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Unique surgical and immunologic features of renal transplantation in children
Unique Surgical and Immunologic Features of Renal Transplantation in Children By Raphael H. Levey, Julie Ingelfinger, Warren E. Grupe, Michele Toper, and Angelo J. Eraklis 9 We have performed 93 renal allografts in recipients having a mean age of 12.6 yr. Sixty percent of the kidneys were from parental donors, 10 from siblings, and 30 from cadavers. Young children present unique surgical, hemodynamic, and immunologic management problems. Modifications of standard transplantation surgical techniques have been developed that allow for routine retroperitoneal placement of adult kidneys in patients as young as 2.4 yr. These modifications include the surgical incision itself, the vascular anastomosis, and the operation's urologic components. Fluid management must allow maximum perfusion of the adult organ without compromise of the child's cardiovascular system. The most critical aspects of the undertaking reside in immunologic matching of the donor-recipient pair and in postoperative immunosuppression. Parent-to-child combinations usually share one HLA haplotype, are stimulatory in mixed lymphocyte cultures, and produce killing in cell-mediated lympholysis assays. Traditional wisdom predicts an unfavorable outcome with such allografts. Immunosuppression has been predicated on the outcome of these tests. In unfavorable parent-to-child pairs, and when poorly matched cadaveric kidneys are used, we have routinely employed a prolonged postoperative intravenous course of whole rabbit antihuman thymocyte sera prepared in our institution. The resuits show thai in both situations the 1-yr kidney survival is 92%. Early rejection episodes have essentially been eliminated, and with them the need for large increments in steroid dosage. The children have eventually been placed on alternate-day steroid therapy, thus allowing for as near normal growth and development as possible. The data indicate not only that the very young child with endstage renal disease is an appropriate recipient for a renal allograft but also that growth failure itself may be an indication for early transplantation. INDEX WORDS: Renal transplantation.
T I L comparatively recently, children sufU Nfering from end-stage renal disease From the Departments of Surgery and Medicine, Children's Hospital Medical Center, and Harvard Medical School, Boston, Mass. Presented before the 9th Annual Meeting of the American Pediatric Surgical Association, Hot Springs, Virginia, May 3-6, 1978. Supported by grants from the USPHS (5-RO1-CA20171-02) and from the NIAMD (5-PO1-AM-16392-06). Address reprint requests to Raphael H. Levey, M.D., 300 Longwood Avenue, Boston, Mass. 02115. 9 1978 by Grune & Stratton, lnc. 0022-3468/78/1307 0003501.00/0 576
(ESRD) were not regarded as suitable candidates for kidney transplantation. This was due in part to lack of miniaturized technology for vascular access and hemodialysis, in part to a reluctance to use adult organs in pediatric patients, and in large measure to an unwillingness to submit the young child and the family to the unknown physical, maturational, and psychosocial hazards associated with one of the more persistently vexatious problems in medicine. Nonetheless, young people with renal failure were dialyzed and underwent transplantation, and reports from a number of centers 1-6 began to indicate that children not only could withstand the ongoing rigors of dialysis and transplantation but in fact may be favored recipients for these modes of therapy. ESRD pediatric patients in general, and infants in particular, do present unique challenges as well as opportunities to the team involved in their care. To deal with these special problems, we have adopted a multidisciplinary approach, and we draw on the clinical and laboratory expertise of a wide range of physicians and nurses to help optimize care at all times. Of particular interest to pediatric surgeons are the techniques of vascular access for hemodialysis, the special features of the transplantation operation, the reconstructive urologic measures performed, and the immunologic management of the recipient--an area that by tradition and training has usually been the domain of the surgeon. It is beyond the scope of this report to deal expansively with each facet of the four areas mentioned. Rather, this paper will summarize and highlight our experiences in renal transplantation at the Children's Hospital Medical Center in Boston during the past 6.5 yr. MATERIALS AND METHODS Between May 1971 and October 1977 a total of 89 children received 93 renal allografts. The mean age of the recipients was 13 yr, with an equal distribution between male and female patients. Sixty-four of the transplants were from living related donors, and 29 were from cadaver donors. One of the second transplants was from a living related donor. Table 1 summarizes this experience as well as the primary diseases that led to end-stage renal failure. Journal of Pediatric Surgery,
Vol. 13, No. 6D (December), 1978
RENAL TRANSPLANTATION
577
Table 2.
