Genetics and congenital
abnormalities
of kidney and urinary tract
М.N. (male), 3 мо
Yong healthy parents
 2-nd normal pregnancy
 Normal perinatal history
 BBW – 3450 g, length – 52 sm
...
MEDICAL HISTORY


Routine
examination
immunization

before

DTP

 WBC

(blood count) 21 th.
 ESR 65 mm/h


Admitted to...
ADMISSION STATUS
 No

fever
 Irritated
 No appetite
 Pale skin with grey shade
 No other disorders
 Belly - round fo...
Date

06.03.08

WBC

28,0

RBC

4,03

HB

103

HT

29,1

PLT

759

SC

2

SN

42

E

1

MON

7

LYMF

43

ESR

59

BLOOD
C...
BIOCHEMICAL BLOOD ANALYSIS
- 0,352 (N 0,100 – 0,200)
 CRP – 0,120
(N до 0,001 г/л)
 АSLO 1:500
(N 1:250)
 Other - norma...
URINE TESTS


Clinical urine analysis(twice)- N



Bacteriuria- negative
Renal US


Вставить картинку!!!!!!









Right kidney 74 х 30 х 33
mm, parenchyma layer 7
mm
Left kidney 96 х 53 х...
INTRAVENOUS UROGRAPHY
Left kidney shadow is approximately absent.
 1,5-hour picture left side – several low
contrasted ro...
TREATMENT
Ceftriaxone 400 mg/24h i/m
 Detoxic therapy
 Syndromal therapy


A serious condition (depressed appetite has
...
LEFT
TRANSCUTANEOUS NEPHROSTOMY

During

the operation received
150.0 ml of cloudy urine with lots
of lush green pus
POSTOPERATIVE TREATMENT
treatment – 14 days
 Immunocorrection
 Detoxic therapy
 A/b
Date

06.03.08

WBC

11,8 (28,0)

RBC

3,58

HB

98 (103)

HT

26

PLT

413

SC

1 (2)

SN

20 (42)

E

4

MON

2

LYMF

7...
RENAL US (FOLLOW-UP)



Left kidney 75 х 29 х 27мм
(96 х 53 х 57)



Calyces (left kidney) up to 10 mm
(19мм)
25 DAYS AFTER NEPHROSTOMY
 No

fever
 Feeling good (gay, active, interested
in toys)
 Appetite satisfied (requests to e...
FOR FUTURE
 Surgical

 Good

correction of urodynamics

prognosis
CONCLUSION
Accidentally

revealed gross
pathology of the kidney
No urinary syndrome
The rapid development of
uroseptice...
CAKUT
Congenital anomalies of kidney and urinary
tract
 1:500 live births
 1:2000 neonatal deaths


Loane M, Dolk H, Ke...
Jeffery Fletcher, Stephen McDonald , Stephen I. Alexander,
on behalf of the Australian and New Zealand Pediatric Nephrolog...
СAKUT
KIDNEY









Renal agenesia- renal absence
Дисплазия почки- kidney contains an
undifferentiated tissue and c...
Stages of renal branching morphogenesis and nephron formation.

35-37 day of
gestation

Shah M M et al. Development 2004;1...
An overview of the major signaling pathways involved in ureteric epithelial branching.

Utip
–
epithelium
CapMtissue

uret...
Nature Rev Genetics 3, 533-43, 2002 Coordinating early kidney development: lessons
from gene targeting
Ontogenic mechanisms involved in the formation of CAKUT. A primary defect in either the
growing ureter or the differentiat...
Genetics and CAKUT

Gene

CAKUT phenotype

Type of mutations identifieda

Mutation detection rate in
unrelated cases

BMP4...
Novel perspectives for investigating congenital anomalies of the
kidney and urinary tract (CAKUT)
Locus

CAKUT
phenotype

...
Kerecuk L et al. (2008) Renal tract malformations: perspectives for nephrologists
Nat Clin Pract Nephrol doi:10.1038/ncpne...
Effect of Drugs on Renal Development
Drug

Effect of Maternal Treatment during
Pregnancy on Offspring Kidney
Development

...
РАЗВИТИЕ ПОЧКИ (В НОРМЕ И ПАТОЛОГИИ)
Гипоплазия почки –
меньше рядов нефронов
при
сохранной
экскреторной функции
Кистозная...
Renal agenesia
HORSESHOE KIDNEY
Hypoplasia of
kidney
MULTICYSTIC DISPLASIA

