Beruflich Dokumente
Kultur Dokumente
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).
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
54
55
99m
DMSA Interpretation
Denition
Cortical defecta
Acute pyelonephritisa
Renal scarringa
Severity (grade) of scarringa
Kidney segmentsa
New scarring
Any scarring
Renal scarring gradea
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.
56
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).
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
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).
58
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.
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
60
References
1. Lebowitz RL: The detection and characterization of vesicoureteral reflux in the child. J Urol 148: 16401642, 1992
2. Venhola M, Hannula A, Huttunen NP, Renko M, Pokka T, Uhari
M: Occurrence of vesicoureteral reflux in children. Acta Paediatr
99: 18751878, 2010
3. Shaikh N, Ewing AL, Bhatnagar S, Hoberman A: Risk of renal
scarring in children with a first urinary tract infection: a systematic review. Pediatrics 126: 10841091, 2010
4. Faust WC, Diaz M, Pohl HG: Incidence of post-pyelonephritic
renal scarring: A meta-analysis of the dimercapto-succinic acid
literature. J Urol 181: 290297, discussion 297298, 2009
5. Mattoo TK: Vesicoureteral reflux and reflux nephropathy. Adv
Chronic Kidney Dis 18: 348354, 2011
6. Wang HH, Gbadegesin RA, Foreman JW, Nagaraj SK, Wigfall
DR, Wiener JS, Routh JC: Efficacy of antibiotic prophylaxis in
children with vesicoureteral reflux: Systematic review and metaanalysis. J Urol 193: 963969, 2015
7. Hoberman A, Greenfield SP, Mattoo TK, Keren R, Mathews R,
Pohl HG, Kropp BP, Skoog SJ, Nelson CP, Moxey-Mims M,
Chesney RW, Carpenter MA; RIVUR Trial Investigators: Antimicrobial prophylaxis for children with vesicoureteral reflux. N
Engl J Med 370: 23672376, 2014
8. Keren R, Carpenter MA, Hoberman A, Shaikh N, Matoo TK,
Chesney RW, Matthews R, Gerson AC, Greenfield SP, Fivush B,
McLurie GA, Rushton HG, Canning D, Nelson CP, Greenbaum L,
Bukowski T, Primack W, Sutherland R, Hosking J, Stewart D, Elder
J, Moxey-Mims M, Nyberg L: Rationale and design issues of the
Randomized Intervention for Children With Vesicoureteral Reflux (RIVUR) study. Pediatrics 122[Suppl 5]: S240S250, 2008
9. Carpenter MA, Hoberman A, Mattoo TK, Mathews R, Keren R,
Chesney RW, Moxey-Mims M, Greenfield SP; RIVUR Trial Investigators: The RIVUR trial: Profile and baseline clinical associations of children with vesicoureteral reflux. Pediatrics 132:
e34e45, 2013
10. Ziessman HA, Majd M: Importance of methodology on (99m)
technetium dimercapto-succinic acid scintigraphic image quality: Imaging pilot study for RIVUR (Randomized Intervention for
Children With Vesicoureteral Reflux) multicenter investigation. J
Urol 182: 272279, 2009
11. Greenfield SP, Carpenter MA, Chesney RW, Zerin JM, Chow J:
The RIVUR voiding cystourethrogram pilot study: Experience
with radiologic reading concordance. J Urol 188[Suppl]: 1608
1612, 2012
12. Ransley PG, Risdon RA: Reflux nephropathy: Effects of antimicrobial therapy on the evolution of the early pyelonephritic scar.
Kidney Int 20: 733742, 1981
13. Shindo S, Bernstein J, Arant BS Jr: Evolution of renal segmental
atrophy (Ask-Upmark kidney) in children with vesicoureteric
reflux: Radiographic and morphologic studies. J Pediatr 102:
847854, 1983
14. Ransley PG, Risdon RA: Renal papillary morphology in infants
and young children. Urol Res 3: 111113, 1975
15. Patterson LT, Strife CF: Acquired versus congenital renal scarring
after childhood urinary tract infection. J Pediatr 136: 24, 2000
16. Piepsz A, Tamminen-Mobius T, Reiners C, Heikkila J, Kivisaari A,
Nilsson NJ, Sixt R, Risdon RA, Smellie JM, Soderborg B; International
Reflux Study Group in Europe: Five-year study of medical or surgical
treatment in children with severe vesico-ureteral reflux dimercaptosuccinic acid findings. Eur J Pediatr 157: 753758, 1998
17. Gleeson FV, Gordon I: Imaging in urinary tract infection. Arch
Dis Child 66: 12821283, 1991
18. Martinell J, Claesson I, Lidin-Janson G, Jodal U: Urinary infection, reflux and renal scarring in females continuously followed for 13-38 years. Pediatr Nephrol 9: 131136, 1995
19. Benador D, Benador N, Slosman D, Mermillod B, Girardin E: Are
younger children at highest risk of renal sequelae after pyelonephritis? Lancet 349: 1719, 1997
20. Ataei N, Madani A, Habibi R, Khorasani M: Evaluation of acute
pyelonephritis with DMSA scans in children presenting after the
age of 5 years. Pediatr Nephrol 20: 14391444, 2005
21. Coulthard MG, Verber I, Jani JC, Lawson GR, Stuart CA, Sharma
V, Lamb WH, Keir MJ: Can prompt treatment of childhood UTI
prevent kidney scarring? Pediatr Nephrol 24: 20592063, 2009
61
Deceased.