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Good set of slides for Molecular abd Genetic aspects of Vur and lower Urinary Pathilogy in children

Good set of slides for Molecular abd Genetic aspects of Vur and lower Urinary Pathilogy in children

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  • 1. A MOLECULAR AND GENETIC VIEW OF HUMAN RENAL AND URINARY TRACT MALFORMATIONS Adrian S Woolf Nephro-Urology Unit Institute of Child Health, University College London, UK
  • 2. CLINICAL IMPORTANCE OF KIDNEY MALFORMATIONS 800 children in the UK have end stage renal failure. The commonest causes are: 1. Agenesis (absent kidney) 2. Dysplasia (undifferentiated) 3. Hypoplasia (too few nephrons)
  • 3. LOWER URINARY TRACT MALFORMATIONS Kidney malformations are often associated with ureter and/or bladder malformations: 1. Vesicoureteric reflux 2. Duplicated lower tracts 3. Obstructed lower tracts
  • 4. CAUSES OF KIDNEY AND LOWER URINARY TRACT MALFORMATIONS 1. Mutations of genes expressed during development 2. Gross changes of fetal kidney milieu e.g. impairment of fetal urine flow 3. Subtle change of fetal kidney milieu e.g. low protein maternal diet
  • 5. PRIMARY VESICOURETERIC REFLUX 1. Occurs in 1% babies 2. ‘Reflux nephropathies’ can be congenital or acquired and account for 10% of end-stage renal failure 2. Excess risk for vesicoureteric reflux in first degree relatives is x20-50 3. Some families have dominant inheritance 4. 1p13 locus and other undefined loci
  • 6. I:1 I:2 ? II:1 II:2 III:1 III:2 III:3 III:4 III:14 III:5 III:6 III:7 III:15 III:8 III:9 III:10 III:11 III:12 II IV:1 IV:2 VESICOURETERIC REFLUX
  • 7. Embryonic urinary bladder Adult urinary bladder Uroplakin Ib Uroplakin III
  • 8. Vesicoureteric Reflux in the UK Establishing a DNA collection www.vur.org.uk
  • 9. DUPLEX KIDNEYS AND LOWER URINARY TRACTS 1. Occur in 1% of individuals 2. Occurs with dysplastic kidneys and vesicoureteric reflux 3. Excess risk in first degree relatives is about x20-30
  • 10. FRASER SYNDROME 1. Autosomal recessive - fused fingers, membrane across eyes and dysplastic or absent kidneys 2. FRAS1 gene is mutated - protein coats the ureteric bud 3. Null mutant mouse metanephros involutes with excess apoptosis
  • 11. Patient Described by George Fraser
  • 12. Fraser Syndrome vs bl/bl Phenotype
  • 13. Spectrum of Renal Defects in Fras1 targeted Mutants (b-d)
  • 14. APOPTOTIC INVOLUTION OF CYSTIC DYSPLASTIC KIDNEY
  • 15. RENAL CYSTS AND DIABETES SYNDROME 1. Autosomal dominant or sporadic 2. Renal agenesis, cysts, dysplasia, hypoplasia, with diabetes (can require insulin) and uterus malformations 3. Hepatocyte Nuclear Factor 1β transcription factor mutations
  • 16. DUK507 Q243fsdelC I 1 2 II 1 2 Small kidneys III 2 1 2 3 4 5 NM NM Bicornuate Single kidney uterus IV 1 2 NM NM
  • 17. HNF1β antisense HNF1β sense m u
  • 18. ORAL FACIAL DIGITAL SYNDROME TYPE 1 1. Male embryonic lethal – only affected females are born 2. X-linked dominant 3. Glomerocystic kidney disease 4. OFD1 gene codes for a centrosomal/basal body protein
