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Renal Embryology.pptx
- 1. S L I D E 0 Embryonic Development of the Kidney Ibrahim Sandokji
- 2. S L I D E 1 A 3-month-old, preterm, male infant born at 36 weeks presents for evaluation of small kidneys incidentally noted on abdominal ultrasonography performed when the infant presented with emesis to the emergency department. His prenatal course was complicated by intrauterine growth restriction. There is no family history of renal disease. Physical examination findings are normal, with a blood pressure of 80/50 mm Hg. Renal ultrasonography reveals a left kidney of 3.6 cm and right kidney of 3.5 cm (<2 SDs below the mean). Of the following, the MOST likely cause of small kidneys in this infant is A. intrauterine growth restriction B. maternal vitamin A deficiency C. PAX2 mutation D. prematurity
- 3. S L I D E 2 The parents of a 19 mo boy with unilateral renal agenesis are expecting another baby. They are curious if their next baby will have the same problem and wonder when the kidneys start to form. You tell them: a) The first signs of the kidney (the metanephros) appear very early on, in the 5th week of gestation b) The lower urinary tract forms first. A ureteric bud will first branch off the early "bladder;" it ascends and takes until the 2nd trimester for it to start forming the kidney c) Rudimentary kidneys called the pronephros and subsequently the mesonephros are present for the first 8 — 12 weeks. The permanent kidney (metanephros) does not form until these involute d) The fetal kidney cannot be detected until urine starts to form, in the early 2nd trimester
- 4. S L I D E 3 You are studying a medication that when given to pregnant women, seems to negatively impact fetal nephrogenesis. In creating an animal model, you must recognize a) Branching of the ureteric bud occurs independently from tubulogenesis and mesenchymal-to-epithelial transition b) The ureteric bud develops into the future calyces, renal pelvis, and ureter, but otherwise does not develop into any part of the renal tubular system c) Inner (deeper) nephrons form first, and development proceeds outwardly such that outer cortical nephrons are the last to complete development d) Nephrogenesis starts slowly and gradually increases to its peak rate between the 30-36 weeks' gestation
- 5. S L I D E 4 You are consulted on an infant whose mother was taking an ACE inhibitor during her pregnancy. Which of the following is a complication of exposure to ACE inhibitors during embryogenesis? a) Vesicoureteral reflux b) Renal Hypo-dysplasia c) Multicystic Dysplastic Kidney d) Posterior Urethral Valves
- 6. S L I D E 5 Your Maternal Fetal Medicine colleagues consult you on a baby with bilateral renal agenesis. There was some amniotic fluid earlier on in the pregnancy but on the 20 week ultrasound there is anhydramnios. This can be explained because a) Urine production commences in mid/late 1st trimester, though doesn't become the major source of amniotic fluid until the 2nd trimester b) Urine production doesn't begin until the 2nd trimester, so this explains how the anhydramnios is a more recent development c) The mesonephros was contributing to the urine production in the first trimester, but as that involuted, anhydramnios developed d) The kidneys must have formed initially, and they subsequently involuted
- 7. S L I D E 6 Stages of Kidney Development Kher et al (2016). Clinical Pediatric Nephrology, 3rd Edition
- 8. S L I D E 7
- 9. S L I D E 8 The parents of a 19 mo boy with unilateral renal agenesis are expecting another baby. They are curious if their next baby will have the same problem and wonder when the kidneys start to form. You tell them: a) The first signs of the kidney (the metanephros) appear very early on, in the 5th week of gestation b) The lower urinary tract forms first. A ureteric bud will first branch off the early "bladder;" it ascends and takes until the 2nd trimester for it to start forming the kidney c) Rudimentary kidneys called the pronephros and subsequently the mesonephros are present for the first 8 — 12 weeks. The permanent kidney (metanephros) does not form until these involute d) The fetal kidney cannot be detected until urine starts to form, in the early in the 2nd trimester
- 10. S L I D E 9 Nephron development • The ureteric bud tips induce the surrounding metanephric mesenchyme to undergo a transition to epithelial cells (mesenchymal-epithelial transition) • The epithelial cells aggregate to form a condensation and a sphere of cells known as the renal vesicle • The vesicle then undergoes a series of morphologic changes to become a comma, and then an S-shape.
