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Familial Vesicoureteral Reflux
0022-5347/03/1695-1804/0 THE JOURNAL OF UROLOGY® Copyright © 2003 by AMERICAN UROLOGICAL ASSOCIATION
Vol. 169, 1804 –1808, May 2003 Printed in U.S.A.
DOI: 10.1097/01.ju.0000058428.00284.d5
Review Article FAMILIAL VESICOURETERAL REFLUX BORIS CHERTIN
AND
PREM PURI
From the Children’s Research Centre, Our Lady’s Hospital for Sick Children, University College Dublin, Dublin, Ireland
ABSTRACT
Purpose: Vesicoureteral reflux is known to occur in families. We summarized worldwide data on the incidence and nature of vesicoureteral reflux in siblings of children with vesicoureteral reflux. Materials and Methods: We searched MEDLINE using the words siblings vesicoureteral reflux, familial vesicoureteral reflux, offspring vesicoureteral reflux and vesicoureteral reflux screening. All articles that we identified that were published from 1972 to 2002 were analyzed for the incidence of renal damage in siblings of patients with vesicoureteral reflux. Results: Siblings of patients with vesicoureteral reflux have a much higher incidence of reflux than the normal population. There is a direct relationship of patient age to the incidence and severity of reflux. Most investigators advocate screening asymptomatic siblings of patients with vesicoureteral reflux. Conclusions: The incidence of sibling reflux is significant. When vesicoureteral reflux is discovered in symptomatic siblings, it is usually high grade and associated with a high incidence of reflux nephropathy. Randomized controlled studies are needed to compare renal damage in patients with reflux detected through screening to renal damage in those diagnosed after urinary tract infection to establish how much renal damage may be prevented by screening in asymptomatic siblings. KEY WORDS: kidney, vesico-ureteral reflux, urinary tract infections, screening, genetic disposition to disease
Primary vesicoureteral reflux is the most common urological anomaly in children and it has been reported in 30% to 50% of those who present with urinary tract infection.1⫺9 The association of vesicoureteral reflux, urinary tract infection and renal damage is well known.10⫺12 Reflux nephropathy is recognized as a major cause of end stage renal failure in children and young adults.1, 13 Parenchymal injury in vesicoureteral reflux occurs early, in most patients before age 3 years.2 Most renal scars are present when reflux is discovered at initial evaluation for urinary tract infection.7, 8 It is generally believed that early prevention of urinary tract infection may decrease the amount of the renal parenchymal damage. Since the prevalence of vesicoureteral reflux in the normal population is less than 1%, it is not feasible to screen the whole population for reflux. The hereditary and familial nature of vesicoureteral reflux is now well recognized and several studies have shown that the siblings of children with vesicoureteral reflux have a much higher incidence of reflux than the general pediatric population.14⫺22 It has been reported that when 1 child in a family has vesicoureteral reflux, the other siblings are at high risk for reflux, warranting evaluation.23 The early diagnosis and treatment of reflux in this group of patients appears to be beneficial and may avoid renal damage associated with vesicoureteral reflux. However, recent results of a survey by the Section on Pediatric Urology, American Academy of Pediatrics showed that approximately 20% of pediatric urologists do not evaluate asymptomatic siblings with vesicoureteral reflux.24 In Europe most physicians do not advocate routine screening of the siblings of children with vesicoureteral reflux. We present an overview summarizing worldwide experience with the incidence and nature of
vesicoureteral reflux in the siblings of children with vesicoureteral reflux.
EPIDEMIOLOGY OF FAMILIAL VESICOURETERAL REFLUX
Transmission of vesicoureteral reflux from parent to child. Noe et al studied a total of 36 offspring of 23 parents with primary vesicoureteral reflux previously demonstrated on radiography.22 Reflux was identified in 24 of the 36 offspring (66%) and all had grade II or higher disease. A striking finding in this study was a high incidence of reflux related morbidity in the parent group. Four of the 23 parents underwent nephrectomy due to nonfunctioning kidneys and 3 were known to have renal scars and hypertension. Scott et al performed a 3-year collaborative study in maternity hospitals in the United Kingdom to estimate the incidence of reflux transmission from parents or close relatives with a documented history of vesicoureteral reflux to a child.25 Of the 186 infants who met study inclusion criteria and underwent voiding cystourethrography after birth vesicoureteral reflux was detected in 20.4%. This incidence was highly significant compared with the 1% frequency of vesicoureteral reflux in the general population. The predominant relationship was through the mother. Furthermore, vesicoureteral reflux was present in 31% of the offspring of linked families. This proportion was significantly higher than that in nonlinked families. Screening asymptomatic siblings. The 3 mechanisms considered potential etiologies for renal scar formation are 1) reflux of infected urine with interstitial inflammation and damage, 2) sterile, usually high grade reflux, which may damage the kidney through a mechanical or immunological
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mechanism and 3) abnormal embryological development with subsequent renal dysplasia.7⫺9, 12, 23 Patients in the latter group may also have urinary tract infection in the postnatal period, resulting in extensive parenchymal damage. It is well recognized that in the first 2 groups of renal parenchymal damage it is essential to discover reflux early before damage can be initiated. In the third group it is clear that congenital damage currently cannot be prevented. However, in these patients it is mandatory to discover reflux at the early stages to prevent exposure to urinary tract infection and avoid the possible progression of renal parenchymal damage. A number of prospective and retrospective studies have investigated the incidence of vesicoureteral reflux and extent of renal parenchymal damage in the siblings of patients with vesicoureteral reflux.21, 23, 26 –34 Table 1 lists the results of the largest studies. In 1992 Noe reported the results of longterm followup of the sibling of patients with vesicoureteral reflux.26 Of the 354 screened siblings 119 (34%) had reflux. There was no statistical significance in the incidence of reflux in female and male siblings. Most siblings discovered to have reflux were asymptomatic and 61% had high grade disease (grades III to IV). Siblings younger than 18 months had a significantly higher rate of reflux than older children. Furthermore, in this younger group there was a statistically significant incidence of renal damage. Noe observed renal parenchymal damage in 13 of the 52 index patients (25%) and in 4 (7%) of the 54 siblings younger than 18 months. Moreover, only patients in the index group went on to have a nonfunctioning kidney, which required nephrectomy in 7 and dialysis in 2. In contrast, none of the siblings in the asymptomatic group presented with renal failure or renal loss. The most striking finding in this study was that none of the patients in the index group who underwent nephrectomy had evidence of renal dysplasia on histological examination. Thus, Noe presumed that renal damage in this group was mainly a result of urinary tract infection, which can be prevented with early diagnosis and intervention. After the Noe series Wan et al reported the results of a dual center retrospective study of the incidence of renal parenchymal damage in asymptomatic siblings with vesicoureteral reflux.27 A total of 422 families comprising 622 siblings were identified. Vesicoureteral reflux was noted in 144 siblings (27%) with a male-to-female ratio of 1:1.77. High grade reflux (grades III to V) was identified in 25% of all refluxing ureters, while 57% showed grade II disease. The incidence of renal scarring as an indication of reflux nephropathy was 13.6%. In this study renal scaring did not correlate with reflux grade and almost 40% of the patients with reflux nephropathy had only grade II reflux. As in many other studies, these results clearly indicate that reflux was a common finding in siblings 7 years and younger, while only a few siblings older than 10 years had reflux. Recently Cascio et al reported the results of a series comparing the incidence of renal damage in the siblings of pa-
tients with vesicoureteral reflux who presented with a documented history of urinary tract infection versus reflux in asymptomatic siblings diagnosed with that condition during a screening program for hereditary reflux.34 They retrospectively reviewed voiding cystourethrograms of children with vesicoureteral reflux in the 11-year period of 1990 to 2000 to identify siblings with reflux. Renal damage was classified using 99mTc-dimercapto-succinic acid (DMSA) renal scans in all patients. Vesicoureteral reflux was discovered in a total of 226 siblings in 107 families, including 96 families with 2, 10 families with 3 and 1 family with 4 siblings. There were 96 boys and 130 girls. Of the 226 patients 107 were index patients and the remaining 119 were siblings of these index patients. Median age of the index patients was 1.5 years (range 1 month to 14 years), median age of the symptomatic siblings was 1.2 years (range 3 months to 11.1 years) and median age of the asymptomatic siblings was 6 months (range 1 month to 8 years). Of the 107 index patients 104 were investigated after a urinary tract infection and 3 had a prenatal diagnosis of hydronephrosis. Of the 119 siblings 64 underwent investigation because of documented urinary tract infection and the remaining 55 with no history of urinary tract infection underwent screening voiding cystourethrography for sibling reflux. Vesicoureteral reflux was unilateral in 100 patients and bilateral in the remaining 126, representing 352 renal refluxing units. Reflux was grades I to V in 25, 30, 149, 120 and 28 refluxing renal units. Reflux was grades III-V in 84% of the screened siblings, in 86% of the siblings with urinary tract infection and in 83% of the index siblings. Renal scintigraphy revealed reflux nephropathy in 67 of the 352 refluxing renal units (19%), including 36 (22%) of the 166 in index patients, 25 (26%) of the 97 in siblings who presented with urinary tract infection and 6 (7%) of the 89 in asymptomatic siblings who underwent screening voiding cystourethrography. Reflux was grades III to V in 91% of the refluxing units with renal nephropathy. Mild renal damage was detected in 20 refluxing renal units (21%) in siblings with urinary tract infection and in 2(2%) in screened siblings. Moderate renal damage was noted in 4 refluxing renal units (4%) in siblings with urinary tract infection and in 2 (2%) in asymptomatic siblings. A shrunken kidney was discovered in 1 (1%) refluxing renal unit in a sibling who presented with urinary tract infection at age 4 months and in 2 (2%) asymptomatic siblings who were 3 and 6 months old, respectively. This study clearly showed that the incidence of mild renal damage was much higher in siblings who presented with urinary tract infection than in asymptomatic siblings. However, the true incidence of moderate and severe renal scarring in asymptomatic siblings was comparable to that in siblings with reflux and urinary tract infection. These results confirm that further randomized controlled trial are needed to compare renal damage in refluxing patients detected through screening with damage in those diagnosed after urinary tract in-
TABLE 1. Results of previously published studies on familial vesicoureteral reflux References
No. Screened Siblings
% Siblings With Reflux
% Reflux Grade I–II
III–V
% Reflux Nephropathy
44 39 75 90 27 – 69 16
56 61 25 10 73 – 31 84
15 13 14 23 5† 6 0‡ 11
% Boys/Girls
104 32 17/73 Jerkins and Noe17 354 34 –/– Noe26,* 532 27 48/52 Wan et al27 105 45 53/47 Kenda et al33 482 37 –/– Connolly et al28,* 65 26 48/52 Bonnin et al30 78 51 25/75 Parekh et al31 226 24 42/57 Cascio et al34 * No statistically significant difference between female and male affected siblings. † In most patients renal ultrasound was done to assess renal damage. ‡ In all patients renal ultrasound was done to assess renal damage.
