Renal
Transplantation
Infants
in
JOHN S. NAJARIAN, M.D., DANIEL J. FREY, M.D., ARTHUR J. MATAS, M.D., KRISTEN J. GILLINGHAM, M.S., SAMUEL S. K. SO, M.D., MARIE COOK, M.P.H., BLANCHE CHAVERS, M.D.,* S. MICHAEL MAUER, M.D.,* and THOMAS E. NEVINS, M.D.*
The timing of renal transplantation in infants is controversial. Between 1965 and 1989, 79 transplants in 75 infants less than 2 years old were performed: 23 who were 12 months or younger, 52 who were older than 12 months; 63 donors were living related, 1 was living unrelated, and 15 were cadaver donors; 75 were primary transplants and 4 were retransplants. Infants were considered for transplantation when they were on, or about to begin, dialysis. All had intra-abdominal transplants with arterial anastomosis to the distal aorta. Sixty-four per cent are alive with functioning grafts. The most frequent etiologies of renal failure were hypoplasia (32%) and obstructive uropathy (20%); oxalosis was the etiology in 11%. Since 1983 patient survival has been 95% and 91% at 1 and 5 years; graft survival has been 86% and 73% at 1 and 5 years. For cyclosporine immunosuppressed patients, patient survival is 100% at 1 and 5 years; graft survival is 96% and 82% at 1 and 5 years. There was no difference in outcome between infants who were 12 months or younger versus those who were aged 12 to 24 months; similarly there was no difference between infants and older children. Sixteen (21%) patients died: 5 after operation from coagulopathy (1) and infection (4); and 11 late from postsplenectomy sepsis (4), recurrent oxalosis (3), infection (2), and other causes (2). Routine splenectomy is no longer done. There has not been a death from infection in patients transplanted since 1983. Rejection was the most common cause of graft loss (in 15 patients); other causes included death (with function) (7), recurrent oxalosis (3), and technical complications (3). Overall 52% of patients have not had a rejection episode; mean creatinine level in patients with functioning grafts is 0.8 ± 0.2 mg/dL. Common postoperative problems include fever, atelectasis, and ileus. At the time of their transplants, the infants were small for age; but with a successful transplant, their growth, head circumference, and development have improved. Transplantation in infants requires an intensive multidisciplinary approach but yields excellent short- and long-term survival rates that are no different from those seen in older children or adults. Living donors should be used whenever possible. Patients with a successful transplantation experience improved growth and development, with excellent rehabilitation.
T n HE FIRST SUCCESSFUL kidney transplants were performed less than 40 years ago. Shortly there-
after Riley' raised ethical concerns about renal transplantation in children and suggested that two factors, 'length of prolongation of life' and 'discomfort,' must be Presented at the I I 0th Annual Meeting of the American Surgical Association, Washington, D.C., April 5-8, 1990. Supported by NIH Grant DK13083. Address reprint requests to John S. Najarian, M.D., Regents' Professor and Chairman, Department of Surgery, University of Minnesota Hospital, 516 Delaware Street S.E., Box 195 UMHC, Minneapolis, MN 55455. Accepted for publication, April 12, 1990.
353
From the Departments of Surgery and Pediatrics, * University of Minnesota Medical School, Minneapolis, Minnesota
balanced. In 1970 Reinhart2 seriously questioned 'the value of chronic dialysis or renal transplant' for children with end-stage renal disease (ESRD). Since then rapid progress had been made, and by 1980 hemodialysis and renal transplantation were accepted treatments for older children and adolescents.3 However the value of such treatment for the young child or infant with renal failure remained in question. As recently as 1988, Fine stated, 'It is difficult to advocate renal transplantation in infants and young children with ESRD as the preferred treatment.'4 We believe the best chance an infant with ESRD has for achieving normal development and a normal lifestyle is a successful transplant. To that end we strongly recommend living related donor transplants for infants and small children; for those without a living donor, we think a cadaver transplant is preferable to chronic dialysis or withdrawal of support. In this paper we review the results of transplantation in 75 infants who were less than 2 years old. With current immunosuppressive protocols, patient and graft survival rates are no different in these smaller and younger patients than in older children and adults. Material and Methods
Recipients Between January 1, 1965 and December 31, 1989, 75 infants less than 2 years old (6 weeks to 24 months) received 79 kidney transplants at the University of Minnesota (Fig. 1). Of these patients 63 had living related donors (LRD); 15 received cadaver organs; and 1 had a living unrelated donor. The etiology of renal failure is listed in Table 1; hypoplasia and obstructive uropathy accounted for 52% of the patients. Infants with kidney disease are initially evaluated by a multidisciplinary team, including pediatric nephrologists, surgeons, neurologists, nutritionists, clinical psychologists, and social workers. Ideally evaluation occurs before dialysis is instituted, thus allowing time to define the disease etiology, explore treatment options, and evaluate potential donors. The rela-
35 30
r
33
32
F
25 I-. co 0
20
co co
15
10
One patient without an LRD received a kidney from a living unrelated donor. The donor workup was as above; in addition the potential donor was interviewed by a psychiatrist to ensure informed consent and altruistic motivation. Patients without a living donor were put on the waiting list for a cadaver donor transplant. Before 1987 an attempt was made to match HLA antigens when cadaver kidneys were used; however a poor match was not considered a contraindication to transplantation. Since 1987 the extant United Network for Organ Sharing (UNOS) point system has been used to allocate cadaver kidneys.
