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CKD - Chronic Kidney Disease

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CKD - Chronic Kidney Disease Powered By Docstoc
					Chronic Kidney Disease

         Dr. Gaylene Hargrove,
                  Nephrologist
             Dr. Nancy Craven,
             Medical Lead CKD
Mr. Hales
 Current Age: 57
 BP 140/85
 Smoking: quit
 Weight: 203 lbs
 BMI: 29.1
 A1C 6.7
 eGFR 53, ACR 38
Reverend Stephen Hales
1677 –1761
 English physiologist, chemist and
inventor
In 1727, first to measure arterial
blood pressure
Inserted brass tube into carotid
artery of a horse
Somewhat invasive, rather
uncomfortable, and uniformly fatal

Mercury sphygmomanometer
developed in 1896 by Scipione
Riva-Rocci
What ‘intervention’ is most effective
in delaying the progression to ESRD?

A.   Dietary protein restriction (0.6 g/kg/d)
B.   Optimal BP control (<130/80)
C.   ACEI/ARB therapy
D.   Optimal glycemic control
E.   Weight reduction
F.   Smoking cessation
Which of the following statements is
true of Mr. Hales?
A. He has established diabetic nephropathy, so he will
   need dialysis/transplant in the future, despite
   ‘optimal’ intervention.
B. His current blood pressure is acceptable.
C. It is possible to normalize the ACR and stabilize
   eGFR with optimal, multi-faceted intervention.
D. He should be referred to a nephrologist urgently.
Mr. Hales is likely to experience a CV
event before he requires renal
replacement therapy.

A. TRUE
B. FALSE
                                 The Challenge In Canada
                            22% of Canadians 18-70 years of age have hypertension
                             50% of Canadians >65 years of age have hypertension

               Hypertensive patients                                    Hypertensive patients
                  who are treated                                         who are treated
                but BP uncontrolled                                      and BP controlled


                                                            13%         9%
                                          21%

                                       22%               43%                      Diabetic patients
                                                                                 Who are treated and
                                                                                   BP controlled



            Patients who are aware
             but remain untreated
                                                                  Hypertensive patients
             and BP uncontrolled
                                                                    who are unaware


Joffres et al. Am J Hyper 2001
      Prevalence of Hypertension in Type 2 Diabetes
            Normoalbuminuria (n = 323)    Macroalbuminuria (n = 75)
            Microalbuminuria (n = 151)    Total (n = 549)

                         100                                93
                                              90
                                                                      80
                                     71

     % Prevalence of
      hypertension
   (BP ≥140/90 mm Hg)
                      50




                            0

Tarnow L et al. Diabetes Care 1994
              Diabetic Nephropathy and Albuminuria

           Diabetic nephropathy is the #1 cause of ESRD in Canada & Western World




          Normal range                 MAU                Macroalbuminuria

                                                                mg/day
                                                                              Albumin
   10                            30                 300
                                                                              excretion
                                                                             rate (AER)
                                                                µg/min
    7                            20                 200


                                                                 ESRD=End Stage Renal Disease
Maher JF Am Fam Physician 1992
Meltzer et al. CMAJ 1998
                                 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
                                                                30
Survival                                         A
             0.8                                     Incidence
curves                                           B
 for CV                                                 (%)    20
             0.7
mortality
             0.6
                                                 C              10
             0.5        Overall: p<0.001

                0                                                 0
                    0 10 20 30 40 50 60 70 80 90                            Stroke          CHD events
                               Months
                                                          U-Prot = Urinary protein concentration
Miettinen H et al. Stroke 1996
                    Relative Importance of Microalbuminuria
                            in Prediction of Mortality

                                     10.02
                        10



                         8

                                                    6.52
                         6

        Odds ratio
                         4
                                                                3.20
                                                                              2.32
                         2



                         0
                                Microalbuminuria   Smoking   Diastolic BP   Cholesterol




Eastman RC et al. Lancet 1997
Preserving Renal Function
Blood Pressure Control/RAS
Blockade

 Best evidence to support target of <130/80 is
 UKPDS data (each 10 mmHg reduces risk by 12%)
 IRMA-2 trial (Irbesartan)
   70% RR in progression from MAU to overt
   nephropathy; normalization of ACR possible
 IDNT trial (Irbesartan)
   Decreased risk of CV death, CHF, doubling of SCr,
   and ESRD in DM2 pts with macroalbuminuria
 RENAAL trial (Losartan)
   Similar composite endpoint reduction in DM2 pts
   with well-established CKD (eGFR < 60 ml/min)
                                       IRMA 2: Study Design
                590 patients with type 2 diabetes, microalbuminuria (albumin
                excretion rate: 20–200 µg/min), normal renal function, and
                hypertension



