Long-Term Survival of Children with End-Stage Renal Disease
http://www.100md.com
《新英格兰医药杂志》
ABSTRACT
Background Although renal-replacement therapy for children with end-stage renal disease has been used for several
decades, data on patients' long-term survival are sparse.
Methods We examined the long-term survival of all children and adolescents who were under 20 years of age when
renal-replacement therapy commenced (study period, April 1963 through March 2002), using data from the Australia
and New Zealand Dialysis and Transplant Registry. Survival was analyzed with the use of Kaplan–Meier methods and
age-standardized mortality rates. Risk factors for death were analyzed with the use of Cox regression analysis with
time-dependent covariates.
Results A total of 1634 children and adolescents were followed for a median of 9.7 years. The long-term survival
rate among children requiring renal-replacement therapy was 79 percent at 10 years and 66 percent at 20 years.
Mortality rates were 30 times as high as for children without end-stage renal disease. Risk factors for death were
a young age at the time renal-replacement therapy was initiated (especially for children under 1 year of age, among
whom the risk was four times as high as for children 15 to 19 years of age) and treatment with dialysis (which was
associated with a risk more than four times as high as for renal transplantation). Overall, a trend toward improved
survival was observed over the four decades of the study.
Conclusions Despite improvement in long-term survival, mortality rates among children requiring renal-replacement
therapy remain substantially higher than those among children without end-stage renal disease. Increasing the
proportion of children treated with renal transplantation rather than with dialysis can improve survival further.
End-stage renal disease, which is a rare but important health problem among children, occurs in about 5 to 10
children per million each year.1 The disease is a chronic condition; even renal transplantation does not mean
lifelong cure. Quality-of-life studies have shown that life without native kidney function is very difficult for
children and their families.2
Forty years ago, children with end-stage renal disease died. Now, almost all such children are treated with
dialysis or renal transplantation. Treatment typically involves multiple therapies, depending upon the availability
of kidneys for transplantation and the long-term survival of the transplants. Long-term survival rates among
children with end-stage renal disease are uncertain, and there are few data to inform patients, families,
clinicians, and policymakers about survival. The available studies are generally short-term,3,4,5,6 are based on
single-center experiences,7 and include only information with regard to patients receiving dialysis, patients
undergoing transplantation, or patients in specific age groups.8
The Australia and New Zealand Dialysis and Transplant (ANZDATA) Registry has prospectively collected data on all
children in whom renal-replacement therapy was started in Australia or New Zealand beginning in 1963. Using data
from this registry, we examined long-term survival among children treated for end-stage renal disease and
identified modifiable and unmodifiable risk factors for death.
Methods
Study Design
We performed a prospective inception-cohort study from the time renal-replacement therapy was initiated for all
children and adolescents younger than 20 years of age in Australia and New Zealand who were registered in the
ANZDATA Registry. The registry collects information every six months from all the renal units in Australia and New
Zealand about all patients receiving renal-replacement therapy who have a diagnosis of chronic renal failure and
for whom indefinite renal-replacement therapy is intended. Details regarding the registry have been reported
elsewhere.9
The data collection is complete from the first use of renal-replacement therapy in Australia and New Zealand and
includes information on the cause of end-stage renal disease, demographic characteristics of the patients, a
limited range of coexisting conditions (which since 1991 have included coronary artery disease, peripheral vascular
disease, cerebrovascular disease, chronic lung disease, hypertension, and smoking), and details of dialysis
treatment and renal transplantation. Nephrologists are asked to provide a cause of death for children who have
died, but death certificates are not directly reviewed by the ANZDATA Registry.
The consent and privacy provisions of the ANZDATA Registry have evolved over time and currently require informed
consent from patients or a parent or legal guardian and include a right of access to personal information.9 The
registry is conducted in accordance with the Australian Commonwealth Privacy Act and associated state legislation
governing health data collection. The anonymity of patient information is maintained by the coding of data during
compilation; only information with personal identifiers removed is released by the registry.
All patients who were younger than 20 years of age when renal-replacement therapy commenced and whose first
treatment occurred before April 1, 2002, were included in our analysis. Patients were followed until death or until
March 31, 2002, whichever occurred first. Children who regained native renal function permanently despite their
initial assessment were excluded; data on those lost to follow-up were censored as of the date of the last follow-
up visit. The sole outcome examined was death, ascertained with the use of the registry data.
Statistical Analysis
The time from the start of renal-replacement therapy to death or the date on which the data were censored was
analyzed with the use of the Kaplan–Meier method and Cox proportional-hazards models. Standardized mortality rate
ratios and age-specific mortality rate ratios were calculated for Australian children only, with the use of
contemporary life-expectancy values derived from life tables of the Australian Bureau of Statistics.
A multivariate Cox proportional-hazards model was constructed with age, sex, the decade in which renal-replacement
therapy was initiated, primary renal disease, and type of dialysis (hemodialysis or peritoneal dialysis) as
predictive variables. A categorical, time-dependent covariate was used for the type of renal-replacement therapy
(hemodialysis, peritoneal dialysis, or transplantation) to allow for changes in type of therapy over time. Age and
the year in which renal-replacement therapy was started were considered as categories in order to avoid the
assumption of linear relationships with outcome. Age was analyzed in five-year categories, except for children
younger than one year of age, who were considered as a separate group because they have a worse prognosis.3,4,6,10
Inclusion in the final model was determined by a backward stepwise process with the use of the likelihood ratio to
evaluate the effect of omitting variables. Stata statistical software (version 7.0, Stata) was used for the
analysis; a P value of 0.05 was considered to indicate statistical significance, and 95 percent confidence
intervals are provided when relevant.
