April 8th 2020

HYPOKALEMIA

M1 nephrology curriculum
LAU Gilbert and Rose-Marie Chagoury School of Medicine
Fadi Tohme, MD
Assistant Professor, LAUMC/RH, Nephrology & Critical care divisions
 LEARNING OBJECTIVES

Explain how serum potassium concentration falls in clinical settings and discuss
the risks and treatment of hypokalemia.
1. Describe the relation of total body potassium to serum potassium
concentration
2. List the clinical conditions most commonly associated with hypokalemia and
describe the mechanisms underlying potassium losses in each
3. Understand the risks associated with hypokalemia
4. Know safe and effective means of potassium replacement
DEFINITION & PATHOPHYSIOLOGY
 DEFINITION

• Hypokalemia is defined as a serum concentration of K+ < 3.5 mEq/L

• It is most often – but not always – related to a depletion in total body K+
stores

Mild 3-3.5 mEq/L

Moderate 2.5-3 mEq/L

SYMPTOMS

Severe <2.5 mEq/L

 PATHOPHYSIOLOGY

1
HYPOKALEMIA
Dietary K
intake
2
Total body K K entry into
stores the cell

4
3
Urine K GI
losses losses
 DECREASED DIETARY K INTAKE

• Normal K intake = 40-120 mEq / day (i.e. 100 mEq / day)

• Normal K excretion
• 92 mEq in the urine
• 8 mEq in the feces
• In hypokalemia:
• K will be reabsorbed (intercalated cells of the DCT/CCD)
• Active K secretion will be stopped (low Aldosterone, direct effect of K etc.)
• K excretion in the urine can be decreased to 5-25 mEq / day (~1% of filtered load)
• Therefore, low K intake alone (i.e. 20 mEq / day) rarely causes significant hypokalemia
 INCREASED K ENTRY INTO THE CELL

1. Increased availability of Insulin

• Exogenous insulin administration (DKA, NKH)
• Refeeding syndrome (due to carbohydrate load)
2. Elevated Beta-2 adrenergic activity
• Drugs: Albuterol (COPD/asthma), Dobutamine (CHF), Terbutaline (premature labor)
• Endogenous catecholamines (Epi) in stress situations (MI, TBI, ETOH withdrawal,
exercise)
3. Alkalosis (both metabolic and respiratory)
• Diuretics, vomiting, hyperaldosteronism (transcellular shifts = minor mechanism)
 INCREASED K ENTRY INTO THE CELL

4. Hypothermia: accidental or induced (i.e. after cardiac arrest, in the OR)

5. Increased blood cell production
• Pseudohypokalemia (K uptake happens outside the body) (i.e. AML)
• GM-CSF, Vitamin B12, Folate (K uptake inside the body (i.e. leukopenia or
megaloblastic anemia)
6. Hypokalemic periodic paralysis (AD disorder)
7. Thyrotoxic periodic paralysis
 PSEUDOHYPOKALEMIA

1. Most commonly seen with acute myeloid leukemia (AML)

• Once the blood sample is drawn
• Large number of abnormal leukocytes will take up K
• Happens when the blood is stored at room temperature for a prolonged period
• Rapid separation of plasma + storage of collection vial at 4ºC  K will be normal

2. Can also happen when blood drawn from arm where IV fluids are infusing
(without stopping the infusion enough time prior to drawing the sample)
 INCREASED K LOSSES FROM GI TRACT

1. Upper GI losses (Vomiting, NG tube drainage)

• Gastric secretions have only ~ 5-10mEq/L of K
• Major mechanism in these situations is renal K wasting (HCO3 = non reabsorbable
anion)
• Clues: alkalosis, high urinary pH (>7) and low urinary chloride (<20)
2. Lower GI losses (diarrhea)
• Small bowel / colon secretions have ~ 20-50 mEq/L of K
• Ex: prolonged infectious diarrhea, villous adenoma,VIPoma
• Clues: acidosis (normal anion gap), negative urine anion gap
 INCREASED K LOSSES IN THE URINE
TALH
1. Loop diuretics
2. Salt-wasting nephropathies
(Bartter Sd types 1 to 5)
DCT
1. Thiazide diuretics
2. Salt-wasting nephropathies
(Gitelman Sd)
CCD
1. Hyperaldosteronism
2. Non-reabsorbable anions
3. Renal tubular acidosis
4. Hypomagnesemia
5. Increased MC-like substances
 Cortisol (Cushing’s, Syndrome of
Apparent MC excess, licorice)
 Deoxycorticosterone (congenital
adrenal hyperplasia)
6. Liddle Sd
7. Geller Sd
8. Amphotericin B
MANIFESTATIONS OF
HYPOKALEMIA
 MANIFESTATIONS OF HYPOKALEMIA

