                   2                                                          2




                   0                                                          0
                   <.5   2.0       2.95    4.4  5.25                         <.5   2.0       2.95   4.4  5.25
                               Albuminuria (g/g)                                          Albuminuria (g/g)


De Zeeuw et al; Circulation 2004
                               ©2006. American College of Physicians. All Rights Reserved.
RENAAL; Baseline Proteinuria as a Determinant
    for RENAL Events in Type 2 Diabetes
                         (adjusted for all conventional risk factors)
                       Primary composite Endpoint                                                ESRD

         15                                                                   30




                                                                    Hazard ratio
    Hazard ratio




         10                                                                   20


                   5                                                          10


                   0                                                               0
                   <.5     2.0       2.95    4.4 5.25                             <.5    2.0     2.95   4.4  5.25
                         Baseline Albuminuria (g/g)                                      Baseline Albuminuria (g/g)
De Zeeuw et al; Kidney Int 2004
                                 ©2006. American College of Physicians. All Rights Reserved.
                                RENAAL: Renal End Points By
                               6-Month Changes in Albuminuria
                                        Renal End Point                                                            Renal End Point
                                                  Unadjusted             Adjusted                                          Unadjusted              Adjusted
                                                 HR    P values     HR     P values                                       HR     P values     HR     P values
Δ Alb: 0<30 vs. <0%                            0.88   0.1570       0.76    0.0028    Δ Alb: 0<30 vs. <0%               0.82    0.1242       0.62    0.0003
Δ Alb: 30 vs. <0%                              0.60   <.0001       0.46    <.0001    Δ Alb: 30 vs. <0%                 0.51    <.0001       0.37    <.0001
Δ Alb: 30 vs. 0<30%                           0.68   0.0003       0.61    <.0001    Δ Alb: 30 vs. 0<30%              0.62    0.0019       0.60    <.0010


                               60                             <0%                                         60

                               50                                    0<30%                               50
      % with renal end point




                               40                                                                         40




                                                                                            % with ERSD
                                                                    30%                                                                <0%

                               30                                                                         30                                   0<30%

                               20                                                                         20
                                                                                                                                              30%
                               10                                                                         10

                                0                                                                          0
                                    0    12     24       36         48                                         0    12    24       36         48
                                               Month                                                                     Month
 De Zeeuw D, et al. Kidney Int. 2004; 65:2309.

                                              ©2006. American College of Physicians. All Rights Reserved.
  RENAAL: Cardiovascular End Points
  by 6-Month Changes in Albuminuria

                                  CV Endpoint                                                       Heart Failure
                                                             <0%
                         40                                                                40

                                                             >30%
   % with CV endpoints




                         30                                                                30




                                                                     % with CV endpoints
                         20                                                                20
                                                                                                                           <0%


                         10                                                                10
                                                                                                                      >30%


                          0                                                                 0
                              0   12     24      36     48                                      0   12    24     36   48

                                       Month                                                             Month


De Zeeuw D, et al. Circulation. 2004;110:921.

                                  ©2006. American College of Physicians. All Rights Reserved.
              Most Common Cause of Failing to Reduce
              Proteinuria with ACE Inhibitor or ARB




   High SALT intake
                     (>5 grams/day)
DeZeeuw D et.al Kidney Int., 1989, Mishra SI et.al, Curr Hypertens Rep, 2005

                  ©2006. American College of Physicians. All Rights Reserved.
             What is the Goal BP and Initial Therapy in
             Kidney Disease or Diabetes to Reduce CV
             Risk?

    Group                           Goal BP (mmHg)                  Initial Therapy
   Am. Diabetes Assoc (2006)            <130/80                ACE Inhibitor or ARB*
   KDOQI (NKF) (2004)                   <130/80                ACE Inhibitor or ARB*
   JNC 7 (2003)                         <130/80                ACE Inhibitor or ARB*
   Canadian HTN Soc. (2002)             <130/80                ACE Inhibitor or ARB
   Am. Diabetes Assoc (2002)            <130/80                ACE Inhibitor or ARB
   Natl. Kidney Fdn.-CKD(2002)          <130/80                ACE Inhibitor or ARB*
   Natl. Kidney Fdn. (2000)             <130/80                ACE Inhibitor*
   British HTN Soc. (1999)              <140/80                ACE Inhibitor
   WHO/ISH (1999)                       <130/85                ACE Inhibitor
   JNC VI (1997)                        <130/85                ACE Inhibitor


    * Indicates use with diuretic


                 ©2006. American College of Physicians. All Rights Reserved.
         Angiotensin-Receptor Blockade versus
         Converting–Enzyme Inhibition in Type 2
         Diabetes and Nephropathy

   DETAIL, a prospective, multicenter, non-
    inferiority trial randomized 250 patients with
    type 2 diabetes, hypertension (BP <180/95
    mm Hg), and evidence of early nephropathy
    (GFR >70 mL/min/1.73 m2) to either
    telmisartan or enalapril.

    Followed for 5 years

                 Barnett AH et.al N Engl J Med 2004;351:1952-1961.

