A new perspective on hypokalemia

A New Perspective on Hypokalemia

Taipei Veterans General Hospital, Hsin-Chu branch

Director of Nephrologist

Steve Chen

K

PotassiumPotassium

Reference Range:3.5 – 5.1 meq/L

PotassiumPotassium

Hypokalemia is K+ < 3.5 meq/L

Symptoms & Signs of Symptoms & Signs of Hypokalemia Hypokalemia

Clinical Features(1)Clinical Features(1)– Symptoms at serum KSymptoms at serum K++ << 2.5 meq/L 2.5 meq/L– CardiovascularCardiovascular

Increased HTNIncreased HTN Orthostatic hypotensionOrthostatic hypotension DysrhythmiasDysrhythmias EKG abnormalitiesEKG abnormalities

– Flat T-waves, prominent U-waves, ST-segment Flat T-waves, prominent U-waves, ST-segment depressiondepression

Symptoms & Signs of Symptoms & Signs of HypokalemiaHypokalemia

Clinical Features (2):Clinical Features (2):– NeuromuscularNeuromuscular

Malaise, weakness, fatigueMalaise, weakness, fatigue Hyporeflexia, cramps, paresthesiasHyporeflexia, cramps, paresthesias

– RenalRenal Increased ammonia production Increased ammonia production

encephalopathyencephalopathy Decreased GFRDecreased GFR

– GastrointestinalGastrointestinal IleusIleus

Major Dangers of Hypokalemia Major Dangers of Hypokalemia

Cardiac arrhythmias Respiratory paralysis Hepatic encephalopathy

Immediate therapy: IV K supply on EKG 200meq/L in NS, 40 ～ 100meq/Hr, femoral vein 60meq/L in 1/2NS, 10 ～ 20meq/Hr, peripheral vein

Diagnosis of HypokalemiaDiagnosis of HypokalemiaIs the rate of excretion of K excessive ?

Excretion of K = Urine K x UV ﹝ ﹞If <15meq/D Extra-renal loss

poor intake, GI loss cellular shift remote vomiting, remote use of diuretics

If >15meq/D Renal loss High CCD flow if TTKG<2 : Osmotic diuresis High urine K ﹝ ﹞ if TTKG>4: Aldosterone plus; ongoing use of diuretics

Urinary potassium excretion < 15meq /D

Assess acid- base status

Metabolic acidosis Metabolic alkalosis

Lower gastrointestinal loss Diuretic, remote use Vomiting, remote K loss via sweat

Extra-renal Loss of Potassium

UKE >15 meq/day TTKG>4 TTKG<2

Metabolic Metabolic acidosis alkalosis +HTN

DKA Proximal RTA No hypertension(-HTN) Distal RTA Vomiting Bartter’s Diuretic abuse Hypomagnesemia

Renal Loss of Potassium

Aldosterone plus Fast Na

Osmotic diuresis

(Mineralocorticoid HTN)

Aldosterone plus Aldosterone plus lumen negative in CCDlumen negative in CCD

Fast Na reabsorption Slow Cl reabsorption

High or normal ECV

Low or high renin

No renal Na wasting

Low ECV

High renin

Renal Na wasting

Liddle syndrome

Amphotericin B

Adrenal Tumors, RAS, MH

Bartter-Gitelman syndrome

Mg depletion

Diuretic

Vomiting

Gitelman’s / Bartter’s Gitelman’s / Bartter’s syndromesyndrome

Gitelman’s Bartter’s

Molecular level ↓TSC in DCT ↓NKCC, ROMK, or Cl

Age at onset Teenage Children

Clinical Tetany Failure to thrive

Mimicked by Thiazides Loop diuretics

Plasma Mg ↓ ↓

D.D. Hypocalciuria Hypercalciuria

Uosm ↓

Transtubular K GradientTranstubular K Gradient

TTKG: to interpret urine K by adjusting ﹝ ﹞it for water reabsorption in renal medulla to reflect K in lumen of CCD﹝ ﹞

TTKG= Uk÷(Uosm/Posm) /Pk﹛ ﹜TTKG, physiological : 6 ～ 8

Trans-cellular shift

Hypokalemia with TTKG 2Hypokalemia with TTKG 2 ～～44

Shift of K into cellsShift of K into cells↑～↑～ 13.5meq/L if NaK-ATPase failed13.5meq/L if NaK-ATPase failed

Anabolism: growth, recovery from DKA, TPN, recovery from pernicious anemia

Acid-base disorder: ↑pH 0.1=↓0.2 ～ 1.7meq/L Acting via hormones: insulin, β2-agonist(↓0.5 ～

0.6meq/L), α-antagonist Hyperosmolality↓ 10 mosmol/Kg:↓ 0.4 ～ 0.8meq/L Exercise: ↑0.3 ～ 2.0meq/L

rebound hypokalemia: ↓0.5meq/L Others: Hypokalemic periodic paralysis Anesthesia? In animals

Therapeutic goalsTherapeutic goals

To correct potassium deficit

To minimize ongoing losses

To prevent life threatening complications

Therapeutic principlesTherapeutic principles

Safer to correct potassium via oral route

A decrement of 1mmol/l in plasma potassium may represent a total body k+ deficit of 200 to 400meq

Dextrose containing solutions avoided

When to treat…..?When to treat…..?

