The incidence and impact of early rejection episodes on graft outcome in recipients of first cadaver kidney transplants.

The objective of this study was to define the incidence and significance of acute rejection occurring in the first year following transplantation. The influence of contemporary induction immunosuppression on rejection, as well as the effect of rejection on graft and patient loss, renal function, and maintenance immunosuppression during the first year in 110 recipients of first cadaver renal transplants were analyzed. All patients received CsA, Aza, and prednisone for 30 days with withdrawal of Aza at 30 days and then prednisone at 105 days; 57 patients were prospectively randomized to receive ALG (Merieux) until serum creatinine was less than 300 mumol/L. Short-term ALG administration did not influence the incidence, severity, nature, or outcome of rejection episodes. Fifty-five (50%) patients had at least 1 rejection in the first 90 days. All patients with delayed graft function and 7/8 (88%) sensitized patients (current PRA greater than 50%) had at least 1 rejection episode; 71% (n = 35) of all rejection episodes occurred in the first 30 days posttransplant. Patients rejection free at 90 days remained rejection free the entire first year. Graft loss was 18% for rejections in the first month, 13% for rejections occurring later (P = NS); 20% (n = 11) of patients had a second rejection and 1% (n = 2) had a third rejection. The risk of graft loss was 9% with a first rejection, 38% with a second rejection, and 50% with a third rejection. Of 12 (22%) rejections that were steroid resistant, 10 (83%) were reversed with OKT3. One-year graft survival for patients without rejection, with steroid-sensitive rejection, and with steroid-resistant rejection was 96%, 88% (P = ns), and 58% (P less than 0.001), respectively; 1 year SCr was 168 +/- 93, 196 +/- 77 (P = ns), and 268 +/- 96 microMol/L (P less than 0.05), respectively. Patients free of rejection and with stable renal function continued to do well on maintenance CsA monotherapy, and they were more likely to be on CsA monotherapy than those with rejection episodes (P less than 0.01).     

The use of antilymphoblast globulin in the treatment of renal allograft rejection: a double-blind, randomized study.

A randomized, double-blind study comparing horse antilymphoblast globulin (ALG) (25 patients) with human IgG (20 patients) in addition to standard antirejection therapy was performed in recipients of first kidney transplants having their first rejection episodes. Patients received ALG (20 mg/kg/day) for 10 days, and a control group was given human IgG (20 mg/kg/day) for 10 days in addition to standard therapy. The groups were comparable with respect to HLA matching, age, time to onset of first rejection episode, and number of diabetics. The number of patients requiring transplant nephrectomy and/or dialysis, having a second rejection episode, having good late function, or dying did not differ in recipients of related kidneys receiving either ALG or human IgG. Recipients of cadaver kidney grafts had fewer (0.05 less than P less than 0.06) second rejection episodes if they received ALG during their first rejection episode. However, the number of patients requiring transplant nephrectomy and/or dialysis, having late good function, and dying did not differ significantly for recipients of cadaver kidneys. We conclude that ALG does not add significantly to standard antirejection therapy for the treatment of first rejection episodes.     

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.     

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.     

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.     

Comparison of OKT3 with ALG for prophylaxis for patients with acute renal failure after cadaveric renal transplantation.

A randomized, prospective comparison of OKT3 vs. ALG (University of Minnesota) was performed in patients who had acute renal failure after a cadaver renal transplantation. Criteria for admission to the study were oliguria or increasing serum creatinine in the first 12 hr after renal transplantation. ALG or OKT3 was administered after randomization beginning 12-36 hours posttransplantation. There were no significant differences in age, sex, original disease, ischemia time, or HLA matching between groups. Graft survivals at 1 and 6 months were 84% and 84%, respectively for the ALG group. One- and 6-month graft survival for the OKT3 group was 88% and 84%, respectively. These differences were not statistically significant. The number of rejection episodes and the number of patients with rejection episodes were greater, and the time to first rejection was shorter in the OKT3 group compared with the ALG group, although none of these differences reached statistical significance. There were significantly less side effects in the ALG group compared with the OKT3 group (P less than .05). The greatest reductions in side effects were in fever and hypotension. Patients were monitored with flow cytometry analysis measuring the number of CD2 (T11) and CD3 (T3) cells to adjust the dose of both OKT3 and ALG. Starting doses were 10 mg/kg/day of ALG and 5 mg/day of OKT3. There were no significant differences in the incidence of infections (viral or bacterial) between the two groups. There were no rejection episodes during the prophylactic therapy with either ALG or OKT3. In summary, both ALG and OKT3 provided effective prophylaxis for patients with acute renal failure after renal transplantation. OKT3 was associated with a statistically significant increase in incidence of symptomatic side effects.     

