Early management and long-term outcomes in primary vesico-ureteric reflux

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1 Early management and long-term outcomes in primary vesico-ureteric reflux Robert Coleman Birmingham Children s Hospital Urology, Birmingham, UK Primary vesico-ureteric reflux is a common condition in childhood associated with bladder dysfunction and an increased risk of urinary tract infection. Recent evidence indicates a lower tract functional abnormality in its pathogenesis. Whilst spontaneous resolution will occur in many, some patients will go on to develop complications in adulthood including reflux nephropathy, hypertension, urinary tract infection, bladder dysfunction and complications of pregnancy. An evolving understanding of the natural history has seen radical changes in management. Evidence for management of the child What s known on the subject? and What does the study add? Despite evolving understanding of pathogenesis and natural history, controversy exists regarding management of childhood vesicoureteric reflux. Surgical correction of the reflux itself may reduce risk of upper tract complications in some but may not in itself constitute appropriate management of lower tract morbidity in many. This review examines the evidence for early management and long term outcomes in primary vesicoureteric reflux. with primary vesico-ureteric reflux is reviewed with a focus on the implications on long-term outcomes in adulthood. KEYWORDS vesico-ureteric reflux, reflux nephropathy, urinary tract infection, hypertension INTRODUCTION VUR is defined as the retrograde flow of urine from the bladder to the upper urinary tract. The terms primary and secondary are widely used to differentiate reflux into distinct aetiological groups. Secondary VUR refers to reflux in the setting of a clear pathogenic cause (e.g. outlet obstruction, neuropathic bladder). Primary VUR refers to patients where no such abnormality is evident and reflux is presumed to occur due to a defect, either anatomical or functional, of the vesico-ureteric junction itself. It should therefore follow that successful surgical correction of primary VUR results in a normal lower urinary tract, and carries no long-term implication. Recent studies have demonstrated functional abnormalities in the lower urinary tract of children with primary VUR and clinical evidence has emerged to suggest that such patients are at risk of chronic urinary tract abnormality. Therefore VUR is not a ureteric pathological entity in itself but an indicator of a lower tract pathology, whether structural or functional. This review examines the literature defining the aetiology of primary VUR, the evidence for early management of primary VUR and the long-term outcomes in the patient with childhood primary VUR. AETIOLOGY A familial component of VUR aetiology is suggested by increased prevalence in first degree relatives of VUR patients. In a review of screening for VUR, Hollowell and Greenfield [ 1 ] report VUR in 32% of siblings of VUR patients. VUR has been reported in up to 66% of offspring of known VUR patients [2 ]. Voiding dysfunction appears to play a significant role in the aetiology and natural history of VUR. Urodynamic studies in infants with dilating VUR have demonstrated high voiding pressures (average 160 cmh 2 O) with low bladder capacities, while infant boys without reflux have a mean voiding pressure of around 80 cmh2o [3,4 ]. Sillen et al. [3,4 ] reported that the majority of refluxing infant boys had detrusor instability and many had a thickened bladder on sonography. Voiding pressures diminished by 2 years of age (average 70 cmh 2 O) and bladder capacities had increased but most still had unstable detrusors. Chandra et al. [5 ] reported similarly high voiding pressures and detrusor overactivity in infant boys and girls with VUR, which improved over time. They report that cessation of VUR appeared to correlate with the improvement in urodynamic parameters. PRESENTATION As antenatal ultrasound has become part of routine maternal screening, upper tract changes as a result of VUR are often detected before any UTI [6,7 ]. VUR is diagnosed in around 12% of neonates with antenatal hydronephrosis [8 ]. Patients with primary VUR not detected with hydronephrosis in the antenatal period are often diagnosed through investigation of UTI. In a recent retrospective analysis of children under 15 years of age undergoing imaging for suspected UTI, Hanulla et al. [9 ] reported the incidence of VUR to be 37.4% of patients with proven UTI with a mean age of 2.0 years. Of these, 18.6% were grade III BJU INTERNATIONAL 2011 BJU INTERNATIONAL 108, SUPPLEMENT 2, 3 8 3

