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THE RELATIONSHIP BETWEEN PHYSICAL ACTIVITY AND RENAL FUNCTION Hematuria

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THE RELATIONSHIP BETWEEN PHYSICAL ACTIVITY AND RENAL FUNCTION Hematuria Powered By Docstoc
					  THE RELATIONSHIP BETWEEN
 PHYSICAL ACTIVITY AND RENAL
FUNCTION. WHAT'S THE ROLE OF
       INFLAMMATION?

      Marquis Hawkins, Ph.D.
       Postdoctoral Scholar
      University of Pittsburgh
Happy Birthday Dr. Hawkins!!!!
                  Defining “CKD”

 Kidney damage for ≥ 3 months, defined by structural
  or functional abnormalities of the kidney, with or
  without decreased GFR, manifest by either
    Pathologic abnormalities, or
    Markers of kidney damage, such as abnormalities
     of the blood or urine, or in imaging tests (but NOT
     HTN).
 GFR < 60 mL/min/1.73 m2 for ≥ 3 months with or
  without kidney damage.
         Defining “Kidney Damage”

 Pathologic Abnormalities?
   By Radiology (US, CT, MR, etc)--e.g.
      Multiple cysts consistent with PKD
      Extensive scarring
      Small kidneys--but be careful of the term “medical
       renal disease”.
      REMEMBER: Renal masses or cysts that are not simple
       should be referred to a UROLOGIST!!
   By Histology--ie, renal biopsy
          Defining “Kidney Damage”

 Markers of Kidney Damage?
   Proteinuria
      Microalbuminuria??
      Macroalbuminuria
   Hematuria (especially when seen with proteinuria)
      Isolated hematuria has a long differential: infection,
       stone, malignancy, etc.
          Prevalence of CKD in the US, 1999-2004
Stage         Description                            GFR                                  Prevalence
                                                     (mL/min/1.73m2)                      (%)


1             Kidney damage with                     >90                                  5.7%
              normal or  GFR
2             Mild  GFR with                        60-89                                5.4%
              kidney damage
3             Moderate  GFR                         30-59                                5.4%

4             Severe  GFR                           15-29                                0.2%

5             Kidney Failure                         < 15 or dialysis                     0.2%

 Prevalence of chronic kidney disease and associated risk factors--United States, 1999-2004. MMWR Morb Mortal Wkly
 Rep, 2007. 56(8): p. 161-5.
          Prevalence of CKD in the US, 1999-2004
Stage         Description                            GFR                                  Prevalence
                                                     (mL/min/1.73m2)                      (%)


1             Kidney damage with                     > 90                                 5.7%
              normal or  GFR
2             Mild  GFR                             60-89                                5.4%

3             Moderate  GFR                         30-59                                5.4%

4             Severe  GFR                           15-29                                0.2%

5             Kidney Failure                         < 15 or dialysis                     0.2%


 Prevalence of chronic kidney disease and associated risk factors--United States, 1999-2004. MMWR Morb Mortal Wkly
 Rep, 2007. 56(8): p. 161-5.
Prevalence of ESRD has been rising
steadily




                                     USRDS ADR, 2007
Costs of Kidney Failure are High
               (in $billions for 2002)


Kidney
Failure
 Care                                          Total NIH
                                                Budget
25.2
                 Kidney Failure Accounts        23.2
                 for 6% of Medicare
                 Payments


                 Lost Income for Patients is
                 $2-4 Billion/Yr



 USRDS, 2004
Survival rates in patients with ESRD
                                                    Age-Standardized Rate of Cardiovascular
                                                          Events (per 100 person-yr)
                                                                                              CKD Predicts CVD




                   Estimated GFR (mL/min/1.73 m2)
Go, et al., 2004
    CKD Patients Are More Likely to Die than to Progress
                         to ESRD




                                                5 year follow-up
                                                N=27998




Keith, et al, Arch Int Med; 2004; 164:659-663
• The Patient with early stage CKD is 5 to 10
  times more likely to die from a
  cardiovascular event than progress to
  ESRD.


