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 Brest feeding Normal physical and mental development BW 3 mo – 5600 г. (normal)

MEDICAL HISTORY

Routine examination before DTP immunization

WBC (blood count) 21 th. ESR 65 mm/h Admitted to a hospital with Ds: acute otitis?

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

BLOOD COUNT IN ADMITION

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

BIOCHEMICAL BLOOD ANALYSIS

Seromucoid - 0,352 (N 0,100 – 0,200) CRP – 0,120 (N до 0,001 г/л) АSLO 1:500 (N 1:250) Other - normal

CMV IG M +

URINE TESTS

Clinical urine analysis(twice)- N

Bacteriuria- negative

Вставить картинку!!!!!!

Renal US 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 left- 26mm, calic- up to 19 mm

The cortex layer - lots of fluid inclusions (d) up to 22 mm.

Iliac dystopia of left kidney

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

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 !!!

LEFTTRANSCUTANEOUS NEPHROSTOMY

During the operation received 150.0 ml of cloudy urine with lots of lush green pus

POSTOPERATIVE TREATMENT

A/b treatment – 14 days Immunocorrection Detoxic therapy

Общий ан. крови

(контроль)

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)

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 eat) Encreases weight

FOR FUTURE

Surgical correction of urodynamics

Good prognosis

CONCLUSION

Accidentally revealed gross pathology of the kidney

No urinary syndrome The rapid development of

urosepticemia

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.

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 childrenPediatr Nephrol, 2012

СAKUT

KIDNEY URINARY TRACT

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

Агенезия- отсутствие «треугольника»

PUJ stenosis Megaurether Post. Urethral

valve VUR

Stages of renal branching morphogenesis and nephron formation.

Shah M M et al. Development 2004;131:1449-1462

35-37 day of gestation

(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.

An overview of the major signaling pathways involved in ureteric epithelial branching.

Little M H , and McMahon A P Cold Spring Harb Perspect Biol 2012;4:a008300©2012 by Cold Spring Harbor Laboratory Press

Utip – urethral epithelium

CapM- mesenchimal tissue

Gdnf, Vegfa, Hgf, Fgf10 – growth factorsAgt- angiotensinogen

Ret/Gfrα1, Kdr, Met, Fgfr2, Egfr, Agtr1/2 - receptor tyrosine kinase

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 differentiating metanephric blastema can cause both ureter and kidney.

POPE J C et al. JASN 1999;10:2018-2028

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%)

HNF1βRenal agenesis, renal hypoplasia,

renal dysplasiaDeletion, splice site

8/99 (8%), 75/377 (20%), 5/50 (10%), 25/80 (31%)

HOXA11/HOXD11Renal agenesis, renal hypoplasia,

renal dysplasiaNone 0/59 (0%)

PAX2 Renal hypoplasia, renal dysplasia Insertion, deletion, splice site, stop 6/99 (6%), 2/20 (10%), respectively

RET Renal agenesis, renal dysplasia Missense, stop 9/33 (27%), 7/101 (7%)

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%)

UPK3ARenal agenesis, renal dysplasia,

renal hypoplasia, PUV, VURMissense 0/76 (0%), 2/170 (1%), 4/17 (24%)

Genetics and CAKUT

LocusCAKUT phenotype Model

Parametric (H)LOD score NPL (P-value)

1p13 VURAutosomal 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 VURNon-

parametric – 4.10 (0.001)

6p21 Hydronephrosis, UPJ obstruction

Autosomal dominant

3.09 –

8q24Renal agenesis,

VURAutosomal recessive 4.20 –

12p11–q13 VURAutosomal recessive 3.60 4.00 (0.0001)

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

Kerecuk L et al. (2008) Renal tract malformations: perspectives for nephrologistsNat Clin Pract Nephrol doi:10.1038/ncpneph0807

Effect of Drugs on Renal Development

Effect of Drugs on Renal Development Michiel F. Schreuder, CJASN January 2011 vol. 6 no. 1 212-217

DrugEffect of Maternal Treatment

during Pregnancy on Offspring Kidney Development

Effect of Treatment during Postnatal Kidney Development

AminoglycosidesTubular 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)