           Screening/Enrollment                         Double-blind Treatment

                                                                Usual care

                                                             Irbesartan 150 mg

                Up to 5 weeks                                Irbesartan 300 mg

                                                           Follow-up: 2 years

Parving H-H et al. N Engl J Med 2001
                             IRMA 2: Primary Endpoint
                           Development of Overt Proteinuria
                                                        RRR=70%
                                                         p<0.001
                               18               RRR=39%
                                                 p=0.08
                               16        14.9
                               14
          Subjects             12
            (%)                10                         9.7
                                 8
                                 6                                             5.2
                                 4
                                 2
                                 0
                                       Usual care       150 mg             300 mg
                                        (n=201)         (n=195)            (n=194)
Parving H-H et al. N Engl J Med 2001                              Irbesartan
                        IRMA 2: Normalization of Urinary
                           Albumin Excretion Rate

                           45                       p=0.006
                           40
                           35                                              34
                           30
             Subjects                                 24
                      25
               (%)                        21
                      20
                           15
                           10
                             5
                             0
                                       Usual care   150 mg            300 mg
                                        (n=201)     (n=195)           (n=194)

Parving H-H et al. N Engl J Med 2001
                                                              Irbesartan
                                    IDNT: Study Design

              1715 patients with type 2 diabetes, proteinuria ≥900 mg/24 h, and hypertension


         Screening/Enrollment                                  Double-blind treatment
                                                                      Irbesartan*

                                                                      Usual care*

                                                                      Amlodipine*

                 Up to 5 weeks                                  Minimum follow-up:
                                                               approximately 2 years
                                                                 (average 3 years)

                                            * Adjunctive antihypertensive therapies (excluding ACE inhibitors,
                                              angiotensin II receptor antagonists and calcium channel blockers)
Lewis EJ et al. N Engl J Med 2001             added to each arm to achieve equal blood pressure reduction.
                                              Collaborative Study Group.
                      IDNT: Primary Composite Endpoint
                           Time to Doubling of Serum Creatinine, ESRD, or Death
                70
                                    Irbesartan
                                                  RRR 23%
                60                                 p=0.006
                                                                  RRR 20%
                                    Amlodipine                     p=0.02
                50                                    p=NS

                                    Usual care
 Subjects
   (%)    40

                30                                                                         n=1715

                20

                10

                  0
                      0        6       12        18          24     30      36   42   48    54      60
                                                        Follow-up (mo)
Lewis EJ et al. N Engl J Med 2001
        IDNT: Time to Doubling of Serum Creatinine
                  70
                                        Irbesartan
                  60                                  RRR 37%
                                                       p<0.001        RRR 33%
                                        Amlodipine                     p=0.003
                  50                                      p=NS

                                        Usual care
  Subjects 40
    (%)
                  30

                  20
                                                                                                 n=1715

                  10

                   0
                       0            6      12        18          24      30      36   42   48   54        60

Lewis EJ et al. N Engl J Med 2001                            Follow-up (mo)
                        IRMA 2 & IDNT: Clinical Impact

       IRMA 2
           Treating (NNT) 10 hypertensive patients with type 2 diabetes and
           microalbuminuria with irbesartan 300 mg for 2 years would prevent one
           patient from developing overt diabetic nephropathy within 2 years

       IDNT
           Treating (NNT) 15 hypertensive patients with type 2 diabetes and proteinuria
           with irbesartan for 2.6 years would prevent one patient from developing a
           doubling of serum creatinine, end stage renal disease, or death



Data on file, Bristol-Myers Squibb and Sanofi-Synthelabo Inc.
                                      RENAAL: Study Design

       Population
           n = 1513                              Primary Endpoints
           NIDDM with albuminuria
           (300 mg/g creatinine)
                                                  Doubling sCr/ESRD*/death
           Serum Creatinine > 1.5-3.0 mg/dL
           1.3 mg/dL (males <60 kg: females)
                                                 Secondary Endpoints

        Treatment                                 CV morbidity/mortality
                                                  Proteinuria
           Losartan vs. placebo
           (+ conventional non-ACEI
           antihypertensive Rx)
           3.4 years average

