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