Pre-emptive renal transplantation from living donors in Australia: Effect on allograft and patient survival

Aim: Pre-emptive renal transplantation has become the preferred first-line therapy for patients with end-stage kidney failure. This study examines the outcome of allograft and patient survival in pre-emptive transplantation compared with non-pre-emptive transplantation from living donors in Australia and New Zealand. Methods: We have performed a retrospective study using the Australian and New Zealand Dialysis and Transplantation Registry. Allograft and patient survival were compared at 1, 5 and 10 years in pre-emptive transplantation and non-pre-emptive transplantation following a living donor transplant. Results: Allograft survival at 1, 5 and 10 years post pre-emptive transplantation was better than post non-pre-emptive transplantation (multivariate hazard ratio (HR) 0.80 [95% confidence interval 0.64–0.99], P = 0.036). Pre-emptive transplantation was associated with a significant patient survival advantage over non-pre-emptive transplantation when analysed from the time of transplantation and adjusted for age and gender (multivariate HR 0.46 [0.27–0.80], P = 0.006). Patient survival for pre-emptive transplantation and non-pre-emptive transplantation was 97% [0.95–0.98] and 93% [0.91–0.94] at 5 years and 93% [0.88–0.96] and 84% [0.82–0.87] at 10 years post transplant respectively. There was no difference in the overall rejection rate between pre-emptive transplantation and non-pre-emptive transplantation. Vascular rejection was less common in pre-emptive transplantation (HR 0.70 [0.50–0.98], P = 0.04). Conclusion: Pre-emptive transplantation from a living donor is associated with both better allograft and patient survival compared with transplantation after a period of dialysis. Pre-emptive transplantation should be the preferred modality of renal replacement therapy in patients who have a living donor.     

Basiliximab in association with tacrolimus and steroids in caucasian cadaveric renal transplanted patients: significant decrease in early acute rejection rate and hospitalization time

Safety and tolerability of basiliximab in renal transplantation have been proven in different immunosuppressive regimens. Few informations are available about the association of basiliximab with tacrolimus and steroids. We present a retrospective analysis performed in Caucasian cadaveric renal transplant recipients, comparing a basiliximab, tacrolimus and steroids induction protocol (GrA: 51 patients) with a tacrolimus and steroids protocol (GrB: 46 patients). A significant decrease in acute rejection rate in the first 3 months (2.0% vs. 17.4%; p < 0.01) was noted. Interestingly, the recipients in GrA were at major immunologic risk for the younger age of recipients, the greater number of mismatches and the higher rate of second transplants. The hospitalization times resulted reduced of 5.3 d in GrA vs. GrB (20.8 d vs. 26.1 d; p < 0.05). The adverse events patterns and profiles were similar in the two treatments groups. One patient in each group had a post-transplant lymphoprolipherative disorder. No significant difference was found in patient and graft survival. According to the results of this study, in a Caucasian adult population, basiliximab in association with tacrolimus and steroids is a safe and efficacious tool for acute rejection prevention and it is cost saving by reducing the hospitalization times.     

An open randomized study comparing immunosuppression therapy initiated before or after kidney transplantation in haploidentical living recipients

BACKGROUND: Acute rejection is the most important risk factor for graft survival. Although many centers start immunosuppressive therapy days before the surgery in living donors, there is no systematic study concerning the possible advantages of this procedure. In this open randomized study, we compared the efficacy and safety of administration of cyclosporine (CSA; Neoral) and azathioprine before renal transplantation with the administration of the same schema after transplantation, in HLA haploidentical grafts. METHODS: Sixty renal transplant recipients of an HLA haploidentical allograft from living donors were randomized in two groups: (A) patients that started immunosuppression 3 d before transplantation (n = 30) and (B) those who started the drug schema on the first day after surgery (n = 30). We analyzed the incidence and severity of acute rejection, graft function and infection during the first 3 months after transplantation. RESULTS: The group of patients who started immunosuppression before had a mean trough level of CSA (299.70 +/- 154.03 ng/mL) in the expected range for an efficacious prevention of acute rejection at the surgery day. Thirteen patients (43.3%) in each group had acute rejection during the follow up (p = 1.00). Two grafts losses (3.3%) occurred, one in each group. Both groups had similar 3-month rejection-free graft survival (56.7 and 56.3%). The incidence of infection was also statistical comparable between groups A and B (56.7 vs. 46.7, p = 0.430). Graft function was similar in patients from both groups. CONCLUSIONS: Pre-transplant administration of immunosuppression did not reduce the incidence or severity of acute rejection episodes during the first 3 months of transplantation. Immunosuppressive drugs administered before engraftment did not increase the incidence of graft dysfunction or infection.     