1. Effect on skeletal muscle cells

 Weakness, paralysis
 Diaphragmatic weakness  respiratory failure
 Muscle cramps
 Rhabdomyolysis
2. Effect on smooth muscle
 Constipation & ileus
3. Effect on cardiac myocyte (arrhythmias)
4. Renal abnormalities (nephrogenic DI, elevation in BP, hypokalemic
nephropathy, NH3 generation etc.)
 CARDIAC MANIFESTATIONS OF LOW K

• Premature Atrial Complexes

• Premature Ventricular Complexes
• Sinus bradycardia
• Supraventricular tachycardia (paroxysmal atrial or junctional)
• AV block
• Ventricular arrhythmias
• Polymorphic VTach (torsades de pointe ⟷ prolonged QTc)
• Ventricular fibrillation
• Usually with very severe hypokalemia (K+ < 2.3 mEq/L)
EKG IN HYPOKALEMIA
SYNDROMES OF RENAL K
WASTING
 CASE

A young man is found to have hypertension and hypokalemia. A resident taking a

careful history discovers that the patient is extremely fond of European licorice.
 WHICH ONE OF THE FOLLOWING
GENETIC DEFECTS PRODUCES A
SIMILAR SYNDROME?

A. A mutation in the gene for the inwardly rectifying potassium channel

ROMK.
B. A mutation in the gene for the basolateral chloride channel CLC-Kb.
C. A mutation in the gene for the NaCl co-transporter.
D. A mutation in the gene for 11-hydroxysteroid dehydrogenase.
E. A chimeric gene with portions of the 11-hydroxylase gene and the
aldosterone synthase gene.
 Hypokalemia and HTN
Hypokalemia

HTN No HTN

↑PRA ↓PRA ↓PRA

↑PAC ↑PAC ↓PAC

Renovascular Primary
Reninoma Malignant hypertension
disease hyperaldosteronism
 ↓PRA ↑PAC

• Primary hyperaldosteronism
• Bilateral adrenal hyperplasia (Idiopathic hyperaldosteronism)  65-70%
• Aldosterone-producing adenoma (Conn’s syndrome) 30-35%
• Unilateral adrenal hyperplasia  1%
• Aldosterone-producing carcinoma  < 0.1%
• Ectopic secretion  extremely rare !
 ↓PRA ↑PAC (CONT.)

• Primary hyperaldosteronism
• Familial hyperaldosteronism type I or Glucocorticoid-remediable aldosteronism
(GRA)  < 0.5% (↑ urine 18-hydroxycortisol and 18-oxocortisol)
• Familial hyperaldosteronism type II  3%
• Familial hyperaldosteronism type III  NA
GLUCOCORTICOID-REMEDIABLE ALDOSTERONISM (GRA)

McMahon GT et al. Cardiology in Review 2004;12:44–48

Hypokalemia, HTN, and ↓PRA/↓PAC
Hypokalemia + HTN
↓PRA
↓PAC

↑Non-Aldosterone ↑Mineralocorticoid-Like
Mineralocorticoid Activity

↑11-deoxycorticosterone
↑Corticosterone
↑Cortisol ↑11-deoxycorticosterone ↑18-
hydroxycorticosterone

↑Synthesis ↓Metabolism ↑Synthesis ↓Metabolism ↓Metabolism

↓11β-hydroxysteroid Congenital Adrenal Congenital Adrenal

dehydrogenase type 2 Deoxycorticosterone Hyperplasia Hyperplasia
Cushing syndrome
SAME producing tumor (11β-hydroxylase (17α-hydroxylase
Licorice deficiency) deficiency)
Hypokalemia, HTN, and ↓PRA/↓PAC (cont.)
Hypokalemia + HTN
↓PRA
↓PAC

↑Non-Aldosterone ↑Mineralocorticoid-
Mineralocorticoid Like Activity

↑Mineralocorticoid
↑ENaC
Receptor

Activating Mutation
of Mineralocorticoid
Liddle syndrome
Receptor “Geller
syndrome”
11Β-HYDROXYSTEROID DEHYDROGENASE
TYPE 2 (11ΒHSD2) DEFICIENCY