Results
Demographic Characteristics
Between April 1, 1963, and March 31, 2002, 1634 children and adolescents under 20 years of age commenced renal-
replacement therapy in Australia or New Zealand (Table 1). Of these patients, 917 were boys (56 percent). A total
of 18,392 person-years of follow-up were available. Of these, 4072 person-years took place during hemodialysis
treatment (including 1435 person-years, or 35 percent, in the form of hemodialysis at home), 1633 person-years of
peritoneal dialysis (including 1473 person-years, or 90 percent, in the form of of peritoneal dialysis at home),
and 12,686 person-years with a functioning renal transplant. Data on 32 children (2 percent) were censored as of
the date of the last follow-up visit, owing to loss to follow-up (primarily as a result of relocation overseas).
The median period of follow-up was 9.7 years (range, 1 month to 35 years; interquartile range, 4.1 to 17.6 years).
Table 1. Number of Children Treated for End-Stage Renal Disease in Australia and New Zealand in the Period from
1963 to 2002, According to Age and Decade of Initial Treatment.
The number of children over five years of age when renal-replacement therapy is initiated has been constant since
the mid-1980s, but the number under five years of age at the start of therapy has increased. Reported causes of
end-stage renal disease were consistent with those in other studies and varied with age. Congenital problems
predominated among younger children, and reflux nephropathy and glomerulonephritis among older children. Twenty-six
percent of children who were younger than 5 years of age when renal-replacement therapy commenced had renal
hypoplasia and dysplasia, as compared with 5 percent of those who were 10 to 19 years of age when the therapy was
initiated. In children younger than five years of age at the initiation of renal-replacement therapy, only 11
percent had glomerulonephritis and 3 percent had reflux nephropathy. In contrast, 44 percent of children 10 to 19
years of age had glomerulonephritis and 25 percent had reflux nephropathy.
Mode of Treatment
Among the 1634 children, 1398 (86 percent) received 1 or more renal transplants (of 1939 transplantations, 136 were
of grafts that were transplanted into patients who had not previously received dialysis treatment, or preemptive
grafts, and 3 were performed outside Australia or New Zealand). Overall, the median waiting time from the
initiation of renal-replacement therapy among the 515 children whose first allograft was from a living donor was
137 days (interquartile range, 10 to 382), and the median waiting time was 402 days (interquartile range, 192 to
785) among those whose first graft was a cadaveric allograft. The proportion of allografts from living donors has
steadily increased over time — from 5 percent to 21 percent, 35 percent, and 64 percent among children commencing
renal-replacement therapy in the decades 1963 to 1972, 1973 to 1982, 1983 to 1992, and 1993 to 2002, respectively.
Median times from the initiation of renal-replacement therapy to the first transplantation among patients who
received dialysis for a period were 161, 334, 324, and 296 days among children who commenced renal-replacement
therapy in the decades 1963 to 1972, 1973 to 1982, 1983 to 1992, and 1993 to 2002, respectively. Monoclonal- or
polyclonal-antibody therapy for prophylaxis against rejection was used after transplantation of 319 allografts (16
percent).
The proportion of children receiving renal transplantation as renal-replacement therapy has remained steady over
time. More older children tended to be treated with dialysis than with renal transplantation. Among children in our
study, the median duration of hemodialysis was 1.7 years (interquartile range, 0.5 to 4.3), that of peritoneal
dialysis 1.1 years (interquartile range, 0.4 to 2.5), and that of a functioning transplant 7.4 years (interquartile
range, 2.7 to 14.3).
Overall Survival and Causes of Death
During the study period there were 436 deaths: 142 deaths occurred in patients with a functioning renal transplant,
97 in patients who were receiving peritoneal dialysis, and 197 in patients who were receiving hemodialysis. The
most common cause of death was cardiovascular disease (45 percent), and the second most common cause was infection
(21 percent). Of the deaths due to cardiovascular causes, 25 percent were attributed to cardiac arrest (cause
uncertain), 16 percent to cerebrovascular accident, 14 percent to myocardial ischemia, 12 percent to pulmonary
edema, 11 percent to hyperkalemia, and 22 percent to other cardiovascular causes.
The cause of death varied with the type of renal-replacement therapy — cardiovascular causes accounted for 57
percent of deaths among children receiving hemodialysis, 43 percent among those receiving peritoneal dialysis, and
only 30 percent among those with a functioning renal transplant. In contrast, malignant diseases were responsible
for 14 percent of deaths among children who had a functioning transplant, but only 1 percent of deaths among
patients receiving hemodialysis and 2 percent among those receiving peritoneal dialysis. Death from malignant
disease generally occurred late, accounting for only 1 percent of deaths in the first four years after renal-
replacement therapy was initiated and 2 percent five to nine years after the start of renal-replacement therapy. In
contrast, malignant disease accounted for 13 percent of deaths that occurred 10 to 14 years after the start of
renal-replacement therapy and 17 percent of deaths 15 or more years after its start.
The proportion of deaths attributed to infection has declined over time, from 39 percent (12 of 31 deaths) between
1963 and 1972 to 16 percent (26 of 163) between 1993 and 2002. Across age groups, cardiovascular death accounted
for 20 percent of deaths (2 of 10) among children younger than 1 year of age at the start of renal-replacement
therapy, 24 percent (6 of 25) among those 1 to 4 years of age at its start, but 47 percent among those 5 to 9 years
of age at the start of renal-replacement therapy (23 of 49), 44 percent among those 10 to 14 years of age at its
start (48 of 110), and 48 percent among those 15 to 19 years of age at its start (117 of 242).
Rates of survival after 5, 10, 15, and 20 years of renal-replacement therapy are shown in Table 2. Contemporary
Australian population data indicate that the expected 20-year survival among children is greater than 97 percent at
all ages11; however, for this cohort with end-stage renal disease, mortality greatly exceeded the population rates
in all age groups (Table 3).
Table 2. Unadjusted Long-Term Survival among Children with End-Stage Renal Disease in Australia and New Zealand,
According to Age at the Start of Renal-Replacement Therapy.
