Renal Development Dysplasia 2


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  • Intermediate mesoderm on either side of the dorsal body wall/notochord gives rise to 3 successive nephric structures of increasingly advanced design
  • Pronephroi- nonfunctional segmental nephrotomes which develop in cervical region-represent a vestige of primitive kidneys seen in lower vertebrates, begin to appear at 24 days and regress in the fourth week Mesonephros – initial appearance of mesonephros and mesonephric duct at 25 days. Metanephric blastema and metanephric ducts appear at 28 days or end of week 4 Mesonephros develop in thoracic and lumbar regions during 4 th week, functional with complete but simple nephrons drained by the mesonephric (Wolffian Ducts) Nephric ducts grow caudally to open into the posterior wall of the primitive urogenital sinus by week 5 Metanephroi-definitive kidneys begin to form during 5 th week by induction of sacral intermediate mesoderm by UBs
  • UBs sprout from the distal end of the mesonephric duct by week 5
  • Renal Development Dysplasia 2

    1. 1. Renal Development & Dysplasia Part I Hsiao Lai, MD Feb 19, 2010 ECU, Brody School of Medicine Nephrology and Hypertension Pediatric Nephrology Core Curriculum
    2. 2. Where will you encounter Renal Dysplasia? <ul><li>Ob-Gyn referal prenatal screening ultrasound at 20wks </li></ul><ul><li>Neonatal nursery/NICU </li></ul><ul><ul><li>Abnormal RUS </li></ul></ul><ul><ul><li>Congenital malformation syndrome with renal anomalies </li></ul></ul><ul><ul><li>Primary renal failure/insufficiency </li></ul></ul><ul><li>Childhood: </li></ul><ul><ul><li>Frequent UTI’s </li></ul></ul><ul><ul><li>Incidental finding on abdominal imaging </li></ul></ul><ul><ul><li>Hypertensive child </li></ul></ul><ul><li>Adolescent </li></ul><ul><ul><li>Present in renal failure/ESRD requiring dialysis or transplantation </li></ul></ul>
    3. 3. Congenital Anomalies of Kidney and Urinary tract (CAKUT) <ul><li>Account for: </li></ul><ul><li>Diverse non-syndromic renal and lower urinary tract malformations </li></ul><ul><li>Most common congenital anomaly </li></ul><ul><li>1/3 of all anomalies detected by routine fetal ultrasound (18-22 wk) </li></ul><ul><li>40% of childhood ESRD </li></ul>Woolf et. Al: in Renal Dysplasia Birth Defects Monitoring Program
    4. 4. Causes of Pediatric ESRD % 23 Other 3 PKD 3 Cystinosis 5 Nephronophthises 8 Congenital Nephrotic Syndrome 18 Acquired GN 40 CAKUT
    5. 5. Common Congenital Renal Anomalies <ul><li>Cystic Dysplastic Kidneys </li></ul><ul><li>Renal agenesis </li></ul><ul><li>Horseshoe Kidney </li></ul><ul><li>Ectopic Kidneys </li></ul><ul><li>Duplicated Kidneys and Ureters </li></ul>
    6. 6. Common Urogenital Anomalies <ul><li>Urinary Outlet Obstruction </li></ul><ul><ul><li>Ureteropelvic Junction Obstruction UPJ </li></ul></ul><ul><ul><li>Ureterovesicle Junction Obstruction UVJ </li></ul></ul><ul><ul><li>Posterior Urethral Valves </li></ul></ul><ul><ul><li>Anterior Urethral Valves </li></ul></ul><ul><ul><li>Congenital Megaureter </li></ul></ul><ul><li>Primary Vesicoureteral Reflux </li></ul><ul><li>Ureterocele </li></ul>
    7. 7. Congenital Renal Anomalies <ul><li>Present at birth </li></ul><ul><li>Occur during the process of organogenesis </li></ul><ul><li>Involves defects: </li></ul><ul><ul><li>Tissue Induction </li></ul></ul><ul><ul><li>Reciprocal feedback between tissue precursors </li></ul></ul><ul><ul><li>Morphogenesis </li></ul></ul><ul><ul><li>Migration </li></ul></ul>
    8. 8. Intermediate mesoderm
    9. 9. Renal Development <ul><li>Intermediate mesoderm </li></ul><ul><li>Pronephros </li></ul><ul><li>Mesonephros </li></ul><ul><li>Nephric (Wolffian) Duct formation </li></ul><ul><li>Metanephros = Fetal Kidney </li></ul>
