Persistent Asymptomatic Isolated Microscopic ...

ORIGINAL CONTRIBUTION

Persistent Asymptomatic Isolated Microscopic
Hematuria in Israeli Adolescents and Young Adults
and Risk for End-Stage Renal Disease

Asaf Vivante, MD Context Few data are available on long-term outcomes among adolescents and young
adults with persistent asymptomatic isolated microscopic hematuria.
Arnon Afek, MD, MHA
Objective To evaluate the risk of end-stage renal disease (ESRD) in adolescents and
Yael Frenkel-Nir, MD young adults with persistent asymptomatic isolated microscopic hematuria.

Dorit Tzur, MBA Design, Setting, and Participants Nationwide, population-based, retrospective
cohort study using medical data from 1 203 626 persons aged 16 through 25 years
Alon Farfel, MD (60% male) examined for fitness for military service between 1975 and 1997 were
linked to the Israeli treated ESRD registry. Incident cases of treated ESRD from Janu-
Eliezer Golan, MD ary 1, 1980, to May 31, 2010, were included. Cox proportional hazards models were
used to estimate the hazard ratio (HR) of treated ESRD among those diagnosed as
Yoram Chaiter, MD, MSc having persistent asymptomatic isolated microscopic hematuria.

Tamy Shohat, MD, MPH Main Outcome Measures Treated ESRD onset, defined as the date of initiation
of dialysis treatment or the date of renal transplantation, whichever came first.
Karl Skorecki, MD
Results Persistent asymptomatic isolated microscopic hematuria was diagnosed in
Ronit Calderon-Margalit, MD, MPH 3690 of 1 203 626 eligible individuals (0.3%). During 21.88 (SD, 6.74) years of follow-
up, treated ESRD developed in 26 individuals (0.70%) with and 539 (0.045%) with-
PERSISTENT ASYMPTOMATIC ISO- out persistent asymptomatic isolated microscopic hematuria, yielding incidence rates
lated microscopic hematuria is of 34.0 and 2.05 per 100 000 person-years, respectively, and a crude HR of 19.5 (95%
a frequent incidental finding on confidence interval [CI], 13.1-28.9). A multivariate model adjusted for age, sex, pa-
routine examination of chil- ternal country of origin, year of enrollment, body mass index, and blood pressure at
dren, adolescents, and young adults.1 baseline did not substantially alter the risk associated with persistent asymptomatic
The most recent American Academy of isolated microscopic hematuria (HR, 18.5 [95% CI, 12.4-27.6]). A substantially in-
Pediatrics guidelines rescinded the rec- creased risk for treated ESRD attributed to primary glomerular disease was found for
ommendation for urine screening dur- individuals with persistent asymptomatic isolated microscopic hematuria compared with
ing the second decade of life.2,3 Micro- those without the condition (incidence rates, 19.6 vs 0.55 per 100 000 person-years,
scopic hematuria is commonly screened respectively; HR, 32.4 [95% CI, 18.9-55.7]). The fraction of treated ESRD attributed
by the urinary dipstick test, and posi- to microscopic hematuria was 4.3% (95% CI, 2.9%-6.4%).
tive results usually prompt micro-
scopic examination, the gold standard Conclusion Presence of persistent asymptomatic isolated microscopic hematuria in
for detecting microscopic hematu- persons aged 16 through 25 years was associated with significantly increased risk of
ria.1,4 The definitions of microscopic he- treated ESRD for a period of 22 years, although the incidence and absolute risk re-
maturia vary from 2 to more than 10 main quite low.
erythrocytes per high-power field.1,4 Mi-
croscopic hematuria can be either an JAMA. 2011;306(7):729-736 www.jama.com
isolated finding accompanied by other
kidney abnormalities or part of a sys- atic isolated microscopic hematuria term outcomes of the condition among
temic condition. It also can be tran- should be evaluated is unclear.5 More- adolescents and young adults, and data
sient or persistent. over, the source frequently remains un- are lacking on long-term outcomes of
detected, and most patients are diag-
The extent to which adolescents and nosed as having persistent asymptomatic Author Affiliations are listed at the end of this article.
young adults with persistent asymptom- isolated microscopic hematuria of un- Corresponding Author: Asaf Vivante, MD, Israeli De-
known origin.1 Only a few population- fense Forces Medical Corps and Talpiot Medical Lead-
For editorial comment see p 764. based studies have addressed the long- ership Program, Edmond and Lily Safra Children’s Hos-
pital, Sheba Medical Center, Tel Hashomer 52621,
Israel ([email protected]).

©2011 American Medical Association. All rights reserved. JAMA, August 17, 2011—Vol 306, No. 7 729