Table 3. Age-Specific Rate Ratios for Death within 10 Years among Children Who Started Renal-Replacement Therapy
in Australia in the Period from 1963 to 2002, as Compared with Age-Specific Mortality among the General Australian
Population.
Rates of long-term survival among infants as compared with older children with end-stage renal disease appear
worse, particularly in the first five years after the initiation of renal-replacement therapy (Table 2). After a
substantial improvement in survival occurred in most age groups in the years from 1963 to 1973, and further
improvement from 1973 to 1983, less change occurred from 1983 onward (Figure 1). In data categorized by calendar
year, the death rates were 11.0 (95 percent confidence interval, 7.9 to 15.4) per 100 patient-years between 1963
and 1972, 4.4 (95 percent confidence interval, 3.7 to 5.3) per 100 patient-years between 1973 and 1982, 2.0 (95
percent confidence interval, 1.7 to 2.4) per 100 patient-years between 1983 and 1992, and 1.8 (95 percent
confidence interval, 1.5 to 2.1) per 100 patient-years since 1993.
Figure 1. Kaplan–Meier Graphs of Overall Rates of Survival among Children and Adolescents with End-Stage Renal
Disease in Australia and New Zealand from 1963 to 2002, According to Age and Decade during Which Treatment Began.
The number of patients at risk at each time point is shown below each graph. Dashes indicate that follow-up data
are not yet available.
Rates of survival also varied with the type of renal-replacement therapy. Overall mortality rates were 4.8 (95
percent confidence interval, 4.2 to 5.6) per 100 patient-years among patients receiving hemodialysis, 5.9 (95
percent confidence interval, 4.9 to 7.2) per 100 patient-years among those receiving peritoneal dialysis, and 1.1
(95 percent confidence interval, 0.9 to 1.3) per 100 patient-years among those with a functioning renal transplant.
Multivariate analysis suggested that a younger age at the start of renal-replacement therapy, receiving dialysis
rather than renal transplantation, and commencing renal-replacement therapy before 1983 were associated with an
increased risk of death. There was a weak interaction between transplantation and the decade in which renal-
replacement therapy was started (P=0.07), but the benefit associated with transplantation at all times was similar
(Figure 2).
Figure 2. Hazard Ratios for Death among Children and Adolescents with End-Stage Renal Disease in Australia and
New Zealand, According to Selected Predictive Variables.
Hazard ratios were derived in a multivariate Cox proportional-hazards model. The asterisks indicate the reference
categories. Horizontal bars indicate 95 percent confidence intervals.
Delay before Transplantation
Delay in kidney transplantation as a potential risk factor for early death was analyzed by comparing mortality
among groups with different lengths of time until transplantation. To account for survival bias, delay as a
predictor of early death was analyzed beginning two years after the initiation of renal-replacement therapy. There
was no significant difference in mortality observed among those who survived to two years among groups with
different lengths of time until transplantation (Figure 3).
Figure 3. Kaplan–Meier Graph of Survival Rates among Children and Adolescents in Australia and New Zealand Who
Survived at Least Two Years after the Start of Renal-Replacement Therapy, According to the Length of Time to
Transplantation.
The numbers at the bottom are patients at risk grouped by period of dialysis treatment before transplantation. P
values are for the comparison with patients who underwent transplantation within 12 months after renal-replacement
therapy was started. Preemptive transplantation refers to renal transplantation in patients who had not previously
received peritoneal dialysis or hemodialysis.
Discussion
Our data indicate that a substantial improvement in the long-term survival of children and adolescents with end-
stage renal disease occurred over the past 40 years. The experimental nature of the use of dialysis and
transplantation among children during the decade from 1963 to 1972 provides a partial explanation, given that the
improvement in mortality subsequently slowed. Ten-year survival remains about 80 percent, and age-specific
mortality is about 30 times as high as among children without end-stage renal disease.
These mortality rates are similar to those reported in a U.S. study for the period from 1990 to 199612 but are
slightly higher than those reported in a Dutch study of a smaller cohort13 that did not include adolescents. The
distribution of primary renal disease and the mortality rates among patients receiving dialysis in our study are
similar to those in recent reports from the North American Pediatric Renal Transplant Collaborative Study
(NAPRTCS), in which the duration of follow-up was shorter for a cohort of pediatric dialysis patients.6 The causes
of death reflect the excess risk of cardiac disease and vascular disease and the high prevalence of left
ventricular hypertrophy and dyslipidemia among children treated with renal-replacement therapy.14,15,16 The number
of deaths from cardiovascular disease among the patients who received dialysis in our study was higher than that
reported by the U.S. Renal Data System (37 percent)17 and by the NAPRTCS (21 percent).18 Detailed comparisons,
however, are hindered by the different coding systems used in the various studies, especially the different
definitions of diagnoses coded "unknown" and "other."
The trend toward improvement in the rates of survival among patients in our study has also been observed since 1987
among patients in the NAPRTCS Registry who have undergone renal transplantation.18 The 2003 NAPRTCS report18 noted
that the overall rate of survival to 36 months was 96.6 percent among recipients of kidney transplants from living
donors and 94.8 percent among those receiving cadaveric kidneys — values similar to the 1.1 percent annual
mortality rate we observed among transplant recipients. The strengths of our study — the large number of children
in the study, prospective data collection, the availability of accurate data on the type of renal-replacement
therapy, and the long duration of follow-up with minimal loss to follow-up — enabled us to provide valid and
reasonably precise estimates of long-term survival and to identify modifiable and unmodifiable risk factors for
death.
The year in which renal-replacement therapy was initiated, the age of patients at the start of renal-replacement
therapy, and the type of dialysis used were associated with the risk of death. Our data suggest that the older a
child is when renal-replacement therapy is required, the better his or her chances for long-term survival. This
improved survival may be due to the less aggressive nature of the underlying renal disease process, to the fact
that associated coexisting conditions are more likely to occur in infants and young children, or to the greater
technical challenges of delivering renal-replacement therapy to young and small children.
