1. 8/29/20151 In the Name of the Lord of soul and wisdom

2. Vesico- ureteral Reflux Alaleh Gheissari Pediatric Nephrologist IUMS 8/29/2015 2

3. Definition  The retrograde flow of urine from the bladder to the kidneys.  VUR:  Primary  Isolated  Secondary  With CAKUT  With Neurogenic Bladder 8/29/20153

4. Prevalence  1-3% post-mortem  1.3% of healthy children  8-50% of children evaluated for UTI  Less severe in African American than Caucasian 8/29/20154

5. Prvalence  Infants with prenatal hydronephrosis:  15% VUR  26% other urogenital anomalies like duplex systems, UPJ stenosis, urethral valves and mega-ureter. 8/29/20155

6. Embryology and Anatomy  Secondary to a pre-existing anatomic abnormality with shortening of the intra-vesical sub- mucosal length of the ureter.  The length of the sub-mucosal ureter :  major component in the prevention of VUR. 8/29/20156

7. Embryology  If the ureteral bud reaches the urogenital sinus too early, due to the absorption pattern of the mesonephric duct, it is eventually located more laterally and proximally in the bladder, resulting in VUR. 8/29/20157

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9. Clinical Presentation of Primary VUR  Following diagnostic evaluation of a UTI,  During follow-up for antenatal hydronephrosis,  Screening a sibling of a patient with VUR. 8/29/20159

10. Presenting Clinical Symptoms of VUR and/or Renal Parenchymal Injury Fever with or without urinary symptoms Urinary symptoms without fever Flank pain Proteinuria Nephrotic syndrome due to focal segmental glomerulosclerosis Hypertension Secondary enuresis due to coexisting voiding dysfunction or diminished urine concentrating ability Renal stone, mostly due to Proteus mirabilis UTI Renal failure, including end-stage renal disease 8/29/201510

11. Voiding Dysfunction and VUR  The symptoms of DES  Daytime wetness,  Urgency  Frequency  Infrequency  Constipation  Faecal incontinence in ‘‘toilet trained’’ children with no underlying anatomic or neurological abnormality 8/29/201511

12. VUR & Renal Scarring  More than 75% of children under the age of 5 years with febrile UTI have acute pyelonephritis.  Renal scarring occurs in 10% to 64% of all children with febrile UTI. 8/29/201512

13. Is VUR dangerous?  Bacterial insult:  intrusion of infected urine ( the most common)  Urodynamic insult:  abnormal urine pressure exerted by reflux on the papillae  Biochemical insult:  abnormal biochemical or immunological reaction caused by urine 8/29/201513

14. Pathophysiology of VUR  The virulence of bacteriae and their reservoirs  Incompetent vesico-ureteric junction  Renal parenchyma  Bladder and bowels dysfunctions.  VUR and UTI seem to be independent pathological factors that may potentiate each other (1). 8/29/201514

15. Hypertension  Five to 27% of children with renal damage will develop hypertension  Twenty five per cent of ESRD (Italy)can be attributed to VUR related parenchymal anomalies. This rate is evaluated at 5 to 10% in the Australian adult population.  Modern approach of VUR is not accompanied by a reduction of the incidence of VUR-related ESRD. 8/29/201515

16. Relationship with bladder dysfunction  In infants :  Higher voiding pressures and a dyssynergic patterns of micturition  Predominates in males,  May be relevant in the pathogenesis of VUR and influences its resolution pattern.  Different voiding patterns are reported in infants with dilating VUR when compared with healthy infants. 8/29/201516

17. Relationship with bladder dysfunction  In older children:  A strong correlation between bladder dysfunction, (instability and dyssynergia) and UTI  Together in 60% of cases  With VUR in 20%  Predominates in female patients  Correlate with persistent VUR and UTI, regardless of surgery  An acquired form of VUR of low grade with no dilatation of the urinary tract. 8/29/201517

18. When to look for VUR?  Prenatal dilatation  Fifteen percent: Related to VUR  Severe VUR is associated with bilateral dilatation and congenital renal damage (60%)  Predominates in males (75% of all)  Lower rates of spontaneous resolution (≤ 50%)  Significant correlation between antenatal degree of dilatation and incidence of VUR.  Normal prenatal renal sonography does not exclude VUR. 8/29/201518

19. When to look for VUR?  Febrile urinary tract infection  40% of cases.  Siblings  As high as 34%.  VUR of low grades (98%)  A low risk of renal damage (11%)  Asymptomatic in 50% of cases.  No prophylaxis is needed. 8/29/201519

20. When to look for VUR?  Other uropathies  Dilated upper urinary tracts,  Urine flow impairments,  Bladder outlet obstruction,  Multicystic renal disease,  Neuropathic bladder,  VUR should be investigated in the 3 first situations, and discussed in the last 2 clinical presentations. 8/29/201520

21. How should we look for VUR?  Conventional contrast cystography  The standard investigation method.  Its specificity is high.  It gives information about the anatomy of upper and lower urinary tract.  Its sensitivity is low.  The evidence and grade of VUR is not influenced by timing. 8/29/201521

22. How should we look for VUR?  Nuclear cystography  The main pros (comparing with VCUG):  Higher sensitivity (91% versus 45% respectively because of continuous imaging, and its lower radiation exposure.  Fails to give anatomical information about the upper tract, and the urethra in males. 8/29/201522