Table 1. Diagnosis
Number of Cases
1.
M.P.G.N. Obstructive u ropathy Dysplasia Polycystic Nephrosclerosis Hemolytic uremic Henoch-Sch6nlein Goodpasture's syndrome Glomerulonephritis Lupus erythematosus and immune complex Other Hypertensive nephropathy Alport's syndrome Cystanosis Radiation nephritis
12 14 1B 1 5 1 1 2 14
2. 3.
Sex distribution Male Female Mean age Cadaver Living related
2 5 2 3 1 2
48 45 13 29 64
Approximately one-third of the patients suffered from hereditary renal disease, primarily obstructive uropathy and dysplasia. Two-thirds of the patients had acquired glomerular diseases, the most common of which were chronic glomerulonephritis and membranoproliferative glomerulonephritis. The methods of management of the child with ESRD are shown in outline form in Table 2. The patient enters the program when irreversible renal failure is present, as determined by serial creatinine elevations, biopsy, or clinical course. Medical, dietary, metabolic, and orthopedic management is then instituted. When it is judged that hemodialysis is imminent, vascular access is created, preferably by means of an arteriovenous fistula. If immediate dialysis is required, an external shunt is used. Plans for transplantation proceed with the family evaluation centering about both the psychosocial parameters of organ donation and the immunologic relationship of the proposed donor-recipient pair. Tissue typing consists of matching for both the major human leukocyte antigens and assessment of cell-mediated immunity by mixed lymphocyte culture (MLC) and cell-mediated lympholysis (CML). Independent donor evaluation is performed at the Peter Bent Brigham Hospital, thus ensuring that donor selection will be entirely in third-party hands. Dialysis is begun, and thereafter correction of the patient's surgical and urologic abnormalities proceeds. Bilateral nephrectomies are performed when irreversible hypertension or infection is present. Bladder reconstruction is carried out when indicated, and parathyroidectomy is performed when medical management fails to control calcuim metabolism. Table 3 summarizes the management of a child with a renal allograft. It is our practice always to place the donated kidney in the retroperitoneal space, and this may be achieved without difficulty in children weighing as little as 9 kg. To gain the needed exposure, a modified transplantation incision
4.
5. 6.
7. 8.
Patient enters program a. Irreversible ren-I failure b, Serial creatinine elevations c, Biopsy d, Clinical Course Medical, dietary (metabolic), orthopedic management Vascular access for hemodialysis a, Fistula Cephalic vein/radial artery Saphenous loop Bovine or other foreign material b. Shunt Plans for transplantation a. Family evaluation b. Tissue typing HLA MLC CML c. Donor workup Dialysis Surgical and Urological Assessment of Patient's Status a. Nephrectomies b. VCUG c. Cystoscopy d. Urologic reconstruction e. Parathyroidectomy Cadaver list Transplantation
is used that divides both rectus muscles above their attachment to the pubis and then swings in a cephalad direction along the right border, reaching when necessary to the costal margin. Venous anastromoses are carried out in an endto-side fashion either to the lilac vein or to the vena cava. The arterial anastomosis is performed to the divided end of the hypogastric artery or to the common iliac artery or to the aorta. In any case, the anastomosis is performed with interrupted horizontal mattress sutures of 7-0 cardiovascular suture material. The ureteroneocystostomy is fashioned in the LeadbetterPolitano fashion. When the bladder is not usable, diversion is carried out. Six patients required urinary conduits. It has been our practice to construct the conduit at the time of transplantation, for we believe that this allows optimal placement of kidney, ureter, and conduit. Routine immunosuppression is carried out using azathioTable 3. Management of ChildWith Renal AIIograft Special surgical considerations Size of organ Size of vessels Urologic difficulties No special I.D. precautions Immunosuppression Imuran (azathiopdne) 2.0-4.0 mg/kg Prednisone 2.0 mg/kg decreasing to alternate-day therapy ALS 9 wk posttransplantation
LEVEY ET AL.
