Diagnosis and Management of VUR after first UTI Ron Keren, MD, MPH Division of General Pediatrics Center for Pediatric Clinical Effectiveness Children’s Hospital of Philadelphia

Case 2.5 year old old white girl with 3 days of: Fever (Tmax = 40°C) Poor appetite Fussiness 2 loose stools a day Urine dip shows moderate leukocyte esterase Treatment with PO TMP/SMZ initiated Urine culture (cath specimen) grows >105 E. coli Child defervesces in 2 days and completely well in 3 days. Next steps? So now that we’ve discussed the epidemiology and pathogenesis of UTIs, let’s proceed to a case and answer some specific questions using the best evidence found in the literature.

Screening for VUR Infants and children 2 months to 2 years with initial UTI should have either a VCUG or RNC performed to detect the presence and severity of VUR. (Strength of evidence: fair) (AAP, Practice Parameter: The Diagnosis, Treatment, and Evaluation of the Initial UTI in Febrile Infants and Young Children, Pediatrics, 103:4; 843-852, 1999)

Screening for VUR Infants and children 2 months to 2 years with initial UTI should have either a VCUG or RNC performed to detect the presence and severity of VUR. (Strength of evidence: fair) (AAP, Practice Parameter: The Diagnosis, Treatment, and Evaluation of the Initial UTI in Febrile Infants and Young Children, Pediatrics, 103:4; 843-852, 1999)

Age at First UTI Conway, P. H. et al. JAMA 2007;298:179-186.

Screening for VUR No recommendations on how to manage VUR Infants and children 2 months to 2 years with initial UTI should have either a VCUG or RNC performed to detect the presence and severity of VUR. (Strength of evidence: fair) (AAP, Practice Parameter: The Diagnosis, Treatment, and Evaluation of the Initial UTI in Febrile Infants and Young Children, Pediatrics, 103:4; 843-852, 1999) No recommendations on how to manage VUR

Management of VUR Scarring at Dx No Yes Age Initial F/U < 1 Proph Abx III-V: Surgery 1-5 B/L grade V: Surgery V: Surgery 6-10 B/L grade III-IV or U/L V: Surgery III-IV: Surgery (AUA, Report on The Management of Primary VUR in Children, Journal of Urology, May, 1997.)

Management of VUR Scarring at Dx No Yes Age Initial F/U < 1 Proph Abx III-V: Surgery 1-5 B/L grade V: Surgery V: Surgery 6-10 B/L grade III-IV or U/L V: Surgery III-IV: Surgery “The recommendations, which generally lack empirical scientific support, reflect the clinical experience and opinion of the panel.” (AUA, Report on The Management of Primary VUR in Children, Journal of Urology, May, 1997.)

Current Conceptual Model

What is the evidence to support current model of diagnosing and treating VUR in children after UTI?

Ecological Evidence Analyses of dialysis and transplant registries Expect reduction in incidence of end stage renal disease attributable to reflux nephropathy following the diagnosis and treatment of VUR started in the 1960’s Not there Broyer M, Chantler C, Donckerwolcke R, Ehrich JH, Rizzoni G, Scharer K. The paediatric registry of the European Dialysis and Transplant Association: 20 years' experience. Pediatr Nephrol. Dec 1993;7(6):758-768. Fenton S, Desmeules M, Copleston P, et al. Renal replacement therapy in Canada: a report from the Canadian Organ Replacement Register. Am J Kidney Dis. Jan 1995;25(1):134-150.

Observational Studies Conway, P. H. et al. JAMA 2007;298:179-186.

Incidence Rates and Follow-up Incidence Rate of First UTI: 0.007/person-year Similar to previous estimates Incidence Rate of Recurrent UTI after first UTI: 0.12/person-year Significantly lower than previous estimates of 21- 48% recurrence with follow-up of 6-12 months Mean observation time was 408 days with a median of 310 days (IQR 150 – 584 days), range of 24 - 1600 days

Conway, P. H. et al. JAMA 2007;298:179-186.

