醫學系『腎臟泌尿學』課程 Inherited Renal Diseases

三軍總醫院腎臟內科 國防醫學院醫科所 楊松昇 醫師、博士 [email protected] 分機 88099, 12648

1 Classification of Renal Diseases

◼ Clinical classification

◼ Etiologic classification 3 ◼ Morphologic classification ⚫ Glomerular diseases 1 4 ⚫ Tubular diseases 2 1) Proxmial tubules (PT) 2) Thick ascending limbs (TAL) 3) Distal convoluted tubules (DCT) 4) Cortical Collecting Duct (CCD) ⚫ Interstitial diseases ⚫ Vascular diseases Physiology Key Molecular Components of Podocyte

2

1 Monogenic forms of nephrotic syndrome and .

SR: Steroid-resistant

1 Finish type NS 2 SRNS Diffuse mesangial sclerosis

SRNS

SRNS

Adult-onset SRNS

SRNS

Front. Med., 12 March 2018 Autosomal Dominant Focal Segmental Glomerulosclerosis

•A 25-year-old male progressive renal failure and persistent proteinuria of unknown cause for 5 years. •His mother had nephrotic-range proteinuria and abnormal renal function at the age of 38. •UR: RBC: 3-5/HPF and proteinuria : 3.1 g/day. •Renal biopsy: FSGS •AD FSGS: •ACTN4 : •CA2AP: •TRPC6: •INF2: R214C (this family)

★ (deafness) Thickiness:250 nm for adults; 80 nm for children ★

TBMN Distribution and Switches of College IV Network in Glomerular Development

Normal Disease Nail-Patella Syndrome

Alport’s Syndrome Nail-Patella Syndrome Fabry Disease

•32 y/o male: dysuria was complained Xq22.1 α-galactosidase A after an URI episode • : RBC:40-50 and mild protenuria (1.3g/day)

Exon1 TGC→CGC C63R

Zebra body (globotriaosylcer amide) Mg 3 Ca

1 4

2

1. Proxmial tubules (PT) 2. Thick ascending limbs (TAL) 3. Distal convoluted tubules (DCT) 4. Cortical Collecting Duct (CCD)

◼ Renal glucosuira (AD; AR?) Na –Glucose Tansporter2 ◼ Harnut disease (AD) B0-Aminoacid transporter 1 ◼ Hereditray hypophoaphatemic rickets withhypercalciuria (AR) Na –Pi cotransporter ◼ Blue diaper syndrome (AR) kidney-specific tryptophan transporter ◼ Urolithiases ⚫ Dent’s disease (X-link) Chloride channel-5 ⚫ Cystinuria (AR) Apical cystine –dibasic amino acid transporter ◼ ⚫ Idiopathic (AR, AD, X-link) ⚫ Wilson’s disease, Galactosemia, Cystinosis,Tyrosinemia, Fructose intolerance ⚫ Aristolochic acid (馬兜鈴 酸), Gentamycin; Heavy metal, Chemotherapy drugs ◼ proximal renal tubule acidosis Proximal (pRTA, Type 2 RTA) (漏鹼)

HCO3 reabsorption 1. Carbonate anhydrase (CA)IV: AD pRTA 2. Na- Cotrasnporter (NBC) 1: AR pRTA 24mEq/L 3. CAII: AR with mixed-type RTA with osteopetrosis 2

1 3

(收鹼) Distal Renal Tubular Acidosis (無法排酸)

1,2 ATP6

4 SLC4A1 3

(排酸)

1. ATP6V1B1: AR dRTA with deafness 2. ATP6V0A4: AR dRTA 3. SLC4A1: AD dRTA (Bicarbonate-Cl anti-porter) 4. CAII: AR Osteopetrosis with mixed-type RTA Urinary acid excretion and ◼ Net H+ production≒60 (40-80) mmol / day ◼ If urine pH:4.5 (0.03mmol/L) x1.5L urine free H+ in urine: 0.045 mmol/day

◼ UNa + UK + U unmeasured cations (UNH4)= UCl + U unmeasured anions ◼ UAG = (UNa + UK) – (UCl) = U unmeasured anions – U unmeasured cations (UNH4)

◼ Range: -20 ~ +50 mEq/L ◼ Negative AG: increased ammonium production (-20 ~ -50) ◼ Positive AG: decreased ammonium production A Hypokalemic Girl with Bilateral Glaucoma and Keratopathy

◼ A 8 y/o girl suffered from generalized weakness, failure to strive and hypokalemia. ◼ Progressive blindness of both eyes due to glaucoma and keratopathy. ◼ Typical bilateral basal ganglion calcification ◼ Her pressure was normal. ◼ Her neonatal period was uneventful and family history was non-revealing. Na+K-Cl=