    10. 10. Formation of Fetal Kidney <ul><li>Wk 4: appearance of Wolffian or Mesonephric Duct </li></ul><ul><li>D28: formation of Ureteric Bud (UB) </li></ul><ul><li>Wk 4-8: Initial MM induction and UB branching </li></ul><ul><li>Week 8: First nephrons are formed </li></ul><ul><li>Week 4-8 kidneys ascend from pelvis to lumbar location </li></ul><ul><li>Wk 10 filtration begins </li></ul>
    11. 11. Renal and Urogenital Development <ul><li>1 st 6-10 UB branches coalesce to form renal pelvis and calyces </li></ul><ul><li>Wk 5 implantation of distal UB into posterior urogenital sinus </li></ul><ul><li>Wk 5-7 ureter becomes occluded </li></ul><ul><li>Wk 7-8 recanalization of ureter </li></ul>
    12. 12. Urogenital Development <ul><li>Wk 4-6: cloaca separates into anterior and posterior portion </li></ul><ul><li>Anterior cloaca develops into urogenital sinus which gives rise to the bladder and urethra </li></ul><ul><li>Posterior cloaca gives rise to the rectum </li></ul><ul><li>Urogenital sinus continuous superiorly with allantois which later regresses. </li></ul><ul><li>Expanded superior portion of urogenital sinus becomes the bladder </li></ul><ul><li>Inferior portion gives rise to pelvic urethra and also the penile urethra in males and the vestibule of the vagina in females </li></ul>
    13. 13. Later Stages of Nephrogenesis <ul><li>In humans the early UB divisions are not associated with nephrogenesis </li></ul><ul><li>Wk 8-15 Period of UB branching with stochastic formation of UB ampulla and nephron units </li></ul><ul><li>UB branching decelerates after 15 wks, however nephron induction continues up until 32-26 weeks </li></ul><ul><li>Wk 15-20 Arcade induction of 5-7 nephrons per ampulla </li></ul><ul><li>Wk 20-36 Serial induction of without UB branching </li></ul><ul><li>Wk 32-36 End of Nephrogenesis </li></ul>
    14. 14. Late Nephrogenesis
    15. 15. Mechanisms of Maldevelopment <ul><li>UB Agenesis </li></ul><ul><li>UB Duplication </li></ul><ul><li>Disruption of Renal Mesenchyme </li></ul><ul><li>Interrupted Cross-talk between UB and MM </li></ul><ul><li>Abnormal apoptosis/proliferation </li></ul><ul><li>Abnormal UB implantation </li></ul><ul><li>Abnormal UB recanalization </li></ul><ul><li>Abnormal renal migration </li></ul>
    16. 16. Edith Louise Potter <ul><li>1901-1993 </li></ul><ul><li>Early training in Minnesota </li></ul><ul><li>Chicago Lying-In Hospital </li></ul><ul><li>Pioneer in understanding perinatal pathology of congenital malformations </li></ul><ul><li>Rh Factor and congenital hemolytic anemia </li></ul><ul><li>Pioneer in renal development </li></ul>Euro J Pediatrics 1994
    17. 17. Potter’s Syndrome <ul><li>Bilateral renal agenesis </li></ul><ul><li>Syndrome of findings: Oligohydramnios, Potter’s facies, skeletomuscular abnormalities, pulmonary hypoplasia resulting from a particular series of developmental events stemming from </li></ul><ul><li>Death usually from respiratory failure within minutes to hours of birth </li></ul>
    18. 18. Normal Kidneys
    19. 19. “ Dysplastic” Kidneys <ul><li>Small or large abnormally shaped kidneys </li></ul><ul><li>Immature/undifferentiated or metaplastic (abnormal) renal structures </li></ul><ul><li>May be associated with cysts in case of cystic dysplastic kidneys or complete agenesis of kidneys </li></ul><ul><li>If dysplasia is extensive, renal dysfunction may necessitate nephrologic care, including renal replacement therapy </li></ul><ul><li>Very little or no excretory function </li></ul><ul><li>Often associated with urogenital anomalies and reflux </li></ul>
    20. 20. Multicystic Dysplastic Kidney <ul><li>Minimal to no functional renal parenchyma usually with primitive tubules and foci of cartilage </li></ul><ul><li>Kidney consists of groups of noncommunicating cysts with fibrous connective tissue </li></ul><ul><li>“ Bunches of grapes” appearance </li></ul>
