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Unilateral vesicoureteric reflux: Low prevalence of contralateral renal damage
Unilateral vesicoureteric reflux: Low prevalence of contralateral renal damage Cesare Polito, MD, Pier Francesco Rambaldi, MD, Luigi Mansi, MD, Rosario Di Toro, MD, and Angela La Manna, MD Objective: We assessed the risk for the occurrence of renal damage in children with vesicoureteric reflux (VUR). Study design: We reviewed the records of 187 consecutive children, aged 3.8 ± (SD) 2.8 years, with unilateral primary VUR diagnosed after urinary tract infection (UTI). Dimercaptosuccinic acid renal scintigraphy was performed 4 to 6 months after the last UTI. Three patterns of renal damage were identified: global reduction (GR) of renal radionuclide uptake (20% to 40% of relative uptake), focal defects (FD) in uptake, and shrunken (relative uptake <20%) kidney (SK). We assumed that in these subjects FD indicated postpyelonephritic damage and that GR indicated congenital renal damage. Results: Scintigraphic renal damage of any type was present in 36.9% of the refluxing and in 3.2% of the nonrefluxing kidneys (odds ratio [OR], 17.6; 95% CI, 7.4 to 41.9). FD were present in 15.5% and 2.7% (OR, 6.7; CI, 2.5-17.6), GR in 19% and 0.5% (OR, 44.3; CI, 6.1 to 327.2), and SK in 6.9% and 0%, respectively. Patients with severe VUR showed a higher probability of renal damage than those with nonsevere VUR. Conclusions: In children with UTI and VUR, the refluxing kidney is most at risk of both congenital and acquired renal damage, and this risk increases with severity of reflux. (J Pediatr 2001;138:875-9)
Since the initial description1 of the association of renal parenchymal damage with vesicoureteric reflux and urinary tract infection, it has been commonly assumed that VUR is an absolute prerequisite for new or acquired
From the Departments of Pediatrics and of Radiological Sciences, Nuclear Medicine, Second University of Naples, Naples, Italy.
Submitted for publication June 14, 2000; revisions received Dec 13, 2000, and Dec 27, 2000; accepted Jan 8, 2001. Reprint requests: Cesare Polito, MD, Via S. Andrea delle Dame, 4, I-80138 Napoli, Italy. Copyright © 2001 by Mosby, Inc. 0022-3476/2001/$35.00 + 0 9/21/114336 doi:10.1067/mpd.2001.114336
renal damage. Indeed, renal damage has been reported in 13% to 62% of children with VUR in various studies,2-5 and its prevalence was higher in more severely refluxing units.3,5-7 Some doubt still remains about the magnitude of the risk for renal damage in patients with VUR and the relative contributions of congenital versus acquired renal damage. However, in the last decade it has been recognized that factors other than VUR such as bacterial virulence, associated bladder disease, and genetic susceptibility may contribute to the development of renal damage8-11 and that most children with pyelonephritis and scintigraphic renal abnormality do not have VUR.6,12-15
In this study we attempted to assess the size of the risk of VUR for the occurrence of renal damage in a sample of children with unilateral VUR diagnosed after UTI. These patients seem to us a good model for our purpose, because both the refluxing and the nonrefluxing kidney-ureter units are inserted to the same bladder, share the same host defenses and genetic susceptibility, and are both subjected to the same bacterial virulence. The prevalence of scintigraphic damage in refluxing kidneys evaluated 4 to 6 months after the last UTI was compared with that in nonrefluxing kidneys. Moreover, an attempt was made to distinguish congenital from acquired renal damage. FD GR SK UTI VUR
Focal defects Global reduction Shrunken kidney Urinary tract infection Vesicoureteric reflux
METHODS We reviewed the records of all children with unilateral VUR diagnosed in our institute after UTI from January 1993 until June 1999. We excluded from the study: (1) patients with myelomeningocele, ureterocele, urethral valves, and duplex kidney, (2) those who received the diagnosis after screening for familial VUR, (3) those evaluated for voiding disturbances without demonstrated UTI, (4) those with solitary kidney, and (5) those who received the diagnosis after prenatal diagnosis of urinary tract dilatation. This led to a sample of 187 children, 54 875
POLITO ET AL
A
THE JOURNAL OF PEDIATRICS JUNE 2001
B
C
Figure. Posterior view of dimercaptosuccinic acid renal scan in 3 children with unilateral reflux-associated renal damage. A, Focal defect of uptake in upper pole of right kidney. B, Global reduction (30% relative uptake) in left kidney uptake. C, Shrunken (8% relative uptake) left kidney.
Table I. Clinical and renal scintigraphic data of 187 children with unilateral reflux diagnosed by different imaging studies
One-cycle fluoroscopic cystourethrography Two-cycle fluoroscopic cystourethrography Fluoroscopic cystourethrography + isotopic cystography
N
M/F
Age (y) (mean ± SD)
Reflux grade ≥4 (n)
Ipsilateral Contralateral renal damage renal damage
139
36:103
4.2 ± 2.9
40
25
10:15
2.5 ± 2.1
6
7†
0
23
8:15
2.8 ± 2.3
6
10‡
0
52
6*
FD, Focal defects in renal radionuclide uptake; GR, global reduction of uptake (relative uptake: 20% to 40%); SK, shrunken kidney (relative uptake <20%). *FD in 5 patients and GR in 1; in the contralateral refluxing kidney: FD in 2 patients, GR in 1, SK in 1, normal kidney in 2. †In 1 patient with FD in the refluxing kidney, reflux was seen only at the second cycle of fluoroscopic cystourethrography. ‡In a patient with GR and in 1 with FD on the refluxing kidney, reflux was seen at isotopic cystography after negative fluoroscopic cystourethrography.