John J. Bissler, Brian J. Siroky and Hong Yin Glomerulocystic kidney
disease Pediatr Nephrol. 2010 ...
KIDNEY DYSPLASIA WITH PUJ STENOSIS
ADPKD
СИНДРОМ MECKEL–GRUBER
(гломерулярно-кистозная болезнь)

fetal glomeruli and surrounding dysplastic tissue
with tubular cys...
Paradigm shift from classic anatomic theories to contemporary cell biological views of
CAKUT
Iekuni Ichikawa, Fumiyo Kuway...
VUR
PUV
Complications of
PUV
Condition

Postnatal 99mTcFetal
Postnatal
DMSA
ultrasonographic ultrasonographic
renography
findings
findings
findings

Re...
No renal uptake by
Kidney should be
Congenital solitary Kidney might be
absent kidney (also
larger than normal if
kidney
l...
RENAL AGENESIA IN NEONATE
POLYCYSTIC KIDNEY IN NEONATES
CYSTIC DYSPLASIA
Cystic dysplasia

MCDK
Novel perspectives investigating CAKUT

Renkema K Y et al. Nephrol. Dial. Transplant.
2011;26:3843-3851
© The Author 2011....
Vicious cycle of progressive functional and structural deterioration shared by many chronic
renal diseases.

©1999 by Amer...
LONG LIVE KIDNEY !!!!!
Nephron
 1 mln in every
kidney
 Length of tubules
– 18-50 мм
 Tubules length of
all nephrons –
1...
2-1. CAKUT. Svetlana Paunova (eng)
2-1. CAKUT. Svetlana Paunova (eng)
2-1. CAKUT. Svetlana Paunova (eng)
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2-1. CAKUT. Svetlana Paunova (eng)