23. How should we look for VUR?  Nuclear cystography  The most valuable contributions :  The evaluation of female patients with normal ultrasound scans  The follow up of VUR managed medically.  Indirect isotopic cystography using Mag 3:  Poor records to detect reflux especially in low grades VUR the advantage to avoid urethral catheterization  15% of false positive VUR is reported making this technique rather poorly accurate. 8/29/201523

24. How should we look for VUR?  Ultrasonography  Low sensitivity  No correlation between sonography, and existence or “severity” of VUR  Fifteen percent of prenatal upper urinary tract dilations are related to VUR.  25% of renal units in children who had prenatal diagnosis and VUR confirmed postnatally, including “high grade” VUR, are normal on postnatal sonography. 8/29/201524

25. How should we look for VUR?  Ultrasonography  The best timing to perform the first postnatal sonography  Between day 7 to 10, because earlier evaluation usually underestimates the severity of dilatation.  It is appropriate to perform ultrasound scan earlier in selected cases such as PUV in boys. 8/29/201525

26. How should we look for VUR?  DMSA renal isotopic scan  The gold standard study for renal damage in VUR with a sensitivity of 100% and a specificity of 80%.  DMSA should be performed 6 months after a febrile UTI, since 83% of acute lesions on initial DMSA during acute pyelonephritis improve or disappear. 8/29/201526

27. How should we look for VUR?  Voiding urosonography (VUS )  Using VCUG as the reference,  Sensitivity: 57–100%,  Specificity: 85–100%  Diagnostic accuracy: 78–96%. 8/29/201527

28. How should we look for VUR?  Other common investigations  Complications (HTN and RF) should be systematically assessed:  To look for hypertension and tubular damage in all children presenting with renal lesions.  To distinguish dysfunctional from malformative VUR:  Assessment of bladder and intestinal behaviour history, uroflowmetry, PVR, bladder wall 8/29/201528

29. How should we look for VUR?  Other common investigations  Abdominal plain X-ray to assess:  constipation  Incidental anomalies (vertebra, stones)  urodynamic studies can be useful especially if a radical treatment of VUR is considered 8/29/201529

30. How should we look for VUR?  Serum Procalcitonin:  High serum procalcitonin seems to be a stong predictor of VUR in children with a first febrile urinary tract infection, with a sensitivity rate of 75% for all-grade VUR, 100% for grade 4 or 5, but with a specificity rate of 43%. 8/29/201530

31. Should we treat VUR?  High rates of spontaneous resolution.  Normal DMSA, normal bladder function and no upper tract dilatation are good predicting factors for spontaneous resolution (100% compared to 30% if kidneys are abnormal on DMSA).  Low grade VUR are mostly associated with bladder dysfunction, while high grade VUR are essentially malformative and more prone to radical treatments. 8/29/201531

32. How should we treat reflux?  Antibioprophylaxis  No publication documents that antibioprophylaxis prevents UTI with or without VUR. The current attitude of giving antibioprophylaxis to all children with VUR is based on the fact that prophylaxis reduces the incidence of renal scars after pyelonephritis. 8/29/201532

33. How should we treat reflux?  Antibioprophylaxis  A recent prospective randomized study shows that antibiotic prophylaxis did not reduce the incidence of UTI in young children with low grade VUR, but it may prevent pyelonephritis in boys with grade III VUR. 8/29/201533

34. How should we treat reflux?  The timing of antibiotic discontinuation:  To wait until the age of 7-8 years,  To wait until the age of toilet training.  To stop antibioprophylaxis in asymptomatic children after a certain age.  A consensus exists on the fact that any symptomatic UTI should be immediately treated by adequate antibiotics without delay. If the appropriate treatment is postponed, renal damage may occur. 8/29/201534

35. How should we treat reflux?  Surgery:  The only advantage of surgery VS medical  significant decrease in the incidence of pyelonephritis,  It does not reduce the number of UTIs neither renal damage (acquired or progressive).  In the hands of experienced surgeons, ureteral reimplantation stops VUR in 98%.  Only in the 10-15% of children not responding to endoscopic treatment and those with severe ureteral anomalies. 8/29/201535

36. How should we treat reflux?  Postoperative morbidity  Ureterovesical obstruction  Persistent VUR  Transient urine retention,  Fluid collections,  UTI  Contra lateral VUR appearing after correction of unilateral reflux : 4.6% of cases, but usually resolves with time. 8/29/201536

37. How should we treat reflux?  Take home message:  Long-term follow-up studies up to 20 years confirm the ongoing risk of UTI including febrile UTIs (46-52%) as well as the development of hypertension (6%) and renal anomalies (20%) despite successful surgery. 8/29/201537

38. How should we treat reflux?  Cystoscopic subureteral injection  “ Five years of antibiotics or one endoscopic injection?”… or no treatment at all! As the best results of injection are found with low grade VUR which tends to resolve with growth and maturation of the bladder in most cases, the question of the indications for injection needs to be addressed. 8/29/201538

39. How should we treat reflux?  Cystoscopic subureteral injection  The success rate of endoscopic treatment is significantly lower, 80.6 to 91%.  In addition, there is a potential risk of migration and toxicity of some “biocompatible” bulking agent used, as well as a risk of ureteral obstruction and recurrence of reflux with this technique. 8/29/201539

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