Arkana Laboratories

Little Rock, Arkansas

Hereditary Tubulointerstitial Kidney Diseases

Stephen M. Bonsib, MD

Hereditary tubulointerstitial diseases – Hereditary chronic tubulointerstitial nephritis –Nephronophthisis –Medullary cystic kidney disease/autosomal dominant tubulointerstitial

disease – Hereditary crystalline nephropathies –Cystinosis –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 cystic kidney disease Strategy – Evolution of terminology – Pathogenesis – Clinical features – Pathologic features

–Gross –Microscopic

NPHP / MCKD Most of the 20th century Diseases were usually referenced as… “Medullary cystic disease/(familial) juvenile nephronophthisis complex Late 20th century Awareness of genetic heterogeneity led to separation into 2 clinical entities

–Nephronophthisis (NPHP) - autosomal recessive –Medullary cystic kidney disease - autosomal dominant

Medullary cystic kidney disease - recognized 2 clinical phenotypes

–MCKD type 1 / familial juvenile hyperuricemic nephropathy –MCKD type 2

NPHP / MCKD (ADTIN) Early 21st century – pathogenesis defined AR Nephronophthisis - recognized as a ciliopathy in 2003

AD MCKD - 4 mutations identified

–Uromodulin –Mucin-1 –Renin –HNF-1β –Other(s) remain to be identified Ekici AB, et al. in 2014 - proposed renaming MCKD autosomal dominant tubulointerstitial disease

Other autosomal recessive chronic tubulointerstitial diseases – Cystinosis – Primary hyperoxaluria – 2,8 dihydroadeninuria – Bartter syndrome – Systemic karyomegaly – Methylmalonic acidemia – Mitochrondrial cytopathies

Nephronophthisis – Most common genetic cause for ESKD in the first 3 decades of life

–10-25% of children with chronic renal failure – Syndromic (extra-renal disease) in 10-20% – Presentation

–Concentration defect with polydipsia, polyuria and enuresis –Severe anemia –Little proteinuria or hematuria –Lack of hypertension due to salt wasting

– Later develop –Growth retardation –Progressive renal failure by age 30 –Renal osteodystrophy

NPHP - 3 clinical phenotypes

Phenotype Age onset Kidney size Cyst location Glom. cyst TBM changes

Cortical inflam.

Infantile < 4yrs (can be antenatal)

Normal to enlarged

Cortex and medulla

Present Absent Mild

Juvenile (most common)

13 years Small to normal

Cortico-medullary

Absent Present Prominent

Adolescent 19 years Small to normal

Cortical medullary

Absent Present Prominent

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

Most common mutations

Gene Locus % of NPHP NPHP1 NPHP1 20-25% NPHP4 NPHP4 3-4% CEP290 NPHP6 2-3% IQCB1 NPHP5 2-3% TMEM67 NPHP11 2-3% INVS NPHP2 1-2% NPHP3 NPHP3 1-2%

Total = 31-42%

Syndromic NPHP - 10-20% NPHP patients Disorder Cerebellar Intellectual

disorder Skeletal dysplasia

Eye Hepatic fibrosis

Situs inversus

Polydactyly

Joubert synd. + + + + + + Bardet-Beidl synd. + + + + + + Jeune synd. + + + + + Meckel-Gruber synd. + + + + Senior-Loken + + + Leber congenital amaurosis

+ +

COACH synd. + + + + Cogan oculomotor apraxia

+ + +

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 – Medullary sponge kidney – Renal dysplasia - may occasionally be limited to medulla

NPHP - biopsy features Chronic inflammation may be prominent

NPHP on biopsy - periglomerular fibrosis

NPHP - interstitial fibrosis

NPHP - TBM replication / splitting

TBM splitting - a nonspecific finding TBM splitting in many causes of CKD Examples: Arterial nephrosclerosis Chronic allograph nephropathy Diabetic Glomerulopathy

