Research

JAMA Internal Medicine | Original Investigation

Association of Adolescent Hypertension

With Future End-Stage Renal Disease
Adi Leiba, MD, MHA; Boris Fishman, MD, MPH; Gilad Twig, MD, PhD; David Gilad, MD, PhD; Estela Derazne, MSc;
Ari Shamiss, MD, MPH; Tamar Shohat, MD, MPH; Ofir Ron, MD; Ehud Grossman, MD

Supplemental content
IMPORTANCE Hypertension is a leading risk factor of cardiovascular morbidity and mortality.
The role of nonmalignant hypertension as the sole initiating factor of end-stage renal disease
(ESRD) in non–African American populations has recently been questioned.

OBJECTIVE To investigate the association between hypertension and future ESRD in

otherwise healthy adolescents.

DESIGN, SETTING, AND PARTICIPANTS This retrospective cohort study examined the data of
16- to 19-year-old healthy candidates for military service in the Israel Defense Forces between
January 1, 1967, and December 31, 2013. Data were obtained from the central conscription
registry of the Israel Defense Forces and the ESRD registry of the Israel Ministry of Health.
Participants underwent a comprehensive medical assessment prior to their military service.
Individuals with evidence of renal damage or kidney-related risk factors were excluded. The
data analysis was conducted from February 12, 2017, to October 16, 2018.

MAIN OUTCOMES AND MEASURES End-stage renal disease as recorded by the Israeli ESRD
registry, including hemodialysis, peritoneal dialysis, renal transplant diagnosed between
January 1, 1990, and December 31, 2014.

RESULTS The cohort included 2 658 238 adolescents (1 596 709 [60.1%] male with a mean
[SD] age of 17.4 [0.5] years), of whom 7997 (0.3%) had an established hypertension
diagnosis. Half of the individuals in the hypertensive group were overweight (1559 [20.1%])
or obese (2243 [28.9%]), and most (7235 [90.5%]) were male. During a median follow-up of
19.6 years (52 287 945 person-years), 2189 individuals developed ESRD, with an incidence
rate of 3.9 per 100 000 person-years. Adolescent hypertension was found to be associated
with future ESRD (crude hazard ratio [HR], 5.07; 95% CI, 3.73-6.88). In a multivariable model
adjusted for sex, age, years of education, body mass index, and other sociodemographic
variables, the HR was 1.98 (95% CI, 1.42-2.77). When excluding participants with severe
hypertension, the association with ESRD remained statistically significant (HR, 1.93; 95% CI,
1.37-2.70). In the subanalysis of nonoverweight adolescents, the association between
hypertension and ESRD was statistically significant as well (HR, 2.11; 95% CI, 1.05-4.24).

CONCLUSIONS AND RELEVANCE Hypertension appears to be associated with a doubling of the

risk of future ESRD in an otherwise healthy adolescent population.

Author Affiliations: Author

affiliations are listed at the end of this
article.
Corresponding Author: Ehud
Grossman, MD, Internal Medicine D
and Hypertension Unit, The Chaim
Sheba Medical Center, 2 Derech
Sheba, Migdal Ishpuz, 1st Floor,
JAMA Intern Med. doi:10.1001/jamainternmed.2018.7632 Ramat Gan 5266202, Israel
Published online February 25, 2019. (grosse@tauex.tau.ac.il).