'a
E
Ann. Surg. * September 1990
NAJARIAN AND OTHERS
354
F
7 5 1 0
1965-69 1970-74 1975-79 1980-84 1985-89 Years
FIG. 1. Number of transplants
in
infants during 5-year intervals (1965
to 1989).
tively few contraindications to transplantation include active infection, malignancy, or serious irreversible brain injury. If parents of children with severe developmental delay prefer transplantation, after being carefully informed that dramatic improvement in neurologic function is unlikely, the transplant is performed. The recipient workup includes structural evaluation of the native kidneys as well as a voiding cystourethrogram (VCUG) to evaluate bladder function and reflux. Renal biopsy may be needed for diagnosis in some patients. Patients with ureteral reflux or polycystic kidneys need bilateral ureteronephrectomy at the time of the transplant. Significant nephrotic syndrome also requires bilateral nephrectomy and at least 6 weeks of dialysis support to correct nutritional defects before the transplant surgery.5 After appropriate surgical treatment, patients with extrarenal congenital anomalies have been accepted for transplantation. Children with primary oxalosis are evaluated and managed as previously described.67 Donors The child's family is encouraged to identify potential LRDs. While the recipient workup is in progress, potential donors are screened and HLA typing is determined. Initial criteria for consideration include ABO compatibility, a negative crossmatch, and no history of disease that might affect the kidneys (e.g., hypertension, diabetes). Further donor workup includes a complete medical history and physical exam, along with laboratory tests to determine that the potential donor is an excellent surgical risk and has two well-functioning kidneys. Once accepted the donor is admitted to the hospital and an arteriogram is performed to define the renal vascular anatomy. Finally, before the transplant, the crossmatch is repeated.
Perioperative Managemnent The surgical technique and perioperative management have been previously described.8-'2 Recipients of living donor transplants are admitted to the hospital at least 3 days before transplantation. This time is used to perform presurgical teaching of the family, while metabolism, anemia, infection, blood pressure, and the need for dialysis are all assessed in the recipient. Perioperative antibiotics (third-generation cephalosporins) are administered on the morning of surgery. The operating room temperature is maintained at 32 C and the recipient is placed on a warming blanket to reduce the risk of hypothermia. In the operating room, after induction of anesthesia, an arterial line is placed to monitor blood pressure; if not already present, a Hickman catheter suitable for hemodialysis is placed. The catheter is used also to measure central venous pressure (CVP), administer medication, and draw blood. A rectal probe is placed to monitor core temperature. Using warmed solutions the entire abdomen and perineum is prepped and draped into the operative field. A Foley catheter or large infant feeding tube is then placed into the bladder. Prepping the perineum and catheter into the field allows manipulation of the catheter during the operation. All infants are surgically approached through TABLE 1. Etiology oJ ESRD in 75 Infants
Etiology
Hypoplasia Obstructive uropathy Oxalosis Congenital nephrotic syndrome Hemolytic uremic syndrome Cortical necrosis Infantile polycystic kidney disease Glomerulonephritis Steroid resistant nephrotic syndrome Birth hypoxia with renal failure Jeune's syndrome Drash syndrome Anatomical problems Unknown
No. of Patients 24 15 8 6 4 3 3 3 2 2 1 I
1 2
Percentage 32 20 11 8 5 4 4 4 3
3 I I I
3
Vol. 212 No. 3 -
RENAL TRANSPLANTATION IN INFANTS
a transabdominal incision. At this point bilateral ureteronephrectomy, if necessary, is done. In all infants the cecum and right colon are mobilized. The aorta is dissected from the inferior mesenteric artery to the external iliac artery on the right. Lumbar branches are ligated and divided; the right external and internal iliac arteries and left common iliac are encircled. The inferior vena cava and common iliac veins are dissected and the lumbar veins ligated. When the donor kidney is ready, the proximal aorta and vena cava and the iliac vessels are occluded; no heparin is given to the recipient. The venous anastomosis is then performed between the donor renal vein and distal vena cava or right iliac vein; an end-to-side arterial anastomosis is then done between the donor renal artery and the distal aorta or common iliac artery. Before reperfusion of the kidney, the infant's CVP is raised to 15 to 18 cm of water by administering plasmanate and/or packed red blood cells. It is vital during reperfusion to maintain adequate blood pressure and filling pressures via volume expansion. Mannitol (250 mg/kg) and furosemide (1 mg/kg) are infused as