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

Grant number: 12/13604-9
Support Opportunities:Regular Research Grants
Duration: December 01, 2012 - November 30, 2014
Field of knowledge:Health Sciences - Medicine - Surgery
Principal Investigator:Norma Sueli Pinheiro Módolo
Grantee:Norma Sueli Pinheiro Módolo
Host Institution: Faculdade de Medicina (FMB). Universidade Estadual Paulista (UNESP). Campus de Botucatu. Botucatu , SP, Brazil


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. In it, the first three items represent the degree of severity and the latter two are 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. Can be mentioned among the biomarkers IL-18, NGAL, KIM-1 and C-cystatin. 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, superoxide overproduction 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 the ischemia-reperfusion is mediated by free radical production. 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 is still unclear, one possibility is raised the protective effect of allopurinol in the ischemic tissue to be mediated by inhibition of free radical formation. After approval by the Ethics Committee on Animal Experimentation, Faculty of Medicine of Botucatu, will be included in the study, 40 Wistar rats, weighing greater than 250 g, supplied by Central Animal Laboratory of the Botucatu campus, allocated to four groups: Group S (Sham) (n = 10) (+ laparotomy right nephrectomy). Group C (Control) (n = 10) (right nephrectomy laparotomy + + allopurinol at a dose of 20 Group A (n = 10) (right nephrectomy laparotomy + + allopurinol at a dose of 20 + 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%. allopurinol be administered orally 24, 12 and 1 h before the clamping of the renal artery at a dose of 100 mg / kg. Fifteen minutes after the nephrectomy is done, clamping the left renal artery and released after 20 minutes. Follows the closing of the suture through the abdomen wall. The postoperative analgesia is achieved with nalbuphine subcutaneous dose of 0.1 mg / kg 12/12 hrs. Twenty-four hours after surgery, the animals are subjected to laparotomy to perform a new left nephrectomy, and then euthanized. Will be assessed in the following parameters: diastolic blood pressure, systolic and mean heart rate, rectal temperature, capnometry, measurement of plasma NGAL (neutrophil gelatinase-associated lipocain) and histological examination of the kidneys. (AU)

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Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
ANDRÉ ROBERTO BUSSMANN; MARCOS ANTÔNIO MARTON FILHO; MARÍLIA PINHEIRO MÓDOLO; RENATA PINHEIRO MÓDOLO; PATRÍCIA AMADO; MARIA APARECIDA CUSTÓDIO DOMINGUES; YARA MARCONDES MACHADO CASTIGLIA; NORMA SUELI PINHEIRO MÓDOLO. Effect of allopurinol on the kidney function, histology and injury biomarker (NGAL, IL 18) levels in uninephrectomised rats subjected to ischaemia-reperfusion injury. Acta Cirurgica Brasileira, v. 29, n. 8, p. 515-521, . (12/13604-9)
BUSSMANN, ANDRE ROBERTO; MARTON FILHO, MARCOS ANTONIO; MODOLO, MARILIA PINHEIRO; MODOLO, RENATA PINHEIRO; AMADO, PATRICIA; CUSTODIO DOMINGUES, MARIA APARECIDA; MACHADO CASTIGLIA, YARA MARCONDES; PINHEIRO MODOLO, NORMA SUELI. Effect of allopurinol on the kidney function, histology and injury biomarker (NGAL, IL-18) levels in uninephrectomised rats subjected to ischaemia-reperfusion injury. Acta Cirurgica Brasileira, v. 29, n. 8, p. 515-521, . (12/13604-9)

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