PEDIATRICS Vol. 119 No. 2 February 2007, pp. e468-e473 (doi:10.1542/peds.2006-1754)
ARTICLE |
Outcomes of Dialysis Initiated During the Neonatal Period for Treatment of End-Stage Renal Disease: A North American Pediatric Renal Trials and Collaborative Studies Special Analysis
a Divisions of Neonatal-Perinatal Medicine
c Pediatric Nephrology, University of California San Francisco Children's Hospital, University of California, San Francisco, California
b EMMES Corporation, Rockville, Maryland
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ABSTRACT |
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 TOP ABSTRACT PATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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OBJECTIVE. We sought to determine the outcomes of initiating long-term dialysis of neonates and children aged >1 to 24 months with end-stage renal disease.
PATIENTS AND METHODS. By querying the North American Pediatric Renal Trials and Collaborative Studies database, we obtained information on 193 neonates (
1 month of age) and 505 children (>1–24 months of age) with a presumptive diagnosis of end-stage renal disease who initiated long-term dialysis. Dialysis characteristics and likelihood of hospitalization were compared using the 
2 test, and duration of hospitalization was compared using the Wilcoxon 2-sample test. Product limit methods were implemented, and the log rank test was used to compare time-to-event analyses. Multivariate analyses were performed using Cox proportional hazards models.
RESULTS. Neonates with end-stage renal disease were more likely to receive peritoneal dialysis versus hemodialysis than older children with end-stage renal disease. Moreover, neonates who initiated dialysis during the first month of life were just as likely to terminate dialysis as were the older children. Rates of renal transplantation were significantly lower in the neonates compared with the older children, but neonates were more likely to recover function of the native kidney. Although neonates were more often hospitalized, their overall risk of mortality was similar to that observed in older children.
CONCLUSIONS. Neonates with a presumptive diagnosis of end-stage renal disease may initiate long-term dialysis during the first month of life with outcomes comparable to those of patients who initiate dialysis later in infancy.
Key Words: neonate • end-stage renal disease • dialysis • renal transplantation • survival
Abbreviations: ESRD—end-stage renal disease • NAPRTCS—North American Pediatric Renal Trials and Collaborative Studies • ARPKD—autosomal recessive polycystic kidney disease • CNS—congenital nephrotic syndrome • CI—confidence interval
End-stage renal disease (ESRD) occurs infrequently during the first month of life, but its implications for the patients and their families are substantial.1,2 Morbidities and mortality related to the disease and its treatment are common,3,4 and the growth and development of surviving infants are often suboptimal.5–7 For families, providing care to a chronically ill child can be overwhelming, in terms of both emotional and capital resources. Thus, the decision to initiate long-term dialysis in neonates with a presumptive diagnosis of ESRD is complex and may present an ethical dilemma for physicians and family members alike.
Although dialysis has been used to treat neonatal renal failure for decades,8 there are limited data regarding the outcomes of initiating long-term dialysis for treatment of ESRD during the first month of life. This lack of information is attributable, in part, to the diverse etiologies of neonatal ESRD and to the small numbers of patients who are available for analysis.9–12 Because of these limitations, the neonatal dialysis experience has been lost in studies that describe the outcomes of infants of a broader age range, often spanning birth to 24 months.1,4,5
This scarcity of published data also may account for the variability of attitudes displayed by those who provide primary and specialty care for neonates with ESRD. In a worldwide survey of pediatric nephrologists, nearly all who responded would offer treatment to some neonates with ESRD, whereas less than half would offer such treatment for all neonates.13 Likewise, many neonatologists consider "unfavorable" the prospect of initiating dialysis as a bridge to renal transplant for their patients, whereas others would be willing to treat their patients through transplantation.14 To provide further insight into this complex issue, we conducted the following study to determine the frequency of key outcomes of initiating long-term dialysis for treatment of presumptive ESRD during the first month of life.
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PATIENTS AND METHODS |
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TOPABSTRACTPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Since January 1, 1992, the North American Pediatric Renal Trials and Collaborative Studies (NAPRTCS) has maintained a voluntary dialysis registry database that includes information on thousands of pediatric patients requiring long-term dialysis.15 For this study, we queried the NAPRTCS database to obtain information about children who initiated long-term dialysis for treatment of ESRD within the first 24 months of life during the calendar years 1992 to 2005. Specifically, we analyzed data regarding patient gender and race, primary renal diagnosis and type of dialysis at the time of initiation, likelihood of and reason for termination of dialysis, time to transplantation, patient mortality, and likelihood and duration of hospitalization.
