Prediction of Diabetic Nephropathy Using Urine Proteomic Profiling 10 Years Prior to Development of Nephropathy
- Hasan H. Otu, PHD12,
- Handan Can, PHD12,
- Dimitrios Spentzos, MD1,
- Robert G. Nelson, MD, PHD3,
- Robert L. Hanson, MD, MPH3,
- Helen C. Looker, MBBS3,
- William C. Knowler, MD, DRPH3,
- Manuel Monroy, MD4,
- Towia A. Libermann, PHD1,
- S. Ananth Karumanchi, MD5 and
- Ravi Thadhani, MD, MPH4
- 1Genomics Center and DF/HCC Cancer Proteomics Core, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
- 2Department of Genetics and Bioengineering, Yeditepe University, Istanbul, Turkey
- 3Diabetes Epidemiology and Clinical Research Section, Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Phoenix, Arizona
- 4Department of Medicine and Renal Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
- 5Division of Nephrology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts
- Address correspondence and reprint requests to Ravi Thadhani, MD, MPH, Bullfinch 127, 55 Fruit St., Massachusetts General Hospital, Boston, MA 02114. E-mail: thadhani.r{at}mgh.harvard.edu
Abstract
OBJECTIVE—We examined whether proteomic technologies identify novel urine proteins associated with subsequent development of diabetic nephropathy in subjects with type 2 diabetes before evidence of microalbuminuria.
RESEACH DESIGN AND METHODS—In a nested case-control study of Pima Indians with type 2 diabetes, baseline (serum creatinine <1.2 mg/dl and urine albumin excretion <30 mg/g) and 10-year urine samples were examined. Case subjects (n = 31) developed diabetic nephropathy (urinary albumin–to–creatinine ratio >300 mg/g) over 10 years. Control subjects (n = 31) were matched to case subjects (1:1) according to diabetes duration, age, sex, and BMI but remained normoalbuminuric (albumin–to–creatinine ratio <30 mg/g) over the same 10 years. Surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF MS) was performed on baseline urine samples, and training (14 cases:14 controls) and validation (17:17) sets were tested.
RESULTS—At baseline, A1C levels differed between case and control subjects. SELDI-TOF MS detected 714 unique urine protein peaks. Of these, a 12-peak proteomic signature correctly predicted 89% of cases of diabetic nepropathy (93% sensitivity, 86% specificity) in the training set. Applying this same signature to the independent validation set yielded an accuracy rate of 74% (71% sensitivity, 76% specificity). In multivariate analyses, the 12-peak signature was independently associated with subsequent diabetic nephropathy when applied to the validation set (odds ratio [OR] 7.9 [95% CI 1.5–43.5], P = 0.017) and the entire dataset (14.5 [3.7–55.6], P = 0.001), and A1C levels were no longer significant.
CONCLUSIONS—Urine proteomic profiling identifies normoalbuminuric subjects with type 2 diabetes who subsequently develop diabetic nephropathy. Further studies are needed to characterize the specific proteins involved in this early prediction.
Footnotes
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A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances.
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- Accepted December 1, 2006.
- Received August 4, 2006.
- DIABETES CARE
