overview of cakut classes/2017... · cakut 2 most common cause of all birth defects 20-30% of all...
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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