The n e w e ng l a n d j o u r na l of m e dic i n e
Original Article
The authors’ affiliations are listed in the
Appendix. Address reprint requests to Dr.
Calderon-Margalit at Hadassah–Hebrew
University Braun School of Public Health,
Hadassah Ein Kerem, Jerusalem, P.O. Box
12272, Jerusalem 9112102, Israel, or at
­ronitcm@​­gmail​.­com or ­ronitc@​­ekmd​.­huji​
.­ac​.­il; or to Dr. Vivante at Pediatric De-
partment B and Pediatric Nephrology Unit,
Edmond and Lily Safra Children’s Hospi-
tal, Sackler Faculty of Medicine,
Sheba
Medical Center, Tel Hashomer, Ramat Gan
5265601, Israel, or at ­asafvivante@​­gmail​
.­com or ­asaf​.­vivante@​­sheba​.­health​.­gov​.­il.
N Engl J Med 2018;378:428-38.
DOI: 10.1056/NEJMoa1700993
Copyright © 2018 Massachusetts Medical Society.
428
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History of Childhood Kidney Disease
and Risk of Adult End-Stage Renal Disease
Ronit Calderon‑Margalit, M.D., M.P.H., Eliezer Golan, M.D., Gilad Twig, M.D., Ph.D.,
Adi Leiba, M.D., Dorit Tzur, M.B.A., Arnon Afek, M.D., M.P.H.,
Karl Skorecki, M.D., and Asaf Vivante, M.D., Ph.D.​​
A BS T R AC T
BACKGROUND
The long-term risk associated with childhood kidney disease that had not pro-
gressed to chronic kidney disease in childhood is unclear. We aimed to estimate
the risk of future end-stage renal disease (ESRD) among adolescents who had
normal renal function and a history of childhood kidney disease.
METHODS
We conducted a nationwide, population-based, historical cohort study of 1,521,501
Israeli adolescents who were examined before compulsory military service in 1967
through 1997; data were linked to the Israeli ESRD registry. Kidney diseases in
childhood included congenital anomalies of the kidney and urinary tract, pyelone-
phritis, and glomerular disease; all participants included in the primary analysis
had normal renal function and no hypertension in adolescence. Cox proportional-
hazards models were used to estimate the hazard ratio for ESRD associated with
a history of childhood kidney disease.
RESULTS
During 30 years of follow-up, ESRD developed in 2490 persons. A history of any
childhood kidney disease was associated with a hazard ratio for ESRD of 4.19
(95% confidence interval [CI], 3.52 to 4.99). The associations between each diag-
nosis of kidney disease in childhood (congenital anomalies of the kidney and
urinary tract, pyelonephritis, and glomerular disease) and the risk of ESRD in
adulthood were similar in magnitude (multivariable-adjusted hazard ratios of 5.19
[95% CI, 3.41 to 7.90], 4.03 [95% CI, 3.16 to 5.14], and 3.85 [95% CI, 2.77 to 5.36],
respectively). A history of kidney disease in childhood was associated with younger
age at the onset of ESRD (hazard ratio for ESRD among adults <40 years of age,
10.40 [95% CI, 7.96 to 13.59]).
CONCLUSIONS
A history of clinically evident kidney disease in childhood, even if renal function
was apparently normal in adolescence, was associated with a significantly in-
creased risk of ESRD, which suggests that kidney injury or structural abnormality
in childhood has long-term consequences.
n engl j med 378;5 nejm.org  February 1, 2018
The New England Journal of Medicine
 Childhood Kidney Disease and Risk of Adult ESRD
C
hronic kidney disease and end-
stage renal disease (ESRD) are global
health problems with increasing preva-
lence.1 Early identification of persons at in-
creased risk may allow for early interventions
that might reduce the incidence of progressive
chronic kidney disease and its associated com-
plications.
World Kidney Day 2016 focused on childhood
kidney disease as a source of chronic kidney dis-
ease in childhood and as a precursor to disease in
adulthood.2 Congenital anomalies of the kidney
and urinary tract and glomerular disease are the
most common diagnoses of kidney disease in
childhood; the incidence of congenital anoma-
lies of the kidney and urinary tract during the
past decade has been estimated to be 0.4 to 4.0
cases per 1000 births,3,4 and the incidence of
primary glomerular disease among children has
been estimated to be 0.1 to 2.0 cases per 100,000
children per year.5 Although most of these con-
ditions have a favorable prognosis, the possibil-
ity of persistent kidney injury and a potentially
increased risk of chronic kidney disease in adult-
hood may be underappreciated. Some case series
and cross-sectional studies have addressed the
outcomes of childhood kidney diseases, with an
emphasis on congenital anomalies of the kidney
and urinary tract.6-9 The long-term kidney health
outcomes of the broader spectrum of childhood
kidney diseases remain largely unknown. There-
fore, we conducted a nationwide, population-
based historical cohort study among 1,521,501
adolescents who were followed for 30 years to
evaluate whether a history of childhood kidney
disease with normal renal function in adoles-
cence was associated with a risk of future devel-
opment of ESRD.
Me thods
Study Participants
We conducted a historical cohort study of Israeli
adolescents. Our study included potential army
recruits who had a mean age of 17.7 years
(range, 16 to 25) at the initial medical assess-
ment. One year before their conscription, all eli-
gible Israeli adolescents receive a medical assess-
ment that includes a review of medical records,
an interview, a physical examination, and, when
indicated, referral for further assessment.10
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We excluded persons from the primary analy-
sis if they had received any of the following
diagnoses that are considered to confer an in-
creased risk of subsequent ESRD: diabetes mel­
A Quick Take
litus, systemic lupus erythematosus, vasculitis is available at
or any rheumatic disease, cancer, hypertension, or NEJM.org
evidence of impaired renal function from any
cause (Fig. 1). Persons with evidence of impaired
renal function from any cause were included in
the secondary analysis.
Because military service is compulsory for
Jewish Israeli citizens but not mandatory for the
majority of non-Jewish Israeli citizens or resi-
dents, the study population included only Jewish
recruits.11 The institutional review boards of both
the Israel Defense Forces and Sheba Medical
Center approved the study and waived the re-
quirement for informed consent on the basis of
preserving participants’ anonymity.
Clinical Assessment and Diagnosis
All future conscripts are asked to provide copies
of all available medical records, and their family
physicians are requested to provide a compre-
hensive health history summary on a structured
form. The summary is reviewed by the physi-
cians who perform the primary medical board
examination. In addition, at the time of that
medical examination, each future conscript under-
goes a physical examination that includes anthro-
pometric measurements, measurement of blood
pressure and heart rate, and a dipstick urinalysis
test. All future conscripts for whom a kidney-
related diagnosis cannot be ruled out on the
basis of the medical record or examination at
the time of the medical board assessment are
sent for additional tests and referred to a board-
certified nephrologist. All future conscripts with
a history of childhood kidney disease are referred
to a board-certified nephrologist for confirma-
tion of the diagnosis. The accuracy and com-
pleteness of the medical information with re-
spect to each diagnosis of childhood kidney
disease, including a diagnosis established by the
nephrologist during subsequent medical evalua-
tion, are additionally assessed and verified by a
committee of two trained military service physi-
cians. Each diagnosis is assigned a numerical
code and recorded in a central database. Future
conscripts who have no indication of childhood
kidney disease in their medical records and have
429
 The n e w e ng l a n d j o u r na l of m e dic i n e

