Trasplante cardíaco: experiencia inicial / Cardiac transplantation: experience inicial

Se presenta la experiencia inicial de 7 trasplantes cardíacos efectuados en un centro privado de la Ciudad de Rosario. Se describen la indicación etiológica, las técnicas empleadas y se analizan sus resultados. Se destaca la importancia del apoyo institucional necesario para este emprendimiento, así como las dificultades inherentes al medio nacional

Trasplante cardíaco: experiencia inicial / Cardiac transplantation: experience inicial

Se presenta la experiencia inicial de 7 trasplantes cardíacos efectuados en un centro privado de la Ciudad de Rosario. Se describen la indicación etiológica, las técnicas empleadas y se analizan sus resultados. Se destaca la importancia del apoyo institucional necesario para este emprendimiento, así como las dificultades inherentes al medio nacional

Factor de necrosis tumoral y terapéutica / Tumor necrosis factor and therapeutic

El factor de necrosis tumoral (TNF) alfa (caquectina) y beta (linfotoxina) son citoquinas involucradas en un amplio espectro de actividades biológicas. La inflamación, reparación tisular, coagulación, crecimiento y diferenciación de células hematopoyéticas progenitoras, mecanismos efectores de la respuesta inmune, bacteremia por gram negativos, choque séptico, actividad antitumoral, reacción injerto versus huésped están relacionadas a la bioactividad de TNF. Sus efectos secundarios han sido neutralizados terapéuticamente mediante el uso de anticuerpos monoclonales antilipopolisacáridos y anti TNF, inmunoadhesina contra el receptor TNF, Pentoxifilina, Cloroquina, Dexametasona y Colchicina. Debido a sus eficaces resultados in vitro, el TNF ha sido usado en enfermedadesmalignas en forma regional mediante la infusión arterial o como inmunoquimioterapia sistémica

Evidence that long-term survival of concordant xenografts is achieved by inhibition of antispecies antibody production.

Antibody and complement have been shown to be of primary importance in the rejection of hamster heart xenografts by rats. Very high anti-hamster antibody titers were detected at the time of rejection of hamster hearts transplanted into untreated or T cell deficient rats. This study demonstrates a method of inhibiting this antibody production by pulse therapy with cyclophosphamide (CyP) and continuous cyclosporine treatment, resulting in a median survival of the hamster heart of greater than 100 days. Controls and CsA-treated rats reject the transplanted hamster heart in a median of 3 days. CyP as a sole therapy resulted in a median survival of 14 days. Prolonged CyP therapy when combined with CsA was associated with increased death among rat recipients due to infection. Antispecies antibody production was suppressed during CyP and CsA therapy and did not recur after cessation of CyP therapy. Cessation of CsA therapy at 60 and 100 days posttransplantation resulted in subsequent rejection of the xenografts (median survival after cessation of therapy of 11 and 19.5 days, respectively) and was associated with production of rat anti-hamster antibodies.

The long-term effects of prophylactic OKT3 monoclonal antibody in cadaver kidney transplantation--a single-center, prospective, randomized study.

We conducted a randomized, prospective study to determine the long-term effects of prophylactic OKT3 in cadaveric renal transplantation. In the first group of patients (n = 56) OKT3 (5 mg/day) was administered for the first 14 postoperative days in association with azathioprine (AZA) and low-dose steroids, cyclosporine (CsA) being introduced on day 11. The other group of patients (n = 52) received CsA from the first POD, together with AZA and steroids. Both protocols were identical from POD 14 on. The total number of infections was higher in OKT3 patients (124/1455 patient-months [P-M] vs. 68/1320 in CsA patients, P less than 0.001) without impact on patient survival (94.5% in OKT3 vs. 93% in CsA patients). OKT3 patients experienced a lower number of rejection episodes (61 per 1455 P-M of risk exposure vs. 81/1320 in CsA patients, P less than 0.05). In addition, the frequency of corticoresistant rejection episodes was lower in OKT3 patients (9 out of 61 vs. 24 out of 81 in CsA patients, P less than 0.05). This resulted in a trend toward improved overall graft survival (83% vs. 75%, P = 0.12) and in a significant increase in immunological graft survival (92% vs. 79%, P = 0.02) in OKT3 patients at 3 years. Taken together, these data suggest that prophylactic OKT3 therapy might have long-term beneficial effects in cadaveric renal transplantation.