PERSISTENT ASYMPTOMATIC ISOLATED MICROHEMATURIA AND ESRD RISK

large cohorts,6-10 leading to consider- of urine quantitative protein excre- on new patients receiving renal
able controversy over appropriate evalu- tion and to a board-certified nephrolo- replacement therapy and changes in
ation, management, and prognosis.11 gist for determination of a specific pro- treatment modality. The database
We conducted a nationwide, population- teinuria-related diagnosis. Participants includes demographic data, a primary
based, retrospective cohort study to with quantitative protein excretion ex- diagnosis, and initial modality of renal
evaluate the risk of treated end-stage re- ceeding 200 mg/24 h were excluded replacement therapy, as well as dates
nal disease (ESRD) in adolescents and from the study cohort. of initiating dialysis, change of dialysis
young adults with persistent asymptom- treatment modalities, renal transplan-
atic isolated microscopic hematuria. Diagnosis of Persistent tation, and death. Validation of the
Asymptomatic Isolated treated ESRD database includes peri-
METHODS odic linkage with the Israeli popula-
Microscopic Hematuria tion registry to update demographic
Study Participants and mortality data. Reports of cadaver-
Participants enrolled in the study were donor transplants in Israel are cross-
One year prior to their conscription initially screened for the presence of mi- checked with the National Laboratory
into military service, all eligible Israeli croscopic hematuria by the urinary dip- for Tissue Matching, and reports on
adolescents undergo obligatory medi- stick test, followed by sediment exami- living donor kidney transplants are
cal board examination for health sta- nation by urine microscopy if the crosschecked with the National Trans-
tus assessment that includes review- dipstick result was positive. The diag- plant Center. A single primary diagno-
ing the medical file obtained from nostic criteria for persistent asymptom- sis is recorded for each new patient in
the primary care physician, taking a atic isolated microscopic hematuria the treated ESRD database.13 The cur-
medical history and conducting a were: (1) 5 or more red blood cells per rent study cohort was linked to the
physical examination (including rou- high-power field for urine specimens Israeli treated ESRD registry using the
tine urinalysis), and, if needed, pro- obtained on 3 separate occasions on dif- identification number given to all
viding referral for further evaluation. ferent days (female participants were in- Israeli citizens at the time of birth or
All potential recruits undergo baseline structed to avoid testing during men- immigration.
measurement of weight and height struation); (2) serum creatinine values
and a sphygmomanometric blood within the normal range; (3) no abnor- The institutional review boards of
pressure measurement obtained at the malities detected on renal imaging stud- both the Israel Defense Forces and
right arm in the seated position.12 ies (which consisted of intravenous py- Sheba Medical Center approved the
elographic contrast imaging performed study and waived the requirement for
Inclusion criteria for the current from 1975 to the late 1980s and renal informed consent on the basis of pre-
study were age 16 through 25 years at urinary tract and bladder ultrasound serving participants’ anonymity.
the time of medical board examina- from the late 1980s to the end of en-
tion between 1975 and 1997. Because rollment in 1997); (4) being other- Outcome Variables and Follow-up
military service is not mandatory for Is- wise asymptomatic, with hematuria as
raeli non-Jews, the study population in- the sole finding and not attributed to Onset of treated ESRD was defined as
cluded only Jewish recruits, for whom other known or apparent disease; and the date of initiation of dialysis treat-
military service is compulsory. Exclu- (5) further evaluation and confirma- ment or the date of renal transplanta-
sion criteria were the presence of any tion of the diagnosis of asymptomatic tion, whichever came first, and all
of the following diagnoses: diabetes isolated microscopic hematuria by a treated ESRD cases from January 1,
mellitus, systemic lupus erythemato- board-certified nephrologist. Partici- 1980, to May 31, 2010, were in-
sus, vasculitis, hypertension, or any pants who fulfilled these criteria for per- cluded. The causes of treated ESRD
known past or current kidney disease sistent asymptomatic isolated micro- were categorized as diabetes, hyper-
at the time of enrollment, including scopic hematuria were then assigned a tension, glomerulonephritis (includ-
congenital or acquired anomalies of the specific code number. ing a subcategory for IgA nephropa-
kidneys or urinary tract, glomerulone- thy), hereditary nephritis, interstitial
phritis, nephrolithiasis, cystic renal dis- The Israeli Treated ESRD Registry nephritis, cystic kidney disease, sec-
ease, urinary tract infection, acute or ondary glomerulonephritis, drug-
chronic kidney injury, and protein- The Israeli treated ESRD database is a induced, and other causes. The etiol-
uria. Proteinuria was defined by urine national administrative registry main- ogy was recorded by the responsible
dipstick testing. Dipstick levels of 1ϩ tained by the Ministry of Health.13 It nephrologist at the medical center
or higher recorded during the initial uri- contains information on patients where the patient was receiving renal
nalysis screen were designated as posi- receiving any form of renal replace- replacement therapy; 23% of patients
tive and triggered 2 subsequent confir- ment therapy, ie, hemodialysis, perito- had missing information on etiology
matory dipstick tests. Participants with neal dialysis, or kidney transplanta- of treated ESRD. Follow-up period
at least 1 positive confirmatory result tion. All nephrology dialysis units in was measured from the initial medical
were referred for 24-hour assessment Israel report to the Ministry of Health

730 JAMA, August 17, 2011—Vol 306, No. 7 ©2011 American Medical Association. All rights reserved.

PERSISTENT ASYMPTOMATIC ISOLATED MICROHEMATURIA AND ESRD RISK

board assessment until the initiation Americas, West Asia, North Africa, and and 88% of the study population, re-
of renal replacement therapy (inci- Israel) and period of baseline exami- spectively, with missing values receiv-
dence of ESRD), death, or May 31, nation by decade. Additional models ing a separate category in the models.
2010, whichever came first. controlled for body mass index (BMI)
below or above the cutoff for over- Stratified analyses were conducted
Statistical Analysis weight (the sex-specific 85th percen- by strata of sex, age at enrollment, de-
tile, ie, 24.2 for male and 24.5 for fe- cade of enrollment, and years of follow-
Summary statistics for the study group male participants, calculated as weight up. Sensitivity analyses were re-
were expressed as mean (SD) or per- in kilograms divided by height in me- stricted to participants who had at least
centage. Cox proportional hazards ters squared) and for mean arterial 5 years of follow-up, treated ESRD di-
models14 were used to estimate the haz- blood pressure, calculated as 2/3 dia- agnosed from 1989, and best-worst sce-
ard ratios (HRs) and 95% confidence stolic blood pressure ϩ 1/3 systolic nario analysis for ESRD due to pri-
intervals (CIs) for comparing the inci- blood pressure and categorized as be- mary glomerular disease. This latter
dence of treated ESRD among partici- low or above the sex-specific 90th per- analysis considered the following di-
pants with and without persistent centile (98.3 mm Hg for male and 96.7 agnoses as ESRD due to primary glo-
asymptomatic isolated microscopic he- mm Hg for female participants). merular disease: hereditary nephritis,
maturia. The proportional hazards as- IgA nephropathy, focal segmental glo-
sumption was tested graphically using Data were complete for all variables merulosclerosis, membranoprolifera-
log–minus-log graphs. Models were except for BMI, mean arterial pres- tive glomerulonephritis, membranous
constructed controlling for age, sex, pa- sure, and paternal country of origin, nephropathy, glomerulonephritis not
ternal country of origin (Europe/ which were available for 96.7%, 91.9%, otherwise specified, and rapidly pro-