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fection to establish how much renal damage may be prevented by screening asymptomatic patients. Recently Parekh et al attempted to determine the efficacy of a prospective screening analysis of an asymptomatic sibling of patients with reflux.31 A total of 40 of the 78 siblings (51%) of 72 index patients had reflux. All except 1 patient were asymptomatic. Of the asymptomatic siblings 77% were followed prospectively with a mean followup of 23 months. Renal ultrasound was done to assess renal parenchymal damage during followup. The previously reported direct relationship of patient age to the incidence and severity of reflux was strongly confirmed in the study. Of the refluxing renal units 60% were in children younger than 2 years. The incidence of grades III to IV vesicoureteral reflux in this group was also higher at 26% than in those older than 2 years. Reflux resolved spontaneously in 84% of the children and was down graded in 13%, while surgery for breakthrough infection was required only in 3%. The most important finding in this study was that no screened siblings had renal scarring on renal ultrasound. Although renal ultrasound is not an optimal tool to diagnose renal scarring, the gross pathological condition can be easily observed. Parekh et al suggested that an improved outcome in terms of renal scarring may have been due to the decrease in urinary tract infection caused by screening and aggressive management. However, they did not rule out the possibility that the response to injury may have been somewhat different in this group of patients. Although most investigators agree that screening asymptomatic siblings is beneficial, Bonnin et al have raised concern about the potential value of such a screening program at birth.30 They recently reported the results of a prospective study of the siblings of patients with vesicoureteral reflux in regard to the incidence of renal parenchymal damage. In a 1-year period direct radionuclide cystography and DMSA renal scan were proposed in all siblings of children with primary vesicoureteral reflux as soon as reflux was diagnosed in the index patient. They identified 46 symptomatic index patients with reflux and 65 siblings of these patients. Reflux was detected in 17 of the 65 siblings (26%), of whom 4 had a history of febrile urinary tract infection and the remaining 13 were asymptomatic. Bonnin et al also performed DMSA scan in siblings free of reflux to detect renal parenchymal damage in these patients. On DMSA renal scan only 6 of all screened siblings (10%) had abnormalities, including asymmetrical differential function in 5 and a parenchymal defect in 1. Only 1 of these 6 patients had reflux at the time of DMSA scan. Based on their finding Bonnin et al concluded that, although there was a significant 26% incidence of reflux in asymptomatic siblings of patients with primary reflux, systematic screening in this group was not beneficial. As described by Noe, there were some limitations of this study.35 Most of the 65 siblings were described as older than 18 months and it was not clear how old they were. The data included few infants. It is well known that the incidence of high grade reflux and subsequent renal injury is highest in infants. Reflux grades were not clear. Noe concluded that systematically screening asymptomatic siblings shows no benefit. The purpose of any screening program is to detect individuals at risk when some benefit and some protection may be provided by appropriate treatment.35 Even in the small series of Bonnin et al it would appear that the damage rate of 50% in index patients was much higher that the 6% in siblings.30 Recently Sweeney et al compared the incidence of renal scarring in infants with high grade vesicoureteral reflux with that in those presenting with urinary tract infection and those who mainly underwent screening for familial vesicoureteral reflux with no history of urinary tract infection.36 A total of 97 patients (148 renal refluxing units) presented clinically with urinary tract infection. DMSA renal scan dem-
onstrated renal scarring in 38% and 67% of refluxing renal units in patients with grades IV and V reflux, respectively. A total of 30 patients (46 renal refluxing units) were diagnosed with reflux before urinary tract infection developed. In this group of patients DMSA renal scan showed evidence of renal scarring in 29% and 36% of grades IV and V refluxing renal units, respectively. These findings of a significantly lower incidence of reflux nephropathy in infants with grade V reflux detected by screening compared with those who presented with a urinary tract infection raises possibility that early intervention in infants with high grade reflux may change its natural history and protect against renal scarring. Renal parenchymal damage in symptomatic siblings of children with vesicoureteral reflux. Most studies of familial reflux have evaluated asymptomatic siblings of children who were previously proved to have vesicoureteral reflux. The incidence of renal parenchymal damage in symptomatic siblings has received little attention. In 1998 Puri et al reported the results of a retrospective review of the medical records of the symptomatic siblings of 624 consecutive patients, including 406 girls and 218 boys, with reflux.37 Reflux was noted in 85 siblings (13%) in 41 families, including 41 index patients and 44 were symptomatic siblings. Of the index patients 15 were boys and 26 were girls, while in the group of symptomatic siblings boys were as commonly affected as girls. Table 2 shows comparative clinical data on index patients and their symptomatic siblings. Mean age of the symptomatic siblings at presentation was 2.7 years (range 1 month to 13 years) and 21 (48%) were younger than 1 year at diagnosis. In the group of symptomatic siblings reflux was grades I to V in 6, 6, 26, 25 and 5 ureters, respectively. Grades III to V disease were present in 82% of the ureters. DMSA renal scans performed in all patients to detect renal scarring was identified in 11 (25%) of the 44 symptomatic siblings, of whom 6 were boys and 5 girls, including 10 with high grade reflux. These data show that symptomatic siblings have higher grades of vesicoureteral reflux and an increased rate of reflux nephropathy compared with data reported in the literature on asymptomatic siblings.26, 30, 31 Thus it appears that early identification and treatment of asymptomatic siblings of index patients may result in a decreased incidence of reflux nephropathy and associated morbidity. Risk factors in the development of renal parenchymal damage in familial vesicoureteral reflux. The major goal of screening siblings is to identify risk factors leading to renal parenchymal damage. Recent developments in the field of molecular genetics have provided the opportunity to detect many clinical conditions early and a unique chance to prevent them. It has been reported that angiotensin-converting enzyme (ACE) I/D gene polymorphism is a risk factor for renal parenchymal damage in some renal diseases, for example diabetic nephropathy, IgA nephropathy and congenital urological anomalies.38⫺42 It also has been previously reported that the ACE genotype is a significant risk factor for renal parenchymal damage in patients with vesicoureteral reflux.40, 43 Recently Yoneda et al performed a study to identify significant independent risk factors, including ACE gene polymorphism, associated with renal parenchymal damage in pa-
TABLE 2. Clinical data on index patients and symptomatic siblings37
No. subjects (M/F) Mean age (yrs.) No. reflux: Unilat. Bilat. No. reflux nephropathy
Index Pts.