Perhaps more important is our finding that dialysis is associated with a risk of death that is four times the risk
associated with renal transplantation. The improvement in survival after renal transplantation is substantial and
sustained. This finding is consistent with the relative survival advantage among adults who have undergone
transplantation, as shown in studies conducted in Australia and New Zealand19 and in the United States.20 The
proportion of children with end-stage renal disease who are treated with transplantation can be increased by
increasing the number of kidneys available for transplantation (that is, by increasing rates of donation from
living donors or by preferentially allocating cadaveric kidneys to children) and by means of improvements in the
preservation of the renal function of allografts. These interventions are being attempted widely, with some
variation among and within countries. Others have shown a survival advantage in the short term among children who
receive "preemptive" transplants from living donors before the need for dialysis arises.5
We did not find that a longer period of dialysis before transplantation was detrimental to survival after
transplantation. However, there was limited statistical power in the present study for this comparison. Although we
looked at survival only among children who survived longer than two years after the onset of end-stage renal
disease, some residual survival bias may account for this lack of difference; the ANZDATA Registry does not collect
enough details about coexisting conditions for us to adjust fully for this potential effect. Nevertheless, patients
who have a longer wait for renal transplantation will have worse overall outcomes, because they are exposed for a
longer period to the increased risk of death that is associated with dialysis treatment. This fact is a clear
incentive to increase the rates of transplantation among children with end-stage renal disease.
There was a low rate of loss to follow-up in the cohort. Informally, the ANZDATA Registry data are believed to be
accurate: information is checked against available data from tissue-typing and organ-donation sources, but formal
audit mechanisms were not in place during the period we studied. Data on deaths were not checked against death
certificates; a previous study that matched the registry's data on deaths with national death-certificate reports21
has confirmed that mortality (though not necessarily cause) was accurately ascertained.
The current study has weaknesses. The ANZDATA Registry does not record details of patients with end-stage renal
disease who are not treated, and treatment thresholds have clearly been lowered over time, particularly among
children. These changing thresholds are likely to be reflected in both referral and selection biases — that is,
sicker children were less likely to be referred for renal-replacement therapy and, after they are referred, are
less likely to be offered such treatment. These biases would lead to the underestimation of improvements in outcome
over time, with an increasing tendency toward treating sicker children. Attitudes among nephrologists toward
offering renal-replacement therapy to very young children vary considerably.22 Although the qualifications of
treating physicians are not specifically collected by the registry, patients under 20 years of age in Australia and
New Zealand are treated almost exclusively by pediatric nephrologists in specialist pediatric centers. Other
information about details of treatment in the registry are limited. Data on hemoglobin concentrations and the use
of erythropoietic agents have been collected only since 2000, and data on lipid levels and blood pressure are not
collected. The use of growth hormone has been sparse; approximately one third of children in Australia and less
than 10 percent in New Zealand have received growth hormone.1
Any misclassifications of data with regard to exposure or outcome are likely to be nondifferential with respect to
study periods and types of treatment; thus, our findings regarding associations between the type of treatment and
outcomes are conservative. The time-dependent covariates used in our model result in the attribution of death to
the type of renal-replacement therapy in use immediately before death. This method may result in an overestimation
of the benefit of transplantation, since deaths that occurred among patients receiving dialysis but that were
related to the recent failure of a renal transplant were attributed to the use of dialysis. Another obvious source
of bias in the comparison of outcomes between dialysis and transplantation is the selection of the healthier
patients to undergo transplantation, although the high proportion of patients in our study cohort who received a
renal transplant suggests this effect is relatively minor.
Our data indicate that long-term survival can be expected for most children with end-stage renal disease.
Transplantation remains the major modifiable factor in improving the long-term survival of children and adults with
this disease. Early transplantation appears indicated to prevent exposure to the increased risks associated with
dialysis therapy. Yet mortality rates among children who undergo transplantation remain in excess of those in the
normal population. The challenge ahead is to reduce the incidence of the cardiovascular and malignant diseases that
account for the bulk of long-term mortality among children with end-stage renal disease.
Supported by the Australian Government Department of Health and Ageing, the New Zealand Department of Health, and
Kidney Health Australia (formerly the Australian Kidney Foundation).
Dr. McDonald reports having received lecture fees from Amgen Australia and Janssen-Cilag Australia; he is employed
by ANZDATA, and although he receives no direct industrial support, part of his salary is funded by a grant from
Amgen Australia to the ANZDATA Registry, which also receives grant support from Janssen-Cilag Australia, Novartis,
Wyeth Australia, and Fresenius. Dr. Craig reports having received grants from Janssen-Cilag Australia, Novartis,
Amgen Australia, Wyeth Australia, and Fresenius.
We are indebted to the staff of all Australian and New Zealand renal units for their efforts in data collection
(the ANZDATA Registry exists because of their dedicated efforts), and to Steven Morrell of the School of Public
Health at the University of Sydney for help with the age-specific mortality rates.
Source Information
From the Australia and New Zealand Dialysis and Transplant (ANZDATA) Registry, Queen Elizabeth Hospital, Adelaide,
Australia (S.P.M.); and the Centre for Kidney Research and the National Health and Medical Research Council Centre
for Clinical Research Excellence in Renal Medicine, Children's Hospital at Westmead, and the School of Public
Health, University of Sydney — all in Sydney (J.C.C.).
Address reprint requests to Dr. McDonald at the ANZDATA Registry, Queen Elizabeth Hospital, 28 Woodville Rd.,
Woodville South SA 5011, Australia, or at stephenm@anzdata.org.au.
References
Walker RG. Paediatric report. In: Disney APS, ed. The twenty-second report: Australia and New Zealand Dialysis and
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Henning P, Tomlinson L, Rigden SP, Haycock GB, Chantler C. Long term outcome of treatment of end stage renal
failure. Arch Dis Child 1988;63:35-40.
