Value of Urodynamic Findings in Predicting Upper Urinary Tract Damage in Neuro-Urological Patients: a Systematic Review

Received: 19 September 2017 | Accepted: 1 December 2017 DOI: 10.1002/nau.23501

REVIEW ARTICLE

Value of urodynamic findings in predicting upper urinary tract damage in neuro-urological patients: A systematic review

1 Department of Neuro-Urology, Careggi University Hospital, Florence, Italy Aim: The main goals of neurogenic lower urinary tract dysfunction (NLUTD) 2 Department of Urology, Hospital management are preventing upper urinary tract damage (UUTD), improving Universitario de Canarias, Universidad de continence, and quality of life. Here, we aimed to systematically assess all available La Laguna, Santa Cruz de Tenerife, Spain evidence on urodynamics predicting UUTD in patients with NLUTD. 3 Department of Urology, Erasmus Medical Center, Rotterdam, The Netherlands Methods: A systematic review according to the Preferred Reporting Items for 4 Neuro-Urology, Swiss Paraplegic Center, Systematic Reviews and Meta-Analyses (PRISMA) Statement was performed in Nottwil, Switzerland March 2017. Only neuro-urological patients assessed by urodynamics were included. 5 Neuro-Urology, Spinal Cord Injury Center Any outcome of upper urinary tract function were evaluated. & Research, University of Zürich, Balgrist Results: Forty-nine studies (1 randomized controlled trial, 9 prospective, and 39 University Hospital, Zürich, Switzerland 6 Department of Urology, University of retrospective case series) reported urodynamic data on 4930 neuro-urological patients. Of Bern, Inselspital, Bern, Switzerland those, 2828 (98%) were spina bifida (SB) children. The total number of adults was 2044, 7 Department of Urology, Aix Marseille mainly having spinal cord injury (SCI) (60%). A low bladder compliance was found in University, Marseille, France 568 (46.3%) and 341 (29.3%) of the paediatric and adult population, respectively. 8 Department of Urology, Pitié-Salpêtrière Hydronephrosis (HDN) was detected in 557 children (27.8%) in 19/28 studies and 178 Academic Hospital, Paris 6 University, Paris Cedex 13, France adults (14.6%), mainly SCI, in 14/21 studies. Nine out of 30 multiple sclerosis (MS) 9 Department of Neuro-Urology, London patients affected by HDN (16.8%) showed low compliance in 4/14 studies. Spinal Injuries Centre, Stanmore, UK Conclusions: Patients with SB and SCI have a higher risk of developing UUTD

Correspondence (mainly reported as HDN) compared to those with MS. Reduced compliance and high Bárbara Padilla-Fernández, Department of DLPP were major risk factors for UUTD. Although our findings clarify the Urology, Hospital Universitario de Canarias mandatory role of urodynamics in the management of NLUTD, standardization and Santa Cruz de Tenerife, Spain. Email: [email protected] better implementation of assessments in daily practice may further improve outcomes of neuro-urological patients based on objective measurements, that is, urodynamics. KEYWORDS DLPP, neurogenic bladder, neuro-urology, upper urinary tract, urodynamics

Stefania Musco and Barbara Padilla-Fernández contributed equally to this work. Hashim Hashim led the peer-review process as the Associate Editor responsible for the paper.

1 | INTRODUCTION Subjects must have received any urodynamic test at baseline and/or follow-up and any morphological and/or functional The main goals in managing neurogenic lower urinary tract evaluation of the upper urinary tract.12 Non-original articles, dysfunction (NLUTD) have traditionally been to prevent studies not published as full text, and those not discriminating upper urinary tract damage (UUTD) and to improve between non-neurological and neurological patients were continence and quality of life.1,2 To achieve these aims, a excluded. No restrictions for treatment type or duration was detrusor leak point pressure (DLPP) higher than applied (ie, conservative, minimally invasive or major

40 cmH2O has been introduced as an objective measure, surgery, mono or multiple interventions). which was based upon the results of a retrospective series of 42 children with myelomeningocele in 1981 described by 2.3 | Data extraction McGuire et al.3 The authors reported ureteral dilatation on intravenous pyelogram in 81% and vesicoureteral reflux in Prognostic urodynamic parameters assessed were: bladder

68% of children with DLPP higher than 40 cmH2O. These compliance (mL/cmH2O), DLPP (cmH2O), duration (sec), findings were considered as a valid tool to define a high risk and amplitude (cmH2O) of detrusor contraction during situation for upper urinary tract deterioration by many storage and voiding phase, cystometric capacity (mL), clinicians, although the value of DLPP to predict UUTD is not volume at first detrusor overactivity (mL), DSD, urethral well known, the measurement lacks standardization and pressure, post-void residual (mL), and vesico-ureteral reflux carries pitfalls,4,5 and the evidence for this cut-off value was (VUR). UUTD was assessed as: (i) the presence of hydro- considered low in a recent systematic review.6 This concept nephrosis (HDN), scarring or any signs of cortical atrophy was further extended to different etiologies of NLUTD in such as cortical thinning, retarded growth, reduction of the adults.4 On the other hand, other authors have proposed kidney's size determined by imaging (including ultrasound, considering in addition to DLPP, the presence of poor bladder urography, scintigraphy); (ii) Low out-of-range glomerular compliance, low functional bladder capacity, detrusor- filtration rate (GFR) determined by scintigraphy and/or serum sphincter dyssynergia (DSD), or the duration of involuntary blood test according to the various cut-offs adopted by detrusor contractions (IDC).7–10 studies; (iii) High out-of-range serum creatinine as stratified The aim of this systematic review was to assess and by authors; (iv) Any lowest value of GFR and/or highest appraise all available evidence onurodynamics predicting serum creatinine among significant changes during follow- UUTD in neuro-urological patients of different age and up; (v) any other outcome as reported by trialists, including aetiologies. death due to renal failure. Abstract screening was performed by three authors (B.P., S.M., M.B.) and bibliography 2 | MATERIAL AND METHODS management software (Endnote X7 Thomson Reuters, Philadelphia, PA) independently considered each publication 2.1 | Publication searches Asystematic literature search was performed (last search on 29 March 2017) using the Medline, Embase, and the Cochrane Central Register of Controlled Trials. No restrictions were placed on time or language of publications. Cited references of all included studies and any relevant review articles were also searched. This systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement.11 Protocol is available on PROSPERO (CRD42015026150; http://www.crd.york.ac.uk/PROSPERO). Supplement 1 lists the search strategies.

2.2 | Study selection Only neuro-urological populations as defined by European Association of Urology (EAU) Guidelines on Neuro- Urology, including children and adults with acquired or congenital specified neurological disease, were considered. FIGURE 1 PRISMA flow diagram MUSCO TABLE 1 Characteristics of neuro-urological children in the included studies

Pts No on AL ET

Study Level of Pts total No Mean age treatment (type Mean follow-up . Authors type evidence (F/M) NU (years) of therapy) (years) UUT outcomes measured Arora16 P 3 30 (5/25) SB 4.5 NA NA Renal scarring at DMSA Augenstein17 P 3 249 SB 4.71 167 (IC) 2.86 Abnormal USS or high serum creatinine (>0.4 infants; >0.7 children; 1.0 adolescents; 1.2 adults) Baek18 R 4 81 (36/45) SB 4.2 81 (AM) 4.2 Renal scarring at DMSA Bouchot19 R 3 200 SB 12 NA 9.02 HDN at urography Bruschini7 R 3 104 (55/49) SB 5a NA NA Renal scars, dilated urinary excretory system, localized cortical atrophy or sequels of pyelonephritis at USS or urography DeLair22 R 3 222 (117/105) SB –– NA Renal cortical loss was defined by scarring on USS, a differential function greater than 15% on nuclear scintigraphy, or difference in renal size of greater than 15% on USS compared with the contralateral kidney Control 201 11.5 49 (IC); 29 (AC) UUTD group 21 9.6 7 (IC); 6 (AC) Edelstein23 P 2 69 (38/31) SB Newborns 33 (IC + AM) 4.5-9 (range) New or worsening HDN at USS and/or urography Flood25 R 3 57 (34/23) SB 5.2-6.1b NA 4.67 The development of moderate/severe HDN ± absence of renal growth or renal size <2 SD below the mean age of Rosenbaun nomogram Galloway26 R 3 171 (109/62) SB 4.8 143 (NA) 2.2 HDN at USS and/or urography Kataria30 R 3 31 (26/5) SB NA NA HDN at USS Khoury31 R 3 33 (18/15) SB 7.7 23 (AC); 10 3-12 (range) HDN at USS (AC + BOP) Khoury32 R 2 41 (26/15) SB 12.8 NA 3 HDN at urography Kim33 R 3 39 SB (36), SCI (3) 0.16-14b 26 (IC) 2 HDN at USS and/or urography Korzeniecka35 R 3 112 (60/52) SB 9.13 62 (IC) 5.53 Serum eGRF (>140 mL/min) Kurzrock36 R 3 90 (49/41) SB 0.25 79 (IC); 15 (AC); 11 HDN or renal cortical loss (retarded growth or 50 (AM) scarring) at USS and/or urography Ma38 R 3 120 (40/80) SB 12.3 8 (IC) NA HDN at USS McGuire3 R 3 42 SB NA NA 7 HDN at urography

(Continues) | 3 4

TABLE 1 (Continued) | Pts No on Study Level of Pts total No Mean age treatment (type Mean follow-up Authors type evidence (F/M) NU (years) of therapy) (years) UUT outcomes measured McLorie39 P 2 213 SB 0-16b NA 2 HDN and renal cortical thinning correlated with the grade of HDN at urography Miklaszewska40 R 3 54 (28/26) SB 54 (IC) 5 Parenchymal damage at renal 99mTc etylenecysteine scintigraphy or No UUTD 20 10.7 14(AM); 7 (AB); 6 (AM + AB) Moderate UUTD 25 12.5 17 (AM); 9 (AB); Kidney parenchymal increase of echogenicity 6 (AM + AB) at USS Severe UUTD 9 15.3 5 (AM); 2 (AB); 2 (AM + AB) Ozel8 R 3 312 (167/145) SB 4.62-6.32c NA NA Renal scarring (contour irregular and defects) at DMSA Petersen43 R 4 43 (26/17) SB NA NA 10 HDN at urography Sager44 R 3 60 (28/32) SB 0.68 NA 0.5 Decrease in relative renal function with a difference >10% and/or hypocapturing area scarring or irregular distribution at DMSA Tanaka49 R 2 22 (7/15) SCI 8.8 16 (IC); 4 (AC); 7.1 HDN at USS 14 (AM) Van Gool51 R 3 76 SB 3.3 12 (IC) 3.3 HDN at urography Wang53 P 3 200 (61/139) SB (167), SCI 10.5 NA NA HDN at USS (33) Wang54 R 3 114 SB Newborns 51 (IC) NA HDN at USS Wide55 R 3 41 SB Newborns 38 (IC); 6 (BT); 11 Renal scarring at DMSA 23 (AM) Yamamoto56 R 3 60 (31/29) SB 14 33 (IC); 2 (AM) 4 HDN at urography

P, prospective cohort study; RCT, randomized controlled trial; R, retrospective case series; NU, neurological disease; Pts, patients; No, number; IC, intermittent catheterization; NA, not available; AM, antimuscarinics; UIC, urethral indwelling catheter; AB, alpha-blockers; SS, surgical sphincterotomy BOP, bladder outlet procedure; SC, suprapubic catheter; SB, spina bifida; SCI, spinal cord injury; AC, augmentation cystoplasty; BT, botulinum toxin; SD, standard deviation; UUTD, upper urinary tract deterioration; IU, international units; PVR, post-voiding residual; HDN, hydronephrosis; GRF, glomerular filtration rate; DMSA, dimercaptosuccinic acid; VUR, vesico-ureteral reflux; VUD, videourodynamics. aMedian. bRange. cMean range. MUSCO TAL ET . MUSCO TABLE 2 Characteristics of neuro-urological adults in the included studies

Mean AL ET

time Mean . Mean from Pts No on follow- Study Level of Pts total No Neurological age NU treatment up Authors type Evidence (F/M) Disease (years) (years) (type of therapy) (years) UUT outcomes measured Çetinel20 R 2 255 (81/174) SCI NA 112 (IC); 24 (UIC); 45 (AM) 2.09 Any grade of HDN or VUR, scars, thinning at USS or scintigraphy or serum creatinine >1.5 mg/dL UUTD 63 (25/38) 34a 17 (IC); 5 (AM) No UUTD 192 (56/136) 32a 95 (IC); 40 (AM) Chen21 RCT 3 72 (29/43) SCI 41.5 8.7 47 (IC) 1 Significant changes of renal function by GRF on 99mTc- DTPA Elmelund10 R 3 73 SCI NA NA Split renal function ≤30% in one kidney at renography or GFR ≤51% of expected according to age and gender UUTD 19 (1/18) 1 (IC) 42 No UUTD 54 (7/47) 3 (UIC); 2 (IC) 41 Fletcher24 R 3 173 (131/42) MS 1-11.5b HDN, caliectasis, cortical scarring, or kidney stone formations at USS Control 163 49 11 23 (AM); 14 (AB); 7 (AM + AB); 1 (AC); 10 (BT); 2 (SS) UUTD group 10 52.5 15 4 (AM); 1 (AM + AB); 3 (BT) Gerridzen27 R 4 140 (17/123) SCI 32 NA NA NA HDN, renal scarring at urography Giannantoni28 P 3 116 (77/39) MS 47.3 14.5 1 (UIC) NA HDN, kidney stones, signs of renal parenchymal disease at USS Giannantoni29 R 3 78 (43/37) SCI 5.4 NA Pyelonephritis, HDN, renal stone formation or VUR at USS and/or urography IC regimen group 57 33.2 6.2 57 (IC) Voiding group 21 36.7 Kim34 R 3 55 (0/55) SCI 50 21 55 (NA) NA HDN, cortical scars, urolithiasis at USS Lemack37 R 3 66 (58/8) MS 50.7 12.9 4 (NA) NA HDN, cortical scarring, caliectasis, kidney stones at USS Linsenmeyer9 R 3 84 (0/84) SCI 34.9 8.5- 16 (AB); 16 (SS) NA Caliectasis or HDN at 99-m 10.4c Technitium Mag (Continues) | 5 6

TABLE 2 (Continued) | Mean time Mean Mean from Pts No on follow- Study Level of Pts total No Neurological age NU treatment up Authors type Evidence (F/M) Disease (years) (years) (type of therapy) (years) UUT outcomes measured Onal41 R 3 230 (142/76) MS 38a NA NA NA HDN at USS Perrouin-Verbe42 P 2 29 (22/7) SCI 35a 9 23 (IC); 3 (UIC); 29 (CS) 5.5 Creatinine clearance (>30 mL/min) Sakota-Maric45 R 3 42 (32/10) SCI 29.4 4 NA NA Nephrolithiasis, pielocaliectasis, HDN, signs of pielonephritis at UUS Shin46 P 3 150 (42/108) SCI 37.81 NA NA 4.99 Significant change of the effective renal plasma flow at Tc-99m MAG3 Shingleton47 R 3 88 SCI 30 HDN, pyelonephritis, kidney stones at USS, urography and renal scan NA DLPP < 40 cmH2O 36 30 28 (IC + AM); 4 (UIC); 1 (SC) 3 DLPP > 40 cmH2O 52 30 12(SS); 22(IC + AM); 3 (SC); 4 12(UIC) Takeda48 R 4 9 (4/5) SB (5), SCI (4) 24.4 NA NA NA Dilated or obstructive pattern on Tc- 99m DPTA, GFR Thorup50 R 3 52 (24/28) SB 29 6a 20 (IC) 8a Renography and isotope GFR (cut off NA) Viart52 P 3 121 (60/61) MS 48 13.8 19 (IC); 4 (UIC); 3 3 HDN at urography and USS (AB + AM) Zhang57 R 3 47 (7/40) SB (23); SCI (24) 29.1 10 47 (IC + AM) 2 HDN at USS or serum creatinine >1.5 mg/dL Zhang58 R 3 52 (23/29) SB (15); SCI (32); 21.7 NA NA 4 HDN at USS, significant changes in other (5) serum creatinine Zhang59 P 2 112 (21/91) SCI 18-60b NA 2 Any grade of VUR, HDN ≥ grade 1 at USS or magnetic resonance urography Control 57 4 (UIC); 1 (SP); 40 (IC) UUTD 55 15 (UIC); 7 (SP); 10 (IC)

