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.     

Renal transplantation in the older recipient

From 1976 to 1983, 13 living related and 54 cadaver renal transplants were done in 62 patients more than 50 years old. Patients with no coronary or myocardial disease upon coronary angiography were selected preferentially for transplantation. Over-all 1-year patient and graft survival rates were 88 and 70 per cent, respectively. Among cadaver recipients graft survival was improved (p less than 0.001) when prophylactic antilymphoblast globulin was used. There were fewer steroid-related complications (p less than 0.001) in recipients managed with a low dose rather than a high dose maintenance prednisone regimen. With careful patient selection and a steroid-sparing immunosuppressive regimen, renal transplantation can be done safely in older recipients with no increased risk of death or graft loss.     

Sequential antilymphoblast globulin and cyclosporine for renal transplantation

The nephrotoxic effects of cyclosporine (CsA) seem to be augmented by co-existing renal injury. A high rate of prolonged delayed function (acute tubular necrosis [ATN]) and non-function (NF) has been associated with the use of CsA prior to and following renal transplantation. Cyclosporine has also been associated with a slower recovery of allograft function and poor baseline renal function even in allografts that function immediately compared with conventionally treated recipients. In 1983 we hypothesized that the rate of ATN and NF following renal transplantation could be decreased and more normal kidney function achieved if renal injury was resolved before adding the nephrotoxic effects of CsA. A group of 300 nonsplenectomized, uremic recipients have received 304 renal transplants and have been initially immunosuppressed with azathioprine, prednisone, and Minnesota antilymphoblast globulin (ALG) prior to starting maintenance CsA and prednisone. The incidence of NF has been 1.9% and the development of ATN has been 7.6% following transplantation with sequential use of ALG and CsA. Other benefits to the renal recipient have also occurred with use of this immunotherapy protocol. Renal allograft survival for recipients of first, second, and third renal allografts has been higher than that generally reported with cyclosporine and prednisone alone. Rejection episodes have been infrequent during the first six months posttransplant, as 75% and 62% of first and second renal allograft recipients have remained rejection-free. Clinically significant infectious complications were infrequent. No cadaver recipient has developed a lymphoma. Moreover, the initial hospitalization following transplantation with sequential ALG/CsA has been short and generally uncomplicated. We conclude that sequential ALG/CsA following renal transplantation provides excellent early posttransplant immunosuppression while avoiding the nephrotoxic effects of CsA and also provides the steroid and infection-sparing benefits derived from maintenance CsA therapy.     

Continuous function of 80 primary renal allografts for 30–47 years with maintenance prednisone and azathioprine/mycophenolate mofetil therapy: A clinical mosaic of long‐term successes

Eighty primary renal allograft recipients, 61 living‐related and 19 deceased donor, transplanted from 1963 through 1984 had continuous graft function for 30–47 years. They were treated with three different early immunosuppression programs (1963–1970: thymectomy, splenectomy, high oral prednisone; 1971–1979: divided‐dose intravenous methylprednisolone; and 1980–1984: antilymphocyte globulin) each with maintenance prednisone and azathioprine, and no calcineurin inhibitor. Long‐term treatment often included the anti‐platelet medication, dipyridamole. Although both recipient and donor ages were young (27.2 ± 9.5 and 33.1 ± 12.0 years, respectively), six recipients with a parent donor had >40‐year success. At 35 years, death‐censored graft survival was 85.3% and death with a functioning graft 84.2%; overall graft survival was 69.5% (Kaplan–Meier estimate). Biopsy‐documented early acute cellular and highly probable antibody‐mediated rejections were reversed with divided‐dose intravenous methylprednisolone. Complications are detailed in an integrated timeline. Hypogammaglobulinemia identified after 20 years doubled the infection rate. An association between a monoclonal gammopathy of undetermined significance and non‐plasma‐cell malignancies was identified. Twenty‐seven azathioprine‐treated patients tested after 37 years had extremely low levels of T1/T2 B lymphocytes representing a “low immunosuppression state of allograft acceptance (LISAA)”. The lifetime achievements of these patients following a single renal allograft and low‐dose maintenance immunosuppression are remarkable. Their success evolved as a clinical mosaic.     

