Clinical significance of posttransplantation vesicoureteral reflux during short-term period after kidney transplantation.

BACKGROUND: Urinary tract infection (UTI) may occur in the form of asymptomatic bacteruria but severe cases may cause life-threatening pyelonephritis or sepsis in immunosuppressed kidney transplant recipients. Vesicoureteral reflux (VUR) is one risk factor in the transplanted kidney. But controversy exists regarding the effect of VUR in terms of graft outcomes. The objective of this study was to analyze the clinical outcomes among patients with posttransplantation VUR. PATIENTS AND METHODS: Between April 2005 and June 2006, we examined 75 patients with functioning grafts for more than 1 year by voiding cystourethrography at 1 year for the grade of posttransplantation VUR: group A, absent (n = 28) including grade I (n = 6) and II (n = 22); group B, including grade III (n = 17) and IV (n = 2). Patient characteristics included etiology of end-stage renal disease, duration of dialysis before transplantation, serum creatinine, creatinine clearance at 1 and 12 months after transplantation, and postoperative complications. The presence/absence of UTI, acute rejection, and graft loss were compared for significance. RESULT: Posttransplantation VUR present in 47/75 patients (61.3%) was over grade III in 19 patients. There was no difference in significant risk factors between the groups as well as between the reflux subgroups. VUR did not influence graft function with the only significant factor being acute cellular rejection. CONCLUSION: We failed to confirm a risk of developing posttransplantation VUR. Posttransplantation VUR did not negatively affect graft function; acute cellular rejection was the only factor that influenced it. Longer follow-up needs to be performed to clarify the long-term effects of posttransplantation VUR on graft function.

Renal transplantation in patients with a small bladder.

BACKGROUND: In patients undergoing kidney transplantation with a small bladder, many surgeons are faced with technical difficulties about the implantation as well as about satisfactory bladder rehabilitation. The objective of this study was to clarify the clinical outcomes of patients with end-stage renal disease who had a bladder capacity of less than 100 mL on preoperative voiding cystourethrogram after renal transplantation using extravesical ureteroneocystostomy. PATIENTS AND METHODS: We retrospectively studied 345 patients with end-stage renal disease who underwent renal transplantation between April 2002 and June 2006. These patients were classified into two groups according to their preoperatively estimated bladder capacity using a voiding cystourethrogram. Group A had a bladder capacity of less than 100 mL (n = 23; 6.7%) and group B had a capacity of 100 mL or more (n = 322; 93.3%). For each group, the clinical outcome, including serum creatinine level at 1 month and 1 year after transplantation, bladder capacity, surgical complications, and prevalence of urinary tract infection (UTI) requiring hospital admission were recorded and the graft survival rate calculated. RESULTS: Compared with group B, group A had undergone a longer duration of dialysis and required cadaveric kidney transplantation more frequently (P < .05). Postoperative surgical complications occurred in nine cases. There was no difference in the frequency of surgical complications and UTI requiring hospital admission between group A and group B. At 1 year posttransplant, bladder capacity was 342.0 +/- 43.8 mL (range, 300-400 mL) and 429.1 +/- 75.9 mL (range, 200-500 mL), respectively (P = .015). There was no statistical difference between the groups in the serum creatinine level and the graft survival rate at 5 years after transplantation (100% vs 92.4%). CONCLUSIONS: Similar to patients with a normal bladder size, renal transplantation can be successfully achieved in patients with a small bladder. Attempts to increase the bladder capacity by programmed training of the bladder and bladder expansion by surgical intervention seem unnecessary.

Reconstitution of human lymphocytes following ex vivo expansion of human umbilical cord blood CD34+ cells and transplantation in Rag2-/- gamma c-/- mice model.

