Stuart Jk

Complications and monitoring of OKT3 therapy

Complications of OKT3 therapy were studied in 122 treatment episodes in renal allograft recipients (83 for rejection treatment, 39 for immunosuppression induction). A febrile first-dose reaction to OKT3 was common; no severe pulmonary complications were encountered. Other toxicities of OKT3 therapy were observed later in the treatment course. Most severe were the occurrence of aseptic meningitis in four patients (3%), and seizures in eight (6%). Seizures occurred only when OKT3 was given to patients with nonfunctioning grafts due to acute tubular necrosis. Infections were the only significant late adverse sequelae of OKT3 therapy and occurred more frequently after multiple exposures to the drug (53%) than after a single exposure (22%). IgG antibodies to OKT3 developed after 45% of exposures to the drug in the 74 patients in whom appearance of anti-OKT3 antibodies was monitored. In two patients (3%), anti-OKT3 antibodies were detected before the end of the OKT3 treatment course, neutralizing the immunosuppressive property of the drug. In five patients (7%), strong anti-OKT3 antibody responses were present at the time of subsequent rejection, which precluded reuse of the drug. In 17 other cases, no or only a weak anti-OKT3 response was detectable at the time of rejection following initial OKT3 exposure. Retreatment with OKT3 was successful in reversing rejection in 15 cases (88%). No untoward sequelae were noted after reexposure to OKT3, except the high incidence of subsequent infections.

OKT3 treatment of steroid-resistant renal allograft rejection.

The monoclonal antibody, Orthoclone OKT3 (OKT3), has been used with great efficacy in a prospective multicenter trial as therapy for first rejection episodes in cadaveric donor (CD) renal allograft recipients treated with azathioprine (AZA) and prednisone (P). However, although almost all rejection episodes were reversed, recurrent rejection occurred in approximately two-thirds of OKT3-treated patients in this earlier trial; infections also occurred in about two-thirds of patients, often related to the additional immunosuppression necessary to reverse the rerejection episodes. In the current series of patients, OKT3 was used to treat rejection in CD renal graft recipients in a protocol differing from the multicenter trial in two respects: (1) baseline immunosuppression was cyclosporine (CsA) and P or CsA, AZA, and P (probably more potent immunosuppressive combinations than the AZA and P in the multicenter trial); and (2) OKT3 treatment was reserved for rejection episodes resistant to 3 bolus infusions of methyl-prednisolone (MP), 5–10 mg/kg, rather than as primary therapy for first rejection episodes. Using this protocol, 46 of 74 rejection episodes (62%) diagnosed between 3/85 and 3/86 in CD renal allograft recipients were treated successfully with MP. Of the remaining 28 steroid-resistant rejection episodes, 27 (96%) were reversed with a 7–14-day course of OKT3, 5 mg/day. Only 5 recurrent rejection episodes (19%) have been observed in the 2–14-month follow-up period after OKT3 treatment; infections have occurred in 10 patients (36%), and three grafts (11%) have been lost in OKT3 treated patients. These results suggest that recurrent rejection and subsequent infection after OKT3 is used to treat rejection may be reduced in a protocol where CD renal allograft recipients are treated with baseline immunosuppression regimens including CsA and where OKT3 is reserved for steroid-resistant rejection. This approach appears to be both more cost-effective than, and as effective therapeutically as, treating all first rejection episodes with the monoclonal antibody.

Mycophenolate mofetil and tacrolimus as primary maintenance immunosuppression in simultaneous pancreas-kidney transplantation: initial experience in 50 consecutive cases.