Figure 1. Participant Assessment, Designation, and Outcomes

1 237 869 Participants in target population

Primary medical evaluation
1. Review of all available medical files
2. Review of health summary filled out by

participant’s family physician
3. Detailed medical interview and physical

examination by physician
4. Measurement of weight, height, and

blood pressure
5. Urine dipstick test

Participants without hematuria and without medical Participants with hematuria and without medical Participants with medical conditions conferring
conditions conferring increased risk for ESRDa conditions conferring increased risk for ESRDa increased risk for ESRDa

Secondary medical evaluation
1. Three additional urine microscopy tests
2. Renal and bladder imaging studies
3. Measurement of serum creatinine level

Evaluation by nephrologist
1. Five or more RBCs per high-power field

on each urine test
2. Serum creatinine values within normal range
3. Normal renal imaging study results
4. Hematuria as sole finding not attributable

to other disease

1 199 936 Without confirmed persistent asymptomatic 3690 With confirmed persistent asymptomatic 34 243 At risk for ESRD excluded from
isolated microscopic hematuria included in isolated microscopic hematuria included primary analysis
primary analysis (control group) in primary analysis
350 Developed ESRD at end of follow-up
539 Developed ESRD at end of follow-up 26 Developed ESRD at end of follow-up
JAMA, August 17, 2011—Vol 306, No. 7 731
ESRD indicates end-stage renal disease; RBC, red blood cell.
a Evaluation by a specialist and additional tests performed as needed.

©2011 American Medical Association. All rights reserved.

PERSISTENT ASYMPTOMATIC ISOLATED MICROHEMATURIA AND ESRD RISK

gressive glomerulonephritis. In best- 3690 (0.3%; annual range, 0.1%- Persistent Asymptomatic
worst scenario analyses, all or none, re- 0.5%) were diagnosed as having per-
spectively, of the missing etiologies were sistent asymptomatic isolated micro- Isolated Microscopic Hematuria
designated as primary glomerular dis- scopic hematuria, and 1 199 936 were
ease. The models used for all 3 sce- negative for this condition (FIGURE 1). and Treated ESRD
narios were the same as those used for The condition at enrollment was twice During 26 278 598 person-years of fol-
the whole cohort. as prevalent among male as female par- low-up, 565 participants developed
ticipants (0.4% and 0.2%, respec- treated ESRD, for an overall incidence
PϽ.05 (2-sided) was considered to tively). Among participants with and rate of 2.15 per 100 000 person-years.
indicate statistical significance. All sta- without persistent asymptomatic iso- The characteristics of those who devel-
tistical analyses were conducted using lated microscopic hematuria, the mean oped treated ESRD, by study group, are
SPSS version 18 (SPSS Inc, Chicago, age at recruitment was 17.6 (SD, 1.2) reported in TABLE 2. Baseline data for
Illinois). and 17.3 (SD, 1.1) years, respectively, participants with persistent asymptom-
and the duration of follow-up was 20.7 atic isolated microscopic hematuria
RESULTS (SD, 5.9) and 21.9 (SD, 6.7) years, re- who developed ESRD (n=26 [0.7%])
spectively. BMI and blood pressure val- were similar to those of participants
Study Population ues at study enrollment according to sex without the condition who developed
subcategories for both groups were ESRD (n=539 [0.04%]) in all aspects
The cohort comprised 1 203 626 male similar (TABLE 1). except for BMI: the former had lower
and female adolescents and young BMI levels compared with the latter
adults (60% male). Of the 1 203 626 (mean, 20.6 [SD, 2.87] and 22.9 (SD,
participants who met entry criteria, 4.33], respectively; P = .001). Partici-
pants with persistent asymptomatic iso-
Table 1. Baseline Characteristics of 1 203 626 Participants Examined between 1975-1997 lated microscopic hematuria were
According to Persistent Asymptomatic Isolated Microscopic Hematuria Category younger at ESRD diagnosis compared
with their counterparts (mean age at di-
All Participants With Hematuria Without Hematuria agnosis, 34.7 [SD, 6.6] and 38.6 [SD,
8.5] years, respectively; P=.02) and had
Characteristic (N = 1 203 626) (n = 3690) (n = 1 199 936) a shorter follow-up (Table 2). The mean
age at the end of follow-up was 38.4 (SD,
Age at assessment, mean (SD), y 17.3 (1.1) 17.6 (1.2) 17.3 (1.1) 8.4) years (range, 18-60 years).