BACKGROUND: Due to ethical issues, in vivo studies of the human immune system have been difficult. Thus, small-animal xenotransplantation models have been employed, although they scarcely sustain a human immune response. In this study, we compared human cell repopulation tendencies and functionality in Rag2-/- gamma c-/- mice following various ex vivo expanded human hematopoietic stem cells (HSCs). METHODS: Human umbilical cord blood (UCB) CD34+ cells were cultured for 7 days with a cytokine combination of stem cell factor, Flk2/Flt3 ligand, and thrombopoietin, with absence or presence of rhIL-3, then transplanted into Rag2-/- gamma c-/- mice. Reconstituted human lymphocytes were analyzed based on the expression of CD45 as well as CD3, CD19, and CD56 in peripheral blood (PB) until 16 weeks after transplantation. BrdU assay and functional analysis of reconstituted human lymphocytes used PHA- or rhIL-2-stimulated splenocytes and bone marrow cells from recipient mice. RESULTS: The percentage of human CD45dim cells, not CD45bright cells, in PB of mice transplanted with cultured HSCs with rhIL-3 was much higher than in the group without rhIL-3 (approximately 2.5-fold at week 10 posttransplantation). The humanized mice showed systemic repopulation with a comprehensive array of human lymphohematopoietic cells, including T, B, natural killer (NK) cells, and even dendritic cells. However, the expression level was also dim. The number of CD3+ T cells and CD56+ NK cells was especially increased in the presence of rhIL-3. In addition, after in vitro restimulation proliferation assays and NK activity of interferon-gamma secretion showed greater effects in the presence of rhIL-3. CONCLUSION: These data suggested that the development of a diverse repopulation of human lymphocytes was possible in Rag2-/- gamma c-/- mice after transplantation of cultured UCB CD34+ HSCs with interleukin-3.

Primary versus salvage living donor liver transplantation for patients with hepatocellular carcinoma: impact of microvascular invasion on survival.

OBJECTIVE: Salvage liver transplantation (LT) has been proposed for patients with a small hepatocellular carcinoma (HCC) and preserved liver function. Few reports have been issued on salvage LT in a living-donor (LD) LT setting. Therefore, we performed this study to evaluate differences in tumor invasiveness and other risk factors on survival after salvage versus primary LDLT. METHODS: Between September 1996 and December 2008, 324 patients with HCC underwent LT. We excluded 138 patient from the analysis, leaving 186 HCC patients for analysis, including 17 (9.1%) who had undergone earlier resection, the salvage LDLT cohort. The other 169 patients underwent primary LDLT. RESULTS: Intrahepatic metastasis, Edmonson-Steiner histologic grade, microscopic vascular invasion, and preoperative serum alpha-fetoprotein levels significantly influenced tumor recurrence. Microscopic vascular invasion, intrahepatic metastasis, Edmonson-Steiner histologic grade, and treatment by salvage LDLT were significantly associated with poor patient survival univariate analysis. However, only microscopic vascular invasion was significant on multivariate analysis. The treatment modality (primary or salvage LDLT) was not observed to affect overall or disease-free survival significantly on multivariate analysis. Disease-free survival was significantly better in the primary than in the salvage LDLT group. Furthermore, patients in the primary LDLT group tended to show better survival. However, when stratified by the presence or absence of microscopic vascular invasion, no significant group difference was found for overall or disease-free survival among those without versus with microscopic vascular invasion. CONCLUSIONS: Five-year overall survival after primary versus salvage LDLT were similar when differences in tumor pathologic features, such as microscopic vascular invasion, were taken into account. Multivariate analysis showed that the treatment itself was not a significant prognostic factor for survival.

Can preemptive kidney transplantation guarantee longer graft survival in living-donor kidney transplantation? Single-center study.