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 Research Original Investigation
H
ypertension is the most important contributor to the
burden of disease and the leading cause of mortality
worldwide, estimated to be responsible for almost 13%
of all deaths.1-3 Although hypertension is much more com-
mon in adults and elderly people, it has increasingly been ob-
served in adolescents and young adults during the past 30
years.4,5 Studies have shown that hypertension, when mani-
fested in this age group, is a risk factor for all-cause mortality,
specifically for cardiovascular mortality and, in some other
studies, cerebrovascular mortality.6-9
End-stage renal disease (ESRD) is a major cause of mor-
tality as well as a leading risk factor for other fatal diseases,
including cardiovascular disease. Worldwide, the number of
individuals with ESRD in 2010 was estimated at 5 to 10 mil-
lion and is expected to rise, owing to the increasing preva-
lence of hypertension, diabetes, population aging, and renal
replacement therapies that prolong the lives of patients with
ESRD.10 Hypertension in adulthood has been recognized as
1 of the 2 leading causes of ESRD, responsible for more than
25% of cases, second only to diabetes (responsible for 44%),
in the United States.11 However, the role of nonmalignant hy-
pertension as the sole initiating factor of ESRD in non–
African American populations is debatable at present.12,13 In
this study, we investigated whether well-established essen-
tial hypertension, presenting between ages 16 and 19 years
without concurrent kidney morbidities, is a substantial initi-
ating risk factor for future ESRD.
Methods
Databases and Study Population
We conducted a large population-based retrospective cohort
study that included all eligible adolescents, males and fe-
males, between 16 and 19 years of age who were called up to
the Israel Defense Forces regional recruitment centers for a
medical health assessment approximately 1 year prior to their
conscription into mandatory military service. The study was
approved by the Israel Defense Forces Medical Corps Institu-
tional Review Board, which waived the requirement for in-
formed consent because the data used were obtained from
medical records without patient participation. The data analy-
sis was conducted from February 12, 2017, to October 16, 2018.
Arab people, Jewish Orthodox females, and Jewish ultra-
Orthodox males do not serve in the Israeli army and therefore
were not included in this study. All candidates for military ser-
vice between January 1, 1967, and December 31, 2013, were ex-
amined. The cohort was created by linking the data obtained
from the central conscription registry of the Israel Defense
Forces with the data from ESRD registry of the Israel Ministry
of Health. Excluded were those who were deceased before the
initiation of the ESRD registry (January 1, 1990). Also ex-
cluded were individuals who, on recruitment, received a di-
agnosis other than hypertension that is believed to affect re-
nal function such as diabetes, systemic lupus erythematosus,
Familial Mediterranean Fever, all types of vasculitis, persis-
tent hematuria (including microhematuria), proteinuria,
chronic nephrolithiasis, recurrent urinary tract infection, cys-
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Association of Adolescent Hypertension With Future End-Stage Renal Disease
Key Points
Question Is established hypertension among otherwise healthy
adolescents associated with increased risk for future end-stage
renal disease?
Findings In this cohort study of 2.65 million adolescent
candidates for military service in Israel, a very small percentage of
participants (0.3%) had a well-established hypertension diagnosis
and end-stage renal disease developed in some participants after
an extensive period.
Meaning Well-established hypertension during adolescence
appears to double the risk for future end-stage renal disease,
irrespective of overweight condition or severity of hypertension.
tic kidney disease, acute kidney injury and chronic kidney dis-
ease, congenital and acquired anomalies of the kidney, and pre-
sent and resolved glomerulonephritis (Figure 1). Individuals
who already received an ESRD diagnosis at the time of the
medical examination were also excluded from the study.
Data Collection at the Regional Recruitment Centers
As part of their medical assessment at the regional recruit-
ment center, all individuals were required to fill out a medi-
cal status form and provide a summary of their medical sta-
tus furnished by their primary care physician. During the
assessment, a detailed medical history was taken and a physi-
cal examination was performed by a trained physician. In ad-
dition, height and weight were measured, and mean systolic
and diastolic blood pressure (BP) (based on the measurement
acquired while sitting) were recorded. Urinalysis was per-
formed using a urine dipstick. If any information was missing
or abnormal during the assessment, the individuals were re-
ferred for further evaluation.
When the systolic and diastolic BP values were higher than
140/90 mm Hg, the individuals were referred to their pri-
mary care physician for an additional 10 consecutive BP mea-
surements over a period of at least 3 weeks. If the urinalysis
results were abnormal, additional tests such as a 24-hour urine
collection were performed and the individual was further ex-
amined by a nephrologist. As with other medical diagnoses,
the diagnosis of essential hypertension was determined only
after the Israel Defense Forces medical board had completed
the evaluations needed to render the diagnosis and assign a
relevant code. The final diagnosis of hypertension was deter-
mined when the mean of the outpatient BP measurements was
higher than 140/90 mm Hg and at least 50% of these measure-
ments were above this level. All individuals with hyperten-
sion underwent a full evaluation to exclude secondary hyper-
tension. Severe hypertension was defined when the mean of
10 measurements taken in the outpatient clinic was higher than
160/100 mm Hg and at least 50% of the measurements were
above this level or when left ventricular hypertrophy or grade