Infantile nephronophthisis NPHP2 / occasionally NPHP3 mutations

Bodaghi, Honarmand , Ahmadhi Infantile nephronophthisis. Int J Ped Nephol 8:207, 1987 Gagnadoux, Bacri, Broyer, Habib Infantile chronic-interstitial nephritis with cortical microcysts: a variant of nephronophthisis or a new entity? Pediatr Nephrol 3:50, 1989

– 10 patients – ESRD by 22 months – 10 renal bxs, 4 autopsy kidneys – 6/10 Congenital hepatic fibrosis

Diagnosis of a NPHP phenotype – NPHP phenotype

–Polyuria and polydipsia – glass of water at bed –Growth retardation –Chronic anemia unresponsive to therapy –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 [Kidney Int 88:676, 2015]

Terminology Gene Previous terminologies

ADTKD-UMOD UMOD Medullary cystic kidney disease Type 2 Uromodulin kidney disease Familial hyperuricemic nephropathy type 1 Uromodulin storage disease

ADTKD-MUC1 MUC1 Medullary cystic kidney disease type 1 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 ??

KDIGO 2014 Consensus Report Kidney Int 88:676-683, 2015

Recommended terminology – ADTID - UMOD – ADTID - MUC1 – ADTID - REN – ADTID - HNF1β

Terminology for this talk – Uromodulin kidney disease – Mucin-1 kidney disease – Renin kidney disease – HNFB-1β kidney disease

ADTIN - differing pathogenesis

– Uromodulin kidney disease

– Mucin-1 kidney disease

– Renin kidney disease

– HNFB-1β kidney disease

– TALG - protein-folding disorder, impairs intracellular trafficking, retention in ER

– DT/CD - truncated protein lacks transmembrane and intracellular domain

– JGA - heterozygous mutation leads to decreased renin production

– Transcription factor primarily expressed in kidney, pancreas and liver essential for embryogenesis

ADTINs are rare diseases

ADTID-UMOD - 1:700,000-1,000,000 ADTID-MUC1 - 100 families reported in US by 2015 ADTID-REN - 14 families reported by 2005 ADTID-HNF1β Most common cause of MODY 10-30% of CAKUT in children and adults CTIN - very rare

ADPKD - 1:500-1,000 TSC - 1:7,000 VHL - 1: 35,000 ARPKD - 1:20-50,000

Uromodulin kidney disease Uromodulin / Tamm-Horsfall glycoprotein Presentation

–Broad range of onset 20-70 years –Hyperuricemia in childhood –Early onset gout in teenagers –Slowly progressive renal failure in

adults –ESRD 20-70 years, average 54 years

Mucin-1 kidney disease Mucin-1/EMA normally expressed in distal tubules and collecting ducts Mutated protein accelerates tubular cell apoptosis – Presents in adults – average 45yr – Progressive renal failure in adulthood

–Decline is rapid once GFR < 50cc – Concentrating defect – No proteinuria, hematuria or gout (due to the

mutation) – No genotype-clinical phenotype

Renin kidney disease Heterozygous mutation of REN leading to decreased renin production in JGA Clinical features

- Hypoproliferative anemia - low retic count relative to low hemoglobin and elevated erythropoietin - May affect children as early as 1 year while asymptomatic - Some have polyuria and enuresis - Hyperuricemia in childhood and gout as adults - Some patients have low blood pressure or elevated potassium - Slowly progressive renal failure in all patients - ESRD in 4-6th decade

HNF-1β kidney disease HNF1β transcription factor: organogenesis of kidney, urinary tract, liver, pancreas Three clinical presentations 1. Insulin-dependent diabetes mellitus of the young

- HNF1β most common cause - Pancreatic hypoplasia or agenesis 2. Congenital anomalies of kidney and urinary tract (CAKUT) in neonates/children 3. Slowly progressive renal failure in adults due to CTIN

- Average onset 24 years - Concentrating defect - Hyperuricemia and early onset gout - Hypoaldosteronism with hypokalemia, decreased plasma renin - Low magnesium

HNF-1β kidney disease Faquer, et al. Diagnosis, management and prognosis of HNF1B nephropathy in adulthood, Kidney Int 80:768, 2011 27 adults from 20 families - Hypokalemia 11/24 - Hypomagnesemia 10/16 - Fanconi syndrome 2/27 - Abnormal liver functions 8/21 - Diabetes 13/27 including 11 with MODY Cysts 15/24 Solitary kidney 5/24 Genital abnormalities in 5/13 females and infertility in 2/14 males

ADTIN - features the 4 types have in common

– Autosomal dominance –Many family members affected –Age of onset/rate of progression varies between and within families

– Progressive chronic kidney disease –Concentrating defect – polyuria, polydipsia, nocturia, enuresis in children –Little or no proteinuria or hematuria

– Cysts commonly present but usually late in disease and not always medullary – Biopsy not recommended! – Genetic testing recommended

NPHP and ADTID - comparison of major clinical and pathology features Mutation Onset/ESRD Labs/

clinical Extra-renal disease

Biopsy Cysts (late)

Other pathology findings

NPHP < 20y / < 30y Conc. defect, severe anemia

20% syndromic Bone disease Growth retard.

CTIN 50-70%

ADTID

UROM 20-70y / 54y Gout, conc. defect None CTIN 40% UROM inclusions GCKD

MUC1 Variable 20-70y / 45y

Conc. defect None CTIN 12-17% None

REN Childhood / 30-40y

Gout, conc. defect, ↓BP, anemia, ↑K+

None CTIN None ↓ Renin JGA Renal tub dysgenesis

HNF1B 24y / adult Conc. defect, gout DM-1, low Mg

Pancreatic hypoplasia/agen.

CTIN 60-80% 30% of CAKUT GCKD

Mucin-1 kidney disease Ultrasound - most have normal to small kidneys Biopsy findings:

Chronic tubulointerstitial nephritis Microcysts in 12%

Uromodulin kidney disease Rampoldi L, et al. Hum Mol Genetics 12:3369, 2003 3 families with “AD-MCKD” 1 family with glomerulocystic kidney disease Uromodulin aggregates retained within TALH endoplasmic reticulum

Renin kidney disease Chronic tubulointerstitial nephritis Periglomerular fibrosis or ischemic changes JGA normal appearing No renal cysts

Renin kidney disease Zivna et al. Am J Hum Genet 85: 204, 2009 Renin and prorenin markedly decreased to absent in JGA

HNF-1β kidney disease Pathology – 2 broad categories Cysts and cystic kidney disease - 60-80% - 10-30% of CAKUT - Glomerulocystic kidney disease Chronic tubulointerstitial nephritis No genotype-clinical phenotype correlations

Diagnosis of ADTIN ADTID phenotype – Concentrating defect, anemia and elevated uric acid in some – Unexplained CKD with little or no proteinuria/hematuria – Exclude:

–Drugs, nephrotoxins –Lower urinary tract obstruction+/or infection

– Cysts frequent (except for REN) but absent or infrequent early on – Genetic testing strategy

–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 - road blocks to the diagnosis Diagnosis challenged by lack of a AD family history – De novo mutation – Early death of affected parent – Late onset of disease in affected parent – Alternative paternity or maternity of affected parent Diagnosis challenged by lack of clinical phenotype – Co-existence of another disease process obscuring an ADTIN phenotype

–Diabetes/metabolic syndrome +/- hyperuricemia or gout –Heavy smoking –Hypertension –NSAIDS, other ingestions

NPHP ADTIN

Incidence common rare

Family history Single generation (sibs) Multiple generations

Average age onset 6 years > 3rd decade

Average ESRD 13 years > 5th decade

Medullary cysts -/ + ( late finding) -/ + ( late finding)

