Low-dose maintenance prednisone and antilymphoblast globulin for the treatment of acute rejection. A steroid-sparing approach to immunosuppressive therapy

The purpose of this prospective randomized trial was to evaluate an immunosuppressive protocol involving reduced maintenance and antirejection steroid dosages in cadaver renal transplantation. The study comprises 23 first cadaver graft recipients who experienced an acute rejection episode. All patients received an initial 14-day course of antilymphocyte globulin (ALG) and azathioprine 1.5 to 2.0 mg/kg/day. In 11 patients (group 1), a low maintenance dose of prednisone (30 mg/day) was administered and first rejection episodes were treated with a second 10-day course of ALG. The remaining 12 patients (group 2) received high maintenance doses of prednisone (2 mg/kg/day with tapering) and intravenous methylprednisolone (IVMP) for first rejection episodes. Subsequent rejections in both groups were treated with high doses of steroids. In group 1, all first rejection episodes were reversed with ALG alone, 6 patients experienced no subsequent rejection, and 10 patients currently have a functioning graft. In Group 2, the first rejection episode was reversed with IMVP alone in 10 patients; in two patients in whom IVMP therapy was unsuccessful, ALG was then administered, and subsequent rejection reversal was effected. In group 2, 4 patients experienced no subsequent rejection, and 9 patients currently have a functioning graft. Patients in group 1 received significantly lower (P less than .01) cumulative steroid doses in the first six months following transplantation, which resulted in a reduced number of major infections, as compared with patients in group 2. We conclude that the steroid-sparing regimen of low maintenance prednisone and ALG for first rejection is as effective immunologically as the established high steroid protocol.     

Acute rejection relapses posttransplant: definition of risk group and evaluation of potent therapeutic regimens

Abstract  A group of 113 patients were investigated after allogenic cadaver renal transplantation to analyse whether the small number of patients presenting acute rejection relapses could be defined by risk factors and whether there is an efficacious regimen for the safe therapy of recurrent rejection episodes. According to these results we are aware of a group of 19 highly reactive rejector especially within the younger recipients and there are further characteristics which can be identified as being associated with an elevated risk of recurrent acute rejection. By adequate antirejection therapy we can achieve a favourable transplant survival rate of 97 % in the critical first year. An additional benefit may result from ALG consolidation related to suppression of the remaining C -positive human natural killer cells.     

Treatment of renal transplant rejection episodes in patients receiving prednisone and azathioprine. A cost-effective approach

Antilymphocyte globulin (ALG) has been advocated for the treatment of renal transplant rejection episodes in patients maintained on prednisone and azathioprine. Treatment with steroids (outpatient) is considerably less expensive than with ALG (inpatient), so we studied whether routine ALG was necessary. Between 3/82 and 11/83, 54 cadaver transplant recipients maintained on prednisone and azathioprine who developed a first rejection episode were randomized to receive--for treatment of their first, and if necessary second, rejection--methylprednisolone (MP) plus ALG (n = 24), or MP alone, with ALG added if treatment failed (n = 30). Treatment failure was defined as continuing deterioration on T131 iodohippuran scan, rising serum creatinine level, or lack of improvement within 7 days. There was no significant difference in patient survival, graft survival, mean number of rejections, and infection rate between the two groups: 60% (18/30) of first and 50% (10/10) of second rejection episodes responded to MP alone. We conclude that patients are not penalized by initial rejection treatment with MP. Many rejection episodes respond to steroids alone; elimination of routine ALG use will save hospitalization time and expense.     