the anastomoses are completed. Before release of the clamps, the kidney is warmed with saline to counteract the hypothermic effect of the cold perfusate used to flush the kidney. At the same time sodium bicarbonate (1 mEq/kg) is given to neutralize the acidotic blood released from the legs. The kidney is then placed in the right retroperitoneal space. The ureter is implanted into the bladder using a standard LeadbetterPolitano technique. Frequently the ureteral anastomosis is stented with a silastic feeding tube. Postoperative management includes meticulous attention to fluid and electrolyte replacement status.9"0 Intravenous fluids are administered on a milliliter-per-milliliter basis to match urine output. The composition of the solution is frequently readjusted, depending on the results of serum and urinary electrolyte determinations performed at least every 6 hours during the first 2 postoperative days. Colloid is used to maintain adequate intravascular volume and replace third-space loss. The adequacy of replacement therapy is assessed by monitoring pulse rate, blood pressure, peripheral perfusion, arterial blood gases, CVP, and, if necessary, chest x-ray. No one factor alone (e.g., CVP) is used to assess intravascular volume. For example some infants can be volume overloaded with CVPs in the range of 3 to 4 cm H20, while others can tolerate much higher CVPs. If hyperglycemia is present, the urine replacement solution is changed to a 1 g/dL glucose base. Calcium levels are carefully followed and calcium is replaced intravenously as needed; there is a significant incidence of hypocalcemia in the early postoperative period. Oliguria associated with an adequate intravascular volume is treated with intravenous furosemide (1 mg/kg). A prolonged ileus is frequent after operation and nasogastric drainage is required. If, before operation, the
355
infant is thought to be nutritionally deficient, hyperalimentation is begun early in the postoperative period. If a ureteral stent has been placed, a dye study through the stent is performed on postoperative day 5 and the stent is removed if the study is normal. The Foley catheter is discontinued on postoperative day 7. By this time a regular diet is usually tolerated.
Immunosuppressive Protocols
The immunosuppressive protocols for pediatric recipients at our institution have been previously described.8'2 Briefly, between January 1965 and June 1984, standard immunosuppression consisted of azathioprine (5 mg/kg/day tapered to 2.5 mg/kg/day at 1 week), prednisone (2 mg/kg/day tapered to 0.2 to 0.3 mg/kg/day at 1 year), Minnesota antilymphoblast globulin (MALG) (30 mg/kg/day for 14 days), and methylprednisolone (20 mg/kg/day for 3 days). In addition, after 1979, all patients received three to five random donor blood transfusions before transplantation, most recently while receiving 1.5 mg/kg/day of azathioprine. Rejection episodes were documented by biopsy and treated with increased prednisone doses to 2 mg/kg/day. In addition first rejection episodes were commonly treated with MALG (20 mg/kg/day for 7 to 10 days). Before 1984 splenectomy was done before or at the time of the transplant in almost all patients. At that time results of a prospective randomized trial indicated that splenectomy had no long-term benefit on graft function.'3 Thus routine splenectomy was abandoned. In June 1984 a protocol evaluating pretransplant donorspecific transfusions (DST) was instituted.'4 Three DSTs were administered before operation, one each at 2-week intervals. Patients were then crossmatched 4 to 6 weeks later to evaluate sensitization; if the crossmatch was negative, we proceeded with transplantation. After operation such patients received MALG, prednisone, and azathioprine. Seven infants entered the DST protocol and underwent transplantation; outcome was identical to other noncyclosporine immunosuppressed patients and the data have been combined. Since 1984 non-DST infants and cadaver transplant recipients have received sequential therapy: MALG (20 mg/kg for 14 days), prednisone, and azathioprine at the time of the transplant with cyclosporine (CSA) (2.5 mg/ kg twice a day) added on postoperative days 10 to 12. Initially infants and children were completely weaned from CSA; currently the CSA dose is reduced at 1 month to 2 mg/kg twice a day and at 2 months to 1.5 mg/kg twice a day. No effort is made to maintain a specified CSA blood level. If rejection is suspected,'5 percutaneous allograft biopsy is done to confirm the diagnosis. Rejection episodes are treated by increasing the steroid dose. Steroidresistant rejections are treated with an additional 7- to
356
Ann. Surg. * September 1990
NAJARIAN AND OTHERS