578
Table 4. Overall Statistics Total number of transplants Number of surviving patients Number of surviving kidneys
Table 6. Death in Renal AIIograft Recipients 93 83 70
prine at a dosage of 2.0-4.0 mg/kg and prednisone 2.0 mg/kg, which is decreased to alternate-day therapy at a rate consistent with the patient's clincial course. Antilymphocyte serum produced in our laboratory is routinely used in poorly matched living related donorrecipient pairs, i.e., when there is marked stimulation in MLC or significant cell killing in the MLC assay, or when cadaveric donors are employed. The antilymphocyte serum is made and delivered according to a regimen that we have previously reported] No special infectious disease precautions are undertaken unless significant granulocytopenia has occurred. RESULTS
Table 4 shows that of the 93 transplants, 75% are still functioning from 6 mo to 7 yr following transplantation. Ten patients have died; the age, diagnosis, source of kidney, and cause of death are shown in Table 5. It can be seen that rejection is the most common contributory cause of death in the renal allograft recipient. Table 6 lists the year in which death occurred and the interval between transplantation and death. This table illustrated that in these 10 patients death occurred within 6 mo following transplantation. N o patient has died during chronic hemodialysis. In July 1975, after extensive clinical trials : with rabbit antihuman thymocyte serum, we u n d e r t o o k a new program in antilymphocyte serum administration. 7 Figure 1 shows the actuarial survival of kidneys in two groups of patients who received either poorly matched living related kidneys or cadaver kidneys. Of the 27 patients in the two groups, all have been followed for at least 12 mo and some for as long
Case
Age
Year
Transplantation to Death
1 2
t3 16
1971 1971
23 hr 17 days
3 4 5 6 7 8 9 10
15 14 11 15 15 19 13 9
1973 1972 1973 1972 1973 1974 1974 1976
2 2 6 2 3 6 3 6
mo mo mo mo mo days mo mo
as 2 yr. It is still too soon to make any statement about the median survival, for the midpoint has not yet been reached. The 1-yr graft survival rate for the 14 living donor grafts is 93% and for the 13 cadaver grafts 100%. The atrition rate by 2 yr is very low, and this is also demonstrated in Fig. 1. Table 7 shows that there is little correlation between MLC and C M L reactivity graft survival when living related donor kidneys are used. Table 8 illustrates that graft survival when cadaver kidneys are used is not related either to the number of shared H L A antigens or to the preexisting state of sensitivity of the recipient. There have been no cases of arterial or venous anastomotic stenosis. Two small bladder leaks closed spontaneously on catheter drainage. There have been no ureteric leaks or stenoses. One patient developed a leak from a renal pelvis that had been injured during the time of donor nephrectomy, but this closed after direct drainage, and the kidney is functioning well 6 yr after transplantation. Infection has not been a problem in this group of patients. Only 2 patients developed infections
Table 5. Death in Pediatric Renal AIIograft Recipients Case
Oiagnosis
Age
Source of Kidney
Cause of Death
1 2 3 4 5 6 7 8 9 10
Glomerulonephritis Hypoplasia Radiation nephritis M.P.G.N. Proliferative glomerulonephritis Glomerulonephritis Membranous glomerulonephritis Radiation nephritis (Wilms) Collagen-vascular Obstructive uropathy
t3 16 15 11 11 15 15 19 13 9
Paternal Paternal Paternal Cadaver Cadaver Maternal Cadaver Sibling Cadaver Paternal
Cardiac arrest Rejection with kidney rupture Rejection, radiation enteritis Rejection, pneumocystic pneumonia Rejection, hypertension C.V.A. Sepsis C.V.A. Rejection, recurrent disease Rejection, pancreatitis
RENAL T R A N S P L A N T A T I O N
579
(43)
(~3)
4OO
H4)
~
(13)
[
(13)
((z)
T~,'? (9) (~---'~
~,
(5)
8o
.~ 6(3 k
4C
Fig, 1 Actuarial survival of 27 cadaver and living related renal allografts in children. All patients have been followed for at least 1 yr after transplantation.
