title: AGE formation blockade with aminoguanidine does not ameliorate chronic allograft nephropathy.
abstract: OBJECTIVE
  Advanced glycation end products (AGEs) are produced by glycoxidation and lipid peroxidation. AGEs induce oxidative stress and inflammation, and accumulate in tubular cells after kidney transplantation. We hypothesize that the AGE formation blocker aminoguanidine (AG) reduces AGE formation and improves renal transplant function.
  
  
  METHODS
  Fisher 344 kidneys were orthotopically transplanted into Lewis recipients. Recipients were treated with AG (100 mg/kg/day), candesartan (CAND; 5mg/kg/day), or vehicle (VEH) for 24 weeks. The major non-cross linking AGE N(ε)-carboxymethyllysine (CML) was measured post-transplantation with gas chromatography-tandem mass spectrometry or immunohistochemistry. As a marker of systemic lipid peroxidation 8-isoprostane was measured by ELISA. We determined intra-arterial blood pressure, heart weight/body weight ratio, size of cardiomyocytes and cardiac hypertrophy as assessed by echocardiography. For biochemical evaluation of cardiac and renal fibrosis we measured hydroxyproline content.
  
  
  RESULTS
  AG significantly reduced serum CML and 8-isoprostane, but did not reduce signs of chronic allograft nephropathy (CAN) or blood pressure. AG did not alter tubular AGE accumulation. AG reduced heart weight/body weight ratio (AG: 2.7 ± 0.1g/kg; CAND: 2.2 ± 0.1, VEH: 3.0 ± 0.4 g/kg), size of cardiomyocytes (P < 0.05) and showed a tendency to reduce cardiac hypertrophy (wall volume average radial AG 7.072 ± 0.83 cm(3) vs. CAND 6.841 ± 0.66 cm(3) vs. VEH 7.839 ± 0.74 cm(3)).
  
  
  CONCLUSIONS
  Despite effective reduction of serum CML and 8-isoprostane, AG did not ameliorate CAN or reduce renal AGE accumulation. On the other hand AG reduced cardiac size suggesting a supportive cardio-protective action which is blood pressure independent.
authors.affiliation: Department of Nephrology, Klinikum rechts der Isar, Technical University Munich, Germany. christoph.schmaderer@lrz.tum.de
authors.forename: Christoph
authors.initials: C
authors.lastname: Schmaderer
authors.forename: Chang Jiang
authors.initials: CJ
authors.lastname: Xing
authors.forename: Gaby
authors.initials: G
authors.lastname: Anderson
authors.forename: Rob
authors.initials: R
authors.lastname: Hermans
authors.forename: Jens
authors.initials: J
authors.lastname: Lutz
authors.forename: Uwe
authors.initials: U
authors.lastname: Heemann
authors.forename: Marcus
authors.initials: M
authors.lastname: Baumann
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D001713:Biphenyl Compounds; D002316:Cardiotonic Agents / Q000494:pharmacology; D015237:Dinoprost / Q000031:analogs & derivatives / Q000097:blood / Q000276:immunology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D017127:Glycation End Products, Advanced / Q000097:blood / Q000378:metabolism*; D006146:Guanidines / Q000494:pharmacology*; D006909:Hydroxyproline / Q000097:blood / Q000276:immunology; D007674:Kidney Diseases / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D007677:Kidney Function Tests; D016030:Kidney Transplantation; D008239:Lysine / Q000031:analogs & derivatives / Q000097:blood; D008297:Male; D018384:Oxidative Stress / Q000502:physiology; D011507:Proteinuria / Q000188:drug therapy; D051381:Rats; D011916:Rats, Inbred F344; D011917:Rats, Inbred Lew; D013777:Tetrazoles / Q000494:pharmacology; D013997:Time Factors; D014184:Transplantation, Homologous
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D002316:Cardiotonic Agents; D004791:Enzyme Inhibitors; D017127:Glycation End Products, Advanced; D006146:Guanidines; D013777:Tetrazoles; C075750:8-epi-prostaglandin F2alpha; C048496:N(6)-carboxymethyllysine; D015237:Dinoprost; D008239:Lysine; D006909:Hydroxyproline; C081643:candesartan; C004479:pimagedine