3/23/2017 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 1 3/23/2017 Hereditary primary tubulointerstitial diseases Primary chronic tubulointerstitial disease – Hereditary chronic tubulointerstitial nephritis Working definition: – Nephronophthisis “Disproportionate” tubulointerstitial injury – Medullary cystic kidney disease/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 cystic kidney disease 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 2 3/23/2017 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 3 3/23/2017 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 4 3/23/2017 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 – Medullary sponge kidney 5 3/23/2017 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 6 3/23/2017 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 7 3/23/2017 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