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Abraham Shaked

Publications and source records attributed to Abraham Shaked.

27 records · Page 2Linked to original sources
PubMed2004

Severe preservation injury induces Il-6/STAT3 activation with lack of cell cycle progression after partial liver graft transplantation.

Partial liver graft transplantation is a surgical advance developed to overcome severe donor shortage. Survival of these grafts involves recovery from cold ischemia and reperfusion (CIR) injury, immediate regeneration and maintenance of function. Here we examined the outcome of partial liver grafts in comparison to whole grafts following CIR injury. Lewis rats subjected to orthotopic liver transplantation (OLT) with whole grafts preserved in Viaspan were compared to rats receiving 50% and 30% grafts. Outcome was analyzed by survival and regeneration. Transplantation was associated with 100% survival for all grafts, whereas 16 h preservation resulted in 100%, 20% and 0% survival in animals receiving whole, 50% and 30% grafts, respectively. CIR induced increased IL-6 levels in 50% and 30% grafts, and activation of STAT3. Cell cycle progression (cyclin D1) and regeneration (BrdU) was initiated in all livers preserved for 1 or 8 h, but not in partial grafts preserved for 16 h. In conclusion, partial grafts recover from CIR injury through similar molecular pathways to whole grafts. Partial grafts with severe injury fail to achieve cellular proliferation despite the early initiating signals. This failure could be attributed to the impaired ability of the parenchyma to respond to initiating signals for regeneration.

Animals↗
PubMed2003

Liver transplantation from controlled non-heart-beating donors: an increased incidence of biliary complications.

BACKGROUND: Hepatic allografts from non-heart-beating donors (NHBD) have been cited as a means to expand the supply of donor livers. Concern exists that donor warm ischemic time in addition to subsequent cold ischemia-reperfusion injury may result in damage to sensitive cell populations within the liver. Because the biliary epithelium is sensitive to ischemia-reperfusion injury, the authors surmised that an increased incidence of biliary complications might occur among recipients of an NHBD allograft. METHODS: This study was a retrospective evaluation of NHBD recipients compared to a group of heart-beating donor (HBD) recipients from a single institution. RESULTS: Fifteen patients received a hepatic allograft from a controlled NHBD donor. NHBD and HBD (n=221) graft survival did not differ at 1 (71.8% vs. 85.4%, P=0.23) or 3 years (71.8% vs. 73.9%, P=0.68). Patient survival at 1 (79% vs. 90.9%, P=0.16) and 3 years (79.0% vs. 77.7%, P=0.8) was also similar. Major biliary complications occurred in five (33.3%) NHBD recipients; 66.6% of the NHBD biliary complications consisted of intrahepatic strictures versus 19.2% among HBD recipients (P<0.01). Major biliary complications in the NHBD recipients resulted in multiple interventional procedures, retransplantation, and death. CONCLUSIONS: Donor warm ischemic time may predispose hepatic allografts to an increased incidence of ischemic type strictures. Although graft and patient survival was similar to a cohort of HBD recipients, caution is urged with the use of these organs.

Adult↗
PubMed2003

Dexamethasone inhibits early regenerative response of rat liver after cold preservation and transplantation.

Regeneration is crucial for the recovery of hepatic mass following liver transplantation. Glucocorticoids, immunosuppressive and antiinflammatory agents commonly used in transplantation, are known to inhibit the expression of specific cytokines and growth factors. Some of these proteins, namely tumor necrosis factor alpha (TNF-alpha) and interleukin 6 (IL-6), play a critical role in the initiation of liver regeneration. Following cold preservation and reperfusion of the transplanted liver, the normal recovery process is marked by increased expression of TNF-alpha and IL-6, followed by activation of cytokine-responsive transcription factors and progression of the cell cycle resulting in hepatocyte proliferation. We hypothesized that glucocorticoids may influence the repair mechanisms initiated after extended cold preservation and transplantation. Using a rat orthotopic liver transplant model, recipient animals were treated with dexamethasone at the time of transplantation of liver grafts with prolonged cold storage (16 hours). Treatment with dexamethasone suppressed and delayed the expression of TNF-alpha and IL-6 compared with animals receiving no treatment and attenuated downstream nuclear factor kappaB (NF-kappaB), signal transduction and activator of transcription 3 (STAT3), and activation protein 1 (AP-1) activation. This suppression was accompanied by poor cell-cycle progression, delayed cyclin D1 nuclear transposition, and impaired hepatocyte proliferation by BrdU uptake. Histologically, the liver grafts in treated animals demonstrated more injury than controls, which appeared to be necrosis, rather than apoptosis. In conclusion, these data provide evidence that the administration of glucocorticoids at the time of transplantation inhibits the initiation of the regenerative process and may have a deleterious effect on the recovery of liver grafts requiring significant regeneration. This may be particularly relevant for transplantation of partial liver grafts in the living donor setting.