Male sex, No. (%) 723 044 (60.0) 2755 (74.7) 720 289 (60.0) FIGURE 2 shows the association be-
tween persistent asymptomatic isolated
Israeli born, No. (%) 1 022 050 (85.0) 3202 (86.7) 1 018 848 (85.0) microscopic hematuria and treated ESRD
507 781 (42.2) 1269 (34.4) 506 512 (42.2) during the follow-up period. The inci-
Country of origin, No. (%)a dence rates of treated ESRD were 34.0
Europe/Americas (95% CI, 22.2-49.9) per 100 000 person-
years among participants with persistent
Asia 304 711 (25.3) 1268 (34.3) 303 443 (25.3) asymptomatic isolated microscopic he-
maturia and 2.05 (95% CI, 1.88-2.23)
North Africa 300 783 (25.0) 926 (25.1) 299 857 (25.0) per 100 000 person-years among those
without the condition, yielding an un-
Israel 58 693 (4.8) 178 (4.8) 58 515 (4.8) adjusted HR of 19.5 (95% CI, 13.1-28.9).
117 (12.2) Controlling for age, sex, paternal coun-
Blood pressure, mean (SD), mm Hgb 117 (12.2) 118 (12.2) try of origin, period of enrollment, BMI,
Systolic and blood pressure at baseline had mini-
All mal effect on these estimated HRs for
treated ESRD (HR, 18.5 [95% CI, 12.4-
Male 119 (12.0) 120 (11.7) 27.6]) (TABLE 3). Restricting the study
population to those who had at least 5
Female 114 (12.0) 114 (11.9) years of follow-up also did not materi-
ally change the HR estimate (19.2 [95%
Diastolic 72.8 (8.12) 72.2 (8.23) 72.8 (8.12) CI, 12.9-28.6]).
All
To exclude the possibility of mis-
Male 72.5 (8.15) 73.5 (8.0) classification bias attributable to less
accurate imaging techniques during
Female 71.1 (8.39) 71.6 (8.10) the initial years of the study and to

Mean 87.7 (8.23) 87.4 (8.27) 87.7 (8.23)
All

Male 88.1 (8.09) 89.0 (7.94)

Female 85.3 (8.47) 85.7 (8.26)

Height, mean (SD), cm 173 (6.91) 174 (6.81)
Male

Female 21.5 (3.07) 162 (6.17) 162 (6.05)
21.2 (3.07) 21.5 (3.07)
BMI, mean (SD)c
All

Male 21.1 (3.07) 21.40 (3.05)

Female 21.5 (3.08) 21.50 (3.17)

Follow-up, mean (SD), y 21.9 (6.7) 20.7 (5.9) 21.9 (6.7)

Died, No. (%) 49 (1.3) 14 418 (1.2)

Abbreviation: BMI, body mass index.
a Data available from 88% of the study population. The country of origin denotes the country of birth of father or pa-

ternal grandfather.
b Data available from 91.9% of the study population.
c Calculated as weight in kilograms divided by height in meters squared. Data available from 96.7% of the study population.

732 JAMA, August 17, 2011—Vol 306, No. 7 ©2011 American Medical Association. All rights reserved.

PERSISTENT ASYMPTOMATIC ISOLATED MICROHEMATURIA AND ESRD RISK

eliminate concern that dates of the incidence of treated ESRD. These relatively low in the period 1975-1979
treated ESRD incidence before 1989 results were independent of potential (0.1%-0.2%) compared with subse-
were inaccurate, we analyzed treated ESRD risk confounders, such as age, quent years (0.2%-0.5%).15 Second,
ESRD in a subgroup of participants sex, country of origin, BMI, and blood data on persistent asymptomatic iso-
enrolled after 1989, all of whom pressure. Our results suggest that per- lated microscopic hematuria were col-
underwent renal ultrasonography. sistent asymptomatic isolated micro- lected from 1975 forward, whereas
Persistent asymptomatic isolated scopic hematuria among adolescents data on treated ESRD were collected
microscopic hematuria among the and young adults may be a strong pre- from 1980 forward. We addressed
587 211 participants diagnosed after dictive risk marker of future ESRD, at- these issues by stratifying our analyses
1989 was still strongly and indepen- tributable mostly to glomerular dis- by year of cohort enrollment and
dently associated with treated ESRD (HR, ease as the primary etiology. follow-up period, which yielded simi-
18.9 [95% CI, 6.81-52.2]). We further lar results.
studied the association for the whole Several limitations of this study
population with logistic regression and warrant consideration. First, the Third, clinical information, such as
with imputation of different incidence annual prevalence of asymptomatic normal baseline creatinine levels and
dates between 1980-1988, and those isolated microscopic hematuria was normal findings from renal imaging
analyses yielded identical estimates. The
fraction of treated ESRD attributed to mi- Table 2. Characteristics of Participants With Treated End-Stage Renal Disease According
crohematuria was 4.3% (95% CI, 2.9%- to Persistent Asymptomatic Isolated Microscopic Hematuria Category
6.4%).
Characteristic With Without P
Risk Factors for Specific Causes Hematuria (n = 26) Hematuria (n = 539) Value

of Treated ESRD No. Value (95% CI) No. Value (95% CI)

