Bartter & Gitelman syndrome 이상헌

Introduction  Bartter & Gitelman syndrome  Autosomal recessive disorder  Hypokalemia, metabolic alkalosis, normal or low blood pressure  Hyper-reninemic & hyper-aldosteronism (d/t Volume contraction)  Prevalence  Bartter (1/1000,000), Gitelman (1/40,000), Caucasian study

Introduction  Bartter syndrome  Present in neonatal or childhood (Growth & Mental retardation)  Hypokalemia, Metabolic alkalosis  Polyuria & polydipsia (urinary concentration ability ↓)  Urine Ca 2+ excretion ↑  nephrocalcinosis  Normal Mg + or mildly decreased  TAL dysfunction  Inactivating mutation of major transport protein (NKCC2  type 1, ROMK  II, CIC-Kb  III, Barttin  IV)  Type V : CaSR mutation, Bartter like syndrome

Pathogenesis (Bartter) Type I Type II Type III Type IV Clinical nephrology 5 th edition

Pathogeneis (Bartter)  Loss of function of any one of 4 transporter  NaCl delivery to distal nephron ↑  NaCl reabsorption is stimulated  But compensate only part for the salt wasting  Loss of NaCl  Volume contraction  low BP, 2 nd hyperaldosteronism  Distal secretion of K + & H + increased  Hypokalemia & M. alkalosis  Hypokalemia & increased angiotensin II  PG E2 ↑  Hypercalciuria  Cl- absorption ↓, inhibit voltage driven paracelluar absorption

Pathogenesis (Bartter)  Role of PG  Renal PG E2 is often markedly elevated in neonatal Bartter syndrome (type I, II, IV)  Entry of NaCl into macula densa cell ↓→ expression of cyclooxygenase 2 ↑  PG E2 stimulate renin release from JG cells

Pathogenesis (Bartter) Clinical nephrology 5 th edition

Clinical manifestation  Type I, II, IV  Severe phenotype, present in the perinatal period  antenatal Bartter  Polyhydramnios (+), premature delivery  Vomiting, polyuria, hypercalciuria, high urine Cl -  Nephrocalcinosis  later in life  Deafness  type IV, barttin-dependent Cl - channel is crucial to endolymph production

Clinical manifestation  Type III  Milder form, Classic Bartter  Mixed Bartter & Gitelman  overlapping distribution of CIC-Kb, which is also expressed in the distal tubule  Hypomagnesemia, hypocalciuria (Gitelman feature)  Presentation age  1 month ~ 29 years  Vomiting, polyuria, dehydration, carpopedal spasm, fatigue  Nephrocalcinosis (-)

Clinical manifestation  Type V  Calcium sensing receptor : express in basolateral membrane of TAL  CaSR mutation  inhibit ROMK K + efflux  NKCC2 activity ↓  Phenotype similar to Bartter syndrome  Distinguished from others by hypocalcemia, hypomagnesemia

Diagnosis  History : newborn baby or young child with vomiting, dehydration, low normal BP, severe hypokalemia, M. alkalosis  High urine Cl & K  Hypomagnesemia (-), hypocalciuria (-)  2 nd hyperaldosteronism  Questionable case  genotyping

Introduction  Gitelman syndrome  Not diagnosed until late childhood or adult  Hypokalemia, Metabolic alkalosis  Polyuria & nocturia, urine concentration intact (TAL is intact)  Chondrocalcinosis  Hypomagnesemia  Distal convoluted tubule, Na-Cl cotransporter mutation

Pathogenesis (Gitelman) Clinical nephrology 5 th edition

Pathogeneis (Gitelman)  Loss of function of NCCT  NaCl wasting  Volume contraction  low BP, 2 nd hyperaldosteronism  Distal secretion of K + & H + increased  Hypokalemia & M. alkalosis  DCT reabsorbs only 7~8% of filterd Na +, Cl -  Volume contraction, RAS system activation, K + loss  less than Bartter syndrome & PGE 2 production (-)  Renal Mg + wasting  downregulation of epithelial Mg channel TRPM6

Clinical manifestation  Gitelman syndrome  Generalized muscle weakness, fatigue  Salt craving, preference for licorice  Cardiac disturbance, muscle cramp, tetany  only exceptional case  Chondrocalcinosis of knee (later in life)  Moderate hypomagnesemia, hypocalciuria  Urine calcium excretion : below normal ↔ Bartter (elevated or high normal)  Urine Ca/Cr < 44mg/g or 24hr urine Ca < 75~100mg/day

