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Welch Center Uniting Medicine & Public Health

Welch Center Uniting Medicine & Public Health

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Welch Center Uniting Medicine & Public Health

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  1. Welch Center Uniting Medicine & Public Health 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 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

  2. Outline • CKD prevalence • Albuminuria by stage & its persistence • CVD risk in relation to: • Albuminuria and eGFR • Creatinine (eGFRMDRD) • Cystatin C (eGFRCysC) • 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 macro micro ”normal” Albumin to Creatinine Ration, mg/g

  5. Prevalence of Diagnosed Diabetes and Hypertension by Albuminuria: NHANES 1988-2004 Proportion ACR mg/g < 5 5-29 30-299 300+ Prevalence 41% (9,920) 50% (13,000) 7.1% (2648) 1.2% (573) Age, y 42 48 56 60

  6. CKD Prevalence Estimates Require GFR Estimation (eGFR) • MDRD Study Equation (GFR ml/min/1.73m2) 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 Estimated GFR, ml/min/1.73m2 The conservative trends analysis eliminated the difference in mean GFR between surveys. The vertical line demarcates an estimated GFR of 60 ml/min/1.73m2 which defines decreased GFR.

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

  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/1.73m2 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. Persistence of Albuminuria – Spot Urine ACR in 2 visits a median of 17 days apart: NHANES III 10 Macro >300 mg/g Micro 30-299 mg/g 5 Log(ACR) – Second Visit 0 Micro 30-299 mg/g Macro >300 mg/g “Normal” -5 0 5 -5 10 Log(ACR) – First Visit

  11. Persistence of Albuminuria: NHANES III * 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 50% CKD Stage 40% eGFRMDRD 15-29 eGFRMDRD 30-59 Stage 4 Stage 3 Persistent albuminuria >30 mg/g Stage 2 30% Stage 1 Prevalence, % 20% 10% 0% 88-94 99-04 88-94 99-04 88-94 99-04 88-94 99-04 Survey years: Age Group: 20-39 40-59 60-69 70+ Coresh et al. JAMA. 2007;298:2038-2047

  13. Prevalence of Elevated Cystatin C in US Women (>1.12 mg/L = 99th %ile for young healthy adults) 100% non-Hispanic white Women non-Hispanic black 80% Mexican American (n=7,596) 60% Proportion with cystatin C >1.12 mg/L 40% 20% 0% 10 20 30 40 50 60 70 80 90 Age(years) Kottgen et al. Am J Kidney Dis 2008;51:385-394

  14. Different Outcomes of CKD *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 Hazard Ratio 20 mg/day (30 mg/g) 200 mg/day (300 mg/g) Micro- albuminuria 5.0 4.0 3.0 2.0 1.0 Urinary Albumin Concentration mg/day PREVEND Study - Hillege HL et al, Circulation 2002;106:1777-82.

  16. 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)

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

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

  19. 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

  20. 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

  21. Association of Kidney Function and AlbuminuriaWith Cardiovascular Mortality in Older vs Younger Individuals: The HUNT II Study • 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 Age & Sex Adjusted IRR 5 50 20 30 eGFR ml/min/1.73m2 ACR, mg/g Hallan et al. Arch Intern Med. 2007;167(22):2490-2496

  22. Cardiovascular Mortality by eGFR and Albuminuria: HUNT II Study • 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. Albuminuria, mg/g (average of 3 spot urines) Hallan et al. Arch Intern Med. 2007;167(22):2490-2496

  23. Adjusted* Cardiovascular Mortality Risk in NHANES III Mortality Follow-Up Study 3 2.5 2 High eGFRMDRD low muscle mass (BAD) eGFRMDRD 1.5 Age > 65 Adjusted Annual Cardiovascular Mortality (%) 1 eGFRCysC Age ≤ 65 .5 0 30 40 50 60 70 80 90 100 110 120 Estimated GFR (mL/min/1.73m2) *Adjusted for 13covariates Astor et al. JASN 2007 abstract

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

  25. 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)

  26. Thank you! CKD-Epi CVD-Epi Stein Hallan CHOICE Study ARIC Staff