Robust Rat and Mouse Models of Bilateral Renal Ischemia Reperfusion Injury.

Background/aim: Acute and chronic kidney diseases are a major contributor to morbidity and mortality worldwide, with no specific treatments currently available for these. To enable understanding the pathophysiology of and testing novel treatments for acute and chronic kidney disease, a suitable in vivo model of kidney disease is essential. In this article, we describe two reliable rodent models (rats and mice) of efficacious kidney injury displaying acute to chronic kidney injury progression, which is also reversible through novel therapeutic strategies such as ischemic preconditioning (IPC).

Determination of a microRNA signature of protective kidney ischemic preconditioning originating from proximal tubules.

Ischemic preconditioning (IPC) is effective in limiting subsequent ischemic acute kidney injury in experimental models. MicroRNAs are an important class of post-transcriptional regulator and show promise as biomarkers of kidney injury. We evaluated the time- and dose-dependence of benefit from IPC in a rat model of functional (bilateral) ischemia-reperfusion injury (IRI).

A Localized Ischemic Preconditioning Regimen Increases Tumor Necrosis Factor α Expression in a Rat Model of Kidney Ischemia-Reperfusion Injury.

Objectives: We evaluated a continuous, immediate, localized ischemic preconditioning regimen in a rat model of ischemia-reperfusion injury and assessed whether it attenuated injury at the histologic and molecular levels.

Materials And Methods: Fifteen adult male Lewis rats received sham operation, left unilateral warm ischemia (45 minutes of cross-clamping of the renal pedicle; ischemia-reperfusion injury group), or 15 minutes of ischemia followed by a 20-minute reperfusion period, 45 minutes of ischemia-reperfusion injury, and subsequent reperfusion (ischemic preconditioning/ischemia-reperfusion injury group). Kidney tissue was retrieved 48 hours later, sectioned, stained with hematoxylin and eosin, and examined.

[Acute cell rejection in ex vivo model of swine-human renal xenotransplantation].

Objective: Ex vivo perfusion model of pig-to-human kidney xenotransplantation to evaluate human antiporcine xenograft rejection once hyperacute rejection (HAR) is avoided.

Methods: Pig kidneys were perfused for 3 hours with pig blood (group 1; n = 5), human blood (group 2; n = 5), complement heat inactivated human blood (group 3; n = 5), platelet-depleted human blood (group 4; n = 5); and xenoreactive natural antibodies (XNA)-depleted human blood (group 5; n = 5). Tissue samples were studied with immunoperoxidase techniques.

Production and characterization of a pig line transgenic for human membrane cofactor protein.

A pig line transgenic for human membrane cofactor protein (hMCP) has been established. Offspring from the founder were produced by crossing the founder with pigs heterozygous for the human decay accelerating factor (hDAF) transgene. As a result, pigs transgenic for both hMCP and hDAF have been produced.

Incidence of hyperacute rejection in pig-to-primate transplantation using organs from hDAF-transgenic donors.

Background: Cynomolgus monkeys or baboons received under immunosuppression kidney or heart grafts from pigs transgenic for human decay-accelerating factor (hDAF) or from control pigs. Hyperacute rejection (HAR) is often difficult to differentiate from nonimmunological causes of organ or recipient dysfunction (NIC), and therefore, a thorough pathology review of all cases with 0-4 days survival (inclusive) was conducted.

Methods: Pathology slides were blinded and together with limited clinical data reviewed by two pathologists.

Histopathology of cardiac xenograft rejection in the pig-to-baboon model.

Background: The use of pig organs transgenic for human decay accelerating factor (hDAF) has largely overcome the problems of hyperacute rejection. With improved immunosuppressive protocols, life supporting grafts are showing greater survival times bringing the possibility of clinical xenotransplantation closer. Examination of the histopathology of the rejection process provides insight into the underlying mechanism and may suggest ways in which new immunosuppressive strategies should be directed.

Life-supporting human complement regulator decay accelerating factor transgenic pig liver xenograft maintains the metabolic function and coagulation in the nonhuman primate for up to 8 days.

Background: It is not known whether the pig liver is capable of functioning efficiently when transplanted into a primate, neither is there experience in transplanting a liver from a transgenic pigs expressing the human complement regulator human complement regulator decay accelerating factor (h-DAF) into a baboon. The objective of this study was to determine whether the porcine liver would support the metabolic functions of non-human primates and to establish the effect of hDAF expression in the prevention of hyperacute rejection of porcine livers transplanted into primates.

Methods: Five orthotopic liver xenotransplants from pig to baboon were carried out: three from unmodified pigs and two using livers from h-DAF transgenic pigs.

Free radical scavengers to prevent reperfusion injury following experimental warm liver ischaemia. Is there a real physiological benefit?

Free radical scavengers have been utilized to prevent the consequences of ischemia, however, results do not seem conclusive. In our study we analyzed the blood flow, function, and histology of rat liver tissue after warm liver ischemia, in order to assess the effect of free radicals in liver reperfusion injury. N-acetyl cysteine (NAC), tocopherol, allopurinol, and superoxide dismutase (SOD), pharmacological agents expected to protect from injury mediated by free radicals, were investigated.

[Transgenic swine as potential organ donors? Results of the ex-vivo hemoperfusion hDAF transgenic kidney with human blood].

Kidney xenotransplantation is not yet a realistic clinical treatment modality. However, during the last decades more than 30 kidneys from other species have been transplanted into humans; some of the kidneys sustained some function up to 60 days. Recent progress in genetic engineering has raised the possibility to create large transgenic animals which express human complement regulatory proteins (CRP).

Orthotopic heart transplantation in a transgenic pig-to-primate model.

Background: Previous studies demonstrated that hearts from transgenic pigs expressing human decay-accelerating factor (hDAF) were not hyperacutely rejected when transplanted heterotopically into the abdomen of cynomolgus monkeys. This study examines orthotopic transplantation of hDAF transgenic pig hearts into baboon recipients.

Methods: Orthotopic xenogeneic heart transplantation was performed using piglets, transgenic for hDAF, as donors.

Characterization of pigs transgenic for human decay-accelerating factor.

Background: To prevent the central role played by complement activation in the hyperacute rejection of pig organs transplanted into primates, pigs transgenic for human decay-accelerating factor (HDAF) have recently been produced. The data presented here extend previous immunohistochemical findings by documenting the immunological characterization and the levels of expression of HDAF in these transgenic pigs.

Methods: Animals from 30 independently derived lines were included in this study.

Morphology of hDAF (CD55) transgenic pig kidneys following ex-vivo hemoperfusion with human blood.

Discordant xenotransplantation of pig kidneys into man may be possible in the future using transgenic organs which regulate complement activity. It was the aim of this experimental study to characterize morphologic alterations of organs transgenic for human decay accelerating factor (hDAF/CD55) perfused with human blood since no data on function of these organs after exposure to human blood are available. An ex-vivo system was developed that allows computer driven pressure-controlled perfusion of kidneys including a separate cartridge oxygenator circuit.