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Gago M.,William von Liebig Transplant Center | Gago M.,Mayo Medical School | Cornell L.D.,Mayo Medical School | Kremers W.K.,Mayo Medical School | And 2 more authors.
American Journal of Transplantation | Year: 2012

This study assessed the development of allograft interstitial fibrosis and inflammation (GIF+"i"), a histologic pattern associated with reduced graft survival. Included are 795 adults, recipients of kidney allografts from 2000 to 2006. GIF+"i" was diagnosed in surveillance and clinical biopsies that had no transplant glomerulopathy. With time, posttransplant increasing number of grafts showed GIF+"i" and these patients had reduced death-censored graft survival (HR = 4.33 (2.49-7.53), p < 0.0001). Development of GIF+"i" was related to prior acute cellular rejection (ACR), BK nephropathy (PVAN), increasing number of HLA mismatches, retransplantation and DGF. However, 46.4% of GIF+"i" cases had no history of ACR or PVAN. Anti-HLA antibodies at transplant did not relate to GIF+"i" and these patients had no increased frequency of new antibody formation posttransplant. Post-ACR biopsies showed that GIF+"i" developed more commonly after clinically and/or histologically more severe ACR. Graft inflammation persisted in 38.7 and 29.6% of grafts 2 and 12 months post-ACR. Twelve months post-ACR, 27.1% of biopsies developed moderate-severe GIF and 51.8% showed GIF and inflammation. Persistent inflammation and progressive GIF is often subclinical but may lead to graft failure. GIF+"i" can be initiated by multiple etiologies but it is often postinfectious or due to persistent cellular immune-mediated injury. This study analyzes "graft interstitial fibrosis associated with inflammation" after kidney transplantation, the factors that relate to its development, and its implications for graft survival. © 2011 The American Society of Transplantation and the American Society of Transplant Surgeons.


Gali B.,Mayo Medical School | Rosen C.B.,Transplant Center | Plevak D.J.,Mayo Medical School
Journal of Intensive Care Medicine | Year: 2012

A perception that living donor liver transplantation can be accomplished with an acceptable donor complication rate and recipient survival rate has led to the acceptance of living donor liver transplantation as a viable alternative to decreased deceased donor transplantation. Careful candidate evaluation and selection has been crucial to the success of this procedure. Advancements in the understanding of the lobar nature of the liver and of liver regeneration have advanced the surgical technique. Initial attempts at adult-to-adult donation utilized the left hepatic lobe, but now have evolved into use of the right hepatic lobe. Size matching is very important to successful graft function in the recipient. There is great concern regarding morbidity and mortality in donors. Biliary complications and infections continue to be among the most highly reported complications, although rates vary among centers and countries. Reports of single center complications have ranged from 9% to 67%. A survey of centers in the United States in 2003 reported complications of 10%. A series from our institution reported complications arising in 13 (33%) of 39 patients. A review focused on documenting donor deaths found 33 living liver donor deaths worldwide. The much publicized immediate postoperative mishap of 2002 that resulted in a donor's death resulted in a drop in the utilization of living donor liver transplantation in the United States, from which this procedure has never fully recovered. The future development and expansion of living donor liver transplantation depends on open communication regarding donor complications and deaths. Close immediate postoperative monitoring and meticulous management will remain an essential aspect in limiting donor complications and deaths. © SAGE Publications 2012.


Folmes C.D.L.,Center for Regenerative Medicine | Nelson T.J.,Center for Regenerative Medicine | Nelson T.J.,Transplant Center | Martinez-Fernandez A.,Center for Regenerative Medicine | And 9 more authors.
Cell Metabolism | Year: 2011

The bioenergetics of somatic dedifferentiation into induced pluripotent stem cells remains largely unknown. Here, stemness factor-mediated nuclear reprogramming reverted mitochondrial networks into cristae-poor structures. Metabolomic footprinting and fingerprinting distinguished derived pluripotent progeny from parental fibroblasts according to elevated glucose utilization and production of glycolytic end products. Temporal sampling demonstrated glycolytic gene potentiation prior to induction of pluripotent markers. Functional metamorphosis of somatic oxidative phosphorylation into acquired pluripotent glycolytic metabolism conformed to an embryonic-like archetype. Stimulation of glycolysis promoted, while blockade of glycolytic enzyme activity blunted, reprogramming efficiency. Metaboproteomics resolved upregulated glycolytic enzymes and downregulated electron transport chain complex I subunits underlying cell fate determination. Thus, the energetic infrastructure of somatic cells transitions into a required glycolytic metabotype to fuel induction of pluripotency. © 2011 Elsevier Inc.


