Markus Gäbel

Livebirth after uterus transplantation

BACKGROUND Uterus transplantation is the first available treatment for absolute uterine infertility, which is caused by absence of the uterus or the presence of a non-functional uterus. Eleven human uterus transplantation attempts have been done worldwide but no livebirth has yet been reported. METHODS In 2013, a 35-year-old woman with congenital absence of the uterus (Rokitansky syndrome) underwent transplantation of the uterus in Sahlgrenska University Hospital, Gothenburg, Sweden. The uterus was donated from a living, 61-year-old, two-parous woman. In-vitro fertilisation treatment of the recipient and her partner had been done before transplantation, from which 11 embryos were cryopreserved. FINDINGS The recipient and the donor had essentially uneventful postoperative recoveries. The recipients first menstruation occurred 43 days after transplantation and she continued to menstruate at regular intervals of between 26 and 36 days (median 32 days). 1 year after transplantation, the recipient underwent her first single embryo transfer, which resulted in pregnancy. She was then given triple immunosuppression (tacrolimus, azathioprine, and corticosteroids), which was continued throughout pregnancy. She had three episodes of mild rejection, one of which occurred during pregnancy. These episodes were all reversed by corticosteroid treatment. Fetal growth parameters and blood flows of the uterine arteries and umbilical cord were normal throughout pregnancy. The patient was admitted with pre-eclampsia at 31 full weeks and 5 days, and 16 h later a caesarean section was done because of abnormal cardiotocography. A male baby with a normal birthweight for gestational age (1775 g) and with APGAR scores 9, 9, 10 was born. INTERPRETATION We describe the first livebirth after uterus transplantation. This report is a proof-of-concept for uterus transplantation as a treatment for uterine factor infertility. Furthermore, the results show the feasibility of live uterus donation, even from a postmenopausal donor. FUNDING Jane and Dan Olsson Foundation for Science.

A Randomized, Doubleblind, Placebo-Controlled, Study of Single-Dose Rituximab as Induction in Renal Transplantation

We performed a prospective, double blind, randomized, placebo-controlled multicenter study on the efficacy and safety of rituximab as induction therapy, together with tacrolimus, mycophenolate mofetil, and steroids. The primary endpoint was defined as acute rejection, graft loss, or death during the first 6 months. Secondary endpoints were creatinine clearance, incidence of infections, and incidence of rituximab-related adverse event. Results. We enrolled140 patients (44 living donor and 96 deceased donor), and of those, 68 rituximab and 68 placebo patients fulfilled the study. In all the patients receiving rituximab, there was a complete depletion of CD19/CD20 cells, whereas there was no change in the number of CD19/CD20 cells in the placebo group. There were 10 treatment failures in the rituximab group versus 14 in the placebo group (P=0.348). There were eight rejection episodes in the rituximab group versus 12 in the placebo group (P=0.317) Creatinine clearance was 66±22 mL/min in the study group and 67±23 mL/min in the placebo group. There was no difference in the number of bacterial infections, cytomegalovirus infections, and BK virus infections or fungal infections. Conclusion. We performed a placebo-controlled study of rituximab induction in renal transplantation. There was a tendency toward fewer and milder rejections during the first 6 months in the rituximab group. Although induction with one dose of rituximab induced a complete depletion B cells, there was no increase in the incidence of infectious complications or leukopenia and it seems safe, therefore, to conduct further studies on the use of rituximab in transplantation.

Fifteen years’ experience of intestinal and multivisceral transplantation in the Nordic countries