2 COLEMAN or higher. They also report a significant negative trend in the occurrence of VUR with increasing age. Venhola et al. [10 ] similarly studied patients with UTI and reported VUR in 34% of patients aged <2 years and in 20% of patients older than 2 years [10 ]. Both groups of authors report similar incidence of VUR in patients suspected to have UTI whether UTI was proven, unlikely or disproven. Each concluded that VUR incidence in the well population is higher than previously estimated. Another potential explanation is that patients with voiding dysfunction and therefore voiding symptoms consistent with, but not caused by, UTI have a higher incidence of VUR. In a study that involved 366 children aged 4 18 years who had symptoms of voiding dysfunction, VUR was present in 20% of patients undergoing voiding cystourethroscopy (VCUG) [11 ]. Other diagnoses included constipation in 30%, day-time wetting (diurnal enuresis) in 89%, night-time wetting (nocturnal enuresis) in 79%, and recurrent UTIs in 60% of the patients. NATURAL HISTORY A decreasing incidence of VUR with age reflects spontaneous resolution in many patients. In a prospective 5-year follow-up study of children younger than 5 years of age who had primary VUR and radiographically normal kidneys, grade I VUR resolved in 82%, grade II in 80% and grade III in 46% of ureters [12 ]. Rate of resolution of grades IV and V over a 5-year period are approximately 30% and 13%, respectively [13 ]. Resolution of VUR correlates with renal and bladder functional status. In a prospective study of 82 patients with grade III or greater VUR followed for at least 2 years, Yeung et al. [14 ] report resolution of VUR in 94% of patients with normal bladder function and 37% of patients with abnormal renal and normal bladder function, but no patient with abnormal bladder function showed resolution of VUR. They concluded that normal renal and bladder function at diagnosis is highly predictive of complete resolution of VUR, whereas abnormal renal and bladder function is prognostic for persistence of VUR. MANAGEMENT The goals of treating the child with VUR are (i) to prevent recurring febrile UTIs, (ii) to prevent renal injury and (iii) to minimize the morbidity of treatment and follow-up [15 ]. HISTORICAL CONSIDERATIONS The debate over medical vs surgical management of VUR has spanned several decades. In 1952 Hutch [16 ] reported on a relationship between VUR and chronic pyelonephritis in the setting of paraplegia and described the successful correction of VUR in seven out of nine paraplegic patients. Four decades ago, the relationship of VUR to UTI and chronic pyelonephritis/ reflux nephropathy gave rise to the now standard term reflux nephropathy [17 ]. Ransley and Risdon [18 ] in 1979 defined the pathophysiology of reflux nephropathy by demonstrating the relationship between infection, VUR, pyelonephritis and scarring. Studies in the 1980s further defined the relationship between UTI and renal scarring. Jodal [19 ] reported increasing risk of scarring with increasing number of UTIs. In a study of patients with a history of UTI found to have VUR, patients with highgrade VUR are four to six times more likely to have scarring than those with low-grade VUR and eight to ten times more likely than those without VUR [19 ]. Understanding the role of VUR in the development of pyelonephritic scarring led to corrective surgery by ureteric reimplantation being widely employed in the management of VUR. However, studies of the effectiveness of this approach in the 1980s and 1990s showed little benefit over antibiotic prophylaxis alone [20,21 ]. MEDICAL/NON-OPERATIVE MANAGEMENT The medical literature has identified pyelonephritis and higher grades of VUR to be risk factors for the development of reflux nephropathy. Lower grades of VUR are more common than high grades and have a high rate of spontaneous resolution. Therefore, in many patients, prevention of UTI (and subsequent pyelonephritis) is the mainstay of management. Two recent studies [22,23 ] showed a small benefit in antibiotic prophylaxis following febrile UTI in the setting of VUR [24 ]. In the PRIVENT study [23 ], 576 children under the age of 18 years who had had one or more microbiologically proven UTIs were randomly assigned to receive either daily trimethoprim sulfamethoxazole suspension or placebo for 12 months. Reflux was present in 42% (grade III in 53% of these). Nineteen per cent developed UTI in the placebo group and 13% in the trimethoprim sulfamethoxazole group ( P = 0.03). The treatment effect did not vary significantly with VUR. The number of children needing to be treated with antibiotic prophylaxis to prevent one UTI was 14. Montini et al. [22 ] performed a controlled, randomized study comparing no prophylaxis with prophylaxis for 12 months following first febrile UTI. In the subgroup of children with reflux (grades I III), the recurrence of febrile UTI was nine (19.6%) of 46 on no prophylaxis and 10 (12.1%) of 82 on prophylaxis. The number of patients to be treated to prevent a febrile recurrence was 41.7 children for 1 year. No significant difference was found in the rate of renal scarring produced by recurrent UTI on DMSA after 12 months. Given the widespread use of prophylactic antibiotics despite the lack of strong supporting evidence, the ongoing Randomized Intervention for Children with Vesicoureteral Reflux (RIVUR) study aims to determine if antimicrobial prophylaxis with trimethoprim sulfamethoxazole prevents recurrent UTI and renal scarring in children who are found to have grades I IV VUR after a first or second UTI [25,26 ]. The AUA Guideline on the management of VUR recommends continuous antibiotic prophylaxis for the children at high risk of UTI and subsequent renal scarring. This includes patients < 1 year of age with VUR with a history of a febrile UTI or with grade III V VUR identified through screening [15 ]. This approach is based on the greater morbidity from recurrent UTI found in this population. The kidney s predilection for post-pyelonephritic scarring is inversely proportional to age. The greatest risk for post-infectious renal scarring occurs within the first year of life [27 ]. 4 BJU INTERNATIONAL 2011 BJU INTERNATIONAL

