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Article

Renal Scarring in the Randomized Intervention for


Children with Vesicoureteral Reflux (RIVUR) Trial
Tej K. Mattoo, Russell W. Chesney,a Saul P. Greenfield, Alejandro Hoberman, Ron Keren, Ranjiv Mathews,
Lisa Gravens-Mueller, Anastasia Ivanova, Myra A. Carpenter, Marva Moxey-Mims, Massoud Majd, and
Harvey A. Ziessman for the RIVUR Trial Investigators

Abstract
Background and objectives The main objectives of the Randomized Intervention for Children with Vesicoureteral
Reux (RIVUR) trial were to evaluate the role of antimicrobial prophylaxis in the prevention of recurrent urinary
tract infection (UTI) and renal scarring in children with vesicoureteral reux (VUR). We present a comprehensive
evaluation of renal scarring outcomes in RIVUR trial participants.
Design, setting, participants, & measurements This multicenter, randomized, placebo-controlled trial enrolled
607 children aged 271 months with grade 14 VUR diagnosed after a rst or second febrile or symptomatic UTI.
Study participants received trimethoprim-sulfamethoxazole or placebo and were followed for 2 years. Renal
scarring was evaluated by baseline and follow-up 99mtechnetium dimercaptosuccinic acid (DMSA) renal scans
that were reviewed independently by two blinded reference radiologists.
Results At the end of the study, 58 (10%) of 599 children and 63 (5%) of 1197 renal units had renal scarring. New
renal scarring did not differ between the prophylaxis and placebo groups (6% versus 7%, respectively). Children
with renal scarring were signicantly older (median age, 26 versus 11 months; P=0.01), had a second UTI
before enrollment (odds ratio [OR], 2.85; 95% condence interval [95% CI], 1.38 to 5.92), were more likely to be
Hispanic (OR, 2.22; 95% CI, 1.13 to 4.34), and had higher grades of VUR (OR, 2.79; 95% CI, 1.56 to 5.0). The
proportion of new scars in renal units with grade 4 VUR was signicantly higher than in units with no VUR (OR,
24.2; 95% CI, 6.4 to 91.2).

Due to the number of


contributing authors,
the affiliations are
provided in the
Supplemental
Material.
Correspondence:
Dr. Tej K. Mattoo,
Childrens Hospital of
Michigan, Wayne
State University
School of Medicine,
3901 Beaubien
Boulevard, Detroit, MI
48201. Email:
tmattoo@med.wayne.
edu

Conclusions Signicantly more renal scarring was seen in relatively older children and in those with a second
episode of febrile or symptomatic UTI before randomization. Preexisting and new renal scars occurred
signicantly more in renal units with grade 4 VUR than in those with low-grade or no VUR. Antimicrobial
prophylaxis did not decrease the risk of renal scarring.
Clin J Am Soc Nephrol 11: 5461, 2016. doi: 10.2215/CJN.05210515

Introduction
Vesicoureteral reux (VUR) is one of the most common congenital urinary tract abnormalities diagnosed
in childhood. The reported prevalence is about 1%,
although some believe that it may actually be higher
(1,2). VUR is believed to predispose to urinary tract
infection (UTI) and renal scarring. In a systematic review, Shaikh et al. (3) reported a relative risk (RR) of
1.5 (95% condence interval [95% CI], 1.1 to 1.9) for
acute pyelonephritis (APN) in children with VUR
compared with those without VUR and an RR of
2.6 (95% CI, 1.7 to 3.9) for renal scarring. Children
with VUR grades 3 or higher have a higher risk of
renal scarring compared with those with lower
grades (RR, 2.1; 95% CI, 1.4 to 3.2) (3). In another
systematic review, Faust et al. (4) reported odds ratios
(ORs) of 2.8 (95% CI, 1.9 to 4.2) and 3.7 (95% CI, 1.3 to
11.1) for renal scarring after APN in children with
VUR and renal units with reuxing ureters, respectively. The authors concluded that children with VUR
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Copyright 2016 by the American Society of Nephrology