10-day course of MALG. For patients experiencing rejection, the CSA dose is increased and an attempt is made to maintain whole blood trough levels, as measured by high-performance liquid chromatography (HPLC), between 75 and 125 ng/mL. After transplantation all patients received daily oral trimethoprim and sulfamethoxazole to prevent pneumocystis carinii, Nocardia, and Listeria infection. Splenectomized patients are also maintained on daily penicillin to reduce the risk of postsplenectomy sepsis. Oral nystatin is always prescribed to minimize the risk of opportunistic fungal overgrowth during the immediate post-transplantation period and during rejection treatments. Infants also receive hepatitis B vaccine and routine childhood immunizations before transplantation. If the normal immunization schedule is interrupted by transplantation, it is resumed about 6 months after transplantation; but live virus vaccines are never used. Data Analysis
The 75 children were followed for a minimum of 3 months after their primary transplants. Graft and patient survival rates for the first transplant were analyzed according to age at transplantation (< 12 months versus 12 to 24 months), donor source (LRD) versus cadaver donor (CAD), era (before 1983 versus after 1983), and immunosuppressive management (non-CSA versus CSA). Graft failure was defined as return to dialysis, transplant nephrectomy, retransplant, or death with a functioning graft. All deaths, including those after return to dialysis, are included. The four retransplants are considered separately. We compared graft and patient survival rates for infants who were less than 2 years old versus older children during the same period. In addition, for infants, we analyzed postoperative complications, cause of graft loss, and cause of death. Growth data were obtained by retrospective chart review. The data were then converted to standard deviation scores (SDS) using the formula:
tistical comparison. " Growth and psychometric data were compared using Student's t test. Results Between January 1, 1965 and December 31, 1989, 75 infants less than 2 years old underwent 79 transplants (75 primary transplants and 4 retransplants). Of the primary transplants, 23 recipients were 12 months old or younger; 52 were between 12 and 24 months old. There were 63 LRD transplants; 15 CADs; and 1 living unrelated transplant. The latter graft continues to function and is not included in the survival analysis. Patient and graft survival rates for all other primary transplant recipients are shown in Fig. 2. For LRD recipients patient survival at 1 and 5 years was 93% and 82%; for CAD recipients patient survival was 60% and 51% at 1 and 5 years (p < 0.01). There was no significant difference in outcome between those children transplanted at age 12 months or younger versus those transplanted between the ages of 12 and 24 months (Table 2). When analyzed by etiology of ESRD, oxalosis was associated with decreased patient and graft survival (p < 0.05). With an average follow-up of 60 months, 48 infants (64%) are alive with a functioning graft (primary or retransplant).
Effect of Era on Graft Survival Of the primary transplants, 47 have been performed since 1983: 41 LRD and 6 CAD. Patient survival at 1 and 5 years was 95% and 91%; graft survival was 86% and 73%. Figure 3A shows significantly worse outcome of transplants before 1983 compared to those after 1983 (p < 0.01). For non-CSA immunosuppressed patients, there was no difference in survival rate between those transplanted before compared to those transplanted after 1983 (Fig. 3B). Even when high-risk patients (e.g., those with 100 90 70
SDS = (Patient value - Mean value)/standard deviation The normal values are those published for American children. 16 The psychometric data was part of a prospective developmental analysis begun in 1980. The youngest children were evaluated before transplantation using the Bayley Scales ofInfant Development. The scales have a mean value of 100, with a standard deviation of 16. Older children were tested with age-appropriate instruments at both the pre- and post-transplantation evaluation. Actuarial graft and patient survival rates were calculated by life-table analysis, and Gehan's test was used for sta-
- .Patient
80
1
60
a)
50
ae
40
---s~~~~~~~~~~~~~~1 --
-
.
%%-%~"
-
at--t
--
30 20 F 10 a v
0
1
2
3
4
5 Years
6
7
8
9
10
FIG. 2. Patient and graft survival for primary transplants in infants (1965 to 1989).
RENAL TRANSPLANTATION IN INFANTS
Vol. 212 * No. 3
TABLE 2. Outcome of 74 Primary Kidney Transplants in Infants
CO)
_
50 40 30
Post 1983
CSA (n-27)
60 Post 1983 Non-CSA (n-20)
50 40
30
20
20
10
10
A A0
%__
1
2
3 Years
4
5
6
B
[
0
1
2
3
4
5
6
Years
FIGS. 6A and B. Comparison of survival in infants receiving primary transplants from maternal versus paternal donors. (A) Paternal donors were associated with improved patient survival (p < 0.05). (B) There was no difference in graft survival.
RENAL TRANSPLANTATION IN INFANTS
Vol. 212-No. 3
100
100 24 Moe (n-339)
90
90
80 70
80 s24 Moe (n-75)
[
60
'a
50 F
0
A
40 [
0
30 F
30 F
20 F
20 F
10
10
0
L 0
s24 Moe (n.75)
50 [
40 F
0.