3 PRIMARY VESICO-URETERIC REFLUX OTHER NON-OPERATIVE MANAGEMENT Prevention of UTI should include behavioural and other forms of risk factor modification beyond antibiotic prophylaxis, including treatment of constipation and dysfunctional elimination disorders, the optimization of fluid intake and family education about appropriate evaluation and management of a febrile illness [ 28 ]. The AUA Guidelines on Management of Primary Vesicoureteral Reflux in Children recommend that if clinical evidence of bladder and bowel dysfunction is present, treatment of the bladder and bowel dysfunction is indicated, preferably before any surgical intervention for VUR is undertaken. Treatment options include behavioural therapy, biofeedback, anticholinergic medications, alpha blockers and treatment of constipation [15 ]. Given the role of bladder dysfunction in the aetiology of VUR, biofeedback therapy shows promise in the management of older children with dysfunctional voiding and VUR and yields greater resolution rates than the historical resolution rates. In a study of 98 refluxing units (grades I IV) in children with voiding dysfunction treated with biofeedback therapy, Kibar et al. [29 ] report that at 6 months of follow-up VUR had resolved on VCUG in 63%, the grade had improved in 29%, and the reflux had remained unchanged in only 8%. SURGICAL INTERVENTION FOR VUR CIRCUMCISION There is emerging evidence of prophylactic benefit of circumcision in selected patients with VUR. In a prospective cohort study of 151 boys with grade IV or V primary VUR, Alsaywid et al. [30 ] reported a significant reduction in the development of UTI and DMSA evidence of scarring before and after circumcision. Continuous antibiotic prophylaxis was given in all patients until at least 2 years of age. UTI occurred in 45.2% and 6.7% of patients before and after circumcision respectively. New permanent defects were seen in 5.2% of circumcised and in 10.2% of uncircumcised boys [30 ]. ENDOSCOPIC TREATMENT Pioneered by Matouschek [31 ] in 1981 and further developed by O Donnell and Puri [32 ] who described subureteric Teflon injection (STING), endoscopic treatment by injection of a bulking agent has largely replaced surgical reimplantation in the surgical correction of VUR. More recently, various techniques have been developed including single intraluminal hydrodistention implantation technique (HIT) or tandem proximal and distal intraluminal injection sites (double HIT) that coapts both the ureteral tunnel and orifice, increasing the success rate significantly [33 35 ]. Thousands of children with VUR have been treated with different substances Teflon paste, silicone paste or collagen being the most common until the introduction of NASHA/Dx gel (Deflux, Oceana Therapeutics Ltd, Edison, NJ, USA) [36,37 ]. NASHA/Dx gel is currently the most commonly used of these [36 ]. Its desirable properties include biodegradability (preventing permanent accumulation within the body), lack of potential for migration from the injection site, and lack of fibrosis or aggressive granulomatous reaction spreading to adjacent tissue [36,38 39 ]. Resolution of VUR following NASHA/Dx injection is inversely related to degree of reflux. Routh et al. [40 ] conducted a recent systematic review of papers reporting resolution of VUR following NASHA/Dx injection. Of 7303 ureters that were injected with NASHA/Dx, the overall per-ureter NASHA/Dx success rate was 77%, whereas those with grade V VUR had only a 62% probability. The Swedish Reflux Trial in Children [41 43 ] studied the clinical benefit of endoscopic antireflux therapy by randomizing small children with dilating (grade III IV) VUR to antibiotic prophylaxis, endoscopic treatment or surveillance. The study included 203 patients (128 girls and 75 boys) between the ages of 1 and 2 years. During a 2-year follow-up period a total of 67 febrile recurrences occurred in 42 girls and a total of eight in seven boys. A difference in the UTI recurrence rate among treatment groups was observed in girls, with fewer infections in the treatment groups than the surveillance group. Febrile infection occurred in eight of 43 (19%) on prophylaxis and 10 of 43 (23%) with endoscopic therapy compared with 24 of 42 (57%) on surveillance [41 ]. New renal damage in a previously unscarred area occurred in 13 girls and two boys, eight on surveillance and five