have an increased risk of renal scarring (4). Renal


scarring associated with VUR is also known as reux
nephropathy (RN). Long-term potential complications of RN include hypertension, proteinuria, and
progression to ESRD (5).
Many prospective studies have evaluated the role of
antimicrobial prophylaxis in the prevention of UTI
recurrence and renal scarring in children with primary
VUR (6). This includes our recently published Randomized Intervention for Children with Vesicoureteral Reux (RIVUR) trial (7). The primary outcome
of the RIVUR trial was recurrence of a febrile or
symptomatic UTI. We found a signicantly lower
risk of UTI recurrence in children receiving antimicrobial prophylaxis than in those receiving placebo
(RR, 0.55; 95% CI, 0.38 to 0.78) (7). Renal scarring
was a prespecied secondary outcome of the RIVUR
trial. The present report represents a comprehensive
evaluation of renal scarring outcomes in RIVUR trial
participants.
www.cjasn.org Vol 11 January, 2016

Clin J Am Soc Nephrol 11: 5461, January, 2016

Table 1. Definitions used for interpretation of

Renal Scarring in VUR and UTI, Mattoo et al.

55

99m

technetium dimercaptosuccinic acid renal scan

DMSA Interpretation

Denition

Cortical defecta
Acute pyelonephritisa
Renal scarringa
Severity (grade) of scarringa
Kidney segmentsa
New scarring

Focal or diffuse decreased uptake with or without volume loss


Cortical defect with preserved contour
Decreased uptake of tracer associated with loss of contours or cortical thinning
A: none; B: mild; C: moderate; D: severe; and E: global atrophy
Each kidney was divided into 12 segments (Supplemental Figure 1)
Presence of scarring in kidney segments that were previously normal
or showed APN
(1) New scarring or (2) presence of scarring at follow-up in patients who had no
baseline renal scan or (3) those with renal scarring on both baseline and any
follow-up scan
Grade 0: no scarring
Grade 1: 12 kidney segments affected
Grade 2: 34 kidney segments affected
Grade 3: .4 kidney segments affected
Grade 4: Global atrophy characterized by diffusely scarred and shrunken kidney

Any scarring
Renal scarring gradea

DMSA, 99mtechnetium dimercaptosuccinic acid; APN, acute pyelonephritis.


a
References 8,10.

Materials and Methods


Details on methods for patient selection, data collection,
and power analysis for the RIVUR trial have been described previously (8,9). The RIVUR trial was a multicenter, randomized, placebo-controlled trial in 607 children
aged 271 months with grade 14 primary VUR diagnosed
after a rst or second febrile or symptomatic UTI. Study
participants received trimethoprim-sulfamethoxazole
(TMP-SMZ) or a closely matched placebo and were followed up on for 2 years.
The Data Coordinating Center ensured that all participants,
clinical site investigators, and radiologists were blinded to
randomization assignment; participants and clinical site

investigators were further blinded to trial outcome data


during the trial. Pilot studies were conducted to ensure
uniformity in methods and imaging quality for 99mtechnetium
dimercaptosuccinic acid scintigraphy (DMSA renal scans)
(10) and voiding cystourethrogram (VCUG) (11). All DMSA
renal scans for the RIVUR trial were reviewed independently
by two blinded reference radiologists (M.M. and H.Z.), and
all differences were adjudicated to obtain a consensus reading between the two.
DMSA Renal Scans
In view of our pilot study results and to facilitate standardization and quality control across multiple participating

Figure 1. | Number of children and renal units included in the analyses. Of the 599 children analyzed, 109 (18%) had abnormal 99mtechnetium
dimercaptosuccinic acid (DMSA) scan findings. Of the 1197 renal units, 116 (10%) had abnormal DMSA scan findings. VUR, vesicoureteral reflux.

