Background

Biotrin International Nephrology SMARTASSAYS enable renal injury to be localised to distinct parts of the nephron enabling improved monitoring of diabetic nephropathy and its therapy.

Collagen IV is the principal component of the glomerular basement membrane and it is released into the urine during its turnover(1). Increased urinary levels of collagen IV are found in several conditions where glomerular injury is found, particularly in diabetic nephropathy(2). Collagen IV is too large to cross the glomerular membrane (MW 540 000) and so urinary collagen IV is a specific sensitive indicator of changes to the structure of extracellular matrix of the kidney. Unlike serum creatinine, that measures changes in glomerular function, increased levels of urinary collagen IV indicate that damage is occurring to the renal tissue. Urinary collagen IV is a very early and specific biomarker for pathological changes to the glomerular membrane, particularly in diabetic nephropathy(3).

Collagen IV

The glutathione S-transferases (GSTs) are found in high concentrations in the cells of the renal tubules from which they are readily released into the urine during injury. Different GST subclasses are localised to specific parts of the renal tubule and their appearance in urine is an early indicator of the site and extent of renal injury. By the simultaneous assay of different GST subclasses, different sections of the nephron can be simultaneously and independently monitored (4). The Biotrin range of Nephrology SMARTASSAYS enable the status of the glomerulus (collagen IV) and proximal and distal renal tubules (αGST and πGST respectively) to be studied simultaneously allowing new insights into renal pathology and physiology.

Diabetic Nephropathy

When studying diabetic nephropathy, the Biotrin SMARTASSAYS biomarkers offer the following advantages:

• Collagen IV may be the earliest indicator of renal dysfunction (5).
• Urinary collagen IV levels correlate with the extent of diabetic nephropathy (3).
• Urinary collagen IV gives insight into the basic pathological changes that affect the glomerulus.
• Elevated urinary collagen IV levels are predictive of progressive albuminuria (5). Subjects with elevated urinary Collagen IV have a 2.7 fold increased risk of progressing to albuminuria
• Urinary collagen IV level is an earlier indicator of therapy response than other biomarkers (6). In subjects treated with ACE inhibitors, urinary collagen IV was the only renal biomarker to distinguish between the treatment groups.
• By the assay of both of αGST and πGST, injury to the distal convoluted tubule could be identified that had not previously been reported, This opens new possibilities for monitoring diabetic nephropathy and its therapy (7)
• Urinary αGST is a proven biomarker for nephrotoxicity (5) but it seems to be little affected by diabetic nephropathy (7). It could therefore offer a cleaner system for studying the renal effects of anti-diabetic therapies.

References:

1. Yagame, M. et al. (1997). Significance of urinary type IV collagen in patients with diabetic nephropathy using a highly sensitive one-step sandwich enzyme immunoassay. Journal of Clinical and Laboratory Analysis 11. 110-116.
2. Makino, H. et al. (1995). Urinary detection of type IV collagen and its increase in glomerulonephritis. Research Communications in Molecular Pathology and Pharmacology. 88(2) 215-223.
3. Okinogi et al. (2001). Urinary Type IV Collagen Excretion Reflects Renal Morphological Alterations and Type IV expression in patients with type 2 Diabetes. Clinical Nephrology 55, 357-364.
4. Sundberg A.G.M. et al. (1994). Urinary pi class glutathione S-transferase as an indicator of tubular damage in the human kidney. Nephron 67: 308-316
5. Ieki, Y. and Takazakura, E. (1999) Analysis of urinary excretion of type IV collagen as a predictor of progression of early diabetic nephropathy. – Two year follow up study. J. Japan Diab. Soc. 42(10) 859-862
6. Nishimura, M. et al (2001) Angiotensin Converting enzyme inhibitors and Probucol suppress the time-dependent increase in urinary collagen excretion of type IV collagen excretion of type II diabetes mellitus patients with early diabetic nephropathy. Clinical Nephrology 56 96-103.
7. Maxwell P-R et al. (2004). Differentiation between renal injury and compensatory responses by the use of specific biomarkers. Poster presented at the 43rd Annual meeting of the American Society of Toxicology, Baltimore March 21-25, 2004.