Induction of specific tolerance to class I-disparate renal allografts in miniature swine with cyclosporine.

Previous studies in miniature swine have suggested that the mechanism underlying the spontaneous development of tolerance in one third of one-haplotype class I disparate renal allografts (i.e., ag----ad) involves a relative T cell help deficit at the time of first exposure to antigen. If this hypothesis were correct, then one might expect the administration of an immunosuppressive agent capable of inhibiting lymphokine production during this period to lead to the induction of tolerance to class I MHC antigens in two-haplotype class I mismatched renal allografts (i.e., gg----dd), which are otherwise uniformly and acutely rejected. This hypothesis was tested in eight two-haplotype class I disparate, class II matched donor-recipient pairs, in which recipients were treated with cyclosporine 10 mg/kg, i.v. q.d. for 12 days. This protocol led to the induction of long-term (greater than 100 days) specific tolerance in 100% of recipients, as compared with control animals that rejected grafts in 13.7 +/- 0.9 days (P less than 0.0001). The specificity of tolerance was assessed both in vivo with subsequent skin grafts and in vitro by mixed lymphocyte response (MLR) and cell-mediated lymphocytotoxicity (CML). Survival of donor-specific skin grafts was prolonged compared with skin grafts bearing third-party class I antigens (19.5 +/- 2.0 versus 11.5 +/- 2.0 days, n = 4, P less than 0.05). Tolerant recipients had markedly diminished or absent anti-donor MLR and CML responses, but maintained normal reactivity to third party. Four of eight CsA-treated recipients showed detectable levels of anti-donor IgM, while none demonstrated the presence of anti-donor IgG, which was found in all rejecting controls.

Evidence that the systematic analysis of bile cytology permits monitoring of hepatic allograft rejection.

Cytologic analysis was performed on 128 bile specimens collected by schedule from 12 liver transplant recipients over a 4-month period. Clinical diagnoses at the time of specimen collection were determined retrospectively, as follows: clinically stable, 75; acute rejection, 15; CMV hepatitis, 1; systemic infection, 8; ischemic injury, 24 (all within the first 4 days postop); nonclassifiable, 5. Bile analysis was done by a blinded investigator. Specimens contained ductal epithelial cells (EC) and inflammatory cells (IC), which were counted using Cytospin slide preparations. Greater than 10 cells/slide were seen in 93.3% of rejections, 91.7% of ischemic injuries, 100% of systemic infections, and 14.6% of stable patients. In samples collected after POD 4, IC were seen in 86.7% of rejections, yielding a specificity of 94.4% (P less than 0.001). If lymphoblastic cells were also seen, the specificity increased to 96.6%. Five specimens were obtained the day before the clinical diagnosis of rejection; all demonstrated IC. Seven specimens were obtained 3 days after beginning therapy for rejection. In 5 the bile contained no IC, and clinical improvement occurred; in the 2 in whom IC were found, further therapy was subsequently required. IC were seen in 5 of 8 specimens taken when systemic infection was present; the clinical setting allowed differentiation from rejection. Only 1 case of CMV hepatitis was included, thus no conclusions can be drawn for this entity. Cytoplasmic vacuolization of EC was observed in 30% of cases, in these, cyclosporine levels were significantly higher (989.9 +/- 356.9 vs. 672.8 +/- 421.2, P = 0.02). In summary, bile cytology analysis aides in the monitoring of the onset and duration of rejection. It may be an indicator of persistent rejection, and it may help prevent overimmunosuppression in those cases with normal cytological findings.

Immunosuppressants.