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.     

Beneficial effect of concomitant induction with antilymphoblast globulin, cyclosporine, and steroids on long-term renal allograft outcome

BACKGROUND: The addition of induction therapy with antilymphocytic antibodies to cyclosporine (CsA) based immunosuppression, has reduced acute rejection incidence and improved short-term survivals, but has not had well-established effects on long-term renal transplant survival. PATIENTS: We analyzed the long-term allograft outcome of patients included in a prospective randomized clinical study conducted in our center 15 years ago by comparing two strategies: (A) horse antilymphoblast globulin (ALG) given at 10 mg/kg on alternate days to a maximum of 6 doses with low-dose CsA started at 8 mg/kg per day and prednisone at 0.25 mg/kg per day, versus (B) CsA started at 15 mg/kg per day and prednisone at 0.5 mg/kg per day. Diabetic and highly sensitized patients (PRA > 70%) were excluded from the study. RESULTS: The characteristics of the 50 patients enrolled in each group were not different. Although patient survival was not different (88% in group A vs 77% in group B), recipients treated with ALG showed a lower incidence of acute rejection episodes (20% vs 44%, P = .01) and better death-censored renal allograft survival (57% vs 41%, P = .03). Among rejection-free patients, graft survival was 15% higher in group A (60% vs 45%, P = .12). Multivariate Cox regression analysis showed that an acute rejection episode (relative risk [RR]: 2.44, 95% confidence interval [CI] 1.36-4.39; P = .0029) rather than ALG immunosuppression (RR 0.74, 95% CI 0.41-1.33; P = NS) was an independent predictor of death-censored graft survival. CONCLUSIONS: In summary, we confirmed that concomitant induction therapy with ALG, CsA, and steroids improves long-term renal allograft survival.     

OKT3 salvage therapy in a quadruple immunosuppressive protocol in cadaveric renal transplantation

Since the introduction of OKT3 at our center in January 1986, we have performed 246 cadaveric renal transplants (220 primary, 26 nonprimary). All patients received quadruple immunosuppression consisting of prednisone, azathioprine, and the sequential use of Minnesota antilymphoblast globulin (MALG) and cyclosporine. OKT3 (Orthoclone OKT3) therapy was reserved for corticosteroid- and/or ALG-resistant rejection. Of the 246 patients, 138 developed one or more rejection episodes (56.1%). Ninety-seven (70.3%) were successfully reversed with prednisone and/or ALG, whereas 41 (29.7%) required additional treatment with OKT3. Initial graft salvage occurred in 34 (82.9%) patients treated with OKT3, but rejection recurred in 18 (52.9%) and was successfully reversed in only 6 patients. However, the rate of recurrent rejection was much lower in patients given OKT3 early (14%), shortly after it was apparent that high-dose corticosteroid therapy was proving ineffective, than in patients who received OKT3 after a prolonged or second course of corticosteroids (64%) or ALG (60%). Graft survival after a mean follow-up interval of 11 months in all OKT3-treated patients was 54%. One or more infections occurred in 19 (46%) patients treated with OKT3. Patients developing infections following OKT3 therapy received significantly larger total doses of prednisone during graft rejection (46.3 mg/kg vs. 27.9 mg/kg, P less than .05) than OKT3-treated patients who did not develop infectious complications. Our experience shows that use of OKT3 for treatment of corticosteroid- and/or ALG-resistant rejection is associated with a high rate of recurrent rejection, except when given early, as soon as it is clear that high-dose corticosteroid therapy is not reversing the rejection episode. It further suggests that prolonged administration of high-dose corticosteroids and possibly ALG for the treatment of rejection prior to beginning OKT3 greatly increases the rate of infection following OKT3 therapy.     

An increased incidence of late acute rejection episodes in cadaver renal allograft recipients given azathioprine, cyclosporine, and prednisone

We studied the incidence of biopsy-proven, acute rejection episodes occurring after 1 year posttransplant in cadaver renal allograft recipients. The 328 patients evaluated were given three immunosuppressive drug protocols. Group I (transplanted 9/80-6/84) (n = 75) received azathioprine, prednisone (P), and antilymphoblast globulin; group II (transplanted 9/80-6/84) (n = 83) received cyclosporine and P; group III (transplanted 7/84-12/86) (n = 170) received ALG, AZA, CsA, and P (sequential therapy). The incidence of first acute rejection episodes occurring up to 1 year posttransplant was 55% in group I and 35% in groups II and III. The incidence of late (greater than 1 year) acute rejection episodes was 6.5% in group I, 2.5% in group II, and 9.5% in group III (group II vs. III, P = 0.02). In group III, 50% of the late rejections were first, 44% second, and 6% third. The primary etiologies of this increased incidence of late acute rejection may have included subtherapeutic CsA levels and lower P doses. Sequential immunosuppressive therapy has been shown to be advantageous in the first posttransplant year. However, unless adequate immunosuppression is maintained, this approach can be associated with a significantly increased incidence of late acute rejection.     

