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ABSTRACT: Renal ischemia-reperfusion injury (IRI) is an unavoidable event in renal transplantation; the effects of IRI can be seen in both the acute and long-term function of the transplanted organ. For this reason, research into the pathophysiology of ischemia-reperfusion is at the forefront of transplantation research. Animal models, particularly in the rat, provide a useful research tool in studying the intricacies of IRI and in evaluating new treatments. We describe a model of right nephrectomy and left renal clamping for 45 minutes and demonstrate the effects of temperature variation during the ischemic period.
Male Sprague-Dawley rats (under isoflurane anesthesia) underwent bilateral flank incision with removal of the right kidney and clamping of the left renal hilum for 45 minutes. The animals were divided into 3 groups (n=6): group 1 had the procedure performed on a heating mat with no temperature control facilities, group 2 used no heating mat, and group 3 used a rectal temperature-controlled homeothermic blanket system (Harvard Medical, United Kingdom). Temperature was taken every 5 minutes throughout the procedure and blood samples were taken on a daily postoperative basis via tail vein venepuncture.
The average temperature at the end of the procedure in group 1 was 39.67 degrees C and the creatinine level at day 3 was 574+/-17.84, in group 2 the temperature was 32.6 degrees C and the creatinine level was 115+/-4.06, and in group 3 the temperature was maintained between 36.5 degrees C-37 degrees C and the serum creatinine level was 329+/-19.18. The temperature of the animal during the ischemia phase of IRI significantly affects the severity of injury. Relative hyperthermia resulted in more severe renal injury and unrecoverable acute renal failure, no source of heat led to a relative hypothermia, and reduction of renal injury. Use of the homeothermic heating blanket led to an increase in creatinine level by day 3, indicating a significant ischemic stimulus; however, by day 10 the creatinine level had returned to normal.
This illustrates the importance of temperature as a variable in animal models of IRI and thus should be clearly stated in all experimental methods to ensure an appropriate ischemic stimulus and for adequate comparisons between various therapeutic interventions.
Transplantation Proceedings 01/2008; 39(10):2983-5. · 1.00 Impact Factor
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ABSTRACT: Ischemia-reperfusion (IR) is one of the strongest nonimmune factors associated with the development of chronic allograft nephropathy (CAN). This effect is often exacerbated by immunosuppressive medications, most notably cyclosporine. Although traditionally the macrophage was thought to stimulate fibroblast activity in CAN, recent evidence supports a role for lymphocytes. FTY720 is a new immunosuppressant that promotes lymphocyte sequestration into lymph nodes and Peyer's patches. This study investigated the effect of FTY720 on renal fibrosis in the rat following an IR insult (IRI).
A rat model of IRI was used in which male Sprague-Dawley rats (under isoflurane anaesthesia) underwent bilateral flank incision with removal of the right kidney and clamping of the left renal hilum for 45 minutes. Five groups of animals were studied (n=4): nephrectomy only, IRI only, IRI+FTY720 (1 mg/kg/d), IRI+cyclosporine (15 mg/kg/d), and IRI+FTY 720 (1 mg/kg/d) and cyclosporine (15 mg/kg/d). Animals were humanely killed at 30 days.
Serum creatinine (SCr) level was significantly reduced in the FTY720-treated animals. IRI alone produced a significant increase in SCr level compared with neprectomized animals (138 micromol/L vs 55 micromol/L; P<.05). This effect was potentiated by treatment with cyclosporine (173 micromol/L vs 55 micromol/L; P<.05). Treatment with FTY720 significantly reduced SCr level in rats following IRI alone (81 micromol/L vs 138 micromol/L; P<.01) and in rats following IRI + cyclosporine (98 micromol/L vs 173 micromol/L; P<.014). Parallel changes were seen in the levels of proteinuria. Fibrosis was assessed using Masson's trichrome (MT) staining. IRI alone produced a significant increase in MT staining compared with nephrectomized animals (0.92 vs 0.03; P<.05). This effect was potentiated by treatment with cyclosporine (1.12 vs 0.92; P=.022). Treatment with FTY720 reduced the level of MT staining in rats following IRI alone (0.34 vs 0.92; P<.05) and in rats following IRI+cyclosporine (70.34 vs 1.12; P<.05). Levels of TGF-beta1 were considerably reduced in FTY720-treated animals (compared with cyclosporine+IRI and IRI only), either alone (196+/-31 pg/mL vs 1105+/-59 pg/mL and 611+/-38; P<.05) or in conjunction with cyclosporine (423+/-26 pg/mL vs 1105+/-59 pg/mL and 611+/-38; P<.05).
Our study shows that treatment with FTY720 can reduce renal fibrosis as a result of IRI, both alone and in conjunction with cyclosporine. This provides promising evidence for using FTY720 in a calcineurin-free or reduced-dose immunosuppression protocol in an effort to reduce the incidence of CAN.
Transplantation Proceedings 12/2007; 39(10):2992-6. · 1.00 Impact Factor
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ABSTRACT: A male patient developed colitis and a thrombotic microangiopathy 3 weeks after renal transplantation. Immunosuppression at the time of presentation was with sirolimus, mycophenolate mofetil, and prednisolone, but without a calcineurin inhibitor. Cytomegalovirus infection was excluded. However, human herpesvirus-6 DNA was detected at high copy number in both blood and colonic epithelium. The patient recovered after reduction in immunosuppression, with nutritional support and ganciclovir therapy.
Transplant Infectious Disease 01/2007; 8(4):226-8. · 2.22 Impact Factor
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ABSTRACT: Gas gangrene is a rare condition, usually associated with contaminated traumatic injuries. It carries a high rate of mortality and morbidity. A number of studies have implicated non-traumatic gas gangrene and colonic neoplasia. This paper reports a patient who presented spontaneously with Clostridium septicum gas gangrene and an occult caecal carcinoma.
Emergency Medicine Journal 08/2005; 22(7):520-1. · 1.44 Impact Factor
