Renal homotransplantation in children

Renal Homotransplantation in Children By L. W. Martin, P. T. McEnery, J. G. Rosenkrantz, J. A. Cox, C. D. West, and C. LeCoultre Cincinnati, Ohio

9 Ninety-six renal transplants in 77 pediatric patients are reported with follow-up as long as 121/2 years. Thirteen of the first 14 patients are living with a functioning kidney after eight to 121/2 years. The patient survival for the entire group is 78%. Sixty-four percent are living with a functioning transplanted kidney. Splenectomy was initially performed at the time of transplant but has been discontinued because of concern that splenectomy in the immunosuppressed patient was related to an increased occurrence of septic complications. Anencephalic newborn infants have been found to be a satisfactory source of cadaver donor kidneys. Growth and development have been satisfactory when the transplant is performed prior to 12 years of age, if it functions well, and if an alternate-day regimen of steroid administration is followed. Both boys and girls have now passed through puberty with their transplanted kidneys, have married, become parents, and are leading essentially normal lives. A plea is made for earlier transplantation in small children with irreversible progressive renal failure before they develop severe stunting of growth and before the need for prolonged dialysis. INDEX WORDS: Renal homotransplantation.

E N A L homotransplantation has been utilized for the treatment of end-stage renal disease in children at the Cincinnati Children's Hospital for the past 13 yr. Prior to that time (1965), considerable reluctance had been expressed nationally regarding the advisability of transplantation for children. J'2 Since then, transplantation has become accepted as the preferred treatment of end-stage renal disease in children and is now performed with satisfactory results at several centers throughout the world? 5 Some of our observations are unique to the pediatric patient and have led to modifications of our original treatment methods. 6'7

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MATERIALS AND METHODS

Since June, 1965, 96 renal transplants were performed on 77 patients, age 9 mo to 21 yr, with end-stage renal disease of varied etiology (Table 1). Living donors were employed in 51 instances, 4 of the donors being unrelated to the recipient. Cadaver donors were employed in 45. A second transplant was required in 15 (1 having rejected her first transplant elsewhere), and 5 patients received a third transplant. In preparation for transplant surgery, either peritoneal

Journal of Pediatric Surgery, Vol. 14, No. 5 (October), t 979

dialysis or hemodialysis were employed in conjunction with 77 transplants whereas in 19, dialysis was not used. The surgical technique for transplantation was similar to that for adult recipients, s An extraperitoneal placement of the graft was employed whenever the size of the patient and kidney would permit. In smaller children, a transperitoneal approach was utilized. The graft was placed posterior to the right colon with revascularization by way of aorta and vena cava or iliac vessels. Our routine immunosuppressive therapy consisted of prednisone and azathioprine, Sporadic efforts since 1969 to change to alternate-day steroid therapy evolved into a routine regimen by 1975. For recipients with good allograft function, the prednisone therapy is changed from a daily to an alternate-day regimen after three months following transplant. Attempts to change earlier resulted in an increased occurrence of episodes of threatened rejection. Histocompatibility determination was not available in the early years of our experience9 but has been carried out in retrospect in all but one, our first cadaver donor. In recent years, consideration has been given to histocompatibility in regard to donor selection, but of greater concern has been ABO blood group compatibility and the microlymphocytotoxic antibody cross match. RESULTS

O f our first 14 p a t i e n t s , 13 ( 9 3 % ) a r e living a n d well, 8 to 121/2 yr f o l l o w i n g t r a n s p l a n t (Fig. 1). O f all 77 p a t i e n t s in o u r series, 60 a r e alive (78%). Fifty, or 64%, a r e living a n d well w i t h a f u n c t i o n i n g t r a n s p l a n t e d kidney. T e n a r e a w a i t ing r e t r a n s p l a n t a t i o n . F o l l o w i n g loss of a transp l a n t e d kidney, a second t r a n s p l a n t was perf o r m e d in 15 p a t i e n t s and a t h i r d t r a n s p l a n t in 5. T h e c a u s e of d e a t h in 17 p a t i e n t s is listed in T a b l e 2. GROWTH AND DEVELOPMENT

Analysis of the data on growth of 28 of our earlier patients (Figs. 2 and 3) indicates that From the Divisions of Pediatric Surgery and Nephrology of the Children's Hospital and the Departments of Surgery and Pediatrics, The College of Medicine, University of Cincinnati, Cincinnati, Ohio. Address reprint requests to Lester IV. Martin, M.D., Children's Hospital, 240 Bethesda Avenue, Cincinnati, Ohio 45229. 9 1979 by Grune & Stratton, Inc. 0022-3468/79/1405-0016501.00/0

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Table 1. Etiology of Renal Failure*

