BACKGROUND.

Previous studies of renal transplantation in children have focused on the

survival of grafts and patients. Little information is available about the cause
of renal disease, the sources of donated organs, or children's growth after
transplantation. The North American Pediatric Renal Transplant Cooperative
Study was organized to identify the diseases that require transplantation and
to analyze factors that affect the success of transplantation in children.

METHODS.
We collected data from 73 pediatric transplantation centers from 1987
through 1990. These data included information about demographic
characteristics of patients, graft function, and therapy one month after
transplantation and every six months thereafter for each patient 17 years of
age or younger.

RESULTS.
Altogether, 1550 children received 1667 renal allografts during this period;
31 percent of the children were five years of age or younger. Forty-three
percent of the transplanted kidneys came from a living related donor, and 57
percent from a cadaver. The two most common causes of renal disease
leading to transplantation were congenital malformations of the kidneys and
urinary tract (42 percent of the patients) and focal segmental
glomerulosclerosis (12 percent). One year after transplantation, the rate of
graft survival in recipients of a kidney from a living related donor was 89
percent; it was 80 percent after three years. For recipients of cadaver kidneys,
the comparable rates were 74 percent and 62 percent, respectively (P<0.001).
The best growth was observed in patients who were no more than five years
old at the time of transplantation. During follow-up, 79 patients died, and
cancer developed in 12 patients.

CONCLUSIONS.
The most common causes of end-stage renal disease in children and
adolescents are congenital malformations of the kidneys and urinary tract and
focal segmental glomerulosclerosis. The rates of graft survival at one and
three years are better in children and adolescents who receive a kidney from a
living related donor than in those who receive a kidney from a cadaver. (N
Engl J Med 1992;326:1727–32.)

CHRONIC renal disease in children is frequently due to a congenital renal

lesion, such as aplasia or dysplasia, which leads to end-stage renal disease in
early infancy. Such children have retarded growth and renal osteodystrophy.
Dialysis therapy tends to exacerbate renal bone disease and leads to early
epiphyseal closure. To avoid this additional injury, physicians frequently
prefer to perform renal transplantation as soon as possible, even before
dialysis is initiated. Because of the small number of procedures performed
annually at individual centers, data on the outcome of renal transplantation in
children are sparse. The North American Pediatric Renal Transplant
Cooperative Study was organized in 1987 to register and follow children up
to 17 years of age in the United States and Canada who receive renal
allografts. This report is based on the 1550 patients who underwent 1667
transplantation procedures that were reported to the registry during its first
four years of operation (1987 through 1990).
Methods

The North American Pediatric Renal Transplant Cooperative Study is made

up of a clinical coordinating center, a data-coordinating center, and 73
medical centers treating children with renal disease in the United States and
Canada. The data for this report, compiled in February 1991, include
transplantations reported during the four preceding years. Since January 1987
each allograft received by a child or adolescent ≤17 years of age at a
participating center has been reported to the study registry, along with
information on graft function and therapy one month after transplantation and
every six months thereafter, as described previously.1 Standard univariate and
multivariate statistical methods, including product—limit estimates of
survival distributions, were used to analyze the data. Proportional-hazards
survival models were constructed that equated an individual patient's hazard
to an underlying hazard multiplied by an estimated exponentiated linear
combination of risk factors. Multivariate models were scaled so that risk
increased with larger values of the covariates; the relative risk for a single
dichotomous risk factor is the exponentiated parameter.

CHARACTERISTICS OF THE
PATIENTS
Both the number of patients who received transplants during each of the four
years and the number of transplantation procedures have decreased slightly
each year since 1987, although a lag in reporting probably accounts for the
small size of the 1990 group. The age, race, and sex distribution of the
patients did not change significantly over time. The youngest patient who
underwent transplantation was five months old. Among the patients five
months to five years of age, 70 percent were boys; the sex ratio was more
nearly equal in the two older age groups, which included 76 percent of the
patients.

The most common causes of renal failure were congenital lesions (renal
dysplasia, obstructive malformations, or both) in 42 percent of the patients
and glomerulonephritis in 18 percent (including focal segmental
glomerulosclerosis in 12 percent). Lupus nephritis (5 percent) and hemolytic
—uremic syndrome (3 percent) were rare, and only one patient had diabetic
nephropathy. Of the patients 5 years of age or younger, 46 percent had
congenital lesions, whereas various forms of glomerulonephritis — such as
focal segmental glomerulosclerosis, membranoproliferative
glomerulonephritis, and lupus nephritis — were the most frequent causes of
renal failure among those 13 to 17 years of age. Although nonwhite patients
made up 31 percent of all transplant recipients, 44 percent of the patients with
focal segmental glomerulosclerosis were nonwhite.

