Sequential conventional immunotherapy with maintenance cyclosporine following renal transplantation.
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Adult↗
Biomedical subjects
R M Ferguson
Publications and source records attributed to R M Ferguson.
Identification and treatment of cyclosporine-associated allograft thrombosis.
Endothelial injury associated with cyclosporine (CSA) therapy in the absence of rejection has resulted in irreversible intrarenal allograft thrombosis and transplant loss. Indium 111 (111In)-labeled platelet scanning is an effective way to identify those transplants that are at risk for acute loss. Two hundred prospective 111In scans were obtained (100 on allografts with normal function and 100 with transplant dysfunction of all causes). 111In scans in patients with dose-dependent CSA nephrotoxicity (N = 58) and biopsy proved acute rejection (N = 22) were negative. Grossly abnormal scans (three to eight times greater than hepatic uptake) were noted in nine recipients identified as having a hemolytic uremic-like syndrome associated with CSA use. Accelerated allograft functional loss was irreversible in six patients despite stopping CSA, systemic anticoagulation, increased steroids and antilymphocyte globulin, and infusion of fresh-frozen plasma. Three patients with grossly positive 111In scans and clinical and laboratory parameters consistent with this syndrome were treated with cessation of CSA and intra-arterial infusion of streptokinase into the renal allograft followed by systemic heparinization. Normal transplant function was regained and continues at 1, 7, and 8 months after transplant. 111In-labeled platelet scanning can noninvasively identify this syndrome of CSA-associated arteriopathy and allow for early therapy to reverse it. Intrarenal arterial streptokinase therapy is a successful way to treat acute CSA-associated arteriopathy.
Blood Platelets↗
Assessment of factors associated with donor-specific sensitization in patients given donor-specific blood transfusions.
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Antibodies↗
In vivo mechanisms of alloreactivity. III. Development of donor-specific antibody in sponge matrix allografts.
The in vivo generation of donor-specific alloantibody was examined using a sponge matrix allograft model. This experimental model has not been previously used to study the humoral immune response during allograft rejection. We chose this model on the basis of its ability to permit recovery of antibody directly from the graft site without the use of elution and dialysis protocols. C57BL/6 (H-2b) mice were implanted with polyurethane sponges injected with DBA/2 (H-2d) splenocytes, C57BL/6 splenocytes, or phosphate-buffered saline (PBS). Thirteen days later, only those sponges injected with allogenic (DBA/2) splenocytes contained high levels of complement-dependent donor-reactive cytolytic antibody. Donor-reactive cytotoxic antibody was detected by its ability to lyse donor-derived target cells but not host-derived target cells. In contrast, cell-free control sponges injected with PBS or syngeneic sponges injected with C57BL/6 splenocytes contained no detectable H-2d-reactive cytolytic activity. Donor specificity of sponge fluid antibody was determined by removal of H-2d cytotoxic activity following absorbtion with DBA/2 thymocytes. Control absorptions with C57BL/6 or third-party C3H/HeJ thymocytes were ineffective in removing this activity. To determine the rate at which antibody would accumulate in sponge implants we examined the sponges for antibody activity at varying times following implantation. Detectable levels of donor-specific antibody were observed as early as 7 days postimplantation. Antibody activity in the sponges subsequently increased to maximal levels by day 10, and was maintained through day 17, which was the last day examined. An accelerated rate of antibody accumulation was observed in alloimmune recipients, which had previously rejected DBA/2 skin grafts. To determine whether antibody activity observed in the sponge fluid reflected similar activity present in the circulation, we compared donor-reactive antibody activity in sera and sponge fluids from the same recipients on various days following sponge implantation. In this experiment donor-specific cytotoxic antibody was first detected in both the sponge fluids and sera on day 10, although the level of activity was higher in the sera than in the sponge fluids. Levels of cytotoxic antibody in sponge fluids remained constant through day 14, and cytotoxic antibody activity in the sera decreased by day 14 to levels observed in the sponge fluids. The cytotoxic antibody activity in sponge allograft fluids paralleled the accumulation of donor-reactive IgM, rather than the accumulation of total donor-reactive antibody.(ABSTRACT TRUNCATED AT 400 WORDS)
Animals↗
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.
Antilymphocyte Serum↗
Metabolic effects of pretreatment with Escherichia coli J5 antiserum on guinea pig gram-negative bacterial sepsis.