Ehrich JH, Rizzoni G, Brunner FP, et al. Renal replacement therapy for end-stage renal failure before 2 years of
age. Nephrol Dial Transplant 1992;7:1171-1177.
Wood EG, Hand M, Briscoe DM, et al. Risk factors for mortality in infants and young children on dialysis. Am J
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North American children: a NAPRTCS study. Transplantation 2000;69:1414-1419.
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in infants. J Pediatr 2000;136:24-29.
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Background Although renal-replacement therapy for children with end-stage renal disease has been used for several
decades, data on patients' long-term survival are sparse.
Methods We examined the long-term survival of all children and adolescents who were under 20 years of age when
renal-replacement therapy commenced (study period, April 1963 through March 2002), using data from the Australia
and New Zealand Dialysis and Transplant Registry. Survival was analyzed with the use of Kaplan–Meier methods and
age-standardized mortality rates. Risk factors for death were analyzed with the use of Cox regression analysis with
time-dependent covariates.
Results A total of 1634 children and adolescents were followed for a median of 9.7 years. The long-term survival
rate among children requiring renal-replacement therapy was 79 percent at 10 years and 66 percent at 20 years.
Mortality rates were 30 times as high as for children without end-stage renal disease. Risk factors for death were
a young age at the time renal-replacement therapy was initiated (especially for children under 1 year of age, among
whom the risk was four times as high as for children 15 to 19 years of age) and treatment with dialysis (which was
associated with a risk more than four times as high as for renal transplantation). Overall, a trend toward improved
survival was observed over the four decades of the study.
Conclusions Despite improvement in long-term survival, mortality rates among children requiring renal-replacement
therapy remain substantially higher than those among children without end-stage renal disease. Increasing the
proportion of children treated with renal transplantation rather than with dialysis can improve survival further.
End-stage renal disease, which is a rare but important health problem among children, occurs in about 5 to 10
children per million each year.1 The disease is a chronic condition; even renal transplantation does not mean
lifelong cure. Quality-of-life studies have shown that life without native kidney function is very difficult for
children and their families.2
Forty years ago, children with end-stage renal disease died. Now, almost all such children are treated with
dialysis or renal transplantation. Treatment typically involves multiple therapies, depending upon the availability
of kidneys for transplantation and the long-term survival of the transplants. Long-term survival rates among
children with end-stage renal disease are uncertain, and there are few data to inform patients, families,
clinicians, and policymakers about survival. The available studies are generally short-term,3,4,5,6 are based on
single-center experiences,7 and include only information with regard to patients receiving dialysis, patients
undergoing transplantation, or patients in specific age groups.8
The Australia and New Zealand Dialysis and Transplant (ANZDATA) Registry has prospectively collected data on all
children in whom renal-replacement therapy was started in Australia or New Zealand beginning in 1963. Using data
from this registry, we examined long-term survival among children treated for end-stage renal disease and
identified modifiable and unmodifiable risk factors for death.
Methods
Study Design
We performed a prospective inception-cohort study from the time renal-replacement therapy was initiated for all
children and adolescents younger than 20 years of age in Australia and New Zealand who were registered in the
ANZDATA Registry. The registry collects information every six months from all the renal units in Australia and New
Zealand about all patients receiving renal-replacement therapy who have a diagnosis of chronic renal failure and
for whom indefinite renal-replacement therapy is intended. Details regarding the registry have been reported
elsewhere.9
The data collection is complete from the first use of renal-replacement therapy in Australia and New Zealand and
includes information on the cause of end-stage renal disease, demographic characteristics of the patients, a
limited range of coexisting conditions (which since 1991 have included coronary artery disease, peripheral vascular
disease, cerebrovascular disease, chronic lung disease, hypertension, and smoking), and details of dialysis
treatment and renal transplantation. Nephrologists are asked to provide a cause of death for children who have
died, but death certificates are not directly reviewed by the ANZDATA Registry.
The consent and privacy provisions of the ANZDATA Registry have evolved over time and currently require informed
consent from patients or a parent or legal guardian and include a right of access to personal information.9 The
registry is conducted in accordance with the Australian Commonwealth Privacy Act and associated state legislation
governing health data collection. The anonymity of patient information is maintained by the coding of data during
compilation; only information with personal identifiers removed is released by the registry.
All patients who were younger than 20 years of age when renal-replacement therapy commenced and whose first
treatment occurred before April 1, 2002, were included in our analysis. Patients were followed until death or until
March 31, 2002, whichever occurred first. Children who regained native renal function permanently despite their
initial assessment were excluded; data on those lost to follow-up were censored as of the date of the last follow-
up visit. The sole outcome examined was death, ascertained with the use of the registry data.
Statistical Analysis
The time from the start of renal-replacement therapy to death or the date on which the data were censored was
analyzed with the use of the Kaplan–Meier method and Cox proportional-hazards models. Standardized mortality rate
ratios and age-specific mortality rate ratios were calculated for Australian children only, with the use of
contemporary life-expectancy values derived from life tables of the Australian Bureau of Statistics.
A multivariate Cox proportional-hazards model was constructed with age, sex, the decade in which renal-replacement
therapy was initiated, primary renal disease, and type of dialysis (hemodialysis or peritoneal dialysis) as
predictive variables. A categorical, time-dependent covariate was used for the type of renal-replacement therapy
(hemodialysis, peritoneal dialysis, or transplantation) to allow for changes in type of therapy over time. Age and
the year in which renal-replacement therapy was started were considered as categories in order to avoid the
assumption of linear relationships with outcome. Age was analyzed in five-year categories, except for children
younger than one year of age, who were considered as a separate group because they have a worse prognosis.3,4,6,10
Inclusion in the final model was determined by a backward stepwise process with the use of the likelihood ratio to
evaluate the effect of omitting variables. Stata statistical software (version 7.0, Stata) was used for the
analysis; a P value of 0.05 was considered to indicate statistical significance, and 95 percent confidence
intervals are provided when relevant.