2 retinopathy was present. Individuals with severe hyperten-
sion were released from military service. If a diagnosis of es-
sential hypertension was verified, the individual received a
code that represented the diagnosis and determined their clas-
sification in the army. Individuals with diagnosis codes that
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 Association of Adolescent Hypertension With Future End-Stage Renal Disease
Figure 1. Study Design
2 716 495 Medically evaluated
from 1967 through 2013
58 257 Excluded
166 Treated with RRT
58 091 Had other medical
conditions causing
renal damage or
putting the kidneys
at risk
2 658 238 Analyzed
7997 Hypertensive 2 650 241 Nonhypertensive
RRT indicates renal replacement therapy.
represented essential hypertension composed the hyperten-
sive group.
In addition to the medical evaluation at the recruitment
center, all candidates for military service completed a psycho-
metric examination and were interviewed with regard to years
of education, place of residence, and country of origin. Coun-
try of origin refers to the country of the person’s birth or, in
cases of Israel born, the father’s or paternal grandfather’s coun-
try of origin; the mother's country of origin was unavailable
in this cohort.
Outcome
The primary outcome of this study was ESRD as recorded by
the Israeli ESRD registry. The registry is a national adminis-
trative database founded in 1990 and maintained by the Is-
rael Center for Disease Control. All nephrology dialysis units
in Israel are obligated to report new patients undergoing re-
nal replacement therapy (ie, hemodialysis, peritoneal dialy-
sis, and renal transplant) to the Israel Center for Disease Con-
trol. The database contains demographic data, type of renal
replacement therapy, and ESRD onset date (the date of renal
replacement therapy initiation). All ESRD cases from January
1, 1990, to December 31, 2014, were included in this study.
Statistical Analysis
The SPSS software, version 23 (IBM), was used to conduct an
unadjusted survival analysis to determine the cumulative in-
cidence of ESRD. The Cox proportional hazards regression mod-
els estimated the crude hazard ratio (HR) and 95% CI for ESRD.
Follow-up began on the day of the original examination at the
recruitment center and concluded when data were conveyed
to the ESRD registry, when death had occurred, or on Decem-
ber 31, 2014, whichever came first.
We included in the multivariable model the variables that
are known from previous studies to have an association with
the outcome and variables that were associated with the pri-
mary outcome in the univariate analyses. The final multivari-
able model was adjusted for the following variables: sex, age
at the medical examination, year of birth, country of origin (ie,
father’s or paternal grandfather’s country of birth), and socio-
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Original Investigation Research
economic status divided into 3 groups according to place of resi-
dence (using a scale provided by the Israel Central Bureau of
Statistics). Educational status was divided into 4 groups (9, 10,
11, or 12 or more years of education). Body mass index (calcu-
lated as weight in kilograms divided by height in meters
squared) for age was divided into 4 percentile groups, as de-
fined by the US Centers for Disease Control and Prevention for
teenagers: underweight (<5% percentile), normal weight (5%-
85% percentile), overweight (85%-95% percentile), and obese
(>95% percentile).
To overcome the lack of an ESRD registry between Janu-
ary 1, 1967, and December 31, 1989, and to estimate the pos-
sible association between this deficit and our findings, we
estimated the rate of ESRD across different ages of the partici-
pants who had enrolled in the study between January 1, 1967,
and December 31, 2013, and among those who had enrolled be-
tween January 1, 1990, and December 31, 2013. An additional
subanalysis was performed for various enrollment periods. To
minimize the period without ESRD data, we performed a sen-
sitivity analysis of the participants who had enrolled in the
study between January 1, 1977, and December 31, 2013. A com-
peting risk analysis for mortality of any cause, for those who
were alive at the establishment of the ESRD registry (January
1, 1990), was also performed. We performed a subanalysis of
participants with severe hypertension and nonoverweight par-
ticipants, and we conducted a separate analysis of the over-
weight and obese participants. Details of these extensive sen-
sitivity analyses are provided in the Supplement.
Results
Characteristics
The final cohort included 2 658 238 individuals, of whom 7997
(0.3%) had a hypertension diagnosis (Figure 1) and 1 596 709
(60.1%) were male with a mean (SD) age of 17.4 (0.5) years. In
the hypertensive group (n = 7997), 7235 (90.5%) were male,
representing 60.1% (1 596 709) of the general cohort. Nearly
half (49.0%) of the individuals in the hypertensive group were
overweight (1559 [20.1%]) or obese (2243 [28.9%]) at the time
of their examination, compared with the 12.9% of those in the
nonhypertensive population (n = 2 650 241) who were either
overweight (225 266 [8.8%]) or obese (104 023 [4.1%]). Most
(63.7%) of the individuals in the hypertensive group origi-
nated from North America and Europe (3335 [42.4%]) as well
as the former Soviet Union (1678 [21.3%]), although their per-
centage (43.7%) in the general cohort was lower (758 776
[29.3%] vs 373 314 [14.4%]). Baseline characteristics of the co-
hort are shown in Table 1.
Rates of End-Stage Renal Disease
During a median (interquartile range [IQR]) follow-up of 19.6
(10.4-31.2) years, within a total of 56 287 945 person-years, 2189
cases of ESRD with a crude incidence rate of 3.9 per 100 000
person-years were found among the nonhypertensive group
(Table 2). Forty-two individuals (0.5%) who had a diagnosis
of established hypertension at conscription later received a di-
agnosis of ESRD with a crude incidence rate of 20.2 per 100 000
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 Research Original Investigation Association of Adolescent Hypertension With Future End-Stage Renal Disease