At the time of entry into the registry, 14 percent of the patients had just
received their second or subsequent transplants, with a median of 46 months
(range, 5 to 178) since the previous transplantation. Transplantation was used
as initial therapy (without dialysis) in 22 percent of the patients; 34 percent of
the transplants from living related donors and 12 percent of those from
cadavers were received by such patients. The rate of transplantation as initial
therapy was similar in all four age groups (≤1, 2 to 5, 6 to 12, and 13 to 17
years). Among the patients treated by dialysis, the median length of time
from the initiation of dialysis to transplantation was 12 months (mean, 21).
All native renal tissue was removed in 29 percent of the patients, and the
existing grafts were removed in 62 percent of the patients who had undergone
a previous transplantation.

CHARACTERISTICS OF DONORS AND

HLA MATCHING
The patient's parent was the source of the allograft in 624 (37 percent) of the
transplantations; in 94 (6 percent) the kidney came from a sibling or other
living relative. Six of the sibling donors were under 18 years of age, and three
were identical twins of the patients; the youngest of these pairs of twins was
13 years old. In 949 (57 percent) of the transplantations, the kidney was
obtained from a cadaver; 39 percent of the cadaver donors were 10 years of
age or younger. In the case of allografts from cadavers, 82 percent were
maintained with an iced electrolyte perfusion; the cold-storage times of the
grafts were at least 24 hours in 56 percent of the cases and more than 48
hours in 1 percent.

The percentage of recipients who received transfusions of blood from the

donor of the allograft decreased during the four years, from 43 percent in
1987 to 19 percent in 1990. Twenty-nine percent of the patients who received
kidneys from living related donors and 53 percent of those who received
cadaver kidneys received more than five transfusions of blood from
unidentified donors. Among the recipients of kidneys from living related
donors, 87 percent had at least one haplotype match with the donor (HLA-B
and HLA-DR), whereas 12 percent had only one HLA-B or one HLA-DR
antigen match. Matches of all A, B, and DR alleles occurred in only 2 percent
of the cases of transplantation of a kidney from a cadaver.
MEDICATION AFTER
TRANSPLANTATION
The median doses of prednisone received by the patients were 0.31 mg per
kilogram of body weight per day 6 months after transplantation and 0.19 mg
per kilogram per day after 30 months. The percentage of transplant recipients
who received prednisone therapy on alternate days increased from 12 percent
to 36 percent during the same period. There was little change in the
proportion of patients who received prednisone, cyclosporine, and
azathioprine at each follow-up evaluation. The dose of azathioprine was
constant throughout the study period (mean, 1.7 mg per kilogram per day);
the median dose of cyclosporine was 6.1 mg per kilogram per day at 6
months and 4.1 mg per kilogram per day at 30 months. The proportion of
recipients of kidneys from living related donors who received triple-drug
therapy at six months increased each year; 54 percent of those who
underwent transplantation in 1987 and 87 percent of those who received
transplants in 1990 received all three drugs. For the recipients of kidneys
from cadavers, the comparable figures were 69 percent and 81 percent. The
dose of each of the three maintenance immunosuppressive medications
correlated positively with age and weight, although the patients who weighed
less received more medication per kilogram of body weight.

One month after transplantation, 72 percent of the patients were receiving

antihypertensive therapy, but this percentage decreased to 53 percent at 30
months. Similarly, 59 percent initially received prophylactic antibiotic
therapy, and 31 percent continued to receive it at 30 months; such treatment
was more frequent among patients who had had obstructive lesions (40
percent).

REJECTION
A total of 1707 episodes of rejection (defined as the initiation of antirejection
therapy or graft failure due to rejection) were reported in 966 recipients, of
whom 404 had 2 or more episodes of rejection (maximum, 7). Overall, half
of all transplant recipients had had an episode of rejection by 66 days after
transplantation (median, 187 days for recipients of grafts from living related
donors and 39 days for recipients of cadaver kidneys). At the end of the
second year, 40 percent of the recipients of kidneys from living related
donors and 27 percent of the recipients of cadaver kidneys had not had an
episode of rejection.

The younger patients were at no disadvantage with respect to the length of

time to the first episode of rejection. The perioperative use of antithymocyte
globulin—antilymphocyte globulin or OKT3 monoclonal antibody was
associated with a significantly longer time to the first episode of rejection
among all kidney-transplant recipients, regardless of the source of the graft.
The recipients of kidneys from donors five years of age or younger had a
higher relative risk of rejection (1.5; 95 percent confidence interval, 1.3 to
1.6; P<0.001) than those who received kidneys from older donors; 18 percent
of the recipients of kidneys from cadaver donors five years of age or younger
had had no rejection episodes after one year, as compared with 35 percent of
the recipients of kidneys from donors more than five years of age.

