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Effects of allopurinol in renal protection by means of plasma NGAL measurement: a study in an experimental model of ischemia and reperfusion in rats under inhalation anesthesia

Grant number: 12/00862-0
Support type:Scholarships in Brazil - Scientific Initiation
Effective date (Start): May 01, 2012
Effective date (End): December 31, 2013
Field of knowledge:Health Sciences - Medicine - Surgery
Principal Investigator:Norma Sueli Pinheiro Módolo
Grantee:Marcos Antonio Marton Filho
Home Institution: Faculdade de Medicina (FMB). Universidade Estadual Paulista (UNESP). Campus de Botucatu. Botucatu , SP, Brazil

Abstract

The term acute renal failure (ARF) was first used in 1951 by Homer Smith. The imprecise definitions of renal dysfunction have impeded progress, there are over 35 different definitions. The study group Acute Dialysis Quality Initiative developed a guideline for the management of acute kidney injury and RIFLE classification suggested when it was proposed to use the term acute kidney injury (AKI) instead of ARF. Here the first three items represent the degree of severity and the latter two are of prognostic criteria. Serum creatinine and urine output are used to indicate renal dysfunction, but with a very low rate of change, limiting its use in early diagnosis of AKI. The literature has presented several biomarkers that promise early detection of AKI. Among the biomarkers can cite IL-18, NGAL, KIM-1 and cystatin-C. The expression of NGAL occurs in neutrophils and other epithelial cells including the proximal convoluted tubule and in a recent systematic review authors concluded that NGAL appears to have diagnostic and prognostic value for ARL. In cellular damage by ischemia, ATP depletion occurs initially with permanent loss of mitochondrial function, preventing the regeneration of ATP after reperfusion. After changes occur in the cytoskeleton, increasing intracellular calcium, activation of enzymes, changes in nitric oxide metabolism, interstitial inflammation, changes in adhesion receptors and integrins and formation of reactive oxygen species (ROS). One source of ROS is enzyme xanthine oxidase (XO). After reperfusion, with the accumulation of the substrate hypoxanthine plus re-entry of molecular oxygen, an overproduction of superoxide occurs. The conversion of hypoxanthine to xanthine via XO is the largest potential source of ROS, which seem to play an important role in the genesis of ischemia-reperfusion. It is known that ischemia-reperfusion is mediated by the production of free radicals. The XO inhibitor, allopurinol has a protective effect on ischemia-reperfusion injury in myocardium of various species. The mechanism of how allopurinol exerts this protective effect remains unclear, one possibility is raised the protective effect of allopurinol in the ischemic tissue to be mediated by inhibiting the formation of free radicals. The overall objective of the research will evaluate whether allopurinol has a protective effect on kidney cells, using an experimental model of ischemia-reperfusion in rats under inhalation anesthesia, and specifically quantify the effectiveness of allopurinol in renal cell protection under stress ischemia reperfusion for histologic analysis and measurement of plasma NGAL. After approval by the Ethics Committee on Animal Experimentation, Faculty of Medicine of Botucatu, will be included in the study 40 male rats, Wistar rats, weighing 250 grams more, provided by the Central Animal Facility of the Campus of Botucatu, allocated into four groups: Group S (Sham) (n = 10) (laparotomy + right nephrectomy). Group C (control) (n = 10) (laparotomy + right nephrectomy + allopurinol at a dose of 20 mg.kg-1.d-1). Group A (n = 10) (laparotomy + right nephrectomy + allopurinol at a dose of 20 mg.kg-1.d-1 + maneuvers left renal ischemia and reperfusion. Group I (n = 10) (right nephrectomy + + laparotomy maneuvers ischemia and reperfusion of the left kidney). All animals will be anesthetized in the same way: induction of anesthesia with isoflurane 3% and maintained with isoflurane in the inspired concentration of 1.5 to 2%. will be assessed the following parameters: diastolic blood pressure, systolic and average heart rate, rectal temperature, capnometry, measurement of plasma NGAL (neutrophil gelatinase-associated lipocain) and histological examination of the kidneys. (AU)