Repeat cadaver kidney transplantation using cyclosporine A immunosuppression

Repeat cadaver kidney transplantation using azathioprine immunosuppression carried a higher risk of graft loss than primary transplants. We analyzed the results of repeat cadaver kidney grafting with cyclosporine A immunosuppression. A total of 33 cyclosporine A-treated patients received the second kidney transplant at varying intervals after failure of the first transplant. Graft survival at 1 year was 66 per cent. A concurrent group of 189 cyclosporine A-treated first cadaver kidney recipients had a 1-year graft survival rate of 75 per cent, although this better result was not statistically significant (p greater than or equal to 0.25). A historical group of 31 azathioprine-treated second graft recipients had a significantly worse 1-year graft survival rate of 45 per cent compared to the cyclosporine A second graft group (p less than 0.1). Patient age, sex, early first graft loss, interval between transplants and the presence of panel reactive antibodies were not factors in predicting second graft outcome. A complete DR mismatch appeared to worsen the second transplant survival. These findings indicate that early graft survival of cyclosporine A-treated repeat cadaveric transplants is acceptable and is better than azathioprine-treated first or second grafts.     

Kidney transplantation in children younger than 1 year using cyclosporine immunosuppression.

OBJECTIVE: The optimal age for transplantation in children with end-stage renal disease remains controversial. Supported by national data, many centers recommend dialysis until the child reaches a certain minimum age. The authors' policy, however, has been to encourage living donor (LD) transplants for young children, with no minimum age restriction. METHODS: Between January 1, 1984, and December 31, 1996, the authors performed 248 kidney transplants in children younger than age 13 years, using cyclosporine as the primary immunosuppressive agent. Recipients were analyzed in three age groups: group 1, younger than age 1 year (n = 26); group 2, age 1 through 4 (n = 92); and group 3, age 5 through 13 (n = 130). Almost all recipients in group 1 underwent a primary LD transplant. Therefore, to compare results more meaningfully among the three age groups, only primary LD transplants were analyzed (group 1, n = 25; group 2, n = 59; group 3, n = 58). RESULTS: In primary LD transplants, no significant difference was noted among the age groups in 1-and 5-year patient or graft survival rates. To date, all 25 recipients from group 1 are alive and well; 19 still have a functional original graft. Causes of graft loss in the remaining six recipients were chronic rejection (n = 3), vascular thrombosis (n = 2), and recurrent disease (n = 1). The incidence of acute rejection in group 1 recipients was lower than in the two older groups. However, the incidence of delayed graft function was slightly higher in the youngest group than in the two older groups. For recipients in group 1, growth (as measured by weight) improved significantly posttransplant: the mean standard deviation score rose from -2.8 pretransplant to -0.2 by age 5 and to +1.8 by age 10. The improvement in height was not as dramatic: the mean standard deviation score rose from -3.2 pretransplant to -1.6 by age 5 and to -1.4 by age 10. CONCLUSIONS: Kidney transplantation in young children, including those younger than 1 year old, can achieve results comparable to those in older children. As long as an adult LD is available, the timing of the transplant should be based on renal function rather than age.     

Improved survival after allogeneic small intestinal transplantation in the rat using cyclosporine immunosuppression

We investigated the effect of cyclosporine on survival after intestinal transplantation between histoincompatible Brown Norway (AgB3/3) and Lewis (AgB1/1) rats. Intestinal grafts were primarily vascularized (by microsurgical techniques) and interposed isoperistaltically in the recipient's jejunum. All animals were weighed and observed daily. Survival of recipients given cyclosporine 20 mg/kg/d (112 +/- 92 days, n = 10) was significantly longer (P less than .02) than that of recipients given no drug (12 +/- 4 days, n = 8). Six out of ten cyclosporine-treated animals remained alive and well at the conclusion of the experiment. One of these was killed and showed no gross or microscopic evidence of rejection. The described experimental model involves a simple operative technique and minimal postoperative care and should permit systematic investigation of the detection and prevention of rejection.     

Optimal perioperative immunosuppression in cardiac transplantation using rabbit antithymocyte globulin

A randomized trial of RATG (polyclonal) vs. OKT3 (monoclonal) antibody prophylaxis was carried out in 82 cardiac transplant recipients who, in addition, received baseline immunosuppression with cyclosporine, azathioprine and prednisone. One-year actuarial survival was comparable between groups (95% and 98%). The incidence of moderate or severe rejection within the first 30 days of transplant was over 7 times greater in patients receiving OKT3 vs. those receiving RATG. Patients receiving OKT3 were more likely to have repeated episodes of rejection and the mean time to rejection for patients receiving OKT3 was shorter (33 days) than for RATG patients (67 days). At 120 days, 52% of RATG patients were free of rejection while only 37% of the OKT3 patients were rejection-free. There was no difference in the incidence of major or minor bacterial or viral infection between groups. Patients receiving OKT3 showed a less-prolonged depression of the CD3 and CD4 T cell subsets than did those receiving RATG. Significant hemodynamic side-effects were seen after the first dose of OKT3 and there was a 5% incidence of aseptic meningitis associated with its use.     