Low tacrolimus concentrations and increased risk of early acute rejection in adult renal transplantation.

BACKGROUND: A retrospective analysis was performed on adult renal transplant recipients to evaluate the relationship between tacrolimus trough concentrations and the development of rejection in the first month after transplant. METHODS: A total of 349 concentrations from 29 patients, measured by enzyme-linked immunosorbent assay (ELISA), were recorded. Based on an increased serum creatinine, 12 patients were considered to have organ rejection. Rejection was confirmed by biopsy in five of these. The median trough concentration of tacrolimus over the first month of therapy, or until the time of first rejection was compared in rejecters vs non-rejecters. RESULTS: Median trough concentrations of tacrolimus were found to be lower in biopsy-proven rejecters vs non-rejecters (P=0.03) and all rejecters vs non-rejecters (P=0.04). The average median concentration (+/-SD) in the biopsy-proven rejecter group was 5.09+/-1.16 ng/ml, compared to 9.20+/-3.52 ng/ml in the non-rejecter group. After exclusion of an outlier, the average median concentration in all rejecters was 5.57+/-1.47 ng/ml, compared with 9.20+/-3.52 ng/ml in non-rejecters. A rejection rate of 55% was found for patients with a median trough concentration between 0 and 10 ng/ml. This compared with no observed rejection in patients with a median concentration between 10 and 15 ng/ml. CONCLUSION: A significant relationship exists between organ rejection and median tacrolimus trough concentrations in the first month post-transplant, with patients displaying low concentrations more likely to reject. In order to minimize rejection in the first month after renal transplantation, trough concentrations greater than 10 ng/ml must be achieved.     

Discontinuation of mycophenolate mofetil from a tacrolimus-based triple regimen 2 months after renal transplantation: a comparative randomized multicentre study

Previous clinical data suggested that with a tacrolimus-based regimen adjunctive immunosuppressives may be withdrawn after an initial treatment period. This study investigated the early discontinuation of mycophenolate mofetil (MMF) from a standard triple regimen. Patients were randomized either to receive a continued tacrolimus/MMF/steroids triple regimen (control group) or to reduce and then stop the MMF dose (MMF stop group). Both groups received identical daily tacrolimus and corticosteroid doses. The initial MMF dose was 1 g/day in both arms, but in the MMF stop group the dose was reduced to 0.5 g/day from week 7 to week 12 and then stopped. The intent-to-treat population consisted of 74 (control) and 78 (MMF stop) patients. MMF was tapered off as planned in 82.9% of the patients in the MMF stop arm. The 6-month incidence of biopsy-proven acute rejection was similar in both arms (21.6% control, 16.7% MMF stop). Graft loss occurred in 5.4% (control) and 3.8% (MMF stop) of the patients. MMF could be safely discontinued from a tacrolimus-based triple therapy early after transplantation without any rebound in efficacy during the 6-month follow-up period. (Name of registry: ClinicalStudyResults.org, number: FG-02-CEE-01, date: 9 June 2006).     

