Difference In Rate Of Acute Rejection Research Articles

Evidence for the Immunosuppressive Potential of Calcineurin Inhibitor-Sparing Regimens in Liver Transplant Recipients with Impaired Renal Function

Patients requiring liver transplantation (LT) frequently experience renal insufficiency (RI), which affects their survival. Although calcineurin inhibitor-sparing immunosuppressive regimens (CSRs) are well known to prevent RI, the immune state in recipients receiving CSR remains to be intensively investigated. In the present study, we investigated the immune state in liver transplant patients suffering from RI received a CSR comprising a reduced dose of calcineurin inhibitor (CNI), methylprednisolone, and mycophenolate mofetil (MMF). For monitoring the immune-state response to anti-donor allostimulation in these patients, we employed a mixed lymphocyte reaction (MLR) assay using an intracellular carboxyfluorescein diacetate succinimidyl ester (CFSE)-labeling technique. Among 60 cases of living-donor LT at our institute, 68% of the patients had none to mild RI (non-RI group) and 32% of the patients had moderate to severe RI (RI group). The RI group received a CSR comprising reduced dose of tacrolimus, methylprednisolone, and MMF, while the non-RI group received a regimen comprising conventional dose of tacrolimus and methylprednisolone. One year after LT, the mean estimated glomerular filtration rate (eGFR) in the non-RI group had significantly deteriorated. In contrast, the mean eGFR in the RI group had significantly improved after LT, although it was still lower than that of the non-RI group. Notably, 53% of the patients in the RI group were completely cured of RI by 1 year after LT. None of the patients had severe RI at 1 year after LT nor required chronic hemodialysis during the observation period. Serial mixed lymphocyte reaction assays revealed that anti-donor T cell responses were adequately suppressed in both groups. To evaluate the immune status of these patients, we employed a serial MLR assay using a CFSE-labeling technique. In both groups, limited CD4+ and CD8+ T-cell proliferation was observed in the anti-donor responses as compared with the anti-third-party responses through the first year. At 1 month after LT, the average of stimulation index (SI) for CD4+ T cells in response to anti-third-party stimulation was >2 (the average value in healthy volunteers without any immunosuppressive treatment) i.e., there was a normal response in the anti-third-party. At 1 year after LT, the average of SIs for CD4+ and CD8+ T cells in response to both anti-donor and anti-third-party stimulation was < 2. There were no significant differences in acute rejection rates, bacterial, fungal, or cytomegalovirus infection rates and patient survival between the groups. In conclusion, patients with pre-transplant RI receiving CSR under immunological monitoring using an MLR assay were associated with less impairment of renal function without an increased frequency of rejection or patient survival. Anti-donor T cell responses were adequately suppressed in these patients as well as in patients who received the conventional immunosuppressive regimen comprising a standard dose of CNI.

Immunosuppression and renal transplant rejection: review of current and emerging therapies

Acute rejection associated with chronic rejection and graft loss was a common complication after renal transplantation. Introduction of the new immunosuppressive agents dramatically decreased its incidence, but the negative impact on graft survival persisted. This has been in part attributed to the fact that the new immunosuppressive agents could only control those rejection episodes, without an effect on graft survival. So, differences in acute rejection rates in clinical trials were not followed by improvements in graft survival. Moreover, recent studies suggest that antibody-mediated injury, which is not controlled by the currently used immunosuppressive agents, plays an important role in long-term graft loss. New immunosuppressive agents, such as rituximab and bortezomib, targeting humoral mechanisms of rejection, or belatacept, which preserves graft function, could improve long-term outcomes.

Response to Questions Regarding the Design and Results of the IMPACT Trial

Response to Questions Regarding the Design and Results of the IMPACT Trial

Continuation of cinacalcet immediately after renal transplantation: a prospective cohort study

Cinacalcet is used for treating secondary hyperparathyroidism in dialysis patients, but it is currently unknown whether it can safely be continued immediately after renal transplantation. We prospectively studied renal transplant recipients with secondary hyperparathyroidism who were receiving cinacalcet before transplantation and continued treatment afterwards (n = 29) at a dose of 30 mg/day. Cinacalcet dose was titrated to serum calcium. Patients were followed for 6 months. Incidence of hypercalcemia, serum calcium and intact PTH (iPTH) were analyzed. Tacrolimus levels, acute rejection rate and renal function were compared with an age and sex matched control group. In 16 patients hypercalcemia was observed after transplantation. Severe hypercalcemia (>= 2.87 mmol/l) (n = 4) and hypocalcemia (n = 2) were infrequent. No difference in acute rejection rate or renal function between the cinacalcet and the control group was found. There also was no clinically relevant influence of cinacalcet on tacrolimus levels. Our study shows that cinacalcet can safely be continued immediately after renal transplantation. Studies are needed to determine if continuation of cinacalcet is better than early withdrawal. Also, the optimum dose of cinacalcet and the long-term effects of cinacalcet after renal transplantation must be defined.

