Inhibition of leukotriene B4 synthesis does not prevent development of acute renal failure following storage and transplantation.
Compound BW B70C, a selective 5-lipoxygenase inhibitor was tested for its ability to reduce inflammatory damage in an in vivo rabbit model of renal storage and transplantation. Kidneys were stored at 0-2 degrees C for 48 hr prior to autografting. In controls, renal vein LTB4 levels rose significantly after 30 min reperfusion but fell after 2 hr to baseline. TxB2 levels remained at baseline for the 6 hr measured. 6-k-PGF1 alpha levels rose significantly after 1 hr of reperfusion and remained elevated thereafter. Histology after 6 hr reperfusion showed moderate-to-severe cortical edema and mild congestion. Infused colloidal carbon was retained in the perivascular area in a narrow band at the corticomedullary junction, indicating a zone of vascular permeability. At 3 days after transplant, kidneys exhibited widespread tubular necrosis and calcification but little inflammation. Serum creatinine and urea peaked between days 3 and 5. 3/6 rabbits showed no symptoms of renal failure after 3 weeks. Pretreatment with BW B70C prevented the increase in LTB4 but had little effect on TxB2 and 6-k-PGF1 alpha levels. Histology showed no amelioration of cortical edema at 6 hr and congestion and hemorrhage were exacerbated. BW B70C had no effect on either colloidal carbon retention or distribution but did significantly reduce tubular necrosis and calcification at day 3. There was very little inflammatory infiltrate. BW B70C treatment did not improve the long-term viability of transplanted kidneys: 2/6 rabbits showed no symptoms of renal failure after 3 weeks. These data indicate that inhibition of LTB4 synthesis by BW B70C does not prevent the development of acute renal failure following 48 hr hypothermic storage and transplantation.
Lane
N J
NJ
Department of Surgical Research, Northwick Park Institute for Medical Research, Northwick Park Hospital, Harrow, Middlesex, United Kingdom.
Thorniley
M S
MS
Manek
S
S
Fuller
B J
BJ
Green
C J
CJ
D058186:Acute Kidney Injury / Q000209:etiology* / Q000378:metabolism / Q000517:prevention & control*; D000818:Animals; D002199:Capillary Permeability / Q000502:physiology; D003404:Creatinine / Q000097:blood; D004195:Disease Models, Animal; D015777:Eicosanoids / Q000097:blood; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006084:Graft Rejection / Q000378:metabolism / Q000517:prevention & control; D006085:Graft Survival / Q000187:drug effects; D006898:Hydroxylamines / Q000494:pharmacology; D006918:Hydroxyurea / Q000031:analogs & derivatives*; D016030:Kidney Transplantation / Q000009:adverse effects* / Q000276:immunology; D007684:Kidney Tubules / Q000098:blood supply / Q000473:pathology; D007975:Leukotriene B4 / Q000096:biosynthesis* / Q000097:blood / Q000502:physiology; D016859:Lipoxygenase Inhibitors; D008782:Methylurea Compounds / Q000494:pharmacology; D009336:Necrosis / Q000473:pathology; D009926:Organ Preservation / Q000009:adverse effects*; D011460:Prostaglandins F / Q000097:blood; D011817:Rabbits; D013929:Thromboxane B2 / Q000097:blood; D014508:Urea / Q000097:blood
D015777:Eicosanoids; D006898:Hydroxylamines; D016859:Lipoxygenase Inhibitors; D008782:Methylurea Compounds; D011460:Prostaglandins F; C080871:BW B70C; D007975:Leukotriene B4; D013929:Thromboxane B2; D014508:Urea; D003404:Creatinine; C100006:prostaglandin F1; D006918:Hydroxyurea