3.5 to 4 meq/L

Increase intake of potassium containing food.

3 to 3.5 meq/L

Only in high risk patients.

< 3 meq/L Needs definitive treatment.

Indications for K supplyIndications for K supply

Absolute Presence of symptoms: hypoventilation

Digitalis therapy

Therapy for DKA

Severe hypokalemia<2.0meq/L

Strong Myocardial disease

Anticipated hepatic encephalopathy

Anticipated ↑ of shift

Modest Development of glucose intolerance

Need for better antihypertensive control

Mild hypokalemia∞ 3.5meq/L

Food: 60meq KFood: 60meq K

Foods Weight(G)

Vegetables

Potatoes and beans

Peas

500

5000

Fruits

Banana

Orange

800

1200

Meats: beef and chicken 600

Oral potassiumOral potassiumSafer Potassium chloride preparation of choicePotassium bicarbonate and citrateMild to moderate hypokalemia: KCl 60 to 80

meq/day in 3 to 4 divided doses8 meq/tab

Oral K supplyOral K supply

Check bowel sounds first before SK 3 ～ 3.5meq/L: 60 ～ 80meq/DSK from 4 to 3 meq/L:

loss of 200 ～ 400meq K

IV potassiumIV potassiumSevere symptomatic hypokalemiaContinuous ECG monitoring & frequent k+

estimationNever give KCl directly IV.Rapid IV correction can cause dangerous

hyperkalemia.Use isotonic salineDo not mix with dextrose containing

solutions.

Preparation of IV KPreparation of IV K KCL

Diuretic or vomitingK citrate, KHCO3

DiarrheaK phosphate

give Pi < 6mmol/Hr to ensure K staying in ICF during anabolism TPN Recovery phase from DKA

IV K supplyIV K supply

GI problemsSevere hypokalemia < 2.0meq/LSevere symptoms: respiratory paralysis,

cardiac arrhythmia, hepatic encephalopathyTherapy for DKADigitalis therapy to keep SK > 4meq/LK deficit in SK 2meq/L: 400 ～ 800meq

Mutations(+) of renal Na Mutations(+) of renal Na channelschannels

Liddle syndrome: β and γ subunits of amiloride-sensitive ENaC

Glucocorticoid remediable aldosteronism(GRA) aldosterone synthase/11 β hydroxylase

Apparent mineralocorticoid excess(AME) mineralocorticoid receptor, 11 βhydroxystreoid dehydrogenase

Congenital adrenal hyperplasia(CAH) 11α hydroxylase/β hydroxylase

Progersterone induced hypertension(PIH) mineralocorticoid receptor

Aldosterone-ENaC Depolarizes Aldosterone-ENaC Depolarizes ROMK in CCD ROMK in CCD

E Na C

ROMK

Na K ATP aseDepolarize

+

Aldosterone+

Na

KV2R

AquaporinH2O CaSR

CaSR

Progesterone in renal collecting duct Progesterone in renal collecting duct not just a sex hormone anymorenot just a sex hormone anymore

Progesterone+

KH

PR bound progesterone

HKα2 mRNA

Mineralocorticoid HTNMineralocorticoid HTN

Causes Diagnostic parametersLiddle Amiloride test

GRA 18-hydroxycortisol(U)

AME(↓11βHSDH) Cortisol/cortisone(U)

CAH(↓11β hydroxylase) Deoxycorticosterone (U)

↓ 17αhydroxylase Deoxycorticosterone(U)

↑Mineralocorticoid receptor mutation Spironolatone test?

DOC-producing adenoma DOC(U); MRI Aldosterone-producing tumor Renin/aldosterone: supine/erect

MRI

Secondary hyperaldosteronism Renin; MRA

Liddle’s GRA AMEMolecular level ↑ENaC

in CCD Chimeric gene: ACTH-driven mineralcorticoid

synthesis

↓11β-HSDH in principal cells

Age at onset Young Young adult Children

Clinical HTN HTN,severe HTNMimicked by AMB Mineralcorticoids Licorice;

carbenoxolone

Plasma Mg N N N

D.D. Amiloride test

Dexamethasone suppression test;18-hydroxycortisol(U)

Cortisol/cortisone(U); THF+5αTHF/THE(U)

Liddle’s GRA AMEMolecular level ↑ENaC

in CCD

Chimeric gene: ACTH-driven mineralcorticoid

synthesis

↓11β-HSDH in principal cells

Age at onset Young Young adult Children

Clinical HTN HTN,severe HTNMimicked by AMB Mineralcorticoids Licorice;

carbenoxolone

Plasma Mg N N N

D.D. Amiloride test

Dexamethasone suppression test;18-hydroxycortisol(U)

