Influence of anti-rejection therapy on the timing of cytomegalovirus disease and other infections in renal transplant recipients

Infections are an important cause of mortality and morbidity in renal transplant recipients. To study the impact of anti-rejection therapy on the timing of infections, the records of 599 consecutive renal transplants, performed prior to 31 December 1996 at the Royal Melbourne Hospital, were reviewed. Patients were grouped according to acute rejection (AR) episode and treatment during the first 6 months after transplantation. Group 1 [n = 168 (35%)] patients did not experience any episode of AR. Group 2 [n = 169 (35%)] patients had one or more episodes of AR and received high doses of steroids. Group 3 [n = 141 (30%)] patients had more than one episode of AR and received anti-lymphocyte antibodies in addition to high doses of steroids. Infections were more common in Groups 2 and 3 but only cytomegalovirus (CMV) disease occurred earlier in patients treated with lympholytics. Given the high incidence and early onset of CMV disease in patients receiving lympholytics and considering that an effective prophylactic protocol remains undetermined, pre-emptive treatment with ganciclovir in this high risk group appears justified.     

OKT3 serum levels as a guide for prophylactic therapy: a pilot study in kidney transplant recipients

The use of OKT3 as prophylaxis in renal transplantation results in a reduced incidence of graft rejection and appears to have beneficial effects on long-term kidney graft survival. However, we and others have observed that patients still experience rejection during the period of OKT3 prophylaxis given at the regular 5 mg/day dose. Many of these patients had no circulating CD3⁺ cells at the time of rejection, but their OKT3 serum levels were distinctly low (<500 ng/ml). This led us to adjust OKT3 doses (5 or 10 mg) daily, according to the patients' OKT3 levels, in order to maintain an OKT3 concentration of around 1000 ng/ml. In addition, patients were randomized to receive either 5 mg (group 1, n=15) or 10 mg (group 2, n=14) OKT3 as the initial three doses. Concomitant immunosuppression consisted of azathioprine and steroids, with the introduction of cyclosporin A on day 11. Patient survival was 100% after 3 months of follow-up. The intensity of OKT3 first-dose reactions was similar in both groups. Intragraft thrombosis, initially observed in a previous group of patients who received a fixed 10 mg/day OKT3 prophylaxis, occurred in three patients in group 1 and resulted in two graft losses. The cumulative OKT3 dose was similar in both groups (mean ± SEM 98±2 mg in group 1 vs 102±3 mg in group 2) and higher than the 70 mg usually administered. Group 2 patients had higher OKT3 serum levels during the first 4 days of therapy. No correlation could be found between patient weight and cumulative OKT3 dose (r=0.29). No patient in either group 1 or 2 experienced rejection during OKT3 therapy. This compared favorably with an historical group of kidney recipients treated with a fixed 5 mg/day OKT3 dose, as 6 out of 32 patients in this group developed rejection (P=0.045). The rejection rate up to 3 months post-transplantation in pooled group 1 and 2 patients was low (six episodes per 81 patientmonths of risk exposure). We conclude that adaptation of the OKT3 dose according to daily OKT3 levels is safe and allows for excellent prevention of early graft rejection.     

Low-dose OKT3 induction therapy following renal transplantation: a controlled study

In a prospective clinical study we tested the immunosuppressiveproperties and toxicity of low-dose OKT3 induction therapy inrenal transplant recipients. 50 consecutive renal transplantrecipients were alternat ingly assigned to low-dose OKT3 inductionor prednisolone/cyclosporin. Low-dose OKT3 induction treatmentconsisted of 0.5 mg OKT3 twice daily for 10 days, initiallycombined with azathioprine and prednisolone maintenance immunosuppressionthat was converted to prednisolone/cyclosporin at the end ofthe course. During a 15–29-month follow-up period, low-doseOKT3 induction therapy was found to reduce significantly theincidence of acute rejections, as com-pared to the usual prednisolone/cyclosporinmainten ance immunosuppression (21 versus 52%, P=0.02). Therealso was a tendency towards an improved graft function afterlow-dose OKT3, although no signific ance was reached. Furthermore,compared to a histor ical control group of renal transplantpatients in whom acute rejection was treated with 5 mg OKT3daily, low-dose OKT3 appeared to cause fewer side-effects. Weconclude that low-dose OKT3 induction therapy is superior toprednisolone/cyclosporin in preventing acute rejection afterrenal transplantation and that it is better tolerated than conventionalOKT3 treatment.     