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Clinical Journal of the American Society of Nephrology

Table 2. Baseline demographic and clinical characteristics of 599 children by scarring status
Characteristics
Age
Median (25th, 75th quartiles), mo
Group
211 mo
1223 mo
2435 mo
3672 mo
Sex
Female
Male circumcised
Male uncircumcised
Race/ethnicityc
White
Black
Multiracial
Other
Hispanicc
Maternal level of education
High school graduate or lower
Some college education or 2-yr degree
College graduate or higher
Health insurance
Commercial
Publicd
Index UTI
First episode
Second episode
Type of index UTI
Only febrile 3839C
Only febrile $39C
Symptomatic only
Febrile and symptomatic
Index UTI organism
Escherichia coli
Other
Index infection resistant to TMP-SMZe
Resistant
Sensitive
Toilet trained
Bladder and bowel dysfunctionf
Constipationg
Ultrasonographic abnormalities
Hydronephrosish
Ureter duplication
Highest degree of VURi
Grade 1
Grade 2
Grade 3
Grade 4
Bilateral VUR

No Scarring
(n=541)

Any Scarring
(n=58)

P Valuea

New Scarring
(n=40)

P Valueb

11 (5, 29)

26 (9, 45)

0.01
,0.001

26 (10, 44)

0.02
,0.001

274 (51)
97 (18)
75 (14)
95 (18)

19 (33)
9 (16)
4 (7)
26 (45)

497 (92)
16 (3)
28 (5)

54 (93)
1 (2)
3 (5)

426 (80)
25 (5)
37 (7)
43 (8)
62 (12)

49 (84)
1 (2)
3 (5)
5 (9)
13 (22)

141 (26)
138 (26)
257 (48)

15 (26)
16 (28)
27 (47)

396 (74)
139 (26)

38 (66)
20 (34)

500 (92)
41 (8)

47 (81)
11 (19)

44 (8)
135 (25)
78 (14)
284 (52)

3 (5)
11 (19)
7 (12)
37 (64)

485 (90)
56 (10)

48 (83)
10 (17)

110 (22)
399 (78)
109 (20)
58 (56)
10 (9)

8 (15)
47 (85)
24 (41)
12 (57)
5 (23)

21 (4)
25 (5)

9 (16)
8 (14)

60 (11)
241 (45)
207 (38)
33 (6)
261 (48)

5 (9)
12 (21)
23 (40)
18 (31)
27 (47)

13 (33)
6 (15)
3 (8)
18 (45)
1.00

0.70
39 (98)
0 (0)
1 (3)

0.70

0.02
0.95

0.50
34 (85)
0 (0)
2 (5)
4 (10)
9 (23)

0.04
0.99

11 (28)
10 (25)
19 (48)
0.17

0.05
24 (60)
16 (40)

0.003

33 (83)
7 (18)

0.42

0.03
0.74

2 (5)
8 (20)
6 (15)
24 (60)
0.11

0.35
34 (85)
6 (15)

0.22
,0.001
0.91
0.08
,0.001
0.01
,0.001

0.81

0.12
4 (11)
33 (89)
15 (38)
9 (60)
4 (27)
6 (15)
5 (13)
4 (10)
9 (23)
15 (38)
12 (30)
20 (50)

0.01
0.76
0.05
0.001
0.04
,0.001

0.83

Values are reported as number (percentage) unless otherwise indicated. Test for association between the sites and age is based on
KruskalWallis test, chi-squared, or Fisher exact test for categorical variables. UTI, urinary tract infection; TMP-SMZ, trimethoprimsulfamethoxazole; VUR, vesicoureteral reux.
a
P values are for any scarring versus no scarring.
b
P values are for new scarring versus no scarring.
c
Race and Hispanic ethnicity categories were self-assigned by parents.
d
Three children with no insurance were classied into public category.
e
Included in this category are children whose index infection was caused by enterococci or Pseudomonas species, not tested for
susceptibility to trimethoprim-sulfamethoxazole and assumed to be resistant. Also included are children whose index infection was
caused by bacteria that were resistant to trimethoprim but that were not tested for resistance to sulfamethoxazole.
f
Dened as a score .6 for female patients and .9 for male patients, based on modication of the Dysfunctional Voiding Scoring System.
g
Dened as $two conditions according to modied Paris Consensus on Childhood Constipation Terminology Group criteria
(frequency of bowel movements fewer than three per week, more than one episode of fecal incontinence per week, passing large stool
that obstructed toilet, retentive posture and behavior, pain during defecation).
h
Hydronephrosis less than Society for Fetal Urology grade 4.
i
One child with central assessment of grade 5 was included in grade 4 (enrollment based on local readings).