o---o Living Related Donors ~. r Cadaveric Donors
I
I
I
I
I
I
4
8
t2
16
20
24
M O N T H $ FOL L0 WING TRIINSPL A N TATIO N
in their transplantation incisions, and these responded well to local and systemic therapy. No routine preoperative or intraoperative antibiotics were used. DISCUSSION
The results reported here show that it is possible to achieve excellent kidney graft survival in young children when either living related or cadaver donors are used. The use of heterologous antilymphocyte serum contributes to the significant decrease in the number of acute rejection episodes, as previously reported, s and in so doing diminishes corticosteroid dosage. Not
only is management facilitated in the early postoperative period but also the long-term adverse complications of intensive prednisone therapy are lessened. The ability to avoid steroid pulse therapy also apparently reduces the mortality, for since 1974 we have lost only 1 patient in the series, and this was from acute pancreatitis during a steroid pulse in a patient who had not received antilymphcyte serum. This success of a renal transplantation program in children depends on a major commitment by the involved children's hospital in terms of personnel, space, dialysis, and logistical
Table 7. Relationship Between Cell-Mediated immunity and Function of Transplanted Living Related Kidney* CMLt (% Specific
Patient
Donor
51Cr Release)
Renal MLC
Function~:
1
Mother
7.2
12
E
2
Father
Negative
10
E
3
Father
3.0
28
E
4 5
Mother Father
NDw ND
25 19
E F
1
3
26
E
2"
1
60
Dialysis
6
Father
31
4
E
3
2
18
E
7
Mother
12
2
Dialysis
4
2
40
F
8
Half-brother
16
8
E
5
2
40
Dialysis
9
Mother
16
Dialysis
10
Mother
ND
1 2
10 0
G E
11
Father
6
12
Mother
1.5
13 14
Mother Mother
5 42
~:E = excellent; F = fair; P = poor,
done.
Shared Antigens
Percentage Sensitization
Renal Function~:
18
E
4
P
8
2
40
E
17
E
9
2t
80
G
9 2
E E
10
3
25
E
11
1
15
E
12
1
30
F
13
0
53
E
*No more than 1 haplotype match.
51Cr release or greater.
Patient
6 7
t Italic values represent significant cytotoxicity:
w
Table 8. Relationship Among Number of Shared Antigens, Maximum Percentage Sensitization, and Function of Transplanted Cadaver Kidney
4% specific
* Second transplant. t Specific antidonor antibody present in past, SE = excellent; G -- good; F = fair.
580
LEVEY ET AL.
support. Children and their families require many aspects of physical and emotional therapy that are not required in the adult population. However, our results and the long-term results of renal transplantation in children in other
institutions s suggest that growth, rehabilitation, and psychosocial maturation may make this modality of therapy appropriate for children of all ages and the benefit-to-pain ratio highly favorable.
REFERENCES 1. Starzl TE, Marchioro TL, Porter KA, et al: The role of organ transplantation in pediatrics. Pediatr Clin North Am 13:381-422, 1966 2. Williams GE, Lee HM, Hume DM: Renal transplants in children. Transplant Proc 1:262-266, 1969 3. Fine RN, Korsch BM, Stiles Q, et al: Renal homotransplantation in children. 76:347-357, 1970 4. Cerrilli J, Evans WE, Sotos JF: Renal transplantation in infants and children. Transplant Proc 4:633-636, 1972 5. Belzer FO, Schweitzer RT, Holliday M: Renal homotransplantation in children. Am J Surg 124:270--278, 1972
6. Shazo CV, Simmons RL, Bernstein DM, et al: Results of renal transplantation in 100 children. Surgery 76:461468, 1974 7. Levey RH, Parkman R: Whole antilymphocyte serum: A potent safe immunosuppressive agent for intravenous use in man. Transplant Proc 9:1019-1022, 1977 8. Fine RN, Malekzadeh MH, Pennisi A J, et al: Longterm results of renal transplantation in children. Pediatrics 61:641-650, 1978
Discussion L. Martin (Cincinnati): Renal transplantation is now the accepted treatment for end-stage renal disease. We have preformed a total of 96 transplants on 77 patients over a period of 13 yr. Growth and maturation have been satisfactory. We have observed their progress through courtship and marriage, and five are now parents of normal, healthy infants. We are willing to accept for transplantation infants as small as 3 kg. For infants over 1 yr of age the results are as good as those with adults. In our experience [slide], 85% of the transplant failures occur during the first year. Nevertheless, close follow-up is still required. The follow-up clinic, therefore, enlarges with each patient, which creates a consuming demand on physicians' time and hospital clinic facilities. One donor source that we have found satisfactory on three occasions is the anencephalic infant [slide]. Subsequent function and growth of the
kidney have been satisfactory with recipients as old as 16 yr. I would like to ask Dr. Levey what problems he has encountered in transplantation of an adult-size kidney to a small infant and what special precautions he recommends. D. Dudgeon (Syracuse): Dr. Levey, you mention in your abstract that one of the reasons you would consider transplants is for the increased growth that might result. Dr. Richard Fine recently reported his 5-yr transplant results and found that only 13 actually achieved close to normal growth after they had been transplanted and subsequently placed on every-other-day steroid therapy. Would you like to comment on the amount of growth you have seen in your transplant patients? Have you noted a significant improvement when you compare transplantation to chronic hemodialysis?
