the relationship between physical activity and renal function. what's the role of inflammation?...
TRANSCRIPT
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
(mL/min/1.73m2)
Prevalence (%)
1 Kidney damage with normal or GFR
>90 5.7%
2 Mild GFR with kidney damage
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 CKD in the US, 1999-2004
Stage Description GFR
(mL/min/1.73m2)
Prevalence (%)
1 Kidney damage with normal or GFR
> 90 5.7%
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.
USRDS ADR, 2007
Prevalence of ESRD has been rising steadily
Costs of Kidney Failure are High(in $billions for 2002)
Kidney FailureCare Total NIH
Budget
25.223.2Kidney Failure Accounts
for 6% of Medicare Payments
Lost Income for Patients is $2-4 Billion/Yr
USRDS, 2004
Survival rates in patients with ESRD
CKD Predicts CVD
Go, et al., 2004
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Estimated GFR (mL/min/1.73 m2)
CKD Patients Are More Likely to Die than to Progress to ESRD
Keith, et al, Arch Int Med; 2004; 164:659-663
5 year follow-up
N=27998
• 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.
CKD
DIABETES HYPERTENSION
AGERACE
DYSLIPIDEMIA
OTHER•GENETICS•AUTO-INNUME
LIFESTYLE FACTORS•PHYSICA ACTIVITY•SMOKING•OBESITY
CKD
DIABETES HYPERTENSION
AGERACE
DYSLIPIDEMIA
OTHER•GENETICS•AUTO-INNUME
LIFESTYLE FACTORS•PHYSICA ACTIVITY•SMOKING•OBESITY
INFLAMMATION
CKD
DIABETES HYPERTENSION
AGERACE
DYSLIPIDEMIA
OTHER•GENETICS•AUTO-INNUME
LIFESTYLE FACTORS•PHYSICA ACTIVITY•SMOKING•OBESITY
INFLAMMATION
• 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
02
00
400
600
800
0 50 100 150Glomerular Filtration Rate
Minutes of Light Intensity Physical Activity Fitted values
p=0.001
Adjusted for sex, age, race, smoking status, BMI, HDL, diabetes status, MAP, CRP
Does CRP mediate the relationship between physical activity and kidney function?
GFR
CRP
PA
Confounders Co-mediators
Age, Gender, Diabetes Status, Race, Smoking Status
BMI, HDL, TC, MAP
PACRPGFR
GFR
CRP
p=0.001PA
PACRPGFR
GFR
CRP
p=0.001PA
p=0.005
PACRPGFR
GFR
CRP
p=0.001
p=0.675
PA
p=0.005
PACRPGFR
GFR
CRP
p=0.001
p=0.675
PA
p=0.005
Mediator Bootstrap Estimate 95% CI
CRP 0.0000 (-0.0003, 0.0006)
Mediation Results
CRP
PA GFR
p=0.0048
BMIp=0.043
p=0.002
p=0.001
TC
p=0.675
p=0.791
p=0.001
HDL
MAP
p=0.012
p=0.368
p=0.134
p=0.248
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