Focal segmental glomerulosclerosis (FSGS) is a kidney disease with progressive glomerular scarring and a clinical presentation of nephrotic syndrome. FSGS is a common primary glomerular disorder that causes renal dysfunction which progresses slowly over time to end-stage renal disease. Most cases of FSGS are idiopathic Although kidney transplantation is a potentially curative treatment, 40% of patients have recurrence of FSGS after transplantation. In this review a brief summary of the pathogenesis causing FSGS in humans is given, and a variety of animal models used to study FSGS is discussed. These animal models include the reduction of renal mass by resecting 5/6 of the kidney, reduction of renal mass due to systemic diseases such as hypertension, hyperlipidemia or SLE, drug-induced FSGS using adriamycin, puromycin or streptozotocin, virus-induced FSGS, genetically-induced FSGS such as via Mpv-17 inactivation and α-actinin 4 and podocin knockouts, and a model for circulating permeability factors. In addition, an animal model that spontaneously develops FSGS is discussed. To date, there is no exact understanding of the pathogenesis of idiopathic FSGS, and there is no definite curative treatment. One requirement facilitating FSGS research is an animal model that resembles human FSGS. Most animal models induce secondary forms of FSGS in an acute manner. The ideal animal model for primary FSGS, however, should mimic the human primary form in that it develops spontaneously and has a slow chronic progression. Such models are currently not available. We conclude that there is a need for a better animal model to investigate the pathogenesis and potential treatment options of FSGS.

mTOR inhibition severely impairs liver regeneration and increases autophagy after PH. These effects are partly reversed by stimulation of the IL-6 and HGF pathways.

Rejection and graft versus host disease are prominent features in small bowel allotransplantation in rats. Cyclosporine treatment of the recipient and irradiation of the donor were used to circumvent these phenomena in the WAG to brown Norway rat model. Irradiation ofthe donor with five or 10 Gy did prevent graft versus host disease but resulted in a more vigorous rejection of small bowel aliografts in untreated recipients (mean (SEM) survival times of 11.5 (0.4) (n=8) and 7*5 (0.9) (n=11) days respectively, versus 16.6 (2.6) days (n=17), p<001 Various experimental studies on the rejection of small bowel allografts have shown that under certain immunological conditions, immunocompetent cells in these grafts can cause graft versus host disease (GVHD).' While the occurrence of this reaction in well defined inbred systems has been conclusively documented, its importance in outbred systems is uncertain. In a previous study we successfully ameliorated GVHD in the WAG to BN rat model using whole body irradiation of the donor with 10 Gy.5 The effectiveness of donor irradiation had been shown previously in a parent to Fl hybrid rat model in which the donors were irradiated with 7, 9.5, and 10 Gy before small bowel transplantation.267 In this study we investigated the effects of combined cyclosporine treatment and donor irradiation because we had evidence that irradiation of the donor leads to accelerated rejection of the graft.5 We wondered whether cyclosporine could reverse this effect. Earlier we found that cyclosporine, used alone, was not effective in consistently producing long term survivors in the WAG to BN donor-host combination.8 In this study we show that the effect of cyclosporine on GVHD is less pronounced than its effect on rejection, as shown earlier by Kirkman.9 In large animal models cyclosporine proved to be less successful than in certain rat strain combinations.'7 Two recent studies in pigs, using ex vivo irradiation of the transplant with 0.5 Gy, a very low dose, combined with cyclosporine therapy of the recipient showed no effect on host survival time compared with cyclosporine monotherapy.'89 Because the immunological problems of large animal models resemble the problems in our WAG to BN rat model, this model is highly suitable for investigating the effect of irradiation combined with cyclosporine treatment. Methods ANIMALSA fully allogeneic donor-host model was employed by using inbred WAG (RT1u) rats as donors and inbred BN (RTLn) rats as recipients. The rats weighed between 200-350 g. OPERATIVE PROCEDURESDonors were fasted for 24 to 48 hours with water ad libitum. All procedures were performed under ether anaesthesia. The method of orthotopic small bowel transplantation has been published recently.5 Briefly, the small bowel was double tied and cut 1 cm distally to the ligament of Treitz and 1-2 cm proximally to the cxcum. The graft was harvested along with the attached vascular pedicles, consisting of the portal vein and the superior mesenteric artery, including an aortic cuff. The graft...

Several groups have demonstrated that it is possible to obtain long-term graft survival of concordant xenografts. One of the important questions that remains is whether xenografts are susceptible to chronic rejection. To answer this question we used the aorta transplantation model. One centimetre of hamster aorta was interposed in the abdominal aorta of Lewis rat recipients. The recipients were either untreated (group 1), or treated with 10 mg/kg cyclosporine (CsA), given intramuscularly three times a week (group 2). Rats were sacrificed at day 7, 14, 21, 28, 56 and 84 and the thickness of the intima, the media and the adventitia was measured. Furthermore, the cellularity of the media and the adventitia was assessed by counting the number of nuclei per 0.05 mm2 and immunohistochemistry of the aortic grafts was performed. Graft arteriosclerosis developed in aortic xenografts of both group 1 and group 2. In group 1, intimal lesions were already present from day 21 onwards in all rats, whereas in group 2 they were present only in 33% (2/6) of the rats. At day 84 all the grafts in group 1 were totally occluded, while those in group 2 were still open. The thickness of the media was slightly increased in both groups during the whole observation period, mainly due to edema. Although a few infiltrating macrophages could be seen, the number of nuclei per 0.05 mm2 of the media remained constant during the first 21 days, but declined sharply from day 21 onwards, as a consequence of disappearing myocytes. Thickness of the adventitia in both groups increased after transplantation due to infiltrating macrophages and T cells, reaching a peak at day 14. After day 14 the adventitial thickness in group 1 decreased rapidly to reach values comparable to group 2 from day 28 onwards. In conclusion, graft arteriosclerosis, as a sign of chronic rejection, occurs in concordant aortic xenografts. The lesions in the xenografts develop extremely rapidly, and compared to data from the literature, faster than in aortic allografts. The process of chronic rejection in aortic xenografts can be reduced by CsA.

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