1

Overview of CAKUT

A. RaesDepartment of pediatric nephrology University hospital Ghent, Belgium

IPNA Junior class, Glasgow 2017

CAKUT 2

Most common cause of all birth defects

20-30% of all anomalies detected by routine fetal ultrasound (18-22 wk)

Incidence:

3-7 per 1000 live newborns1

Spectrum of severity3

Unilateral/bilateral

Different defects often coexist in an individual child

Present in > 20 % of newborns with chromosomal abnormalities2

Most cases are sporadic and non-syndromic

1) Loane et al. EUROCAT, birth defects res 2011 2) Winyard et al. Seminar fetal neonatal med 20083) Wuhl et al. cJASN 2013

Causes of chronic kidney disease in children

glomerulopathies 8%

polycystic kidney disease 6%

metabolic5%

HUS 3%

nephronophtisis4%

Interstitial Nephropathy

2%

Post-ischemic 1%

unknown6%

Other 2%

CAKUT 63%

Harambat et al. Ped nephrol 2012

700 European children with GFR 15-60 ml/min/1,73 m²

Causes of ESRD 4

Harambat et al. Ped nephrol 2012

Primary renal diseases at start of RRT in 2014

ESPN/ERA-EDTA Registry: An update on the registry, December 2016

CAKUT: age at start of RRT 6

Wuhl et al. cJASN 2013

CAKUT: RRT by subcategory7

CAKUT: Etiology8

Many causes of CAKUT are not known yet

Strong genetic component

Familial aggregation reported in 10 % of cases

CAKUT: Familial clustering 9

Offspring of CAKUT patients CAKUT risk 15-20 %

Carter et al. J Hum Genet 1984

Solitary, duplex kidneys, UPJ obstruction in 15% of 1st/2nd degree relatives of children with renal

agenesis/dysplasia

Schwaderer et al. Ped Neph 2007

Positive family history for CAKUT in 22,9 % index cases 51,1% CAKUT in 1st degree asymptomatic relatives (>VUR)

Bulum et al. Ped Neph 2013

CAKUT: Etiology10

Most causes of CAKUT are not known yet

Strong genetic component Familial aggregation reported in 10 % of cases Nonsyndromic forms of CAKUT

PAX 2

HNF 1β (TCF 2)

DSTYK (dual serine-threonine and tyrosine protein kinase )

CAKUT: expansion of detection11

Renkema et al. 2011 Novel perspectives for investigating CAKUT, NDT

Human syndromes associated with CAKUT12

Ocular coloboma

Human syndromes associated with CAKUT13

ObesityDiabetesPolydactylyRetinitis pigmentosa

Human syndromes associated with CAKUT14

Hearing LossPre-auricular pits Auricular fistulae

Human syndromes associated with CAKUT15

MODY Renal cysts

CAKUT 16

Capone et al., Genetics of CAKUT. Int Journal of molecular sciences,2017

Evaluation of a patient with CAKUTinvestigations renal and urologic structural abnormalities,exploration of extrarenal manifestationsa detailed family history

CAKUT: Complex trait (multifactorial)17

CAKUT: Embryology18

Development of kidneys and ureters

Pronephros: nonfunctional

day 22 of human gestation

Mesonephros: functional

end of 4th week, produces urine week 6-10

mesonephric duct (Wolffian duct): ureteric bud

Metanephros or definite kidney

5thweek –begins to develop

Starts to function ~4 weeks later

Rosemary V. Sampogna, and Sanjay K. Nigam Physiology 2004;19:339-347

Definitive kidney: two sources

Interaction between ureteric bud and metanephricmesenchyme Inductive reciprocal signalling

Reciprocal signalling20

Development of urinary bladder and urethra21

4th to 7th week

Cloaca divides

urogenital sinus

Urinary bladder (cranial part)

Urethra (caudal part)

anal canal (rectum)

Anomalies of the urinary system 22

Song R et al., Pediatr nephrol 2011

Spectrum of CAKUT23

Multiple manifestations of defective renal/urinary tract development

Defects in ureteric bud outgrowth/branching

• Vesicoureteral Reflux (VUR)

• Ureterovesical junction obstruction (UVJ)

• Ureteropelvic junction obstruction (UPJ)

• Duplicated collecting system

• Renal agenesis

• Hydronephrosis

• Ectopic kidney

Defects in nephron induction/differentiation

• Agenesis/dysplasia/hypoplasia

• Multicystic dysplastic kidney (MCDK)

Defects in fusion

• Horseshoe kidney

Defects in bladder/urethral development

• Posterior urethral valves (PUV)