T I L comparatively recently, children sufU Nfering from end-stage renal disease From the Departments of Surgery and Medicine, Children's Hospital Medical Center, and Harvard Medical School, Boston, Mass. Presented before the 9th Annual Meeting of the American Pediatric Surgical Association, Hot Springs, Virginia, May 3-6, 1978. Supported by grants from the USPHS (5-RO1-CA20171-02) and from the NIAMD (5-PO1-AM-16392-06). Address reprint requests to Raphael H. Levey, M.D., 300 Longwood Avenue, Boston, Mass. 02115. 9 1978 by Grune & Stratton, lnc. 0022-3468/78/1307 0003501.00/0 576
(ESRD) were not regarded as suitable candidates for kidney transplantation. This was due in part to lack of miniaturized technology for vascular access and hemodialysis, in part to a reluctance to use adult organs in pediatric patients, and in large measure to an unwillingness to submit the young child and the family to the unknown physical, maturational, and psychosocial hazards associated with one of the more persistently vexatious problems in medicine. Nonetheless, young people with renal failure were dialyzed and underwent transplantation, and reports from a number of centers 1-6 began to indicate that children not only could withstand the ongoing rigors of dialysis and transplantation but in fact may be favored recipients for these modes of therapy. ESRD pediatric patients in general, and infants in particular, do present unique challenges as well as opportunities to the team involved in their care. To deal with these special problems, we have adopted a multidisciplinary approach, and we draw on the clinical and laboratory expertise of a wide range of physicians and nurses to help optimize care at all times. Of particular interest to pediatric surgeons are the techniques of vascular access for hemodialysis, the special features of the transplantation operation, the reconstructive urologic measures performed, and the immunologic management of the recipient--an area that by tradition and training has usually been the domain of the surgeon. It is beyond the scope of this report to deal expansively with each facet of the four areas mentioned. Rather, this paper will summarize and highlight our experiences in renal transplantation at the Children's Hospital Medical Center in Boston during the past 6.5 yr. MATERIALS AND METHODS Between May 1971 and October 1977 a total of 89 children received 93 renal allografts. The mean age of the recipients was 13 yr, with an equal distribution between male and female patients. Sixty-four of the transplants were from living related donors, and 29 were from cadaver donors. One of the second transplants was from a living related donor. Table 1 summarizes this experience as well as the primary diseases that led to end-stage renal failure. Journal of Pediatric Surgery,
Vol. 13, No. 6D (December), 1978
RENAL TRANSPLANTATION
577
Table 2.
Table 1. Diagnosis
Number of Cases
1.
M.P.G.N. Obstructive u ropathy Dysplasia Polycystic Nephrosclerosis Hemolytic uremic Henoch-Sch6nlein Goodpasture's syndrome Glomerulonephritis Lupus erythematosus and immune complex Other Hypertensive nephropathy Alport's syndrome Cystanosis Radiation nephritis
12 14 1B 1 5 1 1 2 14
2. 3.
