POTASSIUM

| Major

intracellular cation

| Maintain

resting membrane potential,

regulates electrical excitability

Suparoek Jittikanont
Renal division,
Chiang Mai University

| Key

element of many biochemical processes:

Regulate cell pH and cell volume

Synthesis of structural protein

Enzymatic or hormonal activity

TRANSCELLULAR K+
REGULATION

POTASSIUM
HOMEOSTASIS

50 mEq/kg

RENAL REGULATION OF
POTASSIUM

TRANSCELLULALR
K+REGULATION
K+

Increased cellular uptake

Insulin
2-agonists
-adrenergic antagonists
Alkalosis

ATP

O2
Na+

Decreased cellular uptake

2-antagonists
-agonists
Acidosis
Hyperglycemia
Increase in osmolality
Exercise

RENIN-ANGIOTENSINALDOSTERONE AXIS

CORTICAL COLLECTING
TUBULE (PRINCIPAL CELL)

FACTORS MODIFYING POTASSIUM

SECRETION BY THE DISTAL
NEPHRON
Plasma K+ concentration
Distal flow rate
| Distal sodium delivery
| Transepithelial potential difference
| Anions
| Adrenal hormones: Aldosterone,
Glucocorticoids
| Acidbase factors: System pH, Ammonia
| Other hormones: Vasopressin,
Catecholamines, Insulin
| Dietary K+ intake
|
|

CLINICAL MANIFESTATIONS

DYSKALEMIAS
|

Transcellular Shift

Transcellular Shift

HYPOKALEMIA
Cardiac: hypertension, ventricular
arrhythmias
Neuromuscular
GI: ileