1. © 2010 Universitair Ziekenhuis Gent Future research

2. 22 © 2010 Universitair Ziekenhuis Gent Genetics Refractory enuresis Comorbidities Therapy compliance Renal aspects of nocturnal polyuria Circadian rythms Bladder / brain talking Personalised medecine long term follow up

3. 33 © 2010 Universitair Ziekenhuis Gent 1) genetics

4. 44 © 2010 Universitair Ziekenhuis Gent Suggestions for future research Identify nocturnal enuresis “mono” genes (rare alleles) Sequence DNA contained in linkage regions in affected subjects from 4p, 12q, 13q, 22q and 17p families (capture array and nextgen DNA sequencing) Identify risk genes in nocturnal enuresis (common/rare variants) Genotype SNPs in candidate genes in case-control samples (multiplex SNP genotyping by Sequenom) or candidate gene sequencing GWAS studies (GeneChip SNP array ) or whole genome sequencing

5. 55 © 2010 Universitair Ziekenhuis Gent Subtyping of patients in NMNE /MNE Very important for clinical flow chart in primary care Not for research MNE NMNE Suggestions for future research

6. 66 © 2010 Universitair Ziekenhuis Gent Describe all the characteristics of the patients rather than to force them in a subtype Neglecting The overlap The combined disorders There is no evidence of different pathways International standardisation Suggestions for future research

7. 77 © 2010 Universitair Ziekenhuis Gent 2. Circadian rhythm Hormones Vasopressin

8. 88 © 2010 Universitair Ziekenhuis Gent Mechanisms behind nocturnal polyuria AgII Aldo ANP Hormones Genes Renal factors Intrinsic circadian clock Hemodynamic factors Sleep, light, activity,food AVP Circadian regulation of urine output Urine concentration Tubular reabsorption GFR Centralblood volume Blood pressure

9. 99 © 2010 Universitair Ziekenhuis Gent Circadian rhythm of vasopressin Adapted from: Rittig S et al. Am J Physiol 1989;256:F664–71 Decreased plasma vasopressin overnight leads to Nocturnal polyuria with low urinary osmolality Primary ?? /secundary Is likely to be desmopressin responsive? -Better antidiuretic ?? -In theory yes? -In practice how to do better?

10. 10 © 2010 Universitair Ziekenhuis Gent Circadian rhythm of vasopressin Adapted from: Rittig S et al. Am J Physiol 1989;256:F664–71 Decreased plasma vasopressin overnight leads to Nocturnal polyuria with low urinary osmolality Primary ?? /secundary Is likely to be desmopressin responsive? -Better antidiuretic ?? -In theory yes? -In practice how to do better?

11. 11 © 2010 Universitair Ziekenhuis Gent Mechanisms behind nocturnal polyuria AgII Aldo ANP Hormones Genes Renal factors Intrinsic circadian clock Hemodynamic factors Sleep, light, activity,food AVP Circadian regulation of urine output Urine concentration Tubular reabsorption GFR Centralblood volume Blood pressure

12. 12 © 2010 Universitair Ziekenhuis Gent Circadian rhythm of other vaso-active hormones No direct evidence (certainly not in MNE) Indirect evidence in desmopressin resistant nocturnal polyuria But abnormal circadian rhythm Prostaglandins (Kamperis) Bloodpressure (Rittig) Solute load (Dehoorne) Sodium excretion Correlation hypertension nocturnal hypertension/nocturnal polyuria From treatment increasing desmopressin response Indomethacin ? Furosemide ?

13. 13 © 2010 Universitair Ziekenhuis Gent

14. 14 © 2010 Universitair Ziekenhuis Gent Uniform AVP and AQP2 excretion but excess nocturnal PGE2 production in polyurics U-AQP2 (U/kg/h) 0.00 0.10 0.20 0.30 0.40 U-PGE2 (ng/kg/h) P<0.05 U-AVP (ng/kg/h) 0.00 0.10 0.20 0.30 0.40 NS 100 0 200 300 400 NS controls non-polyurics polyurics dry night

15. 15 © 2010 Universitair Ziekenhuis Gent Vaso-active hormones They should play a role in a subgroup of patients Because vasopressin can not explain all te findings Nor the desmopressin resistant nocturnal polyuria Better subtype the patients Multicenter studies Standardised strategies