Mismatched living, related donor renal transplantation: a prospective, randomized study

A prospective, randomized study of 49 mismatched living, related donor renal transplants was undertaken to compare the effect of donor-specific transfusions (DST) combined with conventional immunosuppressive therapy (azathioprine, prednisone, and antilymphoblast globulin) to cyclosporine and prednisone with and without use of prior DST. The results demonstrated that cyclosporine and prednisone without DST have equal patient and graft survival rates after transplantation and an equal incidence of infectious complications and rejection episodes when compared with recipients who received DST and conventional therapy. Patients who received DST and subsequent cyclosporine had poor graft survival rates with more rejection episodes and infectious complications. Hospitalization and the relative cost of transplantation were decreased when recipients received cyclosporine without prior DST. It is concluded that cyclosporine allows easier access to transplantation, is more cost effective in the initial posttransplant period, and does not subject the recipient to the risk of donor sensitization as is seen with DST recipients given conventional therapy. The nephrotoxic side effects of cyclosporine have been minimal and renal function remains excellent in the recipients treated with cyclosporine.     

Recent results of cadaver kidney retransplantation

The results of secondary cadaver renal transplantation in 42 patients treated from 1980 to 1986 have been reviewed. The initial graft was from a cadaver donor in all cases. All patients were managed with a maintenance immunosuppressive regimen, including either antilymphoblast globulin and/or cyclosporine. The over-all 1 and 2-year patient survival rates were 97 and 94 per cent, respectively. The over-all 1 and 2-year graft survival rates were 69 and 63 per cent, respectively. Graft success was not influenced by patient age greater than 50 years, diabetes, initial graft removal, interval between initial graft removal and retransplantation, duration of initial graft function, level of presensitization or HLA-Dr antigen matching. Currently, cadaver renal retransplantation can be performed safely and with an improved opportunity for graft success. Patients who return to dialysis after losing an allograft should be encouraged to consider another transplant for the same reasons that prompted initial transplantation.     

Effects of HLA-A and B matching on success of cadaver grafts at a single center.

The effect of HLA matching on the success of cadaver renal allografts was examined utilizing computerized multifactoral analysis in a large single renal transplant center. One hundred ninety-one consecutive cadaver transplant recipients (from January 1968 to August 1975) were followed from 2 1/2 to 9 years. During the period surveyed we had not utilized the tissue typing results in a prospective manner to select recipients. The data presented attest to the beneficial effect of utilizing well matched cadaver grafts. HLA matching of two or more antigens results in significantly superior 2- and 4-year patient survival and graft function compared to results for cadaver kidneys matched for zero and one HLA antigen. The results are not greatly influenced when age, sex, or time of transplant are controlled. The importance of tissue typing is particularly clear if higher doses of antilymphoblast globulin (ALG) are administered. The risk inherent in advancing recipient age is markedly reduced by better transplant matches. Graft function is also superior in the diabetic patients receiving good HLA matches, but there are too few patients to make these results statistically significant.     

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).     

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 use of OKT3 in cadaveric renal transplantation for rejection that is unresponsive to conventional anti-rejection therapy

Thirty-one recipients of cadaver kidney transplants were given OKT3 monoclonal anti-T cell antibody for rejection treatment after conventional therapy had failed. Seventy-four percent of steroid or steroid and antithymocyte globulin (ATG) resistant rejections reversed with a standard course of OKT3. Rejections reversed in 85% of 26 patients treated within 90 days of transplantation. Late rejections treated more than 90 days after transplantation were poorly responsive to OKT3 and graft survival for this group of five patients was poor (20%). However, for those patients treated with OKT3 for early resistant rejection, actuarial 4-year graft survival was 66%. Actuarial 4-year patient survival was 97%, and the incidence of serious infection was low. Acute rejections in cadaver transplantation are common and a small percentage of rejections are resistant to steroids and ATG. OKT3 has proven to be useful for reversing these resistant rejections without causing significant morbidity from infection or death.     

Are blood transfusions beneficial in the cyclosporine era?

In patients treated with conventional immunosuppression (azathioprine and prednisone) after renal transplantation, there is a beneficial effect of pre-transplant blood transfusions on graft survival; in patients treated with cyclosporine, this effect may be lost. In 66 children who received living-related donor transplants after donor-specific transfusions (DST) and were treated with azathioprine-prednisone in our center, 1- and 5-year graft survival rates were 99% and 77% respectively. These rates were similar to those reported for children who did not receive DST but were treated with cyclosporine in other centers. There were 634 adult and pediatric recipients of cadaver transplants in our center who were treated with cyclosporine and prednisone (non-sequential therapy,n=89) or antilymphoblast globulin, azathioprine preduisone, and cyclosporin (sequential therapy,n=545). When all patients were considered, graft survival rates were higher in transfused than in non-transfused patients at 3–5 years, but in the sequential therapy group, there were no differences in graft survival rates between transfused and non-transfused patients. The results suggest that transfusions do not improve cadaver graft survival in patients receiving optimal cyclosporine therapy and that equally good related donor graft survival can be achieved with DST and conventional immunosuppression or no DST and cyclosporine.     

