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Disclosure of Relevant Hereditary Tubulointerstitial Kidney Financial Relationships Diseases USCAP requires that all planners (Education Committee) in a position to Stephen M. Bonsib, MD influence or control the content of CME disclose any relevant financial relationship WITH COMMERCIAL INTERESTS which they or their Arkana Laboratories spouse/partner have, or have had, within the past 12 months, which relates to Little Rock, Arkansas the content of this educational activity and creates a conflict of interest.

King Glom - all glamor but little work Tubulointerstitial diseases can be visually esthetic Tubules, the peasantry - all work but little glamor

Primary chronic tubulointerstitial diseases Primary tubulointerstitial disease Limited spectrum of injury despite numerous etiologies Etiologies - Obstruction/chronic infection - Autoimmune - Nephrotoxic - Light chain / paraprotein-related disease - Hereditary tubulointerstitial disease

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Hereditary primary tubulointerstitial diseases Primary chronic tubulointerstitial disease – Hereditary chronic tubulointerstitial nephritis Working definition: – “Disproportionate” tubulointerstitial injury – Medullary cystic /autosomal dominant tubulointerstitial compared to glomerular injury disease – Hereditary crystalline nephropathies – Cystinosis Late stage glomerulosclerosis may catch up – Primary hyperoxaluria – 2,8 dihydroadeninuria – Hereditary tubular transport nephropathies – Dent’s disease – Lowe’s oculo-cerebral-renal syndrome – Bartter’s syndrome – Miscellaneous other hereditary tubulointerstitial kidney diseases – Systemic karyomegaly – Methylmalonic aciduria – Mitochondrial cytopathies

Nephronophthisis / medullary NPHP / MCKD Smith & Graham, Congenital medullary cysts of the kidney Strategy Am J Dis Child 369, 1945 – Evolution of terminology Title captured its major gross finding – Pathogenesis – Clinical features 9 year-old girl – Pathologic features Autopsy findings and clinical course – Gross – Microscopic “Rare congenital lesion…with intractable anemia…severe azotemia …despite minimal urinary findings”

NPHP / MCKD NPHP / MCKD Fanconi VG, et al. Die familiäre juvenile nephronophthisis Helvet Paediat Acta 6:1, 1951 Goldman et al. Hereditary occurrence of cystic disease of the renal medulla Coined the term “familial juvenile nephronophthisis” N Engl J Med 274:716, 1966 – Greek for disintegration of nephrons Autopsy reports on 6 / renal biopsy on 2 – “phthisis” (ti’sis) - to decay – Captured its major histologic features Drew attention to autosomal dominance of some cases Traced 60 family members through 5 generations 2 families - multiple children developed renal failure by age 6 14 died of renal disease – average 25 yrs. old – Polyuria, polydipsia and nocturia – Hypertension and significant proteinuria absent

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NPHP / MCKD NPHP / MCKD

th Chamberlin, et al. Juvenile nephronophthisis and Most of the 20 century medullary cystic kidney disease Diseases usually referenced as… Mayo Clinic Proc 52:485, 1977 “Medullary cystic disease/(familial) juvenile nephronophthisis complex Late 20th century Literature review Awareness of genetic heterogeneity led to separation 7 cases NPHP & 33 cases MCKD – Nephronophthisis (NPHP) - autosomal recessive – Medullary cystic kidney disease - autosomal dominant Argued for their separation into NPHP - AR childhood onset Medullary cystic kidney disease - recognized 2 clinical phenotypes MCKD - AD adult onset – MCKD type 1 / familial juvenile hyperuricemic nephropathy – MCKD type 2

NPHP / MCKD Autosomal recessive chronic tubulointerstitial diseases Early 21st century – pathogenesis defined AR Nephronophthisis - recognized as a ciliopathy in 2003 – Nephronophthisis – Cystinosis AD MCKD - 4 mutations identified – Primary hyperoxaluria – Uromodulin – 2,8 dihydroadeninuria –Mucin-1 – Bartter syndrome – Renin – Systemic karyomegaly – HNF-1β – Methylmalonic acidemia – Other(s) remain to be identified – Mitochrondrial cytopathies