following endoscopic therapy. No child in the prophylaxis arm developed new renal damage. New damage correlated with febrile UTI recurrence (22% with vs 3% without febrile UTI) ( P < 0.001) [42 ]. THE ROLE OF SURGICAL INTERVENTION In the late 1980s, the Birmingham Reflux Study Group [20 ] reported outcomes in children with severe VUR allocated randomly to either operative or non-operative treatment and followed up for 5 years. There were no significant differences between treatment groups in the incidence of breakthrough urinary infection, renal excretory function and concentrating ability, renal growth, progression of existing renal scars or new scar formation. They concluded that neither treatment can claim superiority or fully protect the kidneys from further damage. The International Reflux Study in Children was a multicentre randomized trial to evaluate the effectiveness of ureteric reimplantation for primary grades III and IV VUR. In the European part of the International Reflux Study in Children [21 ] 306 infants and children were randomly allocated to medical or surgical management. Reflux was absent in 97.5% of the reimplanted ureters at the end of 5 years. The number of pyelonephritic episodes during follow-up was significantly less in the surgical group (without chemoprophylaxis) than in the medical group (on chemoprophylaxis); however, the number of new renal scars was equal in the surgical and medical groups (20 in each). Recent studies also suggest that outcomes following medical management of VUR are comparable with surgical outcomes. Venhola et al. [44 ] conducted a meta-analysis of studies comparing medical and surgical management of VUR using the recurrence of UTIs, renal growth and renal scarring as endpoints. They report that operative treatment of VUR was better than medical treatment in terms of abolishing reflux. However, they found no statistically significant differences between surgically and medically treated patients in terms of kidney growth, scarring or recurrence of UTIs. In a systematic review including 11 studies and over 1100 children treated with either BJU INTERNATIONAL 2011 BJU INTERNATIONAL 5

4 COLEMAN antibiotic therapy or surgery, Hodson et al. [45 ] report no significant difference in risk of UTI between medical and surgical groups. Combined treatment resulted in a 50% reduction in febrile UTI by 10 years but no concomitant reduction in risk of new or progressive renal damage by 10 years. They concluded that nine reimplantations would be required to prevent one febrile UTI, with no reduction in the number of children developing any UTI or renal damage [45 ]. OUTCOMES A history of childhood VUR has many implications for the adult patient. REFLUX NEPHROPATHY Lahdes-Vasama et al. [46 ] reported on outcome in kidneys in 127 patients treated for VUR during childhood. Sonographic evidence of renal scars was unilateral in 35% and bilateral in 24% of subjects while 42% had no scarring. GFR showed moderate or severe renal insufficiency in 3% of participants, all with bilateral scars. Renal function was slightly lowered in more than half of the participants (83% of subjects with bilateral scars and 62% of the other participants). In a study of the outcome of childhood VUR, Smellie et al. [47 ] reviewed 226 adults (37 males), mean age 27 years, after years (mean 20.4 years). Of the 226 adults, there was an abnormality of either renal function or blood pressure in 17 (7.5%). Nine had impaired renal function, including two who had received renal transplants and one who had died from a renalassociated cause, all three in their third decade [47 ]. HYPERTENSION In the study by Lahdes-Vasama et al. [46 ], hypertension was diagnosed in 11% of patients. Diastolic blood pressure was significantly lower in subjects without scars compared with those having scars in one or both kidneys [ 46 ]. In the study by Smellie et al. [47 ] hypertension meriting treatment was present in 17 (7.5%) of the total group of 226 adults with VUR in childhood, 15 of whom had renal scarring [47 ]. BLADDER FUNCTION Bladder dysfunction plays a significant aetiological role in the pathophysiology of primary VUR. One might therefore expect urodynamic abnormalities in the adult population with a history of childhood VUR. However, there is relatively little published literature reporting urodynamic findings in such patients. Roihuvuo-Leskinen et al. [48 ] studied a cohort of 120 patients (109 females, 11 males) at early middle age with voiding problems related to childhood VUR. Forty-four patients had had some form of surgical intervention. They report abnormal uroflowmetry in 40%, 30% of non-operated patients and 55% of operated patients. Almost half of the operated patients (45%) had either an interrupted or a weak flow. Figures for stress incontinence and urgency incontinence among the female patients were twice those in the controls (35% vs 16% and 20% vs 11%, respectively). UTIs were diagnosed in significantly more adult patients with a history of VUR than controls (76% and 57% respectively). Twenty-five per cent of the female VUR