INTRODUCTION: The benefit of preemptive kidney transplantation (KTx) for graft survival compared with nonpreemptive KTx is controversial. OBJECTIVE: To analyze the influence of preemptive KTx on graft survival. PATIENTS AND METHODS: The study included 476 of 531 patients who had undergone living-donor KTx between January 2000 and June 2007. Pediatric patients and those who had previously undergone KTx were excluded. Recipients were divided into 2 groups; group 1 included 413 patients (86.8%) who received grafts after institution of maintenance dialysis, and group 2 included 63 patients (13.2%) who underwent preemptive KTx. RESULTS: Donor type and HLA mismatch demonstrated significant differences between the 2 groups. Group 1 had more living donors and fewer HLA mismatches. Warm ischemia time in group 2 was significantly shorter than in group 1. The serum creatinine concentration in group 1 on postoperative day 7 was significantly higher than in group 2. Five- and 10-year graft survival in groups 1 and 2, respectively, were 95.3% and 81.3% vs 92.9% and 92.9%. Graft survival was not significant insofar as duration and method of dialysis. At our institution, independent risk factors for graft survival in living-donor KTx are primary end-stage renal disease, acute cellular rejection episodes, and recipient age. CONCLUSION: We observed no benefit on graft survival in recipients of living-donor KTx insofar as whether they had undergone previous dialysis.

The risk factors of delayed graft function and comparison of clinical outcomes after deceased donor kidney transplantation: single-center study.

INTRODUCTION: The aim of this study was to analyze risk factors for delayed graft function (DGF) after deceased donor kidney transplantation and to compare the clinical outcomes of non-DGF versus DGF recipients. PATIENTS AND METHODS: From January 2004 to June 2008, 75/154 kidneys were transplanted into 74 recipients. We classified the recipients into two groups: group 1 (n=61) without DGF and group 2 (n=13) with DGF. RESULTS: On univariate analysis, recipient age (P=.048) cause of brain death (traumatic brain injury vs disease, P=.016), blood urea nitrogen (P=.002), serum creatinine (P=.001), arterial pH (P=.019), and serum sodium level (P=.012) just before organ procurement showed significant differences. On multivariate analysis, the cause of brain death (P=.015, hazard ratio [HR]: 7.086), the terminal serum creatinine>or=1.5 mg/dL before organ procurement (P=.007, HR: 10.132), and recipient age over >or=50 years (P=.021, HR: 7.767) were independent risk factors for the development of DGF. Graft failures occurred among 5/74 recipients with 5-year graft survivals between group 1 and group 2 of 91.7% and 84.6%, respectively. Patient death occurred in five cases, most by due to infection. The 5-year patient survival between groups 1 and 2 were 93.9% and 84.6%, respectively (P = .106). CONCLUSION: The independent risk factors for DGF were the cause of brain death, the terminal creatinine level, and the recipient age. In deceased donor kidney transplantation, DGF may have less effect on long-term patient and graft survivals.

The effect of cytomegalovirus antigenemia titer on the efficacy of preemptive therapy for the prevention of cytomegalovirus disease after kidney transplantation.

There is some controversy regarding the exact cytomegalovirus (CMV) antigenemia titer that should be used as a guideline for preemptive anti-CMV therapy. We performed 634 consecutive kidney transplantations between January 2000 and June 2007. Preemptive therapy employed intravenous gancyclovir treatment when the CMV antigenemia titer was >or=50/4x10(5) leukocytes after kidney transplantation. The 634 recipients were allocated into 2 groups according to the peak CMV antegenemia: group A, CMV antigenemia titer<50/4x10(5) (n=550); and group B, >or=50/40x10(5) (n=84). Among the 634 recipients, 264 were positive for CMV antigenemia, and 61 developed symptomatic CMV infections. The incidence of symptomatic CMV infections in group B was significantly higher than in group A. Two cases in both groups developed tissue-proven CMV disease: group A CMV colitis and CMV nephritis, and group B, 2 cases of CMV colitis. Graft and patient survival rates in groups A and B at 5 years posttransplantation were not different. The authors concluded that a CMV antigenemia titer of >or=50/4x10(5) leukocytes can be considered an appropriate guideline for preemptive anti-CMV therapy.

Patients with unresectable hepatocellular carcinoma beyond Milan criteria: should we perform transarterial chemoembolization or liver transplantation?

