Effect of deferiprone on in vivo model of autologous renal transplantation (Doctoral thesis)

Τάτσης, Βασίλειος Ι.

Introduction: Ischemia-reperfusion syndrome (IRI) represents the major non-immune factor which leads to renal graft damage. Iron features prominently in IRI processes and several studies have shown a beneficial role of iron-chelating agent desferoxamine. Another chelating agent deferiprone (L1) has been used in iron overload patients showing better results possibly due to its different physicochemical properties. Purpose: The purpose of this study was to assess any possible protective effect of L1 on a kidney autotransplantation model by studying the damage caused to kidney graft during cold ischemia, reperfusion and post-surgery phases. Material and Method: 14 pigs (65-75kg body weight) were used and consisted the control group (7) and the study group (L1-7). Pigs in L1 group received twice daily 50mg/kg of L1 for 3 consecutive days plus another dose just before the implantation of graft. Left nephrectomy and graft (left kidney) implantation to right renal vascular pedicle, with concomitant right nephrectomy, were done with a novel experimental model using total extra-peritoneal approaches. In both groups, after left kidney removal, it was flushed with Custodiol® solution and immediately was connected to an extracorporeal circulatory machine at 4oC with flow of 50-100ml/min, maintaining fluid (KPS-1® solution) pressure not to exceed 35-40 mmHg, for a period of 4h. Then it was cold stored in Custodiol® solution for another 13h (total cold ischemic period: 17h). In L1 group, 0.1gr of L1 were diluted in KPS-1® and Custodiol® solutions. Laboratory and histologic markers of kidney damage were evaluated during a) cold preservation phase (weight of graft, CK/LDH concentrations into the preservation solution), b) at 30mins after reperfusion phase (8-isoprostane, biopsy), c) during post-surgery phase (Urea, Creat serum concentrations) and before sacrifice of animals at 14th postoperative day (biopsy). Biopsy specimens were examined by two independed pathologists to assess the degree of graft damage through the histopathological index and expression of adhesion molecules ICAM-1 and VCAM-1. Results: All animals survived until 14th postoperative day. After 17h cold ischemia period, the mean weight of grafts and CK/LDH concentrations were lower in L1 group compared to control group (p=0.001, p=0.001 and p=0.007, respectively). At 30mins after reperfusion the mean concentration of 8-isoprostanes was lower in L1 group compared to control group (p=0.007). Histopathological index at 30mins after reperfusion was significantly lower in L1 group compared to control group (p=0.001) and the same result was seen at 14th postoperative day (p=0.001). Additionally, between 30mins and 14th postoperative day, the histopathological index was increased in control group (p=0.042), while it remained stable in L1 group (p=0.862). At 30mins after reperfusion, expression of VCAM-1 in L1 group: p=0.083). From 3rd up to 8th postoperative day Urea serum concentrations and from 3rd up to 7th postoperative day Creat serum concentrations were constantly lower in L1 group compared to control group (all p<0.05). Conclusions: Due to above promising results, it seems that deferiprone manifests a clear cytoprotective role in renal autotransplantation model by reducing kidney damage both at preservation period and after reperfusion, resulting in better graft function during postoperative phase and possibly lowering graft’s immunogenicity.
Alternative title / Subtitle: (πειραματική μελέτη σε χοίρους)
(experimental study in pigs)
Institution and School/Department of submitter: Πανεπιστήμιο Ιωαννίνων. Σχολή Επιστημών Υγείας. Τμήμα Ιατρικής
Subject classification: Νεφρά -- Μεταμόσχευση
Keywords: Δεφεριπρόνη,Αυτομεταμόσχευση νεφρού,Πειραματική μελέτη σε χοίρους,Υποθερμική απλή συντήρηση,Υποθερμική μηχανική έκπλυση,Σύνδρομο ισχαιμίας-επαναιμάτωσης,Δεξαμενή ασταθούς σιδήρου,Οξειδωτικό stress,CK/LDH διαλύματος συντήρησης,8-ισοπροστάνια,Ουρία,Κρεατινίνη,Ιστοπαθολογικός δείκτης,Μόρια προσκόλλησης,ICAM-1,VCAM-1,Deferiprone,Kidney autotransplantation,Experimental study in pigs,Static cold storage,Hypothermic machine perfusion,Ischemia-reperfusion syndrome,Labile iron pool,Oxidative stress,CK/LDH of storage solution,8-isoprostane,Urea,Creatinine,Histopathological index,Adhesion molecules
URI: http://olympias.lib.uoi.gr/jspui/handle/123456789/28971
Appears in Collections:Διδακτορικές Διατριβές

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