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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    • "Another study from short-term type 2 DM patients indicated urinary NGAL showed a negative correlation with eGFR, which suggested urinary NGAL might be a promising early marker for monitoring renal impairment in short-term T2DM patients [28]. Study from type 1 DM indicated that urine NGAL levels correlated with albumin/creatinine, and patients with higher albuminuria had higher urine NGAL levels, which suggested that elevated urinary NGAL values might indicate kidney damage [29]. "
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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.
    02/2013; 1(1). DOI:10.1186/2050-7771-1-9
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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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    ABSTRACT: Diabetic nephropathy (DN) is a long-term complication of diabetes mellitus that leads to end-stage renal disease. Microalbuminuria is used for the early detection of diabetic renal damage, but such levels do not reflect the state of incipient DN precisely in type 2 diabetic patients because microalbuminuria develops in other diseases, necessitating more accurate biomarkers that detect incipient DN. Isobaric tags for relative and absolute quantification (iTRAQ) were used to identify urinary proteins that were differentially excreted in normoalbuminuric and microalbuminuric patients with type 2 diabetes where 710 and 196 proteins were identified and quantified, respectively. Some candidates were confirmed by 2-DE analysis, or validated by Western blot and multiple reaction monitoring (MRM). Specifically, some differentially expressed proteins were verified by MRM in urine from normoalbuminuric and microalbuminuric patients with type 2 diabetes, wherein alpha-1-antitrypsin, alpha-1-acid glycoprotein 1, and prostate stem cell antigen had excellent AUC values (0.849, 0.873, and 0.825, resp.). Moreover, we performed a multiplex assay using these biomarker candidates, resulting in a merged AUC value of 0.921. Although the differentially expressed proteins in this iTRAQ study require further validation in larger and categorized sample groups, they constitute baseline data on preliminary biomarker candidates that can be used to discover novel biomarkers for incipient DN.
    Experimental Diabetes Research 03/2012; 2012:168602. DOI:10.1155/2012/168602 · 4.33 Impact Factor
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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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    ABSTRACT: Aims and Objectives. Metabolic dysregulation has failed to explain clinical variability of patients with diabetic nephropathy and hence a renewed interest emerged in haemodynamic factors as determinant of progression and development of diabetic nephropathy. We therefore studied for various factors which can correlate with raised renal vascular resistance in diabetic nephropathy. Material and Methods. Renal vascular resistance was measured in patients with established and incipient diabetic nephropathy and compared with controls using noninvasive color Doppler examinations of intrarenal vasculature. Results. Renal vascular resistance correlated with age, duration of disease, GFR, serum creatinine, and stage of retinopathy. Renal vascular resistance was significantly reduced in patients on treatment with RAAS inhibitors and insulin, than those on OHA and antihypertensives other than RAAS inhibitors. Conclusion. The study implies that renal vascular resistance may help identify diabetics at high risk of developing nephropathy, and these set of patients could be candidates for RAAS inhibition and early insulin therapy even in patients without albuminuria.
    International journal of vascular medicine 06/2011; 2011:656030. DOI:10.1155/2011/656030
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