Strategies of immunosuppression in cardiac transplantation

Immunosuppression for cardiac transplantation, as currently practiced, is based to a large extent on clinical trials that can best be characterized as single-institutional, uncontrolled, or historically controlled studies. While these non-randomized, retrospective studies clearly advanced the science and art of cardiac transplantation to the point that survival rates approaching 90% at 1 year are achievable, the specific immunosuppressive protocols used at any given institution are likely based more on the individual transplant surgeon's or physician's training and experience, than on a firm scientific basis. Thus, a significant lack of uniformity exists among transplant centers in virtually all phases of immunosuppression. More clinical and basic research efforts are needed to unify immunosuppressive strategies following cardiac transplantation. In the future, greater individualization of therapy is likely to occur and more prospectively randomized, multi-center trials are likely to be carried out, particularly in the area of early rejection prophylaxis.     

Control of cyclosporine A-induced tumor progression using 15-deoxyspergualin for rat cardiac transplantation

Immunosuppressive therapy increases the risk of recurrence of initial cancers in organ transplant patients, and compelling therapeutic protocols are needed to suppress the malignancy and protect the allograft. We examined the potential use of 15-deoxyspergualin (DSG) in relation to organ transplantation and cancer. The effect of DSG on established liver metastatic tumors in recipient rats bearing a heart allograft was evaluated using an in vivo luminescent technique with luciferase-expressing RCN-H4 rat colon cancer cells. The inhibition of cell growth by DSG was correlated with NF-kappa B activity and caspase-3/7 activity in vitro. In the cyclosporine A (CsA)-induced cancer progression model of rats, DSG treatment (3 mg/kg) blocked the increase in tumor-derived luciferase activity, while CsA (15 mg/kg) facilitated luciferase activity up to around day 20 after cardiac transplantation. Our data suggest that DSG may be a therapeutic candidate for the control of tumor growth in transplant patients.     

Effects of bisphosphonate treatment on bone repair under immunosuppression using cyclosporine A in adult rats

Summary The effect of cyclosporine A on bone turnover remains unclear. Using adult rats with vascularized bone transplantation, we show that long-term cyclosporine A administration increases bone turnover and zoledronic acid treatment enhances the reconstruction of cyclosporine A-administered skeleton. Bisphosphonates might be efficacious in human bone repair under immunosuppression using cyclosporine A. Introduction Bisphosphonate treatment effectively prevents bone loss after transplantation. However, recent evidence from gain- and loss-of-function experiments has indicated that calcineurin inhibitors, such as cyclosporine A (CsA), reduce bone turnover, and severely suppressed bone turnover might delay the union of human fractured bone. The purpose of this study was to investigate the effects of bisphosphonate treatment on the repair of CsA-administered skeleton. Methods After skeletal reconstruction by vascularized tibial grafting, adult recipient rats were treated with intramuscular CsA (10 mg/kg/day) and low-dose (0.2 μg/kg/week) or high-dose (2 μg/kg/week) subcutaneous zoledronic acid alone or in combination for 8 weeks. Biochemical parameters were measured in blood and urine. The reconstructed skeleton was analyzed using soft X-ray, histology, dual energy X-ray absorptiometry, and three-point bending test. Results CsA induced mild renal dysfunction, hyperparathyroidism and high bone turnover. High-dose zoledronic acid delayed cortical bone union at the distal host-graft junction, but its combination with CsA did not cause such a delay. High-dose zoledronic acid prevented CsA-induced bone loss and bone fragility in the reconstructed skeleton. Conclusion In this rat model, long-term CsA administration increases bone turnover, at least partly, through hyperparathyroidism and high-dose zoledronic acid treatment does not impair the union of CsA-administered bone.     

