Prediction of Diabetic Nephropathy Using Urine Proteomic Profiling 10 Years Prior to Development of Nephropathy

Harvard University, Cambridge, Massachusetts, United States
Diabetes care (Impact Factor: 8.42). 03/2007; 30(3):638-43. DOI: 10.2337/dc06-1656
Source: PubMed


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.
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.
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 nephropathy (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.
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.

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    ABSTRACT: Diabetic kidney disease is the leading cause of end-stage renal disease in developed and developing countries. Microalbuminuria is the gold standard for detection and prediction of diabetic kidney disease and cardiovascular risk disease in clinical practice. However, microalbuminuria has several limitations, such as lower sensitive, larger variability. It is urgent to explore higher sensitivity and specificity for earlier detection of diabetic kidney disease and more accurate prediction of the progression to end stage renal disease. We reviewed some new and important urinary biomarkers, such as: transferrin, immunoglobulin G, immunoglobulin M, Cystanic C, podocytes, type IV collagen, 8-oxo-7, 8-dihydro-2'-deoxyguanosine, ceruloplasmin, monocyte chemoattractant protein-1 and so on. We need good quality, long-term, large longitudinal trials to validate published biomarkers and find new biomarkers, considering biomarkers reviewed here are from small cross-sectional studies.
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    • "Recently, to compare DN patients with non-DN patients, proteomic technologies have been developed to identify urinary marker candidates that are associated with the development of DN. Various proteomic approaches have been used for this purpose, including 2-DE, 2-DE DIGE, and SELDI-TOF [5, 11, 12]. However, because many studies have focused on restricted sets of targeted proteins, alterations in comprehensive urinary protein profiles in type 2 diabetes have not been monitored. "
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    • "Another area of active research has been finding suitable markers for predicting which patients will progress. Many studies addressed biochemical markers but none is specific or sensitive enough for clinical use [17] [18] [19]. Of late researchers have tried to answer all these controversies by a single key and that is hemodynamic alterations [20] which include concepts of intraglomerular hypertension , raised renal vascular resistance and so called ischemic nephropathy, which have been held responsible for discrepancy in behavior of various groups; recently an article by Nosadini et al. established renal vascular resistance as a predictive marker for progressive disease [6]. "
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