Antiserum raised to a rough mutant Escherichia coli, termed J5 (anti-J5 RS), protected against lethal gram-negative bacterial sepsis in a guinea pig model when animals were pretreated with both antiserum and heparin. This same model was used to examine and compare the effects of pretreatment with anti-J5 RS, normal rabbit serum (NRS), or saline, each +/- heparin on physiologic and metabolic parameters during a septic insult. Results demonstrated that leukopenia and thrombocytopenia occurred to a similar degree in all pretreatment groups; no significant leuko- or thrombostasis was noted on examination of histologic specimens; complement activation was maximal in those animals receiving anti-J5 RS alone without heparin; the most abnormal amino acid profile was present in the NRS + heparin group; and only the anti-J5 RS + heparin group did not develop glomerular lesions indicative of disseminated intravascular coagulation. A complement-mediated cell aggregation-type injury does not appear to occur in this model. It is hypothesized that both excessive complement and coagulation system activation occur after bacterial challenge when antibody directed against the bacteria is present (anti-J5 RS) leading to antigen-antibody complex formation and complement and coagulation cascade activation. Heparin may block either or both these cascade systems allowing enhanced, antibody-mediated opsonization and clearance of blood-borne bacteria, thus preventing end-organ alterations and organ failure during sepsis when combined with anti-J5 RS.
Amino Acids↗
Cyclosporine-associated renal arteriopathy resulting in loss of allograft function.
Cyclosporine-associated arteriopathy was the cause of graft loss in 40 percent of all allografts that failed in a series of 200 consecutive cadaveric renal transplants. Arteriopathy was diagnosed by biopsy and renal uptake of indium 111m labeled platelets in the face of acute renal deterioration. A moderate thrombocytopenia and microangiopathic picture of hemolytic uremia was also present on peripheral blood smear. Immunofluorescence and histologic characteristics of the allograft biopsy specimens failed to show evidence for acute rejection: immunoglobulin M, immunoglobulin A, immunoglobulin G, C1q, C3, and C4 were not present, and there was no evidence of an interstitial or vascular mononuclear cellular infiltrate. Two clinical presentations have been described. In Group I (seven patients), anuria occurred rapidly within the first 2 weeks after transplantation. In Group II (nine patients) renal function gradually diminished 1 to 5 months after starting cyclosporine therapy. Fifteen of the 16 recipients had progressive and irreversible loss of renal function which was pathologically associated with fibrin deposition, intimal proliferation, and thrombotic occlusion of the cortical interlobular and arcuate arteries, with subsequent focal glomerular ischemia and cortical infarction. One recipient with rapid loss of renal function received an intraarterial allograft infusion of streptokinase and subsequent systemic heparinization, which resulted in return of normal allograft function. The syndrome of cyclosporine-associated arteriopathy has been linked to a lack of or reduced amounts of prostacyclin-stimulating factor or prostacyclin.
Arterial Occlusive Diseases↗
Cyclosporine in renal transplantation: a single institutional experience.
Cyclosporine (CsA) as immunosuppression in renal transplantation was evaluated in a single institutional experience to answer several controversial questions. CsA was found to be the superior method of immunosuppression for primary cadaveric renal transplantation. Graft survival, with CsA, was improved over that with conventional immunosuppression which included an antilymphocyte preparation. CsA was found to be the immunosuppressive agent of choice in retransplantation for patients who had rejected a previous renal allograft. Also, CsA was indeed the agent of choice for immunosuppression in patients over 50 years of age seeking renal transplantation. The risks of CsA following transplantation were almost exclusively related to the associated nephrotoxicity. The nephrotoxicity, however, was easily manageable through a defined management strategy which titrates the CsA dose to renal function. CsA was also found to be more cost effective when compared to conventional immunosuppression. Morbidity was substantially decreased with CsA as fewer infectious complications and rejection episodes resulted.
Azathioprine↗
Suppression of in vitro CML generation by alloactivated lymphocytes: analysis of antigen-nonspecific suppressive mechanisms.