.24 Moe (n-339)
70
60 CI)
359
1
2
3 Years
4
0
6
5
0
1
FIGS. 7A and B. Comparison of outcome in infants (
Transplantation
Infants
in
JOHN S. NAJARIAN, M.D., DANIEL J. FREY, M.D., ARTHUR J. MATAS, M.D., KRISTEN J. GILLINGHAM, M.S., SAMUEL S. K. SO, M.D., MARIE COOK, M.P.H., BLANCHE CHAVERS, M.D.,* S. MICHAEL MAUER, M.D.,* and THOMAS E. NEVINS, M.D.*
The timing of renal transplantation in infants is controversial. Between 1965 and 1989, 79 transplants in 75 infants less than 2 years old were performed: 23 who were 12 months or younger, 52 who were older than 12 months; 63 donors were living related, 1 was living unrelated, and 15 were cadaver donors; 75 were primary transplants and 4 were retransplants. Infants were considered for transplantation when they were on, or about to begin, dialysis. All had intra-abdominal transplants with arterial anastomosis to the distal aorta. Sixty-four per cent are alive with functioning grafts. The most frequent etiologies of renal failure were hypoplasia (32%) and obstructive uropathy (20%); oxalosis was the etiology in 11%. Since 1983 patient survival has been 95% and 91% at 1 and 5 years; graft survival has been 86% and 73% at 1 and 5 years. For cyclosporine immunosuppressed patients, patient survival is 100% at 1 and 5 years; graft survival is 96% and 82% at 1 and 5 years. There was no difference in outcome between infants who were 12 months or younger versus those who were aged 12 to 24 months; similarly there was no difference between infants and older children. Sixteen (21%) patients died: 5 after operation from coagulopathy (1) and infection (4); and 11 late from postsplenectomy sepsis (4), recurrent oxalosis (3), infection (2), and other causes (2). Routine splenectomy is no longer done. There has not been a death from infection in patients transplanted since 1983. Rejection was the most common cause of graft loss (in 15 patients); other causes included death (with function) (7), recurrent oxalosis (3), and technical complications (3). Overall 52% of patients have not had a rejection episode; mean creatinine level in patients with functioning grafts is 0.8 ± 0.2 mg/dL. Common postoperative problems include fever, atelectasis, and ileus. At the time of their transplants, the infants were small for age; but with a successful transplant, their growth, head circumference, and development have improved. Transplantation in infants requires an intensive multidisciplinary approach but yields excellent short- and long-term survival rates that are no different from those seen in older children or adults. Living donors should be used whenever possible. Patients with a successful transplantation experience improved growth and development, with excellent rehabilitation.
T n HE FIRST SUCCESSFUL kidney transplants were performed less than 40 years ago. Shortly there-
after Riley' raised ethical concerns about renal transplantation in children and suggested that two factors, 'length of prolongation of life' and 'discomfort,' must be Presented at the I I 0th Annual Meeting of the American Surgical Association, Washington, D.C., April 5-8, 1990. Supported by NIH Grant DK13083. Address reprint requests to John S. Najarian, M.D., Regents' Professor and Chairman, Department of Surgery, University of Minnesota Hospital, 516 Delaware Street S.E., Box 195 UMHC, Minneapolis, MN 55455. Accepted for publication, April 12, 1990.
353
From the Departments of Surgery and Pediatrics, * University of Minnesota Medical School, Minneapolis, Minnesota
balanced. In 1970 Reinhart2 seriously questioned 'the value of chronic dialysis or renal transplant' for children with end-stage renal disease (ESRD). Since then rapid progress had been made, and by 1980 hemodialysis and renal transplantation were accepted treatments for older children and adolescents.3 However the value of such treatment for the young child or infant with renal failure remained in question. As recently as 1988, Fine stated, 'It is difficult to advocate renal transplantation in infants and young children with ESRD as the preferred treatment.'4 We believe the best chance an infant with ESRD has for achieving normal development and a normal lifestyle is a successful transplant. To that end we strongly recommend living related donor transplants for infants and small children; for those without a living donor, we think a cadaver transplant is preferable to chronic dialysis or withdrawal of support. In this paper we review the results of transplantation in 75 infants who were less than 2 years old. With current immunosuppressive protocols, patient and graft survival rates are no different in these smaller and younger patients than in older children and adults. Material and Methods
Recipients Between January 1, 1965 and December 31, 1989, 75 infants less than 2 years old (6 weeks to 24 months) received 79 kidney transplants at the University of Minnesota (Fig. 1). Of these patients 63 had living related donors (LRD); 15 received cadaver organs; and 1 had a living unrelated donor. The etiology of renal failure is listed in Table 1; hypoplasia and obstructive uropathy accounted for 52% of the patients. Infants with kidney disease are initially evaluated by a multidisciplinary team, including pediatric nephrologists, surgeons, neurologists, nutritionists, clinical psychologists, and social workers. Ideally evaluation occurs before dialysis is instituted, thus allowing time to define the disease etiology, explore treatment options, and evaluate potential donors. The rela-
35 30
r
33
32
F
25 I-. co 0
20
co co
15
10
One patient without an LRD received a kidney from a living unrelated donor. The donor workup was as above; in addition the potential donor was interviewed by a psychiatrist to ensure informed consent and altruistic motivation. Patients without a living donor were put on the waiting list for a cadaver donor transplant. Before 1987 an attempt was made to match HLA antigens when cadaver kidneys were used; however a poor match was not considered a contraindication to transplantation. Since 1987 the extant United Network for Organ Sharing (UNOS) point system has been used to allocate cadaver kidneys.
