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PubMed1992

Leishmaniasis: a rare cause of unexplained fever in a renal graft recipient.

We report a case of visceral leishmaniasis in a 38-year-old renal transplant recipient living in an endemic country. Antimonial derivatives induced a rapid remission. A review of the literature disclosed 8 cases of this association with a fatal fulminant outcome in 5 cases. We suggest that the specific immunosuppression used in renal transplant patients might facilitate the development of a dormant infection and in these patients the misleading presentation may delay the diagnosis. Moreover special caution with treatment of leishmaniasis must be taken in renal transplant because of possible interactions between antimony compounds and ciclosporin metabolites. In renal transplant patients living in endemic countries, visceral leishmaniasis should be kept in mind as a potential cause of unexplained long-standing fever and considered as an opportunistic infection.

Adult↗
PubMed1992

Prevalence of invasive cytomegalovirus disease with administration of muromonab CD-3 in patients undergoing orthotopic liver transplantation.

OBJECTIVE: To assess the association of cytomegalovirus (CMV) disease with the administration of muromonab CD-3 (OKT-3) in patients undergoing liver transplant; specifically, to assess the risk of OKT-3 use as an agent for rejection prophylaxis and as an agent for therapy of rejection. DESIGN: Retrospective review of medical records. STUDY POPULATION: 83 liver transplant recipients (43 men, 40 women) with a mean age of 41.5 years (range 16-62). DATA EXTRACTION: The medical record for each liver transplant recipient was reviewed and analyzed for the following variables: (1) preoperative recipient CMV serology, (2) donor CMV serology, (3) incidence of invasive CMV disease, (4) administration of OKT-3, (5) postoperative administration time of OKT-3, and (6) the relationship between the administration of OKT-3 and the prevalence of invasive CMV disease. RESULTS: OKT-3 was administered to 34 of 83 (40.9 percent) liver remainder received OKT-3 as rejection rescue. All patients received OKT-3 5 mg iv for 14 days. Seventeen of the 34 patients receiving OKT-3 (50 percent) developed invasive CMV disease; 58.8 percent of the patients (20/34) receiving OKT-3 were given the agent within the first 14 postoperative days. Sixteen of these 20 patients (80 percent) developed invasive CMV disease. One of 14 patients (7.1 percent) who received OKT-3 after the first 14 postoperative days developed invasive CMV disease. Of those patients 94 percent (16/17) received OKT-3 in the first 14 postoperative days. This prevalence differed significantly from those receiving OKT-3 after the 14th postoperative day and those who did not receive OKT-3 at any time during their hospital course. CONCLUSIONS: The patients who received early administration of OKT-3 in our study had a greater risk of invasive CMV disease than did those who received OKT-3 later in the hospital course.

Adolescent↗
PubMed1992

Lymphoproliferative disorders after renal transplantation in patients receiving triple or quadruple immunosuppression.

A retrospective review of 478 renal transplant recipients receiving cyclosporin A (CsA) was conducted to determine the incidence, relative risk, and outcome of lymphoproliferative disease after transplantation. Cases of neoplasm were identified by linking the computerized databases of the British Columbia (B.C.) Transplant Society and the B.C. Cancer Agency. B.C. Cancer Statistics for 1988 were used to determine relative risk. Patients were monitored for a total of 1,054 patient years with a mean follow-up time of 26 months (range, 0.1 to 63 months). A total of 334 patients were treated with triple immunosuppression (CsA), azathioprine, and prednisone), and 144 received adjunctive antilymphocyte globulin as induction immunosuppression. Sixty-nine patients received OKT3 for the treatment of transplant rejection. Twenty-two patients developed 23 malignancies (4.8%) at a mean interval of 16 months (range, 3 to 45 months) after transplantation. Non-Hodgkins lymphoma occurred in five patients, of whom two received triple (0.6%) and three received quadruple (2.1%) therapy. All five patients, in addition, received OKT3 for the treatment of graft rejection. The relative risk of developing a neoplasm among the defined sample adjusted for age and sex was 3.08 overall, increasing to 26.9 (P less than 0.005) for lymphoma. Six of the 22 patients (27%), including all 5 patients with lymphoma, died as a result of their tumor. Renal transplant recipients receiving CsA have a significantly elevated risk of developing a de novo lymphoreticular malignancy, which is comparable to that reported for those receiving azathioprine treatment, and which appears to be increased by the use of quadruple immunosuppression and the administration of OKT3 for the treatment of acute graft rejection.

