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Future research

Future research. Genetics Refractory enuresis Comorbidities Therapy compliance Renal aspects of nocturnal polyuria Circadian rythms Bladder / brain talking Personalised medecine long term follow up. 1) genetics. Suggestions for future research .

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Future research

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  1. Future research

  2. Genetics • Refractory enuresis • Comorbidities • Therapy compliance • Renal aspects of nocturnal polyuria • Circadian rythms • Bladder / brain talking • Personalised medecine • long term follow up

  3. 1) genetics

  4. 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. Suggestions for future research • Subtyping of patients in NMNE /MNE • Very important for clinical flow chart in primary care • Not for research • MNE NMNE

  6. Suggestions for future research • 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

  7. 2. Circadian rhythm • Hormones • Vasopressin

  8. Genes Intrinsic Sleep , light, circadian clock activity , food Urine AVP Circadian concentration regulation of urine output AgII Tubular Hormones Renal factors reabsorption Aldo Hemodynamic GFR ANP factors Blood Central blood pressure volume Mechanismsbehindnocturnal polyuria

  9. Circadian rhythm of vasopressin • 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? Adapted from: Rittig S et al. Am J Physiol 1989;256:F664–71

  10. Circadian rhythm of vasopressin • 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? Adapted from: Rittig S et al. Am J Physiol 1989;256:F664–71

  11. Genes Intrinsic Sleep , light, circadian clock activity , food Urine AVP Circadian concentration regulation of urine output AgII Tubular Hormones Renal factors reabsorption Aldo Hemodynamic GFR ANP factors Blood Central blood pressure volume Mechanismsbehindnocturnal polyuria

  12. 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. 0.40 400 NS 0.30 300 0.20 200 0.10 100 controls 0.00 0 non-polyurics polyurics dry night U-AQP2 (U/kg/h) U-AVP (ng/kg/h) U-PGE2 (ng/kg/h) 0.40 NS P<0.05 0.30 0.20 0.10 0.00 Uniform AVP and AQP2 excretion but excess nocturnal PGE2 production in polyurics Kamperis et al 2006

  14. 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

  15. Genes Intrinsic Sleep , light, circadian clock activity , food Urine AVP Circadian concentration regulation of urine output AgII Tubular Hormones Renal factors reabsorption Aldo Hemodynamic GFR ANP factors Blood Central blood pressure volume Mechanismsbehindnocturnal polyuria

  16. RTX Enuresis Alstrup et al, TransplProc, 2010 Kruse et al, J Urol, 2009 Matthiesen et al, J Urol, 1996 Graugaard-Jensen et al, J Urol, 2006 Nocturia BPH Nocturnal polyuria and blood pressure

  17. Genes Intrinsic Sleep , light, circadian clock activity , food Urine AVP Circadian concentration regulation of urine output AgII Tubular Hormones Renal factors reabsorption Aldo Hemodynamic GFR ANP factors Blood Central blood pressure volume Mechanismsbehindnocturnal polyuria

  18. Abnormal circadian rhytm of diuresis & glomerular filtration rate • Controls : 20% decrease GFR overnight • MNE : no circadian rhytm of GFR A. De Guchtenaere J Urol. 2007 Dec;178(6):2635-9

  19. 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

  20. Kamperis et al 2006

  21. subnormal concentrating capacityin a tertiary enuresis population p < O.O1 * * * * * • Up to 20% does notreachurinaryosmolalityvalues > 850 mosmol/l dDAVP 2 nasal spray A. De Guchtenaere J Urol. 2009 Jan;181(1):302-9;

  22. 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

  23. Genes Intrinsic Sleep , light, circadian clock activity , food Urine AVP Circadian concentration regulation of urine output AgII Tubular Hormones Renal factors reabsorption Aldo Hemodynamic GFR ANP factors Blood Central blood pressure volume Mechanismsbehindnocturnal polyuria

  24. Genes Intrinsic Sleep , light, circadian clock activity , food Urine AVP Circadian concentration regulation of urine output AgII Tubular Hormones Renal factors reabsorption Aldo Hemodynamic GFR ANP factors Blood Central blood pressure volume Mechanismsbehindnocturnal polyuria

  25. Kamperis et al 2006

  26. Acute sleep deprivation in children B. Mahler, Aarhus Univ., PhD Thesis, 2009

  27. Genes Intrinsic Sleep , light, circadian clock activity , food Urine AVP Circadian concentration regulation of urine output AgII Tubular Hormones Renal factors reabsorption Aldo Hemodynamic GFR ANP factors Blood Central blood pressure volume Mechanismsbehindnocturnal polyuria

  28. Nocturnal polyuria Sleep/ arousal Bladder capacity

  29. Does a Bladder-and-Brain Dialogue exist?? Brain dysfunction ? Bladder disorders

  30. Does a Bladder-and-Brain Dialogue exist?? Brain dysfunction ? Bladder disorders

  31. Cognitive disturbances following night-time wetting in children The CK Yeung theory Is there evidence ?

  32. CK Yeung ICCS Hong Kong 2006 • Sleep Architecture and Cortical Arousal • Brainstem Function • Prepulse Inhibition of Startle (PPI) Reflex • Latency P300 event-related brain potential (ERP) • 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

  33. Bladder Behaviour and Sleep Changes Normal Children

  34. Bladder Behaviour and Sleep Changes Enuretic Children

  35. 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

  36. Anima model

  37. Animal modelcerebral dysfunction

  38. Is there evidence ? Comorbidity = yes / causality = No/ = circulusviciosus • 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 • -.

  39. 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

  40. Results: PLMS-index increased

  41. The egg/ chicken sleep Therapy resistance ADHD Cognitive dysfunction Diuresis/Bladder enuresis

  42. ADD ADHD Noct polyuria Sleep disorder Nocturia RR bladder Sodium solutes drugs

  43. Coming this summer • Results prospective study • Children with nocturnal polyuria • Screened • Enuresis characteristics • ADH symptoms • Sleep • Treated with desmopressin melt • Retested.. • And the results…..

  44. 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

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