Hakala, TR

Jensen, CWB

Jordan, ML

Schneck, FX

Shapiro, R

Starzl, TE

Tzakis, A

PubMed

D-Scholarship@Pitt

/~Th Pediatric Renal Transplantation Under FK 506 Immunosuppression C.W.B. Jensen. M.L Jordan. F.X. Schneck. R. Shapiro. A. Tzakis. T.R. Hakala, and T.E. Starzl RENAL transplantation (I: cadaveric and 4 living-related donors' was performed in 16 pediatric recip-ients (mean age 10.8 yean) under FK 506 immunosuppres-sion in combination with prednisone therapy. At a mean foUow-up of 8.5 months. patient and graft survival rates are 100% and 94%. respectively. The only graft loss was due to recurrent hemolytic uremic syndrome (HUS) 4 days after transplantation. In the functioning grafts. the mean serum creatinine is 1.29 :t 0.38 mgldL and the mean BUN is 26.0 :: 9.6 mgldL. Seven pa.tients are taking no pred-nisone. five are receIving 2.5 to 5 mg per day, and three are taking 10 to 15 mg per day. There were a total of nine rejection episodes in six patients and these were all successfuUy reversed. Compli-cations of transplantation included one patient each with cytomegalovirus (CMV). pyelonephritis. a seizure disor-der and headaches: two patients each developed insulin-dependent diabetes mellitus. and a posttransplant lym-phoma WTLD). These results would suggest that FK 506 is a potent immunosuppressant when used in the pediatric age group. The use of FK 506 for the immunosuppression of pediatric renal transplant recipients would appear to have the advantage of allowing for steroid withdrawal in a significant number of patients. thereby minimizing the steroid-related complications of which the pediatric popu-lation is at particular risk. MATERIALS AND METHODS Sixteen renal transplants ( 12 cadaveric and 4 living related) were performed In 16 pedlatnc pauents 17 females and 9 males. mean age 10.8 : 3.7 yean: range 3.3 to 16.2 yean' between December 14. 1989. and July 9. 1991. Twelve of these cases were primary transplantations and four were retransplants. Follow-up in these pallenls ranged from 0.6 to IS.2 months (mean 8.S months'. All pauents receIved FK S06 and prednisone as primary Immunosup-pressIon. Two transplants were performed UStng pediatric en· bloc kid-neys recovered from donors aged 6 months and 3 yean. respec-tively. Excluding these pediatric donon. the mean donor age was 21.6 yean c range 4 to 46 yeanl. Mean cold ischellllc lime of the kidneys was 33.7 = 6.6 hours (range 24 to 44 hoursl. excluding the four living·related donallons. Donor and recIpIent HLA·A. HLA·D. HLA·DR Iypinl were performed In all cases. but intenllonai donor-reCIpient HLA matching was nOI camed OUI. Only one patient had four or more anURen matches. Nine of 16 (S6%)transplanls were done with 0-2 anuRen matches. SIX (38%) had lhree anullCll matches. Ind one had I four'lnllgen malch. Multiple mIsmatches were common with 12 (75%) havtng three or more antiRens mismatched. Two patients were considered to be highly sensitized with panel-reactive anubodies (PRA) of 97CJf and 1009Ii. respectively. All other reClpents had a PRA of less than 109&. AbscMute critena for transplantation were ADO compatibility and a negative Iympho-cytotoxic cross-match usinl current sera. The immunosuppressIon consisted of FK S06 in combination wilh steroid therapy. FK S06 was started in the recovery room with • continuous IV infusion of 0.1 mglkg total daily dose. Oral doses staned at O. IS mglkg twice daily with an IV dose overlap of 121024 hours. SteroId therapy consisted of I g of methylprednis-olone in the operating room followed by a prednisone taper to 20 ma per day by postoperative day 6. Funher reductions in pred-nisone therapy were usually made in decrements of 2.S mg per day starting at the third week posttransplant. Biopsy-confirmed rejection episodes were treated with one-half to I g of IV boluses of methylprednisolone with or without a prednisone recycle. Prednisone recycle consIsted of a starting dose of 100 to 200 mg I day tapered to 20 mg over 6 days. A S- to l!k1ay course of OKTJ. S mg per day IV was insllluted in cases of severe or steroid-reSIstant rejection. RESULTS Patient and Graft Survival and Function The clinical characteristics of the 16 patients are summa-rized in Table I. Patient survival is 100% with a follow-up of I to IS months (mean 8.S months). All grafts achieved primary function defined as clearance of creatinine in the immediate postoperative period with early diuresis. At present. 