'a
E
Ann. Surg. * September 1990
NAJARIAN AND OTHERS
354
F
7 5 1 0
1965-69 1970-74 1975-79 1980-84 1985-89 Years
FIG. 1. Number of transplants
in
infants during 5-year intervals (1965
to 1989).
tively few contraindications to transplantation include active infection, malignancy, or serious irreversible brain injury. If parents of children with severe developmental delay prefer transplantation, after being carefully informed that dramatic improvement in neurologic function is unlikely, the transplant is performed. The recipient workup includes structural evaluation of the native kidneys as well as a voiding cystourethrogram (VCUG) to evaluate bladder function and reflux. Renal biopsy may be needed for diagnosis in some patients. Patients with ureteral reflux or polycystic kidneys need bilateral ureteronephrectomy at the time of the transplant. Significant nephrotic syndrome also requires bilateral nephrectomy and at least 6 weeks of dialysis support to correct nutritional defects before the transplant surgery.5 After appropriate surgical treatment, patients with extrarenal congenital anomalies have been accepted for transplantation. Children with primary oxalosis are evaluated and managed as previously described.67 Donors The child's family is encouraged to identify potential LRDs. While the recipient workup is in progress, potential donors are screened and HLA typing is determined. Initial criteria for consideration include ABO compatibility, a negative crossmatch, and no history of disease that might affect the kidneys (e.g., hypertension, diabetes). Further donor workup includes a complete medical history and physical exam, along with laboratory tests to determine that the potential donor is an excellent surgical risk and has two well-functioning kidneys. Once accepted the donor is admitted to the hospital and an arteriogram is performed to define the renal vascular anatomy. Finally, before the transplant, the crossmatch is repeated.
Perioperative Managemnent The surgical technique and perioperative management have been previously described.8-'2 Recipients of living donor transplants are admitted to the hospital at least 3 days before transplantation. This time is used to perform presurgical teaching of the family, while metabolism, anemia, infection, blood pressure, and the need for dialysis are all assessed in the recipient. Perioperative antibiotics (third-generation cephalosporins) are administered on the morning of surgery. The operating room temperature is maintained at 32 C and the recipient is placed on a warming blanket to reduce the risk of hypothermia. In the operating room, after induction of anesthesia, an arterial line is placed to monitor blood pressure; if not already present, a Hickman catheter suitable for hemodialysis is placed. The catheter is used also to measure central venous pressure (CVP), administer medication, and draw blood. A rectal probe is placed to monitor core temperature. Using warmed solutions the entire abdomen and perineum is prepped and draped into the operative field. A Foley catheter or large infant feeding tube is then placed into the bladder. Prepping the perineum and catheter into the field allows manipulation of the catheter during the operation. All infants are surgically approached through TABLE 1. Etiology oJ ESRD in 75 Infants
Etiology
Hypoplasia Obstructive uropathy Oxalosis Congenital nephrotic syndrome Hemolytic uremic syndrome Cortical necrosis Infantile polycystic kidney disease Glomerulonephritis Steroid resistant nephrotic syndrome Birth hypoxia with renal failure Jeune's syndrome Drash syndrome Anatomical problems Unknown
No. of Patients 24 15 8 6 4 3 3 3 2 2 1 I
1 2
Percentage 32 20 11 8 5 4 4 4 3
3 I I I
3
Vol. 212 No. 3 -
RENAL TRANSPLANTATION IN INFANTS
a transabdominal incision. At this point bilateral ureteronephrectomy, if necessary, is done. In all infants the cecum and right colon are mobilized. The aorta is dissected from the inferior mesenteric artery to the external iliac artery on the right. Lumbar branches are ligated and divided; the right external and internal iliac arteries and left common iliac are encircled. The inferior vena cava and common iliac veins are dissected and the lumbar veins ligated. When the donor kidney is ready, the proximal aorta and vena cava and the iliac vessels are occluded; no heparin is given to the recipient. The venous anastomosis is then performed between the donor renal vein and distal vena cava or right iliac vein; an end-to-side arterial anastomosis is then done between the donor renal artery and the distal aorta or common iliac artery. Before reperfusion of the kidney, the infant's CVP is raised to 15 to 18 cm of water by administering plasmanate and/or packed red blood cells. It is vital during reperfusion to maintain adequate blood pressure and filling pressures via volume expansion. Mannitol (250 mg/kg) and furosemide (1 mg/kg) are infused as the anastomoses are completed. Before release of the clamps, the kidney is warmed with saline to counteract the