P, prospective cohort study; RCT, randomized controlled trial; R, retrospective case series; Pts, patients; No, number; IC, intermittent catheterization; NA, not available; AM, antimuscarinics; UIC, urethral indwelling catheter; AB, alpha-blockers; SS, surgical sphincterotomy; SC, suprapubic catheter; SB, spina bifida; SCI, spinal cord injury; AC, augmentation cystoplasty; CS, continent stoma; BT, botulinum toxin; SD, standard deviation; UUT, upper urinary tract; IU, international units; HDN, hydronephrosis; GRF, glomerular filtration rate; DTPA, diethtlenetriaminepenta-acetic acid; PVUR , vesico-ureteral reflux pressure. aMedian. MUSCO bRange. cMean range. TAL ET . TABLE 3 Urodynamic and UUT outcomes in children MUSCO Compliance DLPP NDO PVR TAL ET Pts No Mean Pts Mean with poor DLPP Pts No Mean Pts Pts Mean No Pts Pts No Pts No Pts No . compliance compliance (±SD) with Pdetmax No No PVR with No with with with Pts (±SD) in in mL/ in high Pts (±SD) in with with (±SD) High with Bilateral Cortical Renal Other Authors No mL/cmH2O cmH2O cmH2O DLPP No mL VUR DSD in mL PVR HDN HDN atrophy scars outcomes Arora16

Control 9 9 3 1 0 8 (hostility score >5) (>25 cmH2O) Renal scars 21 8 6 7 9 3 (creatinine> 1 mg/dL); 7 (>25 cmH2O) (hostility score >5) Augenstein17 249 60 49 9 3 (death for kidney failure) Baek18 81 6.4 (±6.1)a 16a 48a 20a 27a 11.1 (±9.6) 12

Bouchot19 Control 146 24 14 UUTD 54 7 54

Bruschini7 21 13 2 Control 47 19 16 25 VUR 30 18 25 12 30 Renal scars 27 14 25 13 27

Delair22 Control 201 108 22 49 Cortical loss 21 12 15 13 21

Edelstein23 69 2 6 3 10 5 2

Flood25 57 25 57 15 6 5 2 (creatinine >1 mg/dL) Galloway26 Control 116 56 (hostility score >5) UUTD 40 34 (hostility score >5) Kataria30 23 Control 18 5.8 (±4.7) 40.1 (±20.3) 7 0 UUTD 13 9.5 (±19.2) 34.9 (±22.8) 7 4 13

Khoury31 Only AC 23 49.7 13 16 13 AC + outlet 10 42.8 4 2 3 procedure Khoury32 41 19 44 13a 26a 31 (hostility score>5)a | 2 4 21 (hostility 7 score>5) (Continues) 8

TABLE 3 (Continued) | Compliance DLPP NDO PVR

Pts No Mean Pts Mean with poor DLPP Pts No Mean Pts Pts Mean No Pts Pts No Pts No Pts No compliance compliance (±SD) with Pdetmax No No PVR with No with with with Pts (±SD) in in mL/ in high Pts (±SD) in with with (±SD) High with Bilateral Cortical Renal Other Authors No mL/cmH2O cmH2O cmH2O DLPP No mL VUR DSD in mL PVR HDN HDN atrophy scars outcomes Kim33 39 10 13 10 7 9

Korzeniecka35 112 20 53 29 10 50 Mean GRF 161.25 mL/min Kurzrock36 Control 43 13 3 9 2 0 UUTD 47 32 17 33 7 5

Ma38 Control 75 30 10 28 48 0 UUTD 45 27 32 33 40 45

McGuire3 30 7 3 DLPP < 40 20 0 0 2 cmH2O DLPP ≥ 40 22 22 15 18 cmH2O McLorie39 213 51b

Miklaszewska40 Control 20 8 2 GFR 117.4 (±27.8) mL/min Moderate 25 15 3 GFR 118.5 UUTD (±31) mL/min Severe UUTD 9 7 6 GFR 67.5 (±43.1) mL/min Ozel8 Control 240 126 49.4 172 39 102 139 0 (±27.7) UUTD group 72 58 54.4 61 26 48 50 72 (±27.8)

Petersen43 43 17 11 37 7 4 12 3 (reduced renal function at DMSA) 2 deaths for renal failure Sager44 MUSCO Control 42 2 16 10 6 16 UUTD 18 2 10 7 6 6

(Continues) AL ET . MUSCO TABLE 3 (Continued)

Compliance DLPP NDO PVR AL ET

Pts No Mean Pts . Mean with poor DLPP Pts No Mean Pts Pts Mean No Pts Pts No Pts No Pts No compliance compliance (±SD) with Pdetmax No No PVR with No with with with Pts (±SD) in in mL/ in high Pts (±SD) in with with (±SD) High with Bilateral Cortical Renal Other Authors No mL/cmH2O cmH2O cmH2O DLPP No mL VUR DSD in mL PVR HDN HDN atrophy scars outcomes Tanaka49 21027 Early IC 6 0 Delayed IC 10 7 3 UUT changes not better defined Van Gool51 Detrusor & 35 37 (±11.1) 5 3 pelvic areflexia Detrusor & 31 31 72 (±27) 9 31 2 7 (reflux pelvic nephropathy) hyperreflexia Detrusor 10 63 (±23) 3 10 1 3 (reflux areflexia & nephropathy) pelvic hyperreflexia

Wang53 Control 97 25.6 (±17.5) 19 (±12) 10 45 50 47 (±35) 0 4 (UDS risk scorex2009; =3) UUTD sub- 34 15.1 (±12.2) 34 (±16) 13 16 21 108 34 6 (UDS risk group 1 (±92) score = 3) UUTD sub- 34 6.4 (±4.5) 54 (±21) 27 14 21 132 34 20 (UDS risk group 2 (±97) score = 3) UUTD sub- 35 5.9 (±3) 68 (±27) 31 10 20 183 35 20 (UDS risk group 3 (±122) score = 3) Wang54 DLPP 48 52 10 52 21 10 22 ≥40 cmH2O DLPP 66 18 0 7 0 <40 cmH2O Wide55 DLPP 34 0 0 8 4 <30 cmH2O DLPP 730730 1 >30 cmH2O Yamamoto56 UOP 31 75 <35 cmH2O UOP 29 21 22 ≥35 cmH2O