1,544,097 Participants were included

in the target population

Primary medical evaluation included:

Review of all available medical files
Review of health summary filled out
by participant’s family physician
Detailed medical interview and
physical examination by physician
Measurement of weight, height,
and blood pressure
Urine dipstick test

Participants without medical conditions Participants with history of childhood Participants with medical conditions
that confer an increased future risk kidney disease without additional that confer an increased future risk
of ESRD conditions that confer a risk of ESRD of ESRD

Secondary medical evaluation included:

Measurement of serum creatinine
level
Review of renal and bladder imaging
studies
Medical evaluation and establishment
of a diagnosis by a nephrologist
who confirmed that the participant
had normal renal function, normal
blood pressure levels, and no
proteinuria and that participants
with history of pyelonephritis
or glomerular disease had been
disease-free for more than 12 mo

18,592 Participants had a history

of childhood kidney disease, normal
blood pressures, no proteinuria,
and normal serum creatinine level

7231 Had 8611 Had resolved

3198 Had CAKUT
pyelonephritis glomerular disease
1,502,909 Had no medical history 22,596 Were at risk for ESRD and were
of primary childhood kidney disease excluded from the primary analysis

2350 (0.16%) Had development 140 (0.75%) Had development 403 (1.8%) Had development
of ESRD by the end of follow-up of ESRD by the end of follow-up of ESRD by the end of follow-up

Figure 1. Assessment of Study Participants, Designation of Study Groups, and Outcomes.

A total of 445 participants had more than one diagnosis of childhood kidney disease recorded, of whom 3 had all three disease diagno-
ses recorded. CAKUT denotes congenital anomalies of the kidney and urinary tract, and ESRD end-stage renal disease.