Siblings
41 (15/26) 2.2
44 (22/22) 2.7
16 25 11
20 24 11
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Region of Interest
Outcome
Chapman et al49 Middleton et al50 Eccles et al51 Sanyanusin et al52 Woolf and Winyard45 Feather et al53
Dominant inherited allele X chromosome HLA complex PAX 2 Chromosome 10q Genome wide search
Single dominant allele likely to cause reflux X chromosome linked form of reflux inheritance Weak involvement evidence No involvement evidence Unlikely Pos. reflux locus on 20cM cM 1p13 between GATA 176CO1 ⫹ D1S1653
tients with primary familial vesicoureteral reflux.44 They identified 88 families in which 2 or more members had primary vesicoureteral reflux, comprising 162 patients with a mean age of 2.3 years (range 3 weeks to 12 years). Reflux was unilateral and bilateral in 66 and 96 patients, and grades I to V in 19, 18, 110, 84 and 27 ureters, respectively. DMSA renal scans were performed to detect renal scarring. The frequency of allele genotypes in the patients were compared by the chi-square test for independence on univariate analysis. For multivariate analysis risk factors such as gender, age at diagnosis, history of urinary tract infection, reflux grade and ACE genotype were analyzed in a logistic regression model. Renal scarring was detected in 45 of the 162 patients (28%). Mean age at diagnosis of vesicoureteral reflux was 2.6 and 2.3 years in the patients with and without renal damage, respectively. There was no significant difference in mean age in patients with and without renal damage. By the chisquare test a positive history of urinary tract infection and higher reflux grade were significantly associated with renal parenchymal damage. There were no significant differences in ACE genotype distribution or gender distribution in patients with and without renal damage. On univariate analysis by logistic regression a history of urinary tract infection and reflux grade were significant risk factors. Multivariate analysis with all 5 factors, including urinary tract infection, reflux grade, ACE DD genotype, age at diagnosis and gender, revealed that only urinary tract infection, age at diagnosis and reflux grade were significantly associated with renal damage. ACE genotype and gender were not significant in any associations of these 5 risk factors. Therefore, Yoneda et al suggested that early discovery and management of reflux in siblings may prevent potential complications such as: hypertension, renal scarring and renal insufficiency associated with reflux.44 GENETIC BASIS OF FAMILIAL VESICOURETERAL REFLUX
Familial clustering of vesicoureteral reflux implies that genetic factors have an important role in the pathogenesis of reflux.23, 45– 47 Since vesicoureteral reflux may by genetically heterogeneous, linkage analysis would ideally be done on a large, single affected pedigree. However, the greatest problem with such analysis is determining the disease status of an individual. Vesicoureteral reflux may resolve spontaneously. In this particular setting there are no signs that an asymptomatic patient has reflux because the kidney may be normal. Therefore, reflux would appear incompletely penetrant. Table 3 lists the results of some studies regarding a region of genetic interest and the outcome of research. Recently an important role of the renin-angiotensin system in urinary tract development has began to be appreciated.38, 39 Of several genes acting in the renin-angiotensin system it has been reported that the disruption of the angiotensin II type 2 receptor (AT2) gene leads to congenital anomalies of the kidney and ureter in mice, including vesicoureteral reflux.42 In humans a single base A to G transition at position ⫺1332 in intron 1 (A-1332G) of the AT2 gene has been reported to occur significantly more often in patients with ureteropelvic junction obstruction and primary obstructive megaureter than in controls. Hohenfellner et al investigated the A-1332G transition in 23 male patients with pri-
mary sporadic vesicoureteral reflux and noted that the frequency of the A-1332G transition in those with sporadic reflux was not different from that in normal controls.39 On the other hand, recent total gene screening of primary nonsyndrome vesicoureteral reflux identified a possible locus that includes the AT2 gene on the long arm of the X chromosome.48 Since Hohenfellner et al studied only 23 male patients with sporadic disease, there still remains the question of whether the AT2 gene is involved in vesicoureteral reflux, especially primary familial reflux.39 Yoneda et al evaluated the incidence of the A-1332G transition in 82 males and 110 females, in 235 nonaffected family members (111 males and 124 females) from 88 families in which 2 or more members had primary reflux and in 213 controls (106 males and 107 females) unselected for reflux status.48 Genomic DNA was extracted from whole blood samples. Polymerase chain reaction method modified for fluorescence detection was done to type all samples for the A-1332G variant. Furthermore, to identify mutations in the coding sequence of the AT2 gene they selected 61 patients from different families and 15 controls unselected for reflux status. In males the A-1332G transition was identified in 27 of 82 patients with primary familial reflux (33%) and in 41 of 106 controls (38%). In females the incidence of the A-1332G substituted allele in patients and controls was 47% (104 of 220 total alleles) and 50% (107 of 214 total alleles), respectively. Moreover, the transmission-disequilibrium test revealed no significant skewing of genotype transmission from mother to child. None of the 61 patients or 15 controls carried any mutations or polymorphisms in the coding sequence of the AT2 gene. Yoneda et al concluded that the AT2 gene is not involved in the pathogenesis of primary familial vesicoureteral reflux. No doubt further investigations for identifying vesicoureteral reflux genes should be done for other candidates genes. In the long term understanding the genetic basis of vesicoureteral reflux would help design genetic screening tests with a view to early diagnosis and appropriate genetic counseling. CONCLUSIONS
The incidence of sibling vesicoureteral reflux is significant. When reflux is discovered in symptomatic siblings it is usually high grade and associated with a higher incidence of reflux nephropathy. There is a direct relationship of patient age to the incidence of reflux nephropathy and severity of reflux in symptomatic and asymptomatic siblings. In most series there was a higher incidence of high grade vesicoureteral reflux in children younger than 2 years, supporting evaluation of asymptomatic siblings. Furthermore, for primary reflux grade a history of urinary tract infection and age at diagnosis are the most important risk factors. It seems appropriate that, rather than waiting until urinary tract infection develops with the subsequent risk for renal scarring, a preemptive regimen of early detection and treatment should be initiated in these patients. REFERENCES
1. Medical versus surgical treatment of primary vesicoureteral reflux: report of the International Reflux Study Committee. Pediatrics, 67: 392, 1981