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.     

Steroid withdrawal for pancreas after kidney transplantation in recipients on maintenance prednisone immunosuppression

Steroid withdrawal from patients taking prednisone for their renal allograft at the time of reinduction of immunosuppression for subsequent pancreas after kidney (PAK) transplantation has not been explored. Our expectation was that lymphocyte depletion, in conjunction with an augmentation of immunosuppression at the time of pancreas transplantation would protect the recipient from rejection of the renal allograft when chronic maintenance steroids are withdrawn. METHODS: Pancreas transplantation was performed using systemic venous drainage and enteric exocrine drainage. Regardless of preoperative immunosuppression, all patients received induction with antithymocyte globulin, a brief taper of intravenous solumedrol over four to five days, maintenance therapy with tacrolimus and sirolimus and either resumption of chronic maintenance steroids or complete withdrawal of steroids. RESULTS: A total of 30 PAK transplants were performed in 29 recipients and divided into two groups: continuation of chronic steroids (n = 10) or steroid-free (n = 19). One pancreas allograft was lost and there was a single mortality in the steroid free group. There was no significant difference in renal function or incidence of infections. CONCLUSION: Steroids can be safely withdrawn following pancreas after kidney transplantation for recipients already on maintenance prednisone in the setting of rabbit antithymocyte globulin induction and tacrolimus and sirolimus maintenance immunosuppression.     

Comparison of standard immunosuppression with adjuvant antilymphoblast globulin in primary cadaver kidney transplant survival

Adjuvant, prophylactic, antilymphoblast globulin and standard immunosuppression have produced comparable long-term cadaver kidney graft survivals at separate institutions. A comparison was made of 35 primary cadaver kidney grafts into recipients treated with prophylactic, adjuvant antilymphoblast globulin to 55 recipients of primary cadaver kidney grafts treated with standard immunosuppression. Antilymphoblast globulin delayed early rejection episodes (P under 0.05), making early post-transplant management simpler. There were no significant differences between the two groups with respect to graft losses due to rejection at any interval beyond one month.     

Beneficial effects of cyclosporine compared with azathioprine in cadaveric renal transplantation

Recent reports have intimated that the use of antilymphocyte globulin in combination with azathioprine and steroids has ameliorated the beneficial affects of cyclosporine. We believe that even in the absence of significant statistical differences between patient survival rates and graft survival rates of cyclosporine-treated renal transplant patients compared with conventionally treated renal transplant patients, there are distinct advantages to cyclosporine use in renal transplantation. Twenty-three consecutive cadaveric renal transplant patients who received azathioprine, prednisone, and antilymphoblast globulin were compared with 23 cadaveric renal transplant patients who received cyclosporine and prednisone. Fewer statistically significant rejection episodes, multiple rejection episodes, and cytomegalovirus infections were demonstrated in those who received cyclosporine. Most notably, cyclosporine decreased the initial hospital stay, was associated with fewer readmissions, and therefore markedly reduced the initial cost of transplantation.     

Oral steroid pulse without taper for the treatment of asymptomatic moderate cardiac allograft rejection

BACKGROUND: The most frequently administered treatment for asymptomatic ISHLT Grade 3A cardiac allograft rejection is intravenous steroids or oral steroid pulse with a taper. This study analyzes the efficacy of 3-day 100-mg course of prednisone without a tapered regimen for the treatment of asymptomatic moderate cardiac allograft rejection. METHODS: All new episodes of asymptomatic ISHLT Grade 3A rejections were treated with oral steroid pulse without taper, consisting of 100 mg of prednisone for 3 consecutive days followed by resuming the pre-rejection steroid dose on the fourth day. We retrospectively reviewed the histologic response of all treated episodes among all cardiac transplant recipients transplanted between January 1995 through December 1997 who were treated with triple therapy consisting of cyclosporine, azathioprine and steroids. Patients receiving additional or alternative immunosuppressives were excluded from the study. The treated episodes were analyzed as responders if the follow-up biopsy were Grade 0, 1A, 1B, or 2; treatment was counted as non-responders if the follow-up biopsy showed Grade 3A or higher. RESULTS: Of 230 cardiac transplant recipients, 100 patients received a 3-day 100 mg course of prednisone without taper for 174 new episodes of asymptomatic ISHLT Grade 3A rejection. The overall response rate was 75% (130/174 rejection episodes). A significant difference in the response rate was observed depending on the number of days post transplant. A comparison of the success rates among rejections which occurred > 90 days post transplant versus < 30 days revealed responses to be 88% versus 70% (p = 0.02); for rejections treated > 60 days post transplant versus < 30 days showed success rates of 84% versus 70% (p = 0.04). The mean age of the recipient revealed a trend to be lower among the non-responder group (49+/-12 years versus 53+/-9 years, p = 0.07). Having left ventricular assist device as a bridge to transplant did not significantly affect the treatment outcome. The response rates were 69% for the patients who required the assist device versus 77% for those not bridged (p = ns). There was no significant difference in the gender or the baseline immunosuppressive doses between the responders and non-responders. The cost of a 3-day outpatient, visiting nurse supervised intravenous steroid therapy versus 3 days of oral prednisone was $861 vs $6.88. CONCLUSION: Oral steroid pulse without taper is an effective and economical way to treat asymptomatic moderate grade cardiac allograft rejection. A 3-day course of 100 mg of prednisone without taper should be considered as first line of therapy for clinically stable form of moderate cardiac allograft rejection occurring > 60 days post transplant.     