Actuarial Analysis↗
PubMed1992

Sequential therapy in pediatric cadaveric renal transplantation: a critical analysis.

Cadaveric renal transplant survival rates in children are still somewhat inferior to those reported in adults. Sequential therapy, an immunosuppressive program in which a course of antilymphocyte preparation is used immediately postoperatively and followed in sequence by oral maintenance immunosuppression, has a number of features that might be expected to improve pediatric transplant outcome by addressing some of the metabolic and immunologic difficulties encountered in children. This article examines the rationale for sequential therapy in pediatric renal transplantation. It also examines the use of sequential therapy in children. Sequential therapy appears to significantly improve cadaver renal allograft outcome in children without compromising patient survival. There was a slight improvement in 1- and 2-yr graft outcomes when OKT3 was used prophylactically when compared with antithymocyte globulin, but this difference did not reach statistical significance. Almost 60% of patients receiving OKT3 for sequential therapy remained free of rejection. Major drawbacks of sequential therapy include the adverse side effects of the antilymphocyte preparation, infection, and the possibility of lymphoproliferative syndrome. The implications of these problems as well as potential strategies for ameliorating them are discussed.

Adult↗
PubMed1992

Enhanced tumor necrosis factor in anti-CD3 antibody stimulated diabetic NOD mice: modulation by PGE1 and dietary lipid.

Administration of OKT3 anti-CD3 monoclonal antibody (mAb) to patients for transplant rejection, is associated with a distinct and often severe clinical syndrome related to massive cytokine release. Previous reports have similarly demonstrated increased levels of serum tumor necrosis factor alpha (TNF alpha) in normal mice following administration of 1452-C11 anti-CD3 mAb. In this study, we compared serum TNF alpha levels at baseline and after anti-CD3 stimulation among three groups of mice: normal BALB/c controls, pre-diabetic non-obese diabetic (NOD) mice, and diabetic NOD mice. Baseline serum TNF alpha levels, as measured by L929 cell bioassay, were 2xhigher in diabetic NOD and 3xhigher in pre-diabetic NOD compared with BALB/c. Ninety minutes after anti-CD3 mAb stimulation, serum from BALB/c controls and pre-diabetic NOD contained 2- to 8-fold higher levels of TNF-alpha as compared to untreated control mice. In contrast, following anti-CD3 mAb, there was a dramatic 20-fold increase in serum TNF alpha in diabetic NOD mice (levels > 5000 pg/ml). Additionally, anti-CD3 mAb increased the steady-state TNF alpha mRNA transcripts. Spleens from diabetic mice given anti-CD3 mAb had higher steady-state TNF alpha mRNA than spleen from normal mice similarly treated. The enhanced release of circulating TNF alpha after anti-CD3 mAb in diabetic NOD mice was abrogated by pre-treatment of mice with prostaglandin E1 (PGE1) 30 min prior to anti-CD3 mAb stimulation.(ABSTRACT TRUNCATED AT 250 WORDS)

Alprostadil↗
PubMed1992

Activation of coagulation and fibrinolysis following OKT3 administration to renal transplant recipients: association with distinct mediators.

Treatment with OKT3 induces cytokine release and activates the complement system. Since both phenomena may affect coagulation and fibrinolysis we studied these systems in 8 renal transplant recipients during OKT3 treatment. In 8 of 9 patients a similar pattern was observed: plasma thrombin-antithrombin-III-complex, tissue-type plasminogen-activator and plasmin-alpha 2-antiplasmin-complex levels were increased as compared to pretreatment levels (p less than 0.05) at 15 min after the first OKT3 dose and reached peak values at 1 h. No significant changes were observed upon subsequent OKT3 administrations or in a control group of 8 patients. In one patient upon the first OKT3 administration only complement activation, and no cytokine release was observed, whereas plasma thrombin-antithrombin-III-complex, tissue-type plasminogen-activator and plasmin-alpha 2-antiplasmin-complex levels increased only at 15 min. In conclusion, we demonstrate a biphasic activation of coagulation and fibrinolysis upon the first OKT3 dose; the initial phase seems to be associated with complement activation, the later phase with cytokine release.