BACKGROUND The current study examines the use of mycophenolate mofetil (MMF) and tacrolimus as primary immunosuppression in simultaneous pancreas-kidney (SPK) transplantation. In addition, analyses of the rates of conversion from one immunosuppressive agent to another, and its subsequent consequences with respect to outcomes were determined. Quality of graft function, infections, and effect on preexisting essential hypertension are also described. METHODS Immunosuppression consisted of quadruple therapy with antithymocyte globulin induction, tacrolimus, MMF, and prednisone. Patient and graft survival and rejection rates in 50 consecutive SPK recipients, followed for a minimum of 3 months and a mean of 14 months (range: 3-34 months), are described. RESULTS Thirty-nine of 50 (78%) patients tolerated the MMF/tacrolimus combination long-term (mean duration of follow-up: 14+/-7 months). Nine of 50 patients (18%) were converted to Neoral, and 4 patients were converted to azathioprine as a substitute for MMF. The 2-year actuarial patient, kidney, and pancreas survival rates were 97.7%, 93.3%, and 90.0%, respectively. At 6 months after transplant, the overall incidence of acute rejection was 16%. There was a statistically significant (P< or =0.04, Cox-Mantel test) difference in the rate of rejection associated with conversion to Neoral. The incidence of rejection 6 months after transplant in the group maintained on MMF/tacrolimus was 10.2% vs. 44.4% in the group converted to Neoral (P< or =0.04, Cox-Mantel test). Overall, the 1-year actuarial cumulative incidence of tissue-invasive cytomegalovirus disease was 6.6%. There were no cases of fungal infections or post-transplant lymphoproliferative disorders. One patient developed Kaposis sarcoma 10 months after transplant. With respect to hypertensive disease, 60% (12/20) of the patients who required pharmacologic control of blood pressure before transplant were off all antihypertensive medications at 1 year after transplant. An additional 20% (4/20) of patients had a reduction in the number of medications required to control blood pressure at 1 year after transplant. CONCLUSIONS We conclude that the combination of MMF and tacrolimus as primary immunosuppression for SPK transplantation results in excellent patient and graft survival rates, a very low rate of acute rejection, and low rates of infection and malignancy.

Elective conversion from cyclosporine to azathioprine in recipients with stable renal function 6 months after kidney transplantation

The average cost of cyclosporine over the first 6 months after renal transplantation has been

Use of a Brief Steroid Trial Before Initiating OKT3 Therapy for Renal Allograft Rejection

2450/recipient for recipients with stable renal function. Fifty-nine percent of all patients transplanted in 1984 do not have a third-party payment mechanism for outpatient medicines and many cannot afford cyclosporine. The expense of cyclosporine has, thus, mandated developing a protocol for conversion from cyclosporine to azathioprine. Using a protocol, which included a short overlap of cyclosporine and azathioprine and a temporary, modest increase in prednisone dose, 27 renal allograft recipients with stable renal function have undergone conversion of their immunosuppressive regimen approximately 6 months posttransplant with a minimum follow-up of 4 months from conversion. There has been no graft loss or patient death. Mean serum creatinine has been reduced in recipients with stable function after conversion (1.4 mg/dl 3 months postconversion compared to 1.8 mg/dl preconversion). However, acute breakthrough rejection has occurred in four recipients (15%), and, after reversal of rejection, mean serum creatinine is elevated (3.1 mg/dl) in this group. Only a single patient developed an infection during the conversion period. Thus, a policy of conversion from azathioprine appears to be a reasonable compromise for those patients who cannot afford long-term outpatient treatment with cyclosporine.

T cell immunofluorescence flow cytometry cross-match results in cadaver donor renal transplantation

OKT3 (Ortho Pharmaceutical, Raritan, NJ) has been employed in a protocol where all patients received cyclosporine as part of their baseline immunosuppressive regimen and, after the diagnosis of rejection was established, were treated with up to three pulses of methylprednisolone before monoclonal antibody therapy was initiated. Use of this protocol has allowed 46% of rejection episodes encountered to be treated on an outpatient basis without resorting to inpatient use of OKT3, but has avoided delaying OKT3 therapy until after all other methods of rejection treatment were found to be ineffective. Of 83 rejection episodes treated with OKT3 between March 1985 and May 1987, 78 (94%) were reversed. Overall graft survival is 84% and patient survival is 96% in OKT3-treated patients. Of the 17 rejection episodes where OKT3 treatment was a second or third exposure to the drug, rejection was successfully reversed in 15 (88%). In cadaver donor allograft recipients transplanted between March 1985 and May 1986, actual 1-year graft survival is 80% for 30 patients requiring no rejection therapy, 80% for 20 patients with rejection episodes responding quickly to steroids, and 82% for 28 patients with OKT3-treated, steroid-insensitive rejections. Mean serum creatinine at 1 year posttransplant is 1.5 +/- 0.5; 1.9 +/- 0.7; and 2.1 +/- 0.8, respectively, for these groups of patients.(ABSTRACT TRUNCATED AT 250 WORDS)