Clin J Am Soc Nephrol 11: 5461, January, 2016

Renal Scarring in VUR and UTI, Mattoo et al.

Table 3. Prophylaxis and new renal scarring by patients and


renal units

Scarring Status
By patient
Patients, n
New renal
scarring
No new renal
scarring
By renal unit
Unit, n
New renal
scarring
No new renal
scarring

TMP-SMZ
Group

Placebo
Group

P Value

298
19 (6)

301
21 (7)

0.77

279(94)

280 (93)

596
21 (4)

601
22 (4)

575 (96)

579 (96)

0.90

Unless otherwise noted, values are expressed as number


(percentage). TMP-SMZ, trimethoprim-sulfamethoxazole.

sites, we required planar images using parallel-hole collimator


(low-energy high-resolution; 2563256 matrix; 500,000
1,000,000 counts per image) or pinhole collimator (3- to 4mm pinhole insert; 150,000 counts or 10 minutes). DMSA

57

renal scans were obtained 1.53 hours after intravenous administration of an age-appropriate dose of DMSA, 35 mCi/
1.73 m2 body surface area or 50100 mCi/kg body wt (minimum dose of 0.51 mCi). Posterior and posterior-oblique
renal images were acquired. Differential renal function was
calculated on the posterior image by subtracting background
counts and calculating for each kidney the percentage of total
counts for both kidneys. Single-photon emission computed
tomography (SPECT) was not accepted for this study (10).
Per the RIVUR trial protocol, study participants were
scheduled for three DMSA renal scans. The baseline scan
was obtained within 2 weeks of randomization and #112
days from the index UTI. A second DMSA scan was obtained within 21 days of the 12-month follow-up visit. The
outcome scan was targeted within 10 days of the study exit
visit at 24 months after randomization. For all children
with treatment failure, the outcome DMSA scan was obtained approximately 4 months after meeting criteria for
treatment failure. Denition of kidney segments and details on renal units included in the study are shown in
Supplemental Figure 1 and Table 1, respectively.
Statistical Analyses
Of 607 RIVUR trial participants, we excluded six children
with missing DMSA scans, one child with missing central

Figure 2. | Renal units with renal scarring by vesicoureteral reflux (VUR) grade. (A) (Any scarring): The percentage of renal units with any
scarring was highest in grade 4 VUR; four of 311 (1%), six of 109 (6%), 11 of 400 (3%), 25 of 321 (8%), and 17 of 56 (30%) for grades 0, 1, 2, 3,
and 4 VUR, respectively (P,0.001 for grade 4 versus all other grades). (B) (New scarring): The percentage of renal units with new scarring was
highest in grade 4 VUR; three of 311 (1%), five of 109 (5%), nine of 400 (2%), 14 of 321 (4%), and 12 of 56 (21%) for grades 0, 1, 2, 3, and 4 VUR,
respectively (P,0.001 for grade 4 versus all other grades). (C) (Segment increase in new scarring): Grade 1 (one or two segments) scarring was
the most common segment increase in new scarring in 29 of 43 (67%) renal units, occurring in two, five, seven, eight, and seven renal units with
grades 0, 1, 2, 3, and 4 VUR, respectively. A one-segment increase in new renal scarring was present in 33% of children, 35% had a twosegment increase, 21% had a three to four-segment increase, and 12% had a five-segment or greater increase. (D) (Severity grade of any
scarring): Among 63 renal units with any scarring, grade B (mild) renal scarring was seen in more patients than grades C, D, and E (5%, 8%, 11%,
13%, and 11%, respectively, for grades 0, 1, 2, 3, and 4 VUR).

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Clinical Journal of the American Society of Nephrology

VCUG reading, and one child who had a horseshoe kidney,


resulting in a total of 599 children for the present analyses.
Exceptions to the RIVUR criteria for determining renal
scarring on the outcome scan (scan collected 2 years after
enrollment or 4 months after patient was categorized as
having treatment failure) were use of a baseline or followup scan with scarring for six children with no per protocol
outcome scan and use of a follow-up scan with scarring for
six children who had no scarring on their per protocol
outcome scan.
Descriptive statistics and frequency distributions were
used to describe all variables; we compared overall and
new renal units scarring by grade of VUR. With the
exception of age, for which a KruskalWallis test was

performed because of the skewed distribution, we used a


chi-squared test for characteristics according to presence of
scarring for categorical variables; if an expected cell count
was under ve, we used the Fisher exact test. To account
for within-participant correlations and test the association
of treatment group by renal scarring, we used the generalized estimating equation method. All analyses were performed in SAS software, version 9.2.