Conway, P. H. et al. JAMA 2007;298:179-186.

Conway, P. H. et al. JAMA 2007;298:179-186.

Conway, P. H. et al. JAMA 2007;298:179-186.

Survival Analysis Outcome is time to an event (e.g. death, recurrent infection) Observation time varies from one subject to another Different quantity Different start and stop times Censoring

Types of censoring Subject does not experience event of interest Incomplete follow-up Lost to follow-up Withdraws from study Dies X = dies

Hazard Ratio The hazard ratio in survival analysis is the effect of an explanatory variable on the hazard or risk of an event. Consider hazard ratio to be an estimate of relative risk

No. (%) with Recurrent UTI Clinical Trials No. (%) with Recurrent UTI Author, Journal, Year Abx No Abx RR (95% CI) Savage, Lancet, 1975 7/29 (24%) 4/32 (13%) 1.9 (0.6-5.9) Garin, Pediatrics, 2006 13/55 (24%) 12/58 (21%) 1.1 (0.6-2.3) Roussey, JU, 2008 18/103 (17%) 32/122 (26%) 0.7 (0.4-1.1) Garin: Up to age 18 years, febrile UTI, grades 1-3 VUR, unblinded Roussey: 1 mo – 3 years, febrile UTI, grades 1-3 VUR, unblinded In Garin study, recurrent acute pyelo seen in 7/55 (abx) v. 1/58 (placebo) (p=0.03) raising specter of INCREASED risk of APN with prophylactic antibiotics.

Systematic Review “The evidence to support the widespread use of antibiotics to prevent recurrent symptomatic UTI is weak. Large randomized, double blinded studies are needed…” Williams et al, Long-term antibiotics for preventing recurrent UTIs in children. Cochrane Database of Systematic Reviews 2006, Issue 3.

What’s a pediatrician/parent to do?

Maintain Status Quo Absence of evidence is not evidence of absence of benefit Continue to screen all children for VUR after first UTI Continue antibiotic prophylaxis for children with VUR until VUR resolves Conservative, one size fits all approach

Individualize Care 3 y.o. girl with first afebrile UTI concurrent with potty training vs… 5 mo. girl with febrile UTI requiring hospitalization; history of other febrile illnesses that got better with antibiotics; mother with duplicated collecting system and h/o bilateral grade 4 VUR that never completely resolved.

Consider Dysfunctional Elimination Abnormal elimination pattern (frequent/infrequent voids, urgency, constipation) Bladder/bowel incontinence Withholding maneuvers Underdiagnosed and undertreated 40% 1st UTI; 80% recurrent UTI Treatment decreases UTI recurrence and speeds resolution of VUR

Dysfunctional Elimination Treatment Scheduled voids q 2-3 hours Treat constipation Laxatives Increase fluid intake Avoid bladder irritants Caffeine, food coloring, chocolate, citrus, carbonation Urology referral Further evaluation Biofeedback for pelvic floor muscle training Anticholinergics 28

“Top Down” Imaging Approach You don’t need VUR to develop kidney scars after UTI If you have a normal DMSA scan with a febrile UTI, you are VERY unlikely to have high grade (>3/5) VUR

DMSA Renal Scans Normal APN Renal Scarring 30

Renal Scarring on DMSA

Dilating VUR (Grades 3-5) Normal DMSA Abnormal DMSA No VUR 36 64 VUR 1-2 5 16 VUR 3-5 21 Normal DMSA Abnormal DMSA No VUR 133 105 VUR 1-2 7 18 VUR 3-5 1 26

“Top Down” Approach Perform DMSA within 30 days of UTI Normal: reassure parents that kidneys are normal and child unlikely to have dilating VUR  skip the VCUG Abnormal: obtain VCUG, consider antibiotics v. surgery if VUR present, repeat DMSA in 4-6 months to diagnose scars

“Top Down” Approach Spares a lot of children a VCUG (48% in Preda study) DMSA less than half the radiation of a VCUG DMSA less invasive than a VCUG DMSA gives information about the health of the kidneys, which can be followed over time.