Effect of delayed graft function and ALG on the circaseptan (about 7-day) rhythm of human renal allograft rejection

Postimplantation records of 157 kidney transplant recipients with first rejection episodes within 50 days of surgery were studied. Of these 36 had living-related and 121 cadaver donors. Recipients of cadaver donor kidneys were divided into four subgroups: with and without postoperative acute renal failure (ARF), and with and without approximately two weeks of immunosuppression by antilymphoblast globulin (ALG) added to conventional therapy. All recipients with immediate function without ALG showed evidence of periodicity in probability of occurrence of rejection that was highly significant for a 7-day period beginning at the time of surgery. The remaining groups showed less significant periodicity or no significant periodicity beginning at the time of surgery, but they did show a highly significant circaseptan rhythm of rejection episodes beginning with cessation of ALG treatment or with onset of diuresis following ARF in the absence of ALG. It is suggested that clinical manifestation of the immunologic attack of recipient upon graft has an intrinsic development period of about 7 days beginning with implantation. However, initiation of the first period may be blocked by ALG or by low renal blood flow during ARF.     

The Effect of Serum ALG Concentrations on Results Following Renal Transplantation

Seventy-three recipients of renal allografts from cadaver donors, and 121 recipients of kidneys from living related donors were studied to determine whether there were any differences in posttransplant results between patients that had a high average serum concentration of ALG (>/=800 microg/ml) during the two weeks of ALG therapy and patients that had low serum levels (/=800 microg/ml when high risk patients with diabetes mellitus were excluded. There were significantly also fewer rejection episodes at three months in recipients of living related kidney grafts that had serum ALG levels >/=800 microg/ml. When high risk diabetics or patients older than 40 were excluded from the related recipients, the number of rejection episodes was still significantly less in patients with high serum ALG levels. There was significantly less kidney loss 24 and more months posttransplant in recipients of kidneys from living related donors whether or not high risk patients were excluded. These results support previous reports from the University of Minnesota indicating ALG is a safe and effective immunosuppressive agent in renal allograft recipients.     

Acute rejection episodes after renal transplantation in children

46 renal transplants performed in children at the Medizinische Hochschule Hannover between 1975 and 1980 are evaluated for the occurrence of acute rejection episodes. 33 patients received cadaveric donor grafts (CAD) and 13 living donor grafts (LD). Immunosuppression was carried out with prednisone and azathioprine. 14 patients were treated additionally with antilymphocyte globulin (ALG). A total of 68 acute rejection episodes occurred, 38% of them within the first week of transplantation, and the latest 3 years after transplantation. The most important signs of acute rejection were a rise in serum creatinine concentration, a decrease in urine output and fever. Patients with living donor grafts and full-house matched kidneys had fewer reversible and irreversible rejection episodes than did patients with grafts from cadaveric donors and with grafts with 1-4 mismatches. The value of ALG treatment is doubtful: only 1 out of 14 patients who received ALG treatment experienced no rejection episodes compared to 12 out of 33 patients who did not have ALG treatment. 2.4 rejection episodes/patient occurred in patients who had cadaver grafts and had received ALG compared to 1.17 episodes/patient in similar patients who had not received ALG. Irreversible rejection episodes occurred in 4 out of 9 ALG-treated and in 3 out of 23 non-ALG-treated recipients of cadaver grafts.     

Seven years' experience with antilymphoblast globulin for renal transplantation from cadaver donors.