A prospective,double-blind,randomized study of high-versus low-dose OKT3 induction immunosuppression in cadaveric renal transplantation

We undertook a prospective, double-blind study of high-(5-mg) versus low-(2-mg) dose OKT3 for induction immunosuppression (12 days) in cadaveric renal allograft transplantation. Maintenance immunosuppression was identical in both groups and consisted of azathioprine and prednisone initially, with cyclosporine beginning on the 5th postoperative day. Twenty-six patients were randomized. The groups were similar in terms of age, kidney ischemia time, peak PRA, and latest PRA. There were more diabetics and women in the high-dose group. Patient survival at 12 months was 100% in both groups. Graft survival at 12 months was 92% and 100% in the high- and low-dose groups, respectively. Infections were mostly minior and equal in frequency in the two groups. All patients receiving high- or low-dose OKT3 had manifestations of the cytokine release syndrome; these were delayed in onset in the low-dose group. Eleven patients (85%) in each group produced anti-OKT3 andtibodies. Lymphocyte depletion after 1 day was major (>98%) and identical in both groups. CD3 antigens were removed more slowly in the low-dose group but eventually at equal rates in both groups. Cost was significantly lower in the low-dose group. We conclude that while both doses of OKT3 were effective and safe for induction immunosuppression, it may be prudent to use a lower dose of OKT3 for induction immunosuppression because of its potential to reduce cytokine-mediated effects and to avoid the complications of overimmunosuppression and because of the lower costs associated with it.     

Historical controlled trial of OKT3 versus basiliximab induction therapy in simultaneous pancreas-renal transplantation

SUMMARY:   Simultaneous pancreas–kidney (SPK) transplant recipients are at high immunological risk of rejection. Antibody induction is beneficial but lymphocyte-depleting therapy is associated with a high incidence of side-effects. We performed a historical controlled trial to compare OKT3 versus anti-CD25 antibody (basiliximab) induction therapy with regard to patient, kidney and pancreas survival, as well as to examine for any differences in acute rejection, graft function, and infective complications. Twenty-eight consecutive SPK transplants were performed at the Monash Medical Centre between December 1997 and November 2001. Anti CD3 monoclonal antibody (OKT3) was used prior to March 2000 ( n  = 12) and basiliximab was used after ( n  = 16), both in combination with cyclosporin, mycophenolate, and prednisolone. A retrospective comparison of outcomes was performed. At 6 months, patient (100 vs 100%), kidney (91.7 vs 91.7%) and pancreas (75 vs 83.3%) survival were similar in the OKT3 and basiliximab groups, respectively. A minority of subjects in each group remained free from rejection (42% basiliximab vs 25% on OKT3, P  = NS). Renal function was superior in the basiliximab group (mean calculated creatinine clearance 79.4 ± 11.9 vs 54.5 ± 15.9 mL/min for  basiliximab vs OKT3, P  < 0.001). The incidence of major opportunistic infection was lower in basiliximab-treated patients (9 vs 50% in the OKT3 group, P  = 0.033). Basiliximab was associated with similar 6-month patient, kidney and pancreas survival, superior renal function and less opportunistic infection as compared with OKT3 induction therapy in SPK transplants. Basiliximab is at least as effective and is safer than OKT3 for induction therapy in SPK transplantation.     

A single-centre experience of post-renal transplant lymphoproliferative disorder

Post-transplant lymphoproliferative disorder (PTLD) complicates 1 to 10% of all transplantations. Previous clinicopathological studies of PTLD have been limited by small numbers, short follow-up times, outdated data, heterogeneity of pooled solid-organ transplant results, and selective inclusion of early-onset disease. We therefore undertake here a retrospective analysis and identify all cases of PTLD that complicated renal transplantation at the Princess Alexandra Hospital between 30 June 1969 and 31 May 2001. Tumour samples were subsequently retrieved for pathological review and for Epstein-Barr virus-encoded RNA in situ hybridisation (EBER-ISH). Of 2,030 renal transplantation patients, 29 (1.4%) developed PTLD after a median period of 0.5 years (range 0.1 to 23.3 years). PTLD patients were more likely to have received cyclosporine (76% versus 62%, P<0.05), tacrolimus (10% versus 2%, P<0.05) and OKT3 (28% versus 10%, P<0.01). As the burden of immunosuppression increased from dual, to triple, to OKT3 therapy, the risks of early onset, extensive-stage, polymorphic, Epstein-Barr virus (EBV)-associated and fatal PTLD progressively increased. The majority of patients presented with an extra-nodal mass (45%), were afebrile (76%), and had stage-IV disease (60%). EBER-ISH was positive in 58%. Actuarial 5-year disease-free survival was 53.7%. The independent predictors of mortality on multivariate Cox regression were polymorphic histology (HR 7.4, 95% CI 1.5-37) and an international prognostic index (IPI) >1 (HR 2.7, 95% CI 1.1-6.8). Compared with other treatments, chemotherapy was associated with higher survival rates (100% versus 18% at 3 years, P=0.0001). In conclusion, PTLD is more likely, occurs earlier, and is more often fatal, in the setting of intensive immunosuppression. Nevertheless, excellent long-term outcomes are achievable with early recognition and institution of appropriate treatment.     

