title: Renal N(epsilon)-carboxymethyllysine deposition after kidney transplantation.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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<0.05). No glomerular deposition was present. In human graft biopsies, tubular CML deposition was negatively, and glomerular CML deposition was positively associated with transplant dysfunction (r=-0.29 and r=0.34; P<0.05). Megalin was reduced at advanced grades.
  
  
  CONCLUSIONS
  N(epsilon)-carboxymethyllysine deposition increased in rat PTCs with mild transplant dysfunction. In humans, tubular CML deposition decreased in parallel with the reduction of its cellular uptake mechanism (megalin). Furthermore, glomerular deposition could play a pathophysiological role in chronic allograft injury.
authors.affiliation: Department of Pharmacology and Toxicology, University Maastricht, Maastricht, The Netherlands. marcus.baumann@lrz.tum.de
authors.forename: Marcus
authors.initials: M
authors.lastname: Baumann
authors.forename: Marjolein
authors.initials: M
authors.lastname: Caron
authors.forename: Christoph
authors.initials: C
authors.lastname: Schmaderer
authors.forename: Christian
authors.initials: C
authors.lastname: Schulte
authors.forename: Ondreij
authors.initials: O
authors.lastname: Viklicky
authors.forename: Claus Werner Hann
authors.initials: CW
authors.lastname: von Weyhern
authors.forename: Jens
authors.initials: J
authors.lastname: Lutz
authors.forename: Uwe
authors.initials: U
authors.lastname: Heemann
mesh_terms: D000818:Animals; D001706:Biopsy; D006801:Humans; D007249:Inflammation; D007668:Kidney / Q000378:metabolism*; D016030:Kidney Transplantation / Q000009:adverse effects*; D007684:Kidney Tubules / Q000166:cytology; D026561:Low Density Lipoprotein Receptor-Related Protein-2 / Q000378:metabolism; D008239:Lysine / Q000031:analogs & derivatives* / Q000378:metabolism; D008297:Male; D018384:Oxidative Stress; D051381:Rats; D011916:Rats, Inbred F344; D011917:Rats, Inbred Lew; D013045:Species Specificity
chemical_list: D026561:Low Density Lipoprotein Receptor-Related Protein-2; C048496:N(6)-carboxymethyllysine; D008239:Lysine