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