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      Bilirubin, a new therapeutic for kidney transplant?

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          Abstract

          In patients with end-stage renal disease, kidney transplantation has been associated with numerous benefits, including increased daily activity, and better survival rates. However, over 20% of kidney transplants result in rejection within five years. Rejection is primarily due to a hypersensitive immune system and ischemia/reperfusion injury. Bilirubin has been shown to be a potent antioxidant that is capable of potentially reversing or preventing damage from reactive oxygen species generated from ischemia and reperfusion. Additionally, bilirubin has several immunomodulatory effects that can dampen the immune system to promote organ acceptance. Increased bilirubin has also been shown to have a positive impact on renal hemodynamics, which is critical post-transplantation. Lastly, bilirubin levels have been correlated with biomarkers of successful transplantation. In this review, we discuss a multitude of potentially beneficial effects that bilirubin has on kidney acceptance of transplantation based on numerous clinical trials and animal models. Exogenous bilirubin delivery or increasing endogenous levels pre- or post-transplantation may have therapeutic benefits.

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          Angiotensin II stimulates NADH and NADPH oxidase activity in cultured vascular smooth muscle cells.

          K K Griendling, C A Minieri, J D Ollerenshaw … (1994)
          The signaling pathways involved in the long-term metabolic effects of angiotensin II (Ang II) in vascular smooth muscle cells are incompletely understood but include the generation of molecules likely to affect oxidase activity. We examined the ability of Ang II to stimulate superoxide anion formation and investigated the identity of the oxidases responsible for its production. Treatment of vascular smooth muscle cells with Ang II for 4 to 6 hours caused a 2.7 +/- 0.4-fold increase in intracellular superoxide anion formation as detected by lucigenin assay. This superoxide appeared to result from activation of both the NADPH and NADH oxidases. NADPH oxidase activity increased from 3.23 +/- 0.61 to 11.80 +/- 1.72 nmol O2-/min per milligram protein after 4 hours of Ang II, whereas NADH oxidase activity increased from 16.76 +/- 2.13 to 45.00 +/- 4.57 nmol O2-/min per milligram protein. The NADPH oxidase activity was stimulated by exogenous phosphatidic and arachidonic acids and was partially inhibited by the specific inhibitor diphenylene iodinium. NADH oxidase activity was increased by arachidonic and linoleic acids, was insensitive to exogenous phosphatidic acid, and was inhibited by high concentrations of quinacrine. Both of these oxidases appear to reside in the plasma membrane, on the basis of migration of the activity after cellular fractionation and their apparent insensitivity to the mitochondrial poison KCN. These observations suggest that Ang II specifically activates enzyme systems that promote superoxide generation and raise the possibility that these pathways function as second messengers for long-term responses, such as hypertrophy or hyperplasia.
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            Bilirubin is an antioxidant of possible physiological importance.

            A J G McDonagh, R Stocker, Yasuhiro Yamamoto … (1987)
            Bilirubin, the end product of heme catabolism in mammals, is generally regarded as a potentially cytotoxic, lipid-soluble waste product that needs to be excreted. However, it is here that bilirubin, at micromolar concentrations in vitro, efficiently scavenges peroxyl radicals generated chemically in either homogeneous solution or multilamellar liposomes. The antioxidant activity of bilirubin increases as the experimental concentration of oxygen is decreased from 20% (that of normal air) to 2% (physiologically relevant concentration). Furthermore, under 2% oxygen, in liposomes, bilirubin suppresses the oxidation more than alpha-tocopherol, which is regarded as the best antioxidant of lipid peroxidation. The data support the idea of a "beneficial" role for bilirubin as a physiological, chain-breaking antioxidant.
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              Delayed graft function in kidney transplantation.

              Norberto Perico, Dario Cattaneo, Mohamed Sayegh … (2004)
              Delayed graft function is a form of acute renal failure resulting in post-transplantation oliguria, increased allograft immunogenicity and risk of acute rejection episodes, and decreased long-term survival. Factors related to the donor and prerenal, renal, or postrenal transplant factors related to the recipient can contribute to this condition. From experimental studies, we have learnt that both ischaemia and reinstitution of blood flow in ischaemically damaged kidneys after hypothermic preservation activate a complex sequence of events that sustain renal injury and play a pivotal part in the development of delayed graft function. Elucidation of the pathophysiology of renal ischaemia and reperfusion injury has contributed to the development of strategies to decrease the rate of delayed graft function, focusing on donor management, organ procurement and preservation techniques, recipient fluid management, and pharmacological agents (vasodilators, antioxidants, anti-inflammatory agents). Several new drugs show promise in animal studies in preventing or ameliorating ischaemia-reperfusion injury and possibly delayed graft function, but definitive clinical trials are lacking. The goal of monotherapy for the prevention or treatment of is perhaps unattainable, and multidrug approaches or single drug targeting multiple signals will be the next step to reduce post-transplantation injury and delayed graft function.
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                Author and article information

                Journal
                Journal ID (nlm-journal-id): 8804364
                Journal ID (pubmed-jr-id): 7775
                Journal ID (nlm-ta): Transplant Rev (Orlando)
                Journal ID (iso-abbrev): Transplant Rev (Orlando)
                Title: Transplantation reviews (Orlando, Fla.)
                ISSN (Print): 0955-470X
                ISSN (Electronic): 1557-9816
                Publication date Nihms-submitted: 17 May 2019
                Publication date (Electronic): 28 June 2018
                Publication date (Print): October 2018
                Publication date PMC-release: 26 May 2019
                Volume: 32
                Issue: 4
                Pages: 234-240
                Affiliations
                [a ]Department of Urology and Renal Transplant, Toledo, OH 43614, USA
                [b ]Center for Hypertension and Personalized Medicine, Department of Physiology & Pharmacology, University of Toledo College of Medicine, Toledo, OH 43614, USA
                [c ]Internal Medicine Department, Kettering Medical Center, Kettering, OH 45429, USA
                [d ]Department of Physiology & Biophysics, Mississippi Center for Obesity Research, University of Mississippi Medical Center, Jackson, MS 39216, USA
                Author notes
                [* ]Corresponding author at: Department of Physiology and Pharmacology, 3000 Arlington Avenue, Mailstop 1008, University of Toledo College of Medicine, Toledo, OH 43614, USA., Terry.Hinds@ 123456utoledo.edu (T.D. Hinds).
                Article
                Manuscript ID: NIHMS1029861
                DOI: 10.1016/j.trre.2018.06.003
                PMC ID: 6535229
                PubMed ID: 29983261
                SO-VID: 4e082878-0c19-40ef-a98f-95d09fd6fb28
                License:

                This is an open access article under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/).

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                Subject: Article

                Keywords: bilirubin,obesity,oxidative stress,renal transplant,gilbert's syndrome
                Data availability:
                Keywords: bilirubin, obesity, oxidative stress, renal transplant, gilbert's syndrome

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