Background/Aims: The aim of this post-hoc analysis of a prospective study in patients with type 2 diabetic nephropathy was to investigate whether treatment with the angiotensin II type 1 receptor blocker irbesartan leads to a reduction in the serum levels of the advanced glycation end products (AGEs) pentosidine and NΕ-carboxymethyllysine (CML). Methods: One hundred and ninety-six patients of the Irbesartan in Diabetic Nephropathy Trial cohort (mean age 61 ± 6.5 years, 62 female, 134 male) with a mean estimated glomerular filtration rate of 47.7 ml/min were treated with irbesartan (n = 65), the calcium channel blocker amlodipine (n = 61) or by placebo (n = 70). Serum levels of pentosidine and CML were measured at baseline and after follow-up (23.4 months). Results: Estimated glomerular filtration rate decreased in all groups by a mean of 8.6 ml/min. Serum levels of AGEs increased significantly (p < 0.001) during follow-up. After controlling for renal function and total protein concentration, changes were 53, 55, 50% for pentosidine and 29, 24, 23% for CML (irbesartan, amlodipine and placebo group, respectively). The increase was not significantly different between the treatment groups. Conclusion: Irbesartan did not alter the increase in pentosidine and CML in serum of type 2 diabetic patients with progressive nephropathy. This finding suggests that angiotensin receptor blockade alone is insufficient to reduce serum levels of AGEs in diabetic nephropathy.

Keywords:
Advanced glycation end products, Angiotensin II type 1 blockers, Irbesartan, Diabetic nephropathy, Nε-carboxymethyllysine, Pentosidine
1.
Goldin A, Beckman JA, Schmidt AM, Creager MA: Advanced glycation end products sparking the development of diabetic vascular injury. Circulation 2006;114:597–605.
2.
Baynes JW, Thorpe SR: Role of oxidative stress in diabetic complications. Diabetes 1999;48:1–9.
3.
Bohlender JM, Franke S, Stein G, Wolf G: Advanced glycation end products and the kidney. Am J Physiol Renal Physiol 2005;289:645–659.
4.
Schwedler SB, Metzger T, Schinzel R, Wanner C: Advanced glycation end products and mortality in hemodialysis patients. Kidney Int 2002;62:301–310.
5.
Busch M, Franke S, Müller A, Wolf M, Gerth J, Ott U, Niwa T, Stein G: Potential cardiovascular risk factors in chronic kidney disease; AGEs, total homocysteine and metabolites, and the C-reactive protein. Kidney Int 2004;66:338–347.
6.
Busch M, Franke S, Wolf G, Brandstädt A, Ott U, Gerth J, Hunsicker LG, Stein G: The advanced glycation end product Nε-carboxymethyllysine is not a predictor of cardiovascular events and renal outcome in patients with type 2 diabetic kidney disease and hypertension. Am J Kidney Dis 2006;48:571–579.
7.
Ahmed N, Thornalley PJ: Advanced glycation endproducts: what is their relevance to diabetic complications? Diabetes Obes Metab 2007;9:233–245.
8.
Genuth S, Sun W, Cleary P, Sell DR, Dahms W, Malone J, Sivitz W, Monnier VM, for the DCCT Skin Collagen Ancillary Study Group: Glycation and carboxymethyllysine levels in skin collagen predict the risk of 10-year progression of diabetic retinopathy and nephropathy in the diabetes control and complications trial and epidemiology of diabetes interventions and complications participants with type 1 diabetes. Diabetes 2005;54:3103–3111.
9.
Meerwaldt R, Hartog JWL, Graaff R, Huisman RJ, Links TP, den Hollander NC, Thorpe SR, Baynes JW, Navis G, Gans ROB, Smit AJ: Skin autofluorescence, a measure of cumulative metabolic stress and advanced glycation end products, predicts mortality in hemodialysis patients. J Am Soc Nephrol 2005;16:3687–3693.
10.
Miyata T, van Ypersele de Strihou C, Ueda Y, Ichimori K, Inagi R, OnogiH, Ishikawa N, Nangaku M, Kurokawa K: Angiotensin II receptor antagonists and angiotensin-converting enzyme inhibitors lower in vitro the formation of advanced glycation endproducts: biochemical mechanisms. J Am Soc Nephrol 2002;13:2478–2487.