DexamethasoneAltered tubular transporters (36,37), low nephron number (5), similar nephron number (38)

Low nephron number (5,35)

Furosemide Renal concentrating defect (40) —

Antiepileptic drugsMore congenital malformations, specifically MCDK (44)

—

Mycophenolate mofetil Renal agenesis/ectopia (45,46) —

AdriamycinBladder agenesis, hydronephrosis (48)

—

Cyclophosphamide Hydro(uretero)nephrosis (49) —

РАЗВИТИЕ ПОЧКИ (В НОРМЕ И ПАТОЛОГИИ)

Larissa Kerecuk, Michiel F Schreuder and Adrian S Woolf, Renal tract malformations: perspectives for nephrologists Nature Clinical Practice Nephrology (2008) 4, 312-325,

Гипоплазия почки – меньше рядов нефронов при сохранной экскреторной функцииКистозная дисплазия- порочные канальца, маленькие кисты, остаточная экскреторная функция, лоханка не измененаМКДП- нет функции, нет собирательной системыАплазия-нет первичного роста ткани

Renal agenesia

HORSESHOE KIDNEY

Hypoplasia of kidney

MULTICYSTIC DISPLASIA

John J. Bissler, Brian J. Siroky and Hong Yin Glomerulocystic kidney disease Pediatr Nephrol. 2010 October; 25(10): 2049–2059.

KIDNEY DYSPLASIA WITH PUJ STENOSIS

ADPKD

СИНДРОМ MECKEL–GRUBER (гломерулярно-кистозная болезнь)

fetal glomeruli and surrounding dysplastic tissue with tubular cystic changes

Paradigm shift from classic anatomic theories to contemporary cell biological views of CAKUTIekuni Ichikawa, Fumiyo Kuwayama, John C Pope IV, F Douglas Stephens and Yoichi Miyazaki

VUR

PUV

Complications of PUV

ConditionFetal ultrasonographic findings

Postnatal ultrasonographic findings

Postnatal 99mTc-DMSA renography findings

Further postnatal radiological assessment

Renal agenesis

Absent kidney (adrenal gland might be mistaken for kidney)

Absent kidneyNo renal uptake (also rules out ectopic kidney)

Investigation of contralateral kidney (see congenital solitary kidney)

Renal aplasia

Absent kidney (adrenal gland might be mistaken for kidney)

Absent kidneyNo renal uptake (also rules out ectopic kidney)

Investigation of contralateral kidney (see congenital solitary kidney)

Multicystic dysplastic kidney

Large cysts replacing kidney parenchyma and lack of central 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

Investigation of contralateral kidney (see congenital solitary kidney)

Congenital solitary kidney

Kidney might be larger than normal

Kidney should be larger than normal if healthy

No renal uptake by absent kidney (also rules out ectopic kidney)

Detection of any vesicoureteric reflux and/or ureteric obstruction

Hypoplastic kidney Small kidney Small kidney

Smooth kidney outline (pyelonephritic scarring usually produces focal defects)

Detection of any vesicoureteric reflux and/or ureteric obstruction

Cystic dysplastic kidney

Echobright kidney

Echobright kidney with cysts and poor corticomedullary differentiation

Decreased renal uptake30

Detection of any vesicoureteric reflux and/or ureteric obstruction

Autosomal recessive polycystic kidney

Large, bright kidneyEchobright, large kidney with small cysts

Focal defects (but not usually performed)31

Detection of dilated bile ducts (by hepatobiliary iminodiacetic acid isotope scan)

Autosomal dominant polycystic kidney

Large, bright kidney, sometimes with cysts

Cysts that increase in size and number with age

Generalized decreased uptake and focal defects (but not usually performed)32

Detection of any pancreatic or liver cysts or cerebral aneurysms

RENAL AGENESIA IN NEONATE

POLYCYSTIC KIDNEY IN NEONATES

CYSTIC DYSPLASIACystic dysplasia

MCDK

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

Vicious cycle of progressive functional and structural deterioration shared by many chronic renal diseases.

POPE J C et al. JASN 1999;10:2018-2028©1999 by American Society of Nephrology

Why sh

ould we know about C

AKUT!

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