We have investigated the in vitro phenomena associated with antigen-nonspecific suppression of mixed lymphocyte culture (MLC) responses by allocativated lymphocytes. Using an experimental system that we described in a previous communication, we observed that a) the degree of suppressive activity generated by allocativation correlates directly with the intensity of proliferation observed during induction of suppressive activity, b) suppressive activity segregates exclusively with proliferating (lymphoblast) subpopulations of alloactivated lymphocytes, c) when suppressive cells are included in MLC, subsequent [3H]thymidine incorporation is enhanced and accelerated, rather than impaired, and d) a considerable proportion of the cells recovered from suppressed MLC appear to be the progeny of the suppressive population, and not the progeny of the MLC responder population. These data suggest that antigen-nonspecific suppression mediated by alloactivated lymphocytes has two related components: 1) cytokine preemption by suppressive (alloactivated) lymphocytes, and 2) MLC responder cell dilution by the progeny of suppressive lymphocytes. These data are consistent with the hypothesis that the antigen-nonspecific suppressive activity of alloactivated lymphocytes can reflect the coincidental ability of activated T cells to recognize and respond to mitogenic lymphokines in vitro. The data further explain why antigen-nonspecific suppression is difficult to reverse by addition of exogenous lymphokines to suppressed MLC.
Animals↗
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.
Adolescent↗
Comparison of azathioprine-antilymphocyte globulin versus cyclosporine in renal transplantation.
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Antilymphocyte Serum↗
Fatal central nervous system infection with varicella-zoster virus in renal transplant recipients.
Three renal transplant patients with culture-positive central nervous system infections resulting from varicella-zoster virus died of the virus infection. No finding predicting a poor outcome in these patients could be identified. Varicella-zoster infection in transplant recipients is a potentially fatal disease, and upon diagnosis should it be treated by (1) reduction in immunosuppression, and (2) initiation of either vidarabine or acyclovir as specific antiviral therapy.
Acyclovir↗
A functional assay for cyclosporine in patient serum.
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Cell Line↗
Predictive value of thallium stress testing for coronary and cardiovascular events in uremic diabetic patients before renal transplantation.
Coronary artery disease and the ability of noninvasive exercise perfusion imaging with thallium-201 to predict future coronary and cardiovascular events was prospectively evaluated in a group of 85 insulin-dependent diabetic renal transplantation candidates. Sixty patients received renal allografts (36 living related donors, 24 cadaver donors) after a thallium stress test; the actuarial 2 year patient survival rate after transplantation was 84 percent. Twenty-five patients remained on dialysis, and the 2 year actuarial survival rate from onset of dialysis was 41 percent, significantly lower than the actuarial survival rate of transplanted patients (p less than 0.01). Thirteen transplanted patients had positive thallium stress test results, and 6 (46 percent) had cardiovascular events (two fatal). In contrast, of 47 transplant patients with negative thallium stress test results, only 13 (28 percent) had cardiovascular events (four fatal). Five patients treated by hemodialysis only had positive test results and three (60 percent) had cardiovascular events (two fatal), whereas of 20 hemodialysis patients with negative test results, 9 (45 percent) suffered cardiovascular events (four fatal). In this study, cardiovascular events included arrhythmia, stroke, and pulmonary embolism. Within the total group, 4 of 18 patients (22 percent) with a positive test result (22 percent) had a fatal myocardial infarction, whereas only 3 of 67 patients (4 percent) with a negative result had a fatal myocardial infarction (p less than 0.05). In comparison, 24 of 85 patients had a history or electrocardiographic evidence of preexisting cardiovascular disease, and 13 (54 percent) had subsequent cardiovascular events (5 of 11 patients with positive test results and 8 of 13 patients with negative results). In summary, renal transplant candidates with positive thallium stress test results appear to be at increased risk compared with those with negative results for the development of fatal myocardial infarction, but thallium stress testing is no more predictive for future coronary and cardiovascular events than is a history or an abnormal electrocardiogram.
Adult↗
The role of heparin in guinea pig gram negative bacterial sepsis.
The ability of antibody directed against shared antigenic determinants of gram negative organisms to protect against a challenge of diverse gram negative bacterial species remains controversial in the experimental setting. Attention has focused, however, on the use as immunogens of rough mutants of Escherichia coli and Salmonella minnesota, which express a portion of core lipopolysaccharide (LPS) extensively on their cell surface. Core LPS is a structure present on the outer membrane of most, if not all, gram negative bacteria. In this study rabbits were immunized with E. coli J5, a rough mutant of E. coli, to produce anti-E. coli J5 rabbit antiserum (anti-J5 RS). Anti-J5 RS was found to cross react extensively by enzyme-linked immunosorbent assay with various gram negative bacterial whole cell or LPS antigens, compared to normal rabbit serum (NRS). Anti-J5 RS +/- heparin was also compared to NRS +/- heparin pretreatment in a guinea pig model of sepsis utilizing E. coli O111:B4 as the challenge organism. Anti-J5 RS +/- heparin augmented systemic bacterial clearance compared to NRS +/- heparin, but only the combination of anti-J5 RS and heparin enhanced survival 48 hr after bacterial challenge. It was concluded that pretreatment with anti-J5 RS was a necessary, but not sufficient condition for enhanced survival, and that the addition of heparin to anti-J5 RS pretreatment might diminish the otherwise lethal consequences of complement activation and disseminated intravascular coagulation in this model system.
