Clinical impact of replacing Minnesota antilymphocyte globulin with ATGAM.

In August 1992, we replaced Minnesota antilymphocyte globulin (MALG) with lymphocyte immune globulin, antithymocyte globulin (equine) (ATGAM) in our immunosuppression protocols. The clinical impression of increased graft rejection prompted our assessment of the effect of this change on patient and graft outcome. The initial study group consisted of 426 renal transplant recipients transplanted between October 1, 1987, and September 21, 1993. After exclusions, 388 transplant events, with a minimum 8-month follow-up, made up the final study cohort: 323 patients received MALG and 65 received ATGAM. Immunosuppression included intravenous methylprednisolone, oral prednisone, oral AZA, CsA in some cases, and intravenous MALG or ATGAM, 15 mg/kg/day, for 7 to 14 days. Acute rejection was treated with high dose intravenous steroids and steroid-resistant episodes were treated additionally with either MALG or OKT3. Statistical comparisons were stratified for multiple patient characteristics and treatment variations. There was a greater incidence of rejection in general, and a higher incidence of steroid-resistant episodes requiring subsequent antilymphocyte globulin therapy (P = 0.0073) in patients receiving ATGAM versus MALG. No difference was seen in the incidence of CMV infection or blood-borne sepsis. Lymphoma occurred in 3 MALG and 2 ATGAM recipients. MALG recipients were significantly less likely to experience rejection within the first 60 days after transplant (P = 0.0127 using unstratified data; P < 0.0001 when data were stratified for patient characteristics). The relative risk of acute rejection for posttransplant days 5, 7, 10, and 14 was consistently higher for ATGAM-treated patients. We conclude that MALG and ATGAM are not equivalent drugs, and that MALG is a more effective immunosuppressant, and is just as safe as ATGAM in our protocol environment.

Single lung transplantation. Factors in postoperative cytomegalovirus infection.

Thirty-one single lung transplantations were performed between March 17, 1988, and November 1, 1990. Postoperative infection, especially with cytomegalovirus, has been the major cause of morbidity and mortality. Eighteen of the 31 patients were receiving prednisone before transplantation. Every patient was prepared preoperatively with oral cyclosporine 5 mg/kg and azathioprine (Imuran) 2 mg/kg. Every patient received methylprednisolone for 3 days postoperatively, followed by prednisone 1.0 mg/kg/day, oral cyclosporine, and azathioprine. Ten patients additionally had cytolytic therapy with OKT3 and 12 with antilymphocyte globulin. Nine patients had no cytolytic therapy. Cytolytic therapy was chronologic, not randomized. Postoperative infection occurred in 20 patients, 13 of whom had cytomegalovirus infection. Preoperative use of prednisone did not correlate with postoperative infection, cytomegalovirus, or death. Postoperative infection occurred in 17 of 22 patients with cytolytic therapy compared with three of nine without cytolytic therapy (p = 0.035). Cytomegalovirus infection occurred in 13 of 22 with cytolytic therapy and in none of the nine without cytolytic agents (p = 0.003). Therefore preoperative prednisone does not appear to be a contraindication to single lung transplantation. Cytolytic therapy with either OKT3 or antilymphocyte globulin increases the prevalence of postoperative infection with cytomegalovirus and should not be used in patients undergoing lung transplantation.

Apparent cytomegalovirus epithelial keratitis in a cardiac transplant recipient.

A 44-year-old immunosuppressed man developed initial symptoms of intermittent irritation of the left eye three months after cardiac transplantation. Symptoms increased, with decreased vision, photophobia, and lacrimation. Slit lamp examination showed slightly raised, swollen, grayish epithelium in a broad multibranching dendritic pattern associated with fine and medium punctate epithelial erosions that stained slightly with fluorescein. Histopathologic study of the corneal epithelial scraping demonstrated swollen epithelial cells with intranuclear and intracytoplasmic viral inclusions. Viral cultures manifested a cytopathic pattern characteristic of cytomegalovirus 14 days after inoculation on human embryonic lung cells (MRC-5). Pretransplantation cytomegalovirus IgM and IgG serologic titers were negative (less than 1:16 for IgG, no IgM noted) until the onset of symptoms. Subsequently, IgM titers rose against cytomegalovirus consistent with concurrent infection.

Current thinking in transplantation in infants and children.

Renal and liver transplantation are now recognized as therapeutic modalities for children with kidney and liver failure. This article reviews the general indications for transplantation, recipient selection, descriptions of the procedures, and the expected outcome of these two procedures in the pediatric setting.

Relevance of adenosine deaminase to organ transplantation.

We have presented a discussion on the relevance of ADA to organ transplantation with regard to whether or not purine analogue inhibitors of ADA can prevent allograft rejection, and whether or not cells with high ADA activity may be involved in the rejection of allografts. It is clear that ADA inhibitors do have a modest amount of immunosuppressive activity. The potentiation of this modest effect by the addition of a deoxyadenosine analogue supports studies by others suggesting that it is the metabolism of deoxyadenosine and the presence of this compound as a substrate that is biochemically responsible for the immunosuppressive effects observed. In other studies that we are currently conducting, we have found that the ADA inhibitor EHNA causes a rapid and severe depletion of ATP in resting murine lymphocytes and that EHNA potentiates a similar effect of the new immunosuppressive agent cyclosporine in the same model. Investigations are currently underway to see if ADA inhibitors may potentiate the immunosuppressive effect of cyclosporine in vivo. It appears that cells with high ADA activity that are detectable in the peripheral blood mononuclear cells of renal allograft patients may indeed be involved in the rejection of allografts. However, from murine studies allogeneic cells alone do not seem to generate the appearance of these cells nearly as strongly as infection with murine cytomegalovirus. It must be determined if the ADA-rich cells that appear at the time of CMV infection are involved in viral functions or are the ontologic appearance of cytotoxic T cells representing the host's response to the antigens of the virus. The attack of these host cells against allograft cells infected with the virus may then explain the long-standing observation that viral infections seem to trigger allograft rejection responses.

