Prenatal diagnosis of congenital uropathies

Elena LevtchenkoLeuven, Belgium

Moscow, October 22, 2013

Pediatric consult

birth

?

Gifted by R. Kleta

Pediatric consult

Definition of congenital uropaties (CAKUT)

• CAKUT: congenital anomalies of kidney and urinary tract– 20-30% of all anomalies identified in

prenatal period (Queisser et al. 2002)

– Overall rate: 0.3-1.6 per 1000 newborns (life and stillborn) (Wissel et al. 2005, Caiulo et al. 2012)

– 30-60% of pediatric and young adult patients with ESRD (Harambat et al. 2012, Wuhl et al. 2013)

Song et al. Pediatr Nephrol 2011

Development of human pronephros

Prenatal kidney/urinary tract imaging

• Urinary bladder and kidneys can be visualized by ultrasound (US) starting from the 12th week gestational age (GA)

• Cortico-medullary differentiation - starting from 18-20 weeks GA

• Screening US for congenital malformations (including CAKUT) at 2nd trimester of pregnancy

(18-22 weeks GA)

1st prenatal consult

Information from gynecologist

• Inter-polar kidney diameter (in SD for GA) for both kidneys

• Position of the kidneys• Cortico-medullary differentiation, aspect renal

parenchyma• Dilatation of collecting system?

• renal pelvis (AP diameter or grade of hydronephrosis)• ureters

• Presence/dilatation of urinary bladder • Amniotic fluid (eyeballing, AF index or deepest pool)

Aim of prenatal consult

• Diagnosis of CAKUT – Isolated (unilateral vs bilateral/syndromal)

• Prediction of prognosis– Pregnancy:

• Termination of pregnancy (TOP): – 4% in isolated CAKUT, 50% in syndromal cases (Wissel et al. 2005)

• Indications for fetal surgery• Indications for delivery:

– Induction/Delivery in tertiary centrum?

– Child • Survival/Renal outcome• Postnatal treatment

Prenatal postnatal CAKUT diagnosis

EUROSCAN study: Fetal US of 709,030 birth in 12 European Countries

Wiesel et al. EJMG 2005

Gynecological classification of antenatal hydronephrosis

• Antenatal hydronephrosis: incidence 1-5% in general fetal population

• Classification of Society of Fetal Urology

“Pediatric classification” of antenatal hydronephrosis

Grade 4

Grade 1-2Grade 2-3

Bladder filling ?

Lee et al. Pediatrics 2006. Meta-analysis of 1,645 studies -> 17 studies sufficient quality

Prognosis of antenatal hydronephrosis

Termination of pregnancy

Hyndrickx & De Catte, IPNA 2013

N=50 (2008-2013)

Case (prenatal follow-up)

• Gravida 3, Para 2• Two healthy children• 25 weeks gestational age (GA):

– Male, severe oligohydramnios– Talipes equinovarus left – Bilateral hydroureteronephrosis grade 4– Megacystis– Dilatation of the proximal urethra

LUTO (posterior urethral valves)

• 25 weeks GA: placement of vesico-amniotic shunt increase of amniotic fluid

• Spontaneous partus at 33 weeks GA

• TOP?• Fetal

surgery?

Case (postnatal follow-up)

• Birth weight 2.4 kg, Apgar 8/9• Postnatal period:

– Pneumothorax, mild lung dysplasia– Urethra valves, no VUR– Renal function at 1 week:

• creatinine: 2.3 mg/dl

• Treatment:– Urethral valve resection– Intermittent catheterisasion– Intravesical oxybutinin, AB prophylaxis– Supportive treatment of CKD

Glomerular filtration rate at 2 years?

• < 15 ml/min/1,73 m2

• 15-30 ml/min/1,73 m2

• 30-60 ml/min/1,73 m2

• 60-90 ml/min/1,73 m2

Morris et al. Prenatal diagnosis 2007:Mate-analysis of biochemical and US parameters to predict postnatal renal function in congenital lower urinary tract obstruction

Best predictive value: renal cortical appearance, sensitivity 81% and specificity 59%

Klein et al. Sci Transl Med 2013: proteomics study of fetal urine to predict postnatal renal function in congenital lower urinary tract

obstruction

Klein et al. Sci Transl Med 2013

Indications for fetal surgery

Only in Low-Urinary Tract obstruction (LUTO)

Morris et al. Lancet 2013:

Results of PLUTO trial:

N=31 pregnancies with PUV,16 – vesicoamniotic shunt (VAS)15 – concervative treatment (CT)

VAS: • 1 intra-

uterine death

• 3 TOP• 4 death

<28 days• 8 survived• 2 normal

RF

CT: • 1 intra-

uterine death

• 2 TOP• 8 death

<28 days• 4 survived• 0 normal

RF

Indications for delivery induction

• Efforts to continue pregnancy to prevent complications of premature birth:– 34-36 weeks in case of severe

oligohydramnios?