Reported etiologies for ESRD by study Enrollment baseline characteristics 21 80.7 (62.4-92.6) 419 77.7 (74.1-81.1) .72
group are reported in Table 2. We fur- Male sex, % 3 11.5 (3.0-28.3) 156 28.9 (25.2-32.9)
ther analyzed persistent asymptom-
atic isolated microscopic hematuria as Country of origin, %a
a risk factor for specific treated ESRD Europe/Americas
etiologies. Incidence rates of primary
glomerular disease–associated ESRD Asia 9 34.6 (18.4-54.1) 143 26.5 (22.9-30.4) .28
were 19.6 (95% CI, 11.0-32.4) vs 0.55 North Africa 11 42.3 (24.6-61.6) 160 29.6 (25.9-33.7)
(95% CI, 0.47-0.65) per 100 000 per-
son-years among participants with and Israel 1 3.8 (1.9-17.5) 15 2.8 (1.63-4.45) .22
without the condition, respectively. The 23 118 (113-122) 378 121 (120-122)
HR for treated ESRD attributed to pri- Blood pressure, mean, mm Hgb
mary glomerular disease, adjusted for Systolic
age, sex, country of paternal origin,
study period, BMI, and mean arterial Diastolic 23 72.9 (68.9-76.9) 378 74.4 (73.7-75.1) .48
pressure, was 32.4 (95% CI, 18.9-
55.7). In a best-worst sensitivity analy- Mean 23 87.9 (84.1-91.7) 378 90.1 (89.4-90.8) .21
sis, assuming all missing etiologies of BMI, meanc 25 20.6 (19.4-21.8) 474 22.9 (22.5-23.3) .001
ESRD in the control group were attrib-
utable to primary glomerular disease Characteristics at ESRD diagnosis 26 34.7 (32.1-37.3) 539 38.6 (37.9-39.3) .02
yielded an HRof 18.8 (95% CI, 11.1- Age at diagnosis, mean, y
31.8). The assumption that all miss-
ing etiologies in the group with hema- Follow-up time, mean, y 26 15.7 (13.1-18.3) 539 20.6 (19.9-21.3) .004
turia were attributable to primary
glomerular disease yielded an HR of Treated ESRD etiologies, % 1 3.8 111 20.6
43.1 (95% CI, 26.7-69.4). Diabetes

COMMENT Hereditary nephritis 4 15.4 7 1.3

In this long-term, nationwide, popula- IgA nephropathy 4 15.4 30 5.5
tion-based, retrospective cohort study,
persistent asymptomatic microscopic Glomerular disease (excluding 7 26.9 108 20
hematuria was strongly associated with IgA nephropathy)

Hypertension 1 3.8 27 5

Cystic kidney disease 1 3.8 39 7.2

Chronic interstitial nephritis 00 14 2.6

Secondary glomerulonephritis 0 0 42 7.8
or vasculitis

Drug induced 00 9 1.6

Miscellaneous conditions 3 11.5 20 3.7

Uncertain or unrecorded cause 5 19.2 132 24.5
Primary glomerular disease, %d
15 57.7 (38.4-75.4) 145 26.9 (23.3-30.8) .001

Renal transplantation, % 21 80.7 (62.4-92.6) 298 55.2 (51.1-59.5) .01
Died, % .78 e
3 11.5 (3.0-28.3) 80 14.8 (12.0-18.0)

Abbreviations: BMI, body mass index; CI, confidence interval; ESRD, end-stage renal disease.
a Data available from 88% of the study population.
b Data available from 91.9% of the study population.
c Calculated as weight in kilograms divided by height in meters squared. Data available from 96.7% of the study population.
d Defined as any of the following: IgA nephropathy, glomerular disease, hereditary nephritis.
e By Fisher exact test.

©2011 American Medical Association. All rights reserved. JAMA, August 17, 2011—Vol 306, No. 7 733

PERSISTENT ASYMPTOMATIC ISOLATED MICROHEMATURIA AND ESRD RISK

studies for the participants with hema- uria may have remained undetected or patients with microscopic hematu-
turia, were reported rather than mea- unreported during the initial screen- ria.16-18 Nevertheless, even if this were
sured. Therefore, we do not have par- ing; it is possible that some partici- the case, microscopic hematuria would
ticipants’ glomerular filtration rate pants who subsequently developed still represent an important clinical
values. Fourth, we cannot rule out the treated ESRD had microalbuminuria, a marker for an increased risk of renal dis-
possibility that trace dipstick protein- suggested risk factor for ESRD among ease in these participants, in the ab-
sence of abnormal measures for these
Figure 2. Cumulative Incidence of Treated ESRD among Participants With and Without other clinical indices of renal injury at
Persistent Asymptomatic Isolated Microscopic Hematuria the time of screening assessment. Last,
our study was limited to Jewish
0.015 recruits, so its generalizability may be
limited.
Persistent hematuria
Yes The strengths of our study are that
No it included very large cohorts with
detailed clinical assessment para-
Cumulative Incidence 0.010 meters together with a long follow-up
period and comprehensive documen-
Log-rank P<.001 tation of ESRD, thereby enabling the
determination of the risks for this dis-
0.005 ease with relatively low incidence.
Moreover, persistent asymptomatic
0 25 30 35 isolated microscopic hematuria was
0 5 10 15 20 diagnosed only after a nephrologic
1135 244 10 assessment had excluded other renal
Follow-up, y 431 433 212 810 1608 pathologies.

No. at risk The availability of such a large
mass-screening setup enabled us to
Persistent hematuria establish that the prevalence of per-

Yes 3690 3677 3665 2873 1978
947 735 680 092
No 1 199 936 1 196 606 1 193 878

Table 3. Association Between Persistent Asymptomatic Isolated Microscopic Hematuria and Treated End-Stage Renal Disease According to the
Cox Proportional Hazards Models by Sex, Age at Study Enrollment, Decade of Enrollment, and Follow-up Perioda

HR (95% CI)

With Hematuria Without Hematuria Adjusted

Variable No./100 000 No./100 000 Model 1b Model 2c
All ESRD Person-Years All ESRD Person-Years Unadjusted 18.1 (12.2-27.0) 18.5 (12.4-27.6)