Antibody of the IgGab type can be isolated from horses immunized with cultured human lymphoblasts plus complete Freund's adjuvant. The essential steps for the production of a safe, potent anti-human lymphoblast globulin (ALG) are: A) the use of early bleedings after immunization to reduce the titer of antibodies which react with red blood cells and platelets; B) careful absorption with human red blood cell stroma and platelets; C) stabilization with non-crystalline silica dioxide; D) chromatography through QAE sephadex to remove pyrogens, microaggregates and possible inhibitors of ALG activity; E) careful safety testing in animals for toxicity and pyrogenicity; and F) testing in vitro for sterility. Such a purified horse ALG (IgGab) can be administered safely intravenously to patients to supplement a standardized immunosuppressive regimen incorporating azathioprine and prednisone. Under these circumstances, allergic reactions are very rare, antibodies to horse IgG do not develop, skin tests to horse IgG remain negative, and immune elimination of circulating horse IgG from the human circulation cannot be demonstrated. The overall results of ALG patient survival and transplant function after 184 consecutive first cadaver transplants at the University of Minnesota demonstrate a statistically significant improvement in both parameters accompanying increases in ALG dose while rigidly utilizing standardized doses of azathioprine and prednisone. There is a significant reduction in the number of grafts lost to rejection; significant reduction in the number of rejection episodes; significant delay in the onset of rejection episodes; but there is no increase in septic loss of patients or kidneys. These efforts could be seen in the gross data or when subgroups controlling for patient age, tissue typing were analyzed. Excluding patients at high risk did not alter the results. The beneficial effects of ALG were particularly striking in good matches. In the highest doses, ALG may be dangerous for older patients with poor matches who develop an increased incidence of septic loss of kidney and/or life. Thus, ALG appears to be a useful adjunct in the early management of cadaver transplants by reducing the incidence and frequency of rejection episodes. The dose should probably be reduced in the older patients who receive kidneys from badly mismatched donors. One cannot conclude from this study that ALG manufactured in other centers by this or other techniques, will accomplish the same results since the multiplicity of factors involved in the success and failure of transplants must be controlled so that the influence of intravening variables in the assessment of ALG effectiveness can be assessed.     

Renal transplantation for end-stage polycystic kidney disease

From 1963 to 1984, 56 renal transplants were performed in 51 patients with end-stage renal failure due to autosomal dominant polycystic kidney disease (ADPKD). There were 49 cadaver and 7 living-related transplants. Overall patient and graft survival was 88 per cent and 66 per cent at one year, 59 per cent and 49 per cent at five years, respectively. There was no significant difference in patient or graft outcome with cadaver versus living-related donor kidneys. One-year graft success with and without pretransplant bilateral nephrectomy (BN) was 78 per cent versus 58 per cent, respectively (n.s.). Patient survival after return to dialysis after graft loss was not compromised by the earlier performance of BN. In patients who did not undergo pretransplant BN, there were no complications from the retained native kidneys after transplantation. In cadaver recipients, the two-year graft success rate with and without preliminary blood transfusions was 54 per cent versus 61 per cent, respectively (n.s.). Cadaver graft survival with and without adjunctive antilymphocyte globulin (ALG), excluding 3 recipients managed with cyclosporine, was 88 per cent versus 50 per cent at one year, and 70 per cent versus 32 per cent at five years, respectively (p less than 0.05). This beneficial effect of ALG was still evident when only transfused cadaver recipients were analyzed and was achieved with no resulting compromise in patient survival. Follow-up computerized tomography (CT) scanning of the transplant kidney in 10 recipients with a long-term (1-9 years) functioning allograft showed no evidence of recurrent ADKPKD.     

Experimental and clinical experience with urine amylase monitoring for early diagnosis of rejection in pancreas transplantation

Pancreas allograft rejection in dogs with pancreaticocystostomy can be predicted in advance of hyperglycemia by monitoring the urinary amylase (UA) concentration (U/L): In initial experiments, UA values declined to less than 1000 1.3 +/- 0.2 days before hyperglycemia in nonimmunosuppressed dogs, 3.3 +/- 1.0 days in dogs treated with cyclosporine (CsA), and 9.3 +/- 0.7 days in dogs treated with CsA, azathioprine (Aza), and prednisone (triple therapy). Autotransplanted control dogs maintained high urine amylase concentrations indefinitely (mean 125,544 +/- 36,931). In a subsequent experiment, in 19 dogs with bladder-drained pancreas allografts on CsA only for prophylactic immunosuppression, a five-day course of antirejection treatment with Aza (5.0 mg/kg) and antilymphocyte globulin ALG (1 mg/kg) was started in group A (n = 10) when a raise in serum glucose was detected, and in group B (n = 9) when a drop of UA below 1000 was observed. The functional allograft survival rate was 9.2 +/- 0.5 days in group A (treatment started after hyperglycemia) and 29.0 +/- 5.7 days in group B (treatment started after drop in UA) (P = .002). The UA dropped in all dogs before hyperglycemia, at a mean of 2.7 days in group A and 20.8 days in group B. Clinically, 8 patients received a whole cadaver pancreas transplant with urinary drainage of the exocrine secretions. All were followed with UA monitoring. Three recipients lost the grafts for technical reasons. Three recipients lost the grafts for technical reasons. One had a primary non-function and UA was below 1000 U/24 hr; two developed abscesses and the grafts were removed while functioning with high UA values. Five grafts are currently functioning; 3 recipients had no rejection episodes and their UA values ranged from 30,000 to 100,000 U/24 hr during their entire postoperative course. The other two had rejection episodes. In both cases UA decreased to baseline levels 1 and 4 days in advance of the hyperglycemia. After antirejection treatment UA rose again to high values and plasma glucose levels declined. Both patients are currently insulin-independent, with UA values ranging from 10,000 to 200,000 U/24 hr. Both experimentally and clinically UA is an early predictor of pancreas allograft rejection. The institution of early treatment of rejection episodes in dogs, based on UA, significantly improved allograft survival. Urine amylase monitoring in pancreas transplant recipients could lead to an early treatment of rejection and improve graft survival.     