Results
Demographic Characteristics
Between April 1, 1963, and March 31, 2002, 1634 children and adolescents under 20 years of age commenced renal-
replacement therapy in Australia or New Zealand (Table 1). Of these patients, 917 were boys (56 percent). A total
of 18,392 person-years of follow-up were available. Of these, 4072 person-years took place during hemodialysis
treatment (including 1435 person-years, or 35 percent, in the form of hemodialysis at home), 1633 person-years of
peritoneal dialysis (including 1473 person-years, or 90 percent, in the form of of peritoneal dialysis at home),
and 12,686 person-years with a functioning renal transplant. Data on 32 children (2 percent) were censored as of
the date of the last follow-up visit, owing to loss to follow-up (primarily as a result of relocation overseas).
The median period of follow-up was 9.7 years (range, 1 month to 35 years; interquartile range, 4.1 to 17.6 years).
Table 1. Number of Children Treated for End-Stage Renal Disease in Australia and New Zealand in the Period from
1963 to 2002, According to Age and Decade of Initial Treatment.
The number of children over five years of age when renal-replacement therapy is initiated has been constant since
the mid-1980s, but the number under five years of age at the start of therapy has increased. Reported causes of
end-stage renal disease were consistent with those in other studies and varied with age. Congenital problems
predominated among younger children, and reflux nephropathy and glomerulonephritis among older children. Twenty-six
percent of children who were younger than 5 years of age when renal-replacement therapy commenced had renal
hypoplasia and dysplasia, as compared with 5 percent of those who were 10 to 19 years of age when the therapy was
initiated. In children younger than five years of age at the initiation of renal-replacement therapy, only 11
percent had glomerulonephritis and 3 percent had reflux nephropathy. In contrast, 44 percent of children 10 to 19
years of age had glomerulonephritis and 25 percent had reflux nephropathy.
Mode of Treatment
Among the 1634 children, 1398 (86 percent) received 1 or more renal transplants (of 1939 transplantations, 136 were
of grafts that were transplanted into patients who had not previously received dialysis treatment, or preemptive
grafts, and 3 were performed outside Australia or New Zealand). Overall, the median waiting time from the
initiation of renal-replacement therapy among the 515 children whose first allograft was from a living donor was
137 days (interquartile range, 10 to 382), and the median waiting time was 402 days (interquartile range, 192 to
785) among those whose first graft was a cadaveric allograft. The proportion of allografts from living donors has
steadily increased over time — from 5 percent to 21 percent, 35 percent, and 64 percent among children commencing
renal-replacement therapy in the decades 1963 to 1972, 1973 to 1982, 1983 to 1992, and 1993 to 2002, respectively.
Median times from the initiation of renal-replacement therapy to the first transplantation among patients who
received dialysis for a period were 161, 334, 324, and 296 days among children who commenced renal-replacement
therapy in the decades 1963 to 1972, 1973 to 1982, 1983 to 1992, and 1993 to 2002, respectively. Monoclonal- or
polyclonal-antibody therapy for prophylaxis against rejection was used after transplantation of 319 allografts (16
percent).
The proportion of children receiving renal transplantation as renal-replacement therapy has remained steady over
time. More older children tended to be treated with dialysis than with renal transplantation. Among children in our
study, the median duration of hemodialysis was 1.7 years (interquartile range, 0.5 to 4.3), that of peritoneal
dialysis 1.1 years (interquartile range, 0.4 to 2.5), and that of a functioning transplant 7.4 years (interquartile
range, 2.7 to 14.3).
Overall Survival and Causes of Death
During the study period there were 436 deaths: 142 deaths occurred in patients with a functioning renal transplant,
97 in patients who were receiving peritoneal dialysis, and 197 in patients who were receiving hemodialysis. The
most common cause of death was cardiovascular disease (45 percent), and the second most common cause was infection
(21 percent). Of the deaths due to cardiovascular causes, 25 percent were attributed to cardiac arrest (cause
uncertain), 16 percent to cerebrovascular accident, 14 percent to myocardial ischemia, 12 percent to pulmonary
edema, 11 percent to hyperkalemia, and 22 percent to other cardiovascular causes.
The cause of death varied with the type of renal-replacement therapy — cardiovascular causes accounted for 57
percent of deaths among children receiving hemodialysis, 43 percent among those receiving peritoneal dialysis, and
only 30 percent among those with a functioning renal transplant. In contrast, malignant diseases were responsible
for 14 percent of deaths among children who had a functioning transplant, but only 1 percent of deaths among
patients receiving hemodialysis and 2 percent among those receiving peritoneal dialysis. Death from malignant
disease generally occurred late, accounting for only 1 percent of deaths in the first four years after renal-
replacement therapy was initiated and 2 percent five to nine years after the start of renal-replacement therapy. In
contrast, malignant disease accounted for 13 percent of deaths that occurred 10 to 14 years after the start of
renal-replacement therapy and 17 percent of deaths 15 or more years after its start.
The proportion of deaths attributed to infection has declined over time, from 39 percent (12 of 31 deaths) between
1963 and 1972 to 16 percent (26 of 163) between 1993 and 2002. Across age groups, cardiovascular death accounted
for 20 percent of deaths (2 of 10) among children younger than 1 year of age at the start of renal-replacement
therapy, 24 percent (6 of 25) among those 1 to 4 years of age at its start, but 47 percent among those 5 to 9 years
of age at the start of renal-replacement therapy (23 of 49), 44 percent among those 10 to 14 years of age at its
start (48 of 110), and 48 percent among those 15 to 19 years of age at its start (117 of 242).
Rates of survival after 5, 10, 15, and 20 years of renal-replacement therapy are shown in Table 2. Contemporary
Australian population data indicate that the expected 20-year survival among children is greater than 97 percent at
all ages11; however, for this cohort with end-stage renal disease, mortality greatly exceeded the population rates
in all age groups (Table 3).