boys and 133 girls aged 3.8 ± (SD) 2.8 years, selected for the study; 131 of them were investigated for febrile (temperature ≥38.5°C) and 56 for nonfebrile UTI. A diagnosis of UTI required significant bacteriuria, that is, in 1 midstream sample or in 2 bag urine samples ≥105 colony forming units/mL of a single species, or ≥104 in urine obtained by bladder catheterization, with associated leukocyturia (≥5 white blood cells per high power field in a centrifuged specimen or leukocyte-positive dipstick) in children aged <2 years, and leukocyturia or positive nitrite test in those >2 years. Among the 117 patients >2 years of age, the diagnosis of UTI was made on a midstream sample in 105 (89.7%) and by bladder catheterization in 12 (10.3%). Among the 70 patients aged <2 years, the diagnosis was made by bladder catheterization in 59 (87.1%) and by bag urine in 9 (12.9%). 876
VUR was diagnosed by single fluoroscopic cystourethrography in 139 subjects, by 2-cycle fluoroscopic cystourethrography16 in 25, and by fluoroscopic cystourethrography + isotopic cystography17 in 23. Grading of VUR diagnosed at fluoroscopic cystourethrography was assessed according to the International Reflux Study Committee criteria.18 Mild (reflux to ureter or renal pelvis) to moderate (reflux to renal pelvis with mild to moderate dilatation) VUR diagnosed at isotopic cystography was considered to correspond to grades 1-3, and severe (distended redundant collecting system associated with ureteral dilatation) VUR was considered to correspond to grades 4-5 by fluoroscopic cystourethrography. Renal scintigraphy was performed 4 to 6 months after cure of the last UTI and the start of antibacterial prophylaxis; 0.5 MBq/kg body weight (minimum
10 MBq) of technetium 99-dimercaptosuccinic acid was administered intravenously. Two hours later, anterior, posterior, and left and right oblique posterior planar images were obtained by a gamma camera (Siemens Orbiter 75-, Erlangen, Germany) equipped with a Maxdelta computer system. The percentage of tracer uptake by both kidneys was obtained. Computer images were analyzed visually for evidence of cortical loss and photopenia consistent with cortical scarring. Following Crabbe et al,19 the lower limit of normal differential uptake was set at 40%. Three patterns of renal damage were identified: (1) global reduction in radionuclide uptake with differential uptake between 20% and 40%, (2) focal defects in radionuclide uptake (including large polar areas of photon deficiency), (3) shrunken kidney, that is, a small, poorly functioning kidney with relative uptake <20% (Figure). Cysto-
POLITO ET AL
THE JOURNAL OF PEDIATRICS VOLUME 138, NUMBER 6 Table II. Prevalence of different kinds of scintigraphic damage among refluxing and nonrefluxing kidneys
Grade 1-3 reflux
Grade 4-5 reflux
Contralateral Contralateral NonnonnonRefluxing OR refluxing Refluxing OR refluxing Refluxing OR refluxing kidneys (95% CI) kidneys kidneys (95% CI) kidneys kidneys (95% CI) kidneys No. Scintigraphic damage Patterns of scintigraphic damage Shrunken kidney (SK) Focal defect (FD) Global reduction (GR)
187 69
17.6 (7.4-41.9)
3 29‡§ 36‡§
6.7 (2.5-17.6) 44.3 (6.1-327.2)
187 6*
135 30
0
2
5
15‡
1
15†
7.4 (2.8-19.8)
135 5
52 39
0
11
4
14§
1
21§
4.1 (1.3-12.6) 16.7 (2.2-128.7)
15.3 (19.2-1220)
52 1†
0 18.8 (2.3-14.9)
1 0
OR, Odds ratio. *Two boys (1 with GR and 1 with FD), 4 girls with FD; mean age 6.4 years (range, 1.4 to 9.9). One patient showing FD was investigated for nonfebrile UTI, whereas the remaining 5 patients were investigated for febrile UTI. †SK in the refluxing and FD in the nonrefluxing kidney. ‡Two kidneys and §7 kidneys with GR and FD were included in both GR and FD groups.
graphic and scintigraphic tests were read independently. The χ2 test and the Fisher exact test, odds ratio, and χ2 test for trend were used for statistical analysis. A P value <.05 was considered significant.