Cadaveric kidney transplantation under prophylactic polyclonal antibody immunosuppression with anti-lymphoblast globulin versus anti-thymocyte globulin

Objectives

This retrospective study was undertaken to evaluate and compare the clinical and immunologic outcomes following prophylactic induction treatment with Minnesota anti-lymphoblast globulin (MALG) and Upjohn anti-thymocyte globulin (ATGAM) in cadaver renal transplantation.

Methods

From 1990 to 1994, 63 patients with renal transplants from cadavers received MALG and 77 patients received ATGAM for induction treatment. Most pretransplant parameters were equivalent in both groups. There was no significant difference in the total dose and mean duration of MALG/ATGAM administration. The post-transplant outcome in these groups was compared.

Results

There was no difference between the MALG and ATGAM groups with respect to the overall number of rejection episodes, median days to rejection, or the number of steroid-resistant rejection episodes. However, MALG-treated patients experienced a greater number of rejections in the first 60 days postoperatively (P = 0.06). There was no difference in the nadir serum creatinine level in the first 20 postoperative days in the two groups; however, it took fewer days to reach the nadir in the ATGAM group (P = 0.03). The incidence of delayed graft function was higher in the MALG group than in the ATGAM group (38% versus 31%) but not statistically significant.Graft survival at 12 and 24 months was comparable in both groups. However, patient survival was superior at 12 and 24 months in ATGAM-treated transplant recipients (P = 0.03). The mean serum creatinine at 6, 12, and 24 months was similar in both the MALG and ATGAM groups. The mean fall and recovery of CD3, CD4, and CD8 T-lymphocyte subsets while on MALG/ATGAM were similar in both groups. The incidence of infectious complications was greater in the MALG group.

Conclusions

MALG and ATGAM have comparable clinical immunosuppressive effects. Patients receiving ATGAM experienced fewer rejections in the first 2 months, fewer infections, and better survival.     

Improved survival of heart transplants. Graft and/or donor pretreatment with antilymphoblast globulin, cyclophosphamide, or methylprednisolone.

Survival of heart allografts flushed with antilymphoblast globulin (ALG) was significantly prolonged when the grafts were transplanted into minimally immunosuppressed recipients. When no immunosuppression was given, there was no prolongation of survival of ALG-flushed grafts. Donor pretreatment with cyclophosphamide, methylprednisolone, or ALG had no influence in the prolongation of survival of cardiac allografts. We do not have a clear explanation for the prolonged survival of ALG-flushed grafts transplanted into minimally immunosuppressed recipients.     

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.     

Cyclosporine versus azathioprine: a review of 200 consecutive cadaver renal transplant recipients

Most renal transplant centers report an increase in graft survival when cyclosporine is used as a primary immunosuppressant. We report the outcome of 200 consecutive cadaver renal transplant recipients among whom initial immunosuppression and risk factors were similar except for the substitution of cyclosporine for azathioprine in the second 100 recipients. Azathioprine-treated recipients had significantly increased (p less than 0.05) mean hospital stays (31.9 versus 18.3 days), incidence of first rejection episodes (85 versus 31) and methylprednisolone dose (3.38 versus 0.06 gm. per patient). Cyclosporine-treated recipients had a significantly higher 1-year mean serum creatinine level (1.85 versus 1.56 mg. per dl.) and 1-year actual graft survival (83 versus 58 per cent). Despite mild nephrotoxicity, cyclosporine is superior to azathioprine as a primary immunosuppressant in cadaver kidney transplantation.