patients (none of the controls) reported suffering from UTI more often than once a year. In a small study of 17 female VUR patients with abnormal flowmetry, Lahdes-Vasama et al. [49 ] reported urodynamic findings. A third of the patients had a large ( >800 ml) cystometric bladder capacity. Neither the earlier treatment modality nor grade of childhood VUR had an influence on the bladder sensitivity. Overactive detrusor and decreased bladder compliance were uncommon findings; decreased sensitivity and large capacity of the bladder were found frequently. Abnormal sphincteric electromyographic activity during voiding was found in 70% of all patients; in particular patients with weak or fractionated urine flow seemed to suffer from an overactive urethral sphincter [49 ]. PREGNANCY Hollowell [50 ] reviewed the available literature to determine the implication of history of VUR on pregnancy. The incidence of UTI during pregnancy was found to be higher in patients with a history of VUR compared with control groups (mean incidence 38% vs 6%). A history of VUR was found to infer a higher risk of UTI during pregnancy than control groups, with the highest incidence being amongst those with renal scarring. Risk of UTI was not modified by ureteric reimplantation [50 ]. The incidence of hypertension and pre-eclampsia was significantly higher in women whose VUR was associated with renal scarring compared with women with VUR and normal kidneys. Kohler et al. [51 ] reported the outcome of pregnancy in 89 women with a history of VUR. They report the incidence of pre-eclampsia to be similar in groups with unilateral or no reflux nephropathy (6% and 7% respectively) and 12% in the group with bilateral reflux nephropathy. The incidence of pre-eclampsia quoted for the general population is 0.8 7% [50,51 ]. Hollowell concluded that the presence of renal scarring rather than the presence or absence of reflux is the principal determinant of morbidity during pregnancy [49 ]. Smellie et al. [47 ] also reported that hypertension, impaired renal function, acute febrile UTI and complications of pregnancy were significantly related to renal scarring [47 ]. CONCLUSIONS Primary VUR is not simply a condition of the upper tract but is an indicator of a lower tract functional and urodynamic abnormality. Spontaneous resolution of VUR correlates with resolution of dysfunctional voiding. Whilst surgical correction of primary reflux can be undertaken by any of a variety of procedures in the interest of protecting the upper tract and preserving its function, the patient with surgically corrected VUR cannot be considered cured. While the benefit of continuous antibiotic prophylaxis in children with low grade VUR is marginal, it is recommended for all patients younger than 1 year with VUR and a history of a febrile UTI or with grades III V VUR identified through screening, due to the susceptibility of this age group to developing renal scarring. Risks and benefits of continuous antibiotic prophylaxis in low risk VUR should be carefully considered. Prevention of UTI should also include risk factor modification beyond antibiotic prophylaxis including treatment of constipation and voiding abnormalities, 6 BJU INTERNATIONAL 2011 BJU INTERNATIONAL

5 PRIMARY VESICO-URETERIC REFLUX optimization of fluid intake and family education to ensure prompt evaluation and management of a febrile illness. Biofeedback therapy shows promise in the management of older children with dysfunctional voiding and VUR and yields greater resolution rates than the historical resolution rates; however, further research is required. Circumcision reduces the risk of UTI but is not required in most patients. Whilst surgical correction of VUR marginally reduces the risk of febrile UTI, many studies have shown no benefit over medical management in the prevention of renal scarring. It therefore seems appropriate to reserve surgical correction for those patients who suffer breakthrough UTI despite optimal medical and non-operative management. A history of childhood VUR has significant implications for the adult patient. Many patients have abnormal bladder function, most often characterized by a large bladder with reduced sensation and abnormal sphincter function resulting in abnormal uroflowmetry and voiding symptoms. Few studies report on bladder dysfunction in adult patients with a history of childhood VUR. Further research efforts are required. Long-term consequences of VUR include hypertension, reflux nephropathy, and complications of pregnancy including UTI and pre-eclampsia. Bilateral renal scarring carries poorer prognostic implications in terms of development of renal failure than unilateral or non-scarred kidneys; however, patients with scarring whether unilateral or bilateral are at increased risk of hypertension. Long-term follow-up in such patients is essential. CONFLICT OF INTEREST None declared. REFERENCES 1 Hollowell JG, Greenfield SP. Screening siblings for vesicoureteral reflux. J Urol 2002 ; 168 : Noe HN, Wyatt RJ, Peeden JN Jr, Rivas ML. 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