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2. Risdon, R. A.: The small scarred kidney in childhood. Pediatr Nephrol, 7: 361, 1993 3. Polito, C., La Manna, A., Rambaldi, P. F., Nappi, B., Mansi, L. and Di Toro, R.: High incidence of a generally small kidney and primary vesicoureteral reflux. J Urol, 164: 479, 2000 4. Jodal, U.: The natural history of bacteriuria in childhood. Infect Dis Clin North Am, 1: 713, 1987 5. Smellie, J. M., Normand, I. C. and Katz, G.: Children with urinary tract infection: a comparison of those with and those without vesicoureteric reflux. Kidney Int, 20: 717, 1981 6. Marra, G., Barbieri, G., Dell’Agnola, C. A., Caccamo, M. L., Castellani, M. R. and Assael, B. M.: Congenital renal damage associated with primary vesicoureteral reflux detected prenatally in male infants. J Pediatr, 124: 726, 1994 7. Assael, B. M., Guez, S., Marra, G., Secco, E., Manzoni, G., Bosio, M. et al: Congenital reflux nephropathy: a follow-up of 108 cases diagnosed perinatally. Br J Urol, 82: 252, 1998 8. Hinchliffe, S. A., Chan, Y. F., Jones, H., Chan, N., Kerczy, A. and van Velzen, D.: Renal hypoplasia and postnatally acquired cortical loss in children with vesicoureteral reflux. Pediatr Nephrol, 6: 439, 1992 9. Risdon, R. A., Yeung, C. K. and Ransley, P. G.: Reflux nephropathy in children submitted to unilateral nephrectomy: a clinicopathological study. Clin Nephrol, 40: 308, 1993 10. Goldraich, N. P. and Goldraich, I. H.: Followup of conservatively treated children with high and low grade vesicoureteral reflux: a prospective study. J Urol, 148: 1688, 1992 11. Mackie, G. G. and Stephens, F. D.: Duplex kidneys: a correlation of renal dysplasia with position of the ureteral orifice. J Urol, 114: 274, 1975 12. Schwarz, R. D., Stephens, F. D. and Cussen, L. J.: The pathogenesis of renal dysplasia. II. The significance of lateral and medial ectopy of the ureteric orifice. Invest Urol, 19: 97, 1981 13. North, R. A., Taylor, R. S. and Gunn, T. R.: Pregnancy outcome in women with reflux nephropathy and the inheritance of vesicoureteric reflux. Aust N Z J Obstet Gynaecol, 40: 280, 2000 14. Stephens, F. D., Joske, R. A. and Simmons, R. T.: Megaureter with vesicoureteric reflux in twins. Aust New Zeal J Surg, 24: 192, 1955 15. Bredin, H. C., Winchester, P., McGovern, J. H. and Degnan, M.: Family study of vesicoureteral reflux. J Urol, 113: 623, 1975 16. Dwoskin, J. Y.: Sibling uropathology. J Urol, 115: 726, 1976 17. Jerkins, G. R. and Noe, H. N.: Familial vesicoureteral reflux: a prospective study. J Urol, 128: 774, 1982 18. Sirota, L., Hertz, M., Laufer, J., Jonas, P. and Boichis, H.: Familial vesicoureteral reflux: a study of 16 families. Urol Radiol, 8: 22, 1986 19. Van den Abbeele, A. D., Treves, S. T., Lebowitz, R. L., Bauer, S., Davis, R. T., Retik, A. et al: Vesicoureteral reflux in asymptomatic siblings of patients with known reflux: radionuclide cystography. Pediatrics, 79: 147, 1987 20. Kaefer, M., Curran, M., Treves, S. T., Bauer, S., Hendren, W. H., Peters, C. A. et al: Sibling vesicoureteral reflux in multiple gestation births. Pediatrics, 105: 800, 2000 21. Kenda, R. B. and Fettich, J. J.: Vesicoureteral reflux and renal scars in asymptomatic siblings of children with reflux. Arch Dis Child, 67: 506, 1992 22. Noe, H. N., Wyatt, R. J., Peeden, J. N., Jr. and Rivas, M. L.: The transmission of vesicoureteral reflux from parent to child. J Urol, 148: 1869, 1992 23. Noe, H. N.: The current status of screening for vesicoureteral reflux. Pediatr Nephrol, 9: 638, 1995 24. Ferrer, F. A., McKenna, P. H., Hochman, H. I. and Herndon, A.: Results of a vesicoureteral reflux practice pattern survey among American Academy of Pediatrics, Section on Pediatric Urology members. J Urol, 160: 1031, 1998 25. Scott, J. E., Swallow, V., Coulthard, M. G., Lambert, H. J. and Lee, R. E.: Screening of newborn babies for familial ureteric reflux. Lancet, 350: 396, 1997 26. Noe, H. N.: The long-term results of prospective sibling reflux screening. J Urol, 148: 1739, 1992 27. Wan, J., Greenfield, S. P., Ng, M., Zerin, M., Ritchey, M. L. and Bloom, D.: Sibling reflux: a dual center retrospective study. J Urol, 156: 677, 1996 28. Connolly, L. P., Treves, S. T., Connolly, S. A., Zurakowski, D., Share, J. C., Bar-Sever, Z. et al: Vesicoureteral reflux in children: incidence and severity in siblings. J Urol, 157: 2287, 1997 29. Peeden, J. N., Jr. and Norman, N. H.: Is it practical to screen for familial vesicoureteral reflux within a private pediatric prac-
tice? Pediatrics, 89: 758, 1992 30. Bonnin, F., Lottmann, H., Sauty, L., Garel, C., Archambaud, F., Baudouin, V. et al: Scintigraphic screening for renal damage in siblings of children with asymptomatic primary vesicoureteric reflux. BJU Int, 87: 463, 2001 31. Parekh, D. J., Pope, J. C., IV, Adams, M. C. and Block, J. W., III: Outcome of sibling vesicoureteral reflux. J Urol, 167: 283, 2002 32. Buonomo, C., Treves, S. T., Jones, B., Summerville, D., Bauer, S. and Retik, A.: Silent renal damage in symptom-free siblings of children with vesicoureteral reflux: assessment with technetium Tc 99m dimercaptosuccinic acid scintigraphy. J Pediatr, 122: 721, 1993 33. Kenda, R. B., Zupancic, Z., Fettich, J. J. and Meglic, A.: A follow-up study of vesico-ureteric reflux and renal scars in asymptomatic siblings of children with reflux. Nucl Med Commun, 18: 827, 1997 34. Cascio, S., Yoneda, A., Chertin, B. and Corhoun, E.: Renal parenchymal damage in sibling vesicoureteric reflux. Unpublished data 35. Noe, H. N.: Scintigraphic screening for renal damage in siblings of children with asymptomatic primary vesico-ureteric reflux. BJU Int, 89: 792, 2002 36. Sweeney, B., Cascio, S., Velayudham, M. and Puri, P.: Reflux nephropathy in infancy: a comparison of infants presenting with and without urinary tract infection. J Urol, 166: 648, 2001 37. Puri, P., Cascio, S., Lakshmandass, G. and Colhoun, E.: Urinary tract infection and renal damage in sibling vesicoureteral reflux. J Urol, 160: 1028, 1998 38. Yerkes, E., Nishimura, H., Miyazaki, Y., Tsuchida, S., Block, J. W., 3rd and Ichikawa, I.: Role of angiotensin in the congenital anomalies of the kidney and urinary tract in the mouse and the human. Kidney Int, suppl., 67: S75, 1998 39. Hohenfellner, K., Fogo, A. and Kon, V.: Renin-angiotensin genes in renal development and the occurrence and progression of renal diseases. Semin Nephrol, 19: 148, 1999 40. Hohenfellner, K., Hunley, T. E., Brezinska, R., Brodhag, P., Shyr, Y., Brenner, W. et al: ACE I/D gene polymorphism predicts renal damage in congenital uropathies. Pediatr Nephrol, 13: 514, 1999 41. Ozen, S., Alikasifoglu, M., Saatci, U., Bakkaloglyu, A., Besbas, N., Kara, N. et al: Implications of certain genetic polymorphisms in scarring in vesicoureteric reflux: importance of ACE polymorphism. Am J Kidney Dis, 34: 140, 1999 42. Brock, J. W., III, Adams, M., Hunley, T., Wada, A., Trusler, L. and Kon, V.: Potential risk factors associated with progressive renal damage in childhood urological diseases: the role of angiotensinconverting enzyme gene polymorphism. J Urol, 158: 1308, 1997 43. Yoneda, A., Oue, T. and Puri, P.: Angiotensin-converting enzyme genotype distribution in familial vesicoureteral reflux. Pediatr Surg Int, 17: 308, 2001 44. Yoneda, A., Cascio, S., Oue, T., Chertin, B. and Puri, P.: Risk factors for the development of renal parenchymal damage in familial vesicoureteral reflux. J Urol, 168: 1704, 2002 45. Woolf, A. S. and Winyard, P. J.: Advances in the cell biology and genetics of human kidney malformations. J Am Soc Nephrol, 9: 1114, 1998 46. Uehling, D. T., Vlach, R. E., Pauli, R. M. and Friedman, A. L.: Vesicoureteric reflux in sibships. Br J Urol, 69: 534, 1992 47. Heale, W. F.: Hereditary vesicoureteric reflux: phenotypic variation and family screening. Pediatr Nephrol, 11: 504, 1997 48. Yoneda, A., Cascio, S., Green, A., Barton, D. and Puri, P.: Angiotensin II type 2 receptor gene is not responsible for familial vesicoureteral reflux. J Urol, 168: 1138, 2002 49. Chapman, C. J., Bailey, R. R., Janus, E. D., Abbott, G. D. and Lynn, K. C.: Vesicoureteric reflux: segregation analysis. Am J Med Genet, 20: 577, 1985 50. Middleton, G. W., Howards, S. S. and Gillenwater, J. Y.: Sexlinked familial reflux. J Urol, 114: 36, 1975 51. Eccles, M. R., Bailey, R. R., Abbott, G. D. and Sullivan, M. J.: Unravelling the genetics of vesicoureteric reflux: a common family disorder. Hum Mol Genet, 5: 1425, 1996 52. Sanyanusin, P., McNoe, L. A., Sullivan, M. J., Weaver, R. G. and Eccles, M. R..: Mutation of PAX2 in two siblings with renalcoloboma syndrome. Hum Mol Genet, 4: 2183, 1995 53. Feather, S. A., Malcolm, S., Woolf, A. S., Wright, V., Blaydon, D., Reid, C. J. et al: Primary, nonsyndromic vesicoureteric reflux and its nephropathy is genetically heterogeneous, with a locus on chromosome 1. Am J Hum Genet, 66: 1420, 2000
Vol. 169, 1804 –1808, May 2003 Printed in U.S.A.
