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FK 506 is an immunosuppressive drug that holds particular promise for pediatric patients because of its potency, relatively low toxicity, and simplicity of administration.1,2 Above all advantages is elimination of the need for adjuvant steroid therapy in the majority of cases. It was introduced for clinical trials in pediatric patients in September 1989. We report here our total experience with FK 506 in pediatric recipients of commonly transplanted organs up to May 1, 1990 with follow-up to August 1, 1990. In addition, experience with new applications of FK 506 is included. A total of 74 pediatric patients were treated for the diverse indications summarized in Tables 1 to to44.
When needed IV, the FK 506 dose was 0.15 mg/kg/d given as a slow IV infusion. The starting oral dose was 0.15 mg/kg twice per day. At the time of conversion from IV to oral dosing, one day of overlap was usually allowed.1–4
Prednisone was administered at 20 mg/d for heavier children or 10 mg/d for patients lighter than 10 kg. The steroids were rapidly tapered and discontinued when the graft function was stable. Augmented FK 506, increased steroids, or OKT3 were given if rejection occurred.
Thirty patients underwent liver transplantation for the first time under FK 506 (Table 1). Three died. The deaths were due to tension hemothorax after a central venous line placement intraoperatively (1 case), nonreversal of hepatic coma (1 case) and cytomegalovirus (CMV) pneumonitis (1 case). Three of the children required retransplantation, two for hepatic artery thrombosis and one for primary graft dysfunction. Updated clinical data are shown in Table 1. At 90 days posttransplant, 21 (77.7%) of the patients are steroid free and the average daily prednisone dose for the whole surviving group is 0.83 mg/d (Table 1). The rate of removal from prednisone is shown in Fig 1.
Twenty-six patients who had either early or late rejections on conventional immunosuppression were treated with FK 506 as described elsewhere.4,5 Three of these patients died of systemic fungal infection (one case), multifocal bronchopneumonia complicating cystic fibrosis (one case), and tracheostomy failure and respiratory arrest after retransplantation.
Seven of these 26 patients required retransplantation, but in five of the seven examples, the patients were placed on FK 506 at the time of retransplantation after conventional therapy had failed.
Relevant clinical data are shown in Table 1. Steroids have been stopped in 16 of the 23 surviving patients; many were steroid toxic previously because of efforts with augmented prednisone doses to retain the grafts.
Seven primary heart transplant recipients were treated with FK 506.6,7 The only death was of a patient who was severely immunocompromised from lymphocyte depletion and protein-losing enteropathy, a complication of a previous Fontan operation for tricuspid atresia. The patient also had severe preexisting lung disease. Multiple opportunistic infections developed 2 months posttransplantation.
Three patients who suffered intractable rejection on conventional drug therapy were switched to FK 506.7 One of these patients was rejecting her second graft 6 months after retransplantation, which was necessitated by chronic rejection of her first graft over a period of 7 years. All three patients had a good result with clinical improvement and an improvement in endomyocardial biopsies. Their cushingoid appearance was relieved as steroids were reduced or stopped.
A 13-year-old patient underwent primary kidney transplantation on FK 506 for end-stage renal disease due to hemolytic uremic syndrome (HUS).8,9 There has been no evidence of recurrent disease in the transplanted kidney. HUS, at least when it is a complication of cyclosporine (CyA), responds to FK 506.10 Renal function is satisfactory (Table 2).
A 6-year-old patient who underwent heart and liver transplantation in 198411 developed chronic rejection and non-A non-B hepatitis in the liver graft. Liver function improved initially after switching from CyA to FK 506. Later, worsening of the non-A non-B hepatitis necessitated liver replacement in February 1990. She has developed recurrent non-A non-B hepatitis in her second liver graft but is clinically well with good liver function under treatment with interferon alpha (IFN-α)12 (Table 2). She has never had a cardiac rejection and has a normal recent coronary angiogram. The reason for the heart-liver transplantation was homozygous type 2 hyperlipidemia. The serum cholesterol has been lower with FK 506 than at any time previously (see footnote, Table 2).
Two patients with extensive hepatic malignancies and regional metastases were treated with upper abdominal exenteration13,14 followed by liver and pancreatic islet transplantation. One patient died, of tumor recurrence 5 months after transplantation. The other patient is well, without any evidence of recurrence, and with normal liver function (Table 3). She is insulin free, and is the first unambiguous example of a human successful pancreatic islet transplantation.15,16
Two patients were referred to us with severe chronic graft vs host disease 6 months following bone marrow transplantation for leukemia under conventional immunosuppression. Both had skin, intestinal, and hepatic involvement. High dose FK 506 was used at first, with oral doses that peaked at more than 1.0 mg/kg/d (more than three times the usual).
The first patient had a gradual but steady improvement on FK 506 and was discharged and sent home in 4 weeks in good condition. Steroids were tapered rapidly and discontinued on discharge from the hospital.
The second patient’s symptoms persisted for 2 months and then gradually resolved during the third month of FK 506 treatment. The patient is still receiving 10 mg/d of prednisone.
In both cases, the response could be monitored objectively by the slow resolution of jaundice (Table 3, see footnote).
A patient with biopsy proven focal sclerosing glomerulonephritis was started on FK 506 in November 1989 because of the nephrotic syndrome, which was refractory for 13 months to continuous treatment with high doses of prednisone and intermittent treatment with other conventional agents including cyclophosphamide. As reported elsewhere,17 a complete remission was promptly achieved at the same time as steroid therapy was stopped (Table 4).
A 3-year-old child, who had liver failure and the short gut syndrome secondary to perinatal necrotising enterocolitis and chronic IV alimentation, received a liver and complete small bowel. She has normal liver function (Table 3). The ileostomy stoma, which appears normal, has had minimal evidence of rejection on biopsy. This case is included in the present report because of its intrinsic interest, and is the only one treated after the cut-off date of May 1, 1990. Her follow-up is only 3 weeks.
Adverse effects are being monitored systematically through clinical observation and collection of questionnaires that are given periodically to the patients and/or their parents.
In our 74 patients, there were four fatal infections: two in liver rescue patients, one in a primary heart transplant patient, and one in a primary liver patient. Three of the four patients were immunocompromised when switched to or started on FK 506. There has been one example of lymphoproliferative disease of the stomach on a liver rescue patient that disappeared after a reduction of the immunosuppression.
Nonimmunologic side effects of FK 506 are similar to those of CyA and include nephrotoxicity, neurotoxicity, and diabetogenicity.24 De novo development of diabetes mellitus was observed in two liver rescue patients; one later became insulin independent after steroid withdrawal and reduction of the FK 506 dosage. The second patient still requires insulin treatment. Similar events have been reported in adults undergoing liver rescue.18
Neurologic complications such as those reported in adults23 have not yet been seen in infants and children. Transient renal dysfunction has developed mainly in liver rescue patients and also in the heart transplant recipients during the first 2 weeks after transplantation. Inappropriately high IV doses of FK 506 were thought to have been given as a management policy during this learning state of the trials.19
FK 506 appears to be the most effective immunosuppressive agent available today for the treatment of infants and children. Its use should allow improvement in graft and patient survival, as well as allowing an improved quality of steroid-free growth and development. Previously impractical kinds of transplantations should be made easier, and it may be possible to expand this technology to the more widespread treatment of autoimmune disorders in the pediatric population.
Supported by research grants from the Veterans Administration and project grant no. DK 29961 from the National Institutes of Health, Bethesda, MD.