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Inadequate Antioxidative Responses in Kidneys of Brain-Dead Rats

Hoeksma, Dane BSc; Rebolledo, Rolando A. MD, PhD; Hottenrott, Maximilia MD, PhD; Bodar, Yves S. BSc; Wiersema-Buist, Janneke J. PhD; Van Goor, Harry PhD; Leuvenink, Henri G.D. PhD

doi: 10.1097/TP.0000000000001417
Original Basic Science-General

Background: Brain death (BD)-related lipid peroxidation, measured as serum malondialdehyde (MDA) levels, correlates with delayed graft function in renal transplant recipients. How BD affects lipid peroxidation is not known. The extent of BD-induced organ damage is influenced by the speed at which intracranial pressure increases. To determine possible underlying causes of lipid peroxidation, we investigated the renal redox balance by assessing oxidative and antioxidative processes in kidneys of brain-dead rats after fast and slow BD induction.

Methods: Brain death was induced in 64 ventilated male Fisher rats by inflating a 4.0F Fogarty catheter in the epidural space. Fast and slow inductions were achieved by an inflation speed of 0.45 and 0.015 mL/min, respectively, until BD confirmation. Healthy non–brain-dead rats served as reference values. Brain-dead rats were monitored for 0.5, 1, 2, or 4 hours, after which organs and blood were collected.

Results: Increased MDA levels became evident at 2 hours of slow BD induction at which increased superoxide levels, decreased glutathione peroxidase (GPx) activity, decreased glutathione levels, increased inducible nitric oxide synthase and heme-oxygenase 1 expression, and increased plasma creatinine levels were evident. At 4 hours after slow BD induction, superoxide, MDA, and plasma creatinine levels increased further, whereas GPx activity remained decreased. Increased MDA and plasma creatinine levels also became evident after 4 hours fast BD induction.

Conclusion: Brain death leads to increased superoxide production, decreased GPx activity, decreased glutathione levels, increased inducible nitric oxide synthase and heme-oxygenase 1 expression, and increased MDA and plasma creatinine levels. These effects were more pronounced after slow BD induction. Modulation of these processes could lead to decreased incidence of delayed graft function.

The authors investigate the impact of brain death on graft function in a rat renal transplantation model and find that slow brain death induction may increase the incidence of delayed graft function after kidney transplantation.

1 Department of Surgery, University Medical Center Groningen, Groningen, The Netherlands.

2 Department of Digestive Surgery, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.

3 Department of Cardiothoracic Surgery, University Medical Center Groningen, Groningen, The Netherlands.

4 Department of Pathology, University Medical Center Groningen, Groningen, The Netherlands.

Received 29 February 2016. Revision received 29 June 2016.

Accepted 2 July 2016.

The authors declare no funding or conflicts of interest.

D.H., R.A.R., C.M.V.H., and H.G.D.L. designed the experiment. D.H., R.A.R., and Y.S.B. performed the experiment. D.H. and J.J.W,-B. analyzed data. D.H. wrote the article. H.v.G. and H.G.D.L. finalized the article.

Correspondence: Henri G.D. Leuvenink, University Medical Center Groningen, University of Groningen, Department of Surgery, CMC V, Y2144, Hanzeplein 1, 9713 GZ Groningen, the Netherlands. (h.g.d.leuvenink@umcg.nl).

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