A controlled randomized double-blind study of antilymphoblast globulin in cadaver renal transplantation

Herein are presented the results of a controlled prospective randomized double-blind evaluation of antilymphoblast globulin as an immunosuppressive adjunct to azathioprine and prednisone in cadaver renal transplantation. There were 31 patients and 36 patients randomly assigned to therapeutic and control groups, respectively. ALG-treated patients experienced no major side-effects, a delayed onset of rejection following transplantation (P less than .005), a reduced total number of rejection episodes (P less than .05), fewer days in the hospital (P less than .05), a reduced cost of transplantation (P less than .02), improved graft survival (P less than .05), and patient survival equivalent to that of the control group. These data indicate that ALG is safe, cost-effective, and of immunologic benefit in cadaver renal transplantation.     

Improved results of cadaver renal transplantation with azathioprine, prednisone and antilymphoblast globulin

From 1980 to 1982, 100 consecutive cadaver renal transplants were performed. All but 2 recipients received preoperative transfusion and all received an initial 2-week course of antilymphoblast globulin. A prospective controlled evaluation of high versus low maintenance prednisone, and antilymphoblast globulin versus intravenous methylprednisolone for first rejection therapy was done. Over-all 1-year graft and patient survivals were 77 and 96 per cent, respectively. Graft survival was equal in the high and low steroid groups. Antilymphoblast globulin was as effective as intravenous methylprednisolone in reversing first rejections. Graft survival was improved with better donor-recipient matched grafts. We conclude that excellent results can be obtained in transfused cadaver renal allograft recipients managed with azathioprine, prednisone and antilymphoblast globulin. The regimen of prophylactic antilymphoblast globulin, low maintenance prednisone and antilymphoblast globulin alone for first rejections is immunologically effective and steroid sparing.     

The effect of donor age, recipient age, and HLA match on immunologic graft survival in cadaver renal transplant recipients.

We retrospectively analyzed 526 primary cadaver recipients transplanted at a single center to identify pretransplant variables that predict long-term survival with multivariate analysis. All recipients received at least three random blood transfusions and were treated under a quadruple-therapy protocol consisting of ALG, azathioprine, prednisone, and cyclosporine. Of 526 consecutive transplants, 86 grafts were lost from acute or chronic rejection. Thirteen grafts were lost for nonimmunologic reasons and 35 recipients died with a functioning graft. A total of 273 patients (52%) experienced at least one episode of acute rejection. Donor age ranged from 3 to 64 years, with 62% of donors less than 30 years of age and 9% of donors over 50 years of age. Donor age was not predictive of long-term graft survival and neither was the difference between donor and recipient age. Recipient age was predictive of subsequent immunologic graft less, with younger recipients at greater risk (P = 0.011). The rate of first rejection was also inversely related to recipient age, with younger recipients rejecting earlier (P = 0.0001). The degree of DR mismatch was the only other significant predictor of long-term graft success (P = 0.013). Transplant survival correlated with the degree of DR mismatch: 2 DR mismatch was the worst, 1 DR mismatch was intermediate and 0 DR mismatch was the best (P = 0.02). A, B, AB, and BDR did not influence long-term graft outcome. In our center, donor age does not predict graft failure. Younger recipients have a higher rate of early rejection and, combined with a poor DR match, are at higher risk for long-term graft failure.     

Low dose ciclosporin from the early postoperative period yields potent immunosuppression after renal transplantation

This study sought to determine if low doses of ciclosporin (CS) designed to give fasting serum levels of 50-100 ng/ml achieve effective immunosuppression when used from the early postoperative period after renal transplantation. Ninety-four primary renal transplant recipients were studied. Group 1 patients were treated with CS 100 ng/ml and prednisone (0.15 mg/kg/day). Group 2 patients received CS 50 ng/ml, prednisone (0.15 mg/kg/day) and azathioprine (1 mg/kg/day). These patients were compared to a control group of 26 patients (group 3) maintained on only prednisone and azathioprine. CS-treated patients suffered significantly fewer rejection episodes than control subjects (rejection episodes per patient in first year: group 1: 0.3 +/- SD 0.6; group 2: 0.7 +/- SD 0.7; group 3: 1.3 +/- SD 1.1, p less than 0.005). In addition, a greater number of CS-treated patients were completely free of rejection episodes during the first year posttransplant (group 1: 63%; group 2: 64%; group 3: 19%, p less than 0.005). Patient and graft survival were similar in all groups after 1 year (group 1: 92 and 92% respectively; group 2: 95 and 87% respectively; group 3: 96 and 85% respectively). These data suggest that the dose of CS required for effective immunosuppression in vivo is lower than has been previously thought.     