RESULTS Data of children subdivided according to the imaging study that led to the diagnosis of VUR are reported in Table I. Among patients with VUR diagnosed by single fluoroscopic cystourethrography, scintigraphic renal damage was present in 52 (37.4%) of 139 of the refluxing kidneys and in 6 (4.3%) of 139 of the nonrefluxing kidneys. Among patients with VUR diagnosed by 2-cycle fluoroscopic cystourethrography or fluoroscopic cystourethrography + isotopic cystography, scintigraphic renal damage was present in 17 (35.4%) of 48 of the refluxing and in none of the nonrefluxing kidneys. In 3 of these 17 subjects having renal damage on the refluxing
kidney, VUR was diagnosed with only 1 of the 2 cystographic studies. The difference in the prevalence of contralateral renal damage among the patients with VUR diagnosed by single study (6 of 139, ie, 4.3%) and those with VUR diagnosed by double study (0 of 48, ie, 0%) was not significant (P = .323). That difference also was not significant when the children with febrile UTI (P = .44) and those with no febrile UTI (P = .63) were considered separately. Table II reports the prevalence of different kinds of scintigraphic damage among refluxing and nonrefluxing kidneys. Scintigraphic renal damage was present in 69 (36.9%) of 187 of the refluxing and in 6 (3.2%) of 187 of the nonrefluxing kidneys. The prevalence of FD was 29 (15.5%) of 187 in the refluxing and 5 (2.7%) of 187 in the nonrefluxing kidneys. The prevalence of GR was 36 (19%) of 187 in the refluxing and 1 (0.5%) of 187 in the nonrefluxing kidneys, and that of SK was 13 (6.9%) of 187 and 0 (0%) of 187, respectively. The estimated odds ratio in-
dicates a higher probability of any scintigraphic damage for refluxing than for nonrefluxing kidneys in the overall group of patients and in the subgroups with nonsevere (grade 1-3) and severe (grade 4-5) VUR. Patients with grade 4-5 VUR showed a higher probability of renal damage than patients with grade 1-3 VUR (Table II). A significant (χ2 for trend = 118.3; P < .0001) trend in the prevalence of renal damage resulted throughout no refluxing (6 of 187), grade 1-3 refluxing (30 of 135), and grade 4-5 refluxing (39 of 52) kidneys. Renal damage of any type on the refluxing kidney was present in 42.5% of boys and in 33.8% of girls (P = .33), with 9.3% of boys and 6% of girls (P = .64) having SK, 18.5% and 12.8% (P = .43), respectively, having isolated GR, 9.3% and 10.5% (P = .99) isolated FD, and 5.6% and 4.5% (P = .94) GR + FD. The children who presented with febrile UTI had significantly higher prevalences of any type of renal damage (P = .007) and of FD (P = .02) on the refluxing kidney than those with 877
POLITO ET AL
no febrile UTI (43.5% vs 21.4% renal damage of any type and 19.8% vs 5.3% FD, respectively). The prevalence of GR on the refluxing kidney was not significantly (P = .18) different among children presenting with febrile UTI (22.1%) and with no febrile UTI (12.5%).
DISCUSSION The renal parenchymal abnormalities observed in children with VUR can be the end result of more than one type of process, including abnormalities that are either congenital and developmental in origin or those that are acquired postnatally after UTI. The most recent and comprehensive studies on VUR in neonates report that nearly 80%20 or all21 patients with congenital renal damage exhibited GR of renal radionuclide uptake. Moreover, a recent report on urographically detected renal damage in children with UTI22 found that most boys and some girls probably had congenital refluxassociated renal damage, usually appearing as a globally small kidney with smooth renal outlines. Conversely, renal damage acquired after birth is usually characterized by FD in radionuclide uptake.12,19,23 As in another study,24 we postulate that in children with primary VUR, the scintigraphic evidence of GR indicates congenital renal abnormality and that FD indicates damage acquired after birth. Patients with SK were considered separately, because in a poorly functioning kidney it may be difficult to distinguish between GR of congenital origin and a gross pyelonephritic insult (or a combination of both mechanisms). Our study allows establishment of the magnitude of the risk of the occurrence of persistent scintigraphic renal damage with the use of the contralateral nonrefluxing unit as control of the refluxing one in a large series of unilateral primary VUR discovered after UTI. Independence is required by sta878
THE JOURNAL OF PEDIATRICS JUNE 2001 tistical tests, and this seems unlikely in our analysis, because the renal units are from the same individual. Nevertheless, the magnitude of the differences in the prevalence of renal damage we found among refluxing and nonrefluxing units was impressive. This finding indicates “a posteriori” an independence in point of fact, with refluxing units very prone to renal parenchymal damage. Renal damage of any type occurred in 3.2% and FD in 2.7% of nonrefluxing kidneys in our series. In contrast, the presence of VUR was associated with a 36.9% prevalence of renal damage of any type and a 15.5% prevalence of FD in the refluxing kidneys, with the odds ratios indicating a higher probability of any scintigraphic damage and of FD and GR for refluxing than for nonrefluxing kidneys (Table II). SKs were found in 13 (6.9%) of 187 of the refluxing and in none of the nonrefluxing kidneys in our series. No study has specifically addressed the prevalence of scintigraphic abnormalities in refluxing compared with nonrefluxing kidneys of children with unilateral VUR. However, some data can be indirectly drawn by recent reports.5,25 In one study on children with severe VUR,25 4 of the 51 nonrefluxing units showed scintigraphic abnormality, 3 of them being focal defects in uptake. In a report by Goldman et al5 on 74 infants with pyelonephritis and VUR, 19% of the patients had scintigraphic renal damage that was observed only when VUR was present and its grade >3. In this study no abnormality was found in 51 units without reflux, and a positive correlation resulted between the grade of VUR and abnormal scintigraphic scan. The prevalence of renal damage on refluxing units in our series (36.9%) is approximately twofold that (19%) found by Goldman et al5 in infants aged on average 4.12 months at their first pyelonephritic episode. The much higher age of our patients (3.8 years on average) with the possible cumulation
of previous pyelonephritic episodes may explain the difference. In this study the children with severe VUR showed a higher probability of renal damage than those with nonsevere VUR (Table II). Moreover, a significant trend in the prevalence of renal damage resulted throughout no refluxing, grade 1-3 refluxing, and grade 4-5 refluxing kidneys. This result agrees with other studies that found a close correlation between the existence of VUR and its degree and the prevalence of renal damage.3,5-7 In our series the prevalence of FD was significantly higher in children who presented with than in those who presented without febrile UTI. This result confirms our assumption that FD indicates postpyelonephritic renal damage, whereas GR indicates congenital abnormality. In agreement with the urographic findings by Wennerström et al,22 we have recently found that GR of radionuclide uptake suggesting congenital renal damage is frequent even in children with VUR detected after UTI.24 This is not surprising when considering that only some of the congenital VURs are detected at birth and that a number of them are detected later in life, after UTI. This study indicates that congenital renal damage is rare in nonrefluxing kidneys. Indeed, we found an impressively higher probability of GR for refluxing than for nonrefluxing kidneys (Table II) and, in fact, only 1 of 187 patients had GR on nonrefluxing kidneys. In most instances a renal scintigraphic abnormality does not imply a clinically important adverse outcome. This is especially true when only one kidney is affected. Therefore our series may represent a model to study the possible link between VUR and renal damage rather than to establish any adverse patient-centered outcome. Our data indicate a very strong association between the presence of VUR and that of both FD and GR, which is stronger in patients with severe reflux. Although VUR is not a necessary prerequisite for
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THE JOURNAL OF PEDIATRICS VOLUME 138, NUMBER 6 renal damage,6,12-15 in children with UTI and VUR the refluxing kidney is most at risk of both congenital and acquired renal damage, and this risk increases with severity of reflux. We thank Giuseppe Signoriello, MD (Medical Statistics of our University), for statistical support and counseling.