Cyclosporine-induced adenosine triphosphate depletion in murine T and B lymphocytes.

Adenosine metabolism in C57BL/6 mouse spleen cells was studied. Adenosine triphosphate (ATP) levels in resting T cells were 26.9 +/- 3.4 ng/10(5) cells compared with 16.5 +/- 3.1 ng/10(5) cells in resting B cells. Cyclosporine (CSA) caused a prompt and severe ATP depletion in both T and B cells, which could be mitigated by the addition of adenosine. B cell ATP levels were returned to normal while T cell levels were only partially restored. The adenosine deaminase inhibitor erythro-9-(2 hydroxy-3 nonyl) adenine (EHNA) also caused ATP depletion in T and B cells, which could similarly be prevented in part by the addition of adenosine. However, when CSA and EHNA were combined, adenosine could no longer protect ATP pools and severe ATP depletion in T and B cells occurred. This suggests that CSA and EHNA affect different steps in the conversion of adenosine to ATP. Although both T and B cell ATP levels were affected by CSA, the ability of supplementary substrate to restore ATP levels to normal in B cells but not in T cells may explain the apparent selective effect of CSA impairing T cell functions with sparing of B cell functions. Furthermore, if causing ATP depletion is associated with immunosuppressive activity, EHNA may be useful in potentiating the immunosuppressive effects of CSA.

Transplantation of the adult kidney into the very small child. Technical considerations.

Transplantation of adult kidneys into very small children is not performed in most centers because of concerns regarding the technical difficulty of the procedure. Advantages of the procedure include the possibility of living related donor transplantation and the increased availability of adult donor kidneys as compared with pediatric cadaver donor kidneys. We have transplanted adult kidneys into 12 children aged 11 months to 3.5 years who weighed 5,400 to 8,800 g. Ten children received living related donor and two cadaver donor grafts. Herein we describe in detail the pretransplant management, surgical strategies, intraoperative management, surgical techniques, and postoperative management which we use for transplantation of adult kidneys into very small children. Intraoperative and postoperative complications have been described to illustrate the evolving clinical principles in this area. Since 10 of the children are presently alive, 8 with their original grafts, 16 months to 9 years after transplantation, we advocate this approach for suitable small children with terminal renal failure.

Transplantation of adult kidney into the very small child: long-term outcome.

Adult kidneys were transplanted into 12 children weighing between 5,400 and 8,800 gm. Ten received parental and two received cadaver grafts. Ten of the 12 children are alive 18 months to 9 years post transplant; eight have their original grafts and two required retransplantation-their original grafts were lost at 4 and 9 years because of chronic rejection. All but these two surviving children had normal or accelerated growth rates despite growth retardation prior to transplant. All children evidenced moderate to severe delay in psychomotor development prior to transplant. Seven of the ten survivors now have normal psychomotor function. Two are behind in school, and one with a degenerative central nervous system disease prior to transplant remains profoundly retarded. We conclude that because of donor availability, capacity for good donor-recipient matching, and minimization of time on dialysis, transplantation of adult kidneys into pediatric patients is preferable to awaiting the relatively uncommon pediatric cadaver donor. We further conclude that the procedure is warranted.

Kidney allograft survival in dogs treated with total lymphoid irradiation.

Total lymphoid irradiation (TLI) is immunosuppressive and, in rodent, can induce a state where transplantation of allogeneic bone marrow results in chimerism and permanent acceptance of organ allografts from the donor strain. We attempted to apply this treatment to a large animal model. Twelve splenectomized dogs were treated with TLI (150 rads per fraction, total dose 1950-3000 rads) before bilateral nephrectomy and renal allotransplantation. Eight dogs received bone marrow from the kidney donor. In 13 untreated control dogs renal allografts functioned (serum creatinine level less than 2.0 mg/dl) for a mean +/- (SE) of 4.7 +/- 0.3 days. In the four TLI treated dogs who did not receive bone marrow the renal allografts functioned for 15-76 days (two dogs died with functioning grafts). In the eight TLI treated dogs who received donor bone marrow, two died immediately after transplantation, two rejected at 3 and 13 days, one died at 13 days with a functioning graft, and two have had the grafts function for longer than 500 days. Chimerism was not detected in the one dog tested. The response of peripheral blood lymphocytes to stimulation with phytohemagglutinin and in mixed lymphocyte culture was suppressed for at least on month after TLI. The results confirm the immunosuppressive effect of TLI. The absence of kidney rejection in two recipients of donor bone marrow show the potential of this approach to induce long-term immunologic unresponsiveness as to an organ allograft, but the outcome is unpredictable and further experiments are needed to define the optimal conditions for administration of TLI and bone marrow to the recipients.