无透析肾移植与透析后肾移植临床效果的对比研究

目的　比较透析后肾移植与无透析肾移植的临床效果 ,探讨无透析肾移植的安全性与优越性。　方法　回顾分析 1999年 1月到 2 0 0 3年 1月接受无透析肾移植并定期随访的病例 5 0例 ,选择透析后行肾移植病例 5 0例作为对照 ,2组病例年龄、性别、血型、冷 (热 )缺血时间、人类白细胞抗原 (HLA)配型、原发病、免疫抑制治疗方案等条件相匹配 ,比较 2组病例肾移植术后急、慢性排斥反应和移植肾功能延迟恢复的发生率以及人 /肾存活率。　结果　无透析组中术前曾接受输血者 14例( 2 8% ) ,透析组术前接受输血者 32例 ( 6 4 % ) ,2组比较差异有显著性意义 (P <0 .0 0 1)。无透析组 1年、3年人 /肾存活率均为 10 0 % ,透析组术后 1年、3年人 /肾存活率分别为 10 0 % / 98% ( 5 0 / 4 9)、96 % / 94 % ( 4 8/ 4 7) ,2组比较差异无显著性意义 (P >0 .0 5 )。无透析组术后发生急性排斥反应 3例 ,透析组 5例 ,2组比较差异有显著性意义 (P <0 .0 2 5 ) ;术后发生移植肾功能延迟恢复无透析组为 6例 ,透析组为 12例 ,2组比较差异有显著性意义 (P <0 .0 1)。　结论　无透析肾移植可以减少患者术前透析及输血带来的潜在危险 ,同时能降低术后排斥反应发生率 ,有助于术后移植肾功能的恢复 ,提高移植肾长期存活     

Predictors of graft survival at diagnosis of antibody-mediated renal allograft rejection: a retrospective single-center cohort study

Antibody-mediated rejection (ABMR) is a major cause of graft loss in renal transplantation. We assessed the predictive value of clinical, pathological, and immunological parameters at diagnosis for graft survival. We investigated 54 consecutive patients with biopsy-proven ABMR. Patients were treated according to our current standard regimen followed by triple maintenance immunosuppression. Patient characteristics, renal function, and HLA antibody status at diagnosis, baseline biopsy results, and immunosuppressive treatment were recorded. The risk of graft loss at 24 months after diagnosis and the eGFR slope were assessed. Multivariate analysis showed that eGFR at diagnosis and chronic glomerulopathy independently predict graft loss (HR 0.94; P = 0.018 and HR 1.57; P = 0.045) and eGFR slope (beta 0.46; P < 0.001 and beta −5.47; P < 0.001). Cyclophosphamide treatment (6× 15 mg/m²) plus high-dose intravenous immunoglobulins (IVIG) (1.5 g/kg) was superior compared with single-dose rituximab (1× 500 mg) plus low-dose IVIG (30 g) (HR 0.10; P = 0.008 and beta 10.70; P = 0.017) and one cycle of bortezomib (4× 1.3 mg/m²) plus low-dose IVIG (HR 0.16; P = 0.049 and beta 11.21; P = 0.010) regarding the risk of graft loss and the eGFR slope. In conclusion, renal function at diagnosis and histopathological signs of chronic ABMR seem to predict graft survival independent of the applied treatment regimen. Stepwise modifications of the treatment regimen may help to improve outcome.     

Renal graft loss with plasma cell-rich acute rejection in cadaveric renal transplantation: a case report

Abstract:  We reported a case of renal graft loss in cadaveric renal transplantation. An episode biopsy with renal dysfunction showed plasma cell predominant inflammatory infiltration in the interstitium without a finding of vascular or glomerular rejection, and was diagnosed as plasma cell-rich acute rejection (PCAR). Despite intensive immunosuppressive therapy, the renal histology of repeated biopsies showed persistent plasma cell infiltration and the graft was finally lost. Immunohistological staining and immunoglobulin gene rearrangement studies to estimate the clonality of inflammatory cells revealed that the infiltrating plasma cells were polyclonal in origin. Epstein–Barr virus was not detected by in situ hybridization. From these results, we excluded the possibility of post-transplant lymphoproliferative disorder (PTLD); however, a precise definition and differential diagnosis between PCAR and PTLD has not yet been fully determined. As therapeutic regimens for PCAR and PTLD are different, definite guidelines for diagnosis and treatments of PCAR need to be established.     

Efficacy and safety of tacrolimus compared with cyclosporin A microemulsion in renal transplantation: 2 year follow-up results.

