Urinary Collagen IV and πGST: Potential Biomarkers for Detecting Localized Kidney Injury in Diabetes – A Pilot Study

Department of Diabetes and Endocrinology, Christchurch Hospital, Christchurch, New Zealand. tom.cawood @
American Journal of Nephrology (Impact Factor: 2.67). 09/2010; 32(3):219-25. DOI: 10.1159/000317531
Source: PubMed


Urinary biomarkers can identify damage to specific parts of the nephron. We performed a cross-sectional study to characterise the pattern of diabetic nephropathy using urinary biomarkers of glomerular fibrosis (collagen IV), proximal tubular damage (α-glutathione-S-transferase, GST) and distal tubular damage (πGST).
Clinical data from 457 unselected patients attending a hospital diabetes clinic were collected. Spot urine samples were analysed for albumin and creatinine. Biomarkers were measured by enzyme-linked immunosorbent assay, and corrected to urinary creatinine.
All 3 biomarkers correlated weakly with albumin/creatinine ratios (Pearson correlation <0.2, p values <0.001). The most common abnormality was elevated urinary collagen IV (glomerular, 35%) compared to αGST (proximal tubule, 18%) or πGST (distal tubule, 15%). The proportion of patients with abnormal biomarker results increased across the normo-, micro- and macroalbuminuria groups, with collagen IV (26, 58, 65%) and πGST (11, 25, 35%) but not αGST.
In patients with diabetes, these urinary biomarkers appear to identify renal damage that is related to, but distinct from, urine albumin/creatinine ratios. The markers of glomerular fibrosis and distal tubular damage related most closely to the degree of albuminuria. Longitudinal studies are now required to assess whether these biomarkers can detect early renal disease with greater specificity and sensitivity than the albumin/creatinine ratio.

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    • "With the exception of this study, to the best of our knowledge, there are no further reports on π-GST:crea ratio in a pediatric population. In adult diabetic patients, urinary π-GST:crea ratio was found to rise with increasing albuminuria [7]. A similar trend was observed in adult patients with overt renal disease [13]. "
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    ABSTRACT: Renal disease remains a serious threat in patients with insulin-dependent (type1) diabetes. Hence its detection early in the life of patients with type1 diabetes is crucial. Several lines of evidence suggest similar mechanisms for the development of both renal and arterial disease. We sought to investigate in young patients with type1 diabetes whether pi-Glutathione S-transferase to creatinine (pi-GST:crea) and Tamm-Horsfall protein to creatinine (THP:crea) ratios, markers of distal tubular renal function, relate to subclinical markers of arterial disease, which appear to onset early and develop rapidly in type1 diabetes. Seventy-one children and adolescents (median age and diabetes duration 14 and 6 years, respectively) with type1 diabetes for at least 6 months were assessed for timed urine levels of pi-GST, THP, HbA1c, albumin, and plasma C-reactive protein (CRP). Carotid artery intima-media thickness (IMT), brachial artery flow-mediated dilatation (FMD), and cutaneous microvascular function were assessed by high-resolution ultrasound and laser Doppler, respectively. Two patients had microalbuminuria (> 20 mug/min), and were therefore removed from the study population. pi-GST:crea ratio and THP:crea showed no relationship to the demographic, diabetes, or inflammatory indices. Lower pi-GST:crea ratio was associated with greater IMT (p = 0.01, r = -0.29), particularly in female patients (p = 0.004, r = -0.49). The association of pi-GST:crea ratio with IMT was stronger in patients with passive smoke exposure (p = 0.002, r = -0.43). Among post-pubertal patients, lower pi-GST:crea ratio was also associated with lower microvascular response to Ach (acetylcholine; p = 0.03, r = 0.49). In young patients with type1 diabetes, proximal tubular dysfunction as suggested by lower levels of pi-GST:crea ratio seems to be paralleled by changes in arterial structure and microvascular function.
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    ABSTRACT: PURPOSE OF REVIEW: A focused review of the nature, source, physiological role and rapidly expanding evidence for glutathione S-transferase (GST) subtypes π and α as biomarkers of acute kidney injury (AKI) in patients undergoing cardiac surgery. Expanded insights into the site-specific expression of the GSTs in defined parts of the nephron during renal damage are presented, with particular emphasis on the pathogenesis of cardiac surgery and cardiopulmonary bypass (CPB)-associated AKI and the role of GSTs in oxygen radical disposal. RECENT FINDINGS: Recent developments have highlighted a potential role of urinary α-GST and π-GST in the diagnostic evaluation of cardiac surgery-associated AKI. Both urinary α-GST and π-GST are detected in the postoperative period. π-GST performed best at predicting AKI severity at the time of the initial diagnosis of AKI. α-GST was able to predict the future development of both stage 1 and stage 3 AKI. SUMMARY: The current data from a small number of patients suggest a potential role of urinary GSTs in the clinical diagnostic evaluation of AKI following cardiac surgery. The performance of the GSTs for the early diagnosis of AKI needs to be validated in larger multicentre studies and in other patient populations at increased risk of AKI (e.g. patients with acute transplant rejection, septic patients). Comparison with other emerging AKI biomarkers is required to continue the development of π-GST and α-GST. Finally, additional studies examining the pathophysiological role of the GSTs in minimizing oxygen free radical exposure in the renal tubules during CPB may shed further light into their role as promising biomarkers of cardiac surgery-associated AKI.
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    ABSTRACT: Both type 1 and type 2 diabetes are associated with severe complications including diabetic nephropathy. With the rapidly rising number of patients with diabetes worldwide, diabetic nephropathy is becoming one of the most common causes of renal disease. Much research effort is being put into how to identify diabetic nephropathy in patients with diabetes. A considerable number of biomarker studies were recently published on markers in plasma or urine, either with the aim to distinguish patients with or without diabetic nephropathy, or with the aim to predict renal outcome in those patients with diabetic nephropathy. We review the most recent findings on this subject and discuss the lack of histologically proven diabetic nephropathy in the majority of these studies. Most conspicuous in the field of diabetic nephropathy was the recent identification of a number of biomarkers used either in the diagnosis of diabetic nephropathy or in the evaluation of therapies meant to prevent, slow down, or reverse the processes causing diabetic nephropathy. For the histopathology of diabetic nephropathy, a new classification system was launched in 2010, which will be discussed together with future perspectives. Combining histopathological grading of and biomarkers for diabetic nephropathy will further our understanding of this complex disease manifestation.
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