Neutrophils and lymphoid chimerism after adult living-related liver transplantation from a homozygous donor

Chimerism and graft-versus-host disease (GVHD) pose significant risks to liver transplant patients. The risk of chimerism and GVHD is higher among cases of living-related liver transplant (LRLT). Donors homozygous at all HLA loci carry a higher risk for GVHD. Herein we present a case of LRLT. The recipient suffered from end-stage liver disease and received a right lobe graft from his son. After 8 months posttransplant, the patient developed profound bone marrow depression. The patient was negative for CMV, Brucella, HHV6, HHV8, HBV, HCV, and parvovirus. No skin or GI signs of GVHD were noted. The patient and donor were HLA typed by SSP. The donor was homozygous for all HLA loci while the patient shared the class II homozygosity and was class I heterozygous. Chimerism studies were prompted after noting that the neutrophil compartment of the patient was homozygous for all HLA loci. This initiated further studies of the PMN and lymphocytes by microsatellite analysis. A total 15 microsatellites were analyzed. The results suggest that the majority (75%) of the PMNs and 45% of the lymphocytes were of donor origin. The patient was treated with G-CSF; his WBC counts returned to normal. At 2.5 years posttransplant the patient had not developed GVHD, despite the large number of donor lymphocytes circulating in his bloodstream. The only complaint he had was severe arthritis, which was treated with steroids. It must be investigated whether this was the result of GVHD.     

Lack of donor hyporesponsiveness and donor chimerism after clinical transplantation of the hand

BACKGROUND: Composite tissue allografts offer great potential in reconstructive surgery. However, the risks of immunosuppression and graft-versus-host disease (GVHD) after transplantation of vascularized bone in these grafts are significant. Transplantation of vascularized bone also may confer donor hematopoietic chimerism and, potentially, tolerance. We have followed two hand transplant recipients for more than 1 year to determine the level of chimerism and possible donor-specific tolerance, in addition to possible GVHD. METHODS: We performed kinetic studies on peripheral blood of two subjects after hand transplantation that included portions of the radius and ulna. We evaluated donor-specific reactivity, chimerism, and antibody production. RESULTS: Donor-specific tolerance did not develop clinically or in mixed lymphocyte reaction. The first subject recovered an excellent in vitro response to phytohemagglutinin, donor and third-party alloantigen, and by month 4 and at month 12 also recovered the ability to respond to Epstein-Barr virus. The second subject also demonstrated good in vitro proliferative responses, which were attenuated by immunosuppression. No phenotypic changes in mature hematopoietic lineages were detected by four-color flow cytometry other than those expected in response to immunosuppression. Donor chimerism was not detectable using four-color flow cytometry. Microchimerism (approximately 1:75,000 cells) was observed at the level of detection in some of the early posttransplantation specimens and was undetectable thereafter. CONCLUSIONS: In this particular transplantation and immunosuppressive regimen, the composite tissue allograft with vascularized bone marrow did not provide the immunologic benefit of tolerance induction nor cause GVHD.     

肝移植术后急性粒细胞缺乏的治疗

急性粒细胞缺乏是肝移植术后的严重并发症,中山大学附属一院发生3例严重的肝移植急性粒细胞缺乏症病人,现报告如下.     

Hepatopulmonary syndrome after living donor liver transplantation and deceased donor liver transplantation: a single-center experience.

Hepatopulmonary syndrome (HPS) is a progressive, debilitating complication of end-stage liver disease. In contrast to the well-established reversal of HPS after deceased donor liver transplantation (DDLT), little has been written about the natural course of HPS after the newer procedure of living donor liver transplantation (LDLT). We describe HPS in a small series of 4 liver transplant recipients (2 DDLT; 2 LDLT) at a single center. Before transplantation, these 4 patients had a mean shunt fraction of 23.6 +/- 14.3% and a mean PaO2 of 58.5 +/- 11.3 mm Hg. All 4 patients used supplemental oxygen before transplantation. Sixteen weeks after transplantation, all 4 patients had normalized or improved shunt fraction and PaO2. These patients regained normal pulmonary function within a few months, despite the period of hepatic regeneration after LDLT. In conclusion, both DDLT and LDLT are associated with rapid and dramatic reversal of HPS.     

Biliary complications after living donor adult liver transplantation.

The highest rate of complications characterizing the adult living donor liver transplantation (ALDLT) are due to biliary problems with a reported negative incidence of 22-64%. We performed 23 ALDLT grafting segments V-VIII without the middle hepatic vein from March 2001 to September 2005. Biliary anatomy was investigated using intraoperative cholangiography alone in the first five cases and magnetic resonance cholangiography in the remaining 18 cases. In 13 cases we found a single right biliary duct (56.5%) and in 10 we found multiple biliary ducts (43.7%). We performed single biliary anastomosis in 17 cases (73.91%) and double anastomosis in the remaining six (26%) cases. With a mean follow up of 644 days (8-1598 days), patient and graft survivals are 86.95% and 78.26%, respectively. The following biliary complications were observed: biliary leak from the cutting surface: three, anastomotic leak: two, late anastomotic strictures: five, early kinking of the choledochus: one. These 11 biliary complications (47.82%) occurred in eight patients (34.78%). Three of these patients developed two consecutive and different biliary complications. Biliary complications affected our series of ALDLT with a high percentage, but none of the grafts transplanted was lost because of biliary problems. Multiple biliary reconstructions are strongly related with a high risk of complication.     

