Electrolyte Disturbance Lee, Dong Won, MD, PhD Division of Nephrology Department of Internal Medicine Pusan National University School of Medicine

Case 1 50세 남자가 의식이 저하되어 왔다. 피부긴장도는 정상이었다. 10년 전부터 정신분열병으로 치료 중이었다. 진단은? 혈액: glucose 87 mg/dL, BUN/Cr 15/0.9 mg/dL, Na/K 112/3.8 mEq/L, Osm 235 mOsm/L 소변: Protein (-), RBC 0~2/HPF, WBC 0~2/HPF, Na/K 25/10 mEq/L, Osm 45 mOsm/L ① Primary polydipsia ② Adrenal insufficiency ③ Cushing syndrome ④ Central diabetes insipidus ⑤ Syndrome of inappropriate antidiuresis (SIAD)

Case 2 50세 남자가 의식이 저하되어 왔다. 피부긴장도는 정상이었다. 수개월 전부터 기침이 심했다. 진단은? 혈액 : glucose 82 mg/dL, Na/K 112/3.5 mEq/L Osm 240 mOsm/kg H2O Cortisol 12.3μg/dL (참고치; 5~25) TSH 0.9 mIU/L (참고치; 0.34~4.25) 소변 : Na 82 mEq/L, Osm 430 mOsm/kg H2O ① Primary polydipsia ② Adrenal insufficiency ③ Cushing syndrome ④ Central diabetes insipidus ⑤ Syndrome of inappropriate antidiuresis (SIAD)

Hemodynamic stimuli for ADH(AVP) Overfilled arterial circulation Underfilled arterial circulation Upregulated release of AVP Water intake RAS, SNS AVP ↑ Renal tubular Na+ reabsorption Urine Osm ↑ Natriuresis Urine Na+ Water excretion ↓

Case 3 50세 남자가 의식이 저하되어 왔다. 피부긴장도는 감소해 있었다. 5년 전부터 고혈압과 당뇨병으로 치료 중이었다. 원인은? ① Thiazide ② β-blocker ③ Spironolactone ④ Calcium channel blocker ⑤ Angiotensin II receptor blocker 혈액: BUN/Cr 28.0/1.1 mg/dL, Na/K/Cl 112/4.0/98 mEq/L, Osm 230 mOsm/L 소변: SG 1.040, protein (1+), RBC 6-10/HPF, Na 120 mEq/L, Osm 340 mOsm/L

Renal or Extrarenal (GI) Plasma osmolality Pseudo-hyponatremia High Normal Low Hyperglycemia Mannitol Hyperproteinemia Hyperlipidemia Bladder irrigation Maximal volume of maximally dilute urine No Yes ECF volume Primary polydipsia Increased Normal Decreased Primary Na+ gain exceeded by Secondary water gain Heart failure Liver cirrhosis Nephrotic syndrome Renal insufficiency Primary water gain With Secondary Na+ loss SIADH R/O Hypothyroidism R/O Adrenal insufficiency Urine Na+ < 10 mmol/L > 20 mmol/L Primary Na+ loss Renal or Extrarenal (GI) Extrarenal Na+ loss Remote diuretic use Remote vomiting Na+ wasting nephropathy Hypoaldosteronism Diuretics Vomiting

Diagnostic approach to hyponatremia

Case 4 50세 남자가 의식이 저하되어 왔다. 오전 8시부터 고농도(3%) 식염수를 투여한 후 의식이 회복되었으나 저녁 8시경 다시 의식이 저하되었다. 진단은? ① Adrenal adenoma ② Pheochromocytoma ③ Acute cerebral edema ④ Subarachnoid hemorrhage ⑤ Central pontine myelinolysis (Osmotic demyelination syndrome) 오전 8시 혈액: Na/K/Cl 102/3.9/92 mEq/L, Osm 216 mOsm/L 저녁 8시 혈액: Na/K/Cl 138/4.2/105 mEq/L, Osm 290 mOsm/L