Sex distribution Male Female Mean age Cadaver Living related
2 5 2 3 1 2
48 45 13 29 64
Approximately one-third of the patients suffered from hereditary renal disease, primarily obstructive uropathy and dysplasia. Two-thirds of the patients had acquired glomerular diseases, the most common of which were chronic glomerulonephritis and membranoproliferative glomerulonephritis. The methods of management of the child with ESRD are shown in outline form in Table 2. The patient enters the program when irreversible renal failure is present, as determined by serial creatinine elevations, biopsy, or clinical course. Medical, dietary, metabolic, and orthopedic management is then instituted. When it is judged that hemodialysis is imminent, vascular access is created, preferably by means of an arteriovenous fistula. If immediate dialysis is required, an external shunt is used. Plans for transplantation proceed with the family evaluation centering about both the psychosocial parameters of organ donation and the immunologic relationship of the proposed donor-recipient pair. Tissue typing consists of matching for both the major human leukocyte antigens and assessment of cell-mediated immunity by mixed lymphocyte culture (MLC) and cell-mediated lympholysis (CML). Independent donor evaluation is performed at the Peter Bent Brigham Hospital, thus ensuring that donor selection will be entirely in third-party hands. Dialysis is begun, and thereafter correction of the patient's surgical and urologic abnormalities proceeds. Bilateral nephrectomies are performed when irreversible hypertension or infection is present. Bladder reconstruction is carried out when indicated, and parathyroidectomy is performed when medical management fails to control calcuim metabolism. Table 3 summarizes the management of a child with a renal allograft. It is our practice always to place the donated kidney in the retroperitoneal space, and this may be achieved without difficulty in children weighing as little as 9 kg. To gain the needed exposure, a modified transplantation incision
4.
5. 6.
7. 8.
Patient enters program a. Irreversible ren-I failure b, Serial creatinine elevations c, Biopsy d, Clinical Course Medical, dietary (metabolic), orthopedic management Vascular access for hemodialysis a, Fistula Cephalic vein/radial artery Saphenous loop Bovine or other foreign material b. Shunt Plans for transplantation a. Family evaluation b. Tissue typing HLA MLC CML c. Donor workup Dialysis Surgical and Urological Assessment of Patient's Status a. Nephrectomies b. VCUG c. Cystoscopy d. Urologic reconstruction e. Parathyroidectomy Cadaver list Transplantation
is used that divides both rectus muscles above their attachment to the pubis and then swings in a cephalad direction along the right border, reaching when necessary to the costal margin. Venous anastromoses are carried out in an endto-side fashion either to the lilac vein or to the vena cava. The arterial anastomosis is performed to the divided end of the hypogastric artery or to the common iliac artery or to the aorta. In any case, the anastomosis is performed with interrupted horizontal mattress sutures of 7-0 cardiovascular suture material. The ureteroneocystostomy is fashioned in the LeadbetterPolitano fashion. When the bladder is not usable, diversion is carried out. Six patients required urinary conduits. It has been our practice to construct the conduit at the time of transplantation, for we believe that this allows optimal placement of kidney, ureter, and conduit. Routine immunosuppression is carried out using azathioTable 3. Management of ChildWith Renal AIIograft Special surgical considerations Size of organ Size of vessels Urologic difficulties No special I.D. precautions Immunosuppression Imuran (azathiopdne) 2.0-4.0 mg/kg Prednisone 2.0 mg/kg decreasing to alternate-day therapy ALS 9 wk posttransplantation
LEVEY ET AL.
