Randomized Trial of an Inhibitor of Formation of Advanced Glycation End Products in Diabetic Nephropathy

Bolton, W. Kline; Cattran, Daniel C.; Williams, Mark E.; Adler, Sharon G.; Appel, Gerald B.; Cartwright, Kenneth; Foiles, Peter G.; Freedman, Barry I.; Raskin, Philip; Ratner, Robert E.; Spinowitz, Bruce; Whittier, Frederick C.; Wuerth, Jean-Paul

doi:10.1159/000075627

Cited by 404 publications

(262 citation statements)

References 17 publications

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“…Proteinuria in the nephrotic range was noted in a large proportion of our patients. Given the advanced nature of the renal disease in the study population and the implication of previous observations with pimagedine (a drug that also inhibited formation of glycation end products)-that patients with more intact renal function may be more responsive to therapy 16 -we placed into the protocol predefined secondary analyses that used tertiles of baseline serum creatinine concentration, as well as a comparison of performance of the group entering the study with a serum creatinine concentration #2mg/dl versus those with a concentration .2 mg/dl.…”

Section: Discussionmentioning

confidence: 99%

Pyridorin in Type 2 Diabetic Nephropathy

Lewis

Greene

Spitalewiz

et al. 2012

Journal of the American Society of Nephrology

136

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Pyridoxamine dihydrochloride (Pyridorin, NephroGenex) inhibits formation of advanced glycation end products and scavenges reactive oxygen species and toxic carbonyls, but whether these actions translate into renoprotective effects is unknown. In this double-blind, randomized, placebo-controlled trial, we randomly assigned 317 patients with proteinuric type 2 diabetic nephropathy to twice-daily placebo; Pyridorin, 150 mg twice daily; or Pyridorin, 300 mg twice daily, for 52 weeks. At baseline, the mean age 6 SD was 63.969.5 years, and the mean duration of diabetes was 17.668.5 years; the mean serum creatinine level was 2.260.6 mg/dl, and the mean protein-to-creatinine ratio was 297361932 mg/g. Regarding the primary end point, a statistically significant change in serum creatinine from baseline to 52 weeks was not evident in either Pyridorin group compared with placebo. However, analysis of covariance suggested that the magnitude of the treatment effect differed by baseline renal function. Among patients in the lowest tertile of baseline serum creatinine concentration, treatment with Pyridorin associated with a lower average change in serum creatinine concentration at 52 weeks (0.28, 0.07, and 0.14 mg/dl for placebo, Pyridorin 150 mg, and Pyridorin 300 mg, respectively; P=0.05 for either Pyridorin dose versus placebo); there was no evidence of a significant treatment effect in the middle or upper tertiles. In conclusion, this trial failed to detect an effect of Pyridorin on the progression of serum creatinine at 1 year, although it suggests that patients with less renal impairment might benefit.

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Section: Discussionmentioning

confidence: 99%

Pyridorin in Type 2 Diabetic Nephropathy

Lewis

Greene

Spitalewiz

et al. 2012

Journal of the American Society of Nephrology

136

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“…Several studies have investigated the role of AGE blockade in diabetic kidney disease, especially in rodents (Degenhardt et al 2002, Davis et al 2004) and some in humans (Bolton et al 2004, McGill et al 2004), but only a few studies have focused on blockade of RAGE. In a study using db/db mice, administration of sRAGE for 19 weeks ameliorated the increase in glomerular area, mesangial area, UAE and BMT (Wendt et al 2003).…”

Section: Discussionmentioning

confidence: 99%

Renal effects of a neutralising RAGE-antibody in long-term streptozotocin-diabetic mice