Complication due to rapid correction of… Hyponatremia Hypernatremia CPM (ODS) Cerebral edema

Management of Hyponatremia Water restriction - mainstay of therapy in asymptomatic hypoNa and in chronic SIADH - Complications : volume depletion, hypotension – cerebral vasospasm - SAH Salt administration - initial correction rate – neurologic Sx, onset rapidity, magnitude - quantity of Na+ required to increase PNa = (target Na+ – Pt’s Na+) x TBW (50~60% of lean body wt.) - normal saline or hypertonic saline < 8-10 mmol/L/ first 24hrs < 18 mmol/L/ first 48hrs - monitoring of serum Na – fluid Osm > urine Osm

Case 5 50세 남자가 의식이 저하되어 왔다. 피부긴장도는 감소해 있었다. 혈압 70/45 mmHg, 맥박 90회/분, 호흡 20회/분, 체온 36.5℃였다. 치료는? ① 5% D/W ② 0.9% saline (N/S) ③ 3% saline ④ 10% albumin ⑤ Furosemide 혈액: BUN/Cr 54/2.0 mg/dL, Na/K 148/3.5 mEq/L 소변: SG 1.030, protein (+), RBC 1-2/HPF

Case 6 50세 남자가 의식이 저하되어 왔다. 피부긴장도는 정상이었다. 혈압 110/70 mmHg, 맥박 72회/분, 호흡 20회/분, 체온 36.5℃였다. 치료는? ① 5% D/W ② 0.9% saline (N/S) ③ 3% saline ④ 10% albumin ⑤ Furosemide 혈액: BUN/Cr 18/0.8 mg/dL, Na/K 158/4.0 mEq/L 소변: SG 1.030, protein (+), RBC 1-2/HPF

Fluid 1 liter ? - free water, saline, or half saline ? ECF ICF Fluid (1L) Distribution Intravascular Interstitial Intracellular 5% D/W ECF/ICF 85 (1) 250 (3) 665 (8) 0.9% N/S ECF 250 (1) 750 (3) 0.45% saline 500mL water 500mL saline 40 (1) + 125 (1) 125 (3) + 375 (3) 335 (8) + 0

Re-distribution of fluid administered 5% D/W, 1,000 mL Blood volume RBC volume Intravascular volume Interstitial volume 665 85 250 ICF (2/3, 28L) ECF (1/3, 14L)

Re-distribution of fluid administered 0.9% N/S, 1,000 mL Blood volume RBC volume Intravascular volume Interstitial volume 250 750 ICF (2/3, 28L) ECF (1/3, 14L)

Case 7 50세 남자가 근육통이 심해서 왔다. 헬스클럽에서 열심히 운동한 후 친구들과 소맥을 여러 잔 마셨고 집에 돌아와 낮잠을 자고 일어나니 몸이 천근만근이었다. 진단은? ① 담 ② 숙취 ③ 고칼륨혈증 ④ 저칼륨혈증 ⑤ 횡문근융해증 70kg x 60% = 42L ECF (1/3) = 14L ICF (2/3) = 28L

Healthy adults Exercise - Intracellular K - β2-stimulation Diet (Hyperglycemia) - Intracellular water - Cell shrinkage - Insulin release Interstitial accumulation Intracellular K uptake Extracellular movement Intracellular K concentrated Limiting muscle contraction, fatigue Rapid vasodilation, increasing blood supply to exercising muscle Decreasing serum K K efflux (solvent drag) K efflux (favorable gradient) Decreasing glucose

Vasodilation – perfusion↑ Muscular K uptake Vasodilation – perfusion↑ Dietary K uptake PI3-K – phosphatidylinositide 3-kinase PDPK1 – 3-phosphoinositide-dependent protein kinase-1 GLUT4 – glucose transporter protein aPKC – atypical protein kinase C PKA – protein kinase A Exercise Serum glucose↓ Diet

Potassium intake RAPID muscular uptake SLOW renal excretion Adjustments in renal K excretion occur over several hours; therefore, changes in extracellular K concentration are initially buffered by movement of K into or out of skeletal muscle. RAPID muscular uptake SLOW renal excretion

