A comprehensive review for deep learners or medical students

1. A New Perspective
on Hypokalemia
Taipei Veterans General Hospital, Hsin-Chu branch
Director of Nephrology
Steve Chen
K

2. PotassiumPotassium
Reference Range:
3.5 – 5.1 meq/L

3. PotassiumPotassium
Hypokalemia is K+
< 3.5 meq/L

5. Symptoms & Signs ofSymptoms & Signs of
HypokalemiaHypokalemia
 Clinical Features(1)Clinical Features(1)
– Symptoms at serum KSymptoms at serum K++
<< 2.5 meq/L2.5 meq/L
– CardiovascularCardiovascular
 Increased HTNIncreased HTN
 Orthostatic hypotensionOrthostatic hypotension
 DysrhythmiasDysrhythmias
 EKG abnormalitiesEKG abnormalities
– Flat T-waves, prominent U-waves, ST-segmentFlat T-waves, prominent U-waves, ST-segment
depressiondepression

6. Symptoms & Signs ofSymptoms & Signs of
HypokalemiaHypokalemia
 Clinical Features (2):Clinical Features (2):
– NeuromuscularNeuromuscular
 Malaise, weakness, fatigueMalaise, weakness, fatigue
 Hyporeflexia, cramps, paresthesiasHyporeflexia, cramps, paresthesias
– RenalRenal
 Increased ammonia production encephalopathyIncreased ammonia production encephalopathy
 Decreased GFRDecreased GFR
– GastrointestinalGastrointestinal
 IleusIleus

7. Major Dangers of HypokalemiaMajor 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

10. Diagnosis of HypokalemiaDiagnosis of Hypokalemia
Is 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

11. Urinary potassium excretion < 15meq /D
Assess acid- base status
Metabolic acidosis Metabolic alkalosis
Lower gastrointestinal loss Diuretic, remote use
Extra-renal Loss of Potassium

12. 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)

13. Aldosterone plusAldosterone 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

14. Gitelman’s / Bartter’s syndromeGitelman’s / Bartter’s syndrome
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 ↓

15. 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

16. Trans-cellular shift
Hypokalemia with TTKG 2Hypokalemia with TTKG 2 ～～
44

17. 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

19. Therapeutic goalsTherapeutic goals
To correct potassium deficit
To minimize ongoing losses
To prevent life threatening
complications

20. 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

21. 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.

22. 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

23. 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

24. Oral potassiumOral potassium
Safer
Potassium chloride preparation of choice
Potassium bicarbonate and citrate
Mild to moderate hypokalemia: KCl 60 to 80
meq/day in 3 to 4 divided doses
8 meq/tab

25. Oral K supplyOral K supply
Check bowel sounds first before
 SK 3 ～ 3.5meq/L: 60 ～ 80meq/D
SK from 4 to 3 meq/L:
loss of 200 ～ 400meq K

26. IV potassiumIV potassium
Severe symptomatic hypokalemia
Continuous ECG monitoring & frequent k+
estimation
Never give KCl directly IV.
Rapid IV correction can cause dangerous
hyperkalemia.
Use isotonic saline
Do not mix with dextrose containing
solutions.

27. Preparation of IV KPreparation of IV K
 KCL
 Diuretic or vomiting
K citrate, KHCO3
 Diarrhea
K phosphate
give Pi < 6mmol/Hr to ensure K staying
in ICF during anabolism
 TPN
 Recovery phase
from DKA

28. IV K supplyIV K supply
GI problems
Severe hypokalemia < 2.0meq/L
Severe symptoms: respiratory paralysis,
cardiac arrhythmia, hepatic encephalopathy
Therapy for DKA
Digitalis therapy to keep SK > 4meq/L
K deficit in SK 2meq/L: 400 ～ 800meq

30. Mutations(+) of renal Na channelsMutations(+) of renal Na channels
 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

31. Aldosterone-ENaC DepolarizesAldosterone-ENaC Depolarizes
ROMK in CCDROMK in CCD
E Na C
ROMK
Na K ATP ase
Depolarize
+
Aldosterone
+
Na
K
V2R
Aquaporin
H2O CaSR
CaSR

32. Progesterone in renal collecting ductProgesterone in renal collecting duct
not just a sex hormone anymorenot just a sex hormone anymore
Progesterone
+
K
H
PR bound progesterone
HKα2 mRNA

33. Mineralocorticoid HTNMineralocorticoid HTN
Causes Diagnostic parameters
Liddle 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

34. Liddle’s GRA AME
Molecular 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 HTN
Mimicked by AMB Mineralcorticoids Licorice;
carbenoxolone
Plasma Mg N N N
D.D. Amiloride
test
Dexamethasone
suppression
test;18-
hydroxycortisol(U)
Cortisol/cor
tisone(U);
THF+5αTH
F/THE(U)

35. Liddle’s GRA AME
Molecular 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 HTN
Mimicked by AMB Mineralcorticoids Licorice;
carbenoxolone
Plasma Mg N N N
D.D. Amiloride
test
Dexamethasone
suppression
test;18-
hydroxycortisol(U)
Cortisol/cor
tisone(U);
THF+5αTH
F/THE(U)

37. Bartter’s syndrome in THALBartter’s syndrome in THAL
NKCC
ROMK
Na K ATP ase
Ca, Mg pH
Na/K
K
2Cl
CaSR
Negative
Positive
ClC-Kb
2
1
3

38. Gitelman’s syndrome in DCTGitelman’s syndrome in DCT
TSC
Na
2Cl
V2R
Inactive
TSC dimer TSC
monomer
AT1R
MR
SPAK

39. Ca-ATPase
Ca
PTH

41. Feed forward
Feedback

43. 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

44. 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

46. 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/Posm
Uosm excretion= U osm / U Cr﹝ ﹞ ﹝ ﹞

47. Estimate of UK excretionEstimate 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

49. 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

50. Vomiting-induced hypokalemiaVomiting-induced hypokalemia
due 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

51. 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

52. CKD and bone fractureCKD 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
1.31
Nickolas 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

53. Hypokalemia in magnesium deficiencyHypokalemia in magnesium deficiency
Huang 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 ++ ++ ++++

54. ROMK in intracellular magnesiumROMK 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 ase
Depolarize
+
UK 5mM CK 143mM
Aldosterone
+
Na
K
Mg

55. Hypokalemia in magnesium deficiencyHypokalemia in magnesium deficiency
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 ase
Depolarize
+
Urine Blood
Aldosterone
+
Na
K