BACKGROUND: Comparison studies of calcineurin inhibitors as cornerstone immunosuppressants in renal transplantation have demonstrated that tacrolimus consistently reduces acute rejection rates and, in some studies, also improves long-term renal outcome in comparison to cyclosporin A (CsA). The aim of the present 2 year follow-up of the European Tacrolimus vs Cyclosporin A Microemulsion Renal Transplantation Study was to investigate long-term clinical outcome in terms of rate of acute rejection, graft and patient survival and graft function. METHODS: The European Tacrolimus vs Cyclosporin A Microemulsion Renal Transplantation Study was a randomized, comparative 6 month trial of the calcineurin inhibitors tacrolimus and CsA in combination with both azathioprine and steroids. The intent-to-treat population (ITT) consisted of 286 patients in the tacrolimus arm and 271 in the CsA microemulsion (CsA-ME) arm. Whereas whole blood level targets were 10-20 and 5-15 ng/ml for tacrolimus and 100-400 and 100-200 ng/ml for CsA during months 0-3 and 4-6, respectively, during the investigator-driven follow-up after termination of the main study (months 7-24) no specific calcineurin inhibitor target levels were required. Follow-up data were collected at 2 years post-transplantation from 237 (82.9% of the ITT population) patients who received tacrolimus and 222 (81.9% of the ITT population) patients who received CsA-ME. RESULTS: Calculated on ITT populations, mortality (2.0% vs 3.3%; P<0.05 in Kaplan-Meier analysis) was lower, but rate of graft loss (9.3% vs 11.2%; P = 0.12 in Kaplan-Meier analysis) was not significantly different after 2 years with tacrolimus- vs CsA-ME-based immunosuppression. Biopsy-proven acute rejection was significantly lower (19.6%) with tacrolimus than with CsA-ME (37.3%) during months 0-6 (P<0.0001), but was not significantly different during months 7-12 and 13-24 of follow-up (1.7% and 0.8% with tacrolimus and 4.7% and 0.9% with CsA-ME, respectively). A composite endpoint consisting of graft loss, patient death and biopsy-proven acute rejection occurred significantly more frequently in CsA-ME patients than in tacrolimus patients (42.8% vs 25.9%; P<0.001) during 24 months follow-up. Renal function 2 years post-transplant, measured by serum creatinine concentrations, was significantly better in tacrolimus-based compared with CsA-ME-based immunosuppression (136.9 vs 161.6 micromol/l; P<0.01). Cornerstone immunosuppression remained unchanged in 82.5% and 66.2% of patients treated with tacrolimus and CsA-ME, respectively. At 2 years, more patients in the tacrolimus arm were off steroids and received calcineurin inhibitor monotherapy, and fewer tacrolimus patients remained on a triple immunosuppressive regimen. The cardiovascular risk profile was affected favourably in the tacrolimus arm, with lower cholesterol and triglyceride concentrations (despite less use of cholesterol-lowering drugs); no significant difference in requirement for antidiabetic medication was noted. CONCLUSIONS: The 2 year study results confirm that tacrolimus is a highly efficacious cornerstone immunosuppressant in kidney transplantation. Tacrolimus-based immunosuppression may induce long-term benefits with regard to graft function and graft survival. The overall side-effect profile is considered to be favourable.     

Successful conversion from twice-daily to once-daily tacrolimus in liver transplantation: observational multicenter study

Dopazo C, Rodriguez R, Llado L, Calatayud D, Castells L, Ramos E, Molina V, García R, Fabregat J, Charco R. Successful conversion from twice‐daily to once‐daily tacrolimus in liver transplantation: observational multicenter study.
Clin Transplant 2012: 26: E32–E37.
© 2011 John Wiley & Sons A/S. Background: Compliance with immunosuppressive therapy in liver transplant patients is critical to prevent acute organ rejection and/or late graft loss. Strategies to simplify the therapeutic regimen may improve adherence. Aim: To evaluate the safety and efficacy of conversion from a twice‐daily to once‐daily tacrolimus formulation in adult liver transplant patients. Patients and methods: This prospective observational multicenter study included 187 liver transplant patients with at least 10 months post‐transplant follow‐up, no rejection episodes in the last three months, and creatinine levels <2 mg/dL. Conversion from a twice‐daily to a once‐daily formulation was based on a 1:1 proportion. Results: Median age was 61 yr (range: 28–80 yr); 64% were men and 36% women. The main indications for liver transplant were alcoholic cirrhosis in 30%. Median conversion time was 55 months (range: 10–215 months). Serum tacrolimus levels decreased at one month after conversion (pre‐conversion levels = 5.4 ± 3.0 ng/mL vs. post‐conversion levels = 4.4 ± 2.4 ng/mL, p = 0.013); however, these values normalized at six months post‐conversion with no changes in liver function and rejection episodes were observed only in two patients. Conclusion: Conversion from a twice‐daily to a once‐daily tacrolimus formulation is a safe, effective strategy in the management of stable liver transplant patients.     