Primary renal diagnoses were entered in the database as renal a-/hypo-/dysplasia (dysplasia), obstructive uropathy, autosomal recessive polycystic kidney disease (ARPKD), congenital nephrotic syndrome (CNS), and other. Dialysis modalities were characterized as peritoneal dialysis or hemodialysis. The reasons for termination of dialysis included renal transplant, change of dialysis modality, death, recovery of native kidney function, or other (eg, peritonitis, pancreatitis, change of medical center, and family choice).
To describe the outcomes of children with ESRD who initiated long-term dialysis during the neonatal period, patients were categorized on the basis of age as neonates (1 month) or older children (>1–24 months). Patient characteristics, dialysis characteristics, termination characteristics, overall mortality, and hospitalization were compared using the 2 test. Duration of hospitalization was compared using the Wilcoxon 2-sample test. Product limit analyses of termination, time to transplant, and time to death were performed, and data were compared using the log rank test. All of the tests of significance were 2-sided with 
at .05.
To determine whether outcomes had improved over time for neonates with ESRD who initiated dialysis during the first month of life, neonates were subcategorized on the basis of the date on which dialysis was initiated. Specifically, we compared neonates who initiated long-term dialysis during the calendar years 1992–1998 (past) with those who had initiated during the calendar years 1999–2005 (recent).
Plots depicting time to transplant and time to death were created using Kaplan-Meier methods. For analyses involving time to transplant, "time to transplant" was defined as the interval from the date of the first registry-reported initiation of dialysis until the date of transplant. Those patients who were still on the initial dialysis at the last date of contact or those who terminated dialysis for a reason other than transplantation (eg, death) were censored at the last date of contact or at the date of termination or death. For survival analyses, time to death was defined as the interval from the date of the first registry-reported initiation of dialysis until the date of death, irrespective of whether transplantation, modality changes, or recovery of native kidney function had occurred.
Multivariate analyses were performed using Cox proportional hazards models. Confounding factors taken into consideration include: gender, race, primary renal diagnosis, type of dialysis, and center size. To categorize centers based on size, the total number of subjects enrolled in the NAPRTCS registry was computed for each center and then summed. The median value was chosen as the cut point. For analysis purposes, centers that had enrolled >40 patients were categorized as large, whereas those that had enrolled 40 were categorized as small. In all, 98 centers contributed data that were analyzed in this study, each center following the requirements of its local institutional review board for participation in NAPRTCS.
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RESULTS |
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TOPABSTRACTPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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NAPRTCS data were available for 193 patients who initiated long-term dialysis during the first month of life and for 505 patients who initiated between >1 and 24 months of age. Given the mean populations of the United States and Canada during the study period,16,17 NAPRTCS reported an incidence of 0.045 cases of dialysis-treated neonatal ESRD per million population per year. Given the mean number of annual live births in the United States and Canada during the first 12 years of the study period,18,19 NAPRTCS reported an incidence of 0.32 cases per 100000 live births. The gender and race characteristics of the neonates were similar to those of the older children (Table 1). Table 2 details the distribution of primary renal diagnoses and the type of dialysis of each age group. Neonates were more likely to be diagnosed with renal dysplasia or ARPKD, whereas older children were much more likely to suffer from CNS (P < .001). Nearly all of the neonates were treated with peritoneal dialysis (98%), whereas 9% of older children received hemodialysis (P < .001).
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As shown in Table 3, neonates were as likely to terminate dialysis during the study period as were older children (81% vs 83%). However, the reason for terminating dialysis differed significantly between the 2 age groups (P < .001). Neonates were more likely to terminate because of death, and they were less likely to terminate because of transplantation. On the other hand, neonates were more likely to recover native kidney function, and they were less likely to require a change in the type of dialysis. As shown in Fig 1, there also was a significant difference in the time to transplant between the 2 age groups. Over the 5 years after initiation of dialysis, older children were transplanted more quickly than were neonates (P < .001). However, the percentage of neonates receiving transplantation more closely approximated that of the older children within 3 years of the initiation of dialysis. After adjusting for confounding factors, multivariate analysis also revealed that older children have a relative hazard of termination because of transplantation that is 1.55 times that of neonates (95% confidence interval [CI]: 1.19–2.02; Table 4).