    21. 21. Multicystic Dysplastic Kidney <ul><li>1/2400 live births </li></ul><ul><li>Usually unilateral with ureteral atresia </li></ul><ul><li>Increase incidence of reflux incontralateral kidney </li></ul><ul><li>Often regress over several months to years and may account for many cases of unilateral “renal agenesis” </li></ul><ul><li>Uncommonly, the kidney develops tumors or infection, and hypertension may develop </li></ul><ul><li>Most experts recommend observation, although some advocate removing these kidneys, especially if solid tissue is extensive or unusual appearing on ultrasonography </li></ul>
    22. 22. MCDK
    23. 23. ARPKD <ul><li>1 in 20,000 individuals </li></ul><ul><li>Cysts in Kidneys and Liver </li></ul><ul><li>PKD1 gene – polycystin </li></ul><ul><li>Variable severity and presentation, but severe cases usually present in neonatal/infantile period with renal symptoms later cases present with liver-related symptoms </li></ul>
    24. 24. ARPKD <ul><li>30-50% mortality in newborn period mainly from in-utero oligohydramnios leading to pulmonary hypoplasia </li></ul><ul><li>If survive newborn period 1/3 need dialysis or transplantation by age 10 </li></ul><ul><li>Kidneys can have rapid growth over the first few months </li></ul><ul><li>Mild cases present in late childhood or adolescent with symptoms of periportal fibrosis with gastric varicele bleeding and mild renal insufficiency </li></ul>
    25. 25. ARPKD Cortical cysts form in collectng duct
    26. 26. ADPKD on Fetal US
    27. 27. Radiographic Appearance of ARPKD vs ADPKD
    28. 28. ADPKD
    29. 29. Renal Hypoplasia <ul><li>Inadequate ureteral bud branching causes an underdeveloped, small kidney with histologically normal nephrons Small well formed kidneys </li></ul><ul><li>Functional on renogram </li></ul><ul><li>If hypoplasia is segmental, hypertension can occur, and ablative surgery may be needed </li></ul>
    30. 30. Decreased Nephron Number <ul><li>Number of nephrons more than doubles between 20 and 40 weeks </li></ul><ul><li>Majority of nephrons form during final third of gestation </li></ul><ul><li>Final nephron number can be highly variable between 230,000 to 1800,000 </li></ul><ul><li>One branching generation may result in 30-35% less nephrons than wild type- usually undetectable phenotypes </li></ul><ul><li>Decreased nephron number is related to increased risk of hypertension and chronic kidney disease </li></ul>
    31. 31. Duplex Kidney and Ureters <ul><li>~15% of all live births </li></ul><ul><li>Incomplete fusion of upper and lower pole moieties can result incomplete or incomplete duplication of the collecting system </li></ul><ul><li>Two ureteric buds arise from the mesonephric duct, or if a single UB divides into two branches before it invades into the metanephrogenic blastema </li></ul>
    32. 32. Weigert-Meyer Law Upper Pole Moiety: obstructed Lower Pole Moiety: refluxes
    33. 33. Weigert-Meyer Law <ul><li>Upper pole moiety: ureter inserts ectopically, inferomedial to normal site </li></ul><ul><li>Lower pole moiety: ureter inserts orthotopically-posterio-lateral insertion into bladder trigone </li></ul><ul><li>Ectopic insertion often has a urethrocele which obstructs its own collecting system and can distort the lower moiety insertion and cause reflux into lower pole moiety </li></ul>
    34. 34. Duplex Kidney and Ureters <ul><li>Complete duplication results when two entirely separate ureters drain separate upper and lower pole or two individual kidneys </li></ul><ul><li>Partial duplication occurs when the two ureters join before reaching the bladder </li></ul><ul><li>Duplication of the renal pelvis alone can also occur </li></ul>
    35. 36. Abnormalities of Renal Fusion, Ascent and Rotation <ul><li>Horseshoe Kidney </li></ul><ul><li>Cross-fused Ectopia </li></ul><ul><li>Pelvic Kidney </li></ul><ul><li>Pancake Kidney </li></ul>
    36. 37. Abnormalities of Ascent and Rotation Horseshoe kidney Cross fused ectopia