Patients with unresectable, beyond Milan criteria, hepatocellular carcinoma (HCC) invariably undergo palliative transarterial chemoembolization (TACE). The aim of this study was to compare the outcomes of conventional TACE versus liver transplantation (LT) in unresectable (beyond Milan criteria) HCC. Twelve patients underwent LT and 86 TACE for unresectable, beyond Milan criteria HCC. The inclusion criteria were a single tumor60 years, vascular invasion, or extrahepatic spread. Survival rates were calculated using the Kaplan-Meier method. Multivariate analysis showed that TACE was a prognostic factor for survival (hazard ratio, 16.66, P=.000). The LT group showed significantly better survival than the TACE cohort. Two cases (16.7%) in the LT group recurred at a median time of 13.5 months. Survival rates at 1, 3, and 5 years were 100%, 88.9%, and 76.2% in the LT group, and 85.6%, 45.6%, and 21.4% in the TACE group, respectively. Patients with unresectable, beyond Milan criteria HCC should be given the option to receive LDLT, because LT offers a significantly better likelihood of survival than TACE.

Preemptive therapy in adult liver transplant recipients in CMV-endemic area.

Cytomegalovirus (CMV) infection is not only a common complication after liver transplantation but also a significant contributing factor to morbidity and mortality. We investigated whether preemptive therapy can prevent CMV syndrome or tissue-invasive CMV disease in an endemic area. Preemptive therapy was initiated when more than 10 positive CMV pp65 antigen-positive cells per 400,000 white blood cells were detected, regardless of clinical manifestations. Intravenous ganciclovir as preemptive therapy was administered daily for 10 to 14 days until negative results were achieved. The incidence of initial CMV antigenemia and CMV syndrome during the posttransplantation period was 49.7% (353/710) and 5.2% (37/710), respectively. One hundred eight-two patients (51.6%) received ganciclovir as preemptive therapy. Patients with CMV antigenemia who received preemptive therapy had high Model for End-Stage Liver Disease score, repeat operation, renal dysfunction, infection, low hemoglobin concentration, low platelet count, low albumin concentration, high international normalized ratio, high total bilirubin value, high aspartate transaminase concentration, and high CMV peak titer. Cytomegalovirus syndrome and tissue-invasive CMV disease were more common in these patients. The survival curve in patients without CMV syndrome was better than that in those with CMV syndrome (P=.000). Patients with more than 10 pp65 antigen-positive cells per 400,000 white blood cells should be treated aggressively with an antiviral agent as preemptive therapy because CMV infection is common in CMV-endemic areas and patients with CMV syndrome demonstrate poor survival rates.

Living donor liver transplantation in Budd-Chiari syndrome: a single-center experience.

Budd-Chiari syndrome (BCS), which is characterized by hepatic venous outflow obstruction due to occlusion of the major hepatic vein and/or the inferior vena cava (IVC), is rare. Traditionally, a caval resection is advocated for these patients; however, such a maneuver renders living donor liver transplantation (LDLT) impossible. We encountered BCS in 4/377 LDLT patients during a 5-year period (January 2003 to December 2007). This report examine the various surgical modifications in these 4 patients, who underwent to LDLT for BCS. Resection of right hepatic vein (RHV) with an adjacent fibrotic part of the IVC with direct anastomosis of the graft RHV to the IVC was performed in 2 patients. One patient underwent retrohepatic IVC excision and reconstruction with a cryopreserved autologous IVC graft. The fourth patient, with a preexisting mesoatrial shunt for BCS, underwent conversion of this to a RHV atrial shunt. Graft and patient survivals were 100%. There were few complications in either donors or recipients. LDLT for BCS can be performed safely with adequate venous drainage techniques and with anticoagulant therapy and good follow-up for early diagnosis and treatment of recurrence leading to excellent long-term results.

Risk factors for portal vein complications after pediatric living donor liver transplantation with left-sided grafts.