Donor‐specific transfusions

Date written: June 2007Final submission: October 2008

Efficacy of Risk Stratification in Tailoring Immunosuppression Regimens in Kidney Transplant Patients at the National Kidney and Transplant Institute

Objectives To evaluate the efficacy of tailored immunosuppressive regimens prescribed according to a risk stratification scoring system based on the number of HLA mismatches, donor source, panel-reactive antibodies (PRA), and repeat transplant. Methods Patients in a retrospective cohort of 329 kidney transplantations performed from October 2004 to December 2005 were assigned scores of 0, 2, 4, or 6 with higher scores for ≥1 HLA mismatches, PRA > 10%, repeat transplant, and unrelated or deceased donor. Added scores of ≤4 comprised the low-risk group who received a Calcineurin inhibitor (CNI)-based regimen without induction, whereas a score ≥ 6 denoted high risk including a CNI-based regimen with an interleukin-2 receptor antibody. The efficacy analysis compared the incidences of biopsy-proven acute rejection episodes (BPAR) at 1 year. Results Only 227 (69%) of 329 patients had a complete data set and 84 were excluded because they did not follow the prescribed protocol, yielding 113 low- and 30 high-risk patients in the final population. Low-risk patients had a mean PRA of 5.4%, living related donors in 68%, and primary transplants. High-risk patients had a mean PRA of 18.8% (range = 10%–97%), living nonrelated donors in 84%, four deceased donors, and four repeat transplants. The overall 1-year incidence of BPAR was 5.7%. No significant difference ( P = .081) was observed in 1-year BPAR between the low- (4.5%) and high-risk (9.8%) groups. Likewise, no significant difference in the 1-year mean serum creatinine was observed according to the CNI. The mean creatinine was 1.12 for cyclosporine and 1.38 for tacrolimus treatment ( P = .06) in the low-risk group and 1.08 for cyclosporine and 1.2 for tacrolimus ( P = .61) in the high-risk cohort. Conclusion There was no significant difference in acute rejection rates between the immunologically low- or high-risk patients using tailored immunosuppression, which was effective to minimize its occurrence with good renal function at 1 year.

HA-1 Mismatch Has Significant Effect in Chronic Allograft Nephropathy in Clinical Renal Transplantation

Background The minor histocompatibility antigen HA-1 occurs in two allelic forms: H and R. The HA-1 H form presented in the context of HLA A2 can elicit specific cytotoxic lymphocyte (CTL) responses and can cause graft-versus-host disease in marrow transplants. However, its significance in solid organ transplants is unknown. We determined whether incompatibility of the HA-1 resulted in enhanced rejection and whether HA-1 specific CTLs were generated. Materials and methods HLA A2-matched donor/recipient pairs were selected and typed for HA-1 antigens by polymerase chain reaction. Nineteen of 81 pairs were mismatched for HA-1. Peripheral blood mononuclear leucocytes from five recipients, HLA A2 DR-matched with donors, were stimulated for 3 days with third-party donor, matched for HLA A2 DR but mismatched for HA-1. Cells were stained for surface markers, HA-1 H-specific tetramer reagent, and analyzed by flow cytometry. Controls were unstimulated cells; PBML from two patients never exposed to HA-1 H; immunoglobulin G isotype-matched controls. For all patients, acute rejection rates posttransplant was ascertained. Long-term data was available for 36 patients. Results and conclusions There was no difference in acute rejection rates between the HA-1-matched and -mismatched groups, but there was a significant difference in chronic rejection rates, evidenced by increased graft failures during the follow-up period ( P = .0024). Lymphocytes from five HA-1-mismatched recipients were stimulated in vitro with cells from HLA-A2 and DR-matched but HA-1-mismatched surrogate donor. Though there seemed to be an excess of tetramer-positive cells, anti-HA-1-specific CTL responses were not conclusively elicited in vitro.

Outcomes of Renal Transplantation for Recipients With Lupus Nephritis: Analysis of the Organ Procurement and Transplantation Network Database