8.
9. 10.
REFERENCES 1. Hodson CJ, Maling TMJ, McManamon PJ, Lewis MG. The pathogenesis of reflux nephropathy (chronic atrophic pyelonephritis). Br J Radiol 1975(Suppl 13);48:1-26. 2. Smellie JM, Normand ICS, Katz G. Children with urinary infection: a comparison of those with and without vesico-uretric reflux. Kidney Int 1981;20: 717-22. 3. Stokland E, Hellstrom M, Jacobsson B, Jodal U, Sixt R. Renal damage one year after first urinary infection: role of dimercaptosuccinic acid scintigraphy. J Pediatr 1996;129:815-20. 4. Greenfield SP, Manyan NG, Wan J. Experience with vesicoureteral reflux in children: clinical characteristics. J Urol 1997;158:574-7. 5. Goldman M, Bistritzer T, Horne T, Zoareft I, Aladjem M. The etiology of renal scars in infants with pyelonephritis and vesicoureteral reflux. Pediatr Nephrol 2000;14:385-8. 6. Jakobsson B, Berg U, Svensson L. Renal scarring after acute pyelonephritis. Arch Dis Child 1994;70:111-5. 7. Martinell J, Hansson S, Claesson I, Jacobsson B, Lidin-Janson G, Jodal U. Detection of urographic scars in girls with pyelonephritis followed for
11.
12.
13.
14.
15.
16.
17.
13-38 years. Pediatr Nephrol 2000;14: 1006-10. Rushton HG. The evaluation of acute pyelonephritis and renal scarring with technetium 99m-dimercaptosuccinic acid renal scintigraphy: evolving concepts and future directions. Pediatr Nephrol 1997;11:108-20. Sillén U. Vesicoureteral reflux in infants. Pediatr Nephrol 1999;13:355-61. Ozen S, Alikasifoglu M, Saatci U, Bakkaloglu A, Besbas N, Kara N, et al. Implications of certain genetic polymorphism in scarring in vesicoureteric reflux: importance of ACE polymorphism. Am J Kidney Dis 1999;34:140-5. Weiss RA. Update on childhood urinary tract infections and reflux. Semin Nephrol 1998;18:264-9. Rushton G, Majd M, Jantaush B, Wiedermann BL, Belman AB. Renal scarring following reflux and non reflux pyelonephritis: evaluation with 99 m technetium-dimercaptosuccinic acid scintigraphy. J Urol 1992;147:1327-32. Rosemberg AR, Rosseleigh MA, Brydon MP, Bass SJ, Leighton DM, Farnsworth RH. Evaluation of acute urinary tract infection in children by dimercaptosuccinic acid scintigraphy: a prospective study. J Urol 1992;148: 1746-9. Garin EH, Campos A, Homsy Y. Primary vesicoureteral reflux: review of current concepts. Pediatr Nephrol 1998;12:249-56. Gordon I. Vesicoureteric reflux, urinary-tract infection, and renal damage in children. Lancet 1995;346:489-90. Polito C, Moggio G, La Manna A, Cioce F, Cappabianca S, Di Toro R. Cyclic voiding cystourethrography in the diagnosis of occult vesicoureteric reflux. Pediatr Nephrol 2000;14:39-41. Polito C, Rambaldi PF, La Manna A,
18.
19.
20.
21.
22.
23.
24.
25.
Mansi L, Di Toro R. Enhanced detection of vesicoureteric reflux with isotopic cystography. Pediatr Nephrol 2000;14:827-30. Lebowitz RL, Olbing H, Parkkulainen KV, Smellie JM, Tamminen-Möbius TE. International reflux study in children. Pediatr Radiol 1985;15:105-9. Crabbe DCG, Thomas DFM, Gordon AC, Irving HC, Arthur RJ, Smith SEW. Use of 99m technetium-dimercaptosuccinic acid to study patterns of renal damage associated with prenatally detected vesicoureteric reflux. J Urol 1992;148:1229-31. Yeung CK, Godley ML, Dhillon HK, Gordon I, Duffy PG, Ransley PG. The characteristics of primary reflux in male and female infants with prenatal hydronephrosis. Br J Urol 1997;80:319-27. Assael BM, Guez S, Marra G, Secco E, Manzoni G, Bosio N, et al. Congenital reflux nephropathy: a follow-up of 108 cases diagnosed prenatally. Br J Urol 1998;82:252-7. Wennerström M, Hansson S, Jodal U, Stokland E. Primary and acquired renal scarring in boys and girls with urinary tract infection. J Pediatr 2000;136:30-4. Stutley JE, Gordon I. Vesico-ureteric reflux in the damaged non-scarred kidney. Pediatr Nephrol 1992;6:25-9. Polito C, La Manna A, Rambaldi PF, Nappi B, Mansi L, Di Toro R. High incidence of a generally small kidney in primary vesicoureteric reflux. J Urol 2000;164:479-82. Piepsz A, Tamminen-Möbius T, Reiners C, Heikkilä J, Kivisaari A, Nilsson NJ, et al. Five-year study of medical or surgical treatment in children with severe vesico-ureteral reflux: dimercaptosuccinic acid findings. Eur J Pediatr 1998;157:753-8.