Renal agenesis24

The missing kidney

Renal agenesis: bilateral25

POTTER syndrome

Uncommon

1/7000-1/10000 births, M>F

Fatal condition

Oligohydramnios (US at 12 th wk of gestation),

Often, but not always the result of a genetic disorder

> parent(s) with malformed or absent kidney

Edith Louise Potter

Pioneer in renal development

Renal agenesis: bilateral26

Unique characteristics

Dry loose skin

Large low-set ears with lack of cartilage

Wide-set eyes, flattened nose

Micrognathia

Small thorax

Anomalies of the limbs

Hypoplastic hands

Equinovarus

Bowing of distal limbs

Renal agenesis: unilateral27

1/500-1/3200 live births

M> F (1,7/1)

> Left side

Uncomplicated unilateral agenesis

Antenatal US

+ compensatory hypertrophy contralateral kidney (ifhealthy)

- compensatory hypertrophy: further work-up

Renal agenesis: unilateral28

1/3 is associated with

Ipsilateral urogenital malformation

>> VUR (< PUJ, VUJ)

Absent vas deferens, absent adrenals

many syndromes (BOR, RCAD, etc…)

Renal hypoplasia29

Small kidney: lower number of structurally (histologically) normal nephrons

vascular accident during pregnancy (twin to twin transfusion)

genetic cause

isolated: rare

≠ renal dysplasia

Congenital: No scars

Functional on renogram

Renal hypoplasia30

Clinical diagnosis ~ criteria Reduction of renal size by 2 SD for the mean size by age

Exclusion of renal scarring (DMSA scan)

Unilateral renal hypoplasia:

compensatory hypertrophy contralateral kidney (if healthy)

Prognosis Bilateral

Decreased nephron numbers

Related to• increased risk of hypertension

• chronic kidney disease

Renal dysplasia31

Malformed kidney tissue elements Immature /undifferentiated or metaplastic (abnormal) renal

structures

Unilateral (M> F 1,9/1) and bilateral (M> F 1,3/1)

Variable in size:

> Small

Large abnormally shaped kidneys

+ cysts in case of cystic dysplastic kidneys

Often associated with urogenital anomalies

VUR, congenital hydronephrosis, etc..

Renal dysplasia32

Presentation Routine prenatal screening/ dysmorphy / oligohydramnios Undetected untill

Nocturnal enuresis Polyuria and salt-loosing nephropathy (thirst and salt craving)

Failure to thrive

Acute renal failure (on CRF) in case of gastro-enteritis UTI

Prognosis uni/bilateral ~ Severity

renal dysfunction may neccessitate nephrologic care including renal replacement therapy

Multicystic dysplastic kidney33

Minimal to no functional renal parenchyma usually with primitive tubules and foci of cartilage

groups of noncommunicating cysts with fibrous connective tissues

‘Bunches of grapes’ appearance

≠ ARPKD MCDK: Cysts are larger and more variably sized

Multicystic dysplastic kidney34

Most common cystic disorder in children

1/2400 live births > unilateral (<<<bilateral) > afunctional with atretic ureter 25% incidence of VUR in contralateral kidney may account for many cases of unilateral ‘ renal agenesis’

Presentation Prenatal screening > Abdominal mass in neonates Hematuria, UTI

Multicystic dysplastic kidney35

Call for surgery ?????

No

Involution of cysts and regression

over several months to years

Rarely cause of HTN, tumor or infection

PrognosisCompensatory hypertrophy of contralateral kidney

Observation to ensure the healthy kidney is functioningproperly

Ectopic kidney36

Kidney failed to ascend from origin to normal location in renal fossa

Predominantly pelvic location (rarely thoracic)

Small, lobulated kidneys and irregular shape

1/900 live births

More common on left side

Usually asymptomatic

< UTI, hydronephrosis, ID

Duplex system37

Strong familial predisposition

Complete/ partial duplication

> ureter of upperpole

Abnormal origin in trigone (lower position)

+ ureterocoele

sacculation of the terminal portion of the ureter

Ectopic (UTI, ID)

Horseshoe kidneys38

Most common type of renal fusion anomaly

7% of patients with Turner syndrome (<trisomy 18)

2/3 associated genitourinary anomalies

VUR (50%), Ureteral duplication (10%)

Hypospadias / undescended testis (4%)

Bicornuate uterus (7%)

more prone to develop Wilm’s tumor than general

Horseshoe kidney

39

Midline fusion of the lower poles(90%)Malrotated pelvicalyceal system

Horseshoe kidney40

~ 1/3 asymptomatic

Symptoms

Abnormal course of the ureters

> UTI

Pain, hematuria and mass

Posterior urethral valves41

Mucosal folds at the distal prostatic urethra thatcause varying degrees of obstruction

> obstructive uropathy in males, leading to ESRD

1/5000 male births

10% of prenatally diagnosed hydronephrosis

Severe UTI and septicaemia in neonatal period

Rare > prenatal screening

+ Component of renal dysplasia

Diagnosis 42

Antenatal: pathognomonic U/S findings

Voiding cystourethrography (VCUG)