Adult↗
PubMedDate not supplied

Immunosuppressive drugs.

The success rate of clinical transplantation has improved considerably over the last two decades largely due to better immunosuppressive drugs. Allograft rejection remains the major cause of graft loss in renal transplant recipients. This article reviews the mechanisms of action of immunosuppressive drugs and their clinical use.

Animals↗
PubMed1992

[Reduction of TNF-alpha release and clinical effects of the first injection of OKT3].

In order to prevent the adverse effects of a first OKT3 injection in renal transplant recipients, we administered polyclonal antilymphocyte globulins (ATG Fresenius, 4 mg/kg/j) for 3 days before OKT3 injection. Compared with a historical group of 5 patients who did not receive ATG pretreatment before OKT3 injection, the patients who were pretreated by ATG had a significantly lower absolute number of circulating lymphocytes before the first OKT3 injection (363 +/- 107 vs 1,230 +/- 80/mm3, P < 0.001), a lower raise in plasma TNF-alpha level 2 hours after OKT3 injection (178 +/- 42 vs 735 +/- 127 pg/ml, P < 0.005) and a significant decrease in frequency and intensity of clinical symptoms, mainly chills, dyspnea, and headaches. However, fever and peak creatinine level were similar in both groups. A 80 percent success rate of crisis treatment was achieved in both groups and there was no increase in infectious complications. In conclusion, pretreatment with ATG induces a lymphocyte depletion, and decreases the amounts of TNF-alpha released as well as the side-effects of a first OKT3 injection.

Antilymphocyte Serum↗
PubMed1992

Selective immunosuppression with anti-T cell monoclonal antibodies.

Murine monoclonal antibodies specifically directed at the CD3 molecular complex are widely used in clinical practice. They are potent inhibitors of immune function and may be administered in association to conventional immunosuppressants. The main purpose of this review is to summarize our present knowledge on the CD3 molecule, to discuss the available data on the clinical use of anti-CD3 MoAb (therapeutic effectiveness, mode of action and side effects) and the recent information derived from the use of anti-CD3 MoAb in experimental models that are opening new perspectives in the applications of anti-CD3 and will hopefully lead to the extension of its clinical use to settings different from transplantation.

Animals↗
PubMed1992

Antilymphocyte globulin with a small dose of cyclosporine A and prednisone as the induction of immunosuppression in renal allograft recipients.

In attempt to avoid a detrimental synergism between CsA and renal ischemia in the immediate postoperative period, ALG (425 lymphocytotoxic units/kg) with small doses of CsA (6-8 mg/kg) and P were applied as the initial immunosuppressive therapy in 14 recipients of cadaveric kidneys. ALG was administered for 5 to 14 days and 2 days before withdrawing ALG, Aza (2 mg/kg) was introduced. Results of this protocol were compared with those of 19 pts treated with CsA (12 mg/kg) and P. All the pts were followed for at least 12 months. The duration of posttransplant anuria was significantly reduced in the ALG/CsA/P group (p < 0.02). The sCr concentration after 12 months of observation was significantly lower (p < 0.05), no alterations in urinalysis were detected, the number of hypertensive pts was decreased. The acute rejection rates were equivalent in both groups, however 3 of 4 rejections in ALG/CsA/P group were resistant to steroids and occurred in pts with shortened period of ALG administration. The one year patient and graft survival in the ALG/CsA/P and control groups were respectively: 78.5%, 71.4% and 89.4%, 78.9%. Severe infectious complications in the group treated with ALG/CsA/P occurred in pts who were subsequently treated with OKT3.

Acute Disease↗
PubMed1992

Age-related changes in the expression of T cell activation antigens following phytohaemagglutinin stimulation.