Foley RN, Murray AM, Li S, Herzog CA, McBean AM, Eggers PW, Collins AJ. Chronic kidney
    disease and the risk for cardiovascular disease, renal replacement, and death in the
    United States Medicare population, 1998 to 1999. J Am Soc Nephrol 2005; 16:489-95.
               DIABETES                  HYPERTENSION



OTHER
•GENETICS
•AUTO-INNUME
                            CKD                   DYSLIPIDEMIA




                                                 RACE
   AGE               LIFESTYLE FACTORS
                     •PHYSICA ACTIVITY
                     •SMOKING
                     •OBESITY
                          INFLAMMATION

               DIABETES                  HYPERTENSION



OTHER
•GENETICS
•AUTO-INNUME
                            CKD                   DYSLIPIDEMIA




                                                 RACE
   AGE               LIFESTYLE FACTORS
                     •PHYSICA ACTIVITY
                     •SMOKING
                     •OBESITY
                          INFLAMMATION

               DIABETES                  HYPERTENSION



OTHER
•GENETICS
•AUTO-INNUME
                            CKD                   DYSLIPIDEMIA




                                                 RACE
   AGE               LIFESTYLE FACTORS
                     •PHYSICA ACTIVITY
                     •SMOKING
                     •OBESITY
•    Nephrons

• Maladaptive compensation
  (hypertrophy, hypertension, hyperfiltration)

• Shear stress, changes to ECM, proteinuria

• Inflammation

• Glomerulosclerosis, tubulointerstitial fibrosis
•    Nephrons

• Maladaptive compensation
  (hypertrophy, hypertension, hyperfiltration)

• Shear stress, changes to ECM, proteinuria

• Inflammation

• Glomerulosclerosis, tubulointerstitial fibrosis
• Viscous cycle of CKD causing CKD
• Can physical activity slow down this cycle?
• Can physical activity prevent cycle initiation?
   Relative risk of CKD by physical activity
          assessed by questionnaire




Finkelstein, J., A. Joshi, and M.K. Hise, Association of physical activity and renal function in subjects with and without metabolic
syndrome: a review of the Third National Health and Nutrition Examination Survey (NHANES III). Am J Kidney Dis, 2006. 48(3): p.
372-82.
Relative risk of CKD by categories of physical activity
              assessed by questionnaire




  Hallan, S., et al., Obesity, smoking, and physical inactivity as risk factors for CKD: are men more vulnerable? Am J Kidney Dis,
  2006. 47(3): p. 396-405.
•   Cardiovascular Health Study
•   N=5201, >65yrs of age, 1989-1990
•   N=687 AA , 1992-1993
•   GFR estimated with Cystatin C
     – Rapid decline in function = yearly decline of
      3 mL/min or more
• PA assessed subjectively: walking pace +
  leisure time physical activity
Robinson-Cohen, C., et al., Physical activity and rapid decline in kidney function
among older adults. Arch Intern Med, 2009. 169(22): p. 2116-23.
 Baseline Characteristics According to
        Physical Activity Score
                          Physical Activity Score
                  2-3     4-6                       7-8
Age               72.8    72.0                      71.2
White             80.9    80.2                      93.6
AA                19.1    11.8                      6.4
Current Smokers   14      10.5                      7.9
BMI               27.5    26.4                      25.7
Diabetes Status   18.3    12.1                      11.5
Systolic BP       138.4   134.3                     133.9
HDL               54.1    54.3                      54.8
CRP               5.3     4.3                       3.3
GFR               75.1    78.9                      81.1
Rate of rapid kidney function decline by
         physical activity score
             Strong Heart Study
• American Indians, 45-74 years of age, 1989-
  1995
• N=4549
• GFR estimated with serum creatinine
  – Rapid decline in function = yearly decline of
   3 mL/min or more
• Physical activity
  – Modifiable Activity Questionnaire at baseline only
     • Individuals were categorized in to tertiles of activity: no
       LTPA, low/high LPTA
The age adjusted odds of having a rapid decline
  in kidney function by categories of physical
                    activity
The age adjusted odds of having a rapid decline in
kidney function or CVD mortality by categories of
                physical activity
 The age adjusted odds of having a rapid decline in
kidney function or CVD mortality in individuals with
       CKD by categories of physical activity
•   Viscous cycle of CKD causing CKD
•   Can physical activity slow down this cycle?
•   Can physical activity prevent cycle initiation?
•   Are the anti-inflammatory effects of physical
    activity mediating this relationship?
         CKD and Inflammation
• In ESRD, 7 fold increase in inflammation
  – Increase production
  – Dialysis treatment
  – Reduce renal clearance
• Associated with protein-energy wasting and
  atherosclerotic vascular disease
• Il-6 is best predictor of all-cause and CVD
  mortality in ESRD patients
• CRP most widely used, also associated with
  mortality in individuals with CKD
Pharmacological treatments to reduce
          inflammation
 • Statins have been show to reduce
   inflammation in HD patients but no survival
   effect
 • ACEI decrease inflammation and prevented
   wasting
 • Aspirin intake reduced inflammation in HD
   patients
 • Vit D deficiency associated with short term
   mortality
   – Supplementation reduced inflammation
Physical activity and Inflammation
• Current PA is associated with CRP among individuals with
  cardiovascular disease, diabetes, dialysis and in the general
  population,
• PA can decrease pro-inflammatory cytokines (CRP, TNF-α, IL-
  6, and interferon gamma) decreased by 58%
• PA can increase anti-inflammatory cytokines (IL-10, IL-4, and
  TGF-β1) increased by 35%
• Does it mediate the relationship between PA and CKD
  progression or initiation?
     National Health and Nutrition
     Examination Survey (NHANES )
• NHANES 2003-2006
• PA assessed with accelerometer
• GFR estimated using MDRD equation
• Mild-Moderate = Stages 1 – 3
   – Stage 1 = eGFR>90 w/evidence of kidney damage
   – Stage 2 = eGFR 60-89
   – Stage 3 = eGFR 30-60
• Purpose
   – Examine the association between intensity of
     physical activity and renal function
      The association between light intensity
       physical activity and kidney function
800