Live donor liver transplantation.

With ever-increasing demand for liver replacement, supply of organs is the limiting factor and a significant number of patients die while waiting. Live donor liver transplantation has emerged as an important option for many patients, particularly small pediatric patients and those adults that are disadvantaged by the current deceased donor allocation system. Ideally there would be no need to subject perfectly healthy people in the prime of their lives to a potentially life-threatening operation to procure transplantable organs. Donor safety is imperative and cannot be compromised regardless of the implication for the intended recipient. The evolution of split liver transplantation is the basis upon which live donor transplantation has become possible. The live donor procedures are considerably more complex than whole organ decreased donor transplantation and there are unique considerations involved in the assessment of any specific recipient and donor. Donor selection and evaluation have become highly specialized. The critical issue of size matching is determined by both the actual size of the donor graft and the recipient as well as the degree of recipient portal hypertension. The outcomes after live donor liver transplantation have been at least comparable to those of deceased donor transplantation. Nevertheless, all efforts should be made to improve deceased donor donation so as to minimize the need for live donors. Transplant physicians, particularly surgeons, must take responsibility for regulating and overseeing these procedures.     

Renal impairment after living donor liver transplantation

BACKGROUND: There are few reports of postoperative renal impairment after living donor liver transplantation (LDLT). METHODS: We reviewed 246 LDLT recipients to examine the effects of postoperative renal impairment on the results of LDLT. RESULTS: The incidence of renal impairment and the requirements for postoperative renal replacement therapy were 29% and 9%, respectively. Intraoperative blood loss (P<.0001) and preoperative serum creatinine (P=.0002) were significant independent risk factors for the development of early renal dysfunction. Patients who required renal replacement therapy had a lower survival rate (P=.01). CONCLUSIONS: We identified the risk factors for postoperative renal impairment, providing useful metrics to establish a treatment strategy for high risk liver transplant patients.     

Mycophenolate mofetil-induced neutropenia in liver transplantation

BACKGROUND: Mycophenolate mofetil (MMF) is a potent, safe immunosuppressive agent for rescue therapy of acute and chronic rejection in orthotopic liver transplant recipients. It helps to reduce the serious toxic side effects of calcineurin inhibitors (CNIs). The side effects of MMF, such as bone marrow toxicity, have been reported. Herein we report four patients who underwent liver transplantation and developed neutropenia while receiving MMF. METHODS: Between April 2002 and October 2003, we performed 24 liver transplants in 25 patients. Eighteen patients were given MMF for the following reasons: renal failure in nine (50%); treatment of acute rejection in three (16.6%); primary prophylaxis of rejection in five (27.7%); and CNI withdrawal in one (5.5%). RESULTS: Of the 18 patients treated with MMF, there were 11 men (61.1%) and seven women (38.8%), with an overall mean age of 55.5 years. This therapy was ceased in four patients due to neutropenia (22%). Discontinuation of MMF was followed by a rapid and spontaneous rise in neutrophils in two patients. Granulocyte colony stimulating factor (GCSF) was administered to one patient and in another a bone marrow biopsy was performed due to persistent anemia, leukopenia, and thrombocytopenia. The mean time from starting MMF to the development of neutropenia was 4 months. Only the third patient showed elevated levels of MMF. CONCLUSIONS: MMF is a potent immunosuppressive agent in liver transplantation. However, because serious hematologic toxicity has been reported, we recommend caution in administration and careful monitoring of blood levels.     

Early immunosuppression withdrawal after living donor liver transplantation and donor stem cell infusion.

Long-term results of organ transplantation are still limited by serious side effects of immunosuppressive drugs. A major issue, therefore, is to elaborate novel therapeutic protocols allowing withdrawal or minimization of immunosuppressive therapy after transplantation. We report on 3 patients prospectively enrolled in an original protocol designed to promote graft acceptance in living donor liver transplantation, using posttransplant conditioning with high doses of antithymocyte globulin followed by injection of donor-derived stem cells. In 2 patients, early immunosuppression withdrawal was possible, without subsequent graft deterioration. In these 2 cases, in vitro studies showed indices of immunological tolerance as assessed by specific hyporesponsiveness to donor alloantigens in mixed lymphocytes culture. In the third patient, acute rejection rapidly occurred after discontinuation of immunosuppression, and minimal immunosuppression has to be maintained during long-term follow-up. In this case, a clearly distinct immunoreactive profile was observed as compared to tolerant patients, as no specific modulation of the antidonor response was observed in vitro. Of note, no macrochimerism could be detected in any of the 3 patients during the follow-up. In conclusion, these clinical observations demonstrated that, despite the absence of macrochimerism, donor stem cells infusion combined with recipient conditioning may allow early immunosuppression withdrawal or minimization after liver transplantation.     