Table 1. Baseline Characteristics of Participants Examined, 1967-2013

No. (%)
Variable Nonhypertensive Hypertensive Total
Total 2 650 241 7997 2 658 238
Male sex 1 589 474 (60.0) 7235 (90.5) 1 596 709 (60.1)
Age, mean (SD), y 17.4 (0.48) 17.6 (0.53) 17.4 (0.48)
CDC BMI groups (% at each BMI percentile
category)
Underweight (<5th percentile) 165 906 (6.5) 135 (1.7) 166 041 (6.5)
Normal weight (5th to <85th percentile) 2 071 325 (80.7) 3811 (49.2) 2 075 136 (80.6)
Overweight (85th to <95th percentile) 225 266 (8.8) 1559 (20.1) 226 825 (8.8)
Obese (≥95th percentile) 104 023 (4.1) 2243 (28.9) 106 226 (4.1)
Socioeconomic status (% at each category)
Low (1-4) 678 367 (26.2) 1888 (24.1) 680 225 (26.2)
Moderate (5-7) 1 334 343 (51.5) 4002 (51.2) 1 338 345 (51.5)
High (8-10 576 794 (22.3) 1933 (24.7) 578 727 (22.3)
Educational status, years in school
(% at each educational category)
≤9y 195 932 (7.5) 617 (7.8) 196 549 (7.5)
10 y 183 965 (7.1) 579 (7.3) 184 544 (7.1)
11 y 906 453 (34.9) 2030 (25.7) 908 483 (34.9)
≥12 y 1 310 278 (50.5) 4681 (59.2) 1 314 959 (50.5)
Country of origin (% at each origin category Abbreviations: BMI, body mass index
is given)a (calculated as weight in kilograms
Israel 199 672 (7.7) 566 (7.2) 200 238 (7.7) divided by height in meters squared);
CDC, Centers for Disease Control and
USSR 373 314 (14.4) 1678 (21.3) 374 992 (14.4)
Prevention; USSR, Union of Soviet
Asia 612 566 (26.6) 1392 (17.7) 613 958 (26.6) Socialist Republics, or Soviet Union.
Africa 609 293 (23.5) 855 (10.9) 610 148 (23.5) a
Denotes father's country of birth.
Europe + North America 7587 76 (29.3) 3335 (42.4) 762 111 (29.3) If the father was Israeli born, the
paternal grandfather's country of
Ethiopia 37 585 (1.5) 39 (0.5) 37 624 (1.5)
birth is given.