Pts, patients; No, number; DLPP, detrusor leak point pressure; Pdetmax, maximum detrusor pressure; NDO, neurogenic detrusor overactivity; PVR, post-voiding residual; VUR, vesico-ureteral reflux; SD, standard deviation; UUTD, upper urinary tract damage; DMSA, dimercaptosuccinic acid; IU, international units; f(x), function; UOP, urethral opening pressure. aBaseline results. b | Mean maximum urethral closure = 103 cmH2O. 9 10 | MUSCO ET AL. regarding inclusion/exclusion criteria. When selected papers Mean follow-up ranged from 0.5 to 11 years.36,44 In this concerned the same population, only the latest publication young population, 951 (61%) were receiving treatment for and/or the highest number of patients was included. their NLUTD at the time of the inclusion in 16/28 Discrepancies were resolved by one senior reviewer (D.C. studies.17,18,22,23,26,31,33,35,36,38,40,49,51,54–56 Of those, 635 D.). All of the data retrieved from the selected studies were (67%) were managed by intermittent catheterization (IC) recorded in an electronic database (Excel, Microsoft (see Table 1). Corporation, Redmond, WA). In 21/49 studies, adults affected by the following neurological diseases were included: traumatic SCI 2.4 | Risk of bias assessment (n = 1210, 59.2%), multiple sclerosis (MS) (n = 706, 34.5%), spina bifida (n = 112, 5.5%). Non-traumatic SCI An evaluation of level of evidence, based on the Oxford etiology such as myelitis was reported in 11 adults Centre for Evidence-Based Medicine criteria, was performed (<0.05%).48,57–59 Cerebrovascular or peripheral neurological for each included full text.13 The Cochrane Risk of Bias diseases were reported in one and four individuals, Assessment tool was used only for randomized controlled respectively.58 Mean range of age was 21.7-52.5 years.24,58 trials (RCTs).14,15 A list of the main potential confounders Mean range of duration of neurological disease was 4-30 was developed by the EAU Neuro-Urology Guidelines panel: years.45,47 Mean follow-up ranged from 1 to types of treatment, age, onset of disease, and co-morbidities 42 years.21,609,10,20,21,24,28,29,34,37,42,47,50,52,57,59 IC regimen contributing toward UUTD (eg, diabetes, cardiovascular was performed by 428 (56.7%) adults on treatment for their diseases).12 When possible, authors whose studies presented NLUTD9,10,20,21,24,28,29,34,37,42,47,50,52,57,59 (see Table 2). the data in a format not suitable for analysis were contacted and asked for any missing figures. Risk of bias summary was 3.2 | Results in children conducted using the Review Manager v.4.2, software (Cochrane Collaboration, Oxford, UK). Data on bladder compliance were found in 16/28 studies. Of those, four studies (23.5%) reported only the mean value, but the number of patients affected by low compliance was not 2.5 | Statistical analysis defined.18,19,30,53 A reduction of compliance was found in 568 In non-RCTs, no data pooling was planned due to different (46.3%) spina bifida patients by 12/16 reports. The mean study designs and the expected clinical and methodological compliance in children ranged from 5.8 to 25.6 mL/cmH2Oin 18,19,30,35 heterogeneity of included studies. Thus, only qualitative 4/16 studies. Poor compliance cut-off adopted by 36,38,43,49,53 synthesis was conducted. However, forest plots with authors varied from <9 and <20 mL/cmH2O. multivariate modeling for urodynamic parameters were Data on DLPP were found in 14/28 studies, but only in 5 made using the Review Manager v.4.2, software (Cochrane (35.7%) mean values were available, ranging from 18 to 8,31,53,54 Collaboration, Oxford, UK) to show the magnitude of the 68 cmH2O. Categorization of the sample according to ≥ effect and the risk for UUTD. the cut-off value 40 cmH2O was described apart from two reports, which defined high DLPP values higher than 25 and 16,55 30 cmH2O, respectively. Three hundred and forty-eight 3 | RESULTS (36.4%) children showed a DLPP ≥40 cmH2O in 11/14 studies3,7,17,18,36,40,44,49,53 (see Table 3). After screening a total of 5348 records, 49 studies published Neurogenic detrusor overactivity (NDO) was docu- from 1981 to 2017 (1 RCT, 9 prospective, and 39 mented in 649 (45.8%) children by 17/28 studies. Of those, – – retrospective case series) were included.3,7 10,16 59 Figure 1 only 6/17 authors reported the mean detrusor pressure (Pdet) shows the PRISMA flow diagram of the literature search and value during NDO.30,32,43,51,54,55 The maximum mean value results.11 of Pdet (Pdetmax) during involuntary contractions was found

of being 72 ± 27 cmH2O in 31 (40.6%) SB children affected 51 3.1 | Study and patient characteristics by NDO combined with pelvic overactivity. No authors reported data on the duration of IDC in NDO children. Overall, 4930 neurological patients were described. Of those, Five hundred and twenty-nine (36.1%) young patients 2886 (58.5%) were children and 2044 (41.5%) adults. were diagnosed with DSD by 16/28 authors. Only two authors Twenty-seven studies out of 28 included 2828 children reported the mean post-void residual volume (PVR) ranging (98%) affected by spina bifida (SB). One reported data on 22 from 47 to 183 mL.35,53 children suffering from transverse myelitis.49 Two studies The presence of hydronephrosis (HDN) was detected in included 36 children with neurogenic bladder after spinal cord 557 (27.8%) children by 20/28 authors, whereas, 350 (28%) injury (SCI).33,53 Mean range of age was 0-15.3 years.23,40 showed VUR in 17/28 studies. MUSCO ET AL. | 11