Salvage living donor liver transplantation after prior liver resection for hepatocellular carcinoma.

Salvage liver transplantation has been performed for recurrent hepatocellular carcinoma (HCC) or deterioration of liver function after primary liver resection. Because prior liver resection per se is an unfavorable condition for living donor liver transplantation (LDLT), we assessed the technical feasibility of LDLT after prior hepatectomy, and we compared the outcome of salvage LDLT with that of primary LDLT in HCC patients. Of 342 patients with HCC, 17 (5%) underwent salvage LDLT, with 5 having undergone prior major liver resection and 12 prior minor resection. During salvage LDLT, 12 patients received right lobe grafts, 3 received left lobe grafts, and 2 received dual grafts. There was 1 incident (5.9%) of perioperative mortality. Recipient operation time was not prolonged in patients undergoing salvage LDLT, but bleeding complications occurred more frequently than in patients undergoing primary LDLT. Overall survival rates after salvage LDLT were similar to those after primary LDLT, especially when the extent of recurrent tumor was within the Milan criteria. These results indicate that every combination of prior hepatectomy and living donor liver graft is feasible for patients undergoing salvage LDLT, and the acceptable extent of HCC for salvage LDLT is equivalent to that for primary LDLT.     

Management of subcapsular hematoma of the graft after living donor liver transplantation.

Subcapsular hematoma of the graft is a serious complication of liver transplantation (LT), and there has been no discussion in the literature about optimal management except in sporadic case reports. The aim of this work is to review our experience of subcapsular hematoma in living donor liver transplantation (LDLT) and to introduce our management strategy. Among the 818 cases of adult-to-adult LDLT between February 1997 and November 2005, there have been 4 cases of subcapsular hematoma. Two of these developed after percutaneous liver biopsy and the other 2 developed after percutaneous transhepatic biliary drainage (PTBD). Two developed immediately after the procedure, whereas the other 2 developed 8 and 12 days after the procedure, respectively, due to rupture of a pseudoaneurysm. Our management strategy was as follows; after performing dynamic computed tomography for initial diagnosis, these 3 steps were taken: 1) hepatic arteriography and selective embolization of bleeding focus; 2) pigtail catheter drainage (PCD) of subcapsular hematoma; and 3) hepatic vein stenting if there was a sign of outflow disturbance due to compression by a large hematoma. All 4 of our patients recovered from the insult of subcapsular hematoma. In conclusion, our results indicate that patients who develop subcapsular hematoma after LDLT can be treated nonsurgically.     

Hemophagocytic syndrome after adult-to-adult living donor liver transplantation

Hemophagocytic syndrome is a fatal complication after liver transplantation that is rarely reported. Among 260 adult patients who underwent living donor liver transplantation at our hospital, three cases (1%) were complicated with hemophagocytic syndrome. Intensive investigation revealed Aspergillus, cytomegalovirus, and hepatitis C virus as the most likely causative organisms in each patient. Despite the immediate initiation of anti-infectious treatment and supportive care, all patients died. When pancytopenia with possible underlying infectious disease is observed in liver transplant recipients, hemophagocytic syndrome should be suspected and bone marrow biopsy considered. The prognosis of hemophagocytic syndrome remains poor and further investigations are required to establish effective therapeutic options.     

改进供肝处理方法减少肝移植术后早期胆道并发症

目的改进供肝处理方法，以减少肝移植术后的胆道并发症。方法供肝处理进行如下改进：（1）肝门游离仅达胃十二指肠动脉下缘，不游离其上方的肝蒂结构；（2）修整供肝时暂不结扎胃十二指肠动脉本身的断端；（3）修整供肝时暂不切除胆囊，待供肝植入、肝动脉重建后切除。共行99例肝移植，患者的原发病，58％为良性肝病，42％为肝癌。供肝热缺血和冷缺血时间分别控制在5min和16h以内。胆道重建方式均为胆总管-胆总管端端吻合，其中5例放置T管。观察术后早期胆道并发症的发生情况。结果4例（4％，4／99）肝移植术后发生胆道并发症，其中1例术后10d发现胆道吻合口漏；1例术后5个月胆道内有胆树形成；1例为胆道吻合口狭窄；1例为左肝管狭窄。改进前的肝移植术后早期胆道并发症发生率为11．6％（5／43）。结论通过改进供肝的处理方法，可最大限度地保留供肝胆道血液供应，显著减少术后胆道并发症。     

Central pontine myelinolysis after living donor liver transplantation

Central pontine myelinolysis (CPM) is the most serious central nervous system complication that could be seen after liver transplantation and represents an important source of mortality early after liver transplantation. CPM following liver transplantation was reported more and more in literatures, but the true incidence of CPM after living related liver transplantation (LDLT) remains unknown. However, with the introduction of magnetic resonance imaging (MRI), early recognition has become possible. In this report, we present a case of rapid resolution of CPM followed by MRI examinations.