DOI: 10.1097/01.ju.0000058428.00284.d5
Review Article FAMILIAL VESICOURETERAL REFLUX BORIS CHERTIN
AND
PREM PURI
From the Children’s Research Centre, Our Lady’s Hospital for Sick Children, University College Dublin, Dublin, Ireland
ABSTRACT
Purpose: Vesicoureteral reflux is known to occur in families. We summarized worldwide data on the incidence and nature of vesicoureteral reflux in siblings of children with vesicoureteral reflux. Materials and Methods: We searched MEDLINE using the words siblings vesicoureteral reflux, familial vesicoureteral reflux, offspring vesicoureteral reflux and vesicoureteral reflux screening. All articles that we identified that were published from 1972 to 2002 were analyzed for the incidence of renal damage in siblings of patients with vesicoureteral reflux. Results: Siblings of patients with vesicoureteral reflux have a much higher incidence of reflux than the normal population. There is a direct relationship of patient age to the incidence and severity of reflux. Most investigators advocate screening asymptomatic siblings of patients with vesicoureteral reflux. Conclusions: The incidence of sibling reflux is significant. When vesicoureteral reflux is discovered in symptomatic siblings, it is usually high grade and associated with a high incidence of reflux nephropathy. Randomized controlled studies are needed to compare renal damage in patients with reflux detected through screening to renal damage in those diagnosed after urinary tract infection to establish how much renal damage may be prevented by screening in asymptomatic siblings. KEY WORDS: kidney, vesico-ureteral reflux, urinary tract infections, screening, genetic disposition to disease
Primary vesicoureteral reflux is the most common urological anomaly in children and it has been reported in 30% to 50% of those who present with urinary tract infection.1⫺9 The association of vesicoureteral reflux, urinary tract infection and renal damage is well known.10⫺12 Reflux nephropathy is recognized as a major cause of end stage renal failure in children and young adults.1, 13 Parenchymal injury in vesicoureteral reflux occurs early, in most patients before age 3 years.2 Most renal scars are present when reflux is discovered at initial evaluation for urinary tract infection.7, 8 It is generally believed that early prevention of urinary tract infection may decrease the amount of the renal parenchymal damage. Since the prevalence of vesicoureteral reflux in the normal population is less than 1%, it is not feasible to screen the whole population for reflux. The hereditary and familial nature of vesicoureteral reflux is now well recognized and several studies have shown that the siblings of children with vesicoureteral reflux have a much higher incidence of reflux than the general pediatric population.14⫺22 It has been reported that when 1 child in a family has vesicoureteral reflux, the other siblings are at high risk for reflux, warranting evaluation.23 The early diagnosis and treatment of reflux in this group of patients appears to be beneficial and may avoid renal damage associated with vesicoureteral reflux. However, recent results of a survey by the Section on Pediatric Urology, American Academy of Pediatrics showed that approximately 20% of pediatric urologists do not evaluate asymptomatic siblings with vesicoureteral reflux.24 In Europe most physicians do not advocate routine screening of the siblings of children with vesicoureteral reflux. We present an overview summarizing worldwide experience with the incidence and nature of
vesicoureteral reflux in the siblings of children with vesicoureteral reflux.
EPIDEMIOLOGY OF FAMILIAL VESICOURETERAL REFLUX
Transmission of vesicoureteral reflux from parent to child. Noe et al studied a total of 36 offspring of 23 parents with primary vesicoureteral reflux previously demonstrated on radiography.22 Reflux was identified in 24 of the 36 offspring (66%) and all had grade II or higher disease. A striking finding in this study was a high incidence of reflux related morbidity in the parent group. Four of the 23 parents underwent nephrectomy due to nonfunctioning kidneys and 3 were known to have renal scars and hypertension. Scott et al performed a 3-year collaborative study in maternity hospitals in the United Kingdom to estimate the incidence of reflux transmission from parents or close relatives with a documented history of vesicoureteral reflux to a child.25 Of the 186 infants who met study inclusion criteria and underwent voiding cystourethrography after birth vesicoureteral reflux was detected in 20.4%. This incidence was highly significant compared with the 1% frequency of vesicoureteral reflux in the general population. The predominant relationship was through the mother. Furthermore, vesicoureteral reflux was present in 31% of the offspring of linked families. This proportion was significantly higher than that in nonlinked families. Screening asymptomatic siblings. The 3 mechanisms considered potential etiologies for renal scar formation are 1) reflux of infected urine with interstitial inflammation and damage, 2) sterile, usually high grade reflux, which may damage the kidney through a mechanical or immunological
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mechanism and 3) abnormal embryological development with subsequent renal dysplasia.7⫺9, 12, 23 Patients in the latter group may also have urinary tract infection in the postnatal period, resulting in extensive parenchymal damage. It is well recognized that in the first 2 groups of renal parenchymal damage it is essential to discover reflux early before damage can be initiated. In the third group it is clear that congenital damage currently cannot be prevented. However, in these patients it is mandatory to discover reflux at the early stages to prevent exposure to urinary tract infection and avoid the possible progression of renal parenchymal damage. A number of prospective and retrospective studies have investigated the incidence of vesicoureteral reflux and extent of renal parenchymal damage in the siblings of patients with vesicoureteral reflux.21, 23, 26 –34 Table 1 lists the results of the largest studies. In 1992 Noe reported the results of longterm followup of the sibling of patients with vesicoureteral reflux.26 Of the 354 screened siblings 119 (34%) had reflux. There was no statistical significance in the incidence of reflux in female and male siblings. Most siblings discovered to have reflux were asymptomatic and 61% had high grade disease (grades III to IV). Siblings younger than 18 months had a significantly higher rate of reflux than older children. Furthermore, in this younger group there was a statistically significant incidence of renal damage. Noe observed renal parenchymal damage in 13 of the 52 index patients (25%) and in 4 (7%) of the 54 siblings younger than 18 months. Moreover, only patients in the index group went on to have a nonfunctioning kidney, which required nephrectomy in 7 and dialysis in 2. In contrast, none of the siblings in the asymptomatic group presented with renal failure or renal loss. The most striking finding in this study was that none of the patients in the index group who underwent nephrectomy had evidence of renal dysplasia on histological examination. Thus, Noe presumed that renal damage in this group was mainly a result of urinary tract infection, which can be prevented with early diagnosis and intervention. After the Noe series Wan et al reported the results of a dual center retrospective study of the incidence of renal parenchymal damage in asymptomatic siblings with vesicoureteral reflux.27 A total of 422 families comprising 622 siblings were identified. Vesicoureteral reflux was noted in 144 siblings (27%) with a male-to-female ratio of 1:1.77. High grade reflux (grades III to V) was identified in 25% of all refluxing ureters, while 57% showed grade II disease. The incidence of renal scarring as an indication of reflux nephropathy was 13.6%. In this study renal scaring did not correlate with reflux grade and almost 40% of the patients with reflux nephropathy had only grade II reflux. As in many other studies, these results clearly indicate that reflux was a common finding in siblings 7 years and younger, while only a few siblings older than 10 years had reflux. Recently Cascio et al reported the results of a series comparing the incidence of renal damage in the siblings of pa-
tients with vesicoureteral reflux who presented with a documented history of urinary tract infection versus reflux in asymptomatic siblings diagnosed with that condition during a screening program for hereditary reflux.34 They retrospectively reviewed voiding cystourethrograms of children with vesicoureteral reflux in the 11-year period of 1990 to 2000 to identify siblings with reflux. Renal damage was classified using 99mTc-dimercapto-succinic acid (DMSA) renal scans in all patients. Vesicoureteral reflux was discovered in a total of 226 siblings in 107 families, including 96 families with 2, 10 families with 3 and 1 family with 4 siblings. There were 96 boys and 130 girls. Of the 226 patients 107 were index patients and the remaining 119 were siblings of these index patients. Median age of the index patients was 1.5 years (range 1 month to 14 years), median age of the symptomatic siblings was 1.2 years (range 3 months to 11.1 years) and median age of the asymptomatic siblings was 6 months (range 1 month to 8 years). Of the 107 index patients 104 were investigated after a urinary tract infection and 3 had a prenatal diagnosis of hydronephrosis. Of the 119 siblings 64 underwent investigation because of documented urinary tract infection and the remaining 55 with no history of urinary tract infection underwent screening voiding cystourethrography for sibling reflux. Vesicoureteral reflux was unilateral in 100 patients and bilateral in the remaining 126, representing 352 renal refluxing units. Reflux was grades I to V in 25, 30, 149, 120 and 28 refluxing renal units. Reflux was grades III-V in 84% of the screened siblings, in 86% of the siblings with urinary tract infection and in 83% of the index siblings. Renal scintigraphy revealed reflux nephropathy in 67 of the 352 refluxing renal units (19%), including 36 (22%) of the 166 in index patients, 25 (26%) of the 97 in siblings who presented with urinary tract infection and 6 (7%) of the 89 in asymptomatic siblings who underwent screening voiding cystourethrography. Reflux was grades III to V in 91% of the refluxing units with renal nephropathy. Mild renal damage was detected in 20 refluxing renal units (21%) in siblings with urinary tract infection and in 2(2%) in screened siblings. Moderate renal damage was noted in 4 refluxing renal units (4%) in siblings with urinary tract infection and in 2 (2%) in asymptomatic siblings. A shrunken kidney was discovered in 1 (1%) refluxing renal unit in a sibling who presented with urinary tract infection at age 4 months and in 2 (2%) asymptomatic siblings who were 3 and 6 months old, respectively. This study clearly showed that the incidence of mild renal damage was much higher in siblings who presented with urinary tract infection than in asymptomatic siblings. However, the true incidence of moderate and severe renal scarring in asymptomatic siblings was comparable to that in siblings with reflux and urinary tract infection. These results confirm that further randomized controlled trial are needed to compare renal damage in refluxing patients detected through screening with damage in those diagnosed after urinary tract in-
TABLE 1. Results of previously published studies on familial vesicoureteral reflux References
No. Screened Siblings
% Siblings With Reflux
% Reflux Grade I–II
III–V
% Reflux Nephropathy
44 39 75 90 27 – 69 16
56 61 25 10 73 – 31 84
15 13 14 23 5† 6 0‡ 11
% Boys/Girls
104 32 17/73 Jerkins and Noe17 354 34 –/– Noe26,* 532 27 48/52 Wan et al27 105 45 53/47 Kenda et al33 482 37 –/– Connolly et al28,* 65 26 48/52 Bonnin et al30 78 51 25/75 Parekh et al31 226 24 42/57 Cascio et al34 * No statistically significant difference between female and male affected siblings. † In most patients renal ultrasound was done to assess renal damage. ‡ In all patients renal ultrasound was done to assess renal damage.