  1. 1. Genetics and congenital abnormalities of kidney and urinary tract
  2. 2. М.N. (male), 3 мо Yong healthy parents  2-nd normal pregnancy  Normal perinatal history  BBW – 3450 g, length – 52 sm  Brest feeding  Normal physical and mental development  BW 3 mo – 5600 г. (normal) 
  3. 3. MEDICAL HISTORY  Routine examination immunization before DTP  WBC (blood count) 21 th.  ESR 65 mm/h  Admitted to a hospital with Ds: acute otitis?
  4. 4. ADMISSION STATUS  No fever  Irritated  No appetite  Pale skin with grey shade  No other disorders  Belly - round form, abdominal mass about 8 x 10 cm on the left side
  5. 5. Date 06.03.08 WBC 28,0 RBC 4,03 HB 103 HT 29,1 PLT 759 SC 2 SN 42 E 1 MON 7 LYMF 43 ESR 59 BLOOD COUNT IN ADMITION
  6. 6. BIOCHEMICAL BLOOD ANALYSIS - 0,352 (N 0,100 – 0,200)  CRP – 0,120 (N до 0,001 г/л)  АSLO 1:500 (N 1:250)  Other - normal  Seromucoid  CMV IG M +
  7. 7. URINE TESTS  Clinical urine analysis(twice)- N  Bacteriuria- negative
  8. 8. Renal US  Вставить картинку!!!!!!     Right kidney 74 х 30 х 33 mm, parenchyma layer 7 mm Left kidney 96 х 53 х 57 mm (N up do 50 mm) Pelvis sinus left26mm, calic- up to 19 mm The cortex layer - lots of fluid inclusions (d) up to 22 mm. Iliac dystopia of left kidney
  9. 9. INTRAVENOUS UROGRAPHY Left kidney shadow is approximately absent.  1,5-hour picture left side – several low contrasted round shadows d= 0,7 - 2,0 sm, enlarged calyces.  Left kidney function non significant.  Conclusion: left hydronephrosis with severe function reduction 
  10. 10. TREATMENT Ceftriaxone 400 mg/24h i/m  Detoxic therapy  Syndromal therapy  A serious condition (depressed appetite has sharply reduced, the skin earthy shades, weight negative dynamics, ESR 52 mm/h, neutrophilia)  septicemia !!! 
  11. 11. LEFT TRANSCUTANEOUS NEPHROSTOMY During the operation received 150.0 ml of cloudy urine with lots of lush green pus
  12. 12. POSTOPERATIVE TREATMENT treatment – 14 days  Immunocorrection  Detoxic therapy  A/b
  13. 13. Date 06.03.08 WBC 11,8 (28,0) RBC 3,58 HB 98 (103) HT 26 PLT 413 SC 1 (2) SN 20 (42) E 4 MON 2 LYMF 73 (43) ESR 16 (59) Общий ан. крови (контроль)
  14. 14. RENAL US (FOLLOW-UP)  Left kidney 75 х 29 х 27мм (96 х 53 х 57)  Calyces (left kidney) up to 10 mm (19мм)
  15. 15. 25 DAYS AFTER NEPHROSTOMY  No fever  Feeling good (gay, active, interested in toys)  Appetite satisfied (requests to eat)  Encreases weight
  16. 16. FOR FUTURE  Surgical  Good correction of urodynamics prognosis
  17. 17. CONCLUSION Accidentally revealed gross pathology of the kidney No urinary syndrome The rapid development of urosepticemia
  18. 18. CAKUT Congenital anomalies of kidney and urinary tract  1:500 live births  1:2000 neonatal deaths  Loane M, Dolk H, Kelly A, et al Paper 4: EUROCAT statistical monitoring: identification and investigation of ten year trends of congenital anomalies in Europe. Birth Defects Res A Clin Mol Teratol 2011;91 Suppl 1:S31-S43.  Anomalies of UT in 10% of relatives of patients with CAKUT (usually asymptomatic!) Winyard P, Chitty LS. Dysplastic kidneys. Semin Fetal Neonatal Med 2008;13:142-151.
  19. 19. Jeffery Fletcher, Stephen McDonald , Stephen I. Alexander, on behalf of the Australian and New Zealand Pediatric Nephrology Association (ANZPNA) Prevalence of genetic renal disease in children Pediatr Nephrol, 2012
  20. 20. СAKUT KIDNEY      Renal agenesia- renal absence Дисплазия почки- kidney contains an undifferentiated tissue and can be small (APLASIA) and extended due to cysts (cystic dysplasia or MCDK) Hypoplasia of kidney (kidney contains normal nefrons, but few of them, or they are big-oligomeganefronia) The doubling of the collective system (upper part is dysplastic, combined with ureteral obstruction, lower-VUR) Horseshoe kidney URINARY TRACT      Агенезияотсутствие «треугольника» PUJ stenosis Megaurether Post. Urethral valve VUR