Potent Induction Immunotherapy Promotes Long‐Term Insulin Independence After Islet Transplantation in Type 1 Diabetes

The seemingly inexorable decline in insulin independence after islet transplant alone (ITA) has raised concern about its clinical utility. We hypothesized that induction immunosuppression therapy determines durability of insulin independence. We analyzed the proportion of insulin‐independent patients following final islet infusion in four groups of ITA recipients according to induction immunotherapy: University of Minnesota recipients given FcR nonbinding anti‐CD3 antibody alone or T cell depleting antibodies (TCDAb) and TNF‐α inhibition (TNF‐α‐i) (group 1; n = 29); recipients reported to the Collaborative Islet Transplant Registry (CITR) given TCDAb+TNF‐α‐i (group 2; n = 20); CITR recipients given TCDAb without TNF‐α‐i (group 3; n = 43); and CITR recipients given IL‐2 receptor antibodies (IL‐2RAb) alone (group 4; n = 177). Results were compared with outcomes in pancreas transplant alone (PTA) recipients reported to the Scientific Registry of Transplant Recipients (group 5; n = 677). The 5‐year insulin independence rates in group 1 (50%) and group 2 (50%) were comparable to outcomes in PTA (group 5: 52%; p>>0.05) but significantly higher than in group 3 (0%; p = 0.001) and group 4 (20%; p = 0.02). Induction immunosuppression was significantly associated with 5‐year insulin independence (p = 0.03), regardless of maintenance immunosuppression or other factors. These findings support potential for long‐term insulin independence after ITA using potent induction therapy, with anti‐CD3 Ab or TCDAb+TNF‐α‐i.     

OKT3 induction in pediatric renal transplantation

Twenty cadaveric renal transplant patients (mean age 12.5±4.8 years) received 14 days (mean 13.0±2.8 days) of OKT3 (mean dose 0.16±0.09 mg/kg) along with prednisone 0.5 mg/kg per day, azathioprine 2 mg/kg per day and cyclosporine 5 mg/kg per day which was increased to obtain therapeutic levels before the discontinuation of OKT3. Actuarial patient and graft survival were 100% and 50%, respectively, at both 1 and 5 years. Four children lost their grafts within the first 48 h. One loss was technical in origin, the remaining 3 had pathological evidence of vascular thrombosis. Of the remaining 16 children, 12 (75%) experienced rejection episodes within the first 2 months post transplant (mean 27±15 days). Successful reversal of early rejection episodes was achieved in 11 of 12 patients. Clinically significant cytomegalovirus infection occurred in 4 patients and resulted in graft loss in 2 patients. Circulating OKT3 levels ranging from 1,000 to 32,000 ng/ml were seen in all patients within the first 48 h. There was a rapid and total depletion of circulating CD3-positive lymphocytes in all patients. Antiisotypic and anti-idiotypic OKT3 antibodies were assessed by enzyme-linked immunosorbent assay (ELISA), and blocking anti-idiotypic antibodies were detected by immunofluorescence inhibition assay. Positive OKT3 antibody titers were detected in 11 children by ELISA and 10 children by immunofluorescence inhibition assay. In summary, we have found that in pediatric renal transplant patients receiving OKT3 induction therap: (1) there is a high occurrence of vascular thrombosis; (2) the incidence of early acute rejection is high; (3) the time to first rejection is not as long as that reported for adults; (4) there is a substantial rate of sensitization against OKT3; (5) despite successful reversal of early acute rejection, long-term-graft survival does not appear to have been beneficially altered.     

肾移植引起的急性排斥反应的治疗

目的评价肾移植引起的急性排斥反应的治疗措施及影响愈后的相关因素。方法回顾性研究326例首次移植中86例发生急性排斥反应(AR)的治疗措施、结果及愈后的相关因素。结果86例AR经治疗后5例失败,81例成功,其中68例采用甲基强地松龙(MP)冲击治愈者为48例,11例一线用抗胸腺淋巴细胞球蛋白(ATG)治愈10例,7例一线用OKT3 治愈6例;20例MP冲击无效者全部续用ATG或OKT3治疗,14例逆转成功;对上述治疗无效的8例中6例应用环孢素(CSA)的患者改换为普乐可复(FK506)后治愈3例;共5例因AR不能控制,并发感染、移植肾破裂或血管栓塞而切除移植肾。结论MP冲击为治疗AR的常用有效手段,冲击后第2、3天血肌酐(SCr)上升>10%者多疗效较差。发生AR时SCr较高者治愈率低。ATG和OKT3作为一线或二线治疗措施均有良好效果。对于难治性AR,ATG和OKT3亦无效者,改换基础免疫抑制治疗,即CSA 转化为FK506,有一定的治疗效果。     

T-cell chronic lymphocytic leukaemia: Anomalous cell markers,variable morphology,and marked responsiveness to pentostatin (2′-deoxycoformycin)

4 men with an unusual variant of T-cell chronic lymphocytic leukaemia are reported. The clinical features differed from the virus-associated T-cell disease reported from Japan, the Caribbean, and the southeastern United States. Cytology was pleiomorphic: cells with cerebriform nuclei resembling Sézary cells and lymphocytes with cytoplasmic granules resembling T-suppressor cells occurred in the same patients. Immunofluorescence studies with monoclonal antibodies suggested that the leukaemia cells expressed determinants of both helper- (OKT4+) and suppressor-(OKT8+) related antigens. The cells were TdT-negative. In all patients the disease was very refractory to conventional cytotoxic agents, but there was prompt and extensive response to the adenosine deaminase inhibitor pentostatin (2′-deoxycoformycin). This agent merits further study in the treatment of T-cell chronic lymphocytic leukaemia.