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fection to establish how much renal damage may be prevented by screening asymptomatic patients. Recently Parekh et al attempted to determine the efficacy of a prospective screening analysis of an asymptomatic sibling of patients with reflux.31 A total of 40 of the 78 siblings (51%) of 72 index patients had reflux. All except 1 patient were asymptomatic. Of the asymptomatic siblings 77% were followed prospectively with a mean followup of 23 months. Renal ultrasound was done to assess renal parenchymal damage during followup. The previously reported direct relationship of patient age to the incidence and severity of reflux was strongly confirmed in the study. Of the refluxing renal units 60% were in children younger than 2 years. The incidence of grades III to IV vesicoureteral reflux in this group was also higher at 26% than in those older than 2 years. Reflux resolved spontaneously in 84% of the children and was down graded in 13%, while surgery for breakthrough infection was required only in 3%. The most important finding in this study was that no screened siblings had renal scarring on renal ultrasound. Although renal ultrasound is not an optimal tool to diagnose renal scarring, the gross pathological condition can be easily observed. Parekh et al suggested that an improved outcome in terms of renal scarring may have been due to the decrease in urinary tract infection caused by screening and aggressive management. However, they did not rule out the possibility that the response to injury may have been somewhat different in this group of patients. Although most investigators agree that screening asymptomatic siblings is beneficial, Bonnin et al have raised concern about the potential value of such a screening program at birth.30 They recently reported the results of a prospective study of the siblings of patients with vesicoureteral reflux in regard to the incidence of renal parenchymal damage. In a 1-year period direct radionuclide cystography and DMSA renal scan were proposed in all siblings of children with primary vesicoureteral reflux as soon as reflux was diagnosed in the index patient. They identified 46 symptomatic index patients with reflux and 65 siblings of these patients. Reflux was detected in 17 of the 65 siblings (26%), of whom 4 had a history of febrile urinary tract infection and the remaining 13 were asymptomatic. Bonnin et al also performed DMSA scan in siblings free of reflux to detect renal parenchymal damage in these patients. On DMSA renal scan only 6 of all screened siblings (10%) had abnormalities, including asymmetrical differential function in 5 and a parenchymal defect in 1. Only 1 of these 6 patients had reflux at the time of DMSA scan. Based on their finding Bonnin et al concluded that, although there was a significant 26% incidence of reflux in asymptomatic siblings of patients with primary reflux, systematic screening in this group was not beneficial. As described by Noe, there were some limitations of this study.35 Most of the 65 siblings were described as older than 18 months and it was not clear how old they were. The data included few infants. It is well known that the incidence of high grade reflux and subsequent renal injury is highest in infants. Reflux grades were not clear. Noe concluded that systematically screening asymptomatic siblings shows no benefit. The purpose of any screening program is to detect individuals at risk when some benefit and some protection may be provided by appropriate treatment.35 Even in the small series of Bonnin et al it would appear that the damage rate of 50% in index patients was much higher that the 6% in siblings.30 Recently Sweeney et al compared the incidence of renal scarring in infants with high grade vesicoureteral reflux with that in those presenting with urinary tract infection and those who mainly underwent screening for familial vesicoureteral reflux with no history of urinary tract infection.36 A total of 97 patients (148 renal refluxing units) presented clinically with urinary tract infection. DMSA renal scan dem-
onstrated renal scarring in 38% and 67% of refluxing renal units in patients with grades IV and V reflux, respectively. A total of 30 patients (46 renal refluxing units) were diagnosed with reflux before urinary tract infection developed. In this group of patients DMSA renal scan showed evidence of renal scarring in 29% and 36% of grades IV and V refluxing renal units, respectively. These findings of a significantly lower incidence of reflux nephropathy in infants with grade V reflux detected by screening compared with those who presented with a urinary tract infection raises possibility that early intervention in infants with high grade reflux may change its natural history and protect against renal scarring. Renal parenchymal damage in symptomatic siblings of children with vesicoureteral reflux. Most studies of familial reflux have evaluated asymptomatic siblings of children who were previously proved to have vesicoureteral reflux. The incidence of renal parenchymal damage in symptomatic siblings has received little attention. In 1998 Puri et al reported the results of a retrospective review of the medical records of the symptomatic siblings of 624 consecutive patients, including 406 girls and 218 boys, with reflux.37 Reflux was noted in 85 siblings (13%) in 41 families, including 41 index patients and 44 were symptomatic siblings. Of the index patients 15 were boys and 26 were girls, while in the group of symptomatic siblings boys were as commonly affected as girls. Table 2 shows comparative clinical data on index patients and their symptomatic siblings. Mean age of the symptomatic siblings at presentation was 2.7 years (range 1 month to 13 years) and 21 (48%) were younger than 1 year at diagnosis. In the group of symptomatic siblings reflux was grades I to V in 6, 6, 26, 25 and 5 ureters, respectively. Grades III to V disease were present in 82% of the ureters. DMSA renal scans performed in all patients to detect renal scarring was identified in 11 (25%) of the 44 symptomatic siblings, of whom 6 were boys and 5 girls, including 10 with high grade reflux. These data show that symptomatic siblings have higher grades of vesicoureteral reflux and an increased rate of reflux nephropathy compared with data reported in the literature on asymptomatic siblings.26, 30, 31 Thus it appears that early identification and treatment of asymptomatic siblings of index patients may result in a decreased incidence of reflux nephropathy and associated morbidity. Risk factors in the development of renal parenchymal damage in familial vesicoureteral reflux. The major goal of screening siblings is to identify risk factors leading to renal parenchymal damage. Recent developments in the field of molecular genetics have provided the opportunity to detect many clinical conditions early and a unique chance to prevent them. It has been reported that angiotensin-converting enzyme (ACE) I/D gene polymorphism is a risk factor for renal parenchymal damage in some renal diseases, for example diabetic nephropathy, IgA nephropathy and congenital urological anomalies.38⫺42 It also has been previously reported that the ACE genotype is a significant risk factor for renal parenchymal damage in patients with vesicoureteral reflux.40, 43 Recently Yoneda et al performed a study to identify significant independent risk factors, including ACE gene polymorphism, associated with renal parenchymal damage in pa-
TABLE 2. Clinical data on index patients and symptomatic siblings37
No. subjects (M/F) Mean age (yrs.) No. reflux: Unilat. Bilat. No. reflux nephropathy
Index Pts.