Ekici AB, et al. in 2014 - proposed renaming MCKD Autosomal dominant tubulointerstitial disease

Hereditary chronic tubulointerstitial diseases are rare Nephronophthisis NPHP - 1.1 per 1,000,000 - US ADTID-UMOD - 1 per 700,000-1,000,000 – Most common genetic cause for ESKD in the first 3 decades of life - 1 per 50,000 - Canada ADTID-MUC1 - 100 families reported in US – 10-25% of children with chronic renal failure by 2015 – Syndromic NPHP (extra-renal disease) in 10-20% ARPKD - 1 per 20-50,000 ADTID-REN - 14 families reported by 2005 – Presentation VHL - 1 per 35,000 ADTID-HNF1β – Concentration defect with polydipsia, polyuria and enuresis TSC 1 per 7,000 Most common cause of MODY – Severe anemia ADPKD - 1 per 500-1,000 10-30% of Congenital anomalies of the kidney – Little proteinuria or hematuria and urinary tract in children and adults – Lack of hypertension due to salt wasting Chronic tubulointerstitial nephritis - very rare – Later develop – Growth retardation – Renal osteodystrophy – Progressive renal failure by age 30

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NPHP - 20 nephrocystin mutations identified NPHP - 3 clinical phenotypes - Account for only 30-40% of cases

Most common mutations Phenotype Age onset Kidney size Cyst location Glom. cyst TBM Cortical Gene Locus % of NPHP changes inflammation Infantile < 4yrs (can Normal to Cortex and Present Absent Mild NPHP1 NPHP1 20-25% (least common) be antenatal) enlarged medulla NPHP4 NPHP4 3-4% Juvenile 13 years Small to Cortico- Absent Present Prominent (most common) normal medullary CEP290 NPHP6 2-3% Adolescent 19 years Small to Cortical Absent Present Prominent IQCB1 NPHP5 2-3% normal medullary TMEM67 NPHP11 2-3% INVS NPHP2 1-2% NPHP3 NPHP3 1-2%

Nephronophthisis Syndromic NPHP - 10-20% NPHP patients

NPHP is a ciliopathy Disorder Cerebellar Intellectual Skeletal Eye Hepatic Situs Polydactyly – Nephrocystins interact with each disorder dysplasia fibrosis inversus other in at least 3 modules Joubert synd. ++ +++ + – Module mutations associated with Bardet-Beidl synd. ++ +++ + sites of extra-renal involvement Jeune synd. ++++ + Wolf M. Nephronophthisis and Meckel-Gruber synd. ++++ related syndromes Senior-Loken ++ + Curr Opin Pediatr 27: 201, 2015 Leber congenital ++ amaurosis COACH synd. ++ ++ Cogan oculomotor ++ + apraxia

NPHP - a CTIN that may form cysts NPHP - pathology Dorland definition of a cyst: Ivemark BI, et al. - Any closed cavity or sac (diverticulum) lined by Juvenile nephronophthisis epithelium Acta pediatrica 49:480, 1960

Reported incidence of cysts is affected by: 2 autopsy cases - 12 yrs. old - Application of the term cyst – Kidney wts: 40 gms. / 60 gms. Tubular ectasia called cysts (Brouhard et al 1977) – Microcysts in cortex Microcysts - visible in tissue sections – Macrocysts in medulla Macrocysts - visible on imaging or grossly visible – Medullary ray radial tubular - Imaging modalities and sensitivities ectasia - Clinical duration – cysts increase over time – Medullary cysts Loop of Henle flexture - NPHP 50-70% have cysts at autopsy Collecting duct

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NHPH - microdissection NPHP - LM, IF and EM Sherman, et al. Renal lesions of familial juvenile Zollinger et al. Nephronophthisis nephronophthisis examined by microdissection (medullary cystic disease of the kidney) Am J Clin Pathol 55:391, 1971 Helv Paediat Acta 35:309, 1980 3 autopsies 9 NPHP pts - 3 autopsies and 6 biopsies Early microcystic changes Reviewed 95 well-document cases - Diverticuli descending limbs of Henle 68 autopsies and 27 biopsies - Tubular “microcysts” - distal tubules and 68 autopsies collecting ducts – Cortical cysts 16/68 cases – 18% – Medullary cysts 44/68 cases – 65%