  21. 21. Stages of renal branching morphogenesis and nephron formation. 35-37 day of gestation Shah M M et al. Development 2004;131:1449-1462 (A) Stages of renal branching morphogenesis and nephron formation. Ureteric bud (UB) outgrowth from the Wolffian duct is induced by signals from the metanephric mesenchyme (MM) (A). (B,C) Invasion of the MM by the UB is followed by iterative branching of the UB and elongation of UB stalks. (D) At the tips of the branches, the epithelium induces the mesenchyme to form pre-tubular aggregates, which are stimulated to undergo mesenchymal to epithelial transformation (E,F) through the formation of comma-shaped (E) and S-shaped (F) bodies to form components of the nephron (G): renal tubules (proximal and distal) and the epithelial component of the glomerulus. (B) Nephron endowment is thought to be largely determined through branching of the UB. (Left) The UB adopts a strategy of lateral branching followed by bifurcation of a stem into two daughter branches (terminal bifid branching) to form the collecting system of the kidney. Nephrons are induced at UB tips but are also formed around the stem of elongating branches during the later branching iterations (arcades) and late-phase lateral branching. (Right) The segments of the collecting system proximal to the ureter (the renal pelvis and calyces) are formed from early branching segments of the UB that have dilated.
  22. 22. An overview of the major signaling pathways involved in ureteric epithelial branching. Utip – epithelium CapMtissue urethral mesenchimal Gdnf, Vegfa, Hgf, Fgf10 – growth factors Agt- angiotensinogen Ret/Gfrα1, Kdr, Met, Fgf r2, Egfr, Agtr1/2 receptor tyrosine kinase ©2012 by Cold Spring Harbor Laboratory Press Little M H , and McMahon A P Cold Spring Harb Perspect Biol 2012;4:a008300
  23. 23. Nature Rev Genetics 3, 533-43, 2002 Coordinating early kidney development: lessons from gene targeting
  24. 24. Ontogenic mechanisms involved in the formation of CAKUT. A primary defect in either the growing ureter or the differentiating metanephric blastema can cause both ureter and kidney. POPE J C et al. JASN 1999;10:2018-2028
  25. 25. Genetics and CAKUT Gene CAKUT phenotype Type of mutations identifieda Mutation detection rate in unrelated cases BMP4 Renal hypoplasia Missense 5/250 (2%) EYA1 Renal hypoplasia Insertion, deletion 2/99 (2%) GDNF Renal agenesis, renal dysplasia Missense 1/33 (3%) GFRA1 Renal agenesis, renal dysplasia None 0/33 (0%) HNF1β Renal agenesis, renal hypoplasia, renal dysplasia Deletion, splice site HOXA11/HOXD11 Renal agenesis, renal hypoplasia, renal dysplasia None PAX2 Renal hypoplasia, renal dysplasia RET Renal agenesis, renal dysplasia Missense, stop ROBO2 VUR Missense 6/95 (6%) SALL1 Renal hypoplasia Deletion 1/99 (1%) SIX1 Renal hypoplasia Missense 1/99 (1%) SIX2 Renal hypoplasia Missense 5/250 (2%) SOX17 VUR, UPJ obstruction Missense, insertion 6/178 (3%) UMOD Complete CAKUT spectrum None 0/96 (0%) UPK3A Renal agenesis, renal dysplasia, renal hypoplasia, PUV, VUR Missense 8/99 (8%), 75/377 (20%), 5/50 (10%), 25/80 (31%) 0/59 (0%) Insertion, deletion, splice site, stop 6/99 (6%), 2/20 (10%), respectively 9/33 (27%), 7/101 (7%) 0/76 (0%), 2/170 (1%), 4/17 (24%)
  26. 26. Novel perspectives for investigating congenital anomalies of the kidney and urinary tract (CAKUT) Locus CAKUT phenotype Model Parametric (H)LOD score NPL (P-value) VUR Autosomal dominant 3.16 5.76 (0.0002) 1p32–33 Renal agenesis, renal hypoplasia Autosomal dominant 3.50 5.30 (0.00015) 1q41–44 and 11p11 PUV and Prune Belly syndrome Autosomal recessive 3.01 2q37 VUR Nonparametric 6p21 Hydronephrosis, UPJ obstruction Autosomal dominant 3.09 – 8q24 Renal agenesis, VUR Autosomal recessive 4.20 – VUR Autosomal recessive 3.60 1p13 12p11–q13 – – 4.10 (0.001) 4.00 (0.0001)
  27. 27. Kerecuk L et al. (2008) Renal tract malformations: perspectives for nephrologists Nat Clin Pract Nephrol doi:10.1038/ncpneph0807
  28. 28. Effect of Drugs on Renal Development Drug Effect of Maternal Treatment during Pregnancy on Offspring Kidney Development Effect of Treatment during Postnatal Kidney Development Aminoglycosides Tubular alterations (16), low nephron number (17–19) Tubular damage (21), low nephron number (19) Cyclosporin A Low nephron number (22) Prostaglandin synthetase inhibitors Tubular alterations (21), similar nephron number (28) Glomerular and tubular injury (21), similar nephron number (21,26,27) ACEIs/ARBs Renal insufficiency (31) Atrophy of the renal papilla, tubular alterations (32), low nephron number (33) Dexamethasone Altered tubular transporters (36,37), low nephron number (5), similar nephron number (38) Low nephron number (5,35) Furosemide Renal concentrating defect (40) — Antiepileptic drugs More congenital malformations, specifically MCDK (44) — Mycophenolate mofetil Renal agenesis/ectopia (45,46) — Adriamycin Bladder agenesis, hydronephrosis (48) — Cyclophosphamide Hydro(uretero)nephrosis (49) — Effect of Drugs on Renal Development Michiel F. Schreuder, CJASN January 2011 vol. 6 no. 1 212-217