Cortisol/cortisone(U); THF+5αTHF/THE(U)

Bartter’s syndrome in THAL Bartter’s syndrome in THAL

NKCC

ROMK

Na K ATP ase

Ca, Mg pH

Na/K

K

2Cl

CaSRNegative

Positive

ClC-Kb

2

1

3

Gitelman’s syndrome in DCT Gitelman’s syndrome in DCT

TSCNa

2Cl

V2R

Inactive TSC dimer TSC

monomer

AT1R

MR

SPAK

Ca-ATPase Ca

PTH

Feed forward

Feedback

TPP&HPPTPP&HPP TPP HPP

Duration 3～ 36H 1～ 4H

Clinical 20～ 50Y puberty

Interval Total weakness Often subclinical

Glucose-insulin Trigger only hyperthyroidism

Trigger at any time

Molecular Ion channel Ca channel

Therapy

Prophylaxis

K supply

PTU/ β-blocker

K supply

Acetazolamide

K supply in TPPK supply in TPP

Regimen 1: oral KCL, 0.2 ～ 0.4meq/Kg, repeat every 15 ～ 30 minutes

Regimen 2: IV bolus KCL, 0.1meq/Kg repeat every 5～ 10 minutes

Regimen 3: PO 32meq q2H or IV 20 ～40meq/2H in mannitol solution

Regimen 4: IV high dose proprandolol 3mg/Kg

CCD flow rateCCD flow rate

CCD flow rate∞osmole excretion rate under vasopressin action

CCD osmolality=cortical interstitial compartment=Plasma osmolality(Posm)

CCD flow rate= Urine osmoles/PosmUosm excretion= U osm / U Cr ﹝ ﹞ ﹝ ﹞

Estimate of UK excretion Estimate of UK excretion

UK excretion= U K x UV﹝ ﹞Ucr excretion= U Cr x UV ﹝ ﹞

if age<50 Ucr excretion=20mg/Kg x BW=1G/D

UK excretion= U K x UV / U Cr x ﹝ ﹞ ﹝ ﹞UV = U K / U Cr﹝ ﹞ ﹝ ﹞

70mmol K per 1.15g of Cr on a typical diet

Obligate loss of KObligate loss of K

Renal loss: 10meq/D≧Non-renal loss:

Sweat 10meq/L x 0.2 ～ 12L/D = 2 ～120meq/D Stool 100meq/L x 0.1L/D = 10meq/D Diarrhea 40 ～50meq/L

Vomiting-induced hypokalemiaVomiting-induced hypokalemiadue to urinary lossdue to urinary loss

Volume(L/D) K: meq/L

Gastric 1.5 10

Duodenal 3-8 15

Pancreas 0.5 5

Bile duct 0.5 5

Jejunal 3 5

Ileal 0.5 10

Vomiting/DiureticsVomiting/Diuretics

Urine electrolytes

Vomiting Diuretics

Na >20meq/L if recent

<10meq/L if remote

>20meq/L if recent

<10meq/L if remote

K TTKG↑if recent TTKG↑if recent

Cl <10～ 15meq/L >20meq/L if recent

<10meq/L if remote

HCO3 Abundant Zero CAI excluded

CKD and bone fracture CKD and bone fracture Nickolas et al: KI 2008 (Columbia University Medical Center) Nickolas et al: KI 2008 (Columbia University Medical Center)

Study GFR (ml/min) Fracture site Fracture risk Dukas et al < 65 Hip OR 1.57 (2005) Wrist OR 1.79 Vertebral OR 1.31Nickolas et al < 59 Hip OR 2.32 (2006)Ensrud et al 45-59 Hip HR 1.24 (2007) <45 HR 1.41 45-59 Trochanteric HR 3.69 <45 HR 5.04Jamal et al <45 Any fracture OR 1.3 (2007) Vertebral OR 2.5Friend et al <60 Hip HR 1.38 (2007)

Hypokalemia in magnesium deficiencyHypokalemia in magnesium deficiencyHuang et al: JASN 2007 (University of Texas Medical Center)Huang et al: JASN 2007 (University of Texas Medical Center)

Outward ROMK Driving Potassium

conductance force secretion

Mg replete + ++ ++

Mg deficient

Alone ++ + ++

+ Na delivery ++ ++ ++++

+ Aldosterone ++ ++ ++++

ROMK in intracellular magnesium ROMK in intracellular magnesium Huang et al: JASN 2007 (University of Texas Medical Center)Huang et al: JASN 2007 (University of Texas Medical Center)

CCT

E Na C

ROMK

Na K ATP aseDepolarize

+

UK 5mM CK 143mM

Aldosterone+

Na

KMg

Hypokalemia in magnesium deficiencyHypokalemia in magnesium deficiencyHuang et al: JASN 2007 (University of Texas Medical Center)Huang et al: JASN 2007 (University of Texas Medical Center)

CCT

E Na C

ROMK

Na K ATP aseDepolarize

+

Urine Blood

Aldosterone+

Na

K