11.
Fan Q, Liao J, Kobayashi M, Yamashita M, Gu L, Gohda T, Suzuki Y, Wang LN, Horikoshi S, Tomino Y: Candesartan reduced advanced glycation end-products accumulation and diminished nitro-oxidative stress in type 2 diabetic KK/Ta mice. Nephrol Dial Transplant 2004;19:3012–3020.
12.
Nangaku M, Miyata T, Sada T, Mizuno M, Inagi R, Ueda Y, Ishikawa N, Yuzawa H, Koike H, van Ypersele de Strihou C, Kurokawa K: Anti-hypertensive agents inhibit in vivo the formation of advanced glycation end products and improve renal damage in a type 2 diabetic nephropathy rat model. J Am Soc Nephrol 2003;14:1212–1222.
13.
Persson F, Rossing P, Hovind P, Stehouwer CDA, Schalkwijk C, Tarnow L, Parving HP: Irbesartan treatment reduces biomarkers of inflammatory activity in patients with type 2 diabetes and microalbuminuria. Diabetes 2006;55:3550–3555.
14.
Lewis EJ, Hunsicker LG, Clarke WR, Berl T, Pohl MA, Lewis JB, Ritz E, Atkins RC, Rohde R, Raz I, for the Collaborative Study Group: Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med 2001;345:851–860.
15.
Rodby RA, Rohde RD, Clarke WR, Hunsicker LG, Anzalone DA, Atkins RC, Ritz E, Lewis EJ, for the Collaborative Study Group: The Irbesartan type II diabetic nephropathy trial: study design and baseline patient characteristics. Nephrol Dial Transplant 2000;15:487–497.
16.
Miyata T, Ueda Y, Shinzato T, Iida Y, Tanaka S, Kurokawa K, van Ypersele de Strihou C, Maeda K: Accumulation of albumin-linked and free-form pentosidine in the circulation of uremic patients with end-stage renal failure: renal implications in the pathophysiology of pentosidine. J Am Soc Nephrol 1996;7:1198–1206.
17.
Lieuw-A-Fa MLM, van Hinsbergh VWM, Teerlink T, BartoR, Twisk J, Stehouwer CDA, Schalkwijk CG: Increased levels of Nε-(carboxymethyl)lysine and Nε-(carboxyethyl)lysine in type 1 diabetic patients with impaired renal function: correlation with markers of endothelial dysfunction. Nephrol Dial Transplant 2004;19:631–636.
18.
Brownlee M, Vlassara H, Kooney A, Ulrich P, Cerami A: Aminoguanidine prevents diabetes-induced arterial wall protein cross-linking. Science 1986;232:1629–1632.
19.
Nakamura S, Makita Z, Ishikawa S, Yasamura K, Fujii W, Yanagisawa K, Kawata T, Koike T: Progression of nephropathy in spontaneous diabetic rats is prevented by OPB-9195, a novel inhibitor of advanced glycation. Diabetes 1997;46:895–899.
20.
Price DL, Rhett PM, Thorpe SR, Baynes JW: Chelating activity of advanced-glycation end product inhibitors. J Biol Chem 2001;276:48967–48972.
21.
Nakamura S, Li H, Adijang A, Pischetsrieder M, Niwa T: Pyridoxal phosphate prevents progression of diabetic nephropathy. Nephrol Dial Transplant 2007;22:2165–2174.
22.
Degenhardt TP, Alderson NL, Arrington DD, Beattie RJ, Basgen JM, Steffes MW, Thorpe SR, Baynes JW: Pyridoxamine inhibits early renal disease and dyslipidemia in the streptozotocin-diabetic rat. Kidney Int 2002;61:939–950.
23.
Izuhara Y, Nangaku M, Inagi R, Tominaga N, Aizawa T, Kurokawa K, van Ypersele de Strihou C, Miyata T: Renoprotective properties of angiotensin receptor blockers beyond blood pressure lowering. J Am Soc Nephrol 2005;16:3631–3641.
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2008
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