Animals↗
PubMed2003

Treatment of obstructive nephroureteral clot with a rheolytic mechanical thrombectomy device.

Thrombus within the renal collecting system and ureter after percutaneous intervention is usually self-limited, but when it is obstructive enough to produce anuria, it can cause deterioration of renal function. Herein a case of a patient with a transplant kidney in whom clot anuria developed after conversion of a nephroureteral stent to a nephrostomy catheter is presented. Internal urine drainage was restored with the use of a rheolytic mechanical thrombectomy device, with subsequent return of normal renal function.

Humans↗
PubMed2003

Biliary casts after orthotopic liver transplantation: clinical factors, treatment, biochemical analysis.

OBJECTIVES: Biliary casts develop in up to 18% of liver transplant recipients. Casts are associated with morbidity, graft failure, need for retransplantation, and mortality. Proposed etiological mechanisms include acute cellular rejection, ischemia, infection, and biliary obstruction. We aimed to identify clinical features associated with biliary cast formation, review treatments, and analyze the biochemical composition of casts at a single, large, liver transplant center. METHODS: Patient records were reviewed retrospectively to identify patients who developed casts. Data were collected with attention to ischemia, rejection, obstruction, infection, immunosuppression, postoperative biliary drain use, and cast-directed management, and were compared with data from controls. Cast specimens, retrieved at cholangiography, were analyzed with chromatography techniques. RESULTS: Ischemic factors were noted in 70% (7/10) of cast patients versus 15% (6/40) of controls (OR = 13.2; 95% CI = 2.7-66.0; p = 0.001). Biliary strictures were present in 50% of cast patients versus 10% of controls (OR = 9.0; 95% CI = 1.8-45.2; p = 0.01). Differences in cold ischemia time, acute cellular rejection, cyclosporin use, infection, and postoperative biliary drain use were not significant. Casts were successfully treated by endoscopic and percutaneous methods in 60% of patients. One patient died of cast-related complications (mortality 10%). Four casts were in satisfactory condition for biochemical analysis. Bilirubin was the main component ( approximately 10-50%). Bile acid synthesis products and cholesterol comprised smaller percentages, and protein comprised only 5-10%. CONCLUSIONS: Biliary casts are more likely to develop in the setting of hepatic ischemia and biliary strictures. Endoscopic and percutaneous cast extraction might achieve favorable results and should be attempted before surgical therapy.

Adult↗
PubMed2002

Toward further expansion of the organ pool for adult liver recipients: splitting the cadaveric liver into right and left lobes.

BACKGROUND: Current methods of living donor right lobe transplantation can be expanded for use in the cadaveric setting. The aim of this study is to discuss alternative methods for the management of large-for-size cadaveric livers and determine the feasibility of splitting these organs into left and right hemi-livers using similar techniques to those used in the living donor setting. METHODS: The indication for an in situ right-left split procedure was an offer of a large liver for a small recipient with a recipient-donor ratio of greater than 1.5. A total of three livers were split. Mean donor age was 33.3 (range, 22-40) years. Mean weight was 118 (range, 90-150) kg. All donors were without significant medical history and were hemodynamically stable, with normal liver function and short hospital stay. Mean duration of the procurement procedure was 235 (range, 210-270) min. Mean cold ischemia time was 8.5 hr. Mean recipient weight was 58.3 kg, and mean donor to recipient weight ratio was 2.0 (1.6-2.6). United Network for Organ Sharing statuses at the time of transplantation were 1 (n=1), 2A (n=1), and 2B (n=4). RESULTS: Immediate graft function was seen in five recipients. Delayed nonfunction was identified in one recipient of a left lobe, who did not undergo transplantation because of sepsis that resulted in death at 30 days. A second mortality occurred in a left lobe recipient, from a fungal brain abscess at 90 days. Complications related to the split included bile leaks in two patients, one necessitating operative revision. CONCLUSIONS: Splitting of livers from appropriate brain-dead donors into right and left lobes is technically and logistically feasible. The large-for-size organ provides a more substantial amount of liver tissue to each of the adult recipients, which may result in a greater graft to recipient weight ratio than the current standard that is used in the living donor grafting. The importance of this variable will need to be studied, because it may positively impact on the ability of the reduced-size graft to withstand donor-related organ system stress and injury, which is associated with brain death and the inevitable longer period of cold preservation.