Table 2. Duration of Follow-up and Age at Diagnosis of End-Stage Renal Disease

Nonoverweight and Nonobese Participants Only
All Participants (CDC BMI <85th Percentile)
Nonhypertensive Hypertensive Total Nonhypertensive Hypertensive Total
Variable (n = 2 650 241) (n= 7997) (N = 2 658 238) (n = 2 237 231) (n = 3946) (N = 2 241 177)
ESRD overall, No. (%) 2147 (0.1) 42 (0.5) 2189 (0.1) 1444 (0.1) 9 (0.2) 1453 (0.1)
Follow-up period, PY 56 080 135 207 810 56 287 945 48 532 758 110 130 48 642 889
Median follow-up (IQR), y 19.6 (10.4-31.2) 28.6 (13.1-36.7) 19.6 (10.4-31.2) 20.4 (11.1-31.9) 30.4 (19.7-37.2) 20.4 (11.1-31.9)
Age at diagnosis of ESRD, 53.0 (6.6) 49.9 (7.2) 52.9 (6.6) 53.7 (6.3) 49.7 (3.7) 53.7 (6.3)
mean (SD), y
Crude incidence of ESRD 3.8 20.2 3.9 3.0 8.2 3.0
cases, per 100 000 PY

Abbreviations: BMI, body mass index (calculated as weight in kilograms divided by height in meters squared); CDC, Centers for Disease Control and Prevention;
ESRD, end-stage renal disease; PY, person-years.

person-years. Figure 2 describes the cumulative ESRD rate dur-
ing follow-up. The rate of ESRD in individuals younger than
40 years was very low (eFigure 1 in the Supplement).
In an unadjusted Cox regression model (model 1), estab-
lished hypertension was found to be associated with a 5-fold in-
creased risk of ESRD (HR, 5.07; 95% CI, 3.73-6.88). In a multi-
variable model adjusted for year of birth, age at examination at
a recruitment center, and sex (model 2), the association was at-
tenuated but still statistically significant (HR, 3.33; 95% CI, 2.45-
4.52). In the final multivariable model (model 3), also adjusted
for body mass index, country of origin, years of education, and
socioeconomic status, hypertension was found to almost double
the risk of ESRD (HR, 1.98; 95% CI, 1.42-2.77). In a subanalysis
excluding 95 adolescents with a severe hypertension diagno-
sis, the results of the multivariable analyses were similar to the
results found in the entire cohort (HR, 1.93; 95% CI, 1.37-2.70).
Additional subanalyses of various periods of enrollment (1977-
2013 and 1967-1984) found similar results as findings of the
analysis of the entire cohort population.
The results of the models are described extensively in
eTables 1 and 2 and eFigure 2 in the Supplement. In a compet-
ing risk analysis, the association between hypertension
and ESRD remained the same with an HR of 1.96 (95% CI,
1.40-2.75).