Selective treatment of early acute rejection after liver transplantation: Effects on liver,infection rate,and outcome

To evaluate the results of selective treatment of biopsy-proven mild acute rejection episodes, we retrospectively studied 1-week liver biopsies of 103 patients with a primary liver graft in relation to liver function tests. The overall incidence of rejection was 35 %. In four patients the biopsy showed histological features consistent with rejection; in 27 patients it showed mild acute rejection (grade 1), and in 5 patients it showed moderate acute rejection (grade 2). Study group 1 consisted of 19 untreated patients with grade 1 rejection and group 2 of 8 treated patients with grade 1 rejection. At 30 and 90 days, no differences in liver function tests were found. The infection rate, histology after 1 year, and survival in the two groups did not differ. It may, therefore, be concluded that withholding treatment in histologically proven mild acute rejection is possible in selected patients based on histological, biochemical, and clinical criteria. This may reflect the functional diversity of morphologically similar lymphocytic infiltrates observed in graft biopsies showing features of mild acute rejection.Liver Transplant Group     

Selective treatment of early acute rejection after liver transplantation: effects on liver, infection rate, and outcome

Abstract To evaluate the results of selective treatment of biopsy-proven mild acute rejection episodes, we retrospectively studied 1-week liver biopsies of 103 patients with a primary liver graft in relation to liver function tests. The overall incidence of rejection was 35 %. In four patients the biopsy showed histological features consistent with rejection; in 27 patients it showed mild acute rejection (grade 1), and in 5 patients it showed moderate acute rejection (grade 2). Study group 1 consisted of 19 untreated patients with grade 1 rejection and group 2 of 8 treated patients with grade 1 rejection. At 30 and 90 days, no differences in liver function tests were found. The infection rate, histology after 1 year, and survival in the two groups did not differ. It may, therefore, be concluded that withholding treatment in histologically proven mild acute rejection is possible in selected patients based on histological, biochemical, and clinical criteria. This may reflect the functional diversity of morphologically similar lymphocytic infiltrates observed in graft biopsies showing features of mild acute rejection.     

Daclizumab induction/tacrolimus sparing: a randomized prospective trial in renal transplantation

Abstract: Tacrolimus inhibits lymphocyte responses by blocking calcium-dependent signalling pathways important in IL-2 generation. Daclizumab, a humanized monoclonal antibody, binds with high affinity to the Tac subunit of the IL-2 receptor complex. We reasoned therefore that the absence of IL-2R should permit lower doses of tacrolimus and thereby less toxicity. Twenty-eight patients were randomized and followed for 6 months: Group 1, high dose (HD) tacrolimus (trough 12–17 ng/mL; n  = 13); Group 2, low dose (LD) tacrolimus (trough 5–10 ng/mL; n  = 15). All patients received daclizumab induction (2 mg/kg) on days 0 and 14, mycophenolate mofetil (2 g/d except for one patient who received 1 g) and rapid prednisone taper. Serious infections were minimal in both groups. Hospitalizations, for various reasons, were HD ( n  = 12) and LD ( n  = 6). All patients and grafts survived for the 6-month study period. There was one rejection episode in a non-compliant patient at 101 d. LD tacrolimus appears equally effective as HD tacrolimus in preventing rejection episodes and may be associated with fewer adverse events.     