578
Table 4. Overall Statistics Total number of transplants Number of surviving patients Number of surviving kidneys
Table 6. Death in Renal AIIograft Recipients 93 83 70
prine at a dosage of 2.0-4.0 mg/kg and prednisone 2.0 mg/kg, which is decreased to alternate-day therapy at a rate consistent with the patient's clincial course. Antilymphocyte serum produced in our laboratory is routinely used in poorly matched living related donorrecipient pairs, i.e., when there is marked stimulation in MLC or significant cell killing in the MLC assay, or when cadaveric donors are employed. The antilymphocyte serum is made and delivered according to a regimen that we have previously reported] No special infectious disease precautions are undertaken unless significant granulocytopenia has occurred. RESULTS
Table 4 shows that of the 93 transplants, 75% are still functioning from 6 mo to 7 yr following transplantation. Ten patients have died; the age, diagnosis, source of kidney, and cause of death are shown in Table 5. It can be seen that rejection is the most common contributory cause of death in the renal allograft recipient. Table 6 lists the year in which death occurred and the interval between transplantation and death. This table illustrated that in these 10 patients death occurred within 6 mo following transplantation. N o patient has died during chronic hemodialysis. In July 1975, after extensive clinical trials : with rabbit antihuman thymocyte serum, we u n d e r t o o k a new program in antilymphocyte serum administration. 7 Figure 1 shows the actuarial survival of kidneys in two groups of patients who received either poorly matched living related kidneys or cadaver kidneys. Of the 27 patients in the two groups, all have been followed for at least 12 mo and some for as long
Case
Age
Year
Transplantation to Death
1 2
t3 16
1971 1971
23 hr 17 days
3 4 5 6 7 8 9 10
15 14 11 15 15 19 13 9
1973 1972 1973 1972 1973 1974 1974 1976
2 2 6 2 3 6 3 6
mo mo mo mo mo days mo mo
as 2 yr. It is still too soon to make any statement about the median survival, for the midpoint has not yet been reached. The 1-yr graft survival rate for the 14 living donor grafts is 93% and for the 13 cadaver grafts 100%. The atrition rate by 2 yr is very low, and this is also demonstrated in Fig. 1. Table 7 shows that there is little correlation between MLC and C M L reactivity graft survival when living related donor kidneys are used. Table 8 illustrates that graft survival when cadaver kidneys are used is not related either to the number of shared H L A antigens or to the preexisting state of sensitivity of the recipient. There have been no cases of arterial or venous anastomotic stenosis. Two small bladder leaks closed spontaneously on catheter drainage. There have been no ureteric leaks or stenoses. One patient developed a leak from a renal pelvis that had been injured during the time of donor nephrectomy, but this closed after direct drainage, and the kidney is functioning well 6 yr after transplantation. Infection has not been a problem in this group of patients. Only 2 patients developed infections
Table 5. Death in Pediatric Renal AIIograft Recipients Case
Oiagnosis
Age
Source of Kidney
Cause of Death
1 2 3 4 5 6 7 8 9 10
Glomerulonephritis Hypoplasia Radiation nephritis M.P.G.N. Proliferative glomerulonephritis Glomerulonephritis Membranous glomerulonephritis Radiation nephritis (Wilms) Collagen-vascular Obstructive uropathy
t3 16 15 11 11 15 15 19 13 9
Paternal Paternal Paternal Cadaver Cadaver Maternal Cadaver Sibling Cadaver Paternal
Cardiac arrest Rejection with kidney rupture Rejection, radiation enteritis Rejection, pneumocystic pneumonia Rejection, hypertension C.V.A. Sepsis C.V.A. Rejection, recurrent disease Rejection, pancreatitis
RENAL T R A N S P L A N T A T I O N
579
(43)
(~3)
4OO
H4)
~
(13)
[
(13)
((z)
T~,'? (9) (~---'~
~,
(5)
8o
.~ 6(3 k
4C
Fig, 1 Actuarial survival of 27 cadaver and living related renal allografts in children. All patients have been followed for at least 1 yr after transplantation.
o---o Living Related Donors ~. r Cadaveric Donors
I
I
I
I
I
I
4
8
t2
16
20
24
M O N T H $ FOL L0 WING TRIINSPL A N TATIO N
in their transplantation incisions, and these responded well to local and systemic therapy. No routine preoperative or intraoperative antibiotics were used. DISCUSSION
The results reported here show that it is possible to achieve excellent kidney graft survival in young children when either living related or cadaver donors are used. The use of heterologous antilymphocyte serum contributes to the significant decrease in the number of acute rejection episodes, as previously reported, s and in so doing diminishes corticosteroid dosage. Not
only is management facilitated in the early postoperative period but also the long-term adverse complications of intensive prednisone therapy are lessened. The ability to avoid steroid pulse therapy also apparently reduces the mortality, for since 1974 we have lost only 1 patient in the series, and this was from acute pancreatitis during a steroid pulse in a patient who had not received antilymphcyte serum. This success of a renal transplantation program in children depends on a major commitment by the involved children's hospital in terms of personnel, space, dialysis, and logistical
Table 7. Relationship Between Cell-Mediated immunity and Function of Transplanted Living Related Kidney* CMLt (% Specific
Patient
Donor
51Cr Release)
Renal MLC
Function~:
1
Mother
7.2
12
E
2
Father
Negative
10
E
3
Father
3.0
28
E
4 5
Mother Father
NDw ND
25 19
E F
1
3
26
E
2"
1
60
Dialysis
6
Father
31
4
E
3
2
18
E
7
Mother
12
2
Dialysis
4
2
40
F
8
Half-brother
16
8
E
5
2
40
Dialysis
9
Mother
16
Dialysis
10
Mother
ND
1 2
10 0
G E
11
Father
6
12
Mother
1.5
13 14
Mother Mother
5 42
~:E = excellent; F = fair; P = poor,
done.
