1. Welch Center Uniting Medicine & Public Health Prevalence of Albuminuria, and its Relationship to Decreased GFR and Outcomes Josef Coresh, MD, PhD Director, Cardiovascular Epidemiology Program Welch Center Departments of Epidemiology, Medicine & Biostatistics Johns Hopkins University Disclosures: None Proteinuria as a Surrogate Outcome in Chronic Kidney Disease A workshop co-sponsored by the National Kidney Foundation and U.S. Food and Drug Administration

2. Outline CKD prevalence –Albuminuria by stage & its persistence CVD risk in relation to: –Albuminuria and eGFR Creatinine (eGFR MDRD ) Cystatin C (eGFR CysC ) Conclusions

3. Prevalence of CKD: NHANES Surveys Representing the US Adult Population Study Population: stratified random sample –NHANES III (1988 to 1994): n=15,488* –NHANES 1999-2000: n=4,101* –NHANES 2001-2002: n=4,684 –NHANES 2003-2004: n=4,448 Serum creatinine: calibrated to be comparable to the MDRD creatinine assay using frozen serum (Am J Kidney Dis. 2007;50:918-26) GFR Estimate: MDRD Study 4-variable equation Extrapolation to US population: NCHS published survey weights adjusting for age, sex, race and non-response *Coresh et al. JAMA. 2007; 298(17):2038-47

4. Distribution of Albumin to Creatinine Ratio: NHANES 1988-2004 Albumin to Creatinine Ration, mg/g micro ”normal” macro

5. Prevalence of Diagnosed Diabetes and Hypertension by Albuminuria: NHANES 1988-2004 < 55-2930-299300+ ACR mg/g Proportion Prevalence Age, y 41% (9,920) 50% (13,000) 7.1% (2648) 1.2% (573) 42485660

6. CKD Prevalence Estimates Require GFR Estimation (eGFR) MDRD Study Equation (GFR ml/min/1.73m 2 ) eGFR = 186 x (SCr) -1.154 x (age) -0.203 x (0.742 if female) x (1.210 if African American) eGFR = 175 x (Standardized SCr) -1.154 x (age) -0.203 x (0.742 if female) x (1.210 if African American) Cockcroft-Gault (CG ml/min) Ccr = (140-age) x weight x 0.85 (if female)/(SCr) BSA Adjusted = CG * 1.73 / BSA formula Equations in other populations –Children, Chinese, Japanese, Kidney Donors N Engl J Med. 2006; 354(23):2473-83. Clin Chem 2007; 53(4):766-72

7. Estimated GFR Distribution The conservative trends analysis eliminated the difference in mean GFR between surveys. The vertical line demarcates an estimated GFR of 60 ml/min/1.73m 2 which defines decreased GFR. Estimated GFR, ml/min/1.73m 2

8. Relationship of eGFR to Albuminuria & Hypertension: NHANES III Am J Kidney Dis 2002;39:(2) S49 Albuminuria only Normal High BP only Albuminuria & High BP

9. Chronic Kidney Disease (CKD) Definition Kidney damage for 3+ months as defined by structural of functional abnormalities of the kidney, with or without decreased GFR manifest by either: –Pathological abnormalities, or –Markers of kidney damage including abnormalities in the composition of the blood or urine, or abnormalities in imaging tests GFR < 60 ml/min/1.73m 2 for 3+ months with or without kidney damage Am J Kidney Dis 2002;39:(2) S1-S266 Ann Intern Med 2003; 139(2):137-147

10. -5 0 5 10 Log(ACR) – Second Visit -5 05 10 Log(ACR) – First Visit Macro >300 mg/g Micro 30-299 mg/g Macro >300 mg/g Micro 30-299 mg/g “Normal” Persistence of Albuminuria – Spot Urine ACR in 2 visits a median of 17 days apart: NHANES III

11. Persistence of Albuminuria: NHANES III Albuminuria at First Visit,mg/g Albuminuria on a Repeat Visit (median 17 days later) eGFR 90+eGFR <90 Micro, 30-299*50.9% (n=57) 75.0% (n=36) Macro 300+100% * 53.9% and 72.7% for gender specific cutoffs for micro- albuminuria 17-250 mg/g for men and 25-355 mg/g for women

12. US Trends in the Prevalence of CKD by Age and Stage: NHANES 1988-2004 Coresh et al. JAMA. 2007;298:2038-2047 0% 10% 20% 30% 40% 50% 88-9499-04 88-9499-0488-9499-0488-9499-04 Age Group: Prevalence, % Stage 4 Stage 3 Stage 2 Stage 1 CKD Stage 20-3940-5960-69 70+ Survey years: Persistent albuminuria >30 mg/g eGFR MDRD 15-29 eGFR MDRD 30-59

13. Prevalence of Elevated Cystatin C in US Women (>1.12 mg/L = 99 th %ile for young healthy adults) Women 0% 20% 40% 60% 80% 100% Proportion with cystatin C >1.12 mg/L 102030405060708090 Age(years) non-Hispanic white non-Hispanic black Mexican American Kottgen et al. Am J Kidney Dis 2008;51:385-394 (n=7,596)