No Work-up Defer work-up until 2nd or 3rd UTI Heightened vigilance Educate on early signs and symptoms Emphasize need for rapid diagnosis Treat dysfunctional elimination ?Provide urine collection kits and dip sticks Likely that early diagnosis and treatment will prevent most UTI-related scarring.

DMSA results in the acute phase and day of treatment Doganis, D. et al. Pediatrics 2007;120:e922-e928 Copyright ©2007 American Academy of Pediatrics

Refer to RIVUR study Randomized Intervention for Children with VesicoUreteral Reflux CMH KC Site PI: Dr. Uri Alon

Study Design NIDDK funded (U01 contract) Multi-center 15 Clinical Trial Centers across the US Data Coordinating Center at UNC Chapel Hill Randomized Placebo Controlled Trial Initial UTI, presence of grades I-IV VUR Effect of prophylactic TMP/SMZ on: Recurrent UTI Renal scarring Antimicrobial resistance

Inclusion Criteria 2 months – 6 years at time of randomization Diagnosed 1st or 2nd F/SUTI within 16 weeks prior to randomization Presence of Grade I- IV VUR on VCUG

Time Line Recruitment started July 2007 2 years of recruitment 2 years of follow-up Plan to recruit 600 patients

Endpoints Primary Secondary Recurrence of F/SUTI Time to first recurrence of F/SUTI Renal scars on DMSA scan Stool E. coli resistant to TMP/SMZ Recurrent F/SUTI caused by TMP/SMZ resistant organisms

Modified Conceptual Model Prompt diagnosis and Delayed UTI treatment of UTI End Stage Renal diagnosis and Disease Prophylactic antibiotics treatment UTI ( s ) prevent recurrent UTI Renal UTI ( s ) Hypertension Scarring VUR Congenital Pre - eclampsia VUR and renal dysplasia VUR 42

Questions

International Classification of VUR 44

Renal Ultrasound

Deflux

Endoscopic Correction of VUR Deflux procedure Endoscopic injection of bulking agent (Dextranomer/hyaluronic acid) into submucosal layer of bladder just beneath or within the ureteric orifice. “Minimally invasive” compared with open surgery Day surgery Requires sedation

Deflux: Capozza >1 y.o Grades II-IV VUR persistent for at least 6 months Randomly assigned (2:1) to: Dextranomer/Hyaluronic Acid (n = 40) Prophylactic abx (n = 21) 12 months later 69% v. 38% (p=0.03) had bilateral grade I or less VUR. 11 (25%) needed 2nd injection at month 3, only 2 successful Capozza, N, Dextranomer/hyaluronic acid copolymer implantation for VUR: a randomized comparison with antibiotic prophylaxis, J Pediatr, 2002 Feb; 140(2):230-4.

Deflux: Capozza Deflux Proph abx p-value Recurrent UTI 6/40 (15%) 0/21 (0%) 0.08 New renal scars* 3/80 (4%) 1/42 (2%) 0.6 Renal scars healed* 11/80 (14%) 7/42 (16%) 0.4 Parenchymal kidney damage* 1/40 (3%) 3/21 (14%) 0.11 *As determined by renal US, not DMSA.

PIC VUR Recurrent febrile UTIs/ No VUR on conventional VCUG 30/30 Patients Renal Units Interpretation Recurrent febrile UTIs/ No VUR on conventional VCUG 30/30 48/60 (all 48 ureteral orifices lateral and/or patulous) “Explains” recurrent UTIs No febrile UTIs/ No VUR on conventional VCUG 0/15 0/30 (all 30 ureteral orifices normal appearing) Doesn’t show VUR in kids with no h/o UTI Recurrent febrile UTIs/ VUR on conventional VCUG 12/12 20/24 (all 20 ureteral orifices lateral and/or patulous) Shows VUR in kids with h/o UTI

PIC VUR Invasive – Requires general anesthesia and instrumentation of bladder Specificity needs confirmation – 0/15 does not mean no false positives % children with febrile UTI found to have PIC VUR after negative VCUG fell to 82% in small prospective validation study (Edmonson, Urol, 2006) No evidence that treating those found to have PIC VUR prevents recurrent UTI or renal scarring.