Abstract Objective. Intestinal and multivisceral transplantation have gained acceptance as treatment modalities for patients with: intestinal failure and life-threatening complications of parenteral nutrition (PN), rare cases of vascular abdominal catastrophes and selected cases of low-grade neoplastic tumors such as neuroendocrine pancreatic tumors and desmoids involving the mesenteric root. The aim was to describe the survival and nutritional outcome in the transplanted Nordic patients and the complications attributed to this procedure. Method. The authors included all Nordic patients transplanted between January 1998 and December 2013. Information on patients transplanted outside the Nordic region was collected through questionnaires. Results. A total of 34 patients received different types of intestinal allografts. Currently, there are two Nordic transplant centers (n = 29) performing these procedures (Gothenburg, Sweden n = 24, Helsinki, Finland n = 5). The remaining five patients were transplanted in the USA (n = 3) and the UK (n = 2). Most patients were transplanted for life-threatening failure of PN (70%) caused primarily by intestinal motility diseases (59%). Allograft rejection was the most common complication and occurred in 79% of the patients followed by post-transplantation lymphoproliferative disorders (21%) and graft-versus-host disease (18%). The 1- and 5-year survival was 79% and 65% respectively for the whole cohort and nutritional autonomy was achieved in 73% of the adults and 57% of the children at 1 year after transplantation. Conclusion. This collective Nordic experience confirms that intestinal transplantation is a complex procedure with many complications, yet with the possibility to provide long-term survival in selected conditions previously considered untreatable.

Survival of patients evaluated for intestinal and multivisceral transplantation – the Scandinavian experience

Abstract Objective. The current treatment of choice for patients with intestinal failure is parenteral nutrition, whereas medical therapy or resection is preferred for patients with neuroendocrine pancreatic tumors (NEPT) along with liver metastasis. As the survival of patients undergoing intestinal and multivisceral transplantation is improving, the discussion for expansion of treatment options has become a subject of debate. The aim was to investigate the outcome for patients referred for intestinal and multivisceral transplantation and to determine which patient group are the ones most likely to benefit the most from transplantation. Methods. The authors included all patients evaluated for intestinal and multivisceral transplantation at the Sahlgrenska University Hospital and The Queen Silvia Childrens Hospital center between February 1998 and November 2009. Patients were classified according to proposed treatment strategy, and the outcome was evaluated. Results. A total of 43 adults and 19 children with either intestinal failure or NEPT with liver metastases were evaluated for transplantation. Of these patients, 15 adults and 5 children were transplanted. Transplantation was lifesaving for most children – all the children survived after transplantation, but 70% (4/6) died while awaiting transplantation. Among the adult patients with intestinal failure, the survival rate for patients considered to be stable on parenteral nutrition was higher than the transplanted adult patients. The survival rate of patients with NEPT was similar to the results seen among patients transplanted for intestinal failure. Conclusion. The results confirm the poor prognosis of patients with intestinal failure awaiting transplantation and indicate that different transplantation criteria may be applied for adults and children, especially when early transplantation is the preferred treatment. The role of multivisceral transplantation in patients with NEPT remains uncertain.

Chronic kidney disease--a common and serious complication after intestinal transplantation.

Background. Chronic kidney disease after organ transplantation is a serious complication that negatively impacts on long-term patient survival. We describe long-term renal function after intestinal transplantation by serial measurements of glomerular filtration rates (GFR) with 51Chromium EDTA clearance. Materials and Methods. Ten patients with at least 6 months survival form the basis of this report. Glomerular filtration rate measurements were performed at baseline, 3 months posttransplantation, and yearly thereafter. Median follow-up time for the cohort was 1.5 years (0.5–7.8 years). Tacrolimus (Prograf) was discontinued in four patients because of impaired renal function. These four patients were switched to sirolimus (Rapamune) at 11, 18, 24, and 40 months posttransplantation. Results. Median baseline GFR was 67 (22–114) mL/min/1.73 m2. In the adult patients, GFR 3 months posttransplantation had decreased to 50% of the baseline. At 1 year, median GFR in the adult patients was reduced by 72% (n=5). Two patients developed renal failure within the first year and required hemodialysis. One of the pediatric patients fully recovered her renal function, the second pediatric patient lost 20% of her baseline GFR at 6 months posttransplantation. Glomerular filtration rate calculated with the modified diet in renal disease formula consistently overestimated GFR by approximately 30% compared with measured GFR. Conclusion. Chronic kidney disease and renal failure are common after intestinal transplantation. These two factors significantly contribute to poor long-term survival rates. Measurements of GFR may help to identify those individuals at risk for developing chronic kidney disease to implement renal sparing strategies.