All participants 3690 26 34 1 199 936 539 2.05 19.5 (13.1-28.9) 16.8 (10.8-26.1) 17.1 (11.0-26.7)
26.1 (10.5-64.8) 27.0 (10.9-66.9)
Sex 2755 21 36.5 720 289 419 2.64 16.5 (10.6-25.6)
Male 17.5 (10.0-30.5) 17.9 (10.3-31.3)
16.7 (9.30-30.1) 17.3 (9.59-31.1)
Female 935 5 26.3 479 647 120 1.15 25.6 (10.5-62.7)
20.0 (8.88-45.0) 20.8 (9.22-46.7)
Age at enrollment, y 2276 13 27.6 1 022 599 413 1.83 17.9 (10.3-31.2) 18.0 (10.8-30.0) 18.6 (11.1-31.1)
Յ17 16.8 (6.10-46.3) 18.9 (6.81-52.2)

Ͼ17 1414 13 44.4 177 337 126 3.41 14.5 (8.20-25.8) 25.2 (9.00-70.5) 25.5 (9.09-71.4)
28.3 (16.6-48.5) 28.9 (16.9-49.5)
Year of enrollment 206 6 93.1 189 541 256 4.19 23.2 (10.3-52.1) 10.1 (4.75-21.5) 10.5 (4.93-22.3)
1975-1979 18.7 (12.5-27.8) 19.2 (12.9-28.6)

1980-1989 1732 16 37.7 477 761 217 1.84 20.5 (12.3-34.0)

1990-1997 1752 4 14.5 532 634 66 0.79 18.4 (6.72-50.6)

Follow-up, y 3686 0 0 1 199 770 15 0.32
1-4

5-9 3677 4 21.8 1 196 606 51 0.85 25.5 (9.23-70.6)

10-19 3665 15 49.9 1 193 878 163 1.64 30.6 (18.0-51.9)

20-35 1978 7 61.0 680 092 310 6.27 11.4 (5.37-24.1)

Excluding first 5 y of 3677 26 44.8 1 196 606 524 2.58 20.1 (13.6-29.9)
follow-up

Abbreviations: CI, confidence interval; HR, hazard ratio.
a Negative persistent asymptomatic isolated microscopic hematuria is the reference category in all models (PϽ.001 for all).
b Adjusted for age, sex, country of origin, and period of baseline examination by decade of enrollment.
c Adjusted for covariates in model 1 plus body mass index and mean blood pressure.

734 JAMA, August 17, 2011—Vol 306, No. 7 ©2011 American Medical Association. All rights reserved.

PERSISTENT ASYMPTOMATIC ISOLATED MICROHEMATURIA AND ESRD RISK

sistent asymptomatic isolated micro- ute equally to its occurrence. More- diagnosis of asymptomatic isolated
scopic hematuria was 0.3% among over, hereditary nephritis may be microscopic hematuria following
adolescents and young adults. This much more widespread than com- urine screening can provide an alert
value is within the lower range of monly believed, and some cases to the future development of symp-
previously reported prevalence,1,7,9,15 may have been misdiagnosed as toms or renal failure.
most likely because we required per- benign thin basement membrane dis-
sistence of hematuria and micro- ease.23,30 Follow-up ended before the study
scopic confirmation rather than rely- population reached the age at which
ing solely on isolated dipstick tests, Among participants with hematu- ESRD peaks. ESRD is rare in young
which reportedly yield high rates of ria, early detection of ESRD with adults, as reflected by the low inci-
false-positive results.19 In addition, more assiduous follow-up might bias dence rates observed in our study.
the workup of positive hematuria the results. Nevertheless, early detec- However, because ESRD is the tip of
cases (ie, renal function tests and tion of chronic kidney disease likely the iceberg, estimated to represent
kidney imaging studies in addition to would have triggered therapeutic only 2% of all patients with chronic
a nephrologist’s evaluation) excluded interventions with the potential kidney disease, interpretation of our
other known causes of persistent of slowing progression to ESRD, findings should consider the much
microscopic hematuria, such as decreasing rather than increasing the wider spectrum and far larger num-
congenital renal malformations and hazard ratio. Treated ESRD is an bers of individuals with chronic kid-
urolithiasis.20 advanced clinical outcome, and its ney disease.31,32 Therefore, demon-
detection and universal registration in strating that persistent isolated
We found male predominance the Israeli health care system should microscopic hematuria is a risk
among participants with persistent not be influenced by diligence of marker for ESRD highlights the
asymptomatic isolated microscopic health care follow-up, in contrast to importance of early detection of pre-
hematuria. This is in line with the early presymptomatic stages of dialysis chronic kidney disease for
male predominance reported in IgA chronic kidney disease. Another the application of current and future
nephropathy21 and hereditary nephri- potential bias is that intravenous strategies to slow the deterioration to
tis22 and unlike the reported finding pyelographic contrast imaging per- ESRD. It also shows the importance
of possible mild female predomi- formed for evaluation prior to 1989 of considering complications and
nance in thin basement membrane could have caused increased kidney comorbid conditions across the range
disease.23 Those 3 etiologies are con- failure; however, restricting our study of chronic kidney disease.33
sidered by most authors to be pre- population to the post-1989 subgroup
dominant for persistent asymptom- did not materially change the results. Our study was not designed to
atic isolated microscopic hematuria examine the effectiveness of mass
in this age group.24-29 The association In our study, participants with screening for microscopic hematuria
with progression to chronic kidney ESRD and with persistent asymptom- in children and young adults. How-
disease is best established for IgA atic isolated microscopic hematuria ever, the additional cases attributed
nephropathy21 and Alport syn- were considerably younger at ESRD to persistent microhematuria, even if
drome.22 In contrast, thin basement onset compared with those with few, because they represent individu-
membrane disease, a common etiol- ESRD and no similar history (mean als who are younger at ESRD onset,
ogy for microscopic hematuria, had age at diagnosis, 34 vs 38 years, probably represent loss of many
been considered benign by most respectively). This may be related to quality-adjusted life years owing to
authors, although recent studies have the difference in underlying renal productivity loss and to ESRD-
suggested otherwise.23,30 Because diseases between the study groups related comorbid conditions. In light
renal biopsies are not typically part (Table 2). The condition was associ- of our findings, future studies are
of the evaluation of microscopic ated with an increased relative risk warranted to evaluate the utility of
hematuria, it is difficult to estimate for the development of ESRD attrib- population screening in improving
the prevalence of cases clearly attrib- utable to primary glomerular disease clinical outcomes.
utable to each disease category and (multivariate-adjusted HR, 32.4
to efficiently predict the risk for [95% CI, 18.9-55.7]). Consequently, Author Affiliations: Israeli Defense Forces Medical
future chronic kidney disease among our findings suggest that persistent Corps (Drs Vivante, Frenkel-Nir, Farfel, and
patients with persistent asymptom- asymptomatic isolated microscopic Chaiter and Ms Tzur); Department of Pediatrics,
atic isolated microscopic hematuria. hematuria detected during adoles- Talpiot Medical Leadership Program, Edmond and
Among the treated ESRD etiologies cence and young adulthood is an Lily Safra Children’s Hospital, Tel Hashomer (Dr
of those patients in the current early marker for primary glomerular Vivante); Sheba Medical Center, Tel Hashomer
study, we found IgA nephropathy injury and may be the first sign of an (Drs Vivante and Afek); Sackler Faculty of Medicine,
and hereditary nephritis to contrib- occult renal disease. As such, there Tel-Aviv University, Tel-Aviv (Drs Vivante, Afek,
may be a window during which the Golan, and Shohat); Department of Nephrology;
Rambam Health Care Campus, Rappaport Faculty
of Medicine and Research Institute, The Technion–
Israel Institute of Technology, Haifa (Dr Skorecki);
Israel Renal Registry and Department of Nephrology

