Proteinuria as a Surrogate Outcome in Chronic Kidney Disease

1
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

2
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

3
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 lt30 mg/g normoalbuminuria (NA)
• 30-299 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)

4
Age-Sex-Adjusted Death Ratesin Pima Indians 45
Years Old
Age-sex-duration adjusted death rate ratio 3.5
(95 CI, 2.8-4.4)
Diabetes 371499-1504, 1988
5
Prevalence of Elevated Albuminuria
Diabetologia 32870-876, 1989
6
Incidence of Proteinuria by Level of Albuminuria
Baseline
Participants (N) diabetic Pima Indians 15 years old 439
Participants with urine ACR lt30 mg/g (N) 30 mg/g (N) 299 140
Study End
Incidence rate ratio (MA/NA) of proteinuria (PCR 0.5g/g) 95CI 8.5 4.8-15.8
Figure. Age-sex-adjusted incidence of proteinuria
in diabetic Pima Indians by albuminuria category.
Arch Intern Med 1511761-1765, 1991
7
Age-Sex-Adjusted Incidence of SCr 2.0 mg/dl by
Duration of Diabetes and Presence of Proteinuria
Age-sex-duration adjusted incidence rate ratio 42
(95 CI, 24-75)
Kidney Int 35681-687, 1989
8
Cumulative Incidence of ESRDby Duration of
Proteinuria
80
Whites with type 1
Pimas with type 2
60
Percent
40
20
0
0
5
10
15
Duration of Proteinuria (years)
Diabetologia 361087-1093, 1993
9
Mean (SE) Change in GFRAccording to Albuminuria
at Baseline
N Engl J Med 3351636-1642, 1996
10
Sequential Measures of Albuminuria
1st ACR measurement (ACR-1 prior to baseline)
Participants (N) diabetic Pima Indians 15 years old 983 (270 with MA)
Urine ACR median, 25th and 75th percentiles 21 11-67
2nd ACR measurement within 6 years (ACR0 baseline)
Participants (N) 983
Urine ACR median, 25th and 75th percentiles 27 13-121
Early change (Remission to NA lt30 mg/g) (N) 65 (24)
Study End
Incidence of ESRD for each doubling of ACR0 95CI 1.7 1.5-1.9
Death rate from natural mortality for each doubling of ACR0 95CI 1.2 1.1-1.3
Am J Kidney Dis 51759-766, 2008
11
Changes in ACR Categories Between Two ACR
Measurements Taken Within a 6-year Period
ACR 0 ACR 0 ACR 0 ACR 0
lt30 mg/g 30-300 mg/g 300-3000 mg/g 3000 mg/g Total
lt30 mg/g 460 (76.5) 129 (21.5) 11 (1.8) 1 (0.2) 601
ACR -1 30-300 mg/g 65 (24.1) 155 (57.4) 45 (16.7) 5 (1.8) 270
300-3000 mg/g 2 (2.2) 12 (13.0) 46 (50.0) 32 (34.8) 92
3000 mg/g 0 1 (5.0) 2 (10.0) 17 (85.0) 20
Total 527 297 104 55 983
Am J Kidney Dis 51759-766, 2008
12
Incidence Rate Ratio for Diabetic ESRD (N89
cases) Relative to Persistently Normal ACR
ACR 0
Normal Micro Macro
Normal 1 3.1 (1.2-7.7) 24.9 (7.5-82.9)
ACR -1 Micro 1.9 (0.4-8.7) 4.5 (2.0-10.6) 20.5 (9.1-46.1)
Macro 0 3.8 (0.8-17.8) 15.4 (6.6-35.1)
Am J Kidney Dis 51759-766, 2008
13
Incidence of Diabetic ESRD
Kidney Int 701840-1846, 2006
14
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