Table 2. Unadjusted Long-Term Survival among Children with End-Stage Renal Disease in Australia and New Zealand,
According to Age at the Start of Renal-Replacement Therapy.
Table 3. Age-Specific Rate Ratios for Death within 10 Years among Children Who Started Renal-Replacement Therapy
in Australia in the Period from 1963 to 2002, as Compared with Age-Specific Mortality among the General Australian
Population.
Rates of long-term survival among infants as compared with older children with end-stage renal disease appear
worse, particularly in the first five years after the initiation of renal-replacement therapy (Table 2). After a
substantial improvement in survival occurred in most age groups in the years from 1963 to 1973, and further
improvement from 1973 to 1983, less change occurred from 1983 onward (Figure 1). In data categorized by calendar
year, the death rates were 11.0 (95 percent confidence interval, 7.9 to 15.4) per 100 patient-years between 1963
and 1972, 4.4 (95 percent confidence interval, 3.7 to 5.3) per 100 patient-years between 1973 and 1982, 2.0 (95
percent confidence interval, 1.7 to 2.4) per 100 patient-years between 1983 and 1992, and 1.8 (95 percent
confidence interval, 1.5 to 2.1) per 100 patient-years since 1993.
Figure 1. Kaplan–Meier Graphs of Overall Rates of Survival among Children and Adolescents with End-Stage Renal
Disease in Australia and New Zealand from 1963 to 2002, According to Age and Decade during Which Treatment Began.
The number of patients at risk at each time point is shown below each graph. Dashes indicate that follow-up data
are not yet available.
Rates of survival also varied with the type of renal-replacement therapy. Overall mortality rates were 4.8 (95
percent confidence interval, 4.2 to 5.6) per 100 patient-years among patients receiving hemodialysis, 5.9 (95
percent confidence interval, 4.9 to 7.2) per 100 patient-years among those receiving peritoneal dialysis, and 1.1
(95 percent confidence interval, 0.9 to 1.3) per 100 patient-years among those with a functioning renal transplant.
Multivariate analysis suggested that a younger age at the start of renal-replacement therapy, receiving dialysis
rather than renal transplantation, and commencing renal-replacement therapy before 1983 were associated with an
increased risk of death. There was a weak interaction between transplantation and the decade in which renal-
replacement therapy was started (P=0.07), but the benefit associated with transplantation at all times was similar
(Figure 2).
Figure 2. Hazard Ratios for Death among Children and Adolescents with End-Stage Renal Disease in Australia and
New Zealand, According to Selected Predictive Variables.
Hazard ratios were derived in a multivariate Cox proportional-hazards model. The asterisks indicate the reference
categories. Horizontal bars indicate 95 percent confidence intervals.
Delay before Transplantation
Delay in kidney transplantation as a potential risk factor for early death was analyzed by comparing mortality
among groups with different lengths of time until transplantation. To account for survival bias, delay as a
predictor of early death was analyzed beginning two years after the initiation of renal-replacement therapy. There
was no significant difference in mortality observed among those who survived to two years among groups with
different lengths of time until transplantation (Figure 3).
Figure 3. Kaplan–Meier Graph of Survival Rates among Children and Adolescents in Australia and New Zealand Who
Survived at Least Two Years after the Start of Renal-Replacement Therapy, According to the Length of Time to
Transplantation.
The numbers at the bottom are patients at risk grouped by period of dialysis treatment before transplantation. P
values are for the comparison with patients who underwent transplantation within 12 months after renal-replacement
therapy was started. Preemptive transplantation refers to renal transplantation in patients who had not previously
received peritoneal dialysis or hemodialysis.
Discussion
Our data indicate that a substantial improvement in the long-term survival of children and adolescents with end-
stage renal disease occurred over the past 40 years. The experimental nature of the use of dialysis and
transplantation among children during the decade from 1963 to 1972 provides a partial explanation, given that the
improvement in mortality subsequently slowed. Ten-year survival remains about 80 percent, and age-specific
mortality is about 30 times as high as among children without end-stage renal disease.
These mortality rates are similar to those reported in a U.S. study for the period from 1990 to 199612 but are
slightly higher than those reported in a Dutch study of a smaller cohort13 that did not include adolescents. The
distribution of primary renal disease and the mortality rates among patients receiving dialysis in our study are
similar to those in recent reports from the North American Pediatric Renal Transplant Collaborative Study
(NAPRTCS), in which the duration of follow-up was shorter for a cohort of pediatric dialysis patients.6 The causes
of death reflect the excess risk of cardiac disease and vascular disease and the high prevalence of left
ventricular hypertrophy and dyslipidemia among children treated with renal-replacement therapy.14,15,16 The number
of deaths from cardiovascular disease among the patients who received dialysis in our study was higher than that
reported by the U.S. Renal Data System (37 percent)17 and by the NAPRTCS (21 percent).18 Detailed comparisons,
however, are hindered by the different coding systems used in the various studies, especially the different
definitions of diagnoses coded "unknown" and "other."
The trend toward improvement in the rates of survival among patients in our study has also been observed since 1987
among patients in the NAPRTCS Registry who have undergone renal transplantation.18 The 2003 NAPRTCS report18 noted
that the overall rate of survival to 36 months was 96.6 percent among recipients of kidney transplants from living
donors and 94.8 percent among those receiving cadaveric kidneys — values similar to the 1.1 percent annual
mortality rate we observed among transplant recipients. The strengths of our study — the large number of children
in the study, prospective data collection, the availability of accurate data on the type of renal-replacement
therapy, and the long duration of follow-up with minimal loss to follow-up — enabled us to provide valid and
reasonably precise estimates of long-term survival and to identify modifiable and unmodifiable risk factors for
death.