Russo M.W.,Transplant Center
Expert Review of Gastroenterology and Hepatology | Year: 2010

End-stage liver disease from hepatitis C is a leading cause of decompensated cirrhosis, hepatocellular carcinoma, liver transplantation and liver-related deaths. The goals of antiviral therapy are to prevent these sequelae and prolong life. Clinical trials of α-interferons and ribavirin have used sustained viral response as an outcome because it is considered synonymous with cure and is assumed to be associated with decreasing complications caused by cirrhosis. However, it is only recently that data has emerged supporting this assumption. This study demonstrates that meaningful clinical end points are seen in patients who achieve a sustained virologic response (SVR) with a reduction in liver-related deaths, rates of hepatocellular carcinoma (HCC) and liver-related complications. None of the patients who achieved SVR developed variceal bleeding. The rates of HCC were significantly lower in the SVR group, but six cases of HCC occurred in the SVR group, underscoring the importance of continued surveillance in hepatitis C virus patients with SVR who have advanced fibrosis or cirrhosis. © 2010 Expert Reviews Ltd.


A 26-year-old woman who learned at age 16 that she would be unable to have children now has a chance to do so, thanks to the first uterus transplant in the U.S. The transplant provides hope for women who are unable to have babies due to uterus-related issues, said the doctors who completed the transplant. "This is an unbelievable event" and the patient is doing very well, said Dr. Andreas Tzakis, the program director of the Cleveland Clinic's Transplant Center, who led the surgery. A condition called uterine factor infertility — in which a woman is unable to get pregnant because she either does not have a uterus, or the uterus does not function properly — affects an estimated 50,000 women in the United States, according to the Cleveland Clinic. [Donated Uterus Transplanted Into Patient | Animation] A uterus transplant can enable a woman with uterine factor infertility to become pregnant and deliver a baby. The surgery took place February 2016, and required about 9 hours, said Dr. Toby Cosgrove, the CEO and president of the Cleveland Clinic, speaking at a news conference today (March 7). The team included eight surgeons and about 70 other caregivers, including fertility experts and bioethicists, he said. Tzakis and his team worked very closely with doctors in Sweden, who completed the world's first uterus transplant in 2015. In the Cleveland transplant, the uterus was taken from a deceased donor, Tzakis said. The surgeons used transplant techniques that have been well-established for other types of organ transplants. However, the surgery is a little more complex because the transplant site is deep within the pelvis and therefore more difficult to access, Tzakis said. Dr. Rebecca Flyckt, an OB/GYN surgeon who was part of the team, elaborated upon the surgery. The the most important of part of the transplant is to connect blood vessels, Flyckt said at the news conference. First, the uterine arteries and veins were connected to the recipient's blood vessels, she said. Once these were connected, the transplanted uterus started to turn pink, which indicated that blood is flowing, she said. [The 9 Most Interesting Transplants] Next, the surgeons connected the uterus to the vagina, as well as the connective tissue in the pelvis that helps anchor the uterus in place, she said. The transplanted uterus also included the cervix and the upper part of the vagina. The goal of the surgery is to allow the woman to have a baby, but the woman needs to wait at least a year before trying to get pregnant, Flyckt said. The team in Cleveland screened more than 250 women, and ultimately selected 10 who will receive transplants. All of the women were born with normal ovaries that produce healthy eggs, Flyckt said. But without a uterus, the eggs have nowhere to go, she said. Before the transplant, the women will undergo in vitro fertilization, Flyckt said. They will bank six to 10 embryos before they can be considered for the transplant, she said. After the transplant is completed, the women need to wait one full year before pregnancy is considered, Flyckt said. This is to make ensure that the woman is taking lower dosages of anti-rejection medications, which suppress the immune system, she said. Then, the doctors will begin to implant the embryos, Flyckt said. (Because the fallopian tubes were not transplanted, the patient cannot get pregnant through sex.) Dr. Uma Perni, an OB-GYN specializing in high-risk pregnancies, said the team plans to deliver babies via cesarean section on any women who have undergone uterus transplants, because there are many unknowns about vaginal delivery with a transplanted uterus. It isn't clear exactly how a transplanted uterus would respond to normal signs of labor, and it's possible that the complex connections that were made during the transplant could be disrupted during labor, Perni said. Ultimately, it isn't clear how the patient's body would tolerate a vaginal delivery, she said. Perni added that the risk of a preterm delivery is a little higher in women who have undergone a uterus transplant, compared with the average woman. Because of this, the team will be closely monitoring the patient in her third trimester, she said. Ultimately, they hope they can get very close to 37 weeks, which is considered full term, before delivering the baby, she said.

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