Allogeneic hepatocyte transplantation in the rat spleen under cyclosporine immunosuppression

An innovative approach for stimulating the rapid growth of allogeneic hepatocytes implanted into splenic tissue with maintenance of the structural integrity is described. Single cell suspensions of hepatocytes from normal male ACI-strain rats (RTIa) were injected (2 X 10(6) cells) into the spleen of allogeneic male Fischer (RTI1) recipient rats. A 70% partial hepatectomy (PH) was performed at the same time as hepatocyte transplantation. Animals were treated for 4 days prior to, and 1 day after, transplantation with a feeding regimen containing 0.05% 2-acetylaminofluorene (AAF) to inhibit regeneration of the residual host liver. Animals received cyclosporine (CsA) 3 mg/kg/day s.c. posttransplantation. Histological examination of a standard longitudinal section of the recipient spleen two days posttransplant revealed an approximately 0.54-mm2 area replaced by hepatocytes. By 7 days this had increased to 0.97 +/- .15 mm2. Without CsA administration, hepatocytes were undetected at 7 days. Both PH and AAF treatment were necessary for successful colonization and sustained proliferation. Withdrawal of CsA treatment at 10 days after transplantation resulted in rapid rejection of established hepatocytes. This study demonstrates that rapid colonization of the rat spleen with allogeneic hepatocytes can be achieved, and that the viability and structural integrity of these transplanted cells can be maintained for at least 14 days using cyclosporine immunosuppression.     

Bromocriptine as an adjuvant to cyclosporine immunosuppression after heart transplantation

Prolactin, a pituitary hormone, has been shown to have an active role in the regulation of the immune system. Prolactin receptors have been described on the membrane of lymphocyte cells, and competitive binding to these receptors by cyclosporine and circulating prolactin has been demonstrated. Experimental evidence suggests a synergistic effect of cyclosporine and bromocriptine, an inhibitor of pituitary release of prolactin, on immunosuppression. Between July 1986 and January 1988, 54 patients were randomly assigned to two groups of immunosuppression treatment. Thirty patients (group 1) were administered cyclosporine, azathioprine, and prednisone and 24 patients (group 2), a modified protocol aimed at decreasing the level of circulating prolactin by adding bromocriptine to the immunosuppression regimen. The two groups were similar in regard to age, preoperative diagnosis, and duration of follow-up. Minimal side effects related to bromocriptine were observed. The overall incidences of rejection and infection were similar, although actuarial analysis showed that freedom from these complications among patients treated with bromocriptine was significantly higher throughout the first 2 months after heart transplantation compared with that of patients in the control group. Other variables such as serum cyclosporine levels and lymphocyte counts were similar in both groups. In conclusion, suppression of circulating prolactin by bromocriptine appears to improve the immunosuppressive effect of cyclosporine, at least during the early postoperative period when the risk of rejection and infection is higher, and could be a promising avenue to successful hormonal manipulations of the immune process after organ transplantation.     

Improved immunosuppression with aerosolized cyclosporine in experimental pulmonary transplantation.

Rejection remains a major obstacle to long-term success of pulmonary transplantation. Direct delivery of cyclosporine to lung allografts may produce better control of rejection by generating high intragraft concentrations of drug with decreased systemic delivery and toxicity. The efficacy of inhaled cyclosporine in preventing allograft rejection was compared with systemic delivery by intramuscular injections in a rat model of lung transplantation (Brown-Norway to Lewis). Group 1 animals were given no immunosuppression. Group 2 received a single i.m. injection of 25 mg/kg CsA on the day of operation while group 3 received daily doses on postoperative days 0-3. Groups 4-7 received aerosolized CsA daily for seven days. The aerosol generator produced an airborne concentration of CsA of 180 mg/m3 with a mean particle size of 0.7 mu and estimated pulmonary depositions of CsA of 0.98-3.6 mg/kg/day. Animals were killed on POD 7, and the transplanted lungs graded histologically in a blinded fashion. All control animals showed destructive grade 4 changes by POD 7. Animals receiving high-dose aerosolized CsA (groups 6 and 7) showed minimal changes with a mean rejection grade of 1.3. A single i.m. dose of CsA (group 2) failed to prevent rejection; the mean grade was 2.2. Animals given four i.m. doses of CsA had a mean grade of 1.8. Aerosolized CsA provided significantly better control of rejection than did systemic CsA (groups 6 and 7 vs. groups 2 and 3; P less than 0.0002 and less than 0.0054, respectively). Local delivery of CsA by aerosol inhalation is effective in limiting acute rejection of the rat lung allograft.     

