Donor-Specific Antibodies After Starting Hemodialysis in Nonrenal Solid Organ Transplant Recipients: Role of TH17.

BACKGROUND: Nonrenal transplantation could cause a progressive deterioration in renal function until need dialysis. It is important to know if these patients increased their risk to develop de novo donor-specific anti-HLA antibody (DSA) after starting hemodialysis (HD) and if so, try to find the mechanism. MATERIAL AND METHODS: In this double-phase study, we first analyzed the incidence of development DSA in nonrenal transplant recipients after starting HD by a retrospective study. Secondly, a prospective study was designed to analyze the pharmacokinetics of immunosuppressive drugs and the cytokine profile of these patients. RESULTS: Of 179 pancreas transplant recipients, 16 needed to start HD, and 62.5% of these patients developed de novo DSA after starting HD, with 80% of them class I DSA. In the second phase of the study, the plasma levels of the immunosuppressive drugs as measured by a limited sampling strategy of 3 sample time points (C0, C2, and C4) were stable. The cytokine profile showed that there was an increase in Th1 cytokine (interferon gamma of 0.045 ng/mL) and also in Th17 cytokines (transforming growth factor ß >10 ng/mL). CONCLUSION: Our data suggest that the development of DSA after starting HD in nonrenal transplant recipients could be mediated by Th17 immune response mechanisms.

14-Base pair polymorphism of human leukocyte antigen-G as genetic determinant in heart transplantation and cyclosporine therapy monitoring.

The 14-base pair (bp) polymorphism within the HLA-G gene has been investigated in heart transplant patients for the first time. The 14-bp polymorphism is associated with HLA-G mRNA stability and the patterns of alternative isoforms splicing, and therefore may influence the functionality of the HLA-G molecule. In heart transplantation, the highest production of soluble HLA-G was related to the -14/-14-bp genotype in the pre- and post-transplantation periods. Our study findings showed that the 14-bp polymorphism of the HLA-G gene influenced the expression of soluble HLA-G in heart transplantation and accordingly resulted in low rejection rates, being a possible marker of genetic variability associated with heart transplantation. In addition, the 14-bp polymorphism of the HLA-G gene is related to the absorber status of cyclosporine of each individual patient, and is useful for determining the oral dose of cyclosporine to manage patients (to adjust immunosuppressive protocols) so as to minimize the risk of a low or high immunosuppression and the side effects in the early stages of heart transplantation.

Anemia associated with pegylated interferon-alpha2a and alpha2b therapy in hemodialysis patients.

AIMS: Anemia is a well-known side effect of interferon therapy since interferons are potent inhibitors of erythropoiesis. The aim of this study was to compare the anemia associated with pegylated interferon (PEG-IFN) (alpha2a versus alpha2b therapy in hemodialysis patients (HD) with chronic hepatitis C. METHODS: In order to study the anemia, doses of erythropoietic growth factors (EGF), hemoglobin (Hb) and erythropoietin resistance index (ERI) were compared at baseline and after PEG-IFN-alpha2a or alpha2b therapy in 16 HD patients with chronic C hepatitis. Pharmacokinetic studies were performed in 4 of those treated with PEG-IFN-alpha2b and 2 patients treated with PEG-IFN-alpha2a. Secondary end-points were viral response and serious adverse events. RESULTS: At 4-6 months after the beginning of therapy, both PEG-IFN-alpha induced a significant increment in the erythropoietin resistance index. This increment was significantly higher in patients treated with PEG-IFN-alpha2a when compared with alpha2b (45 vs 9.9, p = 0.012). The pharmacokinetics of PEG-IFN-alpha2a and alpha2b in HD patients were different, the C(max), C(min) and the area under the serum concentration time curve, were all higher in patients treated with PEG-IFN-alpha2a compared with PEG-INF-alpha2b. Discontinuation of therapy occurred in 2 (28.5%) of the 7 patients in the PEG-IFN-alpha2a group and in 4 (44%) of the 9 patients in the PEG-IFN-alpha2b group. Three (42%) subjects in the alpha2a group and 5 (55%) in the alpha2b group had a response at the end of the 48 weeks of therapy. In 4 (44.4%) of the 9 patients treated with alpha2b the viral response was sustained. CONCLUSIONS: In summary, patients treated with PEG-IFN-alpha2a have a major inhibitory effect on erythropoiesis. This could be explained by the different pharmacokinetic properties of PEG-IFN-alpha2a and alpha2b. Further studies are needed to clarify how these findings influence the efficacy, safety and cost-effectiveness of the PEG-IFN-alpha2.

sHLA-G levels in the monitoring of immunosuppressive therapy and rejection following heart transplantation.