Considering the evaluation of kidney function using Khoury et al reported the resolution of VUR in 39/41 patients laboratory tests, only two studies reported a serum creatinine with a decrease in the hostility score ≤4 in the overall >1 mg/dL (88.42 μmol/L) in three and two young patients, population after cystoplasty.32 Regarding data after bladder respectively.16,25 Two other authors reported the mean level augmentation, Khoury et al also found that the rate of VUR of GFR ranging from 67.5 to 161.25 mL/min.35,40 was significantly lower (P < 0.05) in augmented bladder Death due to kidney failure was reported by two authors treated with a concomitant bladder outlet procedure (0.2%) respectively in 3 (1.2%) and 2 (4.6%) SB children.17,43 than when only cystoplasty was performed (70%).31 The hostility score ≥5, a scoring system from 0 to 10 Wang et al reported a positive correlation between the formulated by Galloway et al using the sum of 5 measurable urodynamic risk score (DLPP >40 cmH2O + bladder com- urodynamic variables from 0 (absence) to 2 (worst pattern) pliance <9 mL/cmH2O + detrusor acontractility) and such as VUR, NDO, compliance, leak point pressure and UUTD.53 Considering bladder management, Tanaka et al DSD, was significantly related to the UUTD (P < 0.05) at reported better bladder compliance in children who were the time of urodynamicsin three studies.16,26,32 Peculiarly, managed early on by IC (P = 0.02). None of those patients

FIGURE 2 Urodynamic risk factors in children (A) reduced compliance as defined by authors; (B) DLPP ≥40 cmH2O; (C) presence of neurogenic detrusor overactivity; (D) presence of detrusor sphincter dyssynergia (DSD). SCI, spinal cord injury. SB, spina bifida 12 | MUSCO ET AL. developed upper urinary tract changes compared to those and, a significant reduction of Pdetmax during NDO was starting IC later, although no statistical significance was documented in SCI patients by Chen et al after 1-year follow- found.49 up with the use of two different dosages of botulinum toxin Figure 2 shows the risk of UUTD in children with reduced detrusor injection.21 compliance, DLPP ≥40 cmH2O, NDO, and DSD. Whereas, Zhang et al reported better compliance (from 2.96 to 14.07 mL/cmH2O) and a statistically significant reduction of mean serum creatinine level (P < 0.01) in 52 3.3 | Results in adults patients who had undergone sigmoid augmentation. Specifi- cally, after surgery, compliance increased from 2.96 ± 1.55

Data on compliance were not detected in 6/21 stud- up to 14.07 ± 5.45 mL/cmH2O and HDN was solved in 31 ies.27,28,34,37,47,50 Overall, in 341 (29.3%) patients, a low (66%).58 compliance bladder was diagnosed. Poor compliance cut-off Regarding the effect of type of bladder management, 24,52 varied from <10 to <30 mL/cmH2O. Mean compliance UUTD and presence of VUR was reported to be lower in SCI was reported in 9/15 studies, ranging from 2.96 to 42.35 mL/ patients on IC regimen to those who are not (P < 0.05).29 46,58 cmH2O. The risk of UUTD in adults with low compliance, high A mean value ranging from 24 to 68 cmH2O was DLPP, NDO, and DSD is shown in Figure 3. described in 5/7 studies reporting data on DLPP.9,27–29,34 One hundred and twenty-four (63.5%) adults showed a DLPP 34,47,50 3.4 | Risk of bias higher than 40 cmH2O in three studies. NDO was detected at baseline evaluation in 1018 (61.7%) Several confounders were found in all case series. Most by 13/21 authors. Mean Pdetmax at involuntary contraction authors present cohorts at first evaluation that were already during filling cystometry ranged from 36.1 to 115 cmH2Oin treated with a variety of regimens, ranging from early 9/13 studies including NDO adults. Particularly, Shin et al intervention with IC ± combined with antimuscarinics to demonstrated a significant inverse relationship between renal voiding triggered or indwelling catheter. function and maximal detrusor pressure, although no specific Moreover, one study did not report data regarding the cut-off values were defined.46 Conversely, Cetinel et al population's age nor the number of females or males 3 concluded that a Pdetmax ≥75 cmH2O was independent risk included. Data on gender were missing from another 8/51 factor for UUTD.20 Data on the duration of IDC during NDO studies.17,19,33,39,47,51,54,55 was reported in 4/13 studies with a mean value ranging from In addition, none of the studies reported co-morbidities 48 to 236 s.9,28,29,60 In particular, Linsenmeyer et al reported a about the patients’ baseline characteristics, such as diabetes mean duration of contraction of 236.4 ± 139.1 and and cardiovascular diseases, which can negatively influence 113.9 ± 84 s in SCI patients with and without HDN kidney function over time. See supplement 2. respectively, but only Elmelund et al found a statistical significant correlation between the duration of IDC and 4 | DISCUSSION UUTD and they stratified the risk of UUTD according to the DO/cystometry ratio (total duration of IDC during filling 4.1 | Principal findings cystometry divided by the total duration of filling cystometry).3,9 They concluded that the cumulative risk of UUTD at To the best of our knowledge, this is the first systematic 40 years post-injury was 40% for patients witha DO/ review on the role of urodynamic parameters in predicting cystometry ratio >0.33, and 12% for patients with DO/ upper urinary tract damage in NLUTD. Particularly, SB and cystometry ratio <0.333 (see Table 4). SCI patients have been found to have a higher risk of DSD was diagnosed by 11/21 authors in 626 (44.1%) developing UUTD, especially HDN, compared with MS SCI and MS adults. Mean PVR varied from 80 to 185.6 mL (∼25% vs 5%). Thus, our data confirms that the risk of in 6/11 studies including patients showing DSD at developing UUTD is lower in patients with slowly progres- urodynamics.9,21,24,28,37,41 sive non-traumatic neurological disorders than in those with In 14/21 studies, 178 (14.6%) adults showed HDN. Of SCI or SB.2 those, 30 (16.8%) were affected by MS.24,37,41,52 VUR was Although most of the studies included were under- detected in 130 (15.5%) patients according to 9/21 authors. powered with a high risk of bias and confounding, our Unlike children, no hostility score or other urodynamic findings support that the UUTD risk might be associated risk score criteria as defined by authors were found in overall with low detrusor compliance. Considering that, it is worth studies concerning adults. of saying that authors used different parameters for 36,52 A preserved kidney function measured by GFR at 99mTc- low compliance ranging from <9 to <30 mL/cmH2O labeled diethtlenatriamine penta-acetic acid (99mTc-DPA) (see Figure 3). TABLE 4 Urodynamic and UUT outcomes in adult MUSCO Compliance DLPP NDO PVR TAL ET Mean Pts Mean DLPP Pts No Mean Pts Pts Mean No Pts Pts No Pts No Pts No . compliance Pts No (±SD) with Pts Pdetmax No No PVR with No with with with Pts (±SD) in with poor in high No (±SD) in with with (±SD) in High with Bilateral Cortical Renal Other Authors No mL/cmH2O compliance cmH2O DLPP NDO mL VUR DSD mL PVR HDN HDN atrophy scars outcomes Çetinel20