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 Childhood Kidney Disease and Risk of Adult ESRD
normal findings from the physical examination
and laboratory tests performed at the medical
board examination are not referred for further
evaluation. This process is uniform for all future
conscripts.
Diagnosis of History of Childhood Kidney
Diseases
Diagnoses of childhood kidney diseases were
assessed at baseline (the date of the medical
board assessment) and were categorized as con-
genital anomalies of the kidney and urinary
tract, pyelonephritis, or glomerular disease. A
medical history of congenital anomalies of the
kidney and urinary tract included congenital sin-
gle kidney, unilateral renal hypodysplasia, renal
ectopia, horseshoe kidney, hydronephrosis, hydro-
ureter, ureteropelvic junction stenosis, uretero-
vesical junction stenosis, and other congenital
kidney and urinary malformations not otherwise
specified. A total of 3198 participants had a
medical history of congenital anomalies of the
kidney and urinary tract; 1465 of these partici-
pants had undergone complete or partial nephrec-
tomy, pyelostomy or pyeloplasty, or ureterostomy
or other operations involving the ureters and
kidney. A total of 7231 participants with a his-
tory of pyelonephritis were included in the study;
a history of pyelonephritis was defined as docu-
mentation of either a single episode or recurrent
episodes of pyelonephritis, with or without evi-
dence of scarring detected on imaging and with
or without additional anatomical malformations.
A total of 8611 participants with a history of
glomerular disease were included in the study; a
history of glomerular disease was defined as
documentation of glomerulonephritis or the ne-
phrotic syndrome. Participants with a history of
pyelonephritis or glomerular disease had to be
free of the disease for at least 1 year before en-
rollment (i.e., had no clinical event of glomeru-
lonephritis or pyelonephritis, as determined from
the medical records provided by the participants’
primary physicians). A total of 445 participants
(2.4%) had more than one condition registered.
Conscripts were eligible for inclusion if they had
serum creatinine values within the normal range,
had no hypertension or proteinuria, and had
undergone further evaluation and received con-
firmation of the diagnosis of childhood kidney
disease by a board-certified nephrologist. As noted
above, participants who had abnormal renal
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function, active kidney disease, or unresolved
childhood glomerular disease were excluded
from the primary analysis.
The Israeli ESRD Registry
The Israeli ESRD database is a national admin-
istrative registry maintained by the Ministry of
Health.12 The database contains information on
patients who received any form of renal-replace-
ment therapy (i.e., hemodialysis, peritoneal dialy-
sis, or kidney transplantation). All nephrology
and dialysis programs and practices in Israel are
mandated to report annually to the Ministry of
Health on incident and prevalent cases of ESRD
and changes in type of treatment. A single pri-
mary diagnosis is recorded for each new patient
in the ESRD database.12 The current study cohort
was linked to the Israeli ESRD registry through
the identification number given to all Israeli
citizens at birth or immigration.
Outcome Variables and Follow-up
The onset of ESRD was defined as the date of
initiation of dialysis treatment or the date of renal
transplantation, whichever came first. All cases
of ESRD from January 1, 1980, to December 31,
2014, were included in the study. The follow-up
period extended from the initial assessment by
the medical board to the occurrence of ESRD
(defined as the initiation of treatment for ESRD)
or death or to December 31, 2014, whichever
came first. Because cases of ESRD were not reg-
istered between 1967 and 1979, data from par-
ticipants who were enrolled during that period
were left-censored in the survival analyses before
January 1980.
Statistical Analysis
The study participants were grouped according
to whether they had a history of childhood kid-
ney disease (congenital anomalies of the kidney
and urinary tract, pyelonephritis, glomerular dis-
ease, or any such history) or no history of child-
hood kidney disease. Incidence rates of ESRD
were calculated as the number of ESRD cases
divided by the total number of person-years in
each childhood kidney disease diagnosis group
and in all diagnosis groups combined. Life tables
were constructed and plotted to show the inci-
dence of ESRD from any cause among conscripts
with a history of childhood kidney disease as
compared with conscripts without such a history.
431
 The n e w e ng l a n d j o u r na l
In addition, we constructed life tables that in-
cluded three categories — no history of child-
hood kidney disease (1,502,909 participants), a
history of mild or resolved childhood kidney dis-
ease (18,592 participants in all diagnosis groups
combined), and a history of childhood kidney
disease and documented kidney injury at enroll-
ment (1230 participants). Cox proportional-haz-
ards models were used to estimate the hazard
ratios for ESRD in each childhood kidney dis-
ease diagnosis group, as well as for all catego-
ries combined (history of any mild or resolved
disease), as compared with the group with no
such history. We determined the unadjusted as-
sociations and then used models that controlled
for age at study enrollment and sex. Additional
models were adjusted for the father’s place of
birth (categorized as Europe or the Americas,
North Africa, West Asia, or Israel), period of
enrollment (1967 to 1979, 1980 to 1989, or 1990
to 1997), body-mass index (<25, 25 to 29, or ≥30,
calculated as the weight in kilograms divided by
the square of the height in meters), and systolic
blood pressure (<95th percentile or ≥95th percen-
tile). Multiple imputations for missing data were
made with the use of SAS Enterprise Miner soft-
ware, version 14.1 (SAS Institute).
We performed sensitivity analyses that exclud-
ed participants with documentation of micro-
scopic hematuria; that controlled for hematuria;
that controlled for other urologic conditions; that
stratified participants according to sex, number
of childhood diagnoses, period of enrollment,
duration of follow-up, and exemption from either
military service or high-intensity military ser-
vice; and that restricted follow-up according to
age at enrollment and at the end of follow-up. In
addition, in a separate analysis, we investigated
possible interactions between the diagnoses that
were excluded from the primary analysis (noted
above) and a history of childhood kidney disease
associated with the risk of ESRD (see the Supple-
mentary Appendix, available with the full text of
this article at NEJM.org). Analyses were simulta-
neously corrected for multiple comparisons with
the use of Bonferroni correction, and all confi-
dence intervals were adjusted accordingly.
The proportional-hazards assumption was test-
ed graphically with the use of log-minus-log plots.
All statistical analyses were conducted with SPSS
software, version 22 (IBM).
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of m e dic i n e
R e sult s
History of Childhood Kidney Disease
and Risk of ESRD
Table 1 shows the characteristics of the study
population, with stratification according to his-
tory of childhood kidney disease, by diagnosis
group, or no history of childhood kidney dis-
ease. During 46,188,970 person-years of follow-
up (mean duration of follow-up, 30.4 years), ESRD
developed in 2490 participants, yielding an inci-
dence rate of 5.39 cases per 100,000 person-
years. Table 2 shows the characteristics of the
participants in whom ESRD developed during
the study period, with stratification according to
history or no history of childhood kidney dis-
ease. Participants with a history of childhood
kidney disease were younger at the onset of
ESRD than those with no such history (mean
[±SD] age, 41.6±10.7 vs. 48.6±10.0 years; P<0.001)
and had a shorter follow-up period. Among the
participants in whom ESRD developed, the rate
of ESRD caused by diabetic nephropathy was
lower among those with a history of kidney dis-
ease in childhood or adolescence than among
those with no such history (14.3% vs. 35.4%,
P<0.001). Overall, among the 18,592 participants
who had a history of childhood kidney disease,
ESRD developed in 140. In an analysis that con-
trolled for sex, age at enrollment, father’s place
of birth, period of enrollment, body-mass index,
and blood pressure, the hazard ratio for ESRD
among participants with a history of childhood
kidney disease was 4.19 (95% confidence inter-
val [CI], 3.52 to 4.99) (Table 3).
Association According to Diagnosis
Figure 2 shows the incidence of ESRD during the
follow-up period among the participants with a
history of childhood kidney disease (according
to recorded diagnosis) as compared with the
participants with no history of childhood kidney
disease. Among 1,521,501 participants, a total of
3198 (0.2%) had a history of congenital anoma-
lies of the kidney and urinary tract. ESRD devel-
oped in 26 participants with such history (0.8%),
yielding an incidence rate of 27.6 cases per
100,000 person-years and an unadjusted hazard
ratio of 6.07 (95% CI, 4.04 to 9.12) in the com-
parison with persons with no history of kidney
disease. In an analysis that controlled for sex,
 Childhood Kidney Disease and Risk of Adult ESRD

