Antioxidant Lazaroid U-74006f Improves Renal Function and Reduces the Expression of Cytokines, Inducible Nitric Oxide Synthase, and MHC Antigens in a Syngeneic Renal Transplant Model

Abstract

In a recent study, antioxidant therapy at the time of renal transplantation in humans was associated with fewer rejection episodes and extended graft survival. A hypothesis generated by such studies and based on the response-to-injury model is that reducing the oxidative injury during transplantation may dampen certain cellular responses to injury that are important in triggering allograft rejection. To test whether ablation of oxidative injury would limit such responses, kidneys were transplanted between Wistar-Furth rats, with and without antioxidant 21-aminosteroid. 21-Aminosteroid was administered before kidney harvest and, again, before transplant reperfusion. The recipient's left kidneys, removed to accommodate the donor kidneys, were used as normal control. The removal of the right kidneys contralateral to the transplant were delayed to day 4 to provide interim renal support. The transplanted kidneys were harvested on day 7. Administration of 21-aminosteroid was associated with better graft function and reduced lipid peroxidation. Compared with the normal control kidneys, the kidneys transplanted with vehicle had higher cytokine mRNA levels (measured by reverse transcriptase-polymerase chain reaction) for interleukin 2, interleukin 6, tumor necrosis factor-alpha, and interferon-gamma. The levels for these cytokines were reduced in kidneys transplanted with 21-aminosteroid. An increase in inducible nitric oxide synthase mRNA in the transplanted kidney was inhibited by 21-aminosteroid, as were the increase in class I and II MHC antigens. The new finding, that a reduction in transplantation-related oxidative injury in a syngeneic model is accompanied by a reduction in the expression of cytokines, MHC antigens, and inducible nitric oxide synthase, provides partial support for the response-to-injury hypothesis in the setting of renal transplantation. The data also demonstrate for the first time the efficacy of 21-aminosteroid to reduce lipid peroxidation and renal injury in kidneys transplanted after cold preservation.

Cold ischemia and the reduced long-term survival of cadaveric renal allografts

“…A strong colinearity between these two dependent measures on cold ischemic injury is suggested by the fact that introduction of acute injury variable such as discharge serum creatinine had rendered the relationship between CIT and graft survival insignificant. Based on the response-to-injury hypothesis [6][7][8], early injury from cold ischemia may set the stage for indolent, yet chronically progressive, damage leading to higher rates of chronic graft loss noted in this analysis of kidneys subjected to extended cold storage. Whether the chronic loss of graft is a direct effect of cold ischemia or through irreversible acute injury is an intriguing question that requires separate analysis using follow-up renal function.…”

Influence of CIT-Induced DGF on Kidney Transplant Outcomes

“…This may lead to prolonged cold ischemia time (CIT), which may contribute to the ultimate discard of the kidney. Based on the response-to-injury hypothesis (3)(4)(5), early injury from cold ischemia may set the stage for indolent, yet chronically progressive, damage leading to higher rates of chronic graft loss. In addition, many kidneys not accepted by local centers are considered marginal and clinicians may be reluctant to accept kidneys with a long anticipated CIT for fear of an additive deleterious effect (6).…”

Cold ischemic injury of transplanted kidneys: new insights from experimental studies

“…Prolonged cold ischemia of deceased donor kidneys leads to higher graft dysfunction, higher recipient mortality, and higher health care costs. Furthermore, based on the "response-to-injury" hypothesis (21,34,67), injury from cold ischemia may set the stage for chronic injury. The number of patients waiting for transplantation is steadily increasing, and currently this number in the United States is close to 88,000, a threefold increase over the last decade.…”