Long-term alternate day steroid therapy in renal transplantation. A controlled study

Seventy-six adult renal allograft recipients were allocated 5 months post-transplantation to daily or alternate day maintenance methylprednisolone therapy. All 15 recipients of living related kidneys and 23 recipients of cadaver kidneys were placed on the alternate day regimen, while 38 patients with cadaveric grafts remained on daily methylprednisolone. In patients on alternate day methylprednisolone, serum creatinine concentrations, frequency of acute rejection episodes, and prevalence of chronic rejection were similar to those of patients on daily steroids. Furthermore, no differences were noted in the rate of loss of graft function between recipients of cadaver kidneys on daily versus alternate day steroids. There were no differences in body weight, blood pressure, degree of hyperglycemia, or hyperlipidemia between patients on the daily or alternate day schedules. However, the prevalence of clinical osteonecrosis and the rate of infectious complications requiring hospitalization were significantly decreased in patients on alternate day methylprednisolone. We conclude that alternate day methylprednisolone therapy is as effective as daily steroids for the maintenance of graft function in renal transplant recipients. The decreased incidence of osteonecrosis and the lower frequency of infectious complications represent a strong argument in favor of alternate day steroid therapy.     

The value of needle renal allograft biopsy. I. A retrospective study of biopsies performed during putative rejection episodes.

Following renal transplantation, immunosuppression is usually increased to treat presumed rejection episodes. However, a) many conditions mimic rejection in the post-transplant period, and b) many rejection episodes are irreversible. As increased immunosuppressive therapy is associated with an increased risk of infection, it would be ideal to limit antirejection therapy to only the rejection episodes that are reversible. The role of percutaneous allograft biopsy was studied as an aid to decide which patients to treat for rejection, to limit unnecessary immunosuppression and to predict allograft survival. One hundred thirty-five patients with suspected rejection underwent 206 allograft biopsies without complication. Two hundred four biopsies were available for study. Biopsies were coded on a 1-4 scale (minimal, mild, moderate, severe) for acute and chronic tubulointerstitial infiltrate and vascular rejection, as well as no rejection (e.g., recurrence of original disease). Treatment decisions were made on the basis of the biopsy combined with clinical data. All patients have been followed two years and outcome correlated with biopsy findings (death, nephrectomy, and return to dialysis defined as kidney loss). The results were the following: 1) biopsies represented changes within the kidney. Of 16 kidneys removed within one month of biopsy, no nephrectomy specimen showed less rejection than that seen on biopsy. 2) Eighty-one biopsies (39.7%) led to tapering or not increasing immunosuppression (either no rejection, minimal rejection, or irreversible changes). 3) Kidneys having either severe acute or chronic vascular rejection (less than 30% function at three months) had significantly (p less than 0.05) decreased survival three to 24 months postbiopsy than those with minimal or mild vascular rejection or tubulointerstitial infiltrate (83% function at three months). 4) Kidneys with moderate chronic vascular rejection and those with severe acute tubulointerstitial infiltrate had significantly (p less than 0.05) decreased survival at six to 24 months. 5) Kidneys with moderate chronic vascular rejection (MCV) without an acute infiltrate (ATI) had significantly better survival than those having both MCV and ATI. 6) Similarly, kidneys having severe ATI alone had better survival than those with ATI plus vascular rejection. It was concluded that a) percutaneous allograft biopsy can be done without graft loss or infection; b) biopsy represents changes throughout the kidney; c) biopsy aids in deciding when to treat for rejection and in deciding when to withhold increased immunosuppression, and d) allograft biopsy predicts the outcome of treatment of a rejection episode.     