Siblings
41 (15/26) 2.2
44 (22/22) 2.7
16 25 11
20 24 11
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Region of Interest
Outcome
Chapman et al49 Middleton et al50 Eccles et al51 Sanyanusin et al52 Woolf and Winyard45 Feather et al53
Dominant inherited allele X chromosome HLA complex PAX 2 Chromosome 10q Genome wide search
Single dominant allele likely to cause reflux X chromosome linked form of reflux inheritance Weak involvement evidence No involvement evidence Unlikely Pos. reflux locus on 20cM cM 1p13 between GATA 176CO1 ⫹ D1S1653
tients with primary familial vesicoureteral reflux.44 They identified 88 families in which 2 or more members had primary vesicoureteral reflux, comprising 162 patients with a mean age of 2.3 years (range 3 weeks to 12 years). Reflux was unilateral and bilateral in 66 and 96 patients, and grades I to V in 19, 18, 110, 84 and 27 ureters, respectively. DMSA renal scans were performed to detect renal scarring. The frequency of allele genotypes in the patients were compared by the chi-square test for independence on univariate analysis. For multivariate analysis risk factors such as gender, age at diagnosis, history of urinary tract infection, reflux grade and ACE genotype were analyzed in a logistic regression model. Renal scarring was detected in 45 of the 162 patients (28%). Mean age at diagnosis of vesicoureteral reflux was 2.6 and 2.3 years in the patients with and without renal damage, respectively. There was no significant difference in mean age in patients with and without renal damage. By the chisquare test a positive history of urinary tract infection and higher reflux grade were significantly associated with renal parenchymal damage. There were no significant differences in ACE genotype distribution or gender distribution in patients with and without renal damage. On univariate analysis by logistic regression a history of urinary tract infection and reflux grade were significant risk factors. Multivariate analysis with all 5 factors, including urinary tract infection, reflux grade, ACE DD genotype, age at diagnosis and gender, revealed that only urinary tract infection, age at diagnosis and reflux grade were significantly associated with renal damage. ACE genotype and gender were not significant in any associations of these 5 risk factors. Therefore, Yoneda et al suggested that early discovery and management of reflux in siblings may prevent potential complications such as: hypertension, renal scarring and renal insufficiency associated with reflux.44 GENETIC BASIS OF FAMILIAL VESICOURETERAL REFLUX
Familial clustering of vesicoureteral reflux implies that genetic factors have an important role in the pathogenesis of reflux.23, 45– 47 Since vesicoureteral reflux may by genetically heterogeneous, linkage analysis would ideally be done on a large, single affected pedigree. However, the greatest problem with such analysis is determining the disease status of an individual. Vesicoureteral reflux may resolve spontaneously. In this particular setting there are no signs that an asymptomatic patient has reflux because the kidney may be normal. Therefore, reflux would appear incompletely penetrant. Table 3 lists the results of some studies regarding a region of genetic interest and the outcome of research. Recently an important role of the renin-angiotensin system in urinary tract development has began to be appreciated.38, 39 Of several genes acting in the renin-angiotensin system it has been reported that the disruption of the angiotensin II type 2 receptor (AT2) gene leads to congenital anomalies of the kidney and ureter in mice, including vesicoureteral reflux.42 In humans a single base A to G transition at position ⫺1332 in intron 1 (A-1332G) of the AT2 gene has been reported to occur significantly more often in patients with ureteropelvic junction obstruction and primary obstructive megaureter than in controls. Hohenfellner et al investigated the A-1332G transition in 23 male patients with pri-
mary sporadic vesicoureteral reflux and noted that the frequency of the A-1332G transition in those with sporadic reflux was not different from that in normal controls.39 On the other hand, recent total gene screening of primary nonsyndrome vesicoureteral reflux identified a possible locus that includes the AT2 gene on the long arm of the X chromosome.48 Since Hohenfellner et al studied only 23 male patients with sporadic disease, there still remains the question of whether the AT2 gene is involved in vesicoureteral reflux, especially primary familial reflux.39 Yoneda et al evaluated the incidence of the A-1332G transition in 82 males and 110 females, in 235 nonaffected family members (111 males and 124 females) from 88 families in which 2 or more members had primary reflux and in 213 controls (106 males and 107 females) unselected for reflux status.48 Genomic DNA was extracted from whole blood samples. Polymerase chain reaction method modified for fluorescence detection was done to type all samples for the A-1332G variant. Furthermore, to identify mutations in the coding sequence of the AT2 gene they selected 61 patients from different families and 15 controls unselected for reflux status. In males the A-1332G transition was identified in 27 of 82 patients with primary familial reflux (33%) and in 41 of 106 controls (38%). In females the incidence of the A-1332G substituted allele in patients and controls was 47% (104 of 220 total alleles) and 50% (107 of 214 total alleles), respectively. Moreover, the transmission-disequilibrium test revealed no significant skewing of genotype transmission from mother to child. None of the 61 patients or 15 controls carried any mutations or polymorphisms in the coding sequence of the AT2 gene. Yoneda et al concluded that the AT2 gene is not involved in the pathogenesis of primary familial vesicoureteral reflux. No doubt further investigations for identifying vesicoureteral reflux genes should be done for other candidates genes. In the long term understanding the genetic basis of vesicoureteral reflux would help design genetic screening tests with a view to early diagnosis and appropriate genetic counseling. CONCLUSIONS
The incidence of sibling vesicoureteral reflux is significant. When reflux is discovered in symptomatic siblings it is usually high grade and associated with a higher incidence of reflux nephropathy. There is a direct relationship of patient age to the incidence of reflux nephropathy and severity of reflux in symptomatic and asymptomatic siblings. In most series there was a higher incidence of high grade vesicoureteral reflux in children younger than 2 years, supporting evaluation of asymptomatic siblings. Furthermore, for primary reflux grade a history of urinary tract infection and age at diagnosis are the most important risk factors. It seems appropriate that, rather than waiting until urinary tract infection develops with the subsequent risk for renal scarring, a preemptive regimen of early detection and treatment should be initiated in these patients. REFERENCES
1. Medical versus surgical treatment of primary vesicoureteral reflux: report of the International Reflux Study Committee. Pediatrics, 67: 392, 1981