Kidney Disease Hydronephrosis (ureteral obstruction) Posterior urethral valves Polycystic kidneys Multicystic dysplastic kidneys Hypoplastic dysplastic kidneys Medullary cyst disease Eagle-Barrett syndrome (prune belly) Chronic pyelonephritis Chronic focal glomerulosclerosis Idiopathic rapidly progressive glomerulonephritis Congenital nephrosis Hereditary nephritis Chronic glomerulonephritis (unclassified) Hemolytic uremic syndrome Multiple artery stenosis with hypertension Nephritis secondary to anaphalactoid purpura Mernbranoproliferative (mesangiocapillary) glomerulonephritis Recurrent mere branoproliferative glomerulonephritis in graft Rejection of previous transplant Recurrent glomerulosclerosis in graft

Number 4 2 2 4 5 6 3 9 6 7 1 1 5 4 1 1 6 2 15 2

*96 transplants.

following transplantation and while receiving prednisone therapy, the children do grow in height. ~~For those transplanted prior to 12 yr of age, with good renal graft function and receiving prednisone on alternate days, growth rate has paralleled, or in three instances, even advanced upward on the normal curve of the percentile chart. For many of the children with severe growth retardation prior to transplantation, our data indicates that they probably will never attain the stature which they would have if they had never been ill. Nevertheless, their growth rate is impressive and severe stunting of growth, in our opinion, should constitute an indication for proceeding with transplantation at an earlier date than would be advised on the basis of renal function alone. Conversely, subsequent growth in stature has been minimal in those receiving transplants beyond the age of 12 yr. Of 9 girls entering puberty, all experienced the onset of menses between 13 and 15 yr of age (Fig. 3). Four of the girls are now married and two have borne normal infants. Three of the boys are married and one has two children.

Fig. 1. Photograph of our first patient age 8 yr and his mother, who was the donor, taken 2 w k following transplant. He is now 20 yr old and a sophomore in college,

SPLEN ECTOMY

Early in our series, splenectomy was performed routinely at the time of transplantation in 49 patients. It was generally agreed that there were significant immunologic advantages to having the spleen removed. 6-8'11 The phenomenon of post-splenectomy sepsis was thought to be Table 2. Renal Homotransplantation

Causeof Death Sepsis Rejection and sepsis Ureteral necrosis and infection Rejection and hyperkalemia Infected native kidney Recurrent glornerulosclerosis Recurrent hemolytic uremic syndrome Disseminated herpes zoster

No. of Patients

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Fig. 3. G r o w t h curve of 16 girls showing flattening of the g r o w t h curve at approximately 12 yr and menarche at 1 3 - 1 5 yr.

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limited to infants less than 1 yr of age. 12 After 1 death in a 4-yr-old girl from fulminant sepsis, we omitted splenectomy in the younger children. Subsequently, it has been omitted in all patients and a total of 28 have not had splenectomy. Three patients died of fulminant sepsis ~3 3 to 26 mo following transplantation. Their ages were 3, 4, and 14 yr. Splenectomy had been performed in all three. A combination of rejection and sepsis was the cause of death in 6, 4 of whom had undergone splenectomy. Two died because of multiple complications including infection. Both had undergone splenectomy. Sepsis, therefore, was a major factor in the death of 11 children, 9 of whom had been subjected to splenectomy. It would seem reasonable to assume that in the pediatric transplant patient post-splenectomy susceptibility to infection is increased because of the immunosuppressive therapy. To what extent this would apply to adult patients is uncertain. Further experience will be required before the

Fig. 4.

relationship between splenectomy and the rejection phenomenon can be fully evaluated. Our one death attributed to rejection was in a child who had not undergone splenectomy. We are concerned that there may be an increased risk of sepsis in the splenectomized, immunosuppressed patient. In our experience (Table 2), sepsis was a greater hazard than was rejection. We have, therefore, discontinued the practice of performing splenectomy in conjunction with transplantation in children. DIALYSIS

Hemodialysis in the small child is hindered by problems related to vascular access. Maintenance of patency of a tiny shunt or fistula is notoriously difficult since the blood components passing through a 2.0-mm shunt are the same size as those passing through a 10-mm shunt in an adult. The blood cells, platelets and fibrin products do not grow in size as the patient grows. A small opening is therefore more likely to undergo thrombosis. The child is less cooperative

Excretory urogram one month following transplant of anencephalic newborn cadaver kidney to an 11-yr old girl.

RENAL HOMOTRANSPLANTATION

in regard to position or compression of the area of shunt or fistula than the adult would be. Vessel size, even following maturation of an arteriovenous fistula, is often found to be smaller than desired, particularly in children weighing less than 8 kg. The external shunts present many problems in an infant of this size and are generally inadequate for long-term dialysis. Peritoneal dialysis, on the other hand, in our experience, has proven to be entirely satisfactory as a temporary measure while awaiting transplant surgery. The chronic-type silastic dialysis catheter is placed in the peritoneal cavity under direct vision through a small laparotomy incision with the patient under general anesthesia. Some have remained in place and functioned for periods longer than 6 mo, to be discontinued only at the time of transplant. DISCUSSION

The reported success rate with renal transplantation in infants less than one year of age