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For survival analyses, the median follow-up times were 17.8 months for neonates and 14.6 months for older children. Overall, 46 (24%) of 193 neonates and 100 (20%) of 505 older children expired during the study period (P = .192). Seventeen (9%) neonates died during their initial dialysis course, whereas 26 (15%) died having terminated their initial dialysis course for another reason (eg, transplantation, change of modality, or recovery of native kidney function). As shown in Fig 2, there was no significant difference in time to death between the neonates and older children (P = .401). Furthermore, after adjusting for confounding factors, multivariate analysis revealed no significant difference in time to death between the 2 age groups (hazard ratio: 0.80; 95% CI: 0.56-1.14; Table 4).
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Multivariate analyses also indicated that gender, cohort era, and center size had no influence on the time to termination, time to transplant, or time to death of the patients in this study (Table 4). However, a primary renal diagnosis of either dysplasia or obstruction was significantly associated with a reduction in the relative hazard for time to termination and time to death and tended toward a reduced relative hazard for time to transplant (Table 4).
After the initiation of dialysis, the vast majority of both neonates and older children required hospitalization (80% vs 73%; P = .034). Among those ever hospitalized, neonates had a greater mean number of hospital days than older children (54 vs 39; P < .001).
Data were available for 130 neonates who initiated dialysis during 1992-1998 and for 63 neonates who initiated dialysis during 1999-2005. Overall, neonates in the recent and past cohorts transitioned to renal transplantation at similar rates (Fig 3). However, within 3 years of initiating dialysis, 80% of the recent cohort had undergone transplantation, in contrast to only 60% of the past cohort. Similarly, the recent cohort of neonates tended to have better survival during the 3 years after the initiation of dialysis (P = .111); application of the Wilcoxon 2-sample test indicated that this survival advantage was statistically significant (P = .036; Fig 4).
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DISCUSSION |
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TOPABSTRACTPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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For physicians and parents alike, the decision to initiate long-term dialysis for a neonate with presumptive ESRD poses a complex ethical quandary.1,2 This dilemma derives, at least in part, from the paucity of published reports describing the outcomes of infants who initiate dialysis during the first month of life. Using the NAPRTCS database, the goals of our study were to gain further insight into the outcome of neonates with ESRD and to provide information to physicians and families that would assist in the decision-making process.
The age at which dialysis was initiated had no effect on the likelihood of dialysis termination over time, because the neonates in our study were just as likely to terminate dialysis as were older children. Among those infants who initiated dialysis during the first month of life, 
1 in 8 neonates recovered native kidney function. Furthermore, by 5 years postinitiation, 80% of neonates in this study had transitioned to renal transplantation. These findings indicate that a significant proportion of neonatal dialysis patients will successfully transition off long-term dialysis.
The likelihood of mortality was considerable for all of the children in our study, with 1 in 4 neonates expiring after the initiation of dialysis. However, this overall mortality risk was only marginally higher than that observed in older children, and it did not reach statistical significance. Furthermore, product limit analysis revealed no difference in survival between the 2 age groups, even after adjusting for confounding factors. These data suggest that the long-term survival rates of neonates and older infants with ESRD are similar.
In our study, the majority of infants who initiated long-term dialysis during the first 24 months of life required hospitalization. Only 1 in 5 neonates escaped inpatient treatment after the initiation of dialysis. The duration of hospitalization also was longer for neonates, because they spent 8 weeks in the hospital compared with 6 weeks for older children. Because the likelihood and duration of hospitalization were substantially different between the 2 age groups, these findings indicate that neonates with ESRD (and their families) incur significant human and fiscal costs of long-term dialysis.
When we designed this study, we hypothesized that neonates who initiated long-term dialysis in recent years would have better outcomes than those who initiated dialysis 1 decade ago. Indeed, we found that a greater percentage of neonates in the more recent cohort had transitioned to transplantation within 3 years of initiating dialysis. Furthermore, these same neonates enjoyed better survival in comparison with those treated in the earlier cohort. We speculate that the improvement in outcomes in the more recent cohort is attributable, in part, to the advancement of medical and surgical techniques over time, as well as to the accrual of experience by medical centers that provide care for these infants.