Improved results using OKT3 as induction immunosuppression in renal allograft recipients with delayed graft function

Delayed graft function remains a major problem in cadaveric renal allograft transplantation. We have used 2 different immunosuppressive induction regimens in patients with delayed graft function. The first regimen, used in 40 patients from January 1985 to December 1986, consisted of CsA (8 mg/kg/day, orally within 48 hr of cadaveric renal transplantation regardless of graft function), azathioprine (1.5-2.5 mg/kg/day), and steroids (methylprednisolone 375 mg on day 0, then prednisone tapered to 30 mg/day by day 10 with slow tapering to 7.5-10 mg/day over the first 6 months after transplantation). A second regimen, used from January 1987 to March 1989, employed the same doses of azathioprine and steroids; however, OKT3 (5 mg i.v./day for 7-21 days) was administered in the 34 patients who had delayed graft function. CsA was withheld until ATN resolved. The use of OKT3 as induction immunosuppression in patients with ATN led to a significant increase in 1-year graft survival (80% vs. 55%) while markedly decreasing the incidence of rejection episodes (44% vs. 82%) and the duration of nonfunction (9.4 vs. 14.9 days). There were 5 CMV infections in patients treated with OKT3. Antibodies to OKT3 developed in only 1 of 34 patients treated with OKT3. Five of 7 patients who received a second course of OKT3 successfully reversed the rejection episode. Patient survival (89%) was the same in the 2 groups. The benefit of OKT3 on long-term graft survival appears to stem from elimination of early rejection episodes that may be difficult to diagnose in a poorly functioning allograft. We conclude that OKT3 induction provides superior results over CsA induction at doses given in renal allograft recipients with delayed graft function without a significant increase in morbidity or mortality and permits the reuse of OKT3 for treatment of rejection in most cases.     

Long-term results of a controlled prospective study with transfusion of donor-specific bone marrow in 57 cadaveric renal allograft recipients

Experimental studies have shown that antilymphocyte globulin combined with transfusion of donor-specific bone marrow cells can induce partial tolerance to allograft tissue. We have adapted these protocols to clinical use and present the results of 57 cadaveric renal allograft recipients who received Minnesota ALG followed by the transfusion of cryopreserved donor-specific bone marrow. A group of 54 patients received the contralateral kidney and similar immunosuppression without the marrow transfusion and serve as controls. Both groups received quadruple immunosuppression with MALG, cyclosporin, azathioprine, and prednisone. In the bone marrow group, after a 10-14 day induction course of ALG, cryopreserved marrow was transfused on the seventh day after the last dose of ALG. The median follow-up in both groups is 16 months, (range 2.5-33 months). Six grafts have been lost in the bone marrow group, (three rejections, 2 deaths [Cr 2.0, 2.3], 1 recurrent disease). In the control group 16 grafts have been lost (13 rejections, 3 deaths [Cr 1.7, 2.5, 3.0]). Five patients in the control group have biopsy-proved chronic rejection compared to one in the bone marrow group. 17 patients in the bone marrow group have been tapered off the prednisone, and three of these patients have had mild late rejection episodes without graft loss. The two groups were compared for differences in the number of rejection episodes, estimated renal plasma flow, glomerular filtration rate, and urine protein. No differences were found. The allograft survival of the bone marrow group was significantly greater (P less than .01) than the control group. The graft survival rates for the bone marrow group at 12 and 18 months were 90% (confidence limits [CL] 85-94) and 85% (CL 78-90), respectively. In the the control group the 12 and 18 month allograft survival rates were 71% (CL 63-78) and 67% (CL 58-74), respectively. The survival in the control group was similar to our overall transplant experience with quadruple therapy. Mixed lymphocyte culture analysis shows a trend to diminished donor-specific responsiveness in the bone marrow group. The use of cryopreserved donor-specific bone marrow is associated with improved allograft survival in cadaveric kidney allograft recipients. However, a more effective induction protocol is needed to reduce the overall number of rejection episodes.     

