|Year : 2009 | Volume
| Issue : 1 | Page : 57-68
|Evaluating kidney damage from vesico-ureteral reflux in children
M Zaffanello1, M Franchini2, M Brugnara1, V Fanos3
1 Department of Mother-Child and Biology-Genetics, University of Verona, Italy
2 Hymmonohematology and Transfusion Service, University of Parma, ParmaTransfusion Service, Verona Hospital, Verona, Italy
3 Department of Pediatrics and Clinical Medicine, Section of Neonatal Intensive Care Unit, University of Cagliari, Cagliari, Italy
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| Abstract|| |
To review the most relevant clinical studies that evaluate kidney damage in children with primary vesico-ureteral reflux (VUR), we reviewed and compared randomized controlled trials and clinical trials from scientific literature. In these studies, vesico-ureteral reflux was diagnosed by voiding cystourethrogram and kidney damage was assessed by either DMSA scan or urography. Relative risk with 95% confidence intervals was calculated using Review Manager Software (The Cochrane Collaboration, 2000). The overall relative risk of kidney damage shown by DMSA scan and urography was statistically higher in children with vesico-ureteral reflux of various degrees than in controls (3.7 times and 2.8 times, respectively). However, in high-grade VUR, the relative risk of congenital kidney damage was 5.6 times that of controls. We conclude that severe VUR is frequently associated with early kidney damage, perhaps with prenatal onset. Progression of kidney damage may depend on the severity of VUR and untreated urinary tract infections. Prevention of congenital kidney damage from severe VUR is possible when there is early intervention, even during fetal growth.
Keywords: Meta-analysis, Primary vesico-ureteral reflux, Congenital kidney damage, Children
|How to cite this article:|
Zaffanello M, Franchini M, Brugnara M, Fanos V. Evaluating kidney damage from vesico-ureteral reflux in children. Saudi J Kidney Dis Transpl 2009;20:57-68
|How to cite this URL:|
Zaffanello M, Franchini M, Brugnara M, Fanos V. Evaluating kidney damage from vesico-ureteral reflux in children. Saudi J Kidney Dis Transpl [serial online] 2009 [cited 2019 Nov 22];20:57-68. Available from: http://www.sjkdt.org/text.asp?2009/20/1/57/44707
| Introduction|| |
Vesico-ureteral reflux (VUR) occurs when urine flows backward from the bladder up through ureteric junction, and may reach the kidneys in the severe forms of the disease. Children with urinary tract infections (UTI) may have VUR, which must be classified according to severity before it can be treated. Voiding cystourethrogram (VCUG) is the imaging technique most frequently used to diagnose and the ureter if there is incontinence of the vesico-classify VUR. The International Study Classification has established levels of severity from I to V,  which are still generally accepted.
Chronic severe VUR plays a role in the development of chronic kidney damage (KD) such as kidney growth failure and reflux nephropathy (RN). Because the pressure in the bladder is generally greater than that in the kidneys, the reflux of urine exposes the kidneys to unusually high pressure. This increased pressure can damage the kidneys and cause persistent parenchymal abnormalities.
Furthermore, VUR predisposes to pyelonephritis and renal parenchymal abnormalities or "renal scars". Although sterile VUR can cause renal scarring, most studies indicate that the appearance or extent of established renal scars indicates UTI. , The use of antibiotics in mildmoderate VUR does not decrease the incidence of UTIs or reduce renal parenchymal damage any more than in controls;  however, the opposite seems true for high-grade VUR. , More than 20 years ago, a high-grade form of VUR carried 4 to 6 times the risk of KD than lowgrade VUR and 8 to 10 times the risk than nonrefluxing kidneys.  Accordingly, children with low-grade VUR had almost 4 times the risk of developing permanent KD than children with non-refluxing units.
In light of the current management of recurrent UTIs, the level of severity of VUR might play the greatest role in the development of permanent KD in children. Therefore, we have reviewed the correlation between the severity of VUR and permanent KD.
| Methods|| |
Related studies were purchased from the following electronic sources: MEDLINE, EMBASE, and reference lists of relevant articles. Randomized controlled trials (RCTs) and clinical trials (CTs), both retrospective and prospective, which evaluated the prevalence or incidence of KD in children with VUR, were included. Limits were set for children of both sexes, with and without UTIs. Those with VUR were identified during an investigation for pelvic dilation, routine fetal ultrasound, and post-natal clinical follow-up after a UTI. The VCUG was the standard technique to diagnose and grade VUR. Children with all grades of VUR were included in the study. However, children with urinary tract abnormalities different from VUR, even if associated with it, were excluded from the study.
Antibiotics and monitoring for UTIs through periodic microbiological tests were included in the follow-up visits of these children. There were no restrictions between children on antibiotics (even of various duration), whether they underwent periodical urinalysis or not. Renal units (RUs) with VUR of different grades of severity were investigated for prevalence of KD. As controls, KD was studied in RUs without VUR. Appropriate imaging techniques, such as DMSA scintigraphy and urography, allowed physicians to determine KD.