Prior analyses of transplant outcomes in lupus transplant recipients have not consisted of multivariate analyses in the modern immunosuppressive era. Here, we compared patient and graft outcomes in lupus and non-lupus recipients transplanted between 1996 to 2000 using the United Network of Organ Sharing/Organ Procurement Transplant Network database. We evaluated the impact of recipient and donor demographic factors, time on dialysis and the initial immunosuppression regimen on rejection rates and transplant outcomes. Univariate analysis showed similar graft but better patient survival rates for primary lupus and non-lupus transplant recipients (5-year patient survival rates for lupus cohort 85.2% for deceased donor transplants and 92.1% for living donor transplants as opposed to 82.1% and 89.8% respectively for the non-lupus cohort; P=0.05 and 0.03) but similar patient survival rates for deceased donor retransplant patients. After controlling for confounding factors, no differences in patient or graft survival were seen between the two groups. No difference in acute rejection rates were observed in deceased donor transplants, but there was a small but significant increase in the risk of acute rejection in living donor lupus transplant recipients (hazard ratio=1.19, P=0.05). Risk of graft failure was lower for deceased donor recipients receiving MMF (five-year graft loss rate=29.6% for MMF vs. 40.2% for those not receiving MMF, P<0.0001), but no differences were seen among living donor recipients. Outcomes were similar regardless of type of calcineurin inhibitor, induction therapy, and time on dialysis. We conclude that lupus transplant recipients have outcomes generally equivalent to non-lupus transplant recipients.

Histological features of renal allograft biopsies in ABO minor-mismatched kidney transplantation

We examined histological features of allograft biopsies in ABO minor-mismatched kidney transplantation. Forty-five patients who underwent ABO minor-mismatched kidney transplantation between September 1999 and December 2001 at our institute. The mean age was 32.6 years, with 28 males and 17 females. We divided them into five groups based on the donor and recipient ABO blood groups. Group 1, O renal allografts given to A patients (13 patients); Group 2, O to B (9), Group 3, O to AB (2); Group 4, A to AB (9); and Group 5, B to AB (12). From September 1999 to April 2002, we performed 127 allograft biopsies in these 45 ABO minor-mismatched kidney transplant recipients. Among a total of 127 biopsy specimens, 47 specimens were taken as 0- or 1-h biopsies and 6 were protocol biopsies. Pathological analysis of 74 episode biopsy specimens showed: acute humoral rejection (AHR) in 13 (18%); acute cellular rejection (ACR) in 17 (23%); combined AHR and ACR in eight (11%); borderline change in six (8%); chronic rejection in 10 (12%); cyclosporin or tacrolimus nephrotoxicity in seven (10%) and chronic allograft nephropathy in three (4%). In total, some form of acute rejection (AR) was seen histologically in 38 biopsy specimens (48%) from 19 patients (42%). When we investigated AR in two separate categories, i.e. AHR and ACR, AHR was diagnosed in 21 biopsy specimens (26%) from 15 patients (33%) and ACR was seen in 25 biopsy specimens (31%) from 13 patients (29%). We compared the incidence rate of acute rejection in the cases of ABO minor-mismatched renal transplantation with ABO-incompatible and ABO-compatible cases between January 1989 and December 1999. The incidence rate of AR in ABO minor-mismatched cases (42%) was statistically lower than that in ABO-incompatible cases (63%). There was no statistical difference in the incidence rate of AR between ABO minor-mismatched cases and ABO-compatible cases (49%). There was statistical difference in the incidence of AR among the donor and recipient ABO blood groups. Group 4 (A allografts given to AB patients) had the statistically highest rate of AR (89%), followed by Group 1 (54%), Group 5 (33%) and Group 2 (11%), and there was no AR case in Group 3 (O to AB). In conclusion, the incidence rate of AR in ABO minor-mismatched kidney transplantation is statistically lower than ABO-incompatible cases and is not statistically different from that in ABO-compatible cases. The incidence cases of AHR are slightly higher than that of ACR in ABO minor-mismatched kidney transplantation and this finding is similar to findings of ABO incompatible kidney transplantation. Finally, there is a statistical difference in AR incidence among the donor and recipient ABO blood groups.

Optimizing the long-term outcome of renal transplants: opportunities created by sirolimus

This review focuses upon the sirolimus-based cyclosporine elimination studies and the light they shed on choice of the best long-term immunosuppressive strategy for managing the balance between prevention of loss of grafts from antigen specific immune responses or from chronic nephrotoxicity. The underlying strategy of both cyclosporine elimination studies was to treat patients with a uniform therapy for the first 3 months and then wean off the cyclosporine therapy in one cohort. The Phase II study was conducted in 246 recipients in 17 centers in the USA and Europe. Thus 97 patients were treated with full-dose cyclosporine, fixed-dose sirolimus and corticosteroids, and 100 patients received reduced-dose cyclosporine and trough concentration controlled sirolimus with corticosteroids until 3 months when the dose of cyclosporine was tapered progressively. The phase III study was undertaken in 525 patients in 57 centers in Australia, Canada and Europe with randomization for cyclosporine elimination undertaken at 3 months and implemented over the next 4-6 weeks. The primary outcome of renal function was better in the elimination arms of both studies and, in the phase III study, continued to improve for up to 2 years. Both studies demonstrated better renal function, equivalent patient and graft survival and no difference in acute rejection rates. These studies have shown that one of the successful strategies for improving the longer term graft survival rates includes the continuous use of sirolimus and steroids, without calcineurin inhibitors.