Secretion Lumen PCT Blood Reabsorption TALH DCT CCD Solvent drag Paracellular diffusion KCC TALH Type I Bartter’s ------ (Bumetanide) NKCC2 Type II Bartter’s ----------- recycling ROMK KCC Transcellular absorption Paracellular diffusion DCT Gitelman’s ----------------- (Thiazide) NCC Initial K secretion KCC ROMK ENaC ROMK DCT2 ~ CCD – ASDN (aldosterone-sensitive distal nephron) - Identified by the presence of mineralocorticoid receptor (MLR) & 11β-hydroxysteroid dehydrogenase-2 (11βHSD-2) 11βHSD-2 maintain MLR free to only bind aldosterone by metabolizing cortisol to cortisone (no affinity to MLR) K-Cl cotransporter (KCC) Luminal Cl 감소하는 상황 (poorly reabsorbable anions, phosphate, sulfate, bicarbonate 증가)  K, Cl secretion KCC ASDN /c MLR, 11βHSD-2 Main K secretion CCD Liddle’s -------------------- (Amiloride) ENaC (Aldosterone) ROMK Maxi-K KCC

Cortical Collecting Duct LUMEN Principal Cell INTERSTITIUM Distal Na+- water delivery ENaC Na+ Na+ 3Na+ 3Na+ ATP Lumen (-) potential difference 2K+ 2K+ ROMK K+ K+ Mineralocorticoid (Aldosterone) Na-K-ATPase – increase intracellular K concentration ENaC – increase lumen(-) potential difference ROMK, Maxi-K – increase K permeability Distal Na-water delivery Na – increase lumen(-) potential difference Water – decrease luminal K concentration (dilution) Increased intracellular Ca  Maxi-K activation Maxi-K Mineralocorticoid (Aldosterone) ROMK – low-conductance, major K channel in basal (physiologic) condition Maxi-K – large-conductance, flow-sensitive K channel in high flow condition

Case 8 65세 남자가 손발이 저리고 마비되어 왔다. 약 20년간 당뇨병을 앓고 있었고 만성신질환 5기 (eGFR<10 mL/min)로 치료 중이었다. 약 1시간 전 건포도 한 컵을 먹었다고 한다. 원인은? 건포도? 고칼륨혈증? 건포도 한 컵? including K+ 28 mEq K+ 28 mEq/14L ECF K+ 2 mEq/L increased ??? 70kg x 60% = 42L ECF (1/3) = 14L ICF (2/3) = 28L

Healthy adults Diabetics K 28 mEq intake Rapid intracellular uptake (K redistributed into ICF) Na+-K+-ATPase activated by insulin, β2-adrenergics Hyperglycemia Insulin release  Intracellular K uptake Decrease serum K Aldosterone  Renal K excretion ↑ β- > α-adrenergic activity Diabetics K 28 mEq intake Rapid intracellular uptake (K redistributed into ICF) Na+-K+-ATPase activated by insulin, β2-adrenergics Insulin release ↓ Hyperglycemia  Extracellular K release Increase serum K Hypo-Aldosteronism  Renal K excretion ↓ α- > β-adrenergic activity  Intracellular K uptake masked

Case 9 50세 남자가 의식이 저하되어 왔다. 피부긴장도는 증가해 있었다. 10년 전부터당뇨병과 고혈압으로 치료 중이었다. 치료는? ① 혈액 투석을 시행한다. ② 칼륨 제제를 경구로 투여한다. ③ 인 결합제를 정맥으로 투여한다. ④ 고농도 식염수(3%)를 정맥으로 투여한다. ⑤ 자연 회복되므로 24시간 심전도를 측정하면서 관찰한다. 혈액 : BUN/Cr 50/8.7 mg/dL, Hb 7.4 g/dL, Na/K 130/7.2 mEq/L, Ca/P 7.2/9.4 mg/dL

