The goal of this study was to examine whether the lower limit of the graft-to-recipient weight ratio (GRWR) can be safely reduced to make better use of a left-lobe graft in adult-to-adult living donor liver transplantation (LDLT) in combination with portal pressure control.
Beginning in December 2007, our institution actively selected left-lobe grafts for use in liver transplantation seeking to minimize the risks to healthy donors. We gradually decreased the lower limit of the GRWR to preferentially select a left-lobe over a right-lobe graft: from ≥0.7% beginning in December 2007 to ≥0.6% beginning in April 2009. A portal pressure control program, targeting final portal pressures below 15 mm Hg, was also introduced to overcome small-for-size graft problems. The ratio of left-lobe grafts among all adult-to-adult LDLT grafts and the donor complication rate (defined as Clavien grade ≥ III, excluding wound infection) were compared between two time periods: June 1999 to November 2007 (period 1, n = 541) and December 2007 to February 2010 (period 2, n = 119). Overall survival rates were also compared between those recipients of a GRWR < 0.8% and those with a GRWR ≥ 0.8% in 198 recipients who underwent LDLT at our institution between April 2006 and February 2010.
Left-lobe grafts use increased from period 1 (65/541 recipients; 12.0%) to period 2 (50/119 recipients; 42.0%; P < .001). The donor complication rate tended to decrease from 13.8% in period 1 to 9.3% in period 2 (P = .115). The overall survival rate in 52 recipients with a GRWR < 0.8% did not differ from that in 146 recipients with a GRWR ≥ 0.8%.
The lower limit of the GRWR can be safely reduced to 0.6% in adult-to-adult LDLT in combination with portal pressure control.
Posttransplant appearance of donor-specific anti-HLA antibodies is correlated with poor graft survival. Herein, we have provided evidence that an HLA-DRB1*0101 kidney allograft recipent developed anti-DR103 antibody after receiving a transplant from a HLA-DRB1*0103 cadaveric donor, resulting in graft loss. HLA-DRB1*0103 is a rare allele in Caucasian populations. It differs from DRB1*0101 only by three amino-acid substitutions and may play a central role in allorecognition. Nevertheless, our data showed that it induced alloimmunization in a DRB1*0101 recipient. Therefore, this new possibility of immunization must be taken into account before transplantation as well as after grafting.
A great many patients awaiting liver transplantation die because of the inavailability of donor livers. Liver support systems such as the bioartificial liver have been effective alternatives to ease the shortage. However, the problem with these systems is the difficulty to obtain sufficient amounts of hepatocytes with good liver function. This study explored the possibility of employing a human fetal hepatocyte cell line L-02 for a liver support system.
To confirm the hepatocytic functions of L-02 cells and their potential as a novel cell source to treat acute liver failure (ALF) in a liver support system.
Hepatocyte markers were detected by Western blotting and laser confocal microscopy; their gene expression of hepatic markers was examined by polymerase chain reaction (PCR). An in vivo ALF model was established by 90% partial hepatectomy. Ten rats undergoing hepatectomy received 5 × 10(7) L-02 cells intrasplenically and 15 served as controls. Survival and liver functions were assessed in both groups.
In vitro, Western blotting and laser confocal microscopy showed L-02 to express liver function markers: Albumin (ALB), uridine diphosphate glucuronosyltransferase, and cytochrome P450 3A4. PCR showed the expression of liver-specific genes, such as ALB, human glutathione S transferase, and human factor-X. In vivo, rats transplanted with L-02 cells showed significantly improved survival of 70% versus 0% in controls (P < .01). Liver function in the L-02 group was significantly improved versus controls: ALB, 30.2143 ± 2.68665 versus 25.3 ± 7.27942 g/L; alanine transaminase, 1611.333 ± 342.0078 versus 2831.333 ± 110.437 U/L; aspartate aminotransferase, 2210.667 ± 97.57732 versus 3149.333 ± 71.98842 U/L; serum ammonia, 360.4667 ± 74.94656 versus 660.62 ± 63.41681 μmol/L; alkaline phosphates, 408.6667 ± 48.00347 versus 698.5 ± 17.67769 U/L; total bilirubin, 29.8 ± 6.19785 versus 44.6 ± 9.73858 μmol/L; and direct bilirubin, 25.4333 ± 6.60631 versus 32.5 ± 7.07107 μmol/L (P < .05).
L-02 cells, expressing the main molecules of human hepatocytes, improved liver functions and survival of ALF rats, suggesting them to be a feasible source for liver support systems.