The studies were divided into three subsets. The "included studies" subset included those children who were suitable for statistical analysis. Articles taken from this section were included in two other categories. The "excluded studies" included studies that did not make a comparison between KD associated with VUR and controls. Finally, the "other informative studies" group included only descriptive clinical investigations.
Subset 1: Included studies
An average of thirteen studies ,,,,,,,,,,,, published between 1992 and 2006 [Table 1] were included in the meta-analyses. In particular, one study was an RCT multi-center study;  two were CT studies; , seven were retrospective ,,,,,, and three were prospective. ,,
Statistical analyses were categorized according to the particular clinical pattern (i.e., chronic or acute KD and all grades or high-grade VUR) and different imaging techniques (DMSA scan or urography). The first analysis [Figure 1] evaluated persistent KD from all grades of VUR, of which subcategory 1 was chronic KD detected by DMSA scan and subcategory 2 was chronic KD detected by urography. , Furthermore, the 2nd analysis [Figure 2] included acute KD detected by DMSA scan from all grades of VUR. Results 2b [Figure 2] was chronic KD only in high-grade VUR.
Nineteen studies published between 1992-2006 were excluded from the statistical analysis. ,,,,,,,,,,,,,,,,,, [Table 2] summarizes 15 retrospective and 3 prospective studies, and 1 clinical trial including more than 3,300 children with VUR. Finally, [Table 3] describes additional 8 descriptive studies published between 1992-2006. ,,,,,,, These data concern 4 retrospective, 2 prospective, and 2 clinical trials including more than 1,500 children with VUR.
| Statistical analysis|| |
The overall risks of KD in refluxing and nonrefluxing RUs were compared by univariate statistical analysis. The result was the proportion of patients with or without VUR who had KD. The relative risk (RR) was used as a measure of summary effect. The dichotomous outcome showed a RR with 95% confidence intervals (CI) calculated using Review Manager Software (RevMan 4.1 for Windows, Oxford, UK, The Cochrane Collaboration, 2000). Summary statistics were calculated using the random effect model, which takes into account "between study variability" as well as "within study variability". The heterogeneity between studies was analyzed using Cochran's Q statistic with an "α" of 0.05 used for statistical significance
| Results|| |
[Figure 1] and [Figure 2]a-b show the statistical results of our meta-analyses. Ten studies ,,,,,,,,, were included in the section "permanent KD detected by DMSA scan" [Figure 1], (subcate-gory 1). For example, Bonnin et al studied KD in asymptomatic siblings of children with known VUR. Only a few siblings with VUR had KD.  Other studies showed a comparable risk of KD among categories. In particular, Garin et al demonstrated that the risk of permanent KD after UTIs was the same for children with mildmoderate VUR as for those with no VUR.  Again, Orellana et al did not show a statistical difference of permanent KD.  However, after 2 years of follow-up, Taskinen et al showed that both serious UTIs and KD were complications frequently associated with VUR.  Furthermore, six additional studies showed that KD was more frequent in patients with VUR. ,,,,,
Finally, these studies showed an overall RR of permanent KD by DMSA scintigraphy 3.7 times higher in patients with VUR than in controls. In addition, the section including chronic KD measured by urography (subcategory 2) included two other studies , showing a RR of KD 2.4 times higher in children with VUR. Including all data, the overall RR of persistent KD was 3.4 times higher with VUR. In conlusion, the risk of persistent KD measured by urography was lower than that measured by DMSA scan, but always significantly higher than in controls.
[Figure 2a] shows two studies on acute KD after UTIs. , Abnormal DMSA scans were not different between children with and without VUR. In conclusion, the overall RR of acute KD in children with VUR was about 2 times higher than, but not statistically different from, controls.
[Figure 2b] shows four studies on permanent KD associated with high grades of VUR. ,,, The results were statistically significant and showed a RR of persistent KD 5.6 times higher in children with severe VUR than in unaffected children.
[Table 2] shows nineteen studies carried out between 1992 and 2006. ,,,,,,,,,,,,,,,,,, The method most frequently used to investigate KD was by DMSA scan. About 26% of children with VUR developed kidney damage, particularly if associated with high grade VUR. ,,, Interestingly, KD was also observed in asymptomatic siblings of children with VUR, ,, which suggests a congenital condition. ,, There were more male children with high grade VUR and KD, , which worsened after UTIs. , Sometimes, a voiding dysfunction could be associated with the above conditions.23 KD from UTIs was more common before 5 years of life. Still, with close supervision and prompt treatment of recurrent UTIs, children can progress well with either medical or surgical intervention. ,,, VUR diagnosed before the age of 3 years leaves less scarring than when diagnosed at later ages. 