                                                                            p=0.001
600
400
200
      0




          0                       50                       100                            150
                                   Glomerular Filtration Rate

               Minutes of Light Intensity Physical Activity               Fitted values
 Adjusted for sex, age, race, smoking status, BMI, HDL, diabetes status, MAP, CRP
Does CRP mediate the relationship between
  physical activity and kidney function?


     PA                                               GFR




                                CRP


      Confounders                     Co-mediators
      Age, Gender, Diabetes Status,   BMI, HDL, TC, MAP
      Race, Smoking Status
     PACRPGFR


PA                GFR
        p=0.001




          CRP
           PACRPGFR


PA                       GFR
               p=0.001




     p=0.005
                 CRP
           PACRPGFR


PA                                 GFR
               p=0.001




     p=0.005
                         p=0.675
                 CRP
             PACRPGFR


PA                                              GFR
                      p=0.001




       p=0.005
                                      p=0.675
                        CRP


     Mediator    Bootstrap Estimate        95% CI
CRP                   0.0000          (-0.0003, 0.0006)
      Mediation Results

                    CRP
      p=0.0048             p=0.675


                    BMI
     p=0.043               p=0.791



                    TC
     p=0.002               p=0.001

                 p=0.001
PA                                     GFR


     p=0.134        HDL     p=0.012


     p=0.248                 p=0.368
                   MAP
            Mediation Results (cont.)

         Mediator   Bootstrap Estimate        95% CI
CRP                      0.0000          (-0.0003, 0.0006)
BMI                      -0.0000         (-0.0004, 0.0003)
Total Cholesterol        0.0008          (0.0002, 0.0016)
HDL                      0.0002          (0.0001, 0.0006)
MAP                      0.0001          (-0.0001, 0.0006)
               Conclusion
• The relationship between PA and CKD not
  mediated by CRP
• PA can reduce inflammation in people with
  CKD, which may lead to better CV outcomes
Carrero, J.J. and P. Stenvinkel, Persistent inflammation as a catalyst for other risk factors in chronic kidney
disease: a hypothesis proposal. Clin J Am Soc Nephrol, 2009. 4 Suppl 1: p. S49-55.
Carrero, J.J. and P. Stenvinkel, Persistent inflammation as a catalyst for other risk factors in chronic kidney
disease: a hypothesis proposal. Clin J Am Soc Nephrol, 2009. 4 Suppl 1: p. S49-55.
The relationship between physical activity
    and CVD risk factors by CRP levels
The relationship between physical activity
     and history of CVD by CRP levels
                Conclusions
• Physical activity is related to kidney function
• Not mediated through its anti-inflammatory
  effects
• Inflammation is related to CV events in people
  with CKD
• The anti-inflammatory effects of activity may
  be related to reduce CV events and mortality
  in people with CKD

				
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