879
Since the initial description1 of the association of renal parenchymal damage with vesicoureteric reflux and urinary tract infection, it has been commonly assumed that VUR is an absolute prerequisite for new or acquired
From the Departments of Pediatrics and of Radiological Sciences, Nuclear Medicine, Second University of Naples, Naples, Italy.
Submitted for publication June 14, 2000; revisions received Dec 13, 2000, and Dec 27, 2000; accepted Jan 8, 2001. Reprint requests: Cesare Polito, MD, Via S. Andrea delle Dame, 4, I-80138 Napoli, Italy. Copyright © 2001 by Mosby, Inc. 0022-3476/2001/$35.00 + 0 9/21/114336 doi:10.1067/mpd.2001.114336
renal damage. Indeed, renal damage has been reported in 13% to 62% of children with VUR in various studies,2-5 and its prevalence was higher in more severely refluxing units.3,5-7 Some doubt still remains about the magnitude of the risk for renal damage in patients with VUR and the relative contributions of congenital versus acquired renal damage. However, in the last decade it has been recognized that factors other than VUR such as bacterial virulence, associated bladder disease, and genetic susceptibility may contribute to the development of renal damage8-11 and that most children with pyelonephritis and scintigraphic renal abnormality do not have VUR.6,12-15
In this study we attempted to assess the size of the risk of VUR for the occurrence of renal damage in a sample of children with unilateral VUR diagnosed after UTI. These patients seem to us a good model for our purpose, because both the refluxing and the nonrefluxing kidney-ureter units are inserted to the same bladder, share the same host defenses and genetic susceptibility, and are both subjected to the same bacterial virulence. The prevalence of scintigraphic damage in refluxing kidneys evaluated 4 to 6 months after the last UTI was compared with that in nonrefluxing kidneys. Moreover, an attempt was made to distinguish congenital from acquired renal damage. FD GR SK UTI VUR
Focal defects Global reduction Shrunken kidney Urinary tract infection Vesicoureteric reflux
METHODS We reviewed the records of all children with unilateral VUR diagnosed in our institute after UTI from January 1993 until June 1999. We excluded from the study: (1) patients with myelomeningocele, ureterocele, urethral valves, and duplex kidney, (2) those who received the diagnosis after screening for familial VUR, (3) those evaluated for voiding disturbances without demonstrated UTI, (4) those with solitary kidney, and (5) those who received the diagnosis after prenatal diagnosis of urinary tract dilatation. This led to a sample of 187 children, 54 875
POLITO ET AL
A
THE JOURNAL OF PEDIATRICS JUNE 2001
B
C
Figure. Posterior view of dimercaptosuccinic acid renal scan in 3 children with unilateral reflux-associated renal damage. A, Focal defect of uptake in upper pole of right kidney. B, Global reduction (30% relative uptake) in left kidney uptake. C, Shrunken (8% relative uptake) left kidney.
Table I. Clinical and renal scintigraphic data of 187 children with unilateral reflux diagnosed by different imaging studies
One-cycle fluoroscopic cystourethrography Two-cycle fluoroscopic cystourethrography Fluoroscopic cystourethrography + isotopic cystography
N
M/F
Age (y) (mean ± SD)
Reflux grade ≥4 (n)
Ipsilateral Contralateral renal damage renal damage
139
36:103
4.2 ± 2.9
40
25
10:15
2.5 ± 2.1
6
7†
0
23
8:15
2.8 ± 2.3
6
10‡
0
52
6*
FD, Focal defects in renal radionuclide uptake; GR, global reduction of uptake (relative uptake: 20% to 40%); SK, shrunken kidney (relative uptake <20%). *FD in 5 patients and GR in 1; in the contralateral refluxing kidney: FD in 2 patients, GR in 1, SK in 1, normal kidney in 2. †In 1 patient with FD in the refluxing kidney, reflux was seen only at the second cycle of fluoroscopic cystourethrography. ‡In a patient with GR and in 1 with FD on the refluxing kidney, reflux was seen at isotopic cystography after negative fluoroscopic cystourethrography.