The year in which renal-replacement therapy was initiated, the age of patients at the start of renal-replacement
therapy, and the type of dialysis used were associated with the risk of death. Our data suggest that the older a
child is when renal-replacement therapy is required, the better his or her chances for long-term survival. This
improved survival may be due to the less aggressive nature of the underlying renal disease process, to the fact
that associated coexisting conditions are more likely to occur in infants and young children, or to the greater
technical challenges of delivering renal-replacement therapy to young and small children.
Perhaps more important is our finding that dialysis is associated with a risk of death that is four times the risk
associated with renal transplantation. The improvement in survival after renal transplantation is substantial and
sustained. This finding is consistent with the relative survival advantage among adults who have undergone
transplantation, as shown in studies conducted in Australia and New Zealand19 and in the United States.20 The
proportion of children with end-stage renal disease who are treated with transplantation can be increased by
increasing the number of kidneys available for transplantation (that is, by increasing rates of donation from
living donors or by preferentially allocating cadaveric kidneys to children) and by means of improvements in the
preservation of the renal function of allografts. These interventions are being attempted widely, with some
variation among and within countries. Others have shown a survival advantage in the short term among children who
receive "preemptive" transplants from living donors before the need for dialysis arises.5
We did not find that a longer period of dialysis before transplantation was detrimental to survival after
transplantation. However, there was limited statistical power in the present study for this comparison. Although we
looked at survival only among children who survived longer than two years after the onset of end-stage renal
disease, some residual survival bias may account for this lack of difference; the ANZDATA Registry does not collect
enough details about coexisting conditions for us to adjust fully for this potential effect. Nevertheless, patients
who have a longer wait for renal transplantation will have worse overall outcomes, because they are exposed for a
longer period to the increased risk of death that is associated with dialysis treatment. This fact is a clear
incentive to increase the rates of transplantation among children with end-stage renal disease.
There was a low rate of loss to follow-up in the cohort. Informally, the ANZDATA Registry data are believed to be
accurate: information is checked against available data from tissue-typing and organ-donation sources, but formal
audit mechanisms were not in place during the period we studied. Data on deaths were not checked against death
certificates; a previous study that matched the registry's data on deaths with national death-certificate reports21
has confirmed that mortality (though not necessarily cause) was accurately ascertained.
The current study has weaknesses. The ANZDATA Registry does not record details of patients with end-stage renal
disease who are not treated, and treatment thresholds have clearly been lowered over time, particularly among
children. These changing thresholds are likely to be reflected in both referral and selection biases — that is,
sicker children were less likely to be referred for renal-replacement therapy and, after they are referred, are
less likely to be offered such treatment. These biases would lead to the underestimation of improvements in outcome
over time, with an increasing tendency toward treating sicker children. Attitudes among nephrologists toward
offering renal-replacement therapy to very young children vary considerably.22 Although the qualifications of
treating physicians are not specifically collected by the registry, patients under 20 years of age in Australia and
New Zealand are treated almost exclusively by pediatric nephrologists in specialist pediatric centers. Other
information about details of treatment in the registry are limited. Data on hemoglobin concentrations and the use
of erythropoietic agents have been collected only since 2000, and data on lipid levels and blood pressure are not
collected. The use of growth hormone has been sparse; approximately one third of children in Australia and less
than 10 percent in New Zealand have received growth hormone.1
Any misclassifications of data with regard to exposure or outcome are likely to be nondifferential with respect to
study periods and types of treatment; thus, our findings regarding associations between the type of treatment and
outcomes are conservative. The time-dependent covariates used in our model result in the attribution of death to
the type of renal-replacement therapy in use immediately before death. This method may result in an overestimation
of the benefit of transplantation, since deaths that occurred among patients receiving dialysis but that were
related to the recent failure of a renal transplant were attributed to the use of dialysis. Another obvious source
of bias in the comparison of outcomes between dialysis and transplantation is the selection of the healthier
patients to undergo transplantation, although the high proportion of patients in our study cohort who received a
renal transplant suggests this effect is relatively minor.
Our data indicate that long-term survival can be expected for most children with end-stage renal disease.
Transplantation remains the major modifiable factor in improving the long-term survival of children and adults with
this disease. Early transplantation appears indicated to prevent exposure to the increased risks associated with
dialysis therapy. Yet mortality rates among children who undergo transplantation remain in excess of those in the
normal population. The challenge ahead is to reduce the incidence of the cardiovascular and malignant diseases that
account for the bulk of long-term mortality among children with end-stage renal disease.
Supported by the Australian Government Department of Health and Ageing, the New Zealand Department of Health, and
Kidney Health Australia (formerly the Australian Kidney Foundation).
Dr. McDonald reports having received lecture fees from Amgen Australia and Janssen-Cilag Australia; he is employed
by ANZDATA, and although he receives no direct industrial support, part of his salary is funded by a grant from
Amgen Australia to the ANZDATA Registry, which also receives grant support from Janssen-Cilag Australia, Novartis,
Wyeth Australia, and Fresenius. Dr. Craig reports having received grants from Janssen-Cilag Australia, Novartis,
Amgen Australia, Wyeth Australia, and Fresenius.
We are indebted to the staff of all Australian and New Zealand renal units for their efforts in data collection
(the ANZDATA Registry exists because of their dedicated efforts), and to Steven Morrell of the School of Public
Health at the University of Sydney for help with the age-specific mortality rates.
Source Information
From the Australia and New Zealand Dialysis and Transplant (ANZDATA) Registry, Queen Elizabeth Hospital, Adelaide,
Australia (S.P.M.); and the Centre for Kidney Research and the National Health and Medical Research Council Centre
for Clinical Research Excellence in Renal Medicine, Children's Hospital at Westmead, and the School of Public
Health, University of Sydney — all in Sydney (J.C.C.).
Address reprint requests to Dr. McDonald at the ANZDATA Registry, Queen Elizabeth Hospital, 28 Woodville Rd.,
Woodville South SA 5011, Australia, or at stephenm@anzdata.org.au.
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