Inhibition of T-cell activation is the most efficient way to prevent transplant rejection. Protein kinase C (PKC) is an important signaling enzyme in the activation and regulation of T lymphocytes. AEB-071 (AEB) is a low-molecular-weight compound that blocks early T-cell activation via selective inhibition of PKC, a mechanism that differs from that of the calcineurin inhibitors. The present study sought to compare the effects of AEB versus tacrolimus (Tac) to prevent acute rejection in rats that had undergone heterotopic heart transplantation. We investigated the Brown Norway-Lewis rat strain combination for cardiac graft survival over 30 days after transplantation using varying doses of oral AEB and Tac monotherapy. Grafts were monitored by daily palpation; cessation of palpable ventricular contraction was considered to be rejection. Apart from necropsy, we performed histologic examinations of cardiac graft at 7 days after transplantation. In untreated recipients, allograft mean survival times (MST) was 6.83+/-0.41 days. AEB at 15, 30, or 60 mg/kg versus Tac at 1.2 mg/kg significantly prolonged graft survival to a MST of 12.33+/-1.21, 16.67+/-1.21, and 19.33+/-3.83, versus 17.00+/-6.90 days, respectively. Histologic assessment at 7 days after transplantation showed that high-dose AEB significantly decreased the histologic rejection score, indicative of decreased inflammatory cell infiltration into the graft. These results suggested that the administration of AEB (medium or high-dose), a PKC inhibitor, mitigated acute rejection and displayed significantly longer MST, similar to high-dose Tac after heterotopic heart transplantation in the rat.
The purpose of this research was to study the HLA-B39 distribution in 2560 healthy, unrelated, randomly selected individuals living in the southeastern region of Brazil (the states of Rio de Janeiro and São Paulo). Molecular methods were used to type HLA class I and II polymorphism: PCR-SSP, PCR-SSO, and PCR-SBT. HLA-B*39 was found in 7% (n = 182) of these individuals. HLA-B*3901, B*3906, and B*3913 were the most common alleles in this group (n = 57, 36, and 24, respectively). B*3913 was found associated with DRB1*0807 and DQB1*0402 in 16 of the 24 individuals and 13 of these were also associated with A*31012. This haplotype segregation was confirmed by family studies. Furthermore, in 5 of the 13 individuals carrying the A*31012, B*3913, DRB1*0807, and DQB1*0402 haplotype, HLA-DPB1*2701 was also present, suggesting that these alleles were found preferentially in cis association. DRB1-DPB1 linkage disequilibrium analysis was performed in 420 of the 2560 individuals and the association of DRB1*0807 with the uncommon DPB1*2701 was found to be highly significant (P <.0001). Because HLA-B*3913 and HLA-DRB1*0807 have been observed only in South American populations, it is possible that interlocus association has been selected to act on the same haplotype to collaborate in the class I and II restricted immune response to local pathogens and functional adaptation. Although numbers are small to predict which ethnic groups of the Brazilian population display this haplotype prevalently, it is possible to speculate that these data may have clinical application, such as in the selection of unrelated donors for bone marrow transplantation.
We will report here, as a landmark of our continuing efforts, the survival of patients with various end-stage liver diseases after liver transplantation from our own experience in 1,000 hepatic homograft recipients under cyclosporine-steroid therapy. This report, involving 1,000 patients, confirms the earlier assessment. The survival rates of 74% at 1 year and 64% at 5 years are convincing enough to consider liver transplantation as an ultimate therapy for various end-stage liver diseases. Unless agents that are more effective and safer than cyclosporine are used, further significant improvement of overall survival may not be expected, because liver transplantation will be applied for patients of even higher risk than now.
Many studies suggest that 1,25-dihydroxyvitamin D3 (1,25-[OH](2) D3) and its analogues are potent dose-reducing drugs for other immunomodulators, helping to prevent graft rejection. In this study, we retrospectively grouped renal transplant recipients into two cohorts based on 1,25-[OH](2) D3 use to analyze the immunomodulatory effects. Ninety-two subjects were initially enrolled: group A (n = 43) recipients who had osteoporosis and were treated with 1,25-[OH](2) D3, and group B (n = 49) was a control group. We evaluated the effects on the number of acute rejection episodes, the immunosuppressive drug doses, serum calcium levels, and overall graft survival. Although before treatment the number of acute rejection episodes was statistically higher among group A than group B patients, after introduction of 1,25-[OH](2) D3, the difference became nonsignificant. This study showed that osteoporotic renal transplant recipients experienced fewer acute rejection episodes after 1,25-[OH](2) D3 treatment.
To assess 1,25-dihydroxyvitamin D status and the effect of vitamin concentration on transplantation outcome in renal allograft recipients.
