FETAL RENAL CYSTIC DISEASES by Cathy Cluver1,2, Sammya Moura3, Fabricio Costa4 and Simon Meagher14 1.Mercy Hospital for Women, Melbourne University, Australia; 2.Stellenbosch University, South Africa; 3.University of Fortaleza, Brazil; 4. Monash Ultrasound for Women, Melbourne, Australia Normal Autosomal recessive polycystic kidney Multicystic kidney disease (MCKD): Potter II Autosomal dominant polycystic Hydronephrosis: Potter IV Hyperechoic kidneys + Genetic Syndromes/ Unexplained disease (ARPKD): Potter I kidney disease (ADPKD): Potter III aneuploidies Hyperechoic kidneys

Ultrasound Kidneys  Bilateral, hyperechoic enlarged kidneys from  Often unilateral (80%) US findings after 14-16 weeks  Caliectasis: connections visible between calyces and Echogenic kidneys  Unilateral or bilateral Finding 16w  Large hyperechoic kidney  Bilateral enlarged or grossly enlarged pelvis May be enlarged  No other anomalies  Diagnosis only made in 50% at mid trimester  Multiple and non-communicating cysts of variable shapes kidneys  Parenchyma not echogenic Associated with other anomalies  Renal length most valuable in diagnosis and sizes  Hyperechoic cortex only  ‘Eggshell sign’: crescent of increased echogenicity at  1-2 mm non-communicating  Loss of reniform shape  Exaggerated corticomedullary caliceal/ parenchymal interface  Renal cysts, some may have macrocystic  Ultrasound findings after 14 weeks differentiation  Unilateral or bilateral disease  Cysts in pancreas, liver, spleen, and CNS  Associated with megaureter and perinephric urinoma  Cystic fusiform dilatation of the collecting  No cysts seen in kidneys  Present if renal pelvis AP diameter >5mm at less than 32 ducts weeks and >10mm after 32 weeks Bladder Absent Normal Normal Absent/normal/ dilated/thick-walled bladder Normal Normal AFI Develop severe oligohydramnios Normal if unilateral, oligohydramnios if bilateral Usually normal Normal or oligohydramnios (dependent on cause) Normal/reduced Normal Vesicoureteric reflux / obstruction

http://youtu.be/j74CvWUTtGI http://youtu.be/4sT0BPaZv84 http://youtu.be/TcfuHMNqqPA http://youtu.be/oxoFVXGy0Jk http://youtu.be/qD_QXmCu7Pk http://youtu.be/RSXgvWlAiGQ http://youtu.be/VC6rur0JKBM http://youtu.be/Gc2jP4TT9ag http://youtu.be/N89BGCH4uVA http://youtu.be/ZTF5qOBq--8\

Subtypes 1. Unilateral MCKD 2. Unilateral MCKD in 3. Unilateral MCDK Pelvic-ureteric junction obstruction (PUJ) a small atrophic presenting with kidney simple peripheral http://youtu.be/VNAktIZS0pM st 1 Trimester cysts http://youtu.be/EQg2heIa7g ARPKD http://youtu.be/56x9LmRJVM0 http://youtu.be/4y7OjAq84a0 Case 1 http://youtu.be/I-zLC9nWdD8 Case 1 (third trimester) http://youtu.be/rOxYjO6tu0o nd http://youtu.be/5bLKkZJn8HY Case 1 Meckel Gruber Syndrome 2 Trimester http://youtu.be/NKuoqekmvvg http://youtu.be/gEteOD-8mzI Case 1 Case 2 (second trimester) http://youtu.be/ioUX4zQyL5U Case 2 http://youtu.be/Kz2nTj02hy4 http://youtu.be/VihL-6Z5kXI http://youtu.be/zXd48KpJ9oY http://youtu.be/JJgsOz_hTgE http://youtu.be/3Nco-BASv1Y http://youtu.be/fbVHTNYctf0 http://youtu.be/V8ArP8sGvaA Case 2 http://youtu.be/ytNIeeHXOL0 http://youtu.be/Vae5cb2JP6M http://youtu.be/6d51hTe3k_Y http://youtu.be/5keyegsYj_s http://youtu.be/YA81I1TaYao 2 weeks later: http://youtu.be/jyXabNkN7j0 http://youtu.be/CSY2PH2S6wg rd http://youtu.be/tKGz5bkX6Pc MCKD in superior pole http://youtu.be/VOtqpBc_zQ4 3 Trimester http://youtu.be/Ru9Flisd3iA 4 weeks later: http://youtu.be/5Ui-w8ZIoow http://youtu.be/lWwTHrwPKbI http://youtu.be/aO_NbALLiYs http://youtu.be/s0TbTLOClVk 4. Unilateral MCKD in 5. Unilateral pelvic 6. Unilateral MCKD Case 2 http://youtu.be/L0twMtDa4FM one moeity of a ectopic kidney with reniform shape http://youtu.be/F_KeD27DUY4 duplex system MCKD maintained Posterior urethral valves http://youtu.be/katC_ww7j8Y