Analysis of a single-center experience with mycophenolate mofetil based immunosuppression in renal transplantation

Purpose. Acute rejection continues to be a major clinical issue in renal transplantation. Three large multicenter trials have demonstrated a 50% decline in biopsy‐proven rejection when mycophenolate mofetil (MMF) was given to renal transplant recipients with corticosteroids and cyclosporine. The purpose of this study was to compare the 6‐month outcome of renal transplant recipients using MMF and non‐MMF based immunosuppression protocols over a 4‐year period at a single center.
Methods. This retrospective study analyzed three patient groups defined by their immunosuppression protocol. The first group included patients who received a quadruple immunosuppression regimen of antilymphocyte induction (ATG), cyclosporine (CYA), azathioprine (AZA), and corticosteroids (CCS), and were transplanted between October 1993 and May 1995 (AZA group). The second group included patients who received a triple immunosuppression regimen of CYA, MMF, and CCS, and were transplanted between June 1995 and May 1996 (MMF group). The third group included patients who were transplanted between January 1997 and December 1997, and received an immunosuppression regimen of CYA and MMF with a reduced CCS dosing schema (reduced steroid group (RST)). Data were collected from a retrospective review of inpatient and outpatient clinical records.
Results. A total of 325 patients were included in the study (106 AZA, 106 MMF, 113 RST). The demographic characteristics of the three groups were similar; however, the mean donor age for the AZA group was 40±15.1 years versus 33±14.1 years and 34±13.1 years for the MMF and RST groups, respectively (p<0.043). The incidence of acute, biopsy‐proven rejection at 6 months was significantly less in the MMF group when compared with the AZA group [16 (15.1%) versus 35 (33%) patients, p=0.002]. However, the incidence of acute, biopsy‐proven rejection in the RST group (35 patients, 31%) was similar to that of the AZA group. Kaplan–Meier estimates for the cumulative incidence of acute rejection demonstrated a significant difference between the MMF group and the other two groups (p=0.0059). The AZA group had more severe rejection as demonstrated by the more frequent use of antilymphocyte therapy for rejection treatment (68.4% episodes) compared with the MMF (38.9%) and RST (47.6%) groups. After 6 months of follow‐up, 11 patients had lost their grafts (8, AZA; 1, MMF; 2, RST). One patient died in each of the AZA and RST groups due to hemorrhage and a pulmonary embolus, respectively. Four AZA patients were diagnosed with a malignancy (three post‐transplant lymphoproliferative disorder, one squamous skin cell carcinoma) compared with 2 MMF patients (prostate cancer, basal skin cell carcinoma) and no RST patients. Herpes zoster was the only infection that occurred more frequently in the MMF group (p=0.03). No other differences in infection rates were noted among the three groups. The initial length of hospital stay declined significantly over the 4‐year study period [11±4.3 d (AZA), 7.0±4.0 d (MMF), 6.2±3.3 d (RST), p<0.001]. Total number of hospital days for the first 6 months also followed a similar declining pattern. Despite using intravenous cyclosporine immediately post‐transplant in the MMF and RST groups, the incidence of delayed graft function was similar among the three groups. Average serum creatinine at 1 month was significantly lower in the MMF group (p=0.008), but no difference was noted at 3 and 6 months when compared with the AZA and RST groups.
Conclusion. This retrospective analysis indicates that MMF is an effective immunosuppressant. Decreased length of stay and less steroid resistant rejections with MMF is favorable for decreased hospital costs. However, the rebound in rejection rate with the RST group suggests that further study is needed to define the optimal use of this agent in combination with others to maximize effectiveness and minimize negative side effects.     

Impact of immunosuppression on the incidence of early subclinical renal allograft rejection: implications for protocol biopsy policy

In order to determine the impact of immunosuppression (IS) on the incidence of early subclinical rejection (SCR), we studied two groups of patients receiving different immunosuppressive regimens. Patients received cyclosporin (CsA), azathioprine and prednisolone (group 1; n  = 304) or IS according to immunological risk (group 2; n  = 150). The highest-risk patients received basiliximab induction, tacrolimus, mycophenolate mofetil (MMF) and prednisolone; medium-risk patients CsA, MMF and prednisolone; low-risk CsA, azathioprine and prednisolone. Protocol biopsies were performed in all patients, irrespective of graft function, on days 7 and 28 post-transplantation. Only patients with good stable function at the time of biopsy were included for assessment of SCR. Group 2 patients showed significant reductions in total rejection frequency (32.6% vs. 57.2%, P  = <0.0001) and SCR frequency in day 7 protocol biopsies (2% vs. 13%, P  = <0.05). In group 2 patients, all SCRs, but not borderline changes, were treated. Untreated borderline changes did not have an adverse impact on graft function at 1 year post-transplantation. New immunosuppressive regimens may reduce subclinical in addition to clinical rejection-frequency, suggesting that the relative benefit of early protocol biopsies in detecting SCR is also reduced.     