Another eight studies are shown in [Table 3]. ,,,,,,, KD was associated with high grade VUR,  while its correlation with UTIs was not clearly proven.  Furthermore, RN was frequently congenital  and its progression was not predictable.  The choice method to detect KD was DMSA scan. ,,,, The VCUG was the common method to diagnose VUR, ,, whereas magnetic resonance voiding cystography was less sensitive.  In addition, ultrasound (US) detection of pelvic fluctuation facilitated the prediction of VUR grading. 
| Discussion|| |
VUR, either alone or complicated by UTIs, is a risk for permanent kidney damage in small children. In particular, the more serious VUR is the greater the possibility for it to cause chronic KD.  Nevertheless, KD is frequently already evident at birth as a congenital condition that is not easily preventable; ,,, it tends to worsen during the first two years of life  perhaps due to complicated urinary tract infections. , It is more frequent in males.  DMSA scintigraphy is the method of choice to detect KD related to VUR and UTIs ,,, and is more sensitive than urography. 
The relative risk of children with VUR of developing chronic KD is 3.7 times greater when measured by DMSA scan and 2.4 times greater when urography is used, ultimately underestimating the potential for KD. ,, Taken as a whole, our study gave 3.4 times the RR of KD. This must be taken as a mean value because it includes all grades of VUR. A recent investigaion showed comparable renal scarring in mildmoderate VUR compared with controls  and a high risk of permanent KD with high-grade VUR , - 5.6 times that of controls (present data). Moreover, KD may coexist early with high-grade VUR, 11, 17 even during fetal life. On the contrary, the overall RR of acute KD in children with VUR was comparable to controls. , ,present data
To sum up, according to most modern approaches, both UTIs and mild-grade VUR do not cause permanent kidney damage. However, the more severe the reflux, the greater the risk of new or progressive renal scarring, RN, and kidney growth failure. Severity of VUR, patient's age, and presence of KD dictate how and when this condition should be treated.
Options of therapy include surgery and longterm chemoprophylaxis, which we have been using for several decades. Therapeutic approaches to VUR can be clinical in less severe cases or surgical in more serious conditions. The main objectives of treatment are prevention of onset and delay of progression of KD. Unfortunately, a long-term study covering many years showed that neither medical nor surgical therapy was the better choice.  Moreover, modern management of VUR seems to still have conflicting results. On the one hand, neither treatment was able to protect against the progression of chronic KD, , and on the other hand, preservation of renal parenchyma from repeated injuries by means of early surgical and medical treatment has been reported.  Today, the controversy continues as to the suitable approach to VUR aimed at protecting renal function. 
Before resorting to surgery, treatment with antibiotics along with laboratory follow-up can help to prevent KD from recurring UTIs.  However, antimicrobials did not seem to have better results than surgery in reducing the risks of permanent KD.  Still, the inappropriateness of antibiotics has been suggested in mild-grade forms,  but it is recommended for severe cases of VUR,  especially while awaiting surgery. Finally, the only real benefit of surgery and antibiotics is to limit febrile UTIs, but both are insufficient in avoiding permanent KD in children with VUR. ,, This implies that modern treatment of severe VUR does not confer a substantial clinical benefit in children. Perhaps this is because the same etiological conditions of severe VUR might contribute to chronic KD.  Again, permanent KD could have a close connection with severe VUR, whereas UTIs are additional contributors. The main target of modern therapy remains the prevention of renal parenchyma injury instead of simply curing VUR. 
Finally, it is almost certain that severe VUR may lead to RN even during fetal life, but this is very improbable in mild forms. A cause and effect relationship between experimental VUR and KD has been reported in the fetus of animals.  The mechanical action of refluxing urine seems to be sufficient to cause RN, even in animals. On the contrary, it is emerging that the combination of severe VUR and congenital RN may derive from a common mechanism such as the result of a dysfunction in normal embryological evolution. 
| Conclusions|| |
UTIs, if treated in time, will unlikely cause long-term kidney morbidity. KD is unexpected in mild forms of VUR, as opposed to highgrade forms despite existing antimicrobial therapies and surgical procedures. This is in line with the question of whether severe VUR or KD starts first, but it is likely that both begin and progress together. KD could possibly be primarily explained by congenital factors not uncontrolled UTIs. Consequently, prevention of long-term kidney morbidity is not possible until interventions start immediately after birth.
Current postnatal treatment offers few advantages in treating a problem that starts and progresses during fetal life. Severe VUR could be a malignant condition because it is associated with parenchymal damage, which occurs also in the absence of UTIs. Actually, physicians may only attempt an early diagnosis, continue monitoring for UTIs and surgical treatment to delay but unlikely avoid the worsening of KD from severe VUR.
We need an up-to-date pathogenesis of KD to understand why there is a high risk of KD in high-grade forms of VUR but not in mild forms, and we need to adequately utilize surgical, preventive, and state-of-the-art treatment for recurrent UTIs. The situation today requires new preventive strategies and innovative treatment procedures to avoid congenital KD in primary severe VUR. This implies, for example, that the possible goal of new therapies should be early prevention of renal parenchyma injury starting from the uterus.
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Department of Mother-Child and Biology-Genetics, University of Verona, Piazzale L. Scuro, 10 37134 Verona
[Figure 1], [Figure 2], [Figure 2a], [Figure 2b]
[Table 1], [Table 2], [Table 3]
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