Impact of mycophenolate mofetil on recurrent rejection in kidney transplant patients

PURPOSE: Mycophenolate mofetil (MMF) has emerged as a valuable adjunctive agent in renal transplantation. However, due to intolerable adverse effects associated with MMF use in our transplant population, we have used MMF selectively in patients at high risk for recurrent graft rejection, since these patients are known to be at risk for poor long-term graft outcomes. The purpose of this study was to assess the efficacy of MMF in preventing the recurrence of acute rejection following an initial rejection episode in kidney transplant patients in the first year following transplantation. METHODS: Forty-four kidney transplant recipients were given MMF prospectively following treatment of their initial rejection episode to prevent recurrent rejection. MMF 1-2 g/d was given. Doses were adjusted based on tolerance; MMF therapy was to be continued for at least 6 months. The control group consisted of 124 consecutive kidney transplant recipients who had received standard anti-rejection therapy without the addition of MMF. Maintenance immunosuppression consisted predominantly of cyclosporine, prednisone+/-azathioprine. Anti-rejection therapy for both groups consisted of either corticosteroids (methylprednisolone 500 mg i.v. for 3 d or oral prednisone 2 mg/kg/d with rapid taper over 3 wk), OKT3 5 mg/d for 10 d or ATG 15 mg/kg/d for 10 d. All rejection episodes were confirmed by biopsy. RESULTS: The majority of rejection episodes were characterized histologically as mild or moderate. Most patients (76%) received corticosteroids for treatment of their first rejection episode. There was a 68% reduction in the incidence of recurrent rejection episodes within the first year of transplant in patients receiving MMF; only 14% of recipients receiving MMF developed recurrent rejection compared to 44% of patients in the control group (p<0.05). Approximately 50% of patients developed MMF-associated adverse effects (leukopenia, GI toxicity). Only 52% of patients remained on MMF at 6 months. One-yr graft survival was 86% in the MMF group and 89% in the control group (p>0.05). One-year patient survival was 93 and 100%, respectively (p>0.05). CONCLUSIONS: The addition of MMF to maintenance therapy for patients experiencing acute renal allograft rejection may prevent recurrent rejection episodes in the subsequent follow-up year.     

Increased infections associated with the use of OKT3 for treatment of steroid-resistant rejection in renal transplantation

