Meng-Kun Tsai

Pegylated Interferon-α2a With or Without Low-Dose Ribavirin for Treatment-Naive Patients With Hepatitis C Virus Genotype 1 Receiving Hemodialysis: A Randomized Trial

BACKGROUND Data are limited on the efficacy and safety of pegylated interferon plus ribavirin for patients with hepatitis C virus genotype 1 (HCV-1) receiving hemodialysis. OBJECTIVE To compare the efficacy and safety of combination therapy with pegylated interferon plus low-dose ribavirin and pegylated interferon monotherapy for treatment-naive patients with HCV-1 receiving hemodialysis. DESIGN Open-label, randomized, controlled trial. (ClinicalTrials.gov: NCT00491244). SETTING 8 centers in Taiwan. PATIENTS 205 treatment-naive patients with HCV-1 receiving hemodialysis. INTERVENTION 48 weeks of pegylated interferon-α2a, 135 µg weekly, plus ribavirin, 200 mg daily (n = 103), or pegylated interferon-α2a, 135 µg weekly (n = 102). MEASUREMENTS Sustained virologic response rate and adverse event-related withdrawal rate. RESULTS Compared with monotherapy, combination therapy had a greater sustained virologic response rate (64% vs. 33%; relative risk, 1.92 [95% CI, 1.41 to 2.62]; P < 0.001). More patients receiving combination therapy had hemoglobin levels less than 8.5 g/dL than those receiving monotherapy (72% vs. 6%; risk difference, 66% [CI, 56% to 76%]; P < 0.001). Patients receiving combination therapy required a higher dosage (mean, 13 946 IU per week [SD, 6449] vs. 5833 IU per week [SD, 1169]; P = 0.006) and longer duration (mean, 29 weeks [SD, 9] vs. 18 weeks [SD, 7]; P = 0.004) of epoetin-β than patients receiving monotherapy. The adverse event-related withdrawal rates were 7% in the combination therapy group and 4% in the monotherapy group (risk difference, 3% [CI, -3% to 9%]). LIMITATION Open-label trial; results may not be generalizable to patients on peritoneal dialysis. CONCLUSION In treatment-naive patients with HCV-1 receiving hemodialysis, combination therapy with pegylated interferon plus low-dose ribavirin achieved a greater sustained virologic response rate than pegylated interferon monotherapy. PRIMARY FUNDING SOURCE National Center of Excellence for Clinical Trial and Research.

Expanding the donor pool: use of renal transplants from non-heart-beating donors supported with extracorporeal membrane oxygenation

Abstract:  In response to organ shortage, we used the renal grafts from non‐heart‐beating donors (NHBDs). Extracorporeal membrane oxygenation (ECMO) was used to maintain NHBDs before organ procurement. We compared the results of renal transplantation from different donors, including heart‐beating donors (HBDs), living‐related donors (LDs), and NHBDs supported with ECMO. From February 1998 to June 2003, we recruited 219 patients receiving renal transplantation at National Taiwan University Hospital. Among them, 31 received kidneys from NHBDs supported with ECMO, 120 from HBDs, and 68 from LDs. Multiple organ transplant recipients were not included in this study. We compared the graft survival, serum creatinine levels, and estimated glomerular filtration rates of the three groups. The rate of delayed graft function was higher in NHBD recipients (41.9%) than in HBD recipients (27.0%) and LD recipients (10.9%) (p = 0.003). In the NHBD group, the recipients of grafts with delayed function had significantly longer ECMO runs (63.1 ± 3.0 min) than those without delayed function (53.7 ± 2.5 min) (p = 0.024). Estimated glomerular filtration rate (p = 0.472) and mean serum creatinine level (p = 0.286) were not significantly different between the three groups using a longitudinal approach. The 5‐yr graft survival rates for NHBD (88.4%, 95% CI: 0.680–0.962), HBD (83.2%, 95% CI: 0.728–0.899), and LD transplant recipients (89.3%, 95% CI: 0.619–0.974) were not significantly different (p = 0.239). The 5‐yr patient survival rates for NHBD, HBD, and LD transplant recipients were 100, 93.0 (95% CI: 0.859–0.966) and 100% respectively. The long‐term allograft survival and function of kidneys from NHBDs supported by ECMO, HBD, and LD did not differ significantly. Long ECMO running time tended to delay graft function.

Peginterferon alfa-2a with or without low-dose ribavirin for treatment-naive patients with hepatitis C virus genotype 2 receiving haemodialysis: a randomised trial