One potential limitation of this study is the difference between the 2 age cohorts in the frequency of each primary renal diagnosis. We found that neonates were more likely to be diagnosed with renal dysplasia or obstructive uropathy, whereas older children were more likely to suffer from CNS. The associated morbidities of these conditions are quite different (ie, respiratory insufficiency versus infection and thrombosis), so each could uniquely impact the likelihood of transplantation and long-term survival. To address this possible confounding factor, we performed multivariate analyses taking into consideration, among other factors, primary renal diagnosis. Although these analyses revealed that dysplasia and obstruction were associated with better survival outcomes, the relative frequency of these primary renal diagnoses were taken into consideration in our comparisons of age group-specific termination and survival outcomes.
Selection bias also may have been introduced into this study by the difference between the 2 age cohorts in the frequency of each primary renal diagnosis. Neonates with renal dysplasia or obstructive uropathy are at risk for associated congenital anomalies, either true malformations or deformations, because of severe oligohydramnios. In such cases, the presence of significant comorbid conditions may preclude long-term dialysis as a bridge to renal transplantation, thus excluding these neonates from the NAPRTCS database. Hence, the findings presented in this report reflect the outcomes of those neonates whose associated anomalies (if any) were judged to be insufficient to preclude long-term dialysis.
The voluntary nature of the NAPRTCS database is another limitation of this study. Although it is reasonable to speculate that some medical centers may report only their successful cases, such bias likely would be applied equally to both age groups in this study. Furthermore, the calculated rate of dialysis-treated neonatal ESRD in our study is very similar to that reported in Britain and Ireland.1 Moreover, the survival data presented in our study closely resemble that reported for young dialysis patients in Australia and New Zealand, countries in which the outcome of every dialysis patient is recorded in a registry biannually.20 Because the NAPRTCS database seems to be in accord with other published studies and registries, we believe that is it a valid tool to describe the outcomes of long-term dialysis initiated during the first month of life in North America.
The fact that NAPRTCS is a volunteer registry also may have limited our ability to determine the effect of center size on termination and survival outcomes. It is conceivable that some of the centers considered small in this study are actually large institutions that care for many infants with ESRD but lack data entry support for the enrollment of patients in the NAPRTCS database. The converse also may have occurred: a truly small center may have been able to register each of its patients with NAPRTCS, thereby leading us to classify this center as large. If 1 assumes a priori that high-volume centers would achieve better outcomes because of their greater experience, the misclassification of center size could have contributed to our finding that termination and survival outcomes did not vary according to center size.
Finally, this is the largest study designed to determine the outcomes of long-term dialysis initiated in the neonatal period. Based on the results of our analyses, we conclude that the initiation of long-term dialysis during the first month of life is an acceptable option for the parents and clinicians who care for these infants. Recent advances in automated peritoneal dialysis have reduced the rates of peritonitis in young infants while reducing the burden of care imposed on their parents.21 In addition, the introduction of comprehensive enteral feeding programs and growth hormone therapy has improved the growth of these infants considerably.22 With these and other improvements in pretransplant care, many young and small infants are successfully surviving to renal transplant with excellent allograft and patient survival.23,24 Further studies are necessary, however, to determine the influence of the primary etiology of ESRD or attendant comorbid conditions on the outcomes of long-term dialysis in this very select population.
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ACKNOWLEDGMENTS |
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We thank the North American Pediatric Renal Trials and Collaborative Studies for supporting this special analysis. This study was also supported as by a grant from the National Institutes of Health (HD-07162).
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FOOTNOTES |
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Accepted Aug 14, 2006.
Address correspondence to William A. Carey, MD, Division of Neonatal-Perinatal Medicine, UCSF Children's Hospital, University of California San Francisco, 3333 California St, Suite 150K, San Francisco, CA 94118-1245. E-mail: william.carey{at}ucsf.edu
The authors have indicated they have no financial relationships relevant to this article to disclose.
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PEDIATRICS (ISSN 1098-4275). ©2007 by the American Academy of Pediatrics
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