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 Association of Adolescent Hypertension With Future End-Stage Renal Disease
Figure 2. Cumulative ESRD Rate During Follow-up
2.0
Cumulative ESRD Incidence, %
1.5
1.0
0.5
0 The Falkstedt et al7 cohort study of Swedish military con-
0 10
No. at risk
Participants 1 980 568
Cumulative person-years 3 458 926
Cumulative ESRD cases 92
ESRD indicates end-stage renal disease.
Sensitivity Analysis
ESRD in Nonoverweight or Nonobese Participants
We conducted a sensitivity analysis consisting of only indi-
viduals who were not overweight or obese as defined by the
Centers for Disease Control and Prevention. Overall, they com-
prised 87.1% (n = 2 241 177) of the original cohort. Nine cases
(0.2%) of ESRD were observed among the hypertensive group.
The unadjusted HR for ESRD was 2.59 (95% CI, 1.34-4.98). In
the multivariable model adjusted for all of the above vari-
ables, hypertension among individuals was found associated
with ESRD (HR, 2.11; 95% CI, 1.05-4.24). Hypertension in over-
weight and obese individuals was also found to be associated
with ESRD, with an adjusted HR of 1.90 (95% CI, 1.29-2.78)
(eTables 3 and 4 and eFigure 3 in the Supplement).
Discussion
Adolescent hypertension is a public health issue with a grow-
ing prevalence, especially in the developed world, which can
probably be explained by the increasing rates of overweight
condition and obesity among adolescents worldwide as well
as by the increasing awareness of hypertension at this age, lead-
ing to higher rates of diagnosis.14 However, the potential ad-
vantages and harms of essential hypertension screening among
asymptomatic children and adolescents are still unclear,
as stated by the US Preventive Services Task Force 2013
recommendations.15 The rate of hypertension among the ado-
lescents in this study was lower (0.3%) than the rate previ-
ously reported worldwide (1%-5%).15,16 This difference may
stem from the study population; that is, we excluded all indi-
viduals with morbidities known to be associated with hyper-
tension such as diabetes and present and resolved glomeru-
lonephritis. Moreover, most previous studies based their
diagnosis of hypertension on a single BP measurement,
whereas we labeled participants as hypertensive only if their
established hypertension was confirmed by repeated el-
evated BP measurements and a thorough evaluation. We found
that hypertension was much more prevalent among individu-
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Original Investigation Research
als who originated from or were descendants of European and
North American countries, compared with other regions such
as Asia and Africa.
Hypertensive
group The main finding of this study is that hypertension in late
adolescence is associated with an almost 2-fold increased risk
for future ESRD. Numerous previous studies have shown that
hypertension during adolescence is an independent risk fac-
tor for future morbidity and mortality, especially after cardio-
Nonhypertensive
group
vascular and cerebrovascular events.6-9 Leiba et al9 demon-
strated that adolescents with established hypertension have
a 3-fold risk of developing stroke-related mortality in midlife.
20 30 40 50
scripts found that elevated BP was associated with cardiovas-
Follow-up, y
cular morbidity. The Gray et al6 study of undergraduate 18-
1 260 852 719 353 301 465 year-old males found that elevated BP was associated with
14 320 639 28 513 680 43 086 376
330 888 1741 future all-cause death, particularly cardiovascular death. Their
study was unique in that their data related to middle-aged hy-
pertension; thus, they used this information in their statisti-
cal models. Sundin et al17 found in their study of Swedish late-
adolescent male conscripts that hypertension was associated
with future ESRD. However, in their study, as well as in most
other studies, the diagnosis of hypertension was based on only
1 BP measurement, whereas in this present study, the diagno-
sis was based on several elevated measurements.
Obesity during childhood and adolescence has been shown
to be an independent risk factor for future ESRD.18,19 Obesity
is associated with hypertension. This association was mainly
studied in adults; however, in recent years, it has also been ob-
served in adolescents, emphasizing the role of obesity in the
growing prevalence of hypertension.14,20 To separate the as-
sociation between essential hypertension in adolescents and
obesity in future ESRD, we performed a subgroup analysis of
nonoverweight adolescents as defined by the Centers for Dis-
ease Control and Prevention. Albeit the total number of ESRD
cases in nonoverweight participants was much lower, the as-
sociation remained statistically significant with a nearly 2-fold
increased risk (HR, 2.11; 95% CI, 1.05-4.24). This subanalysis
suggests that established hypertension in adolescents is inde-
pendently associated with ESRD (unrelated to obesity).
A previous study using the same cohort found that per-
sistent asymptomatic isolated microscopic hematuria in-
creased the risk of future ESRD by 18.5-fold.21 Hematuria may
suggest an underlying renal disease; therefore, the risk of de-
veloping ESRD is very high. In the present study, individuals
with hematuria were excluded, and only healthy individuals
with hypertension were included. We found that even mild to
moderate hypertension doubles the risk of future ESRD. An-
other previous study showed that overweight condition (HR
of 3.00) and obesity (HR of 6.89) were associated with ESRD.19
The probable risk for adolescents with hypertension to de-
velop ESRD is relatively modest and transpires over an exten-
sive period, but it is of major importance. This finding may sug-
gest that nonmalignant hypertension, while being a close
surrogate and strong promoter of chronic kidney disease pro-
gression, is a relatively modest initiator of the disease.12,13 That
the pathogenesis of hypertension involves a balanced affer-
ent and efferent arteriolar constriction, maintaining a rela-
tively preserved glomerular filtration rate despite reduced
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 Research Original Investigation Association of Adolescent Hypertension With Future End-Stage Renal Disease