We compared the infections encountered in 23 renal transplant patients given the monoclonal anti-T-cell antibody, Orthoclone OKT3 (OKT3), for treatment of steroid-resistant rejection in 1986 and in 23 control patients from 1984 to 1985 with resistant rejection matched demographically, for severity of rejection and for risk factors predisposing to infection, who did not receive OKT3; recipients of OKT3 received substantially less prednisone, cyclosporine, and antilymphocyte globulin (ALG) than control patients for treatment of the rejection episode. Fourteen (61%) patients given OKT3 developed one or more infections in the 3-month period following treatment as compared with 9 control patients (39%) given conventional antirejection therapy with high-dose steroids and, usually, ALG. Patients given OKT3 were significantly more likely to develop serious infections (pneumonia, bacteremia, meningitis, or severe viral infection; 16 episodes vs. 4, P = .02). Six recipients of OKT3 (26%) acquired infections typically encountered in states associated with depressed cell-mediated immunity (CMI)--Listeria sepsis (2), disseminated nocardiosis and Mycobacterium tuberculosis infection (1), cytomegalovirus (CMV) pneumonia (1), Yersinia infection with severe dermatophytosis (1), and Epstein-Barr virus-associated lymphoproliferative syndrome (1)--as compared with 1 case of mild CMV infection in the control group (P = .08). Trimethoprim-sulfamethoxazole (TMP-SMZ) was given to 19 patients in each group; all 4 recipients of OKT3 who did not receive TMP-SMZ prophylaxis developed life-threatening infection, 3, bacteremia (2 with Listeria) and 1, disseminated nocardiosis and M tuberculosis infection. These data suggest that OKT3 given for treatment of resistant rejection in renal transplantation predisposes the patient to serious infection, particularly with opportunistic pathogens characteristically associated with depressed cell-mediated immunity. Prophylaxis with TMP-SMZ, which is safe, well tolerated, and effective for reducing the incidence of infection in renal transplantation, may be especially important during OKT3 therapy.     

The early posttransplant prognosis of acute renal allograft rejection as determined by detection of cytotoxic antibodies to lymphoid B cell lines

We have studied serial samples of pretransplant and posttransplant sera for cytotoxic antibodies to lymphoid B cell lines (LCL) in 45 renal allograft recipients. A total of 48 rejection reactions occurred in 31 patients. A comparison of each patient's most reactive posttransplant serum showed a significantly higher reactivity in the ten patients with early allograft failure when compared with the 21 patients with reversible rejections and the 14 patients who had no rejections. Rejection reactions were easily differentiated by comparing the change in cytotoxic reactivity to LCL of recipients' sera drawn at the time of a rejection episode with the reactivity of their pretransplant sera. In 32 rejections considered non-antibody-associated cytotoxic reactivity of recipients' sera to LCL either decreased or remained essentially unchanged during the rejection. In 16 rejections considered antibody-associated the recipients' sera drawn during the rejection episode showed an increase in cytotoxic reactivity ranging from 40% to 100%. Response to antirejection therapy and three month graft survival had a significant correlation with changes in LCL antibody reactivity during a rejection. Only two of the 32 rejections considered non-antibody-associated failed to reverse compared with eight of the 16 antibody-associated rejections (P less than .001). Graft survival at three months in patients with non-antibody-associated rejections was 90% compared with 27% in the 11 patients who had antibody-associated rejections (P less than .001) Other parameters possibly related to the severity of a rejection reaction or to early allograft prognosis did not differ appreciably between the two types of rejections. This included the time posttransplant to the first rejection episode, the number of patients with multiple rejections in the first three months, and rejections requiring dialysis therapy. Determination of a change in cytotoxic reactivity to LCL during a rejection reaction enables one to predict the response to antirejection therapy and early allograft prognosis. This may ultimately be useful in selecting different types of antirejection therapy for individual patients.     

Clinical Evaluation of Equine Antithymocyte Globulin in Recipients of Renal Allografts: Analysis of Survival, Renal Function, Rejection, Histocompatibility, and Complications

Equine antithymocyte globulin combined with azathioprine and prednisone as immunosuppressive therapy in 50 transplant recipients prolonged allograft survival and seemed to modify the severity of rejection episodes. Although nine patients died from a variety of causes, only three kidneys were lost to rejection, one of which was hyperacute. There were no serious untoward hematologic or systemic effects caused by the ATG, and all patients completed the course of therapy. Infection, a serious and frequent complication of transplant patients, was encountered no more often than in other transplant series not using ALG. The data pertaining to the clinical value of ATG, although suggestive in terms of its immunosuppressive effects, is still not conclusive; and a definitive answer to this question awaits further evaluation in a series of cadaveric recipients in a randomized-double-blind study.     

When Should the Third Renal Transplant Rejection Episode be Treated?