• Indications for delivery in tertiary center:• Anticipated requirement of renal replacement

therapy• Anticipated requirement of complex surgery in

neonatal period• Anticipated requirement in tertiary neonatal care

Can standard prenatal examinations predict postnatal outcome of renal

function?

An Hindryckx

Luc De Catte Anke Raaijmakers

Prenatal imaging studies Postnatal follow-up

Standard examinations

• 2D fetal ultrasound:– Kidney length– Pyelum (grade hydronephrosis,

anterio-posterior diameter) ureter width

– Bladder diameter, aspect

• Amniotic fluid examination• Fetal serum (2-MG, cystatin C,

caryotype, urine (electrolytes, osmol)

Advanced examinations

• 3D fetal ultrasound• Fetal urine production• Fetal cortex blood flow

• Fetal MRI

• Proteomics and metabolomic studies of amniotic fluid

3D renal ultrasound

Kidney/pyelum volume measurement:by Virtual Organ Computer-aided AnaLys (VOCAL) with sono-AVC (automated volume count) for fluid/filled spaces segmentation

3D renal ultrasound

Potential:• Volume is better reflecting

function compared to renal pelvic diameter (Nam et al. 2012)

• Distinction between pyelum and renal parenchyma cortex volumeLimitations:

• Lack of standardization:• Methodology (imaging

planes, anatomical landmarks, repeatability)

• Lack of validated normal values

• Data analysis and storage (depending on producent)Inversion rendering

Reference curve for 3D renal volume

Hindryckx et al. 2013, IPNA Poster P-SUN009

ml

Fetal urine production

Sono-AVC combined with VOCAL-technique

Potential:• (Decreased) fetal

diuresis might predict kidney function

• Limitations:• Lack of

validated normal values

• High variation

Fetal kidney perfusion

• Peak systolic velocity (PSV)• Flow velocity integral in renal vein

correlated to kidney cortex volume (FVI x HR/renal cortex volume)

Normal fetal kidney perfusion

cm/sec

Hindryckx et al. 2013, IPNA Poster P-SUN009

Conclusions

• Interaction between gynecologist and pediatrician for prenatal diagnosis of CAKUT

• Prenatal consult aimes to make diagnosis, define severity and prognosis, pre- and postnatal follow-up; objective information for the parents

• Good prognostic markers for renal function outcome are limited and are a subject of intensive research

Pediatricians/pediatric nephrologists should be involved in prenatal follow-up of patients

with CAKUT!

Acknowledgments

Katholieke Universiteit LeuvenAn Hindryckx Luc De CatteAnke Raaijmakers Djalila Mekahli Karel Allegaert

Inserm ToulouseJoost SchanstraStéphane DecramerJean-Loup Bascands

UCL University College LondonPaul Winyard

Universitätsklinikum HeidelbergFranz SchaeferElke WühlAnke Doyon

THANK YOU!

Fons Sapientiae by Jef Claerhout

Leuven, Belgium

Embriology of kidney development

Song et al. Pediatr Nephrol 2011

Abnormal kidney development

Molecular regulation of kidney development (1)

M. Little et al. Current Topics in Developmental Biology 2010

Molecular regulation of kidney development (2)

Townes-Brocks syndrome

Denis-Drashsyndrome

Brachio-otorenal syndrome

Oculo-renaal syndrome

M. Little et al. Current Topics in Developmental Biology 2010

Role of HNF1 beta in kidney development

Naylor et al. JASN 2013

Renal cysts – diabetes syndrome

Case 1 (prenanal follow-up)

• Gravida 2, Para 0• In vitro fertilization• 24 weeks gestational age (GA):

– Male foetus– Oligohydramnios– Bilateral hydroureteronephrosis grade 4– Megacystis– Dilatation of the proximal urethra

LUTO (posterior urethral valves)

• Weekly follow-up• 26 weeks GA: foetal serum 2-MG:

5.9 mg/L (ref <4.9• Induction of delivery at 34 weeks due

to severe oligohydramnios

Case 1 (postnatal follow-up)

• Birth weight 2.3 kg, Apgar 8/8• Postnatal examinations:

– Prenatal diagnosis is confirmed, VUR 5 Le– Polyuria after placement of bladder catheter– Renal function at 1 week:

• creatinine: 2.3 mg/dl

• Treatment:– Urethral valve resection– Intravesical oxybutinin, AB prophylaxis– Ureter re-implantation at 1.5 years– Supportive treatment of CKD

GFR at 2 years (Cr-EDTA clearance): 59 ml/min/1.73 m2

Morris et al. BJOG 2009. Meta-analysis : antenatal ultrasound to predict postnatal renal function in congenital lower urinary tract obstruction

(13 studies, 215 women)

Best predictive value: renal cortical appearance, sensitivity 0.57 (95% CI 0.37-0.76) and specificity 0.84 (95% CI 0.71-0.94)

AF 4-quadrant index