blood flow, can explain why hypertension, although a major
risk factor of cerebrovascular and cardiac disease, is only a mod-
est risk factor for chronic kidney disease progression and
ESRD.13
The association between hypertension and ESRD does not
necessarily signify that hypertension is the cause of future
ESRD. Although most data, especially from epidemiologic stud-
ies, support the belief that hypertension is a major cause of
ESRD, some studies challenge this point of view, claiming that
often the diagnosis of hypertensive nephrosclerosis, as the
cause of ESRD, is based merely on the clinical judgment of the
treating physician after excluding other known causes.13,22
Studies based on pathologic report findings of kidney
biopsies and autopsies found that many cases of ESRD are
believed to be caused by hypertension and had other
etiologies.23,24 Marcantoni et al23 assessed the kidney biop-
sies of African American and white patients without diabetes
to find the association between elevated BP, proteinuria, and
the pathologic morphologic structure of renal lesions. They
concluded that vascular sclerosis lesions caused by hyperten-
sion were insufficient to account for clinical renal failure.
Hsu’s25 meta-analysis of studies including patients with hy-
pertension treated for at least 1 year with antihypertensive
medications endeavored to explore this controversy. He
showed that antihypertensive treatment did not reduce the risk
of renal dysfunction, questioning again the role of nonmalig-
nant essential hypertension in chronic kidney disease. It has
been shown that the higher rates of ESRD attributable to hy-
pertension in African Americans, compared with white indi-
viduals, were partly explained by the genetic polymorphism
of the APOL1 (Gen Bank 8542) gene rather than by hyperten-
sion alone.26 The results of our study suggest that adoles-
cents with established hypertension are at a greater risk for fu-
ture ESRD, however, it is still ambiguous whether hypertension
is the cause of ESRD.
Limitations and Strengths
This study has several limitations. A noteworthy limitation is
that we did not obtain any relevant clinical information such
as BP levels during the follow-up period that might have af-
fected the risk for future ESRD. However, Gray et al6 found that
a hypertension diagnosis in middle-aged individuals only
slightly attenuated the association between late-adolescence
hypertension and cardiovascular mortality, emphasizing the
potential role of adolescent hypertension itself. Another pos-
sible limitation was the lack of information as to the esti-
mated glomerular filtration rate at the time of the medical ex-
amination. Nevertheless, all individuals with hypertension
were evaluated to exclude renal disease. We excluded indi-
viduals with abnormal urinalysis findings and kidney-
associated comorbidities, thus minimizing the probability that
the study’s participants had an abnormal glomerular filtra-
tion rate. Furthermore, the outcome of the study comprised
only individuals with ESRD without incorporating other lev-
els of chronic kidney disease. In light of our findings, we would
assume that this has yielded an underestimation of the asso-
ciation between hypertension and ESRD. Similar results were
observed when only individuals enrolled from 1977 were in-
cluded. In this subanalysis, the oldest participant would have
been 30 years of age at the beginning of the registry with an
extremely low rate of possibly missed ESRD cases.
This study has several strengths. It is a large population-
based cohort including males and females from different racial/
ethnic and socioeconomic backgrounds. The detailed data de-
rived from the recruitment centers and the ESRD registry
enabled us to adjust for most of the known confounders
of hypertension. This study links well-established late-
adolescence hypertension and ESRD; other studies have de-
fined hypertension based only on 1 BP measurement. This defi-
nition of hypertension is known to be biased, especially in this
population, owing to the stressful situation of the conscrip-
tion examination itself and to the high rates of white-coat hy-
pertension syndrome in this age group.27 Although up to 75%
of hypertension cases in adolescents are essential,28 to ex-
clude cases of secondary hypertension, we labeled individu-
als as hypertensive only if they were designated with diagnos-
tic codes of essential hypertension. We excluded all individuals
with known kidney disease or known to have morbidities that
may reflect kidney disease such as microhematuria. Further-
more, we emphasized the independent role of essential hy-
pertension unrelated to obesity. Finally, we showed that the
association of hypertension with future ESRD was main-
tained among those who had received only a mild or moder-
ate severity hypertension diagnosis.
Conclusions
Late-adolescence well-established essential hypertension ap-
pears to be associated with future ESRD. This association was
found regardless of overweight condition and severity of the
hypertension.