The role of accessory cells (AC) in the temporal expression of several key T-cell-activation-associated antigens has been studied in healthy aged subjects. Compared to responses seen in young adults, phytohaemagglutinin (PHA) induced weak proliferation in peripheral blood mononuclear cells from the aged and lower numbers of T cells expressing CD71, CD25, CD38 or HLA-DR. T cell responses to the monoclonal antibody OKT3, however, were normal. Whereas HLA-DR+ T cell numbers could be increased by raising the AC content (up to 50%) in cultures comprising purified T cells and graded numbers of autologous AC, CD25+ T cell numbers remained largely unaltered. Co-stimulation with PHA + phorbol myristate acetate in the absence of AC restored both proliferation and CD25 expression in the aged. These results indicate that T cells from the healthy aged show selective deficiencies in their capacity to respond to mitogenic stimuli and suggest that impaired PHA responsiveness is due, at least in part, to defective AC-derived signals.

Aged↗
PubMed1992

Day-5 protocol liver allograft biopsies document early rejection episodes and are predictive of recurrent rejection.

METHODS: The day-5 posttransplant protocol biopsy specimens and clinical courses of 27 consecutive orthotopic liver transplant recipients followed up at least 6 months were reviewed. RESULTS: Twelve (44%) of 27 patients had histologic evidence of rejection on the day-5 biopsy; 8 (67%) of these 12 patients required OKT3 for reversal of the rejection. No significant differences in biochemical liver test results, bile output, or cyclosporine levels were observed between this group and the 15 patients (56%) without histologic evidence of rejection on day 5. Eight (67%) of the 12 patients with rejection had recurrent rejection episodes, with one recurrence each in six patients, two recurrences in one patient, and three recurrences in one patient. Of the 15 patients without rejection on day 5, nine (60%) subsequently had rejection at 10 days, 14 days, and 1 1/2, 3 1/2, 4, 5, and 11 months after transplantation. Only one (11%) of these nine patients had a recurrent rejection episode. There were no differences in the incidence of posttransplant cytomegalovirus infections between the two groups. Two cases of posttransplant lymphoma were seen; they developed in two patients without rejection on the day-5 biopsy. No patients or allografts were lost to acute or chronic rejection. No complications occurred as a result of the day-5 protocol biopsy. CONCLUSION: The day-5 protocol biopsy is useful in detecting rejection episodes that may not otherwise be clinically apparent.

Adult↗
PubMed1992

Combination immunotherapy for advanced lung cancer.

Therapeutic strategies using cytokines have not been extensively tested in patients with advanced non-small-cell lung cancer (NSCLC). We developed a basic laboratory and clinical research program to investigate the effective immunotherapeutic manipulations for activating the endogenous immune system with biological agents. Our efforts using low-dose interleukin 2 in conjunction with other biologic response modifiers for the treatment of NSCLC are summarized here.

Antineoplastic Combined Chemotherapy Protocols↗
PubMedDate not supplied

Cytomegalovirus infections in heart transplant recipients: relationship to immunosuppression.

To determine the relationship of cytomegalovirus infections (CMVI) to immunosuppression in heart transplants, we retrospectively compared demographic and clinical variables in 154 consecutive heart transplant patients. Forty-one CMVI were compared; of these, 30 (73%) were identified in tissue, and nine (22%) were identified by blood or urine culture. Twenty (49%) of the CMVI were self-limited, and 21 (51%) were progressive, requiring treatment. When comparing patients with and without CMVI, demographic variables, mean preexisting heart disease, cyclosporine level, cumulative corticosteroid dose, and the use of anti-T-cell antibodies were examined. Only the use of OKT3 was significantly associated with the subsequent development of CMVI. Although CMVI subsequently developed in 30 of 79 (38%) patients who had received OKT3, CMVI developed in only 11 of 75 (15%) patients who had not received OKT3 (p = 0.01). Furthermore, the incidence of CMVI increased with increasing total OKT3 dose (none, 11 of 64 [17%]; < or = 75 mg, 23 of 66 [35%]; > 75 mg, 6 of 14 [43%]; p = 0.01). Logistic regression showed that the only two variables predictive of CMVI were the use of OKT3 (p = 0.0023) and ischemic rather than idiopathic heart disease before transplantation (p = 0.0098). Rejection rates, incidence of allograft vasculopathy, and 1-year actuarial survival were not influenced by previous CMVI. Pneumocystis carinii pneumonia occurred more frequently in patients with CMVI than in those without (13 of 41 [32%] patients versus 3/113 [3%] patients; p < 0.001). No correlation existed between CMVI and lymphoproliferative disorder (p = 0.84).(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