           ©2006. American College of Physicians. All Rights Reserved.
Angiotensin-Receptor Blockade versus
Converting–Enzyme Inhibition in Type 2
Diabetes and Nephropathy-RESULTS

     Baseline GFR 91 ml/min




         Barnett AH et.al N Engl J Med 2004;351:1952-1961.
 ©2006. American College of Physicians. All Rights Reserved.
Effects of ACE Inhibitors or ARBs on Renal
Disease Progression: A Meta-Analysis
Cases J et.al. Lancet 2005;366:2026
   ESRD




   2X SCr




       ©2006. American College of Physicians. All Rights Reserved.
Effects of ACE Inhibitors or ARBs on Renal
Disease Progression: A Meta-Analysis
Cases J et.al. Lancet 2005;366:2026
   ESRD




   2X SCr




       ©2006. American College of Physicians. All Rights Reserved.
      Effect Of Early And Late Changes In GFR When
      Blood Pressure Is Controlled with an ACE Inhibitor
                     Bakris        Nielsen                                Systolic Pressure
                     (N = 18)      (N = 21)                                   Trial End
              0
mL/min/yr.


                                                                                 154
              -2                           -1.3
                                                                   150
              -4
                            -4
              -6
              -8                                  -7

             -10     -9.4
                                                                   140     136



                   Initial GFR Rate
                      of Decline
                     [<4 Months]                                   130
                                             Final GFR Rate
                                                of Decline
                                         [Trial End (1–6 years)]



                                              Bakris GL & Weir M Arch Intern Med. 2000:160:685-693
                            ©2006. American College of Physicians. All Rights Reserved.
               Most Likely Etiologies for
               Increasing Serum Creatinine

   Volume     Depletion
      Heart Failure
      Bilateral Renal Artery Stenosis


Tarif N and Bakris GL. IN: Johnson R and Freehally J (eds.) Principles of Nephrology
 Mosby & Co. London, 2000 pp. 40.1-12,
Ashgar A & Bakris, G Primer in Kidney Disease, 2005


                  ©2006. American College of Physicians. All Rights Reserved.
                   General Concept


  A rise in serum creatinine of up
to 30% of baseline ( given baseline
up to 3 mg/dl) that remains stable
in the absence of hyperkalemia
([K+] > 6) correlates with slower
renal disease progression.

                       Bakris GL & Weir M Arch Intern Med. 2000:160:685-693

       ©2006. American College of Physicians. All Rights Reserved.
                                           Intensive Multiple Risk Factor Management
                                       Patients with Type 2 Diabetes and Microalbuminuria
                                                                                 Adapted from Gæde P et al. N Eng J Med. 2003;348:383-393
   Primary Composite End Point* (%)




                                      60       N=160; follow-up = 7.8 years


                                                             Conventional Therapy
                                      40                                                               20% Absolute
                                                                                                       Risk Reduction

                                      20                                                            Aggressive treatment of†:
                                                                         Intensive Therapy†         – Microalbuminuria with
                                                                                                      ACEIs, ARBs, or combination
                                                                                                    – Hypertension
                                                                                                    – Hyperglycemia
                                                                                                    – Dyslipidemia
                                             12    24    36 48      60 72 84                96      – Secondary prevention of CVD
                                                         Months of Follow-up
Primary composite endpoint: conventional therapy (44%) and intensive therapy (24%).
*Death from CV causes, nonfatal myocardial infarction, coronary artery bypass grafting, percutaneous coronary intervention,

  nonfatal stroke, amputation, or surgery for peripheral atherosclerotic artery disease.
†Behavior modification and pharmacologic therapy.




                                                  ©2006. American College of Physicians. All Rights Reserved.
    Percentage of Adults with Diabetes Who Achieved
  Recommended Goals of Cardiovascular Risk Factors in
                       NHANES
                                   NHANES III        NHANES IV

             50

             40
       %     30

             20

             10

              0
                  HbA1c<7% BP <130/80                  TC <200            Good
                             mmHg                       mg/dl            Control
Saydah S et.al JAMA 2004;291:335
                  ©2006. American College of Physicians. All Rights Reserved.
           If Blood Pressure >130/80 mm Hg in Diabetes or Chronic
                 Kidney Disease with Any Level of Albuminuria

      (if systolic BP< 20 mmHg above goal)                         (if systolic BP >20 mmHg above goal)
     Start ARB or ACE Inhibitor titrate upwards                   START with ACEI or ARB/thiazide diuretic*)
                                                                      Recheck within 2-3 weeks
                                If BP Still Not at Goal (130/80 mm Hg)

         Add Long Acting Thiazide Diuretic*                     Add CCB or b blocker** (titrate dose upward)

                                                                 Recheck within 2-3 weeks

                                  If BP Still Not at Goal (130/80 mm Hg)

                                   Consider low dose aldosterone antagonists#
                                                    or
                                 If used CCB, Add Other Subgroup of CCB
                  (ie, amlodipine-like agent if verapamil or diltiazem already being used and the converse)
                                         OR if b blocker used add CCB
                                                                 Recheck within 4 weeks
                                   If BP Still Not at Goal (130/80 mm Hg)

                                  Add Vasodilator (hydralazine, minoxidil) OR
                              Refer to a Clinical Hypertension Specialist
Ashgar and Bakris, Primer of Kidney Diseases, 2005
                      ©2006. American College of Physicians. All Rights Reserved.
          Messages to Take Home
   Kidney Disease is a silent killer-(no signs or
    symptoms until you loose >70% of your kidney
    function,
   The risk of dying from a cardiovascular event, if
    you’ve lost 50% or more of your kidney function, is
    similar to that having had a heart attack.
   Proteinuria reduction needs to be a key part of
    blood pressure management.



            ©2006. American College of Physicians. All Rights Reserved.