14. Different Outcomes of CKD OutcomeImportance for Different Outcomes CKD StageType of Kidney Disease (Diagnosis)** Proteinuria Concurrent complications* +++++ Prognosis (next 10-years) Risk of CVD or mortality ++++++ Risk of kidney failure ++++++ Rate of decline in GFR ++++ *Hypertension, anemia, malnutrition, bone disease, neuropathy & decreased quality of life **For example, diabetic, glomerular, vascular, tubulointerstitial, & cystic

15. Albuminuria and Risk of Cardiovascular Death General Population: Risk Seen at Very Low Levels PREVEND Study - Hillege HL et al, Circulation 2002;106:1777-82. Micro- albuminuria Urinary Albumin Concentration mg/day 1.0 2.0 3.0 4.0 5.0 Hazard Ratio 20 mg/day (30 mg/g) 200 mg/day (300 mg/g)

16. CKD and Risk of Death: Kaiser Permanente Study Go et al. N Engl J Med 2004;351:1296-305. Also showed adjusted excess risk for: - Mortality - CVD events - Hospitalizations

17. Risk of Death among Elderly Persons: CHS Study Mean Age 74 Years Shlipak et al. N Engl J Med 2005;352:2049-60 Quintile 1 2345a Decreased Kidney Function

18. Glomerular Filtration Rate, Albuminuria, and Risk of Cardiovascular and All-Cause Mortality in the US Population (Astor et al. Am J Epidemiol 2008, April ePUB)

19. Cardiovascular Mortality Models adjusted to incidence rates of a 60-year-old non-Hispanic White male.

20. All-Cause Mortality Models adjusted to incidence rates of a 60-year-old non-Hispanic White male.

21. Adjusted* Cardiovascular Mortality Risk by eGFR and albuminuria *adjusted to the incidence rates of a 60 year-old, non-Hispanic white male. Astor et al. Am J Epidemiol 2008; April

22. Cardiovascular mortality in NHANES III F/U Predicted incidence rates adjusted to the mortality rate of a 60 year ‑ old, non-Hispanic white male Astor et al. Am J Epidemiol 2008; April

23. All-Cause mortality in NHANES III F/U Predicted incidence rates adjusted to the mortality rate of a 60 year ‑ old, non-Hispanic white male Astor et al. Am J Epidemiol 2008; April

24. Association of Kidney Function and Albuminuria With Cardiovascular Mortality in Older vs Younger Individuals: The HUNT II Study Hallan et al. Arch Intern Med. 2007;167(22):2490-2496 eGFR ml/min/1.73m 2 ACR, mg/g Age & Sex Adjusted IRR ACR – average 3 spot urines Optimal < median Men: < 5 Women: < 7 High normal Men: 5 to 19 Women: 7 to 29 Microalbuminuria Men: 20 to 199 Women: 30 to 299 30 505 20

25. Cardiovascular Mortality by eGFR and Albuminuria: HUNT II Study Hallan et al. Arch Intern Med. 2007;167(22):2490-2496 Albuminuria, mg/g (average of 3 spot urines) ACR Optimal < median Men: < 5 Women: < 7 High normal Men: 5 to 19 Women: 7 to 29 Microalbuminuria Men: 20 to 199 Women: 30 to 299 *P.05. †P.01. ‡P.001.

26. 0.5 1 1.5 2 2.5 3 Adjusted Annual Cardiovascular Mortality (%) 30405060708090100110120 Estimated GFR (mL/min/1.73m 2 ) Adjusted* Cardiovascular Mortality Risk in NHANES III Mortality Follow-Up Study Astor et al. JASN 2007 abstract High eGFR MDRD  low muscle mass (BAD) *Adjusted for 13 covariates eGFR MDRD eGFR CysC Age > 65 Age ≤ 65

27. *Adjusted to the age of 60 years, female, Whites, HD and non-smokers. Overall Distorted Associations (Baseline Disease  RF  CVD) Adjusted* 3-year all-cause mortality in Dialysis Patients Presence of Inflammation/Malnutrition Absence of Inflammation/Malnutrition

28. Distorted Associations (Baseline Disease  RF  CVD) Adjusted* 3-year all-cause mortality in Dialysis Patients *Adjusted to the age of 60 years, female, Whites, HD and non-smokers. Overall Presence of Inflammation/Malnutrition Absence of Inflammation/Malnutrition JAMA 2004;291:451-459

29. Conclusions Albuminuria is common in the population –Spot ACR provides a reasonable measure –Cutoffs are somewhat arbitrary: sex dependent cutoffs are more accurate but non-sex dependent cutoff are useful & less complicated –Microalbuminuria varies within an individual – persistence is a useful indicator –Much more common among diabetics; but a substantial proportion of the individuals with microalbuminuria have neither hypertension nor diabetes Albuminuria and eGFR are associated but confer independent risk (mortality, CVD mortality)

30. Thank you! CKD-Epi ARIC Staff CHOICE Study CVD-EpiStein Hallan