Renal N(epsilon)-carboxymethyllysine deposition after kidney transplantation

Accumulation of advanced glycation end products, that is, N(epsilon)-carboxymethyllysine (CML), induces oxidative stress and inflammation, and is present in chronic renal failure. Proximal tubular cells (PTCs) take up advanced glycation end products-bound proteins by apical megalin-receptors and degrade them. We hypothesized that renal transplant dysfunction affects renal CML homeostasis. Therefore, tubular and glomerular deposition of CML was investigated in a rat transplantation model, and in human allograft biopsies. Fisher 344 kidneys were orthotopically transplanted into Lewis recipients. Recipients were treated with placebo, angiotensin II type 1 receptor blocker (candsartan 5 mg/kg/day), or calcium channel blocker (lacidipine 1 mg/kg/day) more than 28 weeks posttransplantation. Grafts were harvested at 12, 20, and 28 weeks posttransplantation. Sixty-two renal transplant patients underwent graft biopsy because of creatinine increase. Biopsies were graded according to interstitial fibrosis and tubular atrophy. N(epsilon)-carboxymethyllysine and megalin were semiquantitatively investigated in rats and humans using immunohistochemistry. In Fisher grafts, the development of transplant dysfunction was associated with a longitudinal increase in CML deposition in PTCs (week 12: 1.0+/-0.0, week 20: 1.5+/-0.3, week 28: 2.1+/-0.2, P