Proteinuria as a Surrogate Outcome in Chronic Kidney Disease Early Diabetes – Microalbuminuria (MA) Type 2 Diabetes in American Indians Robert G Nelson, MD, PhD NIDDK, Phoenix

Population  Pima Indians from the Gila River Indian Community in Arizona  Biennial examinations since 1965 of all community members ≥5 years old  Medical history/physical examination –Height, weight, blood pressure –Blood and urine tests –Retinal examinations and photographs –ECG –Oral Glucose Tolerance Test  Registries –ESRD –Mortality

Definitions Measure of Albuminuria Collection: Daytime untimed “spot” urine specimens Analyte: Urinary Albumin to Creatinine Ratio (ACR; in mg/g) Analytical methods: Albumin – immunonephelometry (Dade Behring, Inc.); Creatinine – modified Jaffe reaction (Envoy 500) Thresholds:<30 mg/g; normoalbuminuria (NA) mg/g; microalbuminuria (MA) ≥300 mg/g; macroalbuminuria Measure of Proteinuria Collection: Daytime untimed “spot” urine specimens Analyte: Urinary Protein to Creatinine Ratio (PCR; in g/g) Analytical methods: Protein – Shevky-Stafford; Creatinine – modified Jaffe reaction (Envoy 500) Thresholds:≥0.5 g/g (or ≥1.0 g/g in some studies)

Age-Sex-Adjusted Death Rates in Pima Indians ≥45 Years Old Diabetes 37: , 1988 Age-sex-duration adjusted death rate ratio 3.5 (95% CI, )

Prevalence of Elevated Albuminuria Diabetologia 32: , 1989

Incidence of Proteinuria by Level of Albuminuria Baseline Participants (N) – diabetic Pima Indians ≥15 years old439 Participants with urine ACR <30 mg/g (N) ≥30 mg/g (N) Study End Incidence rate ratio (MA/NA) of proteinuria (PCR ≥0.5g/g) [95%CI] 8.5 [ ] Arch Intern Med 151: , 1991 Figure. Age-sex-adjusted incidence of proteinuria in diabetic Pima Indians by albuminuria category.

Age-Sex-Adjusted Incidence of SCr ≥2.0 mg/dl by Duration of Diabetes and Presence of Proteinuria Kidney Int 35: , 1989 Age-sex-duration adjusted incidence rate ratio 42 (95% CI, 24-75)

Cumulative Incidence of ESRD by Duration of Proteinuria Duration of Proteinuria (years) Percent Diabetologia 36: , 1993 Whites with type 1 Pimas with type 2

Mean (±SE) Change in GFR According to Albuminuria at Baseline N Engl J Med 335: , 1996

Sequential Measures of Albuminuria 1 st ACR measurement (ACR -1 ; prior to baseline) Participants (N) – diabetic Pima Indians ≥15 years old983 (270 with MA) Urine ACR [median, 25 th and 75 th percentiles] 21 [11-67] 2 nd ACR measurement within 6 years (ACR 0 ; baseline) Participants (N)983 Urine ACR [median, 25 th and 75 th percentiles] 27 [13-121] Early change (Remission to NA <30 mg/g) (N)65 (24%) Study End Incidence of ESRD for each doubling of ACR 0 [95%CI] 1.7 [ ] Death rate from natural mortality for each doubling of ACR 0 [95%CI] 1.2 [ ] Am J Kidney Dis 51: , 2008

Changes in ACR Categories Between Two ACR Measurements Taken Within a 6-year Period ACR 0 <30 mg/g mg/g mg/g≥ 3000 mg/gTotal <30 mg/g 460 (76.5%) 129 (21.5%)11 (1.8%)1 (0.2%)601 ACR mg/g65 (24.1%) 155 (57.4%) 45 (16.7%)5 (1.8%) mg/g2 (2.2%)12 (13.0%) 46 (50.0%) 32 (34.8%)92 ≥ 3000 mg/g01 (5.0%)2 (10.0%) 17 (85.0%) 20 Total Am J Kidney Dis 51: , 2008

Incidence Rate Ratio for Diabetic ESRD (N=89 cases) Relative to Persistently Normal ACR Am J Kidney Dis 51: , 2008 ACR 0 NormalMicroMacro Normal13.1 ( )24.9 ( ) ACR -1 Micro1.9 ( )4.5 ( )20.5 ( ) Macro03.8 ( )15.4 ( )

Incidence of Diabetic ESRD Kidney Int 70: , 2006

Summary  MA occurs frequently in type 2 diabetes  MA predicts development of overt nephropathy  MA frequently regresses to normoalbuminuria  Low current ACR is associated with a good prognosis regardless of earlier values  Proteinuria strongly predicts progression to renal insufficiency, ESRD, and death  Distribution of albuminuria is changing over time