Table 1. Baseline Characteristics of the Study Population.*

Participants with No
History of Childhood
Kidney Disease
Characteristic Participants with History of Childhood Kidney Disease (N = 1,502,909)

CAKUT Pyelonephritis Glomerular Disease Any

(N = 3198) (N = 7231) (N = 8611) (N = 18,592)
Age — yr 18.1±1.24 17.8±0.97 17.8±0.81 17.9±0.96 17.7±1.05
Sex — no. (%)
Male 2020 (63.2) 3978 (55.0) 5553 (64.5) 11,350 (61.0) 928,178 (61.8)
Female 1178 (36.8) 3253 (45.0) 3058 (35.5) 7,242 (39.0) 574,731 (38.2)
Father’s place of birth
— no. (%)
Israel 138 (4.3) 282 (3.9) 405 (4.7) 806 (4.3) 68,310 (4.5)
Europe or the 1301 (40.7) 3180 (44.0) 2946 (34.2) 7,238 (38.9) 643,629 (42.8)
Americas
North Africa 847 (26.5) 1730 (23.9) 2521 (29.3) 4,980 (26.8) 364,152 (24.2)
West Asia 793 (24.8) 1855 (25.7) 2654 (30.8) 5,190 (27.9) 377,179 (25.1)
Unknown 119 (3.7) 184 (2.5) 85 (1.0) 378 (2.0) 49,639 (3.3)
Period of enrollment
— no. (%)
1967–1979 950 (29.7) 4754 (65.7) 2250 (26.1) 7,818 (42.1) 503,310 (33.5)
1980–1989 1150 (36.0) 986 (13.6) 4116 (47.8) 6,105 (32.8) 480,381 (32.0)
1990–1997 1098 (34.3) 1491 (20.6) 2245 (26.1) 4,669 (25.1) 519,218 (34.5)
Body-mass index
— no. (%)†
<25 2700 (84.4) 6441 (89.1) 7721 (89.7) 16,473 (88.6) 1,279,403 (85.1)
25–29 289 (9.0) 408 (5.6) 591 (6.9) 1,255 (6.8) 134,859 (9.0)
≥30 56 (1.8) 103 (1.4) 109 (1.3) 257 (1.4) 24,660 (1.6)
Data missing 153 (4.8) 279 (3.9) 190 (2.2) 607 (3.3) 63,987 (4.3)
Systolic blood pressure
— no. (%)
<95th percentile 2323 (72.6) 2730 (37.8) 6772 (78.6) 11,482 (61.8) 1,027,990 (68.4)
≥95th percentile 166 (5.2) 127 (1.8) 446 (5.2) 719 (3.9) 69,134 (4.6)
Data missing 709 (22.2) 4374 (60.5) 1393 (16.2) 6,391 (34.4) 405,785 (27.0)

* Plus–minus values are means ±SD. Participants may have had more than one kidney disease in childhood. CAKUT denotes congenital
anomalies of the kidney and urinary tract. Percentages may not total 100 because of rounding.
† Body-mass index is the weight in kilograms divided by the square of the height in meters.

age at enrollment, father’s place of birth, period
of enrollment, body-mass index, and blood pres-
sure, this association was altered minimally
(hazard ratio for ESRD, 5.19; 95% CI, 3.41 to
7.90) (Table 3).
Among the 1465 participants with a history of
congenital anomalies of the kidney and urinary
tract who had undergone a reported surgical
intervention and had normal renal function, 540
had undergone either partial or complete nephrec-
tomy. ESRD developed in 7 of these participants
(1.3%), yielding an unadjusted hazard ratio of
8.14 (95% CI, 3.88 to 17.07); an adjusted analysis
was not performed for this subgroup because of
the small numbers.
Among the 7231 participants who had a history

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 The n e w e ng l a n d j o u r na l of m e dic i n e

Table 2. Characteristics of Participants with ESRD, According to History or No History of Childhood Kidney Disease.*

