Leflunomide derivate FK 778 in accelerated renal injury in transgenic rat.
Renal ischaemia/reperfusion (I/R) injury and hypertension represent major alloantigen-independent risk factors contributing to the development of chronic allograft nephropathy. In a model of accelerated major histocompatibility complex-independent renal injury, we evaluated the effect of leflunomide derivate - FK778 - on the progression of accelerated nephropathy. Thirty-six uninephrectomized hypertensive transgenic (m-REN-2)-27 rats received a clip on renal pedicle for 45 minutes. Animals were treated with FK778 3 mg/kg/day (I/R 3 mg, N = 12), 10 mg/kg/day (I/R 10 mg, N = 12) or placebo (N = 12) via gavage for 16 weeks. Eighteen animals were sham-operated and treated with FK778 3 mg/kg/day (sham 3 mg, N = 6), 10 mg/kg/day (sham 10 mg, N = 6) or were untreated (sham, N = 6). Proteinuria and blood pressure were evaluated throughout and the kidneys were harvested for morphological and immunohistochemical analysis at the end of the experiment. At week 16, rats with I/R injury and FK778 treatment had lower proteinuria compared with placebo-treated rats (I/R 3 mg: 48.42 +/- 26.16, I/R 10 mg 27.28 +/- 21.86 vs. Placebo: 70.13 +/- 50.19 mg/day, P < 0.05). The untreated sham group exhibited lower proteinuria compared with FK778-treated sham groups (Sham 3 mg: 24.23 +/- 10.89; Sham 10 mg: 17.37 +/- 4.13; Sham: 14.23 +/- 1.18) There was no difference in glomerulosclerosis and interstitial fibrosis among the treated groups. In the untreated animals the rate of interstitial fibrosis decline reached statistical significance (Placebo vs. Sham: 1.125 +/- 0.641 % vs. 0.250 +/- 0.500 %, P < 0.05). There was higher CD5+ leukocyte infiltration in the placebotreated group. FK778-treated rats displayed amelioration of some changes induced by the I/R injury. Our observation also suggests potential nephrotoxicity of FK778.
Bloudícková
S
S
Department of Nephrology, Transplant Centre, Institute for Clinical and Experimental Medicine, Prague, Czech Republic. sibl@medicon.cz
Rajnoch
J
J
Lodererová
A
A
Honsová
E
E
Viklický
O
O
D000480:Alkynes / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004195:Disease Models, Animal; D007166:Immunosuppressive Agents / Q000494:pharmacology* / Q000627:therapeutic use; D007555:Isoxazoles / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D007668:Kidney / Q000187:drug effects* / Q000473:pathology*; D007674:Kidney Diseases / Q000188:drug therapy / Q000473:pathology*; D000077339:Leflunomide; D008297:Male; D009570:Nitriles / Q000494:pharmacology* / Q000627:therapeutic use; D010919:Placebos / Q000627:therapeutic use; D051381:Rats; D055647:Rats, Transgenic; D015427:Reperfusion Injury / Q000188:drug therapy / Q000473:pathology*
D000480:Alkynes; D007166:Immunosuppressive Agents; D007555:Isoxazoles; D009570:Nitriles; D010919:Placebos; C115284:2-cyano-3-hydroxy-N-(4-(trifluoromethyl)phenyl)-2-hepten-6-ynamide; D000077339:Leflunomide