Nephronophthisis - ESK but no cysts Nephronophthisis - medullary cysts

Syndromic NPHP - renal-retinal dysplasia Medullary cysts - differential diagnosis – Nephronophthisis – Autosomal dominant tubulointerstitial disease

– Autosomal dominant polycystic kidney disease, early onset – Autosomal recessive polycystic kidney disease, childhood form – Acquired cystic kidney disease –

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Autosomal dominant polycystic kidney disease, early onset Acquired cystic kidney disease

Acquired cystic kidney disease Autosomal recessive polycystic kidney disease

ARPKD - childhood onset Medullary sponge kidney

– Developmental disease with bilateral collecting duct cysts – Usually sporadic, rarely autosomal dominant – Isolated to syndromic disease

– Hypercaluria, concentration and acidification defects, hematuria – Moderate risk of CKD – Nephrocalcinosis and nephrolithiasis

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Medullary sponge kidney NPHP - chronic inflammation and Nephrocalcinosis and fibrosis with glomerular sparing Nephrolithiasis

NPHP - TBM replication and Periglomerular fibrosis and TBM periglomerular fibrosis splitting - nonspecific findings Examples: Arterial nephrosclerosis Chronic allograft nephropathy Diabetic glomerulopathy

Infantile NPHP with congenital hepatic fibrosis NPHP clinical phenotype - 7-year old NPHP2 / occasionally NPHP3 mutations Polyuria/polydipsia, CRF, no proteinuria or hematuria

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NPHP - 7-year old NPHP -16-year old Polyuria/polydipsia, Cr 4.9, 9 of 28 GS, 80% IF, US cysts

NPHP - 25-year old Diagnosis of a NPHP – NPHP phenotype – Polyuria and polydipsia – glass of water at bed – Growth retardation – Chronic anemia unresponsive to therapy – Unexplained chronic renal failure – Not resulting from congenital structural disease of kidneys or LUT – Without signs of glomerular disease – Renal ultrasound – small to normal, +/- cysts – Family history - consistent with autosomal recessive inheritance (affected sib)

– Renal biopsy is not required / often not performed! – Genetic testing recommended

Autosomal dominant tubulointerstitial disease KDIGO Classification KDIGO classification [Kidney Int 88:676, 2015]

Terminology Gene Previous terminologies Recommended terminology Terminology for this talk ADTKD-UMOD UMOD Medullary cystic kidney disease Type 2 –ADTID -UMOD – Uromodulin kidney disease Uromodulin kidney disease –ADTID -MUC1 – Mucin-1 kidney disease Familial hyperuricemic nephropathy type 1 Uromodulin storage disease –ADTID -REN – Renin kidney disease ADTKD-MUC1 MUC1 Medullary cystic kidney disease type 1 –ADTID -HNF1β – HNFB-1β kidney disease Mucin-1 kidney disease

ADTKD-REN REN Familial hyperuricemic nephropathy type 2

ADTKD-HNF1β HNF1β Maturity-onset diabetes of the young type 5 Renal cyst and diabetes syndrome

ADTKD-NOS ??

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Uromodulin kidney disease ADTINs differ in pathogenesis Uromodulin / Tamm-Horsfall glycoprotein – Uromodulin kidney disease – TALH - protein-folding disorder, impairs Thick ascending limb of Henle intracellular trafficking, retention in ER Presentation – Mucin-1 kidney disease – DT/CD - truncated protein lacks – Broad range of onset 20-70 years transmembrane and intracellular domain – Hyperuricemia in childhood – Renin kidney disease – JGA - heterozygous mutation leads to – Early onset gout in teenagers decreased renin production – Slowly progressive renal failure – HNFB-1β kidney disease – Transcription factor primarily expressed in – ESRD 20-70 years, average 54 years kidney, pancreas and liver essential for Pathology embryogenesis - Chronic tubulointerstitial nephritis - Glomerular cystic kidney disease