Jensen¹,

Denner²,

Schrijvers³

et al. 2006

Journal of Endocrinology

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Advanced glycation endproducts (AGEs) have been implicated in the pathogenesis of diabetic kidney disease. The actions of AGEs are mediated both through a non-receptor mediated pathway and through specific receptors for AGEs (e.g. RAGE). To explore a potentially specific role for RAGE in renal changes in type 1 diabetes, we examined the renal effects of a neutralising murine RAGE-antibody (ab) in streptozotocin (STZ)-diabetic mice, a model of type 1 diabetes. One group of STZdiabetic mice was treated for two months with the RAGE-ab, while another STZ-diabetic group was treated for the same period with an irrelevant immunoglobulin G (IgG). Two groups of non-diabetic NMRI mice were treated with either RAGE-ab or isotype-matched IgG for two months. Placebo-treated STZ-diabetic mice showed an increase in kidney weight, glomerular volume, basement membrane thickness (BMT), urinary albumin excretion (UAE) and creatinine clearance (CrCl), when compared with non-diabetic controls. In RAGE-abtreated STZ-diabetic mice, the increase in kidney weight and UAE was reduced, while the increase in CrCl was abolished. RAGE-ab administration in NMRI mice caused a reduction in liver weight and an increase in BMT. Renal messenger RNA (mRNA) for connective tissue growth factor and collagen IV 1 was increased in placebo-treated diabetic animals. RAGE-ab treatment had no impact on the expression of these factors. The renal effects of RAGE-ab administration in STZ-diabetic mice were seen without impact on body weight, blood glucose or food consumption. In conclusion, the present data support the hypothesis that RAGE is an important pathogenic factor in the renal changes in an animal model of type 1 diabetes.

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“…[108][109][110][111][112] A human trial of aminoguanidine also demonstrates a slowing of diabetic retinopathy progression, although the trial was terminated early due to side effects of aminoguanidine when administered at high doses. 113 In addition to inhibiting iNOS, aminoguanidine also blocks formation of advanced glycation endproducts and its beneficial effect on diabetic retinopathy could be due to this effect on advanced glycation endproducts. However, aminoguanidine slows the progression of diabetic retinopathy without affecting advanced glycation endproduct levels, 111,112 suggesting that it acts by inhibiting iNOS.…”

Section: Modulation Of Functional Hyperemia In the Retina Oxygen Modumentioning

confidence: 99%

Functional Hyperemia and Mechanisms of Neurovascular Coupling in the Retinal Vasculature

Newman

2013

J Cereb Blood Flow Metab

196

162

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The retinal vasculature supplies cells of the inner and middle layers of the retina with oxygen and nutrients. Photic stimulation dilates retinal arterioles producing blood flow increases, a response termed functional hyperemia. Despite recent advances, the neurovascular coupling mechanisms mediating the functional hyperemia response in the retina remain unclear. In this review, the retinal functional hyperemia response is described, and the cellular mechanisms that may mediate the response are assessed. These neurovascular coupling mechanisms include neuronal stimulation of glial cells, leading to the release of vasoactive arachidonic acid metabolites onto blood vessels, release of potassium from glial cells onto vessels, and production and release of nitric oxide (NO), lactate, and adenosine from neurons and glia. The modulation of neurovascular coupling by oxygen and NO are described, and changes in functional hyperemia that occur with aging and in diabetic retinopathy, glaucoma, and other pathologies, are reviewed. Finally, outstanding questions concerning retinal blood flow in health and disease are discussed. In lower vertebrates that have thinner retinas, including amphibians, reptiles, and some mammals, the retinal vasculature is absent and the choroidal circulation supplies the entire retina. 2 The choroidal circulation is supplied by the long and short ciliary arteries and the anterior ciliary arteries, which feed the large arteries in the outer portion of the choroid. 3 These arteries branch into smaller vessels, which, in turn, feed the highly anastomosed choriocapillaris network lying at the inner border of the choroid, adjacent to the retinal pigment epithelium and retinal photoreceptors. The total blood flow supplying the choroid is much greater than that supplying the retina (606 vs. 25 mg/min/ whole tissue 4 ), to meet the high metabolic demands of the photoreceptors. 5 The retinal vasculature is supplied by the central retinal artery, which enters the retina with the optic nerve at the optic disc. The artery branches into radial arterioles and smaller vessels on the vitreal surface of the retina. 3 Pre-capillary arterioles and capillaries ramify from these surface vessels and form anastomotic networks in the ganglion cell layer, just beneath the retinal surface, and deeper in the inner nuclear layer, supplying horizontal cells, bipolar cells, amacrine cells, and Mü ller glial cells. Blood is returned through radial venules on the retinal surface that empty into the central retinal vein in the optic nerve. Journal of Cerebral BloodThe retinal and choroidal vasculatures differ in several respects. Retinal vessels lack autonomic innervation, 6,7 whereas the choroidal circulation is innervated by both sympathetic and parasympathetic

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Randomized Trial of an Inhibitor of Formation of Advanced Glycation End Products in Diabetic Nephropathy

Cited by 404 publications

References 17 publications

Pyridorin in Type 2 Diabetic Nephropathy

Pyridorin in Type 2 Diabetic Nephropathy

Renal effects of a neutralising RAGE-antibody in long-term streptozotocin-diabetic mice

Functional Hyperemia and Mechanisms of Neurovascular Coupling in the Retinal Vasculature

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