Outcome after liver transplantation for primary sclerosing cholangitis

PRIMARY SCLEROSING CHOLANGITS (PSC) is one of the major indications for liver transplantation in Scandinavia. During the period from 1985 to 1998, 419 liver transplantations were performed at our center. PSC patients received 17% of these grafts. PSC is predominantly a disease of men and is often associated with inflammatory bowel disease (approximately 70%). There is an increased risk of developing cholangiocellular carcinoma that significantly affects outcome. Medical and surgical therapies for PSC are limited, and the natural course of PSC is hard to predict but it has been established that carefully selected patients clearly benefit from OLT. After transplantation the possibility of recurrence of PSC has been debated. It has been argued that the pathological findings that suggest recurrence are indistinguishable from other events such as chronic rejection and bile duct damage due to poor arterial blood flow. The aim of this study was to (a) analyze the outcome of liver transplantations for primary sclerosing cholangitis at our center, (b) review vascular and biliary complications, and (c) identify possible recurrent disease.

Early function of liver grafts preserved with or without portal perfusion

THERE ARE two commonly employed techniques for harvesting of liver grafts regarding preservation. One is to infuse the preservation fluid in the aorta and portal vein, the other is to use only aortic perfusion. Including portal cannulation in the donor operation prolongs operation time and handling of the organs to be retrieved, which could be disadvantageous, especially in the unstable donor. This study was performed to determine if the choice of preservation technique influences early graft function and survival.

Evaluation of reference genes for gene expression studies in human brown adipose tissue.

Human brown adipose tissue (BAT) has during the last 5 year been subjected to an increasing research interest, due to its putative function as a target for future obesity treatments. The most commonly used method for molecular studies of human BAT is the quantitative polymerase chain reaction (qPCR). This method requires normalization to a reference gene (genes with uniform expression under different experimental conditions, e.g. similar expression levels between human BAT and WAT), but so far no evaluation of reference genes for human BAT has been performed. Two different microarray datasets with samples containing human BAT were used to search for genes with low variability in expression levels. Seven genes (FAM96B, GNB1, GNB2, HUWE1, PSMB2, RING1 and TPT1) identified by microarray analysis, and 8 commonly used reference genes (18S, B2M, GAPDH, LRP10, PPIA, RPLP0, UBC, and YWHAZ) were selected and further analyzed by quantitative PCR in both BAT containing perirenal adipose tissue and subcutaneous adipose tissue. Results were analyzed using 2 different algorithms (Normfinder and geNorm). Most of the commonly used reference genes displayed acceptably low variability (geNorm M-values <0.5) in the samples analyzed, but the novel reference genes identified by microarray displayed an even lower variability (M-values <0.25). Our data suggests that PSMB2, GNB2 and GNB1 are suitable novel reference genes for qPCR analysis of human BAT and we recommend that they are included in future gene expression studies of human BAT.

Early outcome of liver transplantation using donors over 60 years of age.

PATIENTS AND METHODSRecipientsWe received 12 patients (five female, seven male) who underwentliver transplantation between 1996 and 1997, and who receivedliver grafts from donors . 60 years of age (Table 1). The studygroup was matched to a control group where all patients receivedliver grafts from donors , 50 years of age. The two groups werematched for recipient age, gender, etiology of end-stage liverdisease, Child grade, and UNOS status.DonorsAll the donors were hemodynamically stable and had normal liverfunction tests (ALT, bilirubin, and PT) at time of harvesting. Aliver biopsy was performed after reperfusion in all cases. All livergrafts were perfused with UW solution.Study VariablesCold ischemia time was recorded. Liver biopsies were analyzed forfatty content and ischemic signs. We compared posttransplant liverfunctions tests, ALT, bilirubin, and PT, from days 1 to 21. We alsorecorded duration of the ICU stay, blood transfusions in ICU, andrejection episodes. The follow-up time was 3 months. Pared datawere analyzed using the Wicoxon signed rank test.RESULTS

Live birth after uterus transplantation

ABSTRACTIn the 3 decades since the birth of the first in vitro fertilization baby in 1978, there have been remarkable advances in infertility treatment. Until now, however, absolute uterine factor infertility remained the only major type of female infertility viewed as untreatable. Absolute uterine