Urine: Na+K+NH4+Cation=Cl+Anion→=Na+K-Cl=Anion- (NH4+Cation)

A 2 y/o male with failure to thrive and nephrocalcinosis

BLOOD URINE Na (mmol/L) 134 pH 7.0 K (mmol/L) 2.2 Na (mmol/L) 67.0 Cl (mmol/L) 111 K (mmol/L) 14.2 Mg (mg/dL) 1.8 Total Ca (mg/dL) 9.3 Cl (mmol/L) 68.0 Free Ca (mg/dL) 4.4 Mg (mg/dL) 3.2 P (mg/dL) 2.1 Ca (mg/dL) 14.6 BUN (mg/dL) 12 P (mg/dL) 28.0 Cr (mg/dL) 0.6 Cr (mg/dL) 59.1 Uric acid 3.8 UN (mg/dL) 605 Hgb (g/dL) 12.1 Osm (mOsm/kg pH 7.25 389 H2O) pO2 (mmHg) 103 FEHCO3 (%) 8 pCO (mmHg) 26 2 UPCO2 (mmHg) 48 HCO3- (mmol/L) 13.9 ATP6V1B1 F (one allele del T)

F M

M (one allele del T)

P (Both allele del T)

Patient Congenital Renal Tubular Acidosis (RTA)

Low serum [K]

Low BP High serum [K] KLHL3 High BP CUL3 Pseudohypoaldosteronism (PHA) Voltage- Classic Mixed-type Dependent Distal RTA RTA Distal RTA type 1 type 1 (PHAII) (PHAI) Congenital Renal Tubular Disorders in TAL and DCT associated with dyskalemia: (BS) vs (GS)

1 2 3 4 B A

A

B WNK4

1 6 3 2 4

5 CaSR

Jeck N et al. AJP 2005 Clinical Approach to Diagnose Gitelman/ Bartter Syndromes

(Lin SH Curr Medicinal Chem 2007, KI 2107, AJM 2017) (Low serum [K+]) (Urine)

Normal 〜low

25

New Variant of X-linked Antenatal Bartter’s Syndrome Chronic Hypokalemia and Renal Failure in a 16 Year-Old Boy Treated with NSAID

◼ A 16-year-old boy was consulted for the evaluation of his chronic hypokalemia found at the age of 2 and progressive renal failure. X ◼ Pertinent history: BS regularly treated with indocid tid ◼ Birth weight: 3400 gm, no polyhydramnios ◼ The most conspicuous blood biochemistry is CLCNKB mutation hypokalemia 2.1 mmol/L and hypoMg 2.0 GG/AG

Moth mg/dl, CR: 6.8 mg/dl, BUN: 50 mg/dl, Hgb: er 16.7 gm/dl, Ca/Cr ratio: 0.01 ◼ Hormone profiles: high PRA and high aldosterone G470E GGG→GAG ◼ What is your clinical and molecular Patie diagnosis? nt 376b p479b p

Enzyme: EcoN I Lin CM, et al. Eur J Ped 2009 Mutant Gene NCC, ClC-Kb WNK1/4, KLHL3, CUl3 GS-causing NCC mutations in Taiwan Laboratory Developed Test (LDT)

WT(Green) WT 開創一種有關診斷遺傳性吉特曼疾病的 ”快速診斷”方法，取代傳統定序診斷方 法或 RFLP，針對國人常見17個 MUT(blue) SLC12A3突變點使用我們創新設計的 反應盤（Custom plate） 作快速的定序方法。主要步驟如下： Hete Homo 步驟一：從病患血液抽取ＤＮＡ。

步驟二：準備創新設計的反應盤（ Custom plate），MasterMix ，水

步驟三：把病患的ＤＮＡ加入反應盤， 再加上MasterMix與水， 在QuantStudio5Real-TimePCR 上機

步驟四：資料分析與判斷突變點。

➢ 優點 1. Rapid: within 4 hours 2. Cheap: NT $500.0 / case 3. High Sensitivity and Specificity

31 7hr/8sample Qbit Chef torrent S5 Type Name Chrom Start End Target(b Missed Covered p) (bp) (%) Region SLC12A3 chr16 56865207 56915850 50,643 3,990 92.12