                                                           * Need for dialysis or transplantation
Brenner BM et al. N Engl J Med 2001
              Primary Composite Endpoint and Components
                     by Intention-to-Treat Analysis


            Primary Composite Endpoint (Doubling sCr + ESRD + Death)

                     16% RR, p=0.024

            Components of Primary Endpoint:

                    Doubling sCr: 25% RR, p=0.006
                    ESRD: 28%, p=0.002
                    ESRD or Death: 20% RR, p=0.01




Brenner BM et al. N Engl J Med 2001
RENAAL Trial: Post-Hoc Analyses
 Most significant risk factor for progressive
 CKD was severity of proteinuria
 Every 10 mmHg increase in SBP increased
 risk of ESRD or death by 6.7%
 18% decrease in risk of CV event for every
 50% decrease in rate of albumin excretion
 For all levels of achieved BP, larger reduction
 in albuminuria correlated with lower risk of
 ESRD
Preserving Renal Function
Primary Prevention of Nephropathy

 ADVANCE trial (Perindopril+ Indapamide)
   11,000 DM2 pts – fewer developed new onset
   MAU compared to controls, 19.6% vs 23.6%)
 BENEDICT trial (Trandolopril)
   1204 DM2 pts – significant reduction in new onset
   MAU in treated vs controls (30 vs 18 events)
Preserving Renal Function
Conclusions from ACEI/ARB Trials

 Blockade of the RAS is renoprotective in pts
 with DM2 and hypertension (prevents onset
 of incipient nephropathy)
 ACEI/ARB Tx stabilizes and can even improve
 renal fn in pts with established nephropathy
 The renoprotective effects of RAS blockade
 are independent of BP control (‘Control
 Group’ in trials had equivalent BP control)
Preserving Renal Function
Dietary Protein Restriction

 2 small trials (NEJM 1991, Lancet 1989)
   0.6 g/kg/d vs ‘usual’ protein intake slowed
   rate of decline in GFR by 60-75%
     ie. From 12 ml/min/yr to 3 ml/min/yr
 Potential problems:
   Compliance
   Increased risk of protein malnutrition
Preserving Renal Function
Combined Therapy
 STENO 2 Trial
   160 pts randomized to standard vs
   intensive multifactorial Tx
     Diet, exercise, smoking cessation
     ACEI Tx (independent of BP)
     ASA Tx in pts with CAD, PVD
     BP goal < 140/85
     HbA1c < 6.5%
     Tchol < 5.0; TG<1.65
Preserving Renal Function
Combined Therapy

 STENO 2 Trial
   Mean F/U 7.8 yrs
   Primary end point – progression to overt
   nephropathy at 4 yrs; composite CV endpoint at 8
   yrs
   Significant improvement in albuminuria (-20 vs
   +30 mg/d)
   Reduced progression to overt nephropathy (20%
   vs 39%)
Preserving Renal Function
Summary/Recommendations
 Parameters to monitor Q3monthly:
   BP (home BP monitoring useful)
   SCr/eGFR
   Urine ACR
   HbA1c
   Lipids Q6-12 monthly
 Therapeutic Goals:
   BP < 130/80; ACEI/ARB first line Tx (consider combined Tx)
   Normalize urine ACR; use ACEI/ARB even if normotensive
   Slow decline in eGFR
   LDL chol < 2.0 mmol/L if CAD
Preserving Renal Function
Summary/Recommendations

Algorithm for treating HTN:
    ACEI or ARB first line Tx
       Titrate to ‘maximum’ dose tolerated
       Repeat SCr, K within 1 week
    Add diuretic (loop diuretic if GFR < 35 ml/min)
    If BP target not reached, add verapamil or
    diltiazem, or beta-blocker
    If persistent albuminuria        combined ACEI/ARB
    Tx
Preserving Renal Function
Lifestyle Modification

 Weight Loss     (can reduce albuminuria, BP,
 improve glycemic control)
 Smoking Cessation
 Regular Exercise
 Dietary Protein, Sodium restriction (1.0
 g/kg/d, Na intake < 100 mmol/d)
 Moderation of ETOH        (re: BP control)
What about Mr. Hales?
 Commend him re:
   Smoking cessation
   Good glycemic control (A1c 6.7%)
 Parameters to treat:
   BP     ACEI/ARB; goal BP < 130/80
   Albuminuria     ACEI/ARB
   Weight     aim for BMI <= 25
   Lipids; goal LDL < 2.0(?)

				
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