Results
The numbers of children and renal units included in
these analyses are shown in Figure 1. Bilateral VUR was
present in 288 children and unilateral VUR in 311. Of 599

Figure 3. | 99mtechnetium dimercaptosuccinic acid (DMSA) uptake in normal renal units with no scarring. A slightly decreasing trend existed
in the right and left kidneys with regard to mean percentage DMSA uptake in normal renal units without vesicoureteral reflux (VUR) and those
with varying degrees of VUR (P=0.01 and P,0.001, respectively). The mean percentage uptakes for the left kidneys were 52%, 50%, 51%,
50%, and 49% and for the right kidney 51%, 50%, 50%, 50%, and 48% for grade 0, 1, 2, 3, and 4 VUR, respectively.

Clin J Am Soc Nephrol 11: 5461, January, 2016

children, 109 (116 renal units) had abnormal DMSA scan


ndings. Of these, 58 (10%) children had renal scarring,
including ve children with bilateral renal scarring. The
other 51 children had APN that did not progress to renal
scarring on follow-up scan(s), or the child had only one
scan that showed APN. Altogether, 63 (5%) of 1197 renal
units had scarring, which included 43 units with new scarring (Supplemental Figure 2).
Baseline demographic and clinical characteristics for
children with renal scarring are shown in Table 2. Children
with any renal scarring were signicantly older than those
with no scarring (median age, 26 versus 11 months;
P=0.01). Signicantly more renal scars were noted in children who had a second febrile or symptomatic UTI before
enrollment (OR, 2.85; 95% CI, 1.38 to 5.92); in Hispanic
children (OR, 2.22; 95% CI, 1.13 to 4.34); in toilet-trained
children (OR, 2.78; 95% CI, 1.59 to 4.89); and in children
with hydronephrosis (OR, 4.61; 95% CI, 2.00 to 10.62), ureteral duplication (OR, 3.34; 95% CI, 1.43 to 7.81), and
higher grades of VUR (OR, 2.79; 95% CI, 1.56 to 5.0). We
found similar results for new scarring versus no scarring
present.
As shown in Table 3, antimicrobial prophylaxis did not
prevent new renal scarring in children receiving prophylaxis compared with those receiving placebo (6% versus
7%, respectively). Similarly, no treatment group difference
in renal scarring was noted in renal units (4% for both)
(Table 3).
The proportions of renal units with any scarring and new
scarring by grade of VUR are shown in Figure 2, A and B,
respectively. The overall proportions of renal units with
any scarring were four of 311 (1%), six of 109 (6%), 11 of
400 (3%), 25 of 321 (8%), and 17 of 56 (30%) for grades 0, 1,
2, 3, and 4 VUR, respectively (P, 0.001 for grade 4 versus
all other grades). For new scarring, corresponding proportions were three of 311 (1%), ve of 109 (5%), nine of 400
(2%), 14 of 321 (4%), and 12 of 56 (21%) for grades 0, 1, 2, 3,
and 4 VUR, respectively (P,0.001 for grade 4 versus all
other grades).
The presence of VUR and segment (grade) increase in
new renal scarring during follow-up in 43 affected renal
units is shown in Figure 2C. Grade 1 (one or two segments)
scarring was the most common segment increase in 29
(67%) renal units, occurring in two, ve, seven, eight,
and seven renal units with grade 0, 1, 2, 3, and 4 VUR,
respectively. Approximately one third (33%) of children
had a one-segment increase in new renal scarring, another third (35%) had a two-segment increase, 21% had a
three- to four-segment increase, and 12% had a ve-segment or greater increase. The proportion of different
grades of severity of any renal scarring in 63 renal units
is shown in Figure 2D. Grade B (mild) renal scarring was
seen in more patients than were grades C, D, and E (5%,
8%, 11%, 13%, and 11%, respectively, for grade 0, 1, 2, 3,
and 4 VUR).
Mean DMSA uptake in renal units with any renal
scarring for the right kidney was 43%69.8% and for the
left kidney 42%68.6%. A slightly decreasing trend on both
the right and left kidneys with regard to mean percentage
DMSA uptake in normal renal units without VUR and
those with varying degrees of VUR was noted (P,0.01
and P,0.001, respectively). The mean percentage uptakes

Renal Scarring in VUR and UTI, Mattoo et al.