DDX  Surreptitious vomiting  Urine Cl level : vomiting  urine Cl < 25meq/L  Bartter or Gitelman urine Cl > 40meq/L  Surreptitious diuretics use  Urine Cl not helpful  Diuretics level check

Clinical nephrology 5 th edition

Treatment  K+ sparing diuretics  Spironolactone : up to 300mg/day  Amiloride : up to 30mg  NSAIDs  Bartter syndrome  PG E 2 ↑  Indomethacin (1 ~ 3mg/kg/24hr) or Ibuprofen  Gitelman  no benefit d/t low PG E 2 level  ACE inhibitor or ARB  Reduce angiotensin II & Aldosterone

Treatment  K + & Mg + supplementation  Kidney transplantation

Clinical nephrology 5 th edition

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Case 김 OO F/37  Chief complain : Vomiting, poor oral intake  Onset : 내원 2 주전  Present illness : 내원 2 주 전부터 구토 하루에 1-2 차례, 식욕감소 호소하여 응급실 통하여 입원함. 하루에 물 3-4L 정도 마시고 있었음.  Past Hx.  2011 년 우울증 진단. 본원 NP 입원치료, 현재 개인병원 F/U  2013/7/10 edema 주소로 본원 MN 입원 24hr urine study  Vol 1320ml, Na(146.5mmol/L) K(36.6) Ca(104.3) T-prt (99mg) (CBC / K, BUN/Cr 7.8/0.6, Electro )

Case  ROS  General weakness, fatigue, nausea, vomiting, insomnia, polydipsia  Physical exam  BP : 100/60 HR: 62 RR: 16 BT: 36.8 ℃  Chronic ill looking appearance with alert mental state  Dehydrated tongue(+), skin turgor ↓  Medicine  triazolam 3T, clonazepam 3T, paroxetin 1T, zolpidem 12.5mg 1T, chlorpromazin 1T, alprazolam 1T

Case  Lab  CBC : / K  BUN/Cr : 39.5 /0.85 eGFR(87.8) Electro ( ) CRP (0.14)  Random urine Na ( 35mmol/L ), K ( 16.1mmol/L ), Cl - ( 30 mmol/L )  aBGA : %, S-osmol ( 256 ↓ ) Urine-osmol ( 209 ↓ )  RUA c micro : Protein (-) Blood(-) RBC <1 WBC <1  FeNa : 1.75  Urine K/Cr ratio : mmol/g Cr  TTKG : 9.3 (Renal K wasting)  Chest x-ray & Abdomen  normal  13/7/11 Abdomen USG  normal

13/7/11 Abdomen USG

Case

Urine K/Cr 116mmol/g TTKG 9.3 Urine Cl 30mmol/L

Case  HAD 1~3 : NS hydration, NP medication D/C, K-contin 6T #3  HAD 4 : R/O Bartter syndrome  Aldactone 25mg 2T start  HAD 5 : Discharge with Aldactone 25mg 4T #2 (14/9/25)  14/9/29 Re-admission d/t vomiting & tinnitus  Lab : CBC / K BUN/Cr 45.6/1.09 Electro  FeNa : 3.45  TTKG : 9.6

Case  Lab  TFT  normal, ACTH stimulation test  normal  14/9/26 Aldactone level : 1010 pg/mL (13~272)  14/9/29 Random urine Ca (6.5mg/dL) Cr (13.8mg/dL)  Ca/Cr molar ration  1.625mmol/L / 2.76mmol/L ( 0.58 )  14/9/30 Renin level : ng/mL/hr (0.15 ~ 3.95)  24hr urine test(14/9/22) : Vol ( 2130 ml) T-protein(106.5) albumin(27.9) Cr (0.2g) Na + (138 mmol/day) K + (62 mmol/day) Cl - (163.6 mmol/day) Ca 2+ ( mg/day)  24hr urine test (14/10/6) : Vol ( 3690 ml) T-protein (236.2) albumin (14) Cr (0.3g) Na + (217.7 mmol/day) K + (106.3 mmol/day) Cl - (247.2 mmol/day) Ca 2+ ( mg/day)

Case Urine K/Cr 116mmol/g TTKG 9.3 Urine Cl 30mmol/L

Case  Na level Discharge Re-admission, aldactone stop d/t azotemia (45.6/1.09) Aldactone 100mg Amiloride 10mg

Case  K level Discharge Re-admission, aldactone stop d/t azotemia (45.6/1.09) K-contin 6T #3 Aldactone Amiloride 10mg

Case  Plan  R/O Bartter syndrome type III  Serum diuretics level check (thiazide)  ACE inhibitor try