Control 192 47 105 71a 075 UUTD 63 17 36 112a 40 22

Chen21 Botox® 38 26.9 (±26.8)b 38b 40.7 137.8 Mean GFR blood 200 IU (±21.3)b (±101.6)b 94.2 ± 22.1 mL/ minb 31.8 (±27.1) 23.1 (±17.6) Mean GRF blood 90.5 ± 24.2 mL/ min Botox® 34 30.6 (±29.1)b 34b 36.1 226.3 Mean GRF blood 300 IU (±22.2)b (±138.2)b 84.2 ± 19.6 mL/ minb 29 (±19.6) 12.9 (±16.9) Mean GRF blood 88 ± 28.2 mL/ min Elmelund10 Control 54 35a 39 37 37a 30 121a UUTD 19 30a 13 13 40a 12 136a

Fletcher24 Control 163a 9a 122a 44a 68a 80a 0a 0a 0a 5 49 41.8 43 205 0 0 0 UUTD group 10a 1a 7.5a 37a 5a 105a 5a 23a 1a 11 3 8 41.4 7 258 3

Gerridzen27 100 Control 117 24 72 0 0 UUTD 23 58 115 7 12 4

Giannantoni28 116 58.4 94 63.4 (±31.7) 6 49 123.2 7 (kidney stones) (±27.4) (±144.4) Giannantoni29 IC regimen 57 12 68 32 73.8 (±26.9) 2 18 2 1 2 (kidney stones) (±24.3) Voiding 21 14 80 (±38) 35 88.6 (±31) 10 26 7 5 6 (kidney stones) Kim34 42.1 43.3 DLPP 36 36 9 24 10 15 (kidney stones)

>40 cmH2O DLPP 19 0 4 3 1 5 (kidney stones)

<40 cmH2O Lemack37 Control 55 43 49 (±22) 18 0

UUTD 11 6 50 (±17) 4 181.1 9 2 (kidney stones) |

(±176.3) 13 (Continues) TABLE 4 (Continued) 14 | Compliance DLPP NDO PVR

Mean Pts Mean DLPP Pts No Mean Pts Pts Mean No Pts Pts No Pts No Pts No compliance Pts No (±SD) with Pts Pdetmax No No PVR with No with with with Pts (±SD) in with poor in high No (±SD) in with with (±SD) in High with Bilateral Cortical Renal Other Authors No mL/cmH2O compliance cmH2O DLPP NDO mL VUR DSD mL PVR HDN HDN atrophy scars outcomes Linsenmeyer9 Control 71 24.9 (±26.4) 65.5 0 181.1 00 (±31) (±176.3) VUR 4 17 (±15.1) 40.5 4 130 00 (±11.7) (±147.6) Stasis 9 25.2 (±24.9) 52.1 0 185.6 96 (±28) (±105.4) Onal41 Control 218 5 51 52 40 27 0 UUTD 12 2 5 147 3 12

Perrouin- 29 5b 16b 35b (median) 1b 2 pts with Verbe42 creatinine clearance >30 mL/minb 0 3 25 (median) 0

Sakota- 26 Maric45 Control 24 23.98 (±22.08) 12 0 UUTD group 17 13.07 (±8.42) 10 2 Nephrolithiasis 24%, ureteropieloectasia 21%, pyelonephritis 10% Shin46 150 42.35 (±43.62) 150 39.43 Mean renal plasma (±30.48) flow 429.44 mL/ min Shingleton47 DLPP 36 0 1 2 (pielonephritis); 4 (kidney stones) <40 cmH2O DLPP 52 52 7 4 2 (pielonephritis); 2 (kidney stones) >40 cmH2O Takeda49 9 30.44 26.61 1 4 3 Mean GFR 43.59 mL/min Thorup50 Control 37 24 9 7 Unilateral 7634 Functional share kidney f(x) median 14%, of total renal function Bilateral 8655 1 kidney

kidney f(x) transplantation MUSCO 7 (median creatinine clearance 65 mL/min) AL ET

(Continues) . MUSCO TAL ET .

TABLE 4 (Continued) Compliance DLPP NDO PVR

Mean Pts Mean DLPP Pts No Mean Pts Pts Mean No Pts Pts No Pts No Pts No compliance Pts No (±SD) with Pts Pdetmax No No PVR with No with with with Pts (±SD) in with poor in high No (±SD) in with with (±SD) in High with Bilateral Cortical Renal Other Authors No mL/cmH2O compliance cmH2O DLPP NDO mL VUR DSD mL PVR HDN HDN atrophy scars outcomes Viart52 Control 117 25 44 82 10 0 UUTD group 4 17.75 4 3 3 3 4

Zhang57 47 11.82 (±14.2) 31.1 (±26.4) 45

Zhang58 52 2.96 (±1.55)b 35 8 31 47b 36b Mean serum creatinine 88.1 μmol/Lb 14.07 (±5.45) 16 77.1 μmol/L Zhang59 Control 57 39 33 30 UUTD 55 48 41 21

Pts, patients; No, number; DLLP, detrusor leak point pressure; Pdetmax, maximum detrusor pressure; NDO, neurogenic detrusor overactivity; PVR, post-voiding residual; VUR, vesico-ureteral reflux; SD, standard deviation; UUTD, upper urinary tract damage; IU, international units; f(x, function; UOP, urethral opening pressure; Pvur, vesico-ureteral reflux pressure. aMedian. bAt baseline. | 15 16 | MUSCO ET AL.