94% of the grafts are functioning. No patient with a functioning graft required dialysis from the postoperative period onward. The only graft loss occurred in a 4-year-old boy with HUS receiving a second transplant with a PRA of 97%. His first graft was lost 3 years earlier owing to recurrent HUS in the graft 10 days after transplantation. With this transplant. the patient's allograft had excellent initial function until his founn postoperative day when he rapidly became anuric. The allograft biopsy demonstrated recurrent HUS. and the graft could not be salvaged despite thrombolytic therapy. The mean serum creatinine (SCR) of the 15 functioning grafts is 1.29 :: 0.38 mgldL and mean blood urea nitrogen (BUN) is 26.0:: 9.6 mgldL. The mean serum uric acid and cholesterol levels are 6.66 !: 1.87 mgldL and 200 :: 54 mgldL. respectively. ImmunosuppreSSIOn The daily maintenance doses of FK 506 and prednisone are shown in Table I. FK S06 dosage was based on achieving From It1e Division of Urology. Dept. of Surgery. UnIVersity of Pittsburgh. Pittsburgh, Pennsytv ..... Address repnnt requestS to C.W.B. Jensen. MD. 4414 Presby-teriln~K Pittsburgh. PA 15213. = 1991 by Appleton & Lange 0041-13451911$3.001 +0 3075 3076 JENSEN. JORDAN. SCHNECK ET AL Table 1. CIInIc:8I ChIIl'IICtertstIca of US Pedlatrtc T ... .,..,.nt P ........ Receiving FK 506 Patient Traneplant Tranaplanl No. CaIe No. 1 12114189 2 06110190 1 3 06113190 1 4 08l26I9O 3 5 08I30I9O 6 09I05I9O 1 7 09119190 1 8 10110190 2 9 11I04I90 2 10 11I09I90 1 11 12/08190 2 12 12122190 13 01122191 14 02108191 15 05128191 16 07109191 'AI. IaslloIkwHIp (mean 8.5 ITIOIIIIW). tPatlenI on ImUfln. ~ RejIdion MIF (y) RejIdion No. F 10 no F 14 yes 2 M 15 no F 7 yes 2 M 10 no F 14 yes M 15 no F 12 yes 2 F 12 yes M 9 no M 4 no M 3 no M 8 no M 8 no M 9 yes F 16 no 12-hour serum trough levels between 1 to 2 ngimL. Aza-thioprine was not used in combination with FK 506. Currently. seven patients (47%) are taking no prednisone. five 03%) are taking 5 mg or less daily. and three patients (20%) are on 10-15 mgld. Rejection Episodes One or more episodes of rejection occurred in 6 (38%) out of 16 grafts. There were a total of nine rejection episodes in these six patients. Six (67%) of the rejection episodes occurred within the first 30 days after transplantation and of these five (56%) occurred within the first 2 weeks. All rejection episodes responded to treatment (steroid in 7 cases. OKT3 in 2) and had a good outcome-that is. a decrease in serum creatinine with continued allograft di-uresis. Seven of the nine rejection episodes were charac-terized as mild based on allograft biopsy results and a minimal rise in serum creatinine. Both episodes requiring treatment with OKT3 occurred within 14 days of trans-plantation in patients with 0% PRA and were successfully reversed. Complications One episode of seizures occurred in a 3-year-old male during intravenous induction therapy with FK 506. Sei-zures in this case were manifested as episodes of unre-sponsiveness. staring. and lip smacking. The patient was treated with phenobarbitol and discontinuation of IV FK 506. This problem has not recurred While the patient has been on oral FK 506 therapy. There were no other neuro-logic sequelae in this patient. The only other neurologic complication was headaches in one patient. which re-solved when the oral FK 506 was decreased. Insulin-dependent diabetes mellitus developed de novo PnId-msone' Faf. F1(' IT1!J'd F1(' Iow-up OKT3 BUN' Cr" IT1!J'd (nI}'ml) Level (rnontIIs) 18 0.9 6 2.5 0.7 15.2 yes 18 1.2 12 0 0.3 13.1 34 1.7 14 0 0.6 13.1 yes 26 1.9 6 5 0.3 10.6 20 0.5 7 0 0.3 9.5 no 15 1.3 6 2.5 0.4 10.4 34 1.8 8 0 0.4 9.9 no 47 2.1 ot 10 0 9.7 no 42 1.8 8 5 2.6 7.9 12 1.2 8 2.5 0.4 8.0 Lost Graft 10 HUS 34 0.6 6 0 0.6 6.2 18 1.2 8 0 0.4 6.0 29 0.8 5 0 0.2 5.3 no 35 1.2 10 10 1.4 1.6 20 1.1 12 15 1.5 0.6 4 months posttransplantation in a 14-year-old patient with spina bifida on FK 506 monotherapy. after the treatment of a rejection episode with high-dose steroids. This patient also developed recurrent allograft pyelonephritis for which she has required hospitalization. This may have been related to the cause of her end-stage renal disease (ESRD) (chronic pyelonephritis with reflux) for which she had undergone a sigmoid colocystoplasty with bilateral ure-teral implantation 6 months prior to transplantation. Six months posttransplantation. this patient developed ab-dominal pain. Radiological investigation and biopsy con-firmed the presence of a pleomorphic lymphoma (PTLDl. One hepatic and two lung lesions have resolved with high-dose intravenous acyclovir and cessation of her im-munosuppression. With resolution of these lesions and the development of moderate rejection 2 months later. the patient resumed low doses of FK 506 and prednisone while receiving oral acyclovir. She currently has excellent graft function with a serum creatinine of 1.3 mgldL and no evidence radiologically of her PTLD. Another patient developed nodular densities in her lungs and lymphadenopathy