Syndromic 10-20% Pancreatic hypoplasia/agenesis (REN) CAKUT (HNB1B), GCKD (UROM, HNB1B)

Laboratory abnormality Hypercalcuria Anemia

Hyperuricemia (UROM and REN) Anemia (REN)

Clinical features Polyuria/polydipsia Enuresis

Polyuria/polydipsia Hypotension (REN)

Clinical course Progressive CKD Progressive CKD

Glomerular findings None to minimal None to minimal

NPHP and ADTIDs - conclusions A group of disorders with overlapping clinical features Differ in pathogenesis NPHP – ciliopathy ADTID - mutation of one of several proteins involved in diverse functional and/or developmental activities Vary in inheritance - AR, AD Some are common - NPHP Some are rare - ADTIN

NPHP and ADTIDs - conclusions Renal biopsy may show Non-specific CTIN: NPHP, most ADTIN Objective findings: UROM deposits, ↓Renin Most form cysts but these appear late 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 new phenotypic-genotypic correlations Genetic testing recommended Mutation responsible in many cases is yet to be defined

Nephrophthisis 1. Smith & Graham, Congenital medullary cysts of the kidney, Am J Dis Child 369, 1945 2.Fanconi, “Die familiäre juvenile nephronophthisis”, Helvet Paediat Acta 6:1, 1951 3. Ivemark BI, et al. juvenile nephronophthisis, Acta pediatrica 49:480, 1960 4. Goldman et al, Hereditary occurrence of cystic disease of the renal medulla, N Engl J Med 274:716, 1966 5. Sherman, et al. Renal lesions of familial juvenile nephronophthisis examined by microdissection, Am J Clin Pathol 55:391, 1971 7. Chamberlin, et al. Juvenile nephronophthisis and medullary cystic kidney disease, Mayo Clinic Proc 52:485, 1977 8. Zollinger et al. Nephronophthisis (medullary cystic disease of the kidney), Helv Paediat Acta 35:309, 1980 9. Cohen A and Hoyer RJ, Nephronophthisis: a primary tubular basement membrane defect, Lab Invest 55: 564, 1986 10. Wolf MTF. Nephronophthisis and related syndromes, Curr Opin Pediatr. 2015; 27(2): 201–211 11. Srivastrava S, Sayer JA. Nephronophthisis, J Ped 3:103, 2014

Autosomal dominant tubulointerstitial disease 1. Eckardt K-U, et al. Autosomal dominant tubulointerstitial kidney disease: diagnosis, classification and management – a KDIGO consensus report, Kidney Int 88:676, 2015 2. Nasr SH, et al. Uromodulin storage disease. Kidney Int 73; 971, 2007 3. Ekici QB, et al. Renal fibrosis is the common denominator of autosomal domiant tubulointerstitial diseases caused by mnutations of mucin 1 and uromodulin. Kidney Int 86:589, 2014 4. Zivna m, et al. Dominant renin gene mutations associated with early-onset hyperuricemia, anemia and chronic kidney disease, Am J Huma Genet 85:204, 2009 5. Bleyer AJ et al. Clinical and molecular characterization of a family with dominant renin gene mutation and response to treatment with fludrocortisone, Clin Nephrol 74: 411-422, 2010 6. Bleyer AJ, et al. Variable clinical presentation of an MUCI1 mutation causing medullary cystic kidney disease type 1, Clin J Am Soc Nephrol 9:527, 2014 7. Heidet L, et al. Spectrum of HN1B mutations in a large cohort of patients who harbor renal diseases. Clin J Am Soc Nephrol 5:1079, 2010 8. Faguer S, et al. Diagnosis, management, and prognosis of HNF1β nephropathy in adulthood, Kidney Int 80:768, 2011 9. Clissold RL, et al. HNF1β -associated renal and extra-renal disease – an expanding clinical spectrum, Nat Rev Nephrol 11: 102, 2015.