History of Childhood No History of Childhood

Kidney Disease Kidney Disease
Characteristic (N = 140) (N = 2350) P Value
At baseline
Age at enrollment — yr 18.2±1.30 18.0±1.55 0.15
Male sex — no. (% [95% CI]) 114 (81.4 [74.3–87.2]) 1973 (84.0 [82.4–85.4]) 0.43
Father’s place of birth — no. (% [95% CI]) 0.41
Israel 5 (3.6 [1.3–7.7]) 65 (2.8 [2.2–3.4])
Europe or the Americas 48 (34.3 [26.8–42.4]) 688 (29.3 [27.5–31.1])
West Asia 32 (22.9 [16.5–30.4]) 667 (28.4 [26.6–30.2])
North Africa 44 (31.4 [24.1–39.5]) 685 (29.1 [27.3–31.0])
Unknown 11 (7.9 [4.2–13.2]) 245 (10.4 [9.2–11.7])
Body-mass index† 23.0±3.84 23.1±4.15 0.61
At ESRD diagnosis
Age — yr 41.6±10.7 48.6±10.0 <0.001
Duration of follow-up — yr 23.4±10.5 30.5±9.9 <0.001
Year of diagnosis 2000±7.75 2006±9.08 <0.001
Cause of ESRD — no. (% [95% CI]) <0.001
Diabetes 20 (14.3 [9.2–20.8]) 832 (35.4 [33.5–37.4])
Nondiabetes 82 (58.6 [50.3–66.5]) 1102 (46.9 [44.9–48.9])
Uncertain or unrecorded 38 (27.1 [20.3–35.0]) 416 (17.7 [16.2–19.3])
Died — no. (%) 51 (36.4) 894 (38.0) 0.70

* Plus–minus values are means ±SD. ESRD denotes end-stage renal disease.
† Data on body-mass index were available for 126 participants with a history of childhood kidney disease and for 2069
participants without a history of of childhood kidney disease.

of pyelonephritis in childhood, ESRD developed among participants with a history of mild or

in 73 (1.0%), yielding an incidence rate of 28.3
cases per 100,000 person-years, an unadjusted
hazard ratio of 3.80 (95% CI, 2.94 to 4.76), and
an adjusted hazard ratio of 4.03 (95% CI, 3.16 to
5.14). Among the 8611 participants who had a
history of glomerular disease in childhood, the
incidence rate of ESRD was 16.3 cases per
100,000 person-years; the risk of ESRD among
such participants was almost four times as high
as the risk among the participants with no such
history (unadjusted hazard ratio, 3.91 [95% CI,
2.83 to 5.41], and adjusted hazard ratio, 3.85
[95% CI, 2.77 to 5.36]) (Table 3).
Sensitivity Analyses
The exclusion of persons with microhematuria did
not materially change the association between a
history of childhood kidney disease and an in-
creased risk of ESRD in adulthood (hazard ratio
resolved childhood kidney disease, 4.11; 95% CI,
3.44 to 4.91). Further sensitivity analyses yielded
similar results (Table S1 in the Supplementary
Appendix). An analysis according to age at the
end of follow-up suggested a markedly increased
risk of ESRD among adults younger than 40 years
of age (hazard ratio, 10.40; 95% CI, 7.96 to 13.59).
An analysis that stratified participants with a
history of childhood kidney disease according to
duration of follow-up showed attenuation of the
increased risk of ESRD with increasing duration
of follow-up (hazard ratio, 13.80 with <10 years
of follow-up, 11.00 with 10 to 19 years of follow-
up, 5.51 with 20 to 29 years of follow-up, 1.85 with
30 to 39 of follow-up, and 1.72 with ≥40 years of
follow-up) (Table S2 in the Supplementary Appen-
dix). In an analysis that stratified participants
with a history of childhood kidney disease ac-
cording to period of enrollment, more recent

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 Childhood Kidney Disease and Risk of Adult ESRD

Table 3. Outcome Variables and Hazard Ratios for ESRD in Adulthood, According to Childhood Kidney Disease Category at Recruitment.*

No History
of Childhood
Kidney Disease
Variable History of Childhood Kidney Disease (N = 1,502,909)

CAKUT Pyelonephritis Glomerular Disease Any

(N = 3198) (N = 7231) (N = 8611) (N = 18,592)
Incident cases of ESRD — no.† 26 73 42 140 2350
Age at ESRD diagnosis — yr 40.5±11.4 43.8±11.3 38.5±8.16 41.6±10.7 48.6±10.0
Total years of follow-up 94,211 257,673 257,940 596,773 45,592,197
Age at end of follow-up — yr 47.5±8.6 53.4±10.0 47.8±7.2 50.0±9.1 48.0±9.3
Incidence rate of ESRD — no. of cases 27.6 28.3 16.3 23.5 5.15
per 100,000 person-years
Died — no. (%) 128 (4.0) 385 (5.3) 224 (2.6) 721 (3.9) 46,286 (3.1)
Hazard ratio (95% CI) for ESRD from
any cause in adulthood
Unadjusted 6.07 (4.04–9.12) 3.80 (2.94–4.76) 3.91 (2.83–5.41) 4.04 (3.49–4.93) Reference
Model 1‡ 5.47 (3.63–8.24) 3.74 (2.94–4.76) 3.84 (2.78–5.31) 4.04 (3.40–4.81) Reference
Model 2§ 5.19 (3.41–7.90) 4.03 (3.16–5.14) 3.85 (2.77–5.36) 4.19 (3.52–4.99) Reference

* Plus–minus values are means ±SD.