Ferrari P. Biochimica et Biophysica Acta. 2010; 1802: 1178–1187

 CAUSES OF 11ΒHSD2 DEFICIENCY

• Genetic deficiency:
• Syndrome of Apparent Mineralocorticoid Excess (SAME)
• Acquired deficiency:
• Glycyrrhetinic acid (European licorice)
• Carbenoxolone (old PUD treatment)
 SUMMARY

Mutation in gene Disease K+ BP

for this protein
ROMK Bartter Sd type II ↓ Normal
ClC-Kb Bartter Sd type III ↓ Normal
NaCl co- Gitelman Sd ↓ Normal
transporter
11βHDS2 SAME ↓ ↑
Chimera of 11β- GRA ↓ ↑
hydroxylase gene
AND aldosterone
synthase gene
 BARTTER SYNDROME

Singh NP et al. J Assoc Physicians India. 2010; 58:283-4

 TYPES OF BARTTER SYNDROME

Type OMIM Chromosome Gene Protein Inheritance Onset Clinical features

I 601678 15q21.1 SLC12A1 NKCC2 AR • Antenatal • Polyhydramnios

• Prematurity
• Nephrocalcinosis
II 241200 11q24.3 KCNJ1 ROMK1 AR • Antenatal • Polyhydramnios
• Prematurity
• Nephrocalcinosis
• Postnatal transient
hyperkalemia
III 607364 1p36.13 CLCNKB ClC-Kb AR • Postnatal • Birth at term
• No nephrocalcinosis
IV 602522 1p32.3 BSND Barttin AR • Antenatal • Polyhydramnios
• Prematurity
• Sensorineural deafness
• No nephrocalcinosis
V 601199 3q21.1 CASR CaSR AD • Postnatal • Familial hypocalcemic
hypercalciuria

Kleta R et al. Nephron Physiol 2006; 104(2):73–80

 POLYHYDRAMNIOS / POLYURIA

• Unable to reabsorb Na+ via NKCC2 (25% of total Na+ reabsorption in

nephron)
• Renal salt wasting
• Volume depletion causes high renin, high aldosterone, high PGE2,
juxtaglomerular hyperplasia
 HYPOSTHENURIA

• Types I, II and IV
• Unable to reabsorb Na+ via NKCC2
• Decreased medullary gradient for water reabsorption in CCD
• Urinary concentration defect
 HYPOKALEMIA

• Increased Na+ delivery to distal nephron (ROMK and Maxi-K channels)

• Secondary hyperaldosteronism
• Metabolic alkalosis
 METABOLIC ALKALOSIS

• Increased Na+ delivery to distal nephron

• Secondary hyperaldosteronism
• Hypokalemia
 HYPOMAGNESEMIA/HYPERCALCIURIA
(NEPHROCALCINOSIS)

• Types I and II
• Unable to recycle K+ via ROMK
• No electrical gradient for paracellular Ca2+ and Mg2+ reabsorption
MG 2+ /CA 2+ TRANSPORT IN TAL

+-
 NEONATAL HYPERKALEMIA

• In Type II Bartter’s (ROMK mutation)

• Caused by delayed maturation of Maxi-K channels until 4th week of life

Satlin LM et al. Am J Physiol Renal Physiol 272:F397-F404, 1997

 GITELMAN SYNDROME

Singh NP et al. J Assoc Physicians India. 2010; 58:283-4

ALGORITHM FOR HYPOKALEMIA
EVALUATION
#1 Rule out transcellular shifts IV insulin, refeeding syndrome, albuterol, dobutamine, terbutaline. H/o AML?
& pseudohypokalemia
Urine K/CRT ratio <13 mEq/g or 24-hour urine K <20 mEq GI losses
#2 Assess urinary K excretion
Urine K/CRT ratio >13 mEq/g or 24-hour urine K >20 mEq Renal losses

#3 Check Mg levels

Acidosis Renal tubular acidosis (1, 2), DKA

#4 Assess acid/base status
Alkalosis
Vomiting, NG suction,
remote diuretics
Normal BP #6.1 check urine chloride
#5 Check blood pressure Diuretics, Bartter, Gitelman
HTN

↑PAC ↓PRPA Primary hyperaldosteronism

#6.2 Aldosterone / Renin levels ↑PAC ↑PRA Renovascular hypertension, malignant hypertension, reninoma
PAC PRA
↓PAC ↓PRA Liddle, Geller, Cushing’s, SAME, Licorice, congenital adrenal
hyperplasia

#7 Assess dietary K intake Contributing factor?