59

for the left kidneys were 52%, 50%, 51%, 50%, and 49%
and for the right kidney 51%, 50%, 50%, 50%, and 48% for
grade 0, 1, 2, 3, and 4 VUR, respectively (Figure 3).

Discussion
RN due to APN, also called acquired RN, can result
from a single episode of APN or may take several years to
develop (12,13). In VUR, scarring tends to occur at the
renal poles because of the presence of extensively fused
(compound) renal papillae, which allows the entry of infected urine into the renal parenchyma (14). RN may also
be a result of abnormal renal development resulting in
focal renal hypoplasia or dysplasia (15), which is called
congenital RN. The DMSA renal scan is the current gold
standard for diagnosing renal scarring but does not help
distinguish acquired from congenital RN. This distinction
made on the basis of a preceding UTI may be arbitrary
because the possibility of a preexisting renal scar
before a UTI cannot always be ruled out.
In the present study, 58 (10%) of 599 children had renal
scarring at the end of the study, which includes 40 (69%)
children with new scarring. Twenty (3%) children had renal
scars in baseline scans, possibly congenital in origin unless
they had UTIs before the documented index UTI, a possibility that could not be ruled out with certainty. In
patients (n=41) with treatment failure, the median time
from randomization to the protocol outcome renal scan
(4 months after treatment failure) was 13 months, and it is
possible that scans in these patients at 2 years would have
revealed more new scars or worsening of existing scars.
Our study revealed that renal scarring is more likely in
older children than younger children and in those with a

Figure 4. | Percentage of female patients in recent prospective


studies. The percentage of study participants with renal scarring in the
Randomized Intervention for Children with Vesicoureteral Reflux
(RIVUR) study was 10%. Comparison of our data with other similar
recent studies shows that the number of patients with scarring in each
study correlated (r=20.7) with the number of females included in the
study. REF# indicates number in the reference list for the study.

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Clinical Journal of the American Society of Nephrology

second episode of UTI. These observations raise important


questions. Are infants truly at a higher risk of renal scarring
with APN compared with older children, as initially
reported in the International Reux Study (16) and subsequently endorsed by others (17,18). Recent studies have
already questioned this conventional wisdom by reporting
that younger age may not be a risk factor for renal scarring
(19,20); the risk in older children may even be higher
(21,22). In addition, the recommendation by the American
Academy of Pediatrics and National Institute for Health
and Clinical Excellence guidelines (23,24) to delay VCUG
until the second episode of UTI may need to be reviewed.
The incidence of new renal scarring in children receiving
antimicrobial prophylaxis did not differ from that in
patients receiving placebo, whether in terms of the proportion of children (6% and 7%) or renal units (4% versus
4%). These results are similar to those reported in other
recent studies that evaluated the role of antimicrobial
prophylaxis in reducing the risk of renal scarring (2529).
However, these results should not be interpreted as conclusive evidence against the role of antimicrobial prophylaxis in preventing renal scarring. None of these studies,
including the RIVUR trial, were designed primarily to
evaluate the role of antimicrobial prophylaxis in preventing scarring. Further, a follow-up of 12 years may have
been too short to determine long-term risk for the development of renal scarring or the effect of antimicrobial prophylaxis in its prevention. The risk may also have been
lowered by extra vigilance during the study period.
Our study revealed a higher risk of preexisting as well as
new renal scarring in renal units with grade 4 VUR
compared with no VUR or grade 13 VUR. After adjustment for correlated outcome data, scarring was 27 times
more likely to be observed in renal units with grade 4 VUR
compared with units with no VUR (95% CI, 8.3 to 89.6)
and six times more likely compared with units with grades
13 VUR (95% CI, 3.4 to 19.7). Few new scars occurred in
renal units with no VUR. Units with grade 4 VUR were 24
times more likely to have new scarring compared with
units with no VUR (95% CI, 6.4 to 91.2) and six times
more likely to have new scarring compared with units
with grade 13 VUR (95% CI, 3.2 to 11.7).These observations support the argument in favor of high-grade VUR
being a risk factor for preexisting as well as new renal
scarring. However, most children diagnosed with VUR
after a UTI have low-grade VUR (grades 13), but they
remain at some, although lower, risk for renal scarring.
Children in our study were followed for 2 years. At the
end of follow-up, approximately two thirds of renal units
with renal scarring had a one-segment (33%) or two-segment (35%) increase in scarring; the remaining third had a
three- to four-segment (21%) or $ve-segment (12%) increase in scarring. The possibility of developing scarring in
additional segments in these renal units in the future cannot be ruled out.
The proportion of children with any renal scars in the
RIVUR trial (10%) was higher than the 6% reported by
Garin et al. (25) and lower than the 30%63% reported in
other recent studies (2629). We believe that the low incidence of renal scarring in our study may be related to the
exclusion of children with more than two febrile or symptomatic UTIs, careful monitoring for UTI recurrence,