Trisomy 18 1st trimester http://youtu.be/HnzKlyWmNII http://youtu.be/-dSDKow2JEM http://youtu.be/GIG4zEWHn7M http://youtu.be/mCDMQSM7yWo http://youtu.be/Ia8vY8tSwTU http://youtu.be/uAW9FRMHUus Trisomy 13 http://youtu.be/RgHDugGR-BY http://youtu.be/qumUDlFdawc http://youtu.be/__wBduHKQck http://youtu.be/UTy8rg0O51M http://youtu.be/5iVsuObnXqQ 7. Unilateral MCKD 8. Unilateral MCKD 9. Bilateral MCKD http://youtu.be/29xUFITZcGo with an abnormal with contralateral contralateral kidney renal aplasia) Bardet-Beidl Syndrome http://youtu.be/DOJ8df_tyvY Urethral agenesis http://youtu.be/YDXm59DVe34 http://youtu.be/nIH_qybQQ_A

1st trimester http://youtu.be/N3gVmSE6JhI http://youtu.be/7WQEpD81YcM 2 weeks later http://youtu.be/PVHAB6OyfoA 2nd trimester http://youtu.be/j7GKPnX91GE http://youtu.be/r8oLEZOiBO8 http://youtu.be/NosvgLPuBDA http://youtu.be/U4RVvdm5NrA 10. Horseshoe MCKD 11. Bilateral MCKD: http://youtu.be/OzVQYjkEJTw Unusual presentation

http://youtu.be/uzOMiIcY3pQ http://youtu.be/94bUyDRy1Nc http://youtu.be/TL5vVyfu0lk http://youtu.be/NRNHsp5thc0

Autosomal recessive polycystic kidney Multicystic kidney disease (MCKD): Potter II Autosomal dominant polycystic Hydronephrosis: Potter IV Hyperechoic kidneys + Genetic Syndromes/ Unexplained disease (ARPKD): Potter I kidney disease (ADPKD): Potter III aneuploidies Hyperechoic kidneys