Uromodulin kidney disease Uromodulin kidney disease

Moskowitz JL, et al Bollee G, et al. Clin J Am Nephrol 8:137-1357, 2013 Clin J Am Soc Nephrol 6:2439, 2011

202 patients / 74 families 109 patients from 45 families – Hyperuricemia 91% 37% renal cysts – Gout 48% – 59 different UROM mutations – ESRD earlier in males – Onset ESRD affected by mutation

Mucin-1 kidney disease Mucin-1 kidney disease

Mucin-1 - epithelial membrane antigen Bleyer, AJ, et al. CJASN 9:527-535, 2014 Distal tubules and collecting ducts Mutated protein accelerates tubular cell apoptosis 206 patients / 24 families – 95 of 186 tested had MUC1 mutations – Progressive renal failure in adulthood – Broad range of ESRD -16 to 81 years – Decline is rapid once GFR < 50cc – Gout 24%! – Concentrating defect – No proteinuria / hematuria

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Mucin-1 kidney disease Renin kidney disease Ekici et al. Kidney Int 86:589,2014 - Heterozygous mutation of REN - decreased renin production in JGA MRI renal cysts - Chronic tubulointerstitial nephritis Homozygous or compound heterozygous mutation of REN Renal cysts - Renal tubular dysgenesis - 1 cyst in13% Clinical features CTIN - 2 or more cysts in 12 - Hypoproliferative anemia - low reticulocyte count relative to low hemoglobin - Medullary cysts - 0% and elevated erythropoietin - May affect children as early as 1 year Renal biopsies in 34 patients - Some have polyuria and enuresis (pathology not shown) - Hyperuricemia in childhood and gout as adults - 34 CTIN - Some patients have low blood pressure or elevated potassium - 4 of 34 microcysts - Slowly progressive renal failure - ESRD in 4-6th decade

HNF-1β kidney disease HNF-1β kidney disease HNF1β transcription factor: organogenesis of kidney, urinary tract, liver, pancreas Faquer, et al. Diagnosis, management and prognosis of HNF1B nephropathy Three clinical presentations in adulthood, Kidney Int 80:768, 2011 1. Maturity-onset diabetes mellitus of the young (MODY) - HNF1β most common cause 27 adults from 20 families - Pancreatic hypoplasia or agenesis - Hypokalemia 11/24 / Hypomagnesemia 10/16 2. Congenital anomalies of kidney and urinary tract (CAKUT) - Fanconi syndrome 2/27 - 10-30% of cases in children and adults - Abnormal liver functions 8/21 3. Slowly progressive renal failure in adults due to CTIN Diabetes 13/27 including 11 with MODY - Average onset 24 years Cysts 15/24 - Concentrating defect Solitary kidney 5/24 - Low magnesium Genital abnormalities in 5/13 females and infertility in 2/14 males

ADTIN - features the 4 types have in common ADTID, of some type – Autosomal dominant – Many family members affected over multiple generations Adult with “MCKD” – Age of onset/rate of progression varies between and within families – Unexplained Bilateral nephrectomy for massive – Concentrating defect – polyuria, polydipsia, nocturia, enuresis in children urinary tract hemorrhage – Hyperurecimia or gout – Little or no proteinuria or hematuria – Cysts commonly present but usually late in disease and not always medullary – Biopsy not recommended! – Genetic testing recommended

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Uromodulin kidney disease Uromodulin kidney disease Nasr, et al. Kidney Int 72:971,2008 Rampoldi L, et al. Hum Mol Genetics 12:3369, 2003 3 families with “AD-MCKD”

Chronic tubulointerstitial nephritis Uromodulin aggregates retained within TALH endoplasmic reticulum

Uromodulin kidney disease Uromodulin kidney disease 18 year-old female – Creatinine 1.8/ no protein or blood – Uric acid 11.1 mg/dl, history of gout – US - bilateral small cysts – Father - ESRD

Mucin-1 kidney disease Renin kidney disease Chronic tubulointerstitial nephritis Biopsy findings: JGA normal appearing Chronic tubulointerstitial nephritis No renal cysts Microcysts in 12% Images - Lynn Cornell / Colvin’s Text Images: Helen Liapis / from Colvin’s Text