prompt intervention during the study period, generally


younger study cohort, and the exclusion of children with
grade 5 VUR in comparison to the study by Craig et al.
(28). However, the number of children with renal scarring
reported in the studies mentioned earlier show a strong
negative correlation (r=20.7) with the percentage of female patients included in each study (Figure 4). This could
be due to a higher incidence of congenital scarring in male
patients and their circumcision status; the latter, which is
practiced widely in the United States, decreases the likelihood of UTI recurrence.
Our incidental nding of a signicant decreasing trend in
mean percentage DMSA uptake in normal renal units with
different grades of VUR in comparison to renal units with
no VUR is interesting. If true, it raises the possibility of
subtle intrinsic renal parenchymal abnormality associated
with high-grade VUR affecting DMSA uptake in such
kidneys with no apparent cortical defect. This observation
needs to be conrmed in a larger cohort and, more
important, in renal units with grade 5 VUR.
We used the DMSA renal scan because of its superiority
over renal ultrasonography for the diagnosis of APN and
renal scarring, which has been demonstrated in multiple
studies, including experimental studies (3033). Of the
various methods available for doing DMSA renal scans,
we used planar images instead of SPECT because the latter would have posed substantial problems in standardization, quality control, and the review process (10).
Furthermore, some studies have reported that the SPECT
images offer no statistically signicant diagnostic advantage
over planar imaging for detection of cortical defects (30,34).
The RIVUR trial was not powered to evaluate renal
scarring as a primary outcome. Therefore, the relatively
small number of children with renal scarring limits the scope
of this study, particularly for subgroup analysis. The
strength, however, is its unprecedented quality in terms of
pilot studies, independent interpretation by two radiologists
blinded to clinical data, and study investigators blinded to
patient assignment of study medication and outcome classication. In view of these, we believe that the data presented
are a true representation of renal scarring as diagnosed by
DMSA renal scans in young children in the United States
with grade 14 VUR diagnosed after UTI.
Acknowledgments
The authors thank the RIVUR participants, their families, and
participating physicians, investigators, and staff for making this
research possible. We also thank Lena Peschansky and Catherine
Klida at Wayne State University for their help.
This research was supported by grants U01 DK074059 (M.A.C.),
U01 DK074053 (A.H.), U01 DK074082 (R.M.), U01 DK074064 (R.K.),
U01 DK074062 (T.K.M.), and U01 DK074063 (S.P.G.) from the National Institute of Diabetes and Digestive and Kidney Diseases,
National Institutes of Health, Department of Health and Human
Services.
The content of this article is solely the responsibility of the authors
and does not necessarily represent the ofcial views of the National
Institute of Diabetes and Digestive and Kidney Diseases or the
National Institutes of Health.
Disclosures
None.

Clin J Am Soc Nephrol 11: 5461, January, 2016

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Received: May 11, 2015 Accepted: September 29, 2015
a

Deceased.

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