MANAGEMENT OF HYPOKALEMIA
 GENERAL PRINCIPLES

• Goal of therapy
• Prevent / treat life-threatening complications
• Replace K deficit
• Correct the underlying etiology
• Correct & look for hypomagnesemia
• Can result from the same process as hypokalemia (diarrhea, diuretics)
• Can cause K urinary losses when the primary process
• Correction of K levels will be refractory to K supplementation if Mg not corrected
• Keep K>4 in cardiac pts, especially those with arrhythmias
 GENERAL PRINCIPLES

• Careful with K supplementation with:

• Transcellular movements of K (risk of rebound hyperkalemia)
• Renal failure (risk of hyperkalemia)
• Start K supplementation earlier in DKA / NKH
• Insulin deficiency and hyperosmolarity cause K+ to shift out of cells
• This masks the profound total K depletion that is sometimes present (osmotic
diuresis, GI losses if vomiting)
• Start K supplementation (add 40 mEq KCl to each bag of NSS) when K<4.5 mEq/L
• Hold IV insulin once K <3.3
• DKA / NKH = most common indication for IV KCl
 GENERAL PRINCIPLES

• Be careful with acidotic patients that are hypokalemic (RTA, diarrhea, DKA)
• Administering bicarbonate can cause rapid shifting of K to the cell  worsening
hypokalemia (will need more K supplementation)
• Be careful hypokalemia with CHF patients on digitalis (digoxin)
• Hypokalemia increases the risk of digitalis toxicity
• Even mild hypokalemia can predispose to arrhythmias
• Digitalis binds on the same side of the Na/K/ATPase as K therefore more binding to
the pump / inhibition when K is low
• K deficit estimation
• 200-400 mEq deficiency in total body K stores for each 1 mEq/L drop in K
 POTASSIUM FORMULATIONS

• Potassium chloride: most commonly used (especially if alkalosis)

• Tablet (8 mEq)  risk of GI irritation, erosions (rare)
• ER formulation
• Liquid form (20 mEq in 15 mL)  unpalatable (use in enteral tubes)
• Potassium bicarbonate (or citrate): use if patient acidotic
• Potassium phosphate
• Use if concurrent hypophosphatemia (Fanconi/prox RTA; refeeding Sd, DKA)
• High potassium food:
• Mostly bound to phosphate or citrate
• Only 40% absorbed
• Ineffective in chloride depletion conditions (remote diuretics, vomiting, NG drainage)
 MILD TO MODERATE HYPOKALEMIA

• Can give oral potassium chloride (safer than IV formulations)

• GI losses: start with 20 mEq KCl 2 times daily (up to 3-4 times per day) – up to 80
mEq/day
• Renal losses:
• May need more K – up to 160 mEq/day (most of the K given will be excreted in
the urine)
• Consider K-sparing diuretic (amiloride, spironolactone, eplerenone)
• Each 10 mEq of KCl expected to raise the serum K by 0.1 mEq/L
• If deficit 200-400 mEq/day, give 50-100 mEq daily, correct K stores slowly
 SEVERE OR SYMPTOMATIC
HYPOKALEMIA

• Oral potassium chloride (KCl) 40 mEq 3-4 times per day

• IV potassium chloride
• Given with saline (not in D5W  insulin secretion  worsening hypokalemia)
• Peripheral vein
• Give at a max rate of 10 mEq/hr (will burn and cause phlebitis at higher rate + risk of
arrhythmias from sudden hyperkalemia)
• Can add 20-60 mEq to 1 Liter of (non-dextrose containing) saline solution
• Can add 10 mEq to a mini-bag (100-200 cc of saline) and give over one hour
• Central vein
• Can give 20 mEq/hr (add 20-40 mEq to 100 cc of saline)
 MONITORING

• Telemetry floor or ICU monitoring with severe hypokalemia or when giving K

rapidly (20 mEq/hr)
• Severe hypokalemia  repeat K in 4-6 hours after correction
• Moderate hypokalemia  repeat K in 12 hours
• Mild hypokalemia: can check daily (when inpatient)
 SUMMARY

1. Hypokalemia often results from depletion of intracellular potassium stores

2. Depletion of potassium stores is often caused by GI or renal losses
3. The most important symptoms of hypokalemia are muscle weakness and
cardiac arrhythmias
4. Assessing acid/base status and blood pressure help identify the etiology of
renal potassium wasting
5. Oral potassium salts are the preferred method of supplementation
6. Intravenous potassium chloride is indicated if hypokalemia is severe
7. Rate of IV K infusion should not exceed 10-20 mEq/hr depending on route of
infusion
END