Objective Data comparing the efficacy and safety of combination therapy with peginterferon plus low-dose ribavirin and peginterferon monotherapy in treatment-naive haemodialysis patients with hepatitis C virus genotype 2 (HCV-2) infection are limited. Design In this randomised trial, 172 patients received 24 weeks of peginterferon alfa-2a 135 μg/week plus ribavirin 200 mg/day (n=86) or peginterferon alfa-2a 135 μg/week (n=86). The efficacy and safety endpoints were sustained virological response (SVR) rate and adverse event (AE)-related withdrawal rate. Results Compared with monotherapy, combination therapy had a greater SVR rate (74% vs 44%, relative risk (RR): 1.68 [95% CI 1.29 to 2.20]; p<0.001). The beneficial effect of combination therapy was more pronounced in patients with baseline viral load ≥800 000 IU/mL than those with baseline viral load <800 000 IU/mL (RR: 3.08 [95% CI 1.80 to 5.29] vs RR: 1.11 [95% CI 0.83 to 1.45]; interaction p=0.001). Patients receiving combination therapy were more likely to have a haemoglobin level of <8.5 g/dL (70% vs 8%, risk difference (RD): 62% [95% CI 50% to 73%]; p<0.001) and required a higher dosage [mean: 13 417vs 6667 IU/week, p=0.027] of epoetin β to manage anaemia than those receiving monotherapy. The AE-related withdrawal rates were 6% and 3% in combination therapy and monotherapy groups, respectively (RD: 2% [95% CI −4% to 9%]). Conclusions In treatment-naive haemodialysis patients with HCV-2 infection, combination therapy with peginterferon plus low-dose ribavirin achieved a greater SVR rate than peginterferon monotherapy. Most haemodialysis patients can tolerate combination therapy. Trial registration number ClinicalTrial.gov number, NCT00491244.

Effects of Calcineurin Inhibitors on Sirolimus Pharmacokinetics During Staggered Administration in Renal Transplant Recipients

Study Objective. To compare the effects of different calcineurin inhibitors on sirolimus pharmacokinetics during long‐term, staggered administration in kidney transplant recipients.

Heart Rate Variability During Hemodialysis and Following Renal Transplantation

Previous studies have shown awareness of uremic dysfunction in end-stage renal disease (ESRD) patients. Dysautonomia in ESRD patients may be reversible after renal transplantation. We used a power spectral analysis (PSA) of heart rate variability (HRV) to assess alterations of autonomic activity in 14 controls and 14 nondiabetic hemodialysis ESRD patients who had undergone renal transplantation. Compared with matched control subjects, the power frequency determinations of low frequency (LF; 3.42 ln(ms(2)) vs 6.38 ln(ms(2)); P < .05 high frequency (HF; 2.29 ln(ms(2)) vs 5.27 ln(ms(2)); P < .05)), and total power (TP; 5.39 ln(ms(2)) vs 7.53 ln(ms(2)); P < .05) were significantly suppressed in ESRD patients undergoing hemodialysis. ESRD patients showed significantly improved HRV after renal transplantation. After renal transplantation, there was no significant difference in the TP (6.82 ln(ms(2)) vs 7.53 ln(ms(2)); P = .15) component between measurements in both patient subgroups. We further divided the ESRD patients into 2 groups based on their pretransplantation HRV, observing alterations in HRV after renal transplantation. Patients with significantly improved HRV were those with more suppressed HRV before transplantation (HF <3 In(ms(2)). Autonomic dysfunction in ESRD patients was not irreversible even if severe, and recovery was observed as early as 6 months after transplantation.

Robot‐assisted renal transplantation in the retroperitoneum

Minimally invasive surgery for renal transplantation is still under development. We employed the robotic surgical system to perform renal transplantation with a minimally invasive wound. The operation was performed with a Gibson incision and two working ports. The space for the transplantation was created by retroperitoneal dissection with the robot lifting the abdominal wall. Vascular reconstruction was performed with two robotic needle drivers. We successfully performed robot‐assisted renal transplantation in five female and five male patients with an average wound length of 7.7 ± 1.04 cm. Nine of the renal allografts functioned immediately, but one with prolonged warm ischemia during the live donor nephrectomy had delayed function. The average creatinine level and estimated glomerular filtration rate at discharge were 1.31 ± 0.31 mg/dl and 58.2 ± 8.1 ml/min, respectively. All the transplants are currently functioning at 6.9 ± 3.9 months after operations. In conclusion, with robot assistance, minimal invasive renal transplantation can be performed successfully in the retroperitoneum.

The role of B7 ligands (CD80 and CD86) in CD152-mediated allograft tolerance: a crosscheck hypothesis.

Background. The regulatory mechanism by which the B7 ligands (CD80 and CD86) direct the CD28/CD152 costimulatory pathways is unclear. This study investigated the role of CD80 and CD86 in a CD152-mediated allograft tolerance model. Methods. A low-responding cardiac transplant model (BALB/c→B10.A) with possible long-term acceptance was used. Immunocytochemical and flow cytometric analyses of the graft-infiltrating cells were conducted to characterize this transplant model. The influence of anti-CD80 and anti-CD86 treatments on the proliferation and interleukin (IL)-2 productions of the tolerated splenocytes (SC) was analyzed. The role of CD80 and CD86 in the induction and maintenance of the graft acceptance in this transplant model were also tested. Results. B10.A mice could accept the BALA/c cardiac allografts (11/22), and an anti-CD152 antibody blocked the graft acceptance (10/10). Immunocytochemical and flow cytometric analyses showed that CD152+ cells were predominant among the CD4+ cells infiltrating the 100-day grafts of the B10.A recipients (B10.A-100). Either anti-CD80 or anti-CD86 treatment significantly enhanced polyclonal proliferation and IL-2 production of the B10.A-100 SC. Blockade of either CD80 or CD86 prohibited the tolerance transmitted by adoptive transfer, and anti-CD80 or anti-CD86 plus skin grafting undermined the established allograft tolerance. Conclusions. Both CD80 and CD86 were essential for the induction and maintenance of the CD152-mediated allograft tolerance.