† A total of 445 participants had more than one recorded diagnosis of childhood kidney disease; ESRD developed in 1 of these participants.
‡ Model 1 was adjusted for age and sex.
§ Model 2 was adjusted for age, sex, father’s place of birth, period of enrollment, body-mass index, and systolic blood pressure.

periods were associated with a higher risk of
ESRD, with hazard ratios of 3.63 (95% CI, 2.95
to 4.47) associated with enrollment in 1967 to
1979 versus 9.68 (95% CI, 4.96 to 18.91) associ-
ated with enrollment in 1990 to 1997.
Discussion
In this population-based cohort study, a history
of childhood kidney disease, with no clinical or
laboratory evidence of compromised glomerular
filtration rate in adolescence, was associated with
a significantly increased risk of ESRD in adult-
hood. The associations between each of the
specific underlying conditions and the risk of
ESRD in adulthood were similar in magnitude
and suggested that among the participants who
had a history of congenital anomalies of the
kidney and urinary tract, pyelonephritis, or glo-
merular disease in childhood, with no apparent
sequelae in adolescence, the risk of ESRD devel-
oping during 30 years of follow-up was approxi-
mately four times as high as the risk among
participants who had no such history.
This study has several limitations. First, owing
to the nature of our data collection, we do not
have precise information on the clinical presen-
tation, the indication for urologic interventions,
the histopathological subtype of the childhood
kidney diseases, or the exact age of the partici-
pants at the time of clinical presentation during
childhood. Therefore, we could not perform analy-
ses according to time from diagnosis or accord-
ing to the severity or subtype of disease in child-
hood. Still, none of the potential conscripts who
were included in the primary analysis had ab-
normal findings on clinical indexes of kidney
injury at the time of the medical evaluation.
Second, we cannot exclude the possibility of
misclassifications of childhood kidney diseases,
because the participants in this study, especially
those who were recruited before the 1980s, prob-
ably would not have received a prenatal diagnosis
and were subjected to a more limited availability
of diagnostic tests or procedures. For example,
we suspect that in the case of diagnoses of pyelo-
nephritis, which were more prevalent in the con-
scription cohorts from the 1960s and 1970s than
in later cohorts, some clinicians might not have
considered underlying, undiagnosed congenital

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 The n e w e ng l a n d j o u r na l of m e dic i n e

A CAKUT B Pyelonephritis
20 20

(no. of cases per 1000 participants)

(no. of cases per 1000 participants)

Cumulative Incidence of ESRD

Cumulative Incidence of ESRD

15 History 15
of CAKUT
History of
pyelonephritis

10 10

5 5

No history of No history of
kidney disease kidney disease
0 0
0 10 20 30 40 0 10 20 30 40
Years Years
No. of Participants No. of Participants
at Risk at Risk
Total 1,506,107 1,496,223 1,300,954 719,349 301,075 Total 1,510,140 1,500,218 1,304,825 722,853 304,334
With incident ESRD 88 319 603 927 439 With incident ESRD 86 334 617 938 448

C Glomerular Disease D All Childhood Kidney Disease and Unresolved Disease with
Kidney Injury
20 200

Unresolved disease
with kidney injury
(no. of cases per 1000 participants)
(no. of cases per 1000 participants)

Cumulative Incidence of ESRD

Cumulative Incidence of ESRD

15 150

10 100
History of
glomerular
disease

5 No history of 50
kidney disease
Mild
No history of or resolved
kidney disease disease
0 0
0 10 20 30 40 0 10 20 30 40
Years Years
No. of Participants No. of Participants
at Risk at Risk
Total 1,511,520 1,501,614 1,306,121 722,233 301,410 Total 1,522,731 1,512,657 1,315,897 728,892 305,633
With incident ESRD 91 321 618 924 438 With incident ESRD 173 408 664 953 450

Figure 2. Life Tables of the Cumulative Incidence of ESRD among Study Participants During the Follow-up Period.
Shown are life-table analyses of the cumulative incidence of ESRD per 1000 persons among participants with a history of childhood kidney
disease as compared with participants with no history of childhood kidney disease. Panel A shows the incidence according to the record-
ed diagnosis of CAKUT; Panel B, according to the recorded diagnosis of pyelonephritis; Panel C, according to the recorded diagnosis of
glomerular disease; and Panel D, according to all three diagnoses combined (categorized as “mild or resolved disease”) and unresolved
disease with kidney injury at enrollment. The number of participants at risk at the beginning of each 10-year interval includes partici-
pants with no history of childhood kidney disease plus participants with the childhood kidney disease diagnosis noted in the panel label.
The number of ESRD cases includes cases that developed among the overall number of participants at risk during each 10-year interval.