ARTICLE INFORMATION
Accepted for Publication: November 9, 2018.
Published Online: February 25, 2019.
doi:10.1001/jamainternmed.2018.7632
Author Affiliations: Division of Nephrology and
Hypertension, Assuta Ashdod Academic Medical
Center, Ben Gurion University, Beer Sheva, Israel
(Leiba); IDF Medical Corps, Tel Hashomer, Ramat
Gan, Israel (Leiba, Fishman, Twig, Gilad, Ron);
Department of Medicine, Mount Auburn Hospital,
Harvard Medical School, Boston, Massachusetts
(Leiba); Internal Medicine D and Hypertension Unit,
The Chaim Sheba Medical Center, Tel Hashomer,
Israel (Fishman, Grossman); Sackler Faculty of
Medicine, Tel Aviv University, Tel Aviv, Israel
(Fishman, Derazne, Shohat, Grossman);
Department of Physiology and Cell Biology, Faculty
of Health Sciences, Ben Gurion University, Beer
Sheva, Israel (Gilad); Assuta Medical Center, Tel
Aviv, Israel (Shamiss); Israel Center for Disease
Control, Israel Ministry of Health, Tel Hashomer,
Israel (Shohat).
Author Contributions: Drs Leiba and Fishman
contributed equally to this manuscript. Drs Lieba
and Fishman had full access to all of the data in the
study and take responsibility for the integrity of the
data and the accuracy of the data analysis.
Concept and design: Leiba, Fishman, Gilad, Derazne,
Shamiss, Shohat, Grossman.
Acquisition, analysis, or interpretation of data:
Leiba, Fishman, Twig, Derazne, Shohat, Ron,
Grossman.
Drafting of the manuscript: Leiba, Fishman, Twig,
Gilad, Ron, Grossman.
Critical revision of the manuscript for important
intellectual content: Leiba, Fishman, Twig, Gilad,
Derazne, Shamiss, Shohat, Grossman.

E6 JAMA Internal Medicine Published online February 25, 2019 (Reprinted) jamainternalmedicine.com

© 2019 American Medical Association. All rights reserved.

Downloaded from jamanetwork.com by Macquarie University user on 02/25/2019
 Association of Adolescent Hypertension With Future End-Stage Renal Disease
Statistical analysis: Leiba, Fishman, Twig, Derazne.
Administrative, technical, or material support:
Fishman, Twig, Shohat, Ron.
Supervision: Grossman.
Conflict of Interest Disclosures: None reported.
Additional Contributions: The authors thank
Mrs Phyllis Curchack Kornspan for her editorial
services. Mrs Kornspan received compensation
for her contribution.
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