16. 16 © 2010 Universitair Ziekenhuis Gent Mechanisms behind nocturnal polyuria AgII Aldo ANP Hormones Genes Renal factors Intrinsic circadian clock Hemodynamic factors Sleep, light, activity,food AVP Circadian regulation of urine output Urine concentration Tubular reabsorption GFR Centralblood volume Blood pressure

17. 17 © 2010 Universitair Ziekenhuis Gent Kruse et al, J Urol, 2009 Enuresis Nocturia Graugaard-Jensen et al, J Urol, 2006 RTX Alstrup et al, Transpl Proc, 2010 BPH Matthiesen et al, J Urol, 1996 Nocturnal polyuria and blood pressure

18. 18 © 2010 Universitair Ziekenhuis Gent Mechanisms behind nocturnal polyuria AgII Aldo ANP Hormones Genes Renal factors Intrinsic circadian clock Hemodynamic factors Sleep, light, activity,food AVP Circadian regulation of urine output Urine concentration Tubular reabsorption GFR Centralblood volume Blood pressure

19. 19 © 2010 Universitair Ziekenhuis Gent Abnormal circadian rhytm of diuresis & glomerular filtration rate Controls : 20% decrease GFR overnight MNE : no circadian rhytm of GFR Control Group MNE-NP−Study Group MNE-NP+ Uvol (ml/min)1.7 ± 0.4/0.8 ± 0.4 1.0 ± 0.3†/1.7 ± 0.5†† GFR ml/min/1.73 m 2 126 ± 25/112 ± 23 121 ± 27/119 ± 29 A. De Guchtenaere J Urol. 2007 Dec;178(6):2635-9

20. 20 © 2010 Universitair Ziekenhuis Gent Abnormal circadian rhytm of sodium excretion High 24 h urinary sodium excretion Kuzenetsova in random population : Yes Kamperis (JAmPhys 2006) :No Abnormal circadian rhythm of sodium-handling Kamperis (J Am Phys 2006): yes A. Raes (J Urol 2006) probably related to primary tubular sodium-handling disorder in distal tubulus A. DeGuchtenaere (J Urol 2008) : positive effect of furosemide in dDAVP resistant nocturnal polyuria

21. 21 © 2010 Universitair Ziekenhuis Gent

22. 22 © 2010 Universitair Ziekenhuis Gent subnormal concentrating capacity in a tertiary enuresis population Up to 20% does not reach urinary osmolality values > 850 mosmol/l Up to 20% does not reach urinary osmolality values > 850 mosmol/l p < O.O1 * * * * * dDAVP 2 nasal spray A. De Guchtenaere J Urol. 2009 Jan;181(1):302-9;

23. 23 © 2010 Universitair Ziekenhuis Gent Renal questions to resolve Why abnormal circadian of Water excretion (not vasopressin related) Sodium excretion Tubular sodium handling Osmotic excretion Calcium-excretion GFR Why 25 % of patients to have suboptimal desmopressin response < 800 mosmol/l

24. 24 © 2010 Universitair Ziekenhuis Gent Mechanisms behind nocturnal polyuria AgII Aldo ANP Hormones Genes Renal factors Intrinsic circadian clock Hemodynamic factors Sleep, light, activity,food AVP Circadian regulation of urine output Urine concentration Tubular reabsorption GFR Centralblood volume Blood pressure

25. 25 © 2010 Universitair Ziekenhuis Gent Mechanisms behind nocturnal polyuria AgII Aldo ANP Hormones Genes Renal factors Intrinsic circadian clock Hemodynamic factors Sleep, light, activity,food AVP Circadian regulation of urine output Urine concentration Tubular reabsorption GFR Centralblood volume Blood pressure

26. 26 © 2010 Universitair Ziekenhuis Gent

27. 27 © 2010 Universitair Ziekenhuis Gent B. Mahler, Aarhus Univ., PhD Thesis, 2009 Acute sleep deprivation in children

28. 28 © 2010 Universitair Ziekenhuis Gent Mechanisms behind nocturnal polyuria AgII Aldo ANP Hormones Genes Renal factors Intrinsic circadian clock Hemodynamic factors Sleep, light, activity,food AVP Circadian regulation of urine output Urine concentration Tubular reabsorption GFR Centralblood volume Blood pressure

29. 29 © 2010 Universitair Ziekenhuis Gent Sleep/ arousal Bladder capacity Nocturnal polyuria

30. 30 © 2010 Universitair Ziekenhuis Gent Brain dysfunction Bladder disorders ? Does a Bladder-and-Brain Dialogue exist??