- 11. S L I D E 10 Stages of Renal Morphogenesis Kher et al (2016). Clinical Pediatric Nephrology, 3rd Edition
- 12. S L I D E 11 Defects in Ureteric Bud Outgrowth or Branching
- 13. S L I D E 12 Signaling Pathways Regulating Ureteric Bud Outgrowth and Branching Kher et al (2016). Clinical Pediatric Nephrology, 3rd Edition Townes Brocks syndrome Branchiootorenal Syndrome Renal Coloboma syndrome Renal Aplasia Renal hypoplasia
- 14. S L I D E 13 Mutations Exhibiting Defects in Renal Morphogenesis
- 15. S L I D E 14 Development of Renal Vasculature Kher et al (2016). Clinical Pediatric Nephrology, 3rd Edition
- 16. S L I D E 15 Development of Renal Vasculature and Kidneys Ascend
- 17. S L I D E 16 • Ureteric bud branching and nephron induction continue until 28 to 36 weeks’ gestation • Nephron number is established at birth (if FT) • LBW and IUGR are associated with decreased nephron number • Studies of premature infants (<36 wk) indicate that although some new nephrons form after birth, nephron formation terminates early, leading to low nephron number • Low nephron number -> proteinuria and chronic kidney disease
- 18. S L I D E 17 Relationship Between Nephron Formation and Gestational Age Solid line: nephron number Dashed line: renal mass
- 19. S L I D E 18 Compensatory Hypertrophy • In the setting of a poorly functioning or atrophic kidney, compensatory growth in the contra-lateral kidney is seen • Unilateral nephrectomy at birth in rats leads to hypertrophy and hyperplasia (not increased numbers of nephrons) • Hypertrophy may begin in utero
- 20. S L I D E 19 Yue Li (2013) Clin Transl Med
- 21. S L I D E 20 Urine Production • It begins in the 9th-10th weeks gestation • Fetal urine steadily becomes the major source of amniotic fluid by the second trimester (20 weeks onwards) • Oligohydramnios/Anhydramnios-> Potter's Sequence
- 22. S L I D E 21 Your Maternal Fetal Medicine colleagues consult you on a baby with bilateral renal agenesis. There was some amniotic fluid earlier on in the pregnancy but on the 20 week ultrasound there is anhydramnios. This can be explained because a) Urine production commences in mid/late 1st trimester, though doesn't become the major source of amniotic fluid until the 2nd trimester b) Urine production doesn't begin until the 2nd trimester, so this explains how the anhydramnios is a more recent development c) The mesonephros was contributing to the urine production in the first trimester, but as that involuted, anhydramnios developed d) The kidneys must have formed initially, and they subsequently involuted
- 23. S L I D E 22 Maternal and Perinatal Factors Associated with Defects in Ureteric Bud Branching and Renal Anomalies
- 24. S L I D E 23 • A 3-month-old, preterm, male infant born at 36 weeks presents for evaluation of small kidneys incidentally noted on abdominal ultrasonography performed when the infant presented with emesis to the emergency department. His prenatal course was complicated by intrauterine growth restriction. There is no family history of renal disease. Physical examination findings are normal, with a blood pressure of 80/50 mm Hg. Renal ultrasonography reveals a left kidney of 3.6 cm and right kidney of 3.5 cm (<2 SDs below the mean). Of the following, the MOST likely cause of small kidneys in this infant is A. intrauterine growth restriction B. maternal vitamin A deficiency C. PAX2 mutation D. prematurity
- 25. S L I D E 24 Schreuder (2011) CJASN
- 26. S L I D E 25 Clinical Indicators to Search for a Renal Anomaly Denis et al (2008). Pediatric Kidney Disease, second edition
- 27. S L I D E 26 You are consulted on an infant whose mother was taking an ACE inhibitor during her pregnancy. Which of the following is a complication of exposure to ACE inhibitors during embryogenesis? a) Vesicoureteral reflux b) Renal Hypo-dysplasia c) Multicystic Dysplastic Kidney d) Posterior Urethral Valves
- 28. S L I D E 27 Congenital Abnormalities of the Kidney and Urinary Tract (CAKUT) • Spectrum of developmental urologic and renal abnormalities • Previously believed to arise from urinary obstruction • Now believed that genetic defects -> disrupt critical signaling processes between the ureteric bud and nephrogenic mesenchyme
- 29. S L I D E 28 Nonsyndromic human congenital anomalies of the kidney and urinary tract (CAKUT) Song (2011) Pediatr Nephrol
- 30. S L I D E 29 You are studying a medication that when given to pregnant women, seems to negatively impact fetal nephrogenesis. In creating an animal model, you must recognize a) Branching of the ureteric bud occurs independently from tubulogenesis and mesenchymal to epithelial transition b) The ureteric bud develops into the future calyces, renal pelvis, and ureter, but otherwise does not develop into any part of the renal tubular system c) Inner (deeper) nephrons form first, and development proceeds outwardly such that outer cortical nephrons are the last to complete development d) Nephrogenesis starts slowly and gradually increases to its peak rate between the 30-36 weeks' gestation
- 31. S L I D E 30 Summary • There are 3 primitive kidneys that form during human kidney development: Pronephros -> Mesonephros -> Metanephros • The ureteric bud reciprocally induces the metanephric mesenchyme -> branching morphogenesis -> immature nephrons (comma- and S-shaped bodies) -> mature nephrons with a fully developed tubular system. • This process starts at approximately the 5th week and ends at approximately the 36th week of gestation. • Defects in ureteric bud outgrowth and branching can lead to congenital abnormalities of the kidney and urinary tract.