posttransplantation. Although the investigations and biopsies failed to disclose the etiology of these lesions. a presumptive diagnosis ofPTLD was made. After the cessation of FK 506 and prednisone and with the administration of intravenous acyclovir. there was com-plete resolution of these lesions. Currently. the patient is being maintained on oral acyclovir. FK 506. and pred-nisone. with stable graft function. The only other episode of infection was CMV in a 12-year-old girl who presented 2 months after transplanta-tion with fever and an increase in serum creatinine. CMV was diagnosed on a culture of the serum buffy coat and PEDIATRIC RENAL TRANSPLANT UNDER FK 506 was treated successfullv with a IO-day course of ganciclo-vir. DISCUSSION Renal transplantation is the treatment of choice for many children with end·stage renal disease because of improve-ments in immunosuppressive drug regimens. Since these regimens rely on combination cyclosporine-prednisone therapy. they carry with them inherent steroid-related complications including cataracts. obesity. Cushing's syn-drome. diabetes. infection. growth retardation. and avas-cular bone necrosis. Several studies in the pediatric pop-ulation have demonstrated the efficacy of limiting steroid use in an effort to avoid steroid complications. panicularly allowing improvement in catch-up growthKD·~ The toxic effects of cyclosporine tCyA) in children are significant and include hirsutism (100%). hypertension 1739(). fine tremor (34%). acute reversible nephrotoxicity (10%1. and hyperuricemia with long·term CyA usage.1.J FK 506. a product of the fungus SlreplOmVCf'S 151111./1-haensis. has a chemical structure and cytosolic binding sites different from C\:\.-I-7 Despite being 100 times more potent than CyA in vitro. FK 506 does share the neuro-toxicity. nephrotoxicity. and diabetogenicity of Cy A. 4.3 The neurotoxicity observed with the intravenous formula-tion (tremors. headaches. insomnia. parathesias. and a sensation of racing) is diminished with oral therapy. in which only 13% of patients report symptoms.s In this study. 137r of patients developed neurotoxicity (seizures and headaches) and two patients had minor infections (recurrent pyelonephritis and CM V syndrome I. The drug's potency has allowed for the discontinuation of. or a significant reduction in. prednisone therapy in 807r of the patients in this study. Additionally. hirsutism and gingival hvperplasia have not been noted in this study group and hyperuricemia was seen in only 53% of our patients. On the other hand. the development of one proven PTLD and one presumed PTLD and the develop-ment of insulin-dependent diabetes meUitus in two patients 30n are significant deterrents to the usage of FK 506. despite the reversal of the two cases of PTLD and the discontin-uation of insulin therapy with the termination of pred-nisone in the two patients with diabetes. Our patient and graft survival rates of lOOo/C and 947f. respectively. with a mean follow-up of 8.5 months. are encouraging. Significantly. the incidence of acute rejection was low 138%1. early (679( occurred within the first month after transplantation). and mild 178%). All rejection epi-sodes were reversed. including the two severe rejection episodes requiring OKT3 treatment. Nevertheless. 80% of our patients were on no prednisone 17 patients) or low dosages (5 patients: ~KR-R mgld) of prednisone. results noted in the adult population.'I Therefore. it would appear that FK 506 is an effective form of immunosuppression in the pediatric renal transplant population. It appears to have the significant advantages of avoiding high-dose prednisone therapy and the specific CyA-related compli-cations. which are both bothersome in the pediatric pop-ulation. The development of one and possibly two post-transplant lymphomas. both reversed. is a concern that will need to be addressed. perhaps by dose reduction in certain patients. REFERENCES I. Conley SB. Ponman RJ. Lemire JM. et al: Transplant Proc :!O:280. 1988 2. So SKS. Gillingham K. Cook M. et al: Transplantation 50:979. 1990 3. Kahan BD: N Engl J Med 32l:1nS. 1989 4. Kino T. Hatanaka H. Hashimoto M. et al: J Antibiot 40: 1249. 1987 5. Kino T. Hatanaka H. Miyata S. et al: J Antibiot 40:1:!56. 1987 6. SiekierkaJJ. Hung SHY. Poe M. et al: Nature .,41:755. 19!N 7. Harding MW. Galat A. Uehling DE. et al: Nature ~41:TKDiUK 1989 8. Shapiro R. Fung JJ. Jain AB. et al: Transplant Proc 22:35. 1990 9. Stanl TE. Fung J. Jordan M. et al: JAMA. :!64:63. 1990 

Pediatric renal transplantation under FK 506 immunosuppression

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Pediatric renal transplantation under FK 506 immunosuppression

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