boys and 133 girls aged 3.8 ± (SD) 2.8 years, selected for the study; 131 of them were investigated for febrile (temperature ≥38.5°C) and 56 for nonfebrile UTI. A diagnosis of UTI required significant bacteriuria, that is, in 1 midstream sample or in 2 bag urine samples ≥105 colony forming units/mL of a single species, or ≥104 in urine obtained by bladder catheterization, with associated leukocyturia (≥5 white blood cells per high power field in a centrifuged specimen or leukocyte-positive dipstick) in children aged <2 years, and leukocyturia or positive nitrite test in those >2 years. Among the 117 patients >2 years of age, the diagnosis of UTI was made on a midstream sample in 105 (89.7%) and by bladder catheterization in 12 (10.3%). Among the 70 patients aged <2 years, the diagnosis was made by bladder catheterization in 59 (87.1%) and by bag urine in 9 (12.9%). 876
VUR was diagnosed by single fluoroscopic cystourethrography in 139 subjects, by 2-cycle fluoroscopic cystourethrography16 in 25, and by fluoroscopic cystourethrography + isotopic cystography17 in 23. Grading of VUR diagnosed at fluoroscopic cystourethrography was assessed according to the International Reflux Study Committee criteria.18 Mild (reflux to ureter or renal pelvis) to moderate (reflux to renal pelvis with mild to moderate dilatation) VUR diagnosed at isotopic cystography was considered to correspond to grades 1-3, and severe (distended redundant collecting system associated with ureteral dilatation) VUR was considered to correspond to grades 4-5 by fluoroscopic cystourethrography. Renal scintigraphy was performed 4 to 6 months after cure of the last UTI and the start of antibacterial prophylaxis; 0.5 MBq/kg body weight (minimum
10 MBq) of technetium 99-dimercaptosuccinic acid was administered intravenously. Two hours later, anterior, posterior, and left and right oblique posterior planar images were obtained by a gamma camera (Siemens Orbiter 75-, Erlangen, Germany) equipped with a Maxdelta computer system. The percentage of tracer uptake by both kidneys was obtained. Computer images were analyzed visually for evidence of cortical loss and photopenia consistent with cortical scarring. Following Crabbe et al,19 the lower limit of normal differential uptake was set at 40%. Three patterns of renal damage were identified: (1) global reduction in radionuclide uptake with differential uptake between 20% and 40%, (2) focal defects in radionuclide uptake (including large polar areas of photon deficiency), (3) shrunken kidney, that is, a small, poorly functioning kidney with relative uptake <20% (Figure). Cysto-
POLITO ET AL
THE JOURNAL OF PEDIATRICS VOLUME 138, NUMBER 6 Table II. Prevalence of different kinds of scintigraphic damage among refluxing and nonrefluxing kidneys
Grade 1-3 reflux
Grade 4-5 reflux
Contralateral Contralateral NonnonnonRefluxing OR refluxing Refluxing OR refluxing Refluxing OR refluxing kidneys (95% CI) kidneys kidneys (95% CI) kidneys kidneys (95% CI) kidneys No. Scintigraphic damage Patterns of scintigraphic damage Shrunken kidney (SK) Focal defect (FD) Global reduction (GR)
187 69
17.6 (7.4-41.9)
3 29‡§ 36‡§
6.7 (2.5-17.6) 44.3 (6.1-327.2)
187 6*
135 30
0
2
5
15‡
1
15†
7.4 (2.8-19.8)
135 5
52 39
0
11
4
14§
1
21§
4.1 (1.3-12.6) 16.7 (2.2-128.7)
15.3 (19.2-1220)
52 1†
0 18.8 (2.3-14.9)
1 0
OR, Odds ratio. *Two boys (1 with GR and 1 with FD), 4 girls with FD; mean age 6.4 years (range, 1.4 to 9.9). One patient showing FD was investigated for nonfebrile UTI, whereas the remaining 5 patients were investigated for febrile UTI. †SK in the refluxing and FD in the nonrefluxing kidney. ‡Two kidneys and §7 kidneys with GR and FD were included in both GR and FD groups.
graphic and scintigraphic tests were read independently. The χ2 test and the Fisher exact test, odds ratio, and χ2 test for trend were used for statistical analysis. A P value <.05 was considered significant.
RESULTS Data of children subdivided according to the imaging study that led to the diagnosis of VUR are reported in Table I. Among patients with VUR diagnosed by single fluoroscopic cystourethrography, scintigraphic renal damage was present in 52 (37.4%) of 139 of the refluxing kidneys and in 6 (4.3%) of 139 of the nonrefluxing kidneys. Among patients with VUR diagnosed by 2-cycle fluoroscopic cystourethrography or fluoroscopic cystourethrography + isotopic cystography, scintigraphic renal damage was present in 17 (35.4%) of 48 of the refluxing and in none of the nonrefluxing kidneys. In 3 of these 17 subjects having renal damage on the refluxing
kidney, VUR was diagnosed with only 1 of the 2 cystographic studies. The difference in the prevalence of contralateral renal damage among the patients with VUR diagnosed by single study (6 of 139, ie, 4.3%) and those with VUR diagnosed by double study (0 of 48, ie, 0%) was not significant (P = .323). That difference also was not significant when the children with febrile UTI (P = .44) and those with no febrile UTI (P = .63) were considered separately. Table II reports the prevalence of different kinds of scintigraphic damage among refluxing and nonrefluxing kidneys. Scintigraphic renal damage was present in 69 (36.9%) of 187 of the refluxing and in 6 (3.2%) of 187 of the nonrefluxing kidneys. The prevalence of FD was 29 (15.5%) of 187 in the refluxing and 5 (2.7%) of 187 in the nonrefluxing kidneys. The prevalence of GR was 36 (19%) of 187 in the refluxing and 1 (0.5%) of 187 in the nonrefluxing kidneys, and that of SK was 13 (6.9%) of 187 and 0 (0%) of 187, respectively. The estimated odds ratio in-
dicates a higher probability of any scintigraphic damage for refluxing than for nonrefluxing kidneys in the overall group of patients and in the subgroups with nonsevere (grade 1-3) and severe (grade 4-5) VUR. Patients with grade 4-5 VUR showed a higher probability of renal damage than patients with grade 1-3 VUR (Table II). A significant (χ2 for trend = 118.3; P < .0001) trend in the prevalence of renal damage resulted throughout no refluxing (6 of 187), grade 1-3 refluxing (30 of 135), and grade 4-5 refluxing (39 of 52) kidneys. Renal damage of any type on the refluxing kidney was present in 42.5% of boys and in 33.8% of girls (P = .33), with 9.3% of boys and 6% of girls (P = .64) having SK, 18.5% and 12.8% (P = .43), respectively, having isolated GR, 9.3% and 10.5% (P = .99) isolated FD, and 5.6% and 4.5% (P = .94) GR + FD. The children who presented with febrile UTI had significantly higher prevalences of any type of renal damage (P = .007) and of FD (P = .02) on the refluxing kidney than those with 877
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no febrile UTI (43.5% vs 21.4% renal damage of any type and 19.8% vs 5.3% FD, respectively). The prevalence of GR on the refluxing kidney was not significantly (P = .18) different among children presenting with febrile UTI (22.1%) and with no febrile UTI (12.5%).