International Reflux Study

Effectiveness of Interventions for VUR Open surgical correction of VUR plus prophylactic antibiotics v. prophylactic antibiotics alone to prevent recurrent UTIs Author, Journal, Year RR recurrent UTI 2 years RR recurrent UTI 5 years Wheeler, ADC, 2003 (meta-analysis) 1.1 (0.6-2.1) 0.99 (0.8-1.3)

Effectiveness of Interventions for VUR Open surgical correction of VUR plus prophylactic antibiotics v. prophylactic antibiotics alone to prevent renal scarring Author, Journal, Year RR new renal scars (2 years) RR new renal scars (5 years) Wheeler, ADC, 2003 (meta-analysis) 1.1 (0.3-3.4) 1.1 (0.8-1.5) “It is not clear whether any intervention for children with primary VUR does more good than harm. Well designed and adequately powered placebo controlled randomized trials of antibiotics alone in children with VUR are now required.” (Wheeler et al, Antibiotics and surgery for VUR: a meta-analysis of RCTs, ADC, 2003)

RIVUR Study

Definitions Appropriately treated UTI Antibiotic therapy continues for a minimum of 7 days AND: There is documented sensitivity of the organism to the antibiotic used for treatment OR There is a documented test of cure (negative urine culture) 1-14 days after initiation of therapy.

Definitions UTI Pyuria on urinalysis >10 WBC/mm3 (uncentrifuged specimen) OR >5 WBC/hpf (centrifuged specimen), OR >1+ leukocyte esterase on dipstick Culture proven infection with a single organism >5 x 104 CFU/mL (catheterized or suprapubic aspiration urine specimen) OR >105 CFU/mL (clean voided specimen).

Definitions Fever Documented temperature of at least 100.4 °F (38 °C), measured anywhere on the body either at home or at doctor’s office Symptoms Suprapubic, abdominal, or flank pain or tenderness Urinary urgency, frequency, hesitancy, or dysuria, or foul smelling urine In infants < 4 months old: failure to thrive, dehydration, or hypothermia

Endpoints Treatment Failures Occurrence of 2 recurrent FUTIs within the study period, OR Total of 4 recurrent F/SUTIs within the study period Additional renal segment involvement at 12 mo. DMSA scan  

X

Renal Scarring Author, Journal, Year VUR No VUR RR (95% CI) Rushton, J Urol, 1992 40% 43% 0.9 (0.4-2) Jakobsson, ADC, 1994 42% 19% 2.2 (1.3-3.8) Hoberman, NEJM, 2003 15% 6% 2.4 (1.1-5.2) Garin, Pediatrics, 2006 1.1 (0.4-3.1)

Renal Scarring Less Common Author, Journal, Year N # (%) F/U Rushton, J Urol, 1992 33 16 (48) 11 mo (mean) Jakobsson, ADC, 1994 76 28 (37) 2 years Stokland, J Peds, 1996 157 59 (38) 1 year Hoberman, NEJM, 2003 275 26 (9) 6 mo Garin, Pediatrics, 2006 118 6 (5) Decreasing rates of renal scarring possibly due to increased awareness and earlier Dx and Rx of UTIs in febrile infants?

Potential Harms and Costs VCUG and RNC are invasive and cause physical discomfort and psychological distress. VCUG involves exposure to ionizing radiation. Diagnosis of VUR and perceived risk of renal scarring causes anxiety to patient and family. Prophylactic antibiotics contribute to antimicrobial resistance in the patient and the community. Recurrent UTIs with bacteria resistant to Cefotaxime = 27% in children receiving prophylactic antibiotics v. 3% in children not receiving them (RR=9.9; 95% CI [4-24.5]). (Lutter et al., Antibiotic resistance patterns in children hospitalized for UTIs, APAM, 2006) Costs of diagnosis and treatment potentially great.