  • 19. OFD1 IMMUNOHISTOCHEMISTRY ub m v WHOLE KIDNEY OFD1Ab Preabsorbed OFD1 Ab EK84 EK75 EK73 EK70 anti ofd1 -120D OFD1 PROTEIN IS EXPRESSED IN HUMAN EMBRYONIC KIDNEYpreabsorbed MESENCHYME IN VIVO AND IN DERIVED CELL LINES
  • 20. C 150 100 75 α-Tubulin OFD1 merge 50 37 25
  • 21. OFD1 PROTEIN - GREEN ACETYLATED TUBULIN - RED
  • 22. CAUSES OF KIDNEY AND LOWER URINARY TRACT MALFORMATIONS 1. Mutations of genes expressed during development 2. Gross changes of fetal kidney milieu e.g. impairment of fetal urine flow 3. Subtle change of fetal kidney milieu e.g. low protein maternal diet
  • 23. ANIMAL MODEL OF POSTERIOR URETHRAL VALVES AND FETAL NEPHROPATHY AND UROPATHY
  • 24. CAUSES OF KIDNEY AND LOWER URINARY TRACT MALFORMATIONS 1. Mutations of genes expressed during development 2. Gross changes of fetal kidney milieu e.g. impairment of fetal urine flow 3. Subtle change of fetal kidney milieu e.g. low protein maternal diet
  • 25. THE EXPERIMENTAL MODEL Pregnant rats were supplied isocaloric diets in which the primary variable was the protein content from the day of conception to the end of pregnancy – 18% protein (control) – 9% protein (mild protein restriction) – 6% protein (severe protein restriction) Welham et al Kidney Int 61:1231-1242, 2002
  • 26. Maternal low protein diet Rat Increased embryonic metanephric day 13 apoptosis Embryonic kidney Embryonic Decreased cell day 15 number Fewer nephron progenitor cells Apoptosis Two weeks Fewer nephrons postnatal Elevated blood Non-renal Adult pressure alterations
  • 27. P<0.05 P<0.01 250 200 Series4 Apoptotic 18% Protein cells/mm2 150 Series5 9% Protein 100 Series10 6% Protein 50 0 Embryonic day 13 Glomerular complement of Systolic blood pressures of offspring offspring at 2 weeks of age. at 4 weeks and 19 weeks of age. Systolic blood pressure 20000 200 * * * * Glomeruli 15000 (mmHg). 150 10000 18% protein 100 9% protein 5000 50 0 0 6% Protein 9% Protein 18% Protein 4 weeks 19 weeks
  • 28. REPRESENTATIONAL DIFFERENCE ANALYSIS • Genes ‘upregulated’ in metanephric kidneys exposed to maternal normal diet: Cofilin-1, Prox-1, Calmodulin • Genes ‘upregulated’ in metanephric kidneys exposed to maternal low protein diet: Cadherin-11
  • 29. CAUSES OF KIDNEY AND LOWER URINARY TRACT MALFORMATIONS 1. Mutations of genes expressed during development 2. Gross changes of fetal kidney milieu e.g. impairment of fetal urine flow 3. Subtle change of fetal kidney milieu e.g. low protein maternal diet
  • 30. ACKNOWLEDGEMENTS FOR STUDIES OF KIDNEY AND URINARY TRACT MALFORMATIONS University College London UK Monica Banerjee, Maria Bitner-Glindzicz, Isky Gordon, Ambrose Gullett, Peter Cuckow, Chris Fry, Maggie Godley, Monika Hermanns, Mike Hubank, Maria Kolatsi-Joannou, Dagan Jenkins, Liam McCarthy, Sue Malcolm, Peter Nyirady, Donald Peebles, Karen Price, Paul Riley, Leila Romio, Peter Scambler, Naima Smeulders, Niki Thiruchelvam, Simon Welham, Melissa Whitten, Duncan Wilcox, Paul Winyard, Su-Ping Yang Elsewhere in UK Coralie Bingham, Sally Feather, Andrew Fry, Judith Goodship, Tim Goodship, Andrew Hattersley, Albert Ong, Jenny Southgate, British Association for Paediatric Nephrology Elsewhere in the world TIGM Naples Italy - Brunella Franco and colleagues NYU New York USA – Tung-Tien Sun and colleagues