©2011 American Medical Association. All rights reserved. JAMA, August 17, 2011—Vol 306, No. 7 735

PERSISTENT ASYMPTOMATIC ISOLATED MICROHEMATURIA AND ESRD RISK

and Hypertension, Meir Medical Center, Kfar Saba (Dr Frenkel-Nir, Tzur, Farfel, Chaiter, Shohat, Skorecki, Funding/Support: Access to anonymized databases was
Golan); Israel Center for Disease Control, Ministry of Calderon-Margalit. provided by the Israel Defense Forces (IDF) Medical
Health, Jerusalem (Drs Shohat and Calderon- Drafting of the manuscript: Vivante, Afek, Frenkel-Nir, Corps and the Israeli Ministry of Health.
Margalit); and Hadassah-Hebrew University Braun Tzur, Farfel, Chaiter, Shohat, Skorecki, Calderon-Margalit. Role of Sponsor: Neither the IDF Medical Corps nor
School of Public Health, Jerusalem (Dr Calderon- Critical revision of the manuscript for important in- the Israeli Ministry of Health were involved in the de-
Margalit), Israel. tellectual content: Vivante, Afek, Farfel, Golan, Chaiter, sign and conduct of the study; the collection, man-
Author Contributions: Drs Vivante and Calderon- Shohat, Skorecki, Calderon-Margalit. agement, analysis, and interpretation of the data; or
Margalit had full access to all of the data in Statistical analysis: Calderon-Margalit. the preparation, review, or approval of the manu-
the study and take responsibility for the integrity Administrative, technical, or material support: script.
of the data and the accuracy of the data analysis. Vivante, Frenkel-Nir, Tzur. Additional Contributions: We thank Amir Tirosh, MD,
Study concept and design: Vivante, Afek, Frenkel-Nir, Study supervision: Vivante, Golan, Skorecki. PhD (Division of Endocrinology, Diabetes, and
Tzur, Farfel, Golan, Shohat, Skorecki, Calderon-Margalit. Conflict of Interest Disclosures: All authors have com- Hypertension, Brigham and Women’s Hospital,
Acquisition of data: Vivante, Afek, Frenkel-Nir, Tzur, pleted and submitted the ICMJE Form for Disclosure Harvard Medical School), for his valuable comments.
Golan, Chaiter, Shohat. of Potential Conflicts of Interest and none were re- Dr Tirosh received no compensation for his contribu-
Analysis and interpretation of data: Vivante, Afek, ported. tions.