FIGURE 3 Urodynamic risk factors in adults (A) reduced compliance as defined by authors; (B) DLPP ≥ 40 cmH2O; (C) presence of neurogenic detrusor overactivity; (D) presence of detrusor sphincter dyssynergia. SCI, spina cord injury. SB, spina bifida. MS, multiple sclerosis

Regarding DLPP, although its value higher than attempts were done to determine different cut-off values since

40 cmH2O might be predictable for UUTD, whether this McGuire et al published their paramount paper in the early parameter could be considered valid or too high for different 1980s.3,16,55 types of populations remains debatable. As a matter of fact, Finally, regarding the UUTD findings, outcome measures apart from two studies including SB children, no further were widely heterogeneous. Overall, most of the authors MUSCO ET AL. | 17 have defined UUTD as varying morphological abnormalities Meta-analysis could not be done due to the significant such as the presence of HDN, kidney scars and/or cortical heterogeneity of data. Moreover, although we included atrophy. Only a few of them have assessed kidney function treatment studies it was not possible to weight the effect of by scintigraphy or serum eGRF and/or other specific urodynamic risk factors on UUTD in patients receiving laboratory tests in both pediatric and adult popula- any kind of intervention because of poor and mainly tions7,10,16,17,20,22,30,40,42,44,45,48,52,57 (see Tables 1 and 2). uncontrolled data. Nonetheless, because our purpose was to provide a 4.2 | Implication for research synthesis, we consider our approach to be acceptable. However, the risk of bias and confounding was substantial. Thus, although

The statement that a DLPP higher than 40 cmH2Oisarisk the value of urodynamics in the management of NLUTD is factor for upper urinary tract deterioration should not be undisputed, well-designed prospective longitudinal studies universally extended to all ages and neurological popula- evaluating all urodynamic parameters combined with imaging tions.3,16,55 Although it is still not possible to establish and renal function tests from the start and during follow-up are specific predictive values for each neuro-urological disease, highly warranted. Moreover, standardization and better the existence of any significant correlations between single implementation of assessments in daily practice will probably or multiple urodynamic parameters and renal function further improve outcomes of neuro-urological patients based on cannot be excluded. Considering our findings, it appears objective measurements, that is, urodynamics. that except for low compliance the other parameters in urodynamic studies have not been extensively evaluated to 5 | CONCLUSIONS quantify the risk of upper tract damage in a wide range of neuro-urological diseases.20,46 Therefore, it would be Patients with spina bifida and SCI have a higher risk of appropriate to urodynamically identify different scenarios developing UUTD (mainly HDN) compared to those with that could warn us of the need for early intervention in order multiple sclerosis. On the basis of our systematic search, to prevent renal damage. To that end, future studies should especially reduced compliance and high DLPP were found as not only evaluate the impact of the various urodynamic predicting factors for UUTD in SB children as well as in parameters on upper tract but should also correlate the neuro-urological adults (SCI and MS). Thus, our findings morphological and functional data. As a matter of fact, our clarify the mandatory role of urodynamics in the management results showed that most of the studies reported only one of NLUTD as recommended by International Guidelines. outcome, in particular HDN without any related data on renal function loss. ORCID 4.3 | Implication for practice Barbara Padilla-Fernández http://orcid.org/0000-0002- 8566-6033 Considering our findings, there is an important need to Jürgen Pannek http://orcid.org/0000-0002-9910-1295 take into account all standardized urodynamic parameters, Thomas M. Kessler http://orcid.org/0000-0002-1991- including post-void residual when urodynamic is indicated 5919 for NLUTD according to the recommendations by the Marc P. Schneider http://orcid.org/0000-0002-3540-6794 1 International Consultation on Incontinence. Moreover, a Tobias Gross http://orcid.org/0000-0002-3843-2672 structural upper urinary tract evaluation by ultrasound scan Gilles Karsenty http://orcid.org/0000-0002-9047-3332 and kidney function by specific blood tests such as serum Véronique Phé http://orcid.org/0000-0002-4997-6763 creatinine and estimated GFR should be concomitantly performed in order to correlate the UUT function and morphology with the grade and type of NLUTD. Again, REFERENCES the same assessment should be reserved during follow-up 1. Drake M, Apostolidis A, Emmanuel A, et al. International to evaluate the benefits and/or harm of different Consultation on Incontinence. 5th ed.; 2012. treatments. 2. Panicker JN, Fowler CJ, Kessler TM. Lower urinary tract dysfunction in the neurological patient: clinical assessment and management. Lancet Neurol. 2015;14:720–732. 4.4 | Limitation of the study 3. McGuire EJ, Woodside JR, Borden TA, Weiss RM. Prognostic value of urodynamic testing in myelodysplastic patients. J Urol. Although this report represents the first systematic review 1981;126:205–209. that aims to identify and determine the available evidence of 4. Tarcan T, Demirkesen O, Plata M, Castro-Diaz D. ICS teaching urodynamic prognostic factors for UUTD in patients module: detrusor leak point pressures in patients with relevant affected by NLUTD, some limitations should be mentioned. neurological abnormalities. Neurourol Urodyn. 2017;36:259–262. 18 | MUSCO ET AL.

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