31. 31 © 2010 Universitair Ziekenhuis Gent Brain dysfunction Bladder disorders ? Does a Bladder-and-Brain Dialogue exist??

32. © 2010 Universitair Ziekenhuis Gent Cognitive disturbances following night-time wetting in children 1. The CK Yeung theory 2. Is there evidence ?

33. 33 © 2010 Universitair Ziekenhuis Gent CK Yeung ICCS Hong Kong 2006 1. Sleep Architecture and Cortical Arousal 2. Brainstem Function Prepulse Inhibition of Startle (PPI) Reflex Latency P300 event-related brain potential (ERP) 3. Cognitive Performance-tests intelligence score (Raven Progressive Matrices Test) focused attention (Digit Cancellation Test) short-term memory (HK List Learning Test) retention ability & long-term memory (HK List Learning Test) shifted attention, learning speed and reaction (Conner’s Continuous Performance Test) In patients with enuresis worse than in controls But normalises after therapy But …. data remain unpublished

34. © 2010 Universitair Ziekenhuis Gent Normal Children Bladder Behaviour and Sleep Changes

35. © 2010 Universitair Ziekenhuis Gent Enuretic Children Bladder Behaviour and Sleep Changes

36. 36 © 2010 Universitair Ziekenhuis Gent

37. 37 © 2010 Universitair Ziekenhuis Gent Theory from CK Yeung Nocturnal enuresis Causes sleep disturbance Overstimulation of central brain Cognitive dysfunction Treatment of nocturnal enuresis Amelioration of sleep Less exhaustion of the brain Amelioration of cognitive function

38. 38 © 2010 Universitair Ziekenhuis Gent Anima model

39. 39 © 2010 Universitair Ziekenhuis Gent Animal model cerebral dysfunction

40. 40 © 2010 Universitair Ziekenhuis Gent -. Is there evidence ? Comorbidity = yes / causality = No/ = circulus viciosus OAB coincides with sleepdeprivation / ADHD symptoms (CK Yeung ) Sleepdeprivation results in nocturnal polyuria (Rittig ). NP associated with higher solute, sodium excretion and bloodpressure Nocturnal polyuria is associated with abnormal superficial sleep and restless legs syndroom (K Dhont Ghent) Association between nocturnal polyuria and OAB (J.Vande Walle) D. Baeyens (Ghent) : Association of enuresis And AD(H)D = cognitive dysfunction And Prepulse inhibition Association AD(H)D with nocturnal polyuria Amelioration of AD(H)D coincides with amelioration of enuresis

41. 41 © 2010 Universitair Ziekenhuis Gent Pilot study 29 patients Refractory enuresis Desmopressin resistant (15) Desmopressin dependent (14) Polysomnography: overnight registration EOG EEG EMG Thor Abd Nasal airflow ECG O2 Video/phono

42. 42 © 2010 Universitair Ziekenhuis Gent Results: PLMS-index increased

43. 43 © 2010 Universitair Ziekenhuis Gent The egg/ chicken sleep enuresis ADHD Cognitive dysfunction Therapy resistance Diuresis/ Bladder

44. 44 © 2010 Universitair Ziekenhuis Gent RR Sleep disorder drugs bladder Noct polyuria solutes ADD ADHD Sodium Nocturia

45. 45 © 2010 Universitair Ziekenhuis Gent Coming this summer Results prospective study Children with nocturnal polyuria Screened Enuresis characteristics ADH symptoms Sleep Treated with desmopressin melt Retested.. And the results…..

46. 46 © 2010 Universitair Ziekenhuis Gent Prospectives for research Genetics Refractory enuresis Comorbidities Therapy compliance Renal aspects of nocturnal polyuria Circadian rythms Bladder / brain talking Personalised medecine long term follow up