Recent reports cite better survival when repeatedly rejecting renal allografts are removed and patients returned to hemodialysis. However, the criteria for graft removal remain undefined; although some reports recommend removing all kidneys undergoing a third rejection. In our series (1968-1973) of 316 patients with technically successful first grafts followed 2(1/2)-8 years, graft survival was inversely related to the number of rejection episodes. One hundred per cent of kidneys without rejection are currently functioning or functioned at the time of death compared to 90% with one rejection, 67.4% with two and 21% with three. However, 40% of kidneys having three rejection episodes functioned longer than one year after treatment of the third rejection episode. In an attempt to determine the predictability of one year graft survival or failure following treatment of the third rejection, a formula was developed that correctly predicted in 33 of 38 (87%) patients. The formula was based on information available prior to treatment of the third rejection episode, and represents an index of baseline renal function (serum creatinine after second rejection episode) and two indices of the severity of rejection episodes (serum creatinine change between the first and second rejection episodes; rapidity of sequential rejection).Following its derivation, the formula was applied to a second group (1974) of 19 patients having had three rejection episodes. The formula correctly predicted one year allograft survival or failure following treatment of the third rejection episode in 68% of these patients. A striking finding of our review was a significant difference in current patient survival between those having no rejection episodes (89%) and those having one or more rejection episodes (65%) (p < .00001). There was no significantly greater long-term curtailment in survival if more than one rejection eipsode was treated. Patients having one rejection eipsode seemed to die from varying causes and at varying time periods. Patients dying after two or more rejection episodes had an increased incidence of deaths due to bacterial infection.     

Improved efficacy of basiliximab over antilymphocyte globulin induction therapy in paediatric renal transplantation.

BACKGROUND: Basiliximab is a chimeric human/mouse monoclonal antibody directed against the alpha chain of the IL-2 receptor, CD25, which has been reported as successfully reducing rejection in adult renal transplant recipients. Reported clinical experience of basiliximab in paediatric renal transplantation is limited. METHODS: Using two intravenous doses on day 0 (pre-operatively) and day 4 with prednisolone and cyclosporin A (dual) maintenance immunosuppression in 42 children undergoing renal transplantation in our unit (SIM group), we have compared patient and graft outcome, rejection rates in the first 6 months, renal function and the incidence of Cytomegalovirus (CMV) infection with 42 consecutive children who previously received antilymphocyte globulin immunoprophylaxis with prednisolone, cyclosporin A and azathioprine (triple) maintenance immunosuppression (ALG group). The two groups were similar, including HLA mismatching, apart from age and size at transplantation (SIM=10.3+/-5.4 years vs ALG=12.4+/-4.2 years, P<0.05). RESULTS: One patient in the SIM group died from food inhalation with a functioning kidney and one patient in the ALG group from Pneumocystis pneumonia and post-transplant lymphoproliferative disorders with a rejecting graft. Both 1- and 2-year actuarial graft survivals were 93% for the SIM group and 86% for the ALG group (NS). Three grafts were lost in the SIM group-none from rejection (thrombosis 2, death 1)-and seven in the ALG group-three from rejection. Occurrence of biopsy documented rejection in the first 6 months after transplantation was 0.15+/-0.22 for the SIM group and 0.35+/-0.51 episodes per pt-month at risk for ALG treatment (P<0.04). Early rejection within 30 post-operative days occurred in only four SIM patients, three of whom had undergone retransplantation. Forty-seven per cent of rejection episodes occurred between days 30 and 44 in SIM treated patients. Switching to tacrolimus was similar in both groups; 24% of the SIM groups were prescribed triple therapy. Estimated glomerular filtration rate was 46.0 and 46.2 ml/min for SIM and ALG groups, respectively, six months after transplantation. Ten per cent of SIM and 19% of ALG treated patients developed clinically significant CMV infection (NS) but none of 16 (R(+)) SIM children had CMV infection compared with 8 out of 15 (R(+)) ALG patients (P<0.01). CONCLUSIONS: Basiliximab immunoprophylaxis and dual therapy reduces rejection episodes in the first six months and maintains graft survival and function after paediatric renal transplantation. Seventy-six per cent of children receiving basiliximab immunoprophylaxis were successfully maintained on long-term dual immunosuppression. This immunosuppressive protocol reduces CMV disease in CMV(+) recipients compared with ALG induction and triple therapy.     