DISCUSSION The renal parenchymal abnormalities observed in children with VUR can be the end result of more than one type of process, including abnormalities that are either congenital and developmental in origin or those that are acquired postnatally after UTI. The most recent and comprehensive studies on VUR in neonates report that nearly 80%20 or all21 patients with congenital renal damage exhibited GR of renal radionuclide uptake. Moreover, a recent report on urographically detected renal damage in children with UTI22 found that most boys and some girls probably had congenital refluxassociated renal damage, usually appearing as a globally small kidney with smooth renal outlines. Conversely, renal damage acquired after birth is usually characterized by FD in radionuclide uptake.12,19,23 As in another study,24 we postulate that in children with primary VUR, the scintigraphic evidence of GR indicates congenital renal abnormality and that FD indicates damage acquired after birth. Patients with SK were considered separately, because in a poorly functioning kidney it may be difficult to distinguish between GR of congenital origin and a gross pyelonephritic insult (or a combination of both mechanisms). Our study allows establishment of the magnitude of the risk of the occurrence of persistent scintigraphic renal damage with the use of the contralateral nonrefluxing unit as control of the refluxing one in a large series of unilateral primary VUR discovered after UTI. Independence is required by sta878
THE JOURNAL OF PEDIATRICS JUNE 2001 tistical tests, and this seems unlikely in our analysis, because the renal units are from the same individual. Nevertheless, the magnitude of the differences in the prevalence of renal damage we found among refluxing and nonrefluxing units was impressive. This finding indicates “a posteriori” an independence in point of fact, with refluxing units very prone to renal parenchymal damage. Renal damage of any type occurred in 3.2% and FD in 2.7% of nonrefluxing kidneys in our series. In contrast, the presence of VUR was associated with a 36.9% prevalence of renal damage of any type and a 15.5% prevalence of FD in the refluxing kidneys, with the odds ratios indicating a higher probability of any scintigraphic damage and of FD and GR for refluxing than for nonrefluxing kidneys (Table II). SKs were found in 13 (6.9%) of 187 of the refluxing and in none of the nonrefluxing kidneys in our series. No study has specifically addressed the prevalence of scintigraphic abnormalities in refluxing compared with nonrefluxing kidneys of children with unilateral VUR. However, some data can be indirectly drawn by recent reports.5,25 In one study on children with severe VUR,25 4 of the 51 nonrefluxing units showed scintigraphic abnormality, 3 of them being focal defects in uptake. In a report by Goldman et al5 on 74 infants with pyelonephritis and VUR, 19% of the patients had scintigraphic renal damage that was observed only when VUR was present and its grade >3. In this study no abnormality was found in 51 units without reflux, and a positive correlation resulted between the grade of VUR and abnormal scintigraphic scan. The prevalence of renal damage on refluxing units in our series (36.9%) is approximately twofold that (19%) found by Goldman et al5 in infants aged on average 4.12 months at their first pyelonephritic episode. The much higher age of our patients (3.8 years on average) with the possible cumulation
of previous pyelonephritic episodes may explain the difference. In this study the children with severe VUR showed a higher probability of renal damage than those with nonsevere VUR (Table II). Moreover, a significant trend in the prevalence of renal damage resulted throughout no refluxing, grade 1-3 refluxing, and grade 4-5 refluxing kidneys. This result agrees with other studies that found a close correlation between the existence of VUR and its degree and the prevalence of renal damage.3,5-7 In our series the prevalence of FD was significantly higher in children who presented with than in those who presented without febrile UTI. This result confirms our assumption that FD indicates postpyelonephritic renal damage, whereas GR indicates congenital abnormality. In agreement with the urographic findings by Wennerström et al,22 we have recently found that GR of radionuclide uptake suggesting congenital renal damage is frequent even in children with VUR detected after UTI.24 This is not surprising when considering that only some of the congenital VURs are detected at birth and that a number of them are detected later in life, after UTI. This study indicates that congenital renal damage is rare in nonrefluxing kidneys. Indeed, we found an impressively higher probability of GR for refluxing than for nonrefluxing kidneys (Table II) and, in fact, only 1 of 187 patients had GR on nonrefluxing kidneys. In most instances a renal scintigraphic abnormality does not imply a clinically important adverse outcome. This is especially true when only one kidney is affected. Therefore our series may represent a model to study the possible link between VUR and renal damage rather than to establish any adverse patient-centered outcome. Our data indicate a very strong association between the presence of VUR and that of both FD and GR, which is stronger in patients with severe reflux. Although VUR is not a necessary prerequisite for
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THE JOURNAL OF PEDIATRICS VOLUME 138, NUMBER 6 renal damage,6,12-15 in children with UTI and VUR the refluxing kidney is most at risk of both congenital and acquired renal damage, and this risk increases with severity of reflux. We thank Giuseppe Signoriello, MD (Medical Statistics of our University), for statistical support and counseling.