Shared Antigens
Percentage Sensitization
Renal Function~:
18
E
4
P
8
2
40
E
17
E
9
2t
80
G
9 2
E E
10
3
25
E
11
1
15
E
12
1
30
F
13
0
53
E
*No more than 1 haplotype match.
51Cr release or greater.
Patient
6 7
t Italic values represent significant cytotoxicity:
w
Table 8. Relationship Among Number of Shared Antigens, Maximum Percentage Sensitization, and Function of Transplanted Cadaver Kidney
4% specific
* Second transplant. t Specific antidonor antibody present in past, SE = excellent; G -- good; F = fair.
580
LEVEY ET AL.
support. Children and their families require many aspects of physical and emotional therapy that are not required in the adult population. However, our results and the long-term results of renal transplantation in children in other
institutions s suggest that growth, rehabilitation, and psychosocial maturation may make this modality of therapy appropriate for children of all ages and the benefit-to-pain ratio highly favorable.
REFERENCES 1. Starzl TE, Marchioro TL, Porter KA, et al: The role of organ transplantation in pediatrics. Pediatr Clin North Am 13:381-422, 1966 2. Williams GE, Lee HM, Hume DM: Renal transplants in children. Transplant Proc 1:262-266, 1969 3. Fine RN, Korsch BM, Stiles Q, et al: Renal homotransplantation in children. 76:347-357, 1970 4. Cerrilli J, Evans WE, Sotos JF: Renal transplantation in infants and children. Transplant Proc 4:633-636, 1972 5. Belzer FO, Schweitzer RT, Holliday M: Renal homotransplantation in children. Am J Surg 124:270--278, 1972
6. Shazo CV, Simmons RL, Bernstein DM, et al: Results of renal transplantation in 100 children. Surgery 76:461468, 1974 7. Levey RH, Parkman R: Whole antilymphocyte serum: A potent safe immunosuppressive agent for intravenous use in man. Transplant Proc 9:1019-1022, 1977 8. Fine RN, Malekzadeh MH, Pennisi A J, et al: Longterm results of renal transplantation in children. Pediatrics 61:641-650, 1978
Discussion L. Martin (Cincinnati): Renal transplantation is now the accepted treatment for end-stage renal disease. We have preformed a total of 96 transplants on 77 patients over a period of 13 yr. Growth and maturation have been satisfactory. We have observed their progress through courtship and marriage, and five are now parents of normal, healthy infants. We are willing to accept for transplantation infants as small as 3 kg. For infants over 1 yr of age the results are as good as those with adults. In our experience [slide], 85% of the transplant failures occur during the first year. Nevertheless, close follow-up is still required. The follow-up clinic, therefore, enlarges with each patient, which creates a consuming demand on physicians' time and hospital clinic facilities. One donor source that we have found satisfactory on three occasions is the anencephalic infant [slide]. Subsequent function and growth of the
kidney have been satisfactory with recipients as old as 16 yr. I would like to ask Dr. Levey what problems he has encountered in transplantation of an adult-size kidney to a small infant and what special precautions he recommends. D. Dudgeon (Syracuse): Dr. Levey, you mention in your abstract that one of the reasons you would consider transplants is for the increased growth that might result. Dr. Richard Fine recently reported his 5-yr transplant results and found that only 13 actually achieved close to normal growth after they had been transplanted and subsequently placed on every-other-day steroid therapy. Would you like to comment on the amount of growth you have seen in your transplant patients? Have you noted a significant improvement when you compare transplantation to chronic hemodialysis?