Incidence 1:20 000-40 000 Unilateral 1: 3 000-5 000, Bilateral: 1: 10 000 1: 800-1 000 Most common uropathy 1: 100 Sporadic/genetic-linked/family-linked/age-linked 10-21% hyperechoic kidneys Associated  Potter sequence develops after 20 weeks  In 30–50% the other kidney is dysplastic or affected by  Not associated with aneuploidies  Aneuploidies: 0,4-1,6% (50% being T21) Extra-renal: None anomalies (oligohydramnios and pulmonary hypoplasia) vesico-ureteric reflux  Polycystic disease of liver, spleen and  Syndromes: 5-10% (VACTERL, Cerebro-digital syndrome,  Cardiac  Liver cysts, hepatic fibrosis, portal  Unilateral: 26% extra-renal anomalies pancreas rarely seen in the fetus but tuberous sclerosis)  Neurological hypertension and biliary duct hypoplasia  Bilateral: 67% extra-renal anomalies common in adults  Facial (clefts, cataracts, macroglossia)  Extra-renal anomalies: cardiac (majority), GIT, CNS, spine,  Spinal and limb single umbilical artery, genital anomalies.  Diaphragmatic hernia  Syndromes: VACTERL, Cerebrodigital, Brachio-oto-renal,  GIT: exomphalos Meckel–Gruber, Bardet–Biedl, Fraser, CHARGE  Genital and urinary tract anomalies Genetic  Autosomal recessive  90% non-genetic- linked  Autosomal dominant (90%)  Usually not genetic linked Syndromes  Normal Karyotype associations/  Significant genetic heterogeneity  10% autosomal dominant  10%: no family history of ADPKD (genetic  Meckel Gruber: cleft lip/palate, encephalocele, polydactyly  Not associated with Aetiology  Single gene disorder: 80% mutation in PKHD1 mutation) Obstructive: and microphthalmia, heart defects and ambiguous syndromes Gene on chr 6P21  Monogenic causes: mutations in individual genes, such as  PKD1 mutations (85%): gene on  Ureteropelvic junction obstruction (UPJ) 10-30% genitalia, Autosomal recessive 17q21-q24 or 11q13.  Aetiology nonspecific  Can be associated with other single gene TCF2, PAX2 and uroplakins chromosome 16p13  Ureterovesical obstruction (UVJ)/megaureter 5-10%  Beckwidth-Weidermann: overgrowth syndrome, anomalies and aneuploidies  Heterozygote mutations in several genes  PKD2 mutations (15%): gene on  Posterior urethral valves (PUV): only males 1-2% exomphalos, Autosomal dominant 11p15.5 •4 types: prenatal, neonatal, infantile and chromosome 4q21-q23  Urethral agenesis (rare)  Simpson-Golabi-Behmel: overgrowth syndrome juvenile Risk of chromosomal anomalies  Can be a component of tuberous  Ectopic ureter, ureterocoele (5-7%) X-linked /mutations in GPC3  Unilateral dysplasia: 2-4% sclerosis: gene TSC2 on chromosome 16  Bardet Biedl: genital anomalies and polydactyly  Bilateral dysplasia: 15-18% Non obstructive Autosomal recessive 2q, 3p,11q,15q and 16q (Trisomy 13 and 18) or inherited conditions (3-10%)  Vesicoureteral reflux (VUR) 10-12%  Pearlman: Diaphragmatic hernia, macrosomia, cleft palate,  Nonrefluxing nonobstructive megaureter dextrocardia, cryptorchidism, Autosomal recessive Risk of non-chromosomal syndromes  Prune belly syndrome (rare)  Zellweger: hepatomegaly, hypotonia, cataracts • 5-10% Autosomal recessive, multiple genes Physiological:  Elejalde- nasal hypoplasia, craniosynostosis, exomphalos,  Physiological transient dilation of collecting system (41- short limbs, hydrops 88%): resolves in pregnancy  Di George: cardiac anomalies, clefts, absent thymus, 22q deletion  VACTERL: vertebral anomalies, anal stenosis or atresia, tracheo-esophageal fistula, radial, renal, cardiac and non- radial limb defects. Sporadic Aneuploidies  Trisomy 8,9,13,18 and 21, 45X, Triploidy Antenatal  Genetics referral  Morphological fetal assessment for other anomalies and  Genetic consultation  Degree of hydronephrosis is significant: AP diameter  Genetic counselling  Genetic analysis may be  Invasive testing should be offered syndromes  Can offer gene sequencing and >4mm in 2nd and 7mm in 3rd trimester. Postnatal risks  Offer karyotype with microarray indicated management nd rd  Ideally microarray and specifically request  Invasive testing is offered if bilateral renal involvement or identification of mutations with greater if >6mm in 2 and >10 in 3 trimester  TOP may be indicated  Serial ultrasounds to assess PKHD1 gene on chromosome 6P21 (80% cases) if associated non-renal abnormality microarray (DR 50 to 75% for PKD1 and  Isolated mild pyelectasis doesn’t incr risk of aneuploidy  Serial ultrasounds to assess liquor volume liquor and kidneys  Parenteral karyotyping may be indicated  Serial US to check liquor volume and contralateral kidney 75 % for APKD2)  Offer karyotype if other anomalies  Often transient  Discuss prognosis and option for termination  Renal and paediatric consultation  If no family history, tuberous sclerosis  Oligohydramnios in 2nd T: poor prognosis, can offer TOP pregnancy in early onset disease  Refer parents and siblings for renal ultrasound should be excluded  Serial US: monitor bladder distension and AFI  Serial ultrasounds to assess liquor volume  Serial ultrasounds to assess liquor  Can assess fetal urinary component in specialized  Renal and paediatric consultation volume centers to determine which fetuses may benefit from  Renal and paediatric input intervention: healthy fetus-hypotonic urine, progressive renal damage –isotonic urine  Refer parents and siblings for renal  Fetal intervention (vesicoamniotic shunting and fetal ultrasound cystoscopic ablation of PUV) improves lung function but not of renal benefit.  Renal and paediatric input Outcomes Prenatal: Unilateral  Recurrent urinary infections  Morbidity and mortality directly linked to cause  Dependent on associated condition  No postnatal  Can develop renal failure in utero  Usually managed conservatively  Gross hematuria (40% adults)  Unilateral: survival 100%, may require surgery later in abnormalities  40–50% develop hepatic fibrosis.  May undergo spontaneous regression and atrophy  Cystic hepatic and liver disease: life  Excellent outcome Postnatal:  Nephrectomy of affected kidney: last resort if recurrent relatively common in adults.  Bilateral with oligohydramnios: worst outcome,  Possible small risk of  30% die in neonatal period infections, haematuria or severe HPT.  50% will progress to ESRD needing develop pulmonary hypoplasia and compression ADPKD in adulthood  55-100% develop hypertension by 15 years of  Involution of cysts occurs in 25% of cases in 1st 2 years. dialysis and renal transplant deformities of skeletal system age Antenatal involution of cysts rarely occurs. ADPKD1: Hypertension in 1st year of life  Oligohydramnios in the 2nd trimester usually fatal  20-45% have end stage renal disease by 15  Often recurrent UTI- need antibiotic prophylaxis ADPPKD2: Asymptomatic until later in life years of age  Must have postnatal follow up of the contralateral kidney Develop hypertension, renal  11-45% develop portal hypertension Bilateral failure, hemangiomas and  May need dialysis and renal transplantation  Most develop chronic renal failure: dialysis and renal aneurisms transplantation Reoccurrence risk 25% Small (2-3%) unless associated with genetic syndrome 50% if one parent is affected Very small Dependent on associated condition Unknown