- 32. S L I D E 31 Extra Slides
- 33. S L I D E 32
- 34. S L I D E 33
- 35. S L I D E 34
- 36. S L I D E 35 Molecular basis for the early formation of the metanephros and ureter
Editor's Notes
- Ureteric bud outgrowth from the wolffian duct is modulated by factors secreted by the metanephric blastema and the mesoderm surrounding the duct (1). Morphologic intermediates formed during nephrogenesis consist of condensation of the metanephric cap around the ureteric bud branch (2) renal vesicle comma shape (3), S shape (4), elongation of the tubule (5), invasion of blood vessels into the glomeruli, and formation of the glomerular corpuscle (6)
- Defects in ureteric bud (UB) outgrowth or branching result in renal anomalies (MM=metanephric mesenchyme)
- Pax2: transcription factor Eya1: transcription factor GDNF: growth factor RET: the GDNF receptor Gene products that control cellular events and induction of the ureteric bud in the wolffian duct. Mesenchymal cells at the caudal end of the nephrogenic cord (light blue cell) express various factors that activate expression of glial-derived neurotrophic factor (GDNF). In addition, mesenchymal cells release gremlin-1 (GREM1), an inhibitor of bone morphogenetic protein (BMP) signaling, and other still unidentified factors. Released GDNF binds to RET and GDNF-family receptor α1 (GFRA1) receptors that are on the epithelial cells of the mesonephric duct (wolffian duct). The combination of these signals induces ureteric budding. Mesenchymal cells at a more rostral level (dark blue cell) express forkhead box protein C1 (FOXC1), slit homologue 2 (SLIT2), and its receptor roundabout homologue 2 (ROBO2), leading to a repression of GDNF. In epithelial cells of the mesonephric duct, the tyrosine kinase inhibitor sprouty 1 (Spry1) suppresses RET activation. Finally, BMP4 also inhibits ureter outgrowth. EYA1, eyes-absent homologue 1; GDF11, growth differentiation factor-11; HOX11, homeobox protein 11; NPNT, nephronectin; WT1, Wilms tumor transcription factor.
- The first vessels are capillaries at the stalk of the ureteric bud. The next vessels to form are the glomerular capillaries” endothelial cells migrate into the cleft of the S-shaped nephron -> form the fenestrated glomerular epithelium.
- Ascend: elongation of the ureters + decrease in body curvature + growth in lumbosacral regions. Early -> branches of the common iliac arteries As the kidneys ascend -> branches from the distal aorta -> then -> abdominal aorta Normally, the distal branches disappear, and the abdominal branches become the permanent renal arteries.
- In the preterm infant, nephrogenesis continues after birth but is subject to damage by diseases and drugs.
- Schematic representation of the relationship between nephron formation and gestational age during human fetal renal development. Renal branching morphogenesis, a principal determinant of nephron number (solid line), is complete by midgestation. Renal mass (dashed line) increases exponentially in the latter half of gestation through the additional induction of new nephrons and hypertrophy of existing nephrons. Blue shading represents postnatal period.
- Although mechanisms have not been completely understood for all factors: Angiotensin II stimulates ureteric bud branching + nephrogenesis + renal vasculature development Maternal vitamin A deficiency likely affects Ret expression
- In this patient, intrauterine growth restriction is the most likely cause of the small kidneys because the infant has a history of intrauterine growth retardation, which is associated with renal hypoplasia. In the absence of family history or abnormal physical findings, a PAX2 mutation (associated with autosomal dominant renal-coloboma syndrome and renal hypoplasia) is less likely in this infant. Although prematurity can lead to a decreased nephron number, this infant was only mildly premature (36 weeks’ gestation), at which time ureteric bud branching is complete. Maternal vitamin A deficiency is associated with renal hypoplasia but is more likely in an underdeveloped country.
- (a) Early induction of metanephros. (b) Branching of ureteric bud. (c) Early tubule formation. FGF, fibroblast growth factor; GDNF, glial cell line-derived neurotrophic factor; LIF, leukemia inhibitory factor.