TTKG (Trans-tubular K gradient) net K secretion by distal nephron before the effect of ADH correcting for Urine Osm changes (water reabsorption) (Urine K / Plasma K) / (Urine Osm / Plasma Osm) Normal 5~10 HyperK Renal K secretion (RAS)↓ Non-renal Distal flow (Na delivery)↓ 8~10 HypoK Non-renal Distal flow (Na delivery)↑ Renal K secretion (RAS)↑ 2~3

Diagnostic approach to hyperkalemia HyperK – TTKG upregulation (>8) >8  RAS (K secretion) 정상  flow (distal Na delivery) 감소 <5  RAS (K secretion) 감소

Managements of hyperkalemia Mechanism Therapy Onset/duration Dose Membrane stabilization Calcium 1-3min/30-60min Calcium gluconate 10% 10ml iv K+ shift Insulin 20min/4-6hr 10U RI iv + 50ml 50% glucose 2-adrenergic agonist 20min/2-4hr Albuterol 0.5mg iv over 15min, 10mg nebulize K+ removal Calcium or sodium polystyrene sulphone 1-2hr/4-6hr 15g every 6hrs orally or 30-60g by retention enema Dialysis Immediate /dialysis duration 2-3hr hemodialysis

Case 10 50세 남자가 손발이 마비되어 왔다. 피부긴장도는 정상이었다. 혈압 140/90 mmHg, 맥박 96회/분, 호흡 20회/분, 체온 37℃였다. 치료는? ① Furosemide ② Spironolactone ③ K-binding resin ④ Calcium gluconate ⑤ Sodium bicarbonate 혈액: BUN/Cr 18/0.8 mg/dL, Na/K/Cl 146/2.8/103 meq/L Renin 0.1 ng (참고치; 0.3~3.0), Aldosteron 20 ng/dL (참고치; 8 미만)

Diagnostic approach to hypokalemia HypoK – TTKG downregulation (2-3) <2  RAS (K secretion) 정상  flow (distal Na delivery) 증가 >4  RAS (K secretion) 증가

CD Hypokalemia Thiazide (DCT) Furosemide (TALH) Hypokalemia Ca2+ – less natriuretic effect than furosemide, BUT - NCC inhibition  more distal Na delivery to immediately downstream principal cells (CNT) and CD - Not hypercalciuric (hypocalciuria)  More lumen (-) potential Hypokalemia Hypokalemia

Defects in multiple renal tubular transport pathways Gitelman’s syndrome Bartter’s syndrome Liddle’s syndrome BS – TALH (furosemide) – NKCC2 – hypercalciuria, hypoMg (20%) GS – DCT (thiazide) – NCC - hypocalciuria, hypoMg (100%) LS – CCD (amiloride) – ENaC – Hypertension

Glucocorticoid CORTISOL equal affinity for MLR CORTISONE 11β-hydroxysteroid dehydrogenase-2 (11βHSD-2) CORTISOL equal affinity for MLR CORTISONE minimal affinity for MLR Systemic glucocorticoids↑ by pituitary ACTH CORTISOL-dependent MLR activation Systemic glucocorticoids↑ by ectopic ACTH SAME (Syndrome of Apparent Mineralocorticoid Excess) Hypertension Hypokalemia Hypercalciuria Metabolic alkalosis Suppressed PRA. Aldo Cushing’s syndrome Hypertension Hypokalemia (10%) Hypertension Hypokalemia (60-100%)

Mg deficiency RAPID muscular uptake SLOW renal excretion K excretion / Reducing Mg-dependent ROMK block Na+-K+-ATPase ROMK K excretion / secretion RAPID muscular uptake SLOW renal excretion

Potassium supplement Supplemental K+ – TMC cause of hyperkalemia Serum K+ start to increase within 72h after administration If, insufficient serum K+ increase within 96h – combined Mg depletion Prescription 1. Peripheral iv route – K < 60mEq/L 2. with Crystalloid solution, without Dextrose solution 3. Infusion rate < 40mEq/h 4. EKG monitoring 5. Check serum [K+] every 4-6 h