hypothermic effect of the cold perfusate used to flush the kidney. At the same time sodium bicarbonate (1 mEq/kg) is given to neutralize the acidotic blood released from the legs. The kidney is then placed in the right retroperitoneal space. The ureter is implanted into the bladder using a standard LeadbetterPolitano technique. Frequently the ureteral anastomosis is stented with a silastic feeding tube. Postoperative management includes meticulous attention to fluid and electrolyte replacement status.9"0 Intravenous fluids are administered on a milliliter-per-milliliter basis to match urine output. The composition of the solution is frequently readjusted, depending on the results of serum and urinary electrolyte determinations performed at least every 6 hours during the first 2 postoperative days. Colloid is used to maintain adequate intravascular volume and replace third-space loss. The adequacy of replacement therapy is assessed by monitoring pulse rate, blood pressure, peripheral perfusion, arterial blood gases, CVP, and, if necessary, chest x-ray. No one factor alone (e.g., CVP) is used to assess intravascular volume. For example some infants can be volume overloaded with CVPs in the range of 3 to 4 cm H20, while others can tolerate much higher CVPs. If hyperglycemia is present, the urine replacement solution is changed to a 1 g/dL glucose base. Calcium levels are carefully followed and calcium is replaced intravenously as needed; there is a significant incidence of hypocalcemia in the early postoperative period. Oliguria associated with an adequate intravascular volume is treated with intravenous furosemide (1 mg/kg). A prolonged ileus is frequent after operation and nasogastric drainage is required. If, before operation, the
355
infant is thought to be nutritionally deficient, hyperalimentation is begun early in the postoperative period. If a ureteral stent has been placed, a dye study through the stent is performed on postoperative day 5 and the stent is removed if the study is normal. The Foley catheter is discontinued on postoperative day 7. By this time a regular diet is usually tolerated.
Immunosuppressive Protocols
The immunosuppressive protocols for pediatric recipients at our institution have been previously described.8'2 Briefly, between January 1965 and June 1984, standard immunosuppression consisted of azathioprine (5 mg/kg/day tapered to 2.5 mg/kg/day at 1 week), prednisone (2 mg/kg/day tapered to 0.2 to 0.3 mg/kg/day at 1 year), Minnesota antilymphoblast globulin (MALG) (30 mg/kg/day for 14 days), and methylprednisolone (20 mg/kg/day for 3 days). In addition, after 1979, all patients received three to five random donor blood transfusions before transplantation, most recently while receiving 1.5 mg/kg/day of azathioprine. Rejection episodes were documented by biopsy and treated with increased prednisone doses to 2 mg/kg/day. In addition first rejection episodes were commonly treated with MALG (20 mg/kg/day for 7 to 10 days). Before 1984 splenectomy was done before or at the time of the transplant in almost all patients. At that time results of a prospective randomized trial indicated that splenectomy had no long-term benefit on graft function.'3 Thus routine splenectomy was abandoned. In June 1984 a protocol evaluating pretransplant donorspecific transfusions (DST) was instituted.'4 Three DSTs were administered before operation, one each at 2-week intervals. Patients were then crossmatched 4 to 6 weeks later to evaluate sensitization; if the crossmatch was negative, we proceeded with transplantation. After operation such patients received MALG, prednisone, and azathioprine. Seven infants entered the DST protocol and underwent transplantation; outcome was identical to other noncyclosporine immunosuppressed patients and the data have been combined. Since 1984 non-DST infants and cadaver transplant recipients have received sequential therapy: MALG (20 mg/kg for 14 days), prednisone, and azathioprine at the time of the transplant with cyclosporine (CSA) (2.5 mg/ kg twice a day) added on postoperative days 10 to 12. Initially infants and children were completely weaned from CSA; currently the CSA dose is reduced at 1 month to 2 mg/kg twice a day and at 2 months to 1.5 mg/kg twice a day. No effort is made to maintain a specified CSA blood level. If rejection is suspected,'5 percutaneous allograft biopsy is done to confirm the diagnosis. Rejection episodes are treated by increasing the steroid dose. Steroidresistant rejections are treated with an additional 7- to
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NAJARIAN AND OTHERS