REFERENCES 12. Israeli E, Schochat T, Korzets Z, Tekes-Manova 24. Kovacevic´ Z, Jovanovic´ D, Rabrenovic´ V,
D, Bernheim J, Golan E. Prehypertension and obesity Dimitrijevic´ J, Djukanovic´ J. Asymptomatic micro-
1. Cohen RA, Brown RS. Microscopic hematuria. in adolescents: a population study. Am J Hypertens. scopic haematuria in young males. Int J Clin Pract.
N Engl J Med. 2003;348(23):2330-2338. 2006;19(7):708-712. 2008;62(3):406-412.
2. American Academy of Pediatrics and Committee 13. Calderon-Margalit R, Gordon ES, Hoshen M, Kark 25. Lee YM, Baek SY, Kim JH, Kim DS, Lee JS, Kim
on Practice and Ambulatory Medicine. American Acad- JD, Rotem A, Haklai Z. Dialysis in Israel, 1989-2005— PK. Analysis of renal biopsies performed in children
emy of Pediatrics, Committee on Practice and Am- time trends and international comparisons. Nephrol with abnormal findings in urinary mass screening.
bulatory Medicine: recommendations for preventive Dial Transplant. 2008;23(2):659-664. Acta Paediatr. 2006;95(7):849-853.
pediatric health care. Pediatrics. 2000;105:645- 14. Andersen PK, Gill RD. Cox’s regression model for 26. Park YH, Choi JY, Chung HS, et al. Hematuria
646. counting processes: a large sample study. Ann Stat. and proteinuria in a mass school urine screening
3. Committee on Practice and Ambulatory Medicine 1982;10:1100-1120. test. Pediatr Nephrol. 2005;20(8):1126-1130.
and Bright Futures Steering Committee. Recommen- 15. Gordon C, Stapleton FB. Hematuria in adolescents. 27. Chow KM, Kwan BC, Li PK, Szeto CC. Asymp-
dations for preventive pediatric health care. Pediatrics. Adolesc Med Clin. 2005;16(1):229-239. tomatic isolated microscopic haematuria: long-term
2007;120:1376. 16. Shen P, He L, Jiang Y, Wang C, Chen M. Useful follow-up. QJM. 2004;97(11):739-745.
4. Sutton JM. Evaluation of hematuria in adults. JAMA. indicators for performing renal biopsy in adult pa- 28. Nieuwhof C, Doorenbos C, Grave W, et al. A pro-
1990;263(18):2475-2480. tients with isolated microscopic haematuria. Int J Clin spective study of the natural history of idiopathic non-
5. Kelly JD, Fawcett DP, Goldberg LC. Assessment and Pract. 2007;61(5):789-794. proteinuric hematuria. Kidney Int. 1996;49(1):
management of non-visible haematuria in primary care. 17. Eardley KS, Ferreira MAS, Howie AJ, Gosling P, 222-225.
BMJ. 2009;338:a3021. Lipkin GW. Urinary albumin excretion: a predictor of 29. Topham PS, Harper SJ, Furness PN, Harris KP, Walls
6. Dodge WF, West EF, Smith EH, Bruce Harvey III. glomerular findings in adults with microscopic J, Feehally J. Glomerular disease as a cause of iso-
Proteinuria and hematuria in schoolchildren: epidemi- haematuria. QJM. 2004;97(5):297-301. lated microscopic haematuria. Q J Med. 1994;
ology and early natural history. J Pediatr. 1976;88 18. Assadi FK. Value of urinary excretion of microal- 87(6):329-335.
(2):327-347. bumin in predicting glomerular lesions in children with 30. Voskarides K, Damianou L, Neocleous V, et al.
7. Vehaskari VM, Rapola J, Koskimies O, Savilahti E, Vilska isolated microscopic hematuria. Pediatr Nephrol. 2005; COL4A3/COL4A4 mutations producing focal
J, Hallman N. Microscopic hematuria in school children: 20(8):1131-1135. segmental glomerulosclerosis and renal failure in
epidemiology and clinicopathologic evaluation. J Pediatr. 19. Rao PK, Jones JS. How to evaluate “dipstick he- thin basement membrane nephropathy. J Am Soc
1979;95(5, pt 1):676-684. maturia”: what to do before you refer. Cleve Clin J Nephrol. 2007;18(11):3004-3016.
8. Murakami M, Yamamoto H, Ueda Y, Murakami K, Med. 2008;75(3):227-233. 31. Keith DS, Nichols GA, Gullion CM, Brown JB,
Yamauchi K. Urinary screening of elementary and ju- 20. Tu WH, Shortliffe LD. Evaluation of asymptom- Smith DH. Longitudinal follow-up and out-
nior high-school children over a 13-year period in Tokyo. atic, atraumatic hematuria in children and adults. Nat comes among a population with chronic kidney dis-
Pediatr Nephrol. 1991;5(1):50-53. Rev Urol. 2010;7(4):189-194. ease in a large managed care organization. Arch
9. Woolhandler S, Pels RJ, Bor DH, Himmelstein DU, 21. Donadio JV, Grande JP. IgA nephropathy. N Engl Intern Med. 2004;164(6):659-663.
Lawrence RS. Dipstick urinalysis screening of asymp- J Med. 2002;347(10):738-748. 32. Coresh J, Selvin E, Stevens LA, et al. Prevalence
tomatic adults for urinary tract disorders, I: hematuria 22. Hudson BG, Tryggvason K, Sundaramoorthy M, of chronic kidney disease in the United States.
and proteinuria. JAMA. 1989;262(9):1214-1219. Neilson EG. Alport’s syndrome, Goodpasture’s syn- JAMA. 2007;298(17):2038-2047.
10. Yamagata K, Yamagata Y, Kobayashi M, Koyama drome, and type IV collagen. N Engl J Med. 2003; 33. Go AS, Chertow GM, Fan D, McCulloch CE,
A. A long-term follow-up study of asymptomatic he- 348(25):2543-2556. Hsu C-Y. Chronic kidney disease and the risks
maturia and/or proteinuria in adults. Clin Nephrol. 23. Tryggvason K, Patrakka J. Thin basement mem- of death, cardiovascular events, and hospital-
1996;45(5):281-288. brane nephropathy. J Am Soc Nephrol. 2006;17 ization. N Engl J Med. 2004;351(13):1296-
11. Hogg RJ. Screening for CKD in children: a global (3):813-822. 1305.
controversy. Clin J Am Soc Nephrol. 2009;4(2):
509-515.

736 JAMA, August 17, 2011—Vol 306, No. 7 ©2011 American Medical Association. All rights reserved.