Basiliximab: a review of its use as induction therapy in renal transplantation.

Basiliximab (Simulect), a chimeric (human/murine) monoclonal antibody, is indicated for the prevention of acute organ rejection in adult and paediatric renal transplant recipients in combination with other immunosuppressive agents. Basiliximab significantly reduced acute rejection compared with placebo in renal transplant recipients receiving dual- (cyclosporin microemulsion and corticosteroids) or triple-immunotherapy (azathioprine- or mycophenolate mofetil-based); graft and patient survival rates at 12 months were similar. Significantly more basiliximab than placebo recipients were free from the combined endpoint of death, graft loss or acute rejection 3 years, but not 5 years, after transplantation. The incidence of adverse events was similar in basiliximab and placebo recipients, with no increase in the incidence of infection, including cytomegalovirus (CMV) infection. Malignancies or post-transplant lymphoproliferative disorders after treatment with basiliximab were rare, with a similar incidence to that seen with placebo at 12 months or 5 years post-transplantation. Rare cases of hypersensitivity reactions to basiliximab have been reported. The efficacy of basiliximab was similar to that of equine antithymocyte globulin (ATG) and daclizumab, and similar to or greater than that of muromonab CD3. Basiliximab was as effective as rabbit antithymocyte globulin (RATG) in patients at relatively low risk of acute rejection, but less effective in high-risk patients. Numerically or significantly fewer patients receiving basiliximab experienced adverse events considered to be related to the study drug than ATG or RATG recipients. The incidence of infection, including CMV infection, was similar with basiliximab and ATG or RATG. Basiliximab plus baseline immunosuppression resulted in no significant differences in acute rejection rates compared with baseline immunosuppression with or without ATG or antilymphocyte globulin in retrospective analyses conducted for small numbers of paediatric patients. Limited data from paediatric renal transplant recipients suggest a similar tolerability profile to that in adults. Basiliximab appears to allow the withdrawal of corticosteroids or the use of corticosteroid-free or calcineurin inhibitor-sparing regimens in renal transplant recipients. Basiliximab did not increase the overall costs of therapy in pharmacoeconomic studies. Basiliximab reduces acute rejection without increasing the incidence of adverse events, including infection and malignancy, in renal transplant recipients when combined with standard dual- or triple-immunotherapy. The overall incidence of death, graft loss or acute rejection was significantly reduced at 3 years; there was no significant difference for this endpoint 5 years after transplantation. Malignancy was not increased at 5 years. The overall efficacy, tolerability, ease of administration and cost effectiveness of basiliximab make it an attractive option for the prophylaxis of acute renal transplant rejection.

Outcome of renal transplantation in adolescents with focal segmental glomerulosclerosis.

Using the NAPRTCS database from January 1987 to January 2001, we examined 2687 adolescent (age 13-17 yr) index renal transplants to analyze differences in demographic treatment, and outcomes in adolescents with FSGS compared to other renal disease. 338 (12.6%) of adolescents had a primary diagnosis of FSGS. Adolescents with FSGS were more likely to be black and less likely to receive pre-emptive transplants (p < 0.001). No differences existed in HLA matching or immunosuppression regimens. Acute tubular necrosis occurred in more FSGS adolescents compared to non-FSGS adolescents following LD (11% vs. 4.7%) or CD (25.1% vs. 17.8%) transplants (p < 0.001). There were no significant differences in acute rejection rates between adolescents with FSGS and other adolescents. Graft survival was worse for LD FSGS adolescents (6 yr, 56%) compared to non-FSGS adolescents (77%) (p < 0.001) and was not significantly different from CD graft survival in FSGS (51%) or non-FSGS groups (61%). The relative risk (RR) of graft failure was greatest in LD transplant with FSGS (RR = 1.75; p < 0.001), compared to LD transplants without FSGS (RR = 1.0). Recurrent primary disease accounted for 15.2% of all graft failures in adolescents transplanted for FSGS with no difference between LD (17%) or CD (13.8%) grafts. Recurrent disease accounted for 3.2% of graft failures in adolescents without FSGS. Recurrent disease was the only cause of graft failure that differed between groups (p < 0.001). When compared to patients up to age 12 yr with FSGS, graft survival in both LD and CD transplants was worse in adolescents with FSGS (LD p = 0.035, CD p < 0.001). In conclusion, FSGS has a negative impact on graft survival in adolescents. Recurrence of FSGS results in a loss of the expected LD graft survival advantage in adolescents. Furthermore, adolescents with FSGS have decreased graft survival compared to younger children with FSGS. These data suggest that the rationale for LD transplantation in adolescents with FSGS should be based on factors other than the increased graft survival typically seen with LD transplantation.