The role and pharmacology of a variety of immunosuppressant agents in the gastrointestinal tract and liver are reviewed in this article. Immunosuppressants covered include cyclosporine, corticosteroids, OKT3, antithymocyte globulin, azathioprine, methotrexate, and FK506. Guidelines for the use and complications of immunosuppressants in liver, pancreas, and small bowel transplantations are presented. Controlled and uncontrolled data for use of immunosuppressants in the management of gastrointestinal and hepatic disorders are also described.

Successful use of Orthoclone OKT 3 for steroid-resistant acute rejection in pediatric renal allograft recipients.

Use of Orthoclone OKT 3 for the treatment of steroid-resistant acute rejection in kidney transplant recipients is well described in the literature. Our experience with the use of OKT 3 in 16 pediatric kidney transplant recipients supports the use of this therapy in the pediatric population by reporting efficacy and lack of major complications. Monitoring of OKT 3 antibodies is recommended because of potential need to reuse OKT 3 in subsequent transplants. In addition, techniques of improving medical compliance, particularly in the adolescent population, is an area identified as needing further study. The combination of improving rejection therapies and specific nursing interventions in preparing children and their families in the use of OKT 3 as well as in enhancing compliance will improve the outlook of pediatric transplant recipients.

Specific monoclonal radioimmunoassay and fluorescence polarization immunoassay for trough concentration and area-under-the-curve monitoring of cyclosporine in renal transplantation.

In order to study the performance of a specific fluorescence polarization immunoassay (FPIA) for monitoring of the area under the concentration time curve (AUC) of cyclosporine (CsA), a total of 170 24-h CsA AUC studies were prospectively collected from 40 consecutive adult renal transplant recipients during the first 6 months after transplantation. Each AUC study included whole blood samples that had been collected at 0, 2, 4, 6, 10, 14, and 24 h after CsA administration. Each sample was subjected to CsA analysis in whole blood using a 3H-tracer specific monoclonal radioimmunoassay (wb-sRIA), specific FPIA (wb-sFPIA), and polyclonal FPIA (wb-pcFPIA). Furthermore, the performance of the specific assays was assessed against high-performance liquid chromatography (HPLC). Correlations between HPLC and specific assays were good, namely correlation coefficients of 0.94. Contrariwise, correlations between specific and nonspecific assay were poorer. As compared to HPLC, wb-sRIA overestimated CsA concentrations by 7.0%, and wb-sFPIA overestimated concentrations by 26.8%. The correlation between the AUC of CsA, as determined by wb-sRIA and wb-sFPIA, was excellent (r = 0.96). The ratio between wb-sFPIA and wb-sRIA was higher at low concentrations and small AUCs of CsA. On the average, CsA AUCs were 14% larger when assayed by wb-sFPIA. However, the appearance of the CsA concentration versus time curve was almost identical for the two assays. The apparent oral clearance (clearance/bioavailability) of CsA decreased with time after transplantation. Furthermore, the oral clearance of CsA was significantly higher in patients experiencing acute rejection than in those who were quiescent (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Clinical trial of FK 506 immunosuppression in adult cardiac transplantation.

The new immunosuppressive agent FK 506 was used as primary immunotherapy in conjunction with low-dose steroids and azathioprine in 72 patients subsequent to orthotopic cardiac transplantation. Overall patient survival at a mean follow-up of 360 days was 92%. The number of episodes of cardiac rejection (grade 3A or greater) within 90 days of transplantation was 0.95 per patient. The actuarial freedom from rejection at 90 days was 41%. Achievement of this level of immunosuppression is comparable with that of cyclosporine-based triple-drug therapy with OKT3 immunoprophylaxis. Thirty percent of patients were tapered off all steroids, and the average steroid dose in the group who received steroids was 8.6 mg of prednisone per day. The incidence of infection reflected the diminished necessity for steroids: seven major infections (10%) and 11 minor infections (16%). Renal dysfunction occurred during the perioperative period in most patients in this trial. However, the incidence of hypertension was 54% compared with 70% during the cyclosporine era. Ten adults underwent successful rescue therapy with FK 506 after cardiac rejection refractory to conventional immunotherapy. Side effects of FK 506 were notably few, and the results of the trial are encouraging for the future of the cardiac transplant recipient.