Non-Hodgkin's lymphoma after kidney or heart transplantation: frequency of occurrence during the first posttransplant year

Abstract The incidence of non-Hodgkin's lymphoma was analysed in over 70000 kidney transplant recipients and over 10000 heart, heart-lung or lung transplant recipients. An increased incidence of lymphomas during the first posttransplant year was observed in cadaver kidney recipients as compared to related kidney recipients, in thoracic organ recipients as compared to kidney recipients, in heart-lung recipients as compared to heart or lung recipients, in patients transplanted in North America as compared to patients transplanted in Europe, in patients receiving cyclosporine in combination with azathioprine as compared to patients with other immunosuppressive regimens, and in patients receiving ATG/ALG or monoclonal OKT3 for rejection prophylaxis.     

Experience with OKT3 in vascularized pancreas transplantation

With refinements in technical aspects of whole organ pancreas transplantation, allograft rejection is currently the major cause of graft failure. The monoclonal antibody OKT3 has emerged as a highly effective antirejection therapy in renal and hepatic allograft recipients, but its efficacy in pancreas transplantation remains to be determined. During a 12-month period, 28 vascularized whole organ pancreas transplants were performed with pancreatico-cystostomy. Sixteen episodes of allograft rejection were treated with monoclonal antibody OKT3. Indications for OKT3 use included steroid- or antilymphocyte globulin (ALG)-resistant allograft rejection in isolated pancreas (n = 8) or simultaneous kidney-pancreas (n = 8) transplants. A total of 34 rejection episodes occurred in the 16 patients (mean, 2.1; range, one to five). The diagnosis of rejection was based on clinical criteria, a reduction in urinary amylase clearance, radionuclide scanning, hyperglycemia, or associated renal allograft dysfunction in combined engraftments. Postoperative immunosuppression consisted of cyclosporine, prednisone, azathioprine, and prophylactic ALG. OKT3 was administered for a full 14-day course concomitant with low-dose steroids, azathioprine, and cyclosporine. The mean age of the patient population was 32.1 years (range 24 to 39) with a mean duration of insulin-dependent diabetes mellitus (IDDM) of 20.9 years. Monoclonal antibody therapy was instituted in two clinical settings: early rejection (within 3 months of transplant, n = 10); and late rejection (after 3 months, n = 6). OKT3 successfully reversed allograft rejection in ten (62.5%) cases, including six early (60%) and four late (66.7%) episodes. In isolated pancreas transplants, OKT3 therapy reversed pancreas allograft rejection in only two patients (25%).(ABSTRACT TRUNCATED AT 250 WORDS)     

Phase I study of an engineered aglycosylated humanized CD3 antibody in renal transplant rejection

BACKGROUND: The potential therapeutic benefits of CD3 monoclonal antibodies, such as OKT3, have been limited by their immunogenicity and their propensity to activate a severe cytokine release syndrome. This has constrained the clinical use of OKT3 to the treatment of acute rejection episodes of organ allografts. METHODS: We have humanized a rat CD3 antibody and created a single amino acid substitution in position 297 of the IgG1 heavy chain to prevent glycosylation and, consequently, binding of the therapeutic antibody to Fc receptors and to complement. This antibody has been given as first line antirejection therapy in nine kidney transplant recipients with biopsy-proven acute rejection episodes. RESULTS: None of the patients demonstrated any antiglobulin response nor any significant cytokine release syndrome. Seven of the nine showed evidence of resolution of their rejection, although some patients experienced re-rejection. CONCLUSIONS: These findings suggest that CD3 antibodies can be engineered to lose their toxicity while retaining their potency as immunosuppressants. Nonactivating humanized CD3 monoclonal antibodies now merit further investigation in the management of transplant patients and in therapy of autoimmune diseases.