in urine, with AGE-peptides occurring to a lesser extent but accumulating in the plasma of patients with chronic kidney failure. Larger, extracellularly derived AGE proteins cannot pass through the basement membrane of the renal corpuscle and must first be degraded into AGE peptides and AGE free adducts. Peripheral macrophage as well as liver sinusoidal endothelial cells and Kupffer cells have been implicated in this process, although the real-life involvement of the liver has been disputed. Large AGE proteins unable to enter the Bowman's capsule are capable of binding to receptors on endothelial and mesangial cells and to the mesangial matrix. Activation of RAGE induces production of a variety of cytokines, including TNFβ, which mediates an inhibition of metalloproteinase and increases production of mesangial matrix, leading to glomerulosclerosis and decreasing kidney function in patients with unusually high AGE levels. Although the only form suitable for urinary excretion, the breakdown products of AGE—that is, peptides and free adducts—are more aggressive than the AGE proteins from which they are derived, and they can perpetuate related pathology in diabetic patients, even after hyperglycemia has been brought under control. Some AGEs have an innate catalytic oxidative capacity, while activation of NAD(P)H oxidase through activation of RAGE and damage to mitochondrial proteins leading to mitochondrial dysfunction can also induce oxidative stress. A 2007 study found that AGEs could significantly increase expression of TGF-β1, CTGF, Fn mRNA in NRK-49F cells through enhancement of oxidative stress, and suggested that inhibition of oxidative stress might underlie the effect of ginkgo biloba extract in diabetic nephropathy. The authors suggested that antioxidant therapy might help prevent the accumulation of AGEs and induced damage. In the end, effective clearance is necessary, and those suffering AGE increases because of kidney dysfunction might require a kidney transplant. In diabetics who have an increased production of an AGE, kidney damage reduces the subsequent urinary removal of AGEs, forming a positive feedback loop that increases the rate of damage. In a 1997 study, diabetic and healthy subjects were given a single meal of egg white (56 g protein), cooked with or without 100 g of fructose; there was a greater than 200-fold increase in AGE immunoreactivity from the meal with fructose. Potential therapy AGEs are the subject of ongoing research. There are three therapeutic approaches: preventing the formation of AGEs, breaking crosslinks after they are formed and preventing their negative effects. Compounds that have been found