De novo malignancy is associated with renal transplant tourism

Despite the objections to transplant tourism raised by the transplant community, many patients continue travel to other countries to receive commercial transplants. To evaluate some long-term complications, we reviewed medical records of 215 Taiwanese patients (touring group) who received commercial cadaveric renal transplants in China and compared them with those of 321 transplant recipients receiving domestic cadaveric renal transplants (domestic group) over the same 20-year period. Ten years after transplant, the graft and patient survival rates of the touring group were 55 and 81.5%, respectively, compared with 60 and 89.3%, respectively, of the domestic group. The difference between the two groups was not statistically significant. The 10-year cumulative cancer incidence of the touring group (21.5%) was significantly higher than that of the domestic group (6.8%). Univariate and multivariate stepwise regression analyses (excluding time on immunosuppression, an uncontrollable factor) indicated that transplant tourism was associated with significantly higher cancer incidence. Older age at transplantation was associated with a significantly increased cancer risk; however, the risk of de novo malignancy significantly decreased with longer graft survival. Thus, renal transplant tourism may be associated with a higher risk of post-transplant malignancy, especially in patients of older age at transplantation.

Hand-Assisted Versus Total Laparoscopic Live Donor Nephrectomy

Background and Purpose: The optimal minimally invasive procedure to procure live donor kidneys for renal transplantation has not been established. This study compared the donor outcome of hand-assisted laparoscopic live donor nephrectomy (H-LLDN) with total laparoscopic live donor nephrectomy (T-LLDN). Methods: The outcomes of 12 donors undergoing H-LLDN were compared to that of a subsequent series of 12 donors undergoing T-LLDN. Body mass index, operation time, warm ischemia time, hospital stay, surgical complications, and short-term graft function were compared between the 2 groups. Results: LLDN was successfully performed in all 24 donors. Both approaches resulted in excellent early graft function. The mean operation time in T-LLDN (215 minutes) was slightly shorter than that in H-LLDN (258 minutes), suggesting that the skills developed as surgeons learned the I-I-LLDN procedure had transferred to their performance of T-LLDN. The mean warm ischemia time of the T-LLDN group (4.5 minutes) was longer than that of the H-LLDN group (3.8 minutes), although this difference was not significant. One minor tear of the lumbar vein occurred in the H-LLDN group and the resultant bleeding necessitated blood transfusion. One mechanical failure occurred when the renal vein was divided by endoscopic gastrointestinal anastomosis in the T-LLDN group. The length of hospital stay, resumption of diet, and the use of narcotic analgesics were not different between the 2 groups. Conclusions: Both H-LLDN and T-LLDN are safe and effective approaches for the procurement of live donor kidneys. The benefits of the I-I-LLDN technique include direct manual control of the operative field and increased safety margin. The development of a hospital LLDN program by starting with a hand-assisted approach may reduce the potential bleeding complications and facilitate the safe transition to the cosmetically preferable total laparoscopic approach.

Reduction of human-to-pig cellular response by alteration of porcine MHC with human HLA DPW0401 exogenes.

BACKGROUND In pig-to-human discordant xenotransplantation, the xenograft can be rejected by a formidable human xenogenic T-cell response, even if the graft has gone through hyperacute rejection or delayed xenograft rejection (acute vascular rejection). We therefore examined, in this study, whether the human-to-pig cellular response could be attenuated through the generation of a transgenic pig for human HLA II. METHODS With the technique of microinjection, we produced the HLA DPw0401 transgenic pig. The expression of the HLA DPw0401 gene on peripheral blood mononuclear cells (PBMCs) of the transgenic pig was examined by reverse transcriptase-polymerase chain reaction and flow cytometry. The antigenicity of the transgenic HLA DPw0401 molecule was tested by the HLA DPw0401-primed lymphocyte test reagent. The cellular response was analyzed by xenogenic mixed lymphocyte culture. RESULTS The mRNA and protein of HLA DPw0401 were expressed in the PBMCs of the transgenic pig. The PBMCs of the HLA transgenic pig induced a stronger cellular reaction to HLA DPw0401-primed lymphocyte test reagents than the nontransgenic littermate pig (n=7, P<0.01). In direct xenogenic mixed lymphocyte culture with responders from HLA DPw0401(+) humans, the PBMCs from the HLA DPw0401 transgenic pig, as compared with those from the normal pig, induced a lower degree of xenogenic cellular response to human PBMCs (n=4, P=0.08). CONCLUSIONS Our preliminary data demonstrated the possibility that the human HLA DPw0401 phenotype can be transferred onto porcine cells through the generation of HLA transgenic pigs and make the PBMCs of humans more tolerant to porcine cells.