Adult↗
PubMed2002

The outcome of liver grafts procured from hepatitis C-positive donors.

BACKGROUND: The growing prevalence of hepatitis C virus (HCV) infection in the general population has resulted in an increased frequency of potential organ donors that carry the virus. The survival of grafts from HCV+ donors has not been studied in detail. METHODS: Two study populations were examined retrospectively to assess the survival of liver grafts procured from HCV+ donors. First, we evaluated the survival of all 13 HCV+ and 103 HCV- grafts that were transplanted at our institution to HCV+ recipients from January 1, 1995 to December 31, 1999. In parallel, we analyzed a subset of the United Network for Organ Sharing (UNOS) liver transplant database from the same 5-year time period that was comprised of 14,195 adult patients for whom donor and recipient HCV serologies were known. Kaplan-Meier graft survival for both patient populations was calculated based on donor and recipient HCV serologic status. A Cox proportional hazards analysis was performed on UNOS data to identify variables independently predicting graft survival. RESULTS: For transplants performed at our institution, we found no statistically significant difference in the Kaplan-Meier graft survival of HCV+ and HCV- grafts transplanted to HCV+ recipients (P=0.68). The incidence of biopsy-proven, recurrent HCV posttransplant was similar in recipients receiving either HCV+ or HCV- grafts (4/13 vs. 18/103, chi-square P=0.211). Analysis of UNOS data revealed that the survival of HCV+ grafts in HCV+ recipients was equivalent to the survival of HCV- grafts in HCV+ recipients. Unexpectedly, the survival of grafts in HCV+ recipients in general was significantly inferior to that of grafts in HCV- recipients. Multivariate analysis of all patients found recipient but not donor HCV status to be independently predictive of graft survival. CONCLUSIONS: Analysis of data from a single center and the national UNOS database suggests that transplantation of liver allografts from HCV+ donors to HCV+ recipients results in graft survival comparable to HCV- grafts transplanted to HCV+ recipients. In contrast, recipient HCV positivity is an independent predictor of graft failure compared with patients transplanted for other causes of liver disease.

Graft Survival↗
PubMed2002

Interleukin-6 from intrahepatic cells of bone marrow origin is required for normal murine liver regeneration.

Interleukin-6 (IL-6) is required for normal liver regeneration, but the specific cellular source of this growth factor is unknown. We investigated whether this signal originates from the resident macrophage, the Kupffer cell. Using a murine model of bone marrow transplantation, we replaced recipient bone marrow-derived cells, including Kupffer cells, with cells of donor genetic phenotype. Recipients deficient in IL-6 (IL-6(-/-)) were lethally irradiated, then rescued with 10(7) donor bone marrow cells capable of expressing IL-6 (IL-6(+/+)). Conversely, IL-6(+/+) recipients received IL-6(-/-) marrow. Successful engraftment was measured by the presence of the Y chromosome SRY locus in the livers of female recipients receiving male marrow, in situ IL-6 expression by Kupffer cells, and up-regulation of IL-6 in splenocytes after activation with lipopolysaccharide (LPS). Kupffer cell isolation in IL-6(-/-) females receiving IL-6(+/+) male marrow clearly showed the presence of the SRY locus and IL-6 disrupted allele, whereas males receiving female marrow demonstrated no SRY or IL-6 signals, confirming the extent of replacement. Replacement of these cells in IL-6(-/-) mice with IL-6(+/+) bone marrow successfully restored the regenerative response after partial hepatectomy (PHx) as indicated by signal transduction and activator of transcription 3 (STAT3) activation and hepatocyte DNA replication. Alternatively, complete replacement of Kupffer cells in IL-6(+/+) mice by transplantation with IL-6(-/-) cells significantly inhibited liver regeneration and was partially restored by administration of IL-6. This investigation demonstrates a paracrine mechanism by which cells of bone marrow origin, most likely Kupffer cells, regulate the regenerative capacity of the hepatocyte through IL-6 expression.

Animals↗