1. THE RELATIONSHIP BETWEEN PHYSICAL ACTIVITY AND RENAL FUNCTION. WHAT'S THE ROLE OF INFLAMMATION? Marquis Hawkins, Ph.D. Postdoctoral Scholar University of Pittsburgh

2. Happy Birthday Dr. Hawkins!!!!

3. 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 m 2 for ≥ 3 months with or without kidney damage.

4. 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

5. 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.

6. Prevalence of CKD in the US, 1999-2004 StageDescriptionGFR (mL/min/1.73m2) Prevalence (%) 1Kidney damage with normal or  GFR >905.7% 2 Mild  GFR with kidney damage 60-895.4% 3 Moderate  GFR 30-595.4% 4 Severe  GFR 15-290.2% 5Kidney Failure< 15 or dialysis0.2% Prevalence of chronic kidney disease and associated risk factors--United States, 1999-2004. MMWR Morb Mortal Wkly Rep, 2007. 56(8): p. 161-5.

7. Prevalence of CKD in the US, 1999-2004 StageDescriptionGFR (mL/min/1.73m2) Prevalence (%) 1Kidney damage with normal or  GFR > 905.7% 2 Mild  GFR 60-895.4% 3 Moderate  GFR 30-595.4% 4 Severe  GFR 15-290.2% 5Kidney Failure< 15 or dialysis0.2% Prevalence of chronic kidney disease and associated risk factors--United States, 1999-2004. MMWR Morb Mortal Wkly Rep, 2007. 56(8): p. 161-5.

8. USRDS ADR, 2007 Prevalence of ESRD has been rising steadily

9. Costs of Kidney Failure are High (in $billions for 2002) Kidney Failure Care Total NIH Budget 25.2 23.2 Kidney Failure Accounts for 6% of Medicare Payments Lost Income for Patients is $2-4 Billion/Yr USRDS, 2004

10. Survival rates in patients with ESRD

11. CKD Predicts CVD Go, et al., 2004 Age-Standardized Rate of Cardiovascular Events (per 100 person-yr) Estimated GFR (mL/min/1.73 m2)

12. 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

13. 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.

14. CKD DIABETES HYPERTENSION AGE RACE DYSLIPIDEMIA OTHER GENETICS AUTO-INNUME LIFESTYLE FACTORS PHYSICA ACTIVITY SMOKING OBESITY

15. CKD DIABETES HYPERTENSION AGE RACE DYSLIPIDEMIA OTHER GENETICS AUTO-INNUME LIFESTYLE FACTORS PHYSICA ACTIVITY SMOKING OBESITY INFLAMMATION

16. CKD DIABETES HYPERTENSION AGE RACE DYSLIPIDEMIA OTHER GENETICS AUTO-INNUME LIFESTYLE FACTORS PHYSICA ACTIVITY SMOKING OBESITY INFLAMMATION

17. Nephrons Maladaptive compensation (hypertrophy, hypertension, hyperfiltration) Shear stress, changes to ECM, proteinuria Inflammation Glomerulosclerosis, tubulointerstitial fibrosis

18. Nephrons Maladaptive compensation (hypertrophy, hypertension, hyperfiltration) Shear stress, changes to ECM, proteinuria Inflammation Glomerulosclerosis, tubulointerstitial fibrosis

19. Viscous cycle of CKD causing CKD Can physical activity slow down this cycle? Can physical activity prevent cycle initiation?

20. 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.

21. 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.

22. 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.

23. Baseline Characteristics According to Physical Activity Score Physical Activity Score 2-34-67-8 Age72.872.071.2 White80.980.293.6 AA19.111.86.4 Current Smokers1410.57.9 BMI27.526.425.7 Diabetes Status18.312.111.5 Systolic BP138.4134.3133.9 HDL54.154.354.8 CRP5.34.33.3 GFR75.178.981.1

24. Rate of rapid kidney function decline by physical activity score

25. 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

26. The age adjusted odds of having a rapid decline in kidney function by categories of physical activity

27. The age adjusted odds of having a rapid decline in kidney function or CVD mortality by categories of physical activity

28. The age adjusted odds of having a rapid decline in kidney function or CVD mortality in individuals with CKD by categories of physical activity

29. 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?

30. 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

31. 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

32. 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?

33. 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

34. The association between light intensity physical activity and kidney function p=0.001 Adjusted for sex, age, race, smoking status, BMI, HDL, diabetes status, MAP, CRP

35. Does CRP mediate the relationship between physical activity and kidney function? GFR CRP PA ConfoundersCo-mediators Age, Gender, Diabetes Status, Race, Smoking Status BMI, HDL, TC, MAP

36. PA  CRP  GFR GFR CRP p= 0.001 PA

37. PA  CRP  GFR GFR CRP p= 0.001 PA p= 0.005

38. PA  CRP  GFR GFR CRP p= 0.001 p=0.675 PA p= 0.005

39. PA  CRP  GFR GFR CRP p= 0.001 p=0.675 PA p= 0.005 MediatorBootstrap Estimate95% CI CRP0.0000(-0.0003, 0.0006)

40. Mediation Results CRP PA GFR p=0.0048 BMI p=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

41. Mediation Results (cont.) MediatorBootstrap Estimate95% CI CRP0.0000(-0.0003, 0.0006) BMI-0.0000(-0.0004, 0.0003) Total Cholesterol0.0008(0.0002, 0.0016) HDL0.0002(0.0001, 0.0006) MAP0.0001(-0.0001, 0.0006)

42. 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

43. 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.

46. The relationship between physical activity and CVD risk factors by CRP levels

47. The relationship between physical activity and history of CVD by CRP levels

48. 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