Renal N(epsilon)-carboxymethyllysine deposition after kidney transplantation.
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.
Baumann
Marcus
M
Department of Pharmacology and Toxicology, University Maastricht, Maastricht, The Netherlands. marcus.baumann@lrz.tum.de
Caron
Marjolein
M
Schmaderer
Christoph
C
Schulte
Christian
C
Viklicky
Ondreij
O
von Weyhern
Claus Werner Hann
CW
Lutz
Jens
J
Heemann
Uwe
U
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
D026561:Low Density Lipoprotein Receptor-Related Protein-2; C048496:N(6)-carboxymethyllysine; D008239:Lysine