    37. 38. Horseshoe Kidney <ul><li>1 in 400 live births </li></ul><ul><li>Kidneys fuse together early during ascent usually at lower poles </li></ul><ul><li>Connecting isthmus can be renal parencyhmal or fibrous tissue </li></ul><ul><li>Ureters usually drain medially and anteriorly to isthmus </li></ul><ul><li>Asymptomatic in the majority of cases </li></ul><ul><li>May be associated with reflux nephropathy if ureters implant more superiorly that causes CKD, or with more complex developmental syndromes </li></ul>
    38. 39. Crossed-Fused Ectopia <ul><li>Kidneys fuse early in development </li></ul><ul><li>Both fused kidneys lie on one side of the spine, and the ureters cross the midline in order to enter the bladder with upper ureter implanting posteriorly </li></ul><ul><li>Often the upper kidney is obstructed, while the lower ureter refluxes </li></ul>
    39. 40. Pelvic/Ectopic Kidney <ul><li>Kidney fails to ascend to normal location in the renal fossa </li></ul><ul><li>Predominantly pelvic location, rarely thoracic </li></ul><ul><li>Incidence is 1/900 live births, more commonly on left </li></ul><ul><li>Usually clinically asymptomatic and found coincidentally </li></ul><ul><li>Often associated with genital anomalies, but cardiovascular and skeletal anomalies are also common </li></ul>
    40. 41. <ul><li>1/3 of siblings affected </li></ul><ul><li>Likely AD inheritance with widely variable penetrance </li></ul><ul><li>Structural abnormality of vesicoureteral junction with abnormally short submucosal segment of the ureter or deficiency in the musculature of the intravesical ureter </li></ul>
    41. 43. Bladder Outlet Obstruction <ul><li>UPJ </li></ul><ul><li>UVJ </li></ul><ul><li>PUV </li></ul><ul><li>Ureteral Duplication </li></ul><ul><li>Ectopic Ureters </li></ul><ul><li>Congenital Megaureter </li></ul>
    42. 44. UPJ Obstruction <ul><li>Most common upper urinary tract obstruction in children </li></ul><ul><li>Incidence 1/1000-1/2000 newborns </li></ul><ul><li>Most common cause of pediatric hydronephrosis </li></ul><ul><li>Account for 50% of hydronephrosis on prenatal ultrasound </li></ul><ul><li>More commonly on left, 20-30% bilateral </li></ul><ul><li>Often associated with other congenital anomalies especially MCDK </li></ul>
    43. 45. UPJ Obstruction <ul><li>UPJ is formed during Wk 5 of gestation </li></ul><ul><li>The UPJ is the last area of the UB to recanalize </li></ul><ul><li>Abnormal or incomplete recanalization of the UB during development leads to UPJ obstruction </li></ul><ul><li>UPJ functional obstruction can also result from an aperistaltic portion of UPJ </li></ul>
    44. 46. UPJ Obstruction
    45. 47. Posterior Urethral Valves <ul><li>Occurs only in males </li></ul><ul><li>1/5000 male births </li></ul><ul><li>Most common cause of urinary tract obstruction in males </li></ul><ul><li>Accounts for 20% of all childhood ESRD </li></ul><ul><li>Wide range of severity with mild disease often missed until presentation with renal failure in adolescence, severe disease can present with Eagle Barrett Syndrome </li></ul>
    46. 48. Posterior Urethral Valves <ul><li>Results from persistent obstructing urogenital membrane </li></ul><ul><li>Disrupted embryological development of male urethra between Wk 9-14 </li></ul><ul><li>There seems to a also a component of renal dysplasia along with obstruction that does not necessarily resolve with correction of obstruction </li></ul>
    47. 49. PUV
    48. 50. Management PUV <ul><li>Foley catheter decompression at birth </li></ul><ul><li>Management of associated renal dysfunction </li></ul><ul><li>Valve ablation within weeks of birth </li></ul><ul><li>Management of post ablation urinary incontinence </li></ul><ul><li>Monitor for VUR and CKD </li></ul><ul><li>Supravesical diversion prior to 21 wks, has not proved very successful </li></ul>
    49. 51. Congenital Syndromes with Renal Anomalies <ul><li>Many widely diverse syndromes </li></ul><ul><li>Not enough time to summarize here </li></ul><ul><li>Maybe a later presentation? </li></ul><ul><li>Enjoy your weekend! </li></ul>