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 Childhood Kidney Disease and Risk of Adult ESRD
anomalies of the kidney and urinary tract. Never-
theless, we did not identify any significant dif-
ference in the risk of chronic kidney disease
across the various causes of childhood kidney
disease. Third, the clinical information on base-
line creatinine levels was reported as a dichoto-
mous variable (normal or abnormal) in our data-
base. Therefore, we do not have the baseline
measures of estimated glomerular filtration rates
for the participants. Fourth, our study was limit-
ed to Jewish recruits, and although our study
population was highly representative of the Jew-
ish male adolescent population, it was less repre-
sentative of the Israeli Jewish female adolescent
population. Fifth, we did not have information
about persons who emigrated from Israel. How-
ever, for that factor to substantively bias the re-
sults, we would have to assume that emigrants
who had no medical history of childhood kidney
disease were particularly prone to ESRD, which
is an unlikely occurrence. Finally, in the current
study, we were not able to consider directly the
development during the follow-up period of
other medical conditions, such as diabetes melli-
tus that may be associated with an increased
risk of ESRD.
The strengths of our study include the use of
a large, nationwide cohort with detailed data
from clinical assessment. During the enrollment
period, the study participants underwent an ini-
tial medical evaluation that followed standard-
ized and thorough protocols, and all had a long
follow-up period and comprehensive documen-
tation of ESRD. The medical assessments of all
the study participants during adolescence were
performed under similar protocols. All kidney-
related diagnoses were confirmed by board-certi-
fied nephrologists. Therefore, we were able to
adhere to consistent inclusion and exclusion
criteria and to uniquely study the question of the
association between kidney diseases in child-
hood and the development of ESRD in adulthood
prospectively in our cohort.
The prevalence of congenital anomalies of the
kidney and urinary tract in our cohort (0.2%)
was similar to the rates reported in other stud-
ies.13,14 Congenital anomalies of the kidney and
urinary tract are a leading cause of chronic kid-
ney disease in children2,15-17 and are responsible
for 2.2% of the cases of ESRD in adults.18 Few
data are available on renal function in adolescence
among persons who have congenital anomalies
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of the kidney and urinary tract and in whom
ESRD develops in adulthood. There is evidence
suggesting an increased risk of ESRD among
otherwise healthy kidney donors — a finding
that is consistent with our results regarding ne-
phrectomy.19,20
We found that the risk of ESRD among ado-
lescents with a history of pyelonephritis was
nearly four times as high as the risk among
those with no history of childhood kidney dis-
ease. Many studies have related chronic kidney
disease to postinfection renal scarring and vesi-
coureteral reflux.21,22 A 2011 review suggested
that concomitant congenital anomalies of the
kidney and urinary tract may contribute to poor
outcomes among patients with pyelonephritis
and emphasized a distinction between primary
renal damage that precedes infection and scars
related to urinary tract infections.23 Our current
finding of an increased risk of ESRD among
adolescents with a history of apparently resolved
glomerular disease is consistent with the in-
creased risk of hypertension in adulthood that
we found in a subgroup of this population in a
previous study.24
The current study suggests that mild kidney
abnormalities or injury in childhood may confer
a risk of ESRD in adulthood, even when there is
no overt compromise of renal function in adoles-
cence. This finding is consistent with the formu-
lation that low nephron endowment or loss of
nephrons can increase susceptibility to chronic
kidney disease as a result of the hyperfiltration
of residual nephrons.25-27 Despite the low abso-
lute incidence of ESRD, the interpretation of our
findings should take into account that ESRD is
estimated to represent only 0.1 to 2.0% of all
patients with chronic kidney disease, which in-
cludes earlier stages before ESRD.1 We used
ESRD as a well-delineated end point that is reg-
istered in a database in Israel. However, the find-
ing of a possible risk of ESRD associated with
childhood kidney diseases implies that there is
an even greater, albeit unmeasured, risk of the
considerably more prevalent antecedent stages of
chronic kidney disease. Overall, our study sug-
gests that childhood kidney diseases are possi-
ble risk factors for future ESRD.
No potential conflict of interest relevant to this article was
reported.
Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.
437
 Childhood Kidney Disease and Risk of Adult ESRD

Appendix
The authors’ affiliations are as follows: Hadassah–Hebrew University Braun School of Public Health (R.C.-M.) and the Director’s Office,
Israel Ministry of Health (A.A.), Jerusalem, the Department of Nephrology and Hypertension, Meir Medical Center, Kfar-Saba, and the
Israel Renal Registry, Tel Aviv (E.G.), the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv (E.G., A.L., A.A., A.V.), the Israel
Defense Forces Medical Corps, Tel HaShomer (G.T., A.L., D.T., A.V.), Talpiot Medical Leadership Program (G.T., A.V.), Chaim Sheba
Medical Center Management (A.A.), and Pediatric Department B and Pediatric Nephrology Unit, Edmond and Lily Safra Children’s
Hospital (A.V.), Chaim Sheba Medical Center, Tel Hashomer, the Institute of Nephrology and Hypertension, Assuta Ashdod Academic
Medical Center, Ashdod, and the Faculty of Health Sciences, Ben Gurion University of the Negev, Beer Sheva (A.L.), and the Department
of Nephrology, Rambam Health Care Campus, Rappaport Faculty of Medicine and Research Institute, Technion–Israel Institute of
Technology, Haifa (K.S.) — all in Israel; and the Department of Medicine, Mount Auburn Hospital, Harvard Medical School, Cambridge
(A.L.), and the Division of Nephrology, Department of Medicine, Boston Children’s Hospital and Harvard Medical School, Boston (A.V.)
— both in Massachusetts.