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has been low. Our youngest recipient was 9 mo. On the basis of our experience as well as that of others, 3 it appears doubtful that transplantation should be recommended for newborn infants or infants less than 3 kg in weight. For those over 1 yr of age, the success rate has been comparable to that of older children and adults. Progressive renal osteodystrophy and stunting of growth together with problems related to long-term dialysis, have influenced our decision to recommend transplantation at an earlier stage than would be customary for the adult. Indeed, when the renal disease is progressive and the subsequent course readily predictable, we would now prefer to proceed to transplantation prior to the need for dialysis or, at most, only a short period of preoperative dialysis. The donor and recipient are rarely the same size. One kidney from a 45-kg donor was transplanted to a 6-kg recipient. The donor artery was larger than the recipient aorta. Blood transfusion must be administered rapidly as the anastomosis

Fig. 5. Excretory urogram of same patient as in Fig. 4 obtained 6 mo following transplant showing growth of transplanted kidney. Metal clips are on upper and lower poles of the kidney in each photograph,

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is completed to prevent exsanguination of the i n f a n t into the large denervated graft. Kidneys from anencephalic newborn infants Were utilized in 6 instances with 3 being successful. 14 W e prefer to harvest both kidneys en bloc with a segment of aorta and vena cava. Studies performed on a 4-yr-old recipient receiving a newborn kidney ~5suggested that the kidney behaved physiologically as a kidney from an older child in that there was an initial period of diuresis, and sodium excretion was essentially the same as for a m a t u r e kidney. Growth and hypertrophy of the t r a n s p l a n t e d n e o n a t a l kidney have been d r a m a t i c (Fig. 4, Fig. 5). W i t h i n 6 wk, a neonatal kidney u n d e r w e n t sufficient growth to support a 16-yr-old recipient

with return of B U N and c r e a t i n i n e to n o r m a l levels, Technical problems were encountered in t r a n s p l a n t i n g a newborn kidney to the 16-yr-old recipient whose ureters had been removed at the time of a previous transplant. T h e entire length of the donor ureter was required for the s u b m u cosal neocystostomy. The t r a n s p l a n t e d kidney on the ends of the internal iliac vessels was sutured to the bladder wall permitting it to rise and fall as the bladder filled and emptied. R e n a l function b e c a m e n o r m a l within six weeks a n d has remained so for 31/2 yr. O u r long-term patient survival of 78% is c o m p a r a b l e to that of DeShazo 16 77%; Well 17 61%; Starzl 5 52%; and Fine 4 78%.

REFERENCES

1. Riley CM: Thoughts about kidney homotransplantation in children. J Pediatr 65:797-800, 1964 2. Reinhart JB: The doctor's dilemma. J Pediatr 77:505507, 1970 3. Hodson EM, Najarian JS, Kjellstrand CM, et al: Renal transplantation in children ages 1 to 5 years. Pediatrics 61:458-464, 1978 4. Fine RN, Malekzadeh MH, Pennisi AJ, et al: Long term results of renal transplantation in children. Pediatrics 61:641-650, 1978 5. Starzl TE, Porter KA, Halgrimson CG, et al: A decade followup in early cases of renal homotransplantation. Ann Surg 180:606-616, 1974 6. Martin LW, Gonzalez LL, West CD, et al: Clinical problems encountered in renal homotransplantation in children. J Pediatr Surg 5:207-214, 1970 7. Gonzalez LL, Martin LW, West CD, et al: Renal homotransplantation in children. Arch Surg 101:232-240, 1970 8. Starzl TE: Experiencein Renal Transplantation. Philadelphia, Saunders, 1964 9. Patel R, Mickey MR, Terasaki PI: Serotyping for homotransplantation of kidneys from unrelated donors. N Engl J Med 279:501-506, 1968 I0. McEnergy PT, Gonzalez LL, Martin LW, et al:

Growth and developmentof children with renal transplants: Use of alternate day steroid therapy. J Pediatr 83:806-814, 1973 11. Pierce JC, Hume DM: The effect of splenectomy on the survival of first and second renal homotransplantation in man. Surg Gynecol Obstet 127:1300-1306, 1968 12. King H. Shumacker H Jr: Splenic studies: Susceptibility to infection after splenectomy performed in infancy. Ann Surg 136:239-242, 1952 13. McEnergy PT, Flanaghan J: Fulminant sepsis in splenectomized children with renal allografts. Transplantation 24:154-155, 1977 14. Itaka K, Martin LW, Cox JA, et al: Transplantation of cadaver kidneys from anencephalic donors. J Pediatr 93:216-220, 1978 15. Martin LW, Gonzalez LL, West CD, et al: Homotransplantation of both kidneys from an anencephalic monster to a 17-pound boy with Eagle-Barrett syndrome. Surgery 66:603-607, 1969 16. DeShazo CV, Simmons RL, Bernstein DM, et al: Results of renal transplantation in 100 children. Surgery 76:461-468, 1974 17. Weil R, Putnam CW, Porter KA, et al: Transplantation in children. Surg Clin North Am 56(2):467-476, 1976