PURPOSE: Portal vein complications (PVC) after pediatric living donor liver transplantation (LDLT) have rarely been reported. We evaluated the long-term incidence and of the risk factors for PVC after pediatric LDLT. METHODS: From April 1997 to November 2008, 96 pediatric patients underwent LDLT using left lateral segments or left lobes. We investigated recipient factors, donor factors, and operative factors through medical records. The portal vein sizes in 96 recipients ranged from 2.7 mm to 13.0 mm (median=5.0 mm). Portal vein reconstruction was usually performed with the graft portal vein anastomosed to the bifurcation of the recipient right and left portal veins, the so-called "branch patch". RESULTS: PVC occurred in 11 patients (11.5%) including early PVC (n=3), late PVC (n=8). The disease-free survivals at 1, 5, and 10 years after LDLT were 94.7%, 88.7%, and 86.0%. Upon univariate analysis, a portal vein size<5 mm graft-to-recipient weight ratio (GRWR)>or=4%, transfusion volume>or=270 mL were significant risk factors for PVC. Body weight<8 kg and previous operative history tendes to be adverse for PVC. Upon multivariate analysis by Cox regression, portal vein size<5 mm was a highly significant factor for PVC after pediatric LDLT (hazard ratio=5.627, P=.027). CONCLUSION: The disease-free survival at 10 years after LDLT was 86.0%. If the recipient's portal vein size<5 mm received a large-for-size graft (GRWR>or=4%), it is important to observe by regular Doppler ultrasonography follow-up to detect PVC.

Early and delayed onset cytomegalovirus infection of liver transplant recipients in endemic areas.

BACKGROUND: The delayed onset of cytomegalovirus (CMV) infection after liver transplantation can place patients at risk for graft failure and mortality. METHODS: We compared early versus delayed onset of CMV infection to identify risk factors for mortality among liver transplant recipients in an endemic area. RESULTS: Among 710 consecutive adult liver transplant recipients, incidence of CMV infection was 47.5% (337/710). Male gender, biliary complications, acute rejection episodes, antilymphocyte antibodies high hemoglobin, and high total bilirubin were significantly different among patients with delayed versus early onset CMV infections. The overall incidence of early versus delayed CMV infections was 43.1% (306/710) versus 4.4% (31/710). Among them, 11.1% (34/306) and 25.8% (8/31) of patients developed CMV disease. CONCLUSION: These results showed that a higher proportion of patients developed disease among delayed CMV infected patients (P=.039). The overall and graft survival curves for patients with early onset CMV infections were better than those of patients who had delayed onset CMV infections (P=.026 and P=.014). Recurrence of hepatitis B virus, hepatic dysfunction, and retransplantation were associated with increased mortality among patients who had a delayed CMV infection.

Risk factors for posttransplant lymphoproliferative disorder in pediatric liver transplant recipients with cytomegalovirus antigenemia.

Epstein-Barr virus (EBV) infections, associated with posttransplant lymphoproliferative disorder (PTLD) are known to develop in cytomegalovirus (CMV)-infected transplant recipients due to the indirect effects of CMV. This study evaluated risk factors for PTLD among pediatric liver transplant recipients with CMV infections. We reviewed the medical records of 119 patients

The risk factors for cytomegalovirus syndrome and tissue-invasive cytomegalovirus disease in liver transplant recipients who have cytomegalovirus antigenemia.