References
1. Levey AS, Coresh J. Chronic kidney
disease. Lancet 2012;​379:​165-80.
2. Ingelfinger JR, Kalantar-Zadeh K,
Schaefer F. Averting the legacy of kidney
disease: focus on childhood. Nephrol Dial
Transplant 2016;​31:​327-31.
3. Postoev VA, Grjibovski AM, Kovalenko
AA, Anda EE, Nieboer E, Odland JØ. Con-
genital anomalies of the kidney and the
urinary tract: a Murmansk County Birth
Registry study. Birth Defects Res A Clin
Mol Teratol 2016;​106:​185-93.
4. Tain YL, Luh H, Lin CY, Hsu CN. Inci-
dence and risks of congenital anomalies
of kidney and urinary tract in newborns:
a population-based case-control study in
Taiwan. Medicine (Baltimore) 2016;​95(5):​
e2659.
5. McGrogan A, Franssen CF, de Vries CS.
The incidence of primary glomerulone-
phritis worldwide: a systematic review of
the literature. Nephrol Dial Transplant
2011;​26:​414-30.
6. Abou Jaoudé P, Dubourg L, Bacchetta J,
Berthiller J, Ranchin B, Cochat P. Con-
genital versus acquired solitary kidney: is
the difference relevant? Nephrol Dial
Transplant 2011;​26:​2188-94.
7. Westland R, Schreuder MF, Böken-
kamp A, Spreeuwenberg MD, van Wijk JA.
Renal injury in children with a solitary
functioning kidney — the KIMONO study.
Nephrol Dial Transplant 2011;​26:​1533-41.
8. Vu KH, Van Dyck M, Daniels H, Proes-
mans W. Renal outcome of children with
one functioning kidney from birth: a study
of 99 patients and a review of the litera-
ture. Eur J Pediatr 2008;​167:​885-90.
9. Skrzypczyk P, Panczyk-Tomaszewska
M, Roszkowska-Blaim M, et al. Long-term
outcomes in idiopathic nephrotic syn-
drome: from childhood to adulthood.
Clin Nephrol 2014;​81:​166-73.
10. Vivante A, Afek A, Frenkel-Nir Y, et al.
Persistent asymptomatic isolated micro-
scopic hematuria in Israeli adolescents
and young adults and risk for end-stage
renal disease. JAMA 2011;​306:​729-36.
11. Twig G, Yaniv G, Levine H, et al.
Body-mass index in 2.3 million adoles-
cents and cardiovascular death in adult-
hood. N Engl J Med 2016;​374:​2430-40.
12. Calderon-Margalit R, Gordon ES,
Hoshen M, Kark JD, Rotem A, Haklai Z.
Dialysis in Israel, 1989-2005 — time
trends and international comparisons.
Nephrol Dial Transplant 2008;​23:​659-64.
13. European Surveillance of Congenital
Anomalies. EUROCAT prevalence data:​
urinary (per 10,000 births) for all full
member registries, from 1980–2014.
Ispra, Italy:​EUROCAT, 2016 (http://www​
­
.eurocat-network​.eu/​accessprevalencedata/​
prevalencetables).
14. Andrés-Jensen L, Jørgensen FS, Thorup
J, et al. The outcome of antenatal ultra-
sound diagnosed anomalies of the kidney
and urinary tract in a large Danish birth
cohort. Arch Dis Child 2016;​101:​819-24.
15. United States Renal Data System. 2016
USRDS annual data report:​epidemiology
of kidney disease in the United States —
Table 81:​number of incidence and point
prevalence ESRD pediatric patients (aged
0-21) by modality, 1996-2014. Bethesda,
MD:​National Institutes of Health, National
Institute of Diabetes and Digestive and
Kidney Diseases, 2016.
16. Ishikura K, Uemura O, Ito S, et al.
Pre-dialysis chronic kidney disease in
children: results of a nationwide survey
in Japan. Nephrol Dial Transplant 2013;​
28:​2345-55.
17. Harambat J, van Stralen KJ, Kim JJ,
Tizard EJ. Epidemiology of chronic kidney
disease in children. Pediatr Nephrol 2012;​
27:​363-73.
18. Wühl E, van Stralen KJ, Verrina E, et al.
Timing and outcome of renal replacement
therapy in patients with congenital mal-
formations of the kidney and urinary tract.
Clin J Am Soc Nephrol 2013;​8:​67-74.
19. Grams ME, Sang Y, Levey AS, et al.
Kidney-failure risk projection for the liv-
ing kidney-donor candidate. N Engl J Med
2016;​374:​411-21.
20. Muzaale AD, Massie AB, Wang M-C,
et al. Risk of end-stage renal disease fol-
lowing live kidney donation. JAMA 2014;​
311:​579-86.
21. Shaikh N, Craig JC, Rovers MM, et al.
Identification of children and adolescents
at risk for renal scarring after a first uri-
nary tract infection: a meta-analysis with
individual patient data. JAMA Pediatr 2014;​
168:​893-900.
22. Gordon I, Barkovics M, Pindoria S,
Cole TJ, Woolf AS. Primary vesicoureteric
reflux as a predictor of renal damage in
children hospitalized with urinary tract
infection: a systematic review and meta-
analysis. J Am Soc Nephrol 2003;​14:​739-
44.
23. Montini G, Tullus K, Hewitt I. Febrile
urinary tract infections in children. N Engl
J Med 2011;​365:​239-50.
24. Vivante A, Twig G, Tirosh A, Skorecki
K, Calderon-Margalit R. Childhood history
of resolved glomerular disease and risk of
hypertension during adulthood. JAMA
2014;​311:​1155-7.
25. Hoy WE, Bertram JF, Denton RD,
Zimanyi M, Samuel T, Hughson MD.
­
Nephron number, glomerular volume, re-
nal disease and hypertension. Curr Opin
Nephrol Hypertens 2008;​17:​258-65.
26. Luyckx VA, Brenner BM. The clinical
importance of nephron mass. J Am Soc
Nephrol 2010;​21:​898-910.
27. Ingelfinger JR. Is microanatomy des-
tiny? N Engl J Med 2003;​348:​99-100.
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