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2. Risdon, R. A.: The small scarred kidney in childhood. Pediatr Nephrol, 7: 361, 1993 3. Polito, C., La Manna, A., Rambaldi, P. F., Nappi, B., Mansi, L. and Di Toro, R.: High incidence of a generally small kidney and primary vesicoureteral reflux. J Urol, 164: 479, 2000 4. Jodal, U.: The natural history of bacteriuria in childhood. Infect Dis Clin North Am, 1: 713, 1987 5. Smellie, J. M., Normand, I. C. and Katz, G.: Children with urinary tract infection: a comparison of those with and those without vesicoureteric reflux. Kidney Int, 20: 717, 1981 6. Marra, G., Barbieri, G., Dell’Agnola, C. A., Caccamo, M. L., Castellani, M. R. and Assael, B. M.: Congenital renal damage associated with primary vesicoureteral reflux detected prenatally in male infants. J Pediatr, 124: 726, 1994 7. Assael, B. M., Guez, S., Marra, G., Secco, E., Manzoni, G., Bosio, M. et al: Congenital reflux nephropathy: a follow-up of 108 cases diagnosed perinatally. Br J Urol, 82: 252, 1998 8. Hinchliffe, S. A., Chan, Y. F., Jones, H., Chan, N., Kerczy, A. and van Velzen, D.: Renal hypoplasia and postnatally acquired cortical loss in children with vesicoureteral reflux. Pediatr Nephrol, 6: 439, 1992 9. Risdon, R. A., Yeung, C. K. and Ransley, P. G.: Reflux nephropathy in children submitted to unilateral nephrectomy: a clinicopathological study. Clin Nephrol, 40: 308, 1993 10. Goldraich, N. P. and Goldraich, I. H.: Followup of conservatively treated children with high and low grade vesicoureteral reflux: a prospective study. J Urol, 148: 1688, 1992 11. Mackie, G. G. and Stephens, F. D.: Duplex kidneys: a correlation of renal dysplasia with position of the ureteral orifice. J Urol, 114: 274, 1975 12. Schwarz, R. D., Stephens, F. D. and Cussen, L. J.: The pathogenesis of renal dysplasia. II. The significance of lateral and medial ectopy of the ureteric orifice. Invest Urol, 19: 97, 1981 13. North, R. A., Taylor, R. S. and Gunn, T. R.: Pregnancy outcome in women with reflux nephropathy and the inheritance of vesicoureteric reflux. Aust N Z J Obstet Gynaecol, 40: 280, 2000 14. Stephens, F. D., Joske, R. A. and Simmons, R. T.: Megaureter with vesicoureteric reflux in twins. Aust New Zeal J Surg, 24: 192, 1955 15. Bredin, H. C., Winchester, P., McGovern, J. H. and Degnan, M.: Family study of vesicoureteral reflux. J Urol, 113: 623, 1975 16. Dwoskin, J. Y.: Sibling uropathology. J Urol, 115: 726, 1976 17. Jerkins, G. R. and Noe, H. N.: Familial vesicoureteral reflux: a prospective study. J Urol, 128: 774, 1982 18. Sirota, L., Hertz, M., Laufer, J., Jonas, P. and Boichis, H.: Familial vesicoureteral reflux: a study of 16 families. Urol Radiol, 8: 22, 1986 19. Van den Abbeele, A. D., Treves, S. T., Lebowitz, R. L., Bauer, S., Davis, R. T., Retik, A. et al: Vesicoureteral reflux in asymptomatic siblings of patients with known reflux: radionuclide cystography. Pediatrics, 79: 147, 1987 20. Kaefer, M., Curran, M., Treves, S. T., Bauer, S., Hendren, W. H., Peters, C. A. et al: Sibling vesicoureteral reflux in multiple gestation births. Pediatrics, 105: 800, 2000 21. Kenda, R. B. and Fettich, J. J.: Vesicoureteral reflux and renal scars in asymptomatic siblings of children with reflux. Arch Dis Child, 67: 506, 1992 22. Noe, H. N., Wyatt, R. J., Peeden, J. N., Jr. and Rivas, M. L.: The transmission of vesicoureteral reflux from parent to child. J Urol, 148: 1869, 1992 23. Noe, H. N.: The current status of screening for vesicoureteral reflux. Pediatr Nephrol, 9: 638, 1995 24. Ferrer, F. A., McKenna, P. H., Hochman, H. I. and Herndon, A.: Results of a vesicoureteral reflux practice pattern survey among American Academy of Pediatrics, Section on Pediatric Urology members. J Urol, 160: 1031, 1998 25. Scott, J. E., Swallow, V., Coulthard, M. G., Lambert, H. J. and Lee, R. E.: Screening of newborn babies for familial ureteric reflux. Lancet, 350: 396, 1997 26. Noe, H. N.: The long-term results of prospective sibling reflux screening. J Urol, 148: 1739, 1992 27. Wan, J., Greenfield, S. P., Ng, M., Zerin, M., Ritchey, M. L. and Bloom, D.: Sibling reflux: a dual center retrospective study. J Urol, 156: 677, 1996 28. Connolly, L. P., Treves, S. T., Connolly, S. A., Zurakowski, D., Share, J. C., Bar-Sever, Z. et al: Vesicoureteral reflux in children: incidence and severity in siblings. J Urol, 157: 2287, 1997 29. Peeden, J. N., Jr. and Norman, N. H.: Is it practical to screen for familial vesicoureteral reflux within a private pediatric prac-
tice? Pediatrics, 89: 758, 1992 30. Bonnin, F., Lottmann, H., Sauty, L., Garel, C., Archambaud, F., Baudouin, V. et al: Scintigraphic screening for renal damage in siblings of children with asymptomatic primary vesicoureteric reflux. BJU Int, 87: 463, 2001 31. Parekh, D. J., Pope, J. C., IV, Adams, M. C. and Block, J. W., III: Outcome of sibling vesicoureteral reflux. J Urol, 167: 283, 2002 32. Buonomo, C., Treves, S. T., Jones, B., Summerville, D., Bauer, S. and Retik, A.: Silent renal damage in symptom-free siblings of children with vesicoureteral reflux: assessment with technetium Tc 99m dimercaptosuccinic acid scintigraphy. J Pediatr, 122: 721, 1993 33. Kenda, R. B., Zupancic, Z., Fettich, J. J. and Meglic, A.: A follow-up study of vesico-ureteric reflux and renal scars in asymptomatic siblings of children with reflux. Nucl Med Commun, 18: 827, 1997 34. Cascio, S., Yoneda, A., Chertin, B. and Corhoun, E.: Renal parenchymal damage in sibling vesicoureteric reflux. Unpublished data 35. Noe, H. N.: Scintigraphic screening for renal damage in siblings of children with asymptomatic primary vesico-ureteric reflux. BJU Int, 89: 792, 2002 36. Sweeney, B., Cascio, S., Velayudham, M. and Puri, P.: Reflux nephropathy in infancy: a comparison of infants presenting with and without urinary tract infection. J Urol, 166: 648, 2001 37. Puri, P., Cascio, S., Lakshmandass, G. and Colhoun, E.: Urinary tract infection and renal damage in sibling vesicoureteral reflux. J Urol, 160: 1028, 1998 38. Yerkes, E., Nishimura, H., Miyazaki, Y., Tsuchida, S., Block, J. W., 3rd and Ichikawa, I.: Role of angiotensin in the congenital anomalies of the kidney and urinary tract in the mouse and the human. Kidney Int, suppl., 67: S75, 1998 39. Hohenfellner, K., Fogo, A. and Kon, V.: Renin-angiotensin genes in renal development and the occurrence and progression of renal diseases. Semin Nephrol, 19: 148, 1999 40. Hohenfellner, K., Hunley, T. E., Brezinska, R., Brodhag, P., Shyr, Y., Brenner, W. et al: ACE I/D gene polymorphism predicts renal damage in congenital uropathies. Pediatr Nephrol, 13: 514, 1999 41. Ozen, S., Alikasifoglu, M., Saatci, U., Bakkaloglyu, A., Besbas, N., Kara, N. et al: Implications of certain genetic polymorphisms in scarring in vesicoureteric reflux: importance of ACE polymorphism. Am J Kidney Dis, 34: 140, 1999 42. Brock, J. W., III, Adams, M., Hunley, T., Wada, A., Trusler, L. and Kon, V.: Potential risk factors associated with progressive renal damage in childhood urological diseases: the role of angiotensinconverting enzyme gene polymorphism. J Urol, 158: 1308, 1997 43. Yoneda, A., Oue, T. and Puri, P.: Angiotensin-converting enzyme genotype distribution in familial vesicoureteral reflux. Pediatr Surg Int, 17: 308, 2001 44. Yoneda, A., Cascio, S., Oue, T., Chertin, B. and Puri, P.: Risk factors for the development of renal parenchymal damage in familial vesicoureteral reflux. J Urol, 168: 1704, 2002 45. Woolf, A. S. and Winyard, P. J.: Advances in the cell biology and genetics of human kidney malformations. J Am Soc Nephrol, 9: 1114, 1998 46. Uehling, D. T., Vlach, R. E., Pauli, R. M. and Friedman, A. L.: Vesicoureteric reflux in sibships. Br J Urol, 69: 534, 1992 47. Heale, W. F.: Hereditary vesicoureteric reflux: phenotypic variation and family screening. Pediatr Nephrol, 11: 504, 1997 48. Yoneda, A., Cascio, S., Green, A., Barton, D. and Puri, P.: Angiotensin II type 2 receptor gene is not responsible for familial vesicoureteral reflux. J Urol, 168: 1138, 2002 49. Chapman, C. J., Bailey, R. R., Janus, E. D., Abbott, G. D. and Lynn, K. C.: Vesicoureteric reflux: segregation analysis. Am J Med Genet, 20: 577, 1985 50. Middleton, G. W., Howards, S. S. and Gillenwater, J. Y.: Sexlinked familial reflux. J Urol, 114: 36, 1975 51. Eccles, M. R., Bailey, R. R., Abbott, G. D. and Sullivan, M. J.: Unravelling the genetics of vesicoureteric reflux: a common family disorder. Hum Mol Genet, 5: 1425, 1996 52. Sanyanusin, P., McNoe, L. A., Sullivan, M. J., Weaver, R. G. and Eccles, M. R..: Mutation of PAX2 in two siblings with renalcoloboma syndrome. Hum Mol Genet, 4: 2183, 1995 53. Feather, S. A., Malcolm, S., Woolf, A. S., Wright, V., Blaydon, D., Reid, C. J. et al: Primary, nonsyndromic vesicoureteric reflux and its nephropathy is genetically heterogeneous, with a locus on chromosome 1. Am J Hum Genet, 66: 1420, 2000