Ninety patients underwent renal transplantation between 2002 and 2005. All received alfacalcidol supplementation before surgery. 1,25-Dihydroxyvitamin D concentration was determined on day 3 posttransplantation and at 1-, 6-, 12-, 18-, and 24-month follow-up.
Severe 1,25-dihydroxyvitamin D deficiency was noted in 83% of patients immediately posttransplantation. From 1 to 12 months thereafter, concentrations increased almost 3-fold, and remained constant to 24 months. In 50% of patients, the 1,25-dihydroxyvitamin D concentration reached a concentration of more than 30 pg/mL, similar to that in healthy volunteers; in the other 50%, the concentration reached 17.2 pg/mL. A high incidence of delayed graft function was observed in patients with 1,25-dihydroxyvitamin D deficiency (44% vs 6%). There was a negative correlation between the initial 1,25-dihydroxyvitamin D and serum creatinine concentrations at day 3 and month 6 (P < .03). Similarly, the 1,25-dihydroxyvitamin D concentration at 1 month was negatively correlated with creatinine concentration at months 1 through 24 (P < .01). Poor outcome was observed primarily in patients with 1,25-dihydroxyvitamin D deficiency; 2 patients developed cancer, 5 grafts were lost, and 4 patients died of cardiovascular events.
1,25-Dihydroxyvitamin D deficiency is highly prevalent in renal allograft recipients. Patients with 1,25-dihydroxyvitamin D deficiency are at greater risk of delayed graft function, and the graft is more likely to be lost. These findings suggest the necessity of adequate vitamin D supplementation both before and after transplantation.
Vitamin D plays an important role in the regulation of cellular growth and cell proliferation as well as exerting immunoregulatory activities. We sought to show the influence of vitamin D on renal graft survival. Among 102 patients, 40 were treated with vitamin D (group D) and the remaining 62 cases were not, forming a control group (group C). We studied human leukocyte antigen (HLA)-DR expression on tubules, interstitial cells, peritubular capillaries (PTCs), and evaluated macrophage infiltration of the interstitium and the PTCs. Compared to group C, group D patients showed fewer acute rejection episodes. Compared to group C patients group D patients showed significantly lower degrees of tubular and interstitial HLA-DR expression as well as interstitial and PTC macrophage infiltration. In addition in the PTC, HLA-DR expression was greater and therefore PTC destruction less in group D patients (P<.001). Twenty-seven (43.5%) of 62 group C patients lost their grafts at 29.2±15 months, whereas only 7/40 (17.5%) group D patients lost their grafts at 43.2±13 months. A significant difference was noted between the two groups in regard to the time of graft loss (P<.01). Testing vitamin D therapy along with several other covariates showed an independent effect on 5-year graft survival (P<.001). These data confirmed that vitamin D therapy shows an independent positive impact on long-term graft survival, which may be explained by its immunosuppressive effects of to reduce renal HLA-DR expression and renal macrophage infiltration and in turn mitigate PTC destruction. In conclusion, these results highlighted the potential use of vitamin D in renal allograft patients.
1,25-Dihydroxyvitamin D(3) (calcitriol) therapy has been extensively used for posttransplant osteoporosis. Beside its effect on bone metabolism, calcitriol has an important immunomodulatory effect. We evaluated the effects of oral calcitriol therapy on allograft function and parathyroid hormone levels after renal transplantation. The patients were retrospectively selected from a renal transplant patient population who received calcitriol (group 1, n = 59, 36 male/23 female, follow-up: 52.8 +/- 12.2 months) compared with group (group 2, n = 52, 42 male/9 female, follow-up: 62.0 +/- 24.4 months) without calcitriol therapy after renal transplantation. Calcitriol therapy was started 24.0 +/- 19.1 months posttransplantation. All patients were under three-drug immunosuppression. The pretransplant and posttransplant data were studied retrospectively. Additionally, creatinine levels before and after the initiation of calcitriol therapy were recorded at 6 months intervals for 3 successive years. Our results were analyzed according to the first and third year on therapy data. According to the first year data, there were no differences in patient groups in terms of creatinine and iPTH levels. In the third year, the patients in group 1 showed significantly lower creatinine (P = .01) and iPTH (P < .04) levels and needed lower pulse steroid doses (P < .04). According to a Friedman repeated measures variance test, the creatinine level was significantly lower among group I (P < .04) at 3-year follow-up. In conclusion, even a delayed start of calcitriol therapy after renal transplantation exerts a protective effect on renal allograft function and prevents the development of hyperparathyroidism.