Promising effects of ischemic preconditioning in renal transplantation.
BACKGROUND
Ischemic preconditioning, a phenomenon induced by brief ischemia and reperfusion periods, renders an organ tolerant to subsequent prolonged ischemia. This study evaluated different schedules of preconditioning the kidney to assess the role of nitric oxide (NO) and determine the effects of preconditioning on kidney transplantation.


METHODS
In study design A, to determine the optimum procedure of preconditioning, one-cycle schedules were assayed by occluding/releasing renal pedicles according to various warm ischemic (5, 10, 15, 20 min) and reperfusion (10, 20, 40 min) windows in Sprague-Dawley rats. Thereafter, warm renal ischemia was induced by clamping both pedicles for 40 minutes. Design B used the most suitable schedule found from the first study to obtain several groups, using either a direct nitric oxide donor (spermine NONOate) or two nitric oxide synthase (NOS) blockers (L-NAME and aminoguanidine), to determine whether NO mediates in renal preconditioning. To establish whether preconditioning reduces cold preservation damage, in Design C the optimum preconditioning schedule was used in syngeneic Lewis rats where preconditioned and non-preconditioned kidneys were transplanted after five hours of cold storage in Euro-Collins solution.


RESULTS
The best preconditioning schedule consisted of 15 minutes of warm ischemia and 10 minutes of reperfusion (Prec 15/10), since it was the only schedule that offered both functional and histological protection. The NO donor reproduced the ischemic preconditioning. Non-selective NOS blockade abolished the preconditioning and exacerbated ischemic damage, which was overcome by the addition of the NO donor. Selective blocking of inducible NOS also abolished the effects of preconditioning. Renal NO increased at the end of preconditioning in the Prec 15/10 group. Prolongation of the reperfusion window (20 or 40 min) abolished the preconditioning protection, although it was associated with a further increase in renal NO. As renal DNA oxidative injury paralleled NO, increasing with prolongation of reperfusion, it may account for the disappearance of preconditioning. Finally, the one-cycle preconditioning schedule offered an effective functional and histological protection against cold preservation damage in rat renal transplantation.


CONCLUSIONS
Fifteen minutes of warm ischemia and 10 minutes of reperfusion in the kidney is the most suitable one-cycle schedule for preconditioning since it protects from both warm and cold ischemia. The beneficial effect of preconditioning is related to the local production of NO, and we believe it has promising therapeutic value in clinical renal transplantation.
Torras
Joan
J
Department of Nephrology and Laboratory of Experimental Nephrology, Hospital of Bellvitge, L'Hospitalet, Barcelona, Spain.
Herrero-Fresneda
Immaculada
I
Lloberas
Nuria
N
Riera
Marta
M
Ma Cruzado
Josep
J
Ma Grinyó
Josep
J
D000818:Animals; D003080:Cold Temperature; D004247:DNA / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006146:Guanidines / Q000494:pharmacology; D006358:Hot Temperature; D019194:Ischemic Preconditioning / Q000379:methods; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D016030:Kidney Transplantation; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D020030:Nitric Oxide Donors / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D052247:Nitric Oxide Synthase Type II; D009589:Nitrogen Oxides; D010084:Oxidation-Reduction; D051381:Rats; D017207:Rats, Sprague-Dawley; D013096:Spermine / Q000031:analogs & derivatives* / Q000494:pharmacology; D013997:Time Factors
D004791:Enzyme Inhibitors; D006146:Guanidines; D020030:Nitric Oxide Donors; D009589:Nitrogen Oxides; C091861:spermine nitric oxide complex; D013096:Spermine; D009569:Nitric Oxide; D004247:DNA; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; C004479:pimagedine; D019331:NG-Nitroarginine Methyl Ester