A randomized prospective trial of OKT3 induction in the current immunosuppression era

Recent improvements in immunosuppression and subsequent decreases in the incidence of acute rejection have brought into question the benefit of the use peri-transplant antibody therapy (i.e. induction therapy). In the current era of immunosuppression that includes mycophenolate mofetil (MMF) and cyclosporine emulsion (Neoral, Novartis, Basle, Switzerland), we designed and have completed a prospective, randomized trial to address this question. Cadaveric and living donor renal allograft recipients were randomized to receive either OKT3/MMF/delayed Neoral/prednisone or MMF/immediate Neoral/prednisone without OKT3. The incidence of rejection episodes was the primary end point. Patients with delayed graft function were excluded. All rejection episodes were biopsy proven and all patients have been followed for a minimum of 2 yr. Fifty-four patients received OKT3 induction, of which 6 patients suffered a rejection episode (11%), while 13 patients (27%) not receiving OKT3 (p=0.04) had a rejection episode. Four patients in the no OKT3 group suffered multiple rejections, while there were only 2 with more than one episode in the OKT3 group. There was no increased incidence of infectious complications in the group receiving OKT3. Hospital costs tended to be higher in the OKT3-treated group, but were not significantly different. The low incidence of rejection in the OKT3-treated group was intriguing and validates the use of antibody therapy in the early post-operative periods even in the era of improved baseline immunosuppression.     

Use of anticoagulation in cadaver renal transplants

The effect of anticoagulation was studied in 92 consecutive cadaver renal transplants performed in 90 patients from 1977 to 1980. Patients were randomized to receive prophylactic anticoagulation with warfarin and antiplatelet drugs beginning on the second post-transplant day, or therapeutic heparin for acute rejection episodes with vascular involvement, only. These patients were later converted to long-term anticoagulation with warfarin and antiplatelet drugs. All first rejection episodes were diagnosed by percutaneous renal biopsy and scored as to the degree of cellular infiltrate and vascular change. Immunosuppression consisted of azathioprine, prednisone, methylprednisolone, and, in 19 patients, antilymphoblast globulin (ALG) given for 14 days post-transplant. Rejection episodes were treated in 76 patients. Severe rejection did not respond to any form of treatment and all these grafts failed in less than 3 months. Severe cellular rejection did not occur in ALG-treated patients. Heparin treatment improved the 3-month graft survival in patients with acute rejection and mild vascular changes but did not alter the results in any other category. Chronic rejection was not prevented by any method of anticoagulation. Bleeding complications occurred in 18.4% of patients receiving warfarin and 7.7% of the patients receiving heparin. Anticoagulation with heparin may be useful in the treatment of acute rejection with mild vascular changes. Biopsy-proven severe rejection accurately predicts early graft failure regardless of treatment and should prompt transplant nephrectomy.     

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.     

Plasmapheresis and cyclophosphamide in the treatment of humoral rejection after heart transplantation.

BACKGROUND: Clinical reports on humoral rejection after heart transplantation showed that these episodes were often more severe than those mediated through T lymphocytes and that the patient's prognosis was significantly worsened. METHODS: To evaluate the impact of plasmapheresis on the course of humoral rejection with hemodynamic compromise (HRHC) episodes, we retrospectively investigated the records of 1,108 heart transplant patients. All patients received triple-drug immunosuppression (cyclosporine a, azathioprine, prednisone) and cytolytic antibodies for induction. Between April 1986 and December 1990, HRHC episodes were treated with cortisone boli and cytolytic antibodies for at least 3 days (Group A). Between January 1991 and April 1999, HRHC episodes were treated with cortisone boli, cytolytic antibodies, and plasmapheresis for at least 3 days (Group B). All patients who survived their first HRHC episode received cyclophosphamide instead of azathioprine as maintenance immunosuppression. RESULTS: Altogether we observed 29 HRHC episodes. In 11 cases, no therapy could be administered or the therapy regimen did not correspond to either Protocol A or B. In the remaining 18 HRHC episodes, 7 episodes in 7 patients were treated without plasmapheresis (Group A), but only 2 patients survived, whereas in 11 HRHC episodes in 6 patients, therapy included plasmapheresis (Group B) and all patients survived (p = 0.002). Four of 6 patients who received cyclophosphamide after their first HRHC episode experienced at least 1 further HRHC episode. CONCLUSIONS: Plasmapheresis seems to improve outcomes in HRHC. However, cyclophosphamide as a maintenance immunosuppressive drug failed to prevent further humoral rejection episodes.