Cytomegalovirus (CMV) infection is not only a common complication after liver transplantation (OLT), but also a significant contributing factor to morbidity and mortality. We investigated risk factors for CMV syndrome and tissue-invasive CMV disease in CMV antigenemia patients after OLT in a CMV endemic area. CMV antigenemia was regarded to be >1 positive CMV pp65 antigen positive cell per 400,000 white blood cells. We examined the epidemiology, clinical characteristics, and laboratory findings of liver transplant patients with CMV syndrome and tissue-invasive CMV disease. The incidence of CMV syndrome among patients with CMV antigenemia was 10.5% (37/353) and that of tissue-invasive CMV disease, 3.1% (11/353). Upon multivariate analysis the risk factors for CMV syndrome and tissue-invasive CMV disease were infection, low albumin level, high total bilirubin content, and high CMV peak titer. The 1-y, 2-y, and 3-year survival rates of subjects without CMV syndrome were 96.2%, 85.4% and 82.2% versus without tissue-invasive CMV disease, 86.9%, 83.0%, and 80.1%, or 70.3%, 56.1% and 51.8% for CMV syndrome or 72.7%, 62.3%, 49.9% for tissue-invasive CMV disease. The survival curve of patients without were superior to those with CMV syndrome (P=.000). Because OLT recipients had risk factors such as infection, low albumin level, high total bilirubin content, and high CMV peak titer, they were carefully monitored and aggressively managed due to the poor survivals of patients with CMV syndrome.

Development of functional human immune system with the transplantations of human fetal liver/thymus tissues and expanded hematopoietic stem cells in RAG2-/-gamma(c)-/- MICE.

BACKGROUND: There is an increasing need for suitable animal models for the study of the human immune system and disease. The purpose of this study was to develop a practical in vivo model of human immune cell repopulation using ex vivo expanded human fetal liver-derived CD34(+) hematopoietic stem cells and subrenally coimplanted fetal liver/thymus tissues. METHODS: Freshly isolated fetal liver-derived CD34(+) hematopoietic stem cells were frozen until injected and ex vivo expanded with various cytokines for 7 days. After fetal liver/thymus tissues were subrenally coimplanted into preirradiated Rag2(-/-)gamma(c)(-/-) mice, frozen and ex vivo expanded CD34(+) cells were injected intravenously. The peripheral blood of the mice was monitored for the detection of human cell engraftment using flow cytometry. Then we confirmed human T-cell function by in vitro function assays. RESULTS: After fetal liver/thymus tissues were coimplanted into the irradiated Rag2(-/-)gamma(c)(-/-) mice, with frozen and ex vivo expanded CD34(+) hematopoietic stem cells, human cell engraftments were determined using hCD45 and multilineage markers. The cultured cells with the cytokine combination of stem cell factor, thrombopoietin, Flk2/Flk3 ligand (FL), and interleukin-3 showed stable and long-term engraftment compared to other combinations. The ex vivo expanded human fetal liver-derived CD34(+) hematopoietic stem cells, under our culture conditions, accomplished a large volume of expanded cells that were sustained, demonstrating self-renewal of the evaluated markers, which may have indicated long- term repopulation activity. CONCLUSION: The results of this study demonstrated a practical mouse model of expanded human immune cells especially T cells in Rag2(-/-)gamma(c)(-/-) mice.

Essential moiety for antimutagenic and cytotoxic activity of hederagenin monodesmosides and bisdesmosides isolated from the stem bark of Kalopanax pictus.

For the elucidation of the antimutagenic and cytotoxic principles from the stem bark of Kalopanax pictus, seven isolated components of this crude drug were tested in the Ames test and the MTT test. Hederagenin and its monodesmosides, kalopanaxsaponin A and I in addition to its bisdesmosides, kalopanaxsaponin B and H, showed potent antimutagenic activities against aflatoxin B1 (AFB1). However, they had no inhibitory effects on mutagenicity induced by the direct mutagen, N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). This suggested that hederagenin glycosides might effectively prevent the metabolic activation of AFB1 or scavenge the electrophilic intermediate capable of inducing mutation. Hederagenin was found to be an essential moiety for the exhibition of antimutagenicity. Moreover, hederagenin and its 3-O-glycosides were found to be cytotoxic on various tumor cell lines, P-388, L-1210, U-937, HL-60, SNU-5 and HepG2, while 3,28-di-O-glycosides of hederagenin were not cytotoxic. Hence, hederagenin and its 3-O-glycosides could be suitable for cancer treatment chemopreventive drugs.