Delayed graft function: risk factors and the relative effects of early function and acute rejection on long-term survival in cadaveric renal transplantation

Delayed graft function (DGF) and acute rejection have both been associated with reduced renal allograft survival. In some studies, they have been shown to have an interactive effect. We studied the risk factors for DGF and the relative impact of DGF and rejection on both short- and long-term survival in recipients of cadaveric renal transplants. Data from the Oxford Transplant Centre Database were assessed on 710 cadaver allografts over a 10-yr period, during which time all recipients received cyclosporin-based immunosuppressive protocols. The interaction between DGF and acute rejection was examined using logistic and Cox multivariate regression. Long cold ischaemia time (CIT), sensitisation and older donor age were found to be independent predictors of DGF. The occurrence of DGF resulted in a reduced 5-yr survival (56 vs. 75%). However, the effect of DGF was confined to the first year post-transplant, as there was no significant difference in survival, as measured by half-life (t1/2) of grafts functioning at 1 yr, with DGF alone and a group with good early function (t1/2 = 21.3 vs. 20.0 yr). There was no increase in acute rejection in grafts with DGF. However, the combination of DGF and acute rejection resulted in the worst short-term graft survival (68% at 1 yr, compared to 92.3% in those grafts with no DGF or acute rejection) and this continued over the long term (t1/2 = 10.5 yr). These data suggest that early function is critical to the success of renal transplantation. The effects of DGF are limited to the first year post-transplant. Long-term graft survival may be improved by efforts to limit CITs, particularly for grafts from older donors and sensitised recipients.     

Clinical application of sirolimus in renal transplantation: an update

In addition to an analysis of the final results of phase I/II and phase III clinical trials of sirolimus (SRL), this review focuses on the recent results of several studies in renal transplantation, which include diverse combinations of SRL with other immunosuppressive agents. While SRL was initially introduced as an adjunctive agent to calcineurin inhibitors, it is now serving as the base for therapies that spare or avoid these nephrotoxic drugs. However, to optimize the use of SRL as base therapy, further work is necessary to determine target concentrations, requirement for concomitant steroids and/or nucleoside synthesis blockers, and countermeasure therapy to overcome the drug's adverse effects.     

Soluble tumor necrosis factor-receptors are not a useful marker of acute allograft rejection: a study in patients with renal or cardiac allografts

In this study, we investigated soluble tumor necrosis factor receptor (sTNF-R) levels in plasma of patients with either a kidney or cardiac allograft when clinical suspicion of acute rejection was raised. In plasma of patients with acute renal graft rejection, the sTNF-R levels were strongly enhanced (20–150 ng/ml) as compared to plasma of patients with stable renal function. Following successful treatment of the rejection, a gradual decline in sTNF-R levels occurred with improving renal function, and an inverse correlation between creatinine clearance and sTNF-R was found. To determine whether the increase was caused by an accumulation of constitutively released sTNF-R and lack of clearance by the kidney, or whether the immunological process of the rejection caused the enhancement, we measured sTNF-R in patients suffering from acute cardiac graft rejection but with predominantly stable kidney function. Rejection of a cardiac graft did not lead to a significant enhancement of sTNF-R levels. However, treatment with ATG or OKT3 did cause enhanced sTNF-R levels, followed by a decline that reached starting values after 7 days. These results provide evidence that the immune reaction that occurs during rejection of a graft does not per se induce discernible changes in sTNF-R levels, whereas that induced by ATG or OKT3 does. Thus, sTNF-R levels are not a reliable marker in transplant recipient monitoring.