Animals↗
Aspergillosis in 25 renal transplant patients. Epidemiology, clinical presentation, diagnosis, and management.
In immunocompromised renal transplant patients, aspergillosis can be a life-threatening opportunistic infection. During an 8-year period, 25 renal transplant recipients at the University of Minnesota Hospitals developed unequivocal invasive aspergillosis that occurred in epidemic-like patterns in immunocompromised patients throughout the hospital. The premortem diagnosis was made in only 14 of the 25 patients. Seventeen patients died, and three of the eight survivors lost their allografts. The prognosis was dependent upon the clinical pattern of illness: three clinical patterns emerged: (1) cavitary lung disease, (2) diffuse pulmonary disease, and (3) central nervous system disease. All patients in the latter two categories died. The best results were with those patients treated with both amphotericin B and excision of cavitary lung lesions. All three patients treated in this manner survived with functioning grafts. Traditionally, sputum cultures have been thought to be unreliable because Aspergillus is a common colonizer of the upper respiratory tract and a contaminant in laboratories. In this study, false positive sputum cultures were common. A positive sputum culture can be helpful, however, all patients with two positive sputum cultures proved to have invasive aspergillosis. In addition, 86% of patients with positive sputum cultures who were clinically ill proved to have invasive infection. Bronchoscopy is a useful technique to follow up a positive sputum culture or investigate negative sputum cultures with typical clinical patterns. Routine bronchoscopy, unfortunately, also yields a high incidence of false positive cultures. Since the use of covered brush bronchoscopy technique, however, no false positive transbronchial cultures have been found. Transbronchial biopsy is a useful adjunct and is proof of the presence of invasive disease when the results are positive. However, false negative results are also found. Overall, the highest diagnostic yield is obtained both with transbronchial lung biopsy and covered brush bronchoscopy culture. All eight patients with both these procedures were correctly identified as having invasive pulmonary aspergillosis.
Adult↗
Clinical renal transplantation.
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Adrenal Cortex Hormones↗
Total lymphoid irradiation.
Total lymphoid irradiation by itself can produce sufficient immunosuppression to prolong the survival of a variety of organ allografts in experimental animals. The degree of prolongation is dose-dependent and is limited by the toxicity that occurs with higher doses. Total lymphoid irradiation is more effective before transplantation than after, but when used after transplantation can be combined with pharmacologic immunosuppression to achieve a positive effect. In some animal models, total lymphoid irradiation induces an environment in which fully allogeneic bone marrow will engraft and induce permanent chimerism in the recipients who are then tolerant to organ allografts from the donor strain. If total lymphoid irradiation is ever to have clinical applicability on a large scale, it would seem that it would have to be under circumstances in which tolerance can be induced. However, in some animal models graft-versus-host disease occurs following bone marrow transplantation, and methods to obviate its occurrence probably will be needed if this approach is to be applied clinically. In recent years, patient and graft survival rates in renal allograft recipients treated with conventional immunosuppression have improved considerably, and thus the impetus to utilize total lymphoid irradiation for its immunosuppressive effect alone is less compelling. For example, in our institution, the current one-year patient and graft survival rates in recipients of kidneys from cadaver donors are 91 and 84 per cent in those treated with cyclosporine and 94 and 80 per cent in those treated with conventional immunosuppression. Similar results might also be achieved by protocols that use total lymphoid irradiation as an immunosuppressant, but it will be difficult to improve over the current results with cyclosporine or conventional immunosuppression, at least for primary transplantation. The future of total lymphoid irradiation probably lies in devising protocols in which maintenance immunosuppression can be eliminated, or nearly eliminated, altogether. Such protocols are effective in rodents. Whether they can be applied to clinical transplantation remains to be seen.
Adolescent↗