Ekici et al Kidney Int 86:589, 2014

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Renin - homozygous or compound Renin kidney disease heterozygous mutation Zivna et al. Renal tubular dysgenesis Am J Hum Genet 85: 204, 2009 - Failure of proximal tubule differentiation - Antenatal or neonatal death Chronic TIN Renin and prorenin markedly Renal tubular dysgenesis 1. Homozygous or compound heterozygous decreased to absent in JGA mutation of renin or other angiotensin system genes 2. Complications of maternal drug use – Angiotensin converting enzyme inhibitors – Angiotensin type II receptor antagonist – Non steroidal anti-inflammatory drugs 3. Twin-twin transfusion syndrome

HNF-1β kidney disease HNF1β Kidney disease Pathology – 2 broad categories CAKUT – major malformations Cysts and cystic kidney disease - 60-80% Chronic tubulointerstitial nephritis - ? Renal dysplasia Renal hypoplasia No genotype-clinical phenotype correlations Renal fusion, ectopia and duplication Ureteral-pelvic junction and uretero-vesical junction obstruction Ureteral duplication and ectopia, and ureterocele Bladder extrophy, persistent cloaca, rectal-vesicle fistula Urethral atresia and posterior urethral valve

HNF-1β Kidney disease Glomerular cystic kidney disease CTIN - the least common renal manifestation Classification of GCK Sporadic glomerulocystic kidney disease Heidet L, et al. Spectrum of HNF1B mutations Hereditary glomerulocystic kidney diseases Clin J Am Soc Nephrol 5:1079,2010 – Autosomal dominant GCKD due to UROM mutation 75 heterozygous HNF1B mutations – Familial hypoplastic GCKD due to - 12 of 75 had hyperuricemia or gout! HNF1B mutation – Hereditary GCKD, nos Glomerular cysts associated with hereditary syndromes: Syndromic and non-syndromic renal dysplasia

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ADTID kidney disease, nos Diagnosis of ADTIN 28 year-old white male – Cr. 2.2, concentrating defect ADTID phenotype – US normal size kidneys / no cysts – Autosomal dominant family history of CKD - multiple generations affected – Father – carries a dx of MCKD – Concentrating defect, anemia and elevated uric acid (UROM and REN) – Grandfather - ERSD unknown cause – Unexplained CKD with little or no proteinuria/hematuria Exclude: – Drugs, nephrotoxins – Lower urinary tract obstruction +/or infection Cysts absent or infrequent early on Genetic testing strategy (from GeneReview) – UROM if gout is a significant portion of the disease – REN if anemia, hyperkalemia or low blood pressure are an issue – MUC1 if gout, anemia and hyperkalemia are absent – HNF1β if low magnesium, cysts or diabetes are present

ADTIN - obstacles to the diagnosis NPHP and ADTIDs - conclusions Autosomal dominant family history absent A group of rare (possibly underdiagnosed) disorders with overlapping – De novo mutation clinical and morphologic features – Early death of affected parent – Late onset of disease in affected parent Vary in inheritance - AR, AD – Alternative paternity or maternity of affected parent Differ in pathogenesis NPHP – ciliopathy Lack of clinical or morphologic phenotype do to a 2nd disease process ADTID - mutation of one of several proteins involved in diverse functional – Diabetes/metabolic syndrome +/- hyperuricemia or gout and/or developmental activities – Smoking – Hypertension – NSAIDS, other ingestions

NPHP and ADTIDs - conclusions Hereditary CTIDs - NPHP and ADTIDs A diagnostic black hole hopefully slightly less deep? Most form cysts but these appear late Renal biopsy shows Non-specific CTIN in most cases Objective findings: UROM deposits, ↓Renin in JGA

Renal biopsy is not recommended, or rarely performed, which deprives us of… Opportunity to acquire diagnostic experience Learn the nuances of their earliest stages Make phenotypic-genotypic correlations as new mutations are identified

Genetic testing is recommended Mutation responsible in many cases yet to be identified UROM, REN and MUCI1 Registries – [email protected]