  29. 29. РАЗВИТИЕ ПОЧКИ (В НОРМЕ И ПАТОЛОГИИ) Гипоплазия почки – меньше рядов нефронов при сохранной экскреторной функции Кистозная дисплазияпорочные канальца, маленькие кисты, остаточная экскреторная функция, лоханка не изменена МКДП- нет функции, нет собирательной системы Аплазия-нет первичного роста ткани Larissa Kerecuk, Michiel F Schreuder and Adrian S Woolf, Renal tract malformations: perspectives for nephrologists Nature Clinical Practice Nephrology (2008) 4, 312-325,
  30. 30. Renal agenesia
  31. 31. HORSESHOE KIDNEY
  32. 32. Hypoplasia of kidney
  33. 33. MULTICYSTIC DISPLASIA John J. Bissler, Brian J. Siroky and Hong Yin Glomerulocystic kidney disease Pediatr Nephrol. 2010 October; 25(10): 2049–2059.
  34. 34. KIDNEY DYSPLASIA WITH PUJ STENOSIS
  35. 35. ADPKD
  36. 36. СИНДРОМ MECKEL–GRUBER (гломерулярно-кистозная болезнь) fetal glomeruli and surrounding dysplastic tissue with tubular cystic changes
  37. 37. Paradigm shift from classic anatomic theories to contemporary cell biological views of CAKUT Iekuni Ichikawa, Fumiyo Kuwayama, John C Pope IV, F Douglas Stephens and Yoichi Miyazaki
  38. 38. VUR
  39. 39. PUV Complications of PUV
  40. 40. Condition Postnatal 99mTcFetal Postnatal DMSA ultrasonographic ultrasonographic renography findings findings findings Renal agenesis Absent kidney (adrenal gland Absent kidney might be mistaken for kidney) No renal uptake (also rules out ectopic kidney) Renal aplasia Absent kidney (adrenal gland Absent kidney might be mistaken for kidney) No renal uptake (also rules out ectopic kidney) Large cysts replacing kidney parenchyma and Multicystic lack of central dysplastic kidney pelvis, or tiny remnant kidney (if organ involuted) Large hypoechogenic cysts not communicating with the renal pelvis, or tiny remnant kidney (if organ involuted) No or very little renal uptake19, 30 Further postnatal radiological assessment Investigation of contralateral kidney (see congenital solitary kidney) Investigation of contralateral kidney (see congenital solitary kidney) Investigation of contralateral kidney (see congenital solitary kidney)
  41. 41. No renal uptake by Kidney should be Congenital solitary Kidney might be absent kidney (also larger than normal if kidney larger than normal rules out ectopic healthy kidney) Smooth kidney outline (pyelonephritic Hypoplastic kidney Small kidney Small kidney scarring usually produces focal defects) Echobright kidney Cystic dysplastic with cysts and poor Decreased renal Echobright kidney kidney corticomedullary uptake30 differentiation Echobright, large Autosomal recessive Large, bright kidney kidney with small polycystic kidney cysts Focal defects (but not usually performed)31 Generalized Autosomal Large, bright Cysts that increase decreased uptake dominant polycystic kidney, sometimes in size and number and focal defects kidney with cysts with age (but not usually performed)32 Detection of any vesicoureteric reflux and/or ureteric obstruction Detection of any vesicoureteric reflux and/or ureteric obstruction Detection of any vesicoureteric reflux and/or ureteric obstruction Detection of dilated bile ducts (by hepatobiliary iminodiacetic acid isotope scan) Detection of any pancreatic or liver cysts or cerebral aneurysms
  42. 42. RENAL AGENESIA IN NEONATE
  43. 43. POLYCYSTIC KIDNEY IN NEONATES
  44. 44. CYSTIC DYSPLASIA Cystic dysplasia MCDK
  45. 45. Novel perspectives investigating CAKUT Renkema K Y et al. Nephrol. Dial. Transplant. 2011;26:3843-3851 © The Author 2011. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com
  46. 46. Vicious cycle of progressive functional and structural deterioration shared by many chronic renal diseases. ©1999 by American Society of Nephrology POPE J C et al. JASN 1999;10:2018-2028
  47. 47. LONG LIVE KIDNEY !!!!! Nephron  1 mln in every kidney  Length of tubules – 18-50 мм  Tubules length of all nephrons – 100 km  80% in cortex 
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