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REFERENCES 1. Hodson CJ, Maling TMJ, McManamon PJ, Lewis MG. The pathogenesis of reflux nephropathy (chronic atrophic pyelonephritis). Br J Radiol 1975(Suppl 13);48:1-26. 2. Smellie JM, Normand ICS, Katz G. Children with urinary infection: a comparison of those with and without vesico-uretric reflux. Kidney Int 1981;20: 717-22. 3. Stokland E, Hellstrom M, Jacobsson B, Jodal U, Sixt R. Renal damage one year after first urinary infection: role of dimercaptosuccinic acid scintigraphy. J Pediatr 1996;129:815-20. 4. Greenfield SP, Manyan NG, Wan J. Experience with vesicoureteral reflux in children: clinical characteristics. J Urol 1997;158:574-7. 5. Goldman M, Bistritzer T, Horne T, Zoareft I, Aladjem M. The etiology of renal scars in infants with pyelonephritis and vesicoureteral reflux. Pediatr Nephrol 2000;14:385-8. 6. Jakobsson B, Berg U, Svensson L. Renal scarring after acute pyelonephritis. Arch Dis Child 1994;70:111-5. 7. Martinell J, Hansson S, Claesson I, Jacobsson B, Lidin-Janson G, Jodal U. Detection of urographic scars in girls with pyelonephritis followed for
11.
12.
13.
14.
15.
16.
17.
13-38 years. Pediatr Nephrol 2000;14: 1006-10. Rushton HG. The evaluation of acute pyelonephritis and renal scarring with technetium 99m-dimercaptosuccinic acid renal scintigraphy: evolving concepts and future directions. Pediatr Nephrol 1997;11:108-20. Sillén U. Vesicoureteral reflux in infants. Pediatr Nephrol 1999;13:355-61. Ozen S, Alikasifoglu M, Saatci U, Bakkaloglu A, Besbas N, Kara N, et al. Implications of certain genetic polymorphism in scarring in vesicoureteric reflux: importance of ACE polymorphism. Am J Kidney Dis 1999;34:140-5. Weiss RA. Update on childhood urinary tract infections and reflux. Semin Nephrol 1998;18:264-9. Rushton G, Majd M, Jantaush B, Wiedermann BL, Belman AB. Renal scarring following reflux and non reflux pyelonephritis: evaluation with 99 m technetium-dimercaptosuccinic acid scintigraphy. J Urol 1992;147:1327-32. Rosemberg AR, Rosseleigh MA, Brydon MP, Bass SJ, Leighton DM, Farnsworth RH. Evaluation of acute urinary tract infection in children by dimercaptosuccinic acid scintigraphy: a prospective study. J Urol 1992;148: 1746-9. Garin EH, Campos A, Homsy Y. Primary vesicoureteral reflux: review of current concepts. Pediatr Nephrol 1998;12:249-56. Gordon I. Vesicoureteric reflux, urinary-tract infection, and renal damage in children. Lancet 1995;346:489-90. Polito C, Moggio G, La Manna A, Cioce F, Cappabianca S, Di Toro R. Cyclic voiding cystourethrography in the diagnosis of occult vesicoureteric reflux. Pediatr Nephrol 2000;14:39-41. Polito C, Rambaldi PF, La Manna A,
18.
19.
20.
21.
22.
23.
24.
25.
Mansi L, Di Toro R. Enhanced detection of vesicoureteric reflux with isotopic cystography. Pediatr Nephrol 2000;14:827-30. Lebowitz RL, Olbing H, Parkkulainen KV, Smellie JM, Tamminen-Möbius TE. International reflux study in children. Pediatr Radiol 1985;15:105-9. Crabbe DCG, Thomas DFM, Gordon AC, Irving HC, Arthur RJ, Smith SEW. Use of 99m technetium-dimercaptosuccinic acid to study patterns of renal damage associated with prenatally detected vesicoureteric reflux. J Urol 1992;148:1229-31. Yeung CK, Godley ML, Dhillon HK, Gordon I, Duffy PG, Ransley PG. The characteristics of primary reflux in male and female infants with prenatal hydronephrosis. Br J Urol 1997;80:319-27. Assael BM, Guez S, Marra G, Secco E, Manzoni G, Bosio N, et al. Congenital reflux nephropathy: a follow-up of 108 cases diagnosed prenatally. Br J Urol 1998;82:252-7. Wennerström M, Hansson S, Jodal U, Stokland E. Primary and acquired renal scarring in boys and girls with urinary tract infection. J Pediatr 2000;136:30-4. Stutley JE, Gordon I. Vesico-ureteric reflux in the damaged non-scarred kidney. Pediatr Nephrol 1992;6:25-9. Polito C, La Manna A, Rambaldi PF, Nappi B, Mansi L, Di Toro R. High incidence of a generally small kidney in primary vesicoureteric reflux. J Urol 2000;164:479-82. Piepsz A, Tamminen-Möbius T, Reiners C, Heikkilä J, Kivisaari A, Nilsson NJ, et al. Five-year study of medical or surgical treatment in children with severe vesico-ureteral reflux: dimercaptosuccinic acid findings. Eur J Pediatr 1998;157:753-8.
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