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NPHP ADTIN Incidence common rare Family history Single generation (sibs) Multiple generations Thank you. Average age onset 6 years > 3rd decade Average ESRD 13 years > 5th decade Cysts -/ + (late finding) -/ + (late finding except for HNB1β) Syndromic 10-20% Pancreatic hypoplasia/agenesis (REN) CAKUT (HNB1β), GCKD (UROM, HNB1β) Laboratory abnormality Hypercalcuria Hyperuricemia (UROM and REN) Anemia Anemia (REN) Clinical features Polyuria/polydipsia Polyuria/polydipsia Enuresis Hypotension (REN) Clinical course Progressive CKD Progressive CKD Glomerular findings None to minimal None to minimal

NPHP and ADTID - comparison of major clinical and pathology features Mutation Onset/ESRD Labs/ Extra-renal Biopsy Cysts Other pathology 14 male Cr. 7 clinical disease (late) findings NPHP < 20y / < 30y Conc. defect, 20% syndromic CTIN 50-70% severe anemia Bone disease Growth retard.

ADTID

UROM 20-70y / 54y Gout, conc. defect None CTIN 40% UROM inclusions GCKD MUC1 Variable 20- Conc. defect, gout None CTIN 12-17% None 70y / 45y REN Childhood / Gout, conc. defect, None CTIN None ↓ Renin JGA 30-40y ↓BP, anemia, ↑K+ Renal tub dysgenesis HNF1B 24y / adult Conc. defect, gout Pancreatic CTIN 60-80% 30% of CAKUT DM-1, low Mg hypoplasia/agen. GCKD

14 male - 57 of 65 GS 14 male - multiple UTI, hypertension and >1gm prot.

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NPHP – 19 mutations identified Bleyer, Kmoch - Autosomal dominant tubulointerstitial kidney 30-40% of cases - NPHP1 accounts for 20% of cases disease: of names and genes [Kidney Int 86:459, 2014]

Autosomal dominant tubulointerstitial disease NPHP Differentiating features Cohen A and Hoyer RJ Feature UMOD MUC1 REN HNF1β Nephronophthisis: a primary Clinical Hypertension Risk of AKI in Glom cystic kid childhood dis tubular basement membrane Low-normal BP Renal cysts and defect. diabetes Lab Invest 55: 564, 1986 syndrome Genital abnormalities 4 patients: 10-18 years old Presentati Onset renal ESRD 3-7th Early onset Presents in – TBM thinning and splitting on failure 5-40 decade ESRD 4-6th decade childhood years – Morphologically analogous ESRD 4-7th to decade Laboratory Early Anemia, Anemia Pancreatic hyperuricemia hyperuricemia, Hyperuricemia insufficiency and gout especially in males

Importance of the correct diagnosis of NPHP and ADTID Hereditary tubulointerstitial nephritis 1962 - MB Strauss – Identify potential kidney donors 18 cases (prior to that only 7 cases reported) – Avoid need for biopsy in other family members – Age 8-56 year – Provide prognostic and family consoling information – Hg 4-11.5 gm – Allow family members to participate in, or support, research for their rare – Specific gravity < 1.099 condition – Average serum calcium 7.2 mg/dl – Some have treatment options, REN kidney disease – “Renal rickets” in young patients – Family history of renal disease present in 2 of 18 patients (Likely includes both nephronophthisis and medullary cystic kidney disease)

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Infantile nephronophthisis Mixed epithelial and stromal tumor family NPHP2 / occasionally NPHP3 mutations – 10 patients Bodaghi, et al. Infantile nephronophthisis. – ESRD by 22 months Int J Ped Nephol 8:207, 1987 – 10 renal bxs, 4 autopsy kidneys – 6/10 Congenital hepatic fibrosis Gagnadoux, et al. Infantile chronic- interstitial nephritis with cortical microcysts: a variant of nephronophthisis or a new entity? Pediatr Nephrol 3:50, 1989

ADPKD in children may differ form adults Medullary dysplasia Prune belly syndrome

Fetus - elective termination Family history of NPHP

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