Overall, 54 percent of the episodes of rejection were completely reversed, 38

percent were partially reversed, and 8 percent ended in graft failure or death.
The rates of complete reversal declined with an increasing number of
rejection episodes, from 62 percent for the first episode to 30 percent when
four or more episodes had occurred. Treatment with antithymocyte globulin-
antilymphocyte globulin or OKT3 antibody at the time of transplantation did
not affect the probability that a later episode of rejection would be completely
reversed. Among the 28 patients who received OKT3 antibody at the time of
transplantation and again for the treatment of an episode of rejection, 18 had
complete reversal and 8 partial reversal of the rejection episode. OKT3
antibody was given during 469 (27 percent) of the episodes of rejection, and
intravenous methylprednisolone during 1187 (70 percent), whereas dialysis
was used during 242 (14 percent) of the episodes.
GROWTH OF CHILDREN
At the time of transplantation, the mean height for all patients was 2.2 SD
below the appropriate age- and sex-adjusted mean for normal children and
adolescents (z score). This deficit was comparable in both sexes, although it
was greater among younger patients ( — 2.8 SD for patients ≤5 years of age)
and those with previous transplantations ( — 3.2 SD). The mean height
scores remained relatively constant after transplantation in all but the two
youngest groups of children (Fig. 2). The recipients who were 1 year old or
younger at the time of transplantation had an increase of 0.3 SD in height
during the first 6 months after the procedure; this increase was 0.8 SD by the
12th month. Accelerated growth did not continue, however, and the z score
for height changed little in subsequent months. An anticipated adolescent
growth spurt or catchup growth was not observed during the three years of
observation after transplantation. In particular, patients who were 13 years
old or older at the time of transplantation had decreases in the mean z score.
All but the youngest age group had increases of 1.0 SD in weight scores by
the 12th month after transplantation. After two and three years, the mean
weight values were comparable to those in normal children and adolescents.

MORBIDITY AND MORTALITY

The median length of hospitalization at the time of transplantation decreased
from 19 to 16 days during the study; the median stay was 2 days longer for
the recipients of cadaver kidneys than for the recipients of kidneys from
living related donors. The number of hospital days after the procedure was
negatively correlated with the patient's age; the median hospital stay was 24
days for children 1 year old or younger, 19 days for those 2 to 5 years old, 17
days for those 6 to 12 years old, and 15 days for those 13 to 17 years old.
During the first one to five months after transplantation, 58 percent of the
recipients were rehospitalized (mean duration of hospital stay, nine days), 30
percent for symptoms of rejection. Bacterial infection (12 percent), viral
infection (12 percent), and hypertension requiring hospital treatment (8
percent) were the other major causes of hospitalization. Both the frequency
and the length of hospitalizations decreased with increasing follow-up.

Cancer developed in 12 patients, of whom 6 had a lymphoproliferative

disorder, 5 sarcoma, and 1 a thyroid carcinoma. Eight of the patients with
cancer died, five within a month of diagnosis. Four of these 12 patients had
received more than one renal allograft.

Seventy-nine of the patients (including the 8 with cancer) died during the
study period; infection was the cause of death in 32 patients. In 38 patients
the graft was reported to be functioning at the time of death. Nineteen deaths
occurred within 30 days after the initial transplantation during the study
period, and 10 during the first postoperative week. At two years, 95 percent
of the patients who received kidneys from living related donors and 92
percent of those who received kidneys from cadavers were alive (P = 0.03).
Sixteen (15 percent) of the patients one year old or younger died, nine of
them with functioning grafts; they accounted for 20 percent of all deaths.
Discussion

The North American Pediatric Renal Transplant Cooperative Study was

established to study systematically the effects of renal transplantation in a
large population of children and adolescents and to generate data that could
ultimately improve the probability of successful transplantation in such
patients. The problems of the adverse effects of immunosuppression, growth
deficits, and questions about the optimal timing of transplantation surgery are
apparent in our results. These observations also highlight several factors
affecting prognosis that are different from those in adults.

The geometric mean hospital stay authorized for adults undergoing renal
transplantation under the Medicare system of prospective payment according
to diagnosis-related groups was 15.8 days in 1987—1988 and 15.4 days in
19881989.3 The median length of the hospital stay after transplantation
surgery in children was 17.6 days, but the number of hospital days was
negatively correlated with the patient's age; thus, the median hospital stay for
transplant recipients one year old or younger was 24.5 days.