43

Gold standard for diagnosing PUV

Typical findings

Clinical presentation44

Prenatal ultrasound

Newborn: Palpable abdominal mass, ascites

RDS from pulmonary hypoplasia (oligohydramnios)

Dribbling / poor urinary stream

Renal insufficiency

Early infancy Urosepsis/ failure to thrive/ renal insufficiency

Toddlers Voiding dysfunction/UTI/ Incontinence

Management PUV45

Bladder drainage

5 or 8 FR pediatric feeding tube is ideal

Foley catheter can occlude the ureteral orifice: secondaryobstruction

Antibiotic coverage

Correction of metabolic derangements Asses renal function and metabolic abnormalities

Acidosis, hyperkalemia

Key to initial care

Management of PUV46

Surgical intervention> Transurethral valve ablation (cystoscopy)

< Vesicostomy / upper tract diversion

Prevention of UTI (50-60%)

Treatment of bladderdysfunction

Incontinence

Treatment of renal insufficiency

Progression to CKD47

CAKUT and CKD Nephron numbers at birth

Preterm birh

Unilateral /bilateralinvolvement

Kidney dysplasia

Type of CAKUT

Genetic basisAcquired nephron loss

Childhood: obstruction, UTI

Puberty

Renal outcome in CAKUT 48

Sanna-chershi S , Kid Int 2009

Potential subclinical defects

~300 CAKUT followed > 30 years

58 patients started RRTRisk for RRT unexpectedly higher for SK

Solitary kidney: risk factors for CKD49

Ipsilateral CAKUT

Small renal size

Low birth weight

Prematurity

History of UTI

Short stature

Socioeconomic (lower income and maternaleducation)

Furth et al., Clin J Am soc Nephrol,2011, Hidalgo et al., Am J Kidney Dis , 2013

Solitary kidney: guidelines for follow up50

Clinical parameter CAKUT - CAKUT + GFR<60ml/min/1,73 m²or proteinuria/hypertension

Blood pressure Annually Q6 months Q3-Q6 months

Microalbuminuria Annually Q6 months Q3-Q6 months

Serum creatinine Q5 years Q5 years Q3-Q6 months

Ultrasound Q 5years As indicated As indicated

Adapted from Westland R et al., Clin J Amer Soc Neph, 2014

Management of CKD in CAKUT51

ACE inhibitors (nephroprotection)

Avoidance of NSAIDs, Aminoglycosides

Puberty

Dietary Management

Obesity

Protein restriction

Monitor

Hypertension

Microalbuminuria

Key points 52

Renal tract malformations are, collectively, the major cause of childhood end-stage renal disease

Renal tract malformations are sporadic, but it can be familial, and specific mutations of renal tract developmental genes can be found in some affected individuals

Renal tract malformations can present not only prenatally, but also in childhood or adulthood

Q and A53

1) If CAKUT is not detected prenatally, when should it be suspected?

Male neonates with dribbling or poor urinary stream Infants with UTI , particularly those

with sepsis or those with PN requiring hospitalization other pathogens than E. coli

diurnal incontinence (>continuously), EN Polyuria Failure to thrive Abdominal mass Kidney stones Syndromic characteristics Hypertension ARF

Q and A54

2) What could be the cause of non-visualization of kidney in R/L renal fossa?

Unilateral agenesis

MCDK which has involved

Ectopic kidney/ cross fused ectopy

(Severely hypoplastic kidney or dysplastickidney)

Nephrectomy

Q and A55

3) What is the risk of developing CKD/ ESRD and factors that influence this?

o depends on the number of functioning nephrons at birth,

o history of preterm birth, low protein diet, maternal ingestions or medications

o the degree of renal dysplasia and the presence of bilateral or unilateral involvement,

o as well as acquired nephron loss,

which in children is mostly due to the co-occurrence of upper UTI and/or persistent obstruction

treatment with nephrotoxic agents

Clinical case: Marion 8 y 56

Initial presentation

EN and ID

No failure to thrive

No history of UTI

What is your next step?

Detailed history/ questionnaire

Urinalysis

VCUG

Ultasound

Clinical case: Marion 8 y 57

Ultrasound reveals a solitary kidney. What is your next step?

DMSA scan

CT abdomen

VCUG

IVP

Clinical case: Marion 8 58

DMSA scan shows a solitary kidney with compensatory hypertrophy. What is your next step?

Further investigation

Wait and see

Treatment with anticholinergics

Pelvic floor therapy

Clinical case: Marion 8 y 59

No improvement in ID and EN on different anticholinergictreatments. Daytime alarm reveals very frequent loss of urinary drops. Development of fever and evacuation of pus from genitourinary region. What is your most probablediagnosis?

Foreign body

Ectopic ureter

Dysplastic kidney

PUV