Improved immunosuppression for heart transplant patients using intravenous doses of cyclosporine

Inducing immunosuppression in heart transplant patients with intravenous doses of CsA may decrease the incidence of severe rejection in the 1st month after operation. In our initial series, 16 consecutive patients (group A) who had no contraindications to this type of therapy received an i.v. dose of CsA, 1 mg/kg/day, postoperatively, which was then increased by 1 mg/kg every 24 hr until a full maintenance dose of 4 mg/kg/day was achieved (total time, 72 hr). The gradual increase in dosage was designed to prevent nephrotoxicity associated with higher doses of CsA. Intravenous administration was continued for 2 weeks, at which time oral administration of CsA, 14 mg/kg/day, was begun. In a subsequent series, 21 similar patients (group B) received the same amount of CsA, except that doses were increased every 12 hr, so that the full maintenance dose was achieved 36 hr postoperatively. In group B, the i.v. dose of CsA was continued for only 1 week, at which time oral administration of CsA, 14 mg/kg/day, was begun. All patients received the same standard steroid taper (30 mg/day by day 10). Patients from both groups who were greater than or equal to 55 years old and had serum creatinine greater than or equal to 1.5 mg/dl and patients from group B who had creatinine clearance less than or equal to 55 ml/min also received azathioprine, 2 mg/day, which was adjusted to maintain the white blood cell count at a level greater than or equal to 5000/cc. There was a similar number of such patients in both groups. Severe rejection was defined by endomyocardial biopsy with frequent foci of myocyte degeneration. Three (18.7%) patients in group A experienced severe rejection, and 2 (9.4%) in group B did. No patients developed renal failure. All patients survived the 1st month. The overall survival rate for group A at 12.2 +/- 1.5 months was 94%, and for group B it was 86% at 7.5 +/- 1.4 months. Both these groups compared favorably with our historical control group of patients who received oral doses of CsA to induce immunosuppression, in which 59 of 165 (35.8%) had severe rejection in the 1st month, with a 1-year actuarial survival rate of 76%. Based on this experience, we believe that i.v. administration of CsA enhances the induction of immunosuppression, thereby reducing the incidence of severe rejection. This protocol is likely to be effective because it minimizes the problems of oral absorption in the perioperative period.(ABSTRACT TRUNCATED AT 400 WORDS)     

Specific immunosuppression in cardiac allografting using antithymocyte sera and soluble transplantation antigen

Two techniques of specific immunosuppression, using antithymocyte globulin (ATG) alone and in combination with soluble transplantation antigen (STA) prior to treatment, were studied in heterotopic outbred canine cardiac allografts. Both techniques resulted in prolonged survival of dogs having cardiac allografts with a low incidence of infections and drug toxicity complications as compared to animals treated with Prednisone and Imuran. This study demonstrates the ability of short-course ATG treatment to produce long-term (greater than 2 to 3 months) cardiac allograft survival without chronic immunosuppression. Combined ATG and STA pretreatment gave the longest allograft survival (mean, 93 days) in a small group of animals. This improved allograft survival, associated with a reduction in infections and drug toxicity complications, suggests that these techniques of specific immunosuppression may have the potential for improving survival and reducing the complications of immunosuppressive therapy following cardiac transplantation.     

Beneficial effects of prostglandin on rat cardiac allografts with cyclosporine immunosuppression

Graft rejection is characterized by cellular infiltration, reduction in blood flow, and intravascular coagulation, finally resulting in graft failure and absolute increase in thromboxane and relative decrease in prostacyclin synthesis. It is also suspected that prostaglandin itself could cause prolongation of allograft survival. In this experimental study, after successful heterotopic cardiac transplantation in rats, CyA was administered by intramuscular injection and prostaglandin E1 (PGE1) given into the peritoneal cavity. Each dose was according to the experimental designs. The authors found that PGE1 in addition to CyA could provide beneficial effects with significantly increased cardiac allograft survival, with amelioration of pathological changes in allograft rejection reaction.     

Hypertension after renal transplantation. A comparison of cyclosporine and conventional immunosuppression

Hypertension is a common complication after renal transplantation and is associated with increased mortality. Cyclosporine is known to be nephrotoxic and raises blood pressure in recipients of cardiac and bone marrow transplants, but there is conflicting data on the role of cyclosporine after renal transplantation. We have examined this question in patients entered into the second Oxford prospective randomized comparison of short-term cyclosporine treatment alone with conversion to azathioprine and prednisolone at 90 days (CsA group), and conventional therapy with azathioprine and prednisolone throughout (AP group). Blood pressure and antihypertensive medication were similar in the CsA and AP treatment groups during the first 90 days. Following conversion from cyclosporine, mean blood pressure fell from 155/94 to 142/81 within 7 days, and this fall correlated with the change in plasma creatinine over the same period (r = 0.44, P less than 0.05). Blood pressure was subsequently lower in the converted patients than in those treated with AP throughout. Six months after transplantation patients converted from cyclosporine not only had lower blood pressure but also required fewer antihypertensive drugs than AP patients. This study demonstrates that cyclosporine may elevate the blood pressure in recipients of renal transplants. This effect may either be direct or mediated through the effect of cyclosporine on renal function. Administration of corticosteroids during the first three months after transplantation is implicated as a possible cause of persisting high blood pressure.