Region CLCNKb chr1 16043777 16057308 13,531 323 97.61

Region HNF1B chr17 37686432 37745247 58,815 1,498 97.45

Gene KCNJ1 2,958 0 100 (CDS+UT R) Gene SLC12A1 5,085 0 100 (CDS+UT R) https://f1.media.brightcove.com/4/3663210762001/3663210762001 32 _4823610548001_4823596815001.mp4?pubId=3663210762001&videoId=4823596815001 Gene CLDN10 2,999 0 100 (CDS+UT R) Seizure, sensorineural deafness, ataxia, mental retardation, and imbalance (SeSAME syndrome) caused by mutation in KCNJ10 (Kir4.1) Congenital Renal Tubular Disorders in TAL and DCT associated with dysmagnesiemia and dyscalciuria

(1) (2) (3) (2) (1) (3)

(A) (1) FHHNC: familial hypomagnesemia with hypercalciuria and nephrocalcinosis. (2) ADH, autosomal-dominant hypoparathyroidism ( gain-of-function); (3) FHH/NSHPT, familial hypomagnesemia/neonatal severe hyperparathyroidism (loss-of-function). (B): (1) HSH: hypomagnesemia with secondary hypocalcemia; (2) GS, Gitelman syndrome; (3) IDH, isolated dominant hypomagnesemia. Aldosterone-regulated Transporter Disorders Hypokalemic and Hypertension Hyperkalemia and Hypotension 1. Glucocorticoid-remedial aldosteronism (GRA) 1. Pseudohypoaldosteronism type I 2. Apparent mineralocorticoid excess (AME): (AME- • Mineralocorticoid Receptor (AD); like syndrome: Licorice) • ENaC (AR) 3. Liddle’s sydnrome: ENaC (βorγ PY motif mutation) (AD) ACTH

AngII

ACTH

1. GRA

11B Hydroxylase

3. Liddle syndrome

2. AME Monogenic Form of Hypertension

Aquaporins (AQPs) in Kidney

AQP3 CCD AQP2

(S3) 2003 Nobel Prize in Chemistry : Dr. Peter Agre

CHIP28 from CHIP28 RBC plasma expressed in membrane Xenopus Oocyte

(Preston G.M et al.1991 PNAS (Preston G.M et al. 1992 USA) Science) Water Deprivation Test Congenital DDX: Post- dDAVP: heart rate or Factor VIII •X-link (V2R) : no change •AD or AR ( AQP2): increase

Cystic Diseases

Classification of Renal Cysts

(PKD1; PKD2) (PKHD1)

(MCKD) (Nephronophthisis; NPH1-6 ) (ADTKD:UMOD, MUC1, REN, HNF1B) (AD, dRTA, stones)

(TSC1 ,TSC2) (3p25-26) Classification of Renal Cysts (UMOD, MUC1, REN, HNF1B) (ADTKD)

X-linked ADPKD ARPKD

Colonic diverticuli 83% Hepatic cysts 50-75% Mitral valve prolapse 26% Intracranial aneurysms 5% • The clinical presentation of ARPKD is highly variable. • Up to 50% of affected neonates die of pulmonary hypoplasia, the result of ologohydramnios from severe intrauterine . • About 80% of those who survive the neonatal period are still alive after 10 years; however, one-third of them will have developed ESRD. • Enlarged kidneys may be detected soon after birth as bilateral abdominal masses. • Kidney function deteriorates progressively from childhood into early adult life. • Longer-term survivors frequently develop portal hypertension, esophageal varices,, and hypersplenism from periportal fibrosis. Medullary Cystic Kidney Disease Medullary (ADTKD) Sponge Kidney Tuberous Sclerosis Von Hippel-Lindau Complex Syndrome

RCC

G

T

The Nobel Prize in Physiology or Medicine 2019 "for their discoveries of how cells sense and adapt to oxygen availability."

1. Proximal convoluted tubule 2. Distal convoluted tubule3. Cortical collecting duct - HCO3 , Glucose, NaClCa+2 Amino acids, phosphate Pseudhohypoaldo Na+ X steronism type I X K+ •MR antagonist/ X •Gitelman ENaC antagonist •Fanconi syndrome NaCl syndrome •Thiazide High excretion NaCl wasting of glucose, Secondary K+ wasting NaCl wasting - +2 Low K+ excretion HCO3 phosphate, Mg wasting urate, amino Low Ca+2 excretion Uosm max intact Cortex acid…. Uosm max intact….

Medulla 4. Loop of Henle 5. Medullary collecting duct NaCl Na+ K+ X H2O Ca+2 •Batter X +2 NaCl syndrome Mg X Defect •Furosemide Conc

Na+, Cl-, Ca+2 and Mg+2 wasting Na+ and Cl- wasting, but Secondary K+ wasting, Low Uosm max. no K+, Ca+2, or Mg+2 wasting

Lin SH, et al. Clin Nephrol 1998; 50:352-60