The aim of this study was to further determine the immediate influence, over a 12-h period, after the initiation of daily immunosuppressive treatment on the serum levels of sHLA-G in heart transplant patients during the post-transplant period (1 month). It was found that there are two patterns of patients in term of the changes observed in their levels of sHLA-G in response to the immunosuppressive treatment. One group (group A) showed no changes on sHLA-G while the other group (group B) a significant rise in sHLA-G levels was observed at 2 to 4 h post dose. Interestingly, it was observed that the patients in group B have better prognosis of acceptance of the heart graft than those of group A. On the other hand it was found that the patients with high levels of sHLA-G (77.3+/-34.8 ng/ml) in pre-transplant sera have a better prognosis of acceptance of the heart graft than those with low sHLA-G levels (9.7+/-7.1 ng/ml). In conclusion, both the intensity of changes of sHLA-G levels induced by immunosuppression and basal levels in pre-transplant could be used in the monitoring of the immunosuppression as well as the heart transplant evolution.

Soluble HLA-G in heart transplantation: their relationship to rejection episodes and immunosuppressive therapy.

The aims of this study were to quantify the level of soluble HLA-G in heart transplant patients, to determine the relationship between the sHLA-G levels and the appearance of acute rejection episodes, and to identify the influence of immunosuppressive therapy on sHLA-G levels. Analysis of sHLA-G, measured by enzyme-linked immunosorbent assay in the transplant patients, revealed the existence of two similarly sized groups of patients. One group displayed a significant increase (p < 0.001) in sHLA-G during the first month after transplantation while the other group maintained low levels of the molecule (0-30 ng/ml) throughout the study. The latter group displayed a high incidence of recurrent severe rejection. A significant increase (p < 0.01) in sHLA-G 2 hours after administration of immunosuppressive treatment (mycophenolate mofetil, cyclosporine A/FK506, corticoids) was found. These results suggest that sHLA-G participates in the induction of certain levels of immunological tolerance in these recipients.

Relationship between pharmacokinetic parameters of cyclosporin and the incidence of acute rejection after heart transplantation.

Despite two decades of use, there are limited data on the best way to monitor Cyclosporine (CsA) for heart transplantation. The aim of our study was to determine the relationships between pharmacokinetic parameters and clinical outcomes after heart transplantation and to evaluate the range of CsA trough levels provided the most effective protection against graft rejection. We retrospectively analyzed the clinical outcomes of all adult patients who received a heart transplant between January 1998 and February 2005. All had routine monitoring of CsA trough levels and scheduled endomyocardial biopsies. Rejection was defined as grade > or =3, based on International Society for Heart and Lung Transplantation (ISHLT) criteria. Follow-up period was 1 year. All patients were on CsA, corticosteroids, and azathioprine/mycophenolate mofetil with or without antilymphocyte induction (eight patients with basiliximab). Data were analyzed by unpaired Student t-test, Cox regression model, and ROC curve. Among 70 patients (60 men and 10 women) who entered the study, 34 (48.6%) had at least one acute rejection episode of grade > or =3 during the first posttransplant year. Mean CsA trough level (C(0)) measured at first week posttransplant was significantly lower in the rejection than the no-rejection group (125.17 +/- 56.9 ng/mL versus 169.33 +/- 48.27 ng/mL, P = .001). C(0) was the strongest predictor of acute graft rejection (P = .000, HR = .985.) The risk decreased by 1.5% for each unit increase of the C(0) value. ROC analysis showed that C(0) of 150 ng/mL provided the optimal cutoff. Patients with mean C(0) >150 ng/mL over the first week had less incidence of acute rejection than patients with levels <150 ng/mL (30.3% versus 64.9%) (P = .009, Cochran-Mantel-Haenszel test). In conclusion, our data suggest that in heart transplant patients it may be crucial to target early trough levels above 150 ng/mL during the first days postsurgery to avoid rejection.