10-day course of MALG. For patients experiencing rejection, the CSA dose is increased and an attempt is made to maintain whole blood trough levels, as measured by high-performance liquid chromatography (HPLC), between 75 and 125 ng/mL. After transplantation all patients received daily oral trimethoprim and sulfamethoxazole to prevent pneumocystis carinii, Nocardia, and Listeria infection. Splenectomized patients are also maintained on daily penicillin to reduce the risk of postsplenectomy sepsis. Oral nystatin is always prescribed to minimize the risk of opportunistic fungal overgrowth during the immediate post-transplantation period and during rejection treatments. Infants also receive hepatitis B vaccine and routine childhood immunizations before transplantation. If the normal immunization schedule is interrupted by transplantation, it is resumed about 6 months after transplantation; but live virus vaccines are never used. Data Analysis
The 75 children were followed for a minimum of 3 months after their primary transplants. Graft and patient survival rates for the first transplant were analyzed according to age at transplantation (< 12 months versus 12 to 24 months), donor source (LRD) versus cadaver donor (CAD), era (before 1983 versus after 1983), and immunosuppressive management (non-CSA versus CSA). Graft failure was defined as return to dialysis, transplant nephrectomy, retransplant, or death with a functioning graft. All deaths, including those after return to dialysis, are included. The four retransplants are considered separately. We compared graft and patient survival rates for infants who were less than 2 years old versus older children during the same period. In addition, for infants, we analyzed postoperative complications, cause of graft loss, and cause of death. Growth data were obtained by retrospective chart review. The data were then converted to standard deviation scores (SDS) using the formula:
tistical comparison. " Growth and psychometric data were compared using Student's t test. Results Between January 1, 1965 and December 31, 1989, 75 infants less than 2 years old underwent 79 transplants (75 primary transplants and 4 retransplants). Of the primary transplants, 23 recipients were 12 months old or younger; 52 were between 12 and 24 months old. There were 63 LRD transplants; 15 CADs; and 1 living unrelated transplant. The latter graft continues to function and is not included in the survival analysis. Patient and graft survival rates for all other primary transplant recipients are shown in Fig. 2. For LRD recipients patient survival at 1 and 5 years was 93% and 82%; for CAD recipients patient survival was 60% and 51% at 1 and 5 years (p < 0.01). There was no significant difference in outcome between those children transplanted at age 12 months or younger versus those transplanted between the ages of 12 and 24 months (Table 2). When analyzed by etiology of ESRD, oxalosis was associated with decreased patient and graft survival (p < 0.05). With an average follow-up of 60 months, 48 infants (64%) are alive with a functioning graft (primary or retransplant).
Effect of Era on Graft Survival Of the primary transplants, 47 have been performed since 1983: 41 LRD and 6 CAD. Patient survival at 1 and 5 years was 95% and 91%; graft survival was 86% and 73%. Figure 3A shows significantly worse outcome of transplants before 1983 compared to those after 1983 (p < 0.01). For non-CSA immunosuppressed patients, there was no difference in survival rate between those transplanted before compared to those transplanted after 1983 (Fig. 3B). Even when high-risk patients (e.g., those with 100 90 70
SDS = (Patient value - Mean value)/standard deviation The normal values are those published for American children. 16 The psychometric data was part of a prospective developmental analysis begun in 1980. The youngest children were evaluated before transplantation using the Bayley Scales ofInfant Development. The scales have a mean value of 100, with a standard deviation of 16. Older children were tested with age-appropriate instruments at both the pre- and post-transplantation evaluation. Actuarial graft and patient survival rates were calculated by life-table analysis, and Gehan's test was used for sta-
- .Patient
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-
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6
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8
9
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FIG. 2. Patient and graft survival for primary transplants in infants (1965 to 1989).
RENAL TRANSPLANTATION IN INFANTS
Vol. 212 * No. 3
TABLE 2. Outcome of 74 Primary Kidney Transplants in Infants
CO)
_
50 40 30
Post 1983
CSA (n-27)
60 Post 1983 Non-CSA (n-20)
50 40
30
20
20
10
10
A A0
%__
1
2
3 Years
4
5
6
B
[
0
1
2
3
4
5
6
Years
FIGS. 6A and B. Comparison of survival in infants receiving primary transplants from maternal versus paternal donors. (A) Paternal donors were associated with improved patient survival (p < 0.05). (B) There was no difference in graft survival.
RENAL TRANSPLANTATION IN INFANTS
Vol. 212-No. 3
100
100 24 Moe (n-339)
90
90
80 70
80 s24 Moe (n-75)
[
60
'a
50 F
0
A
40 [
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30 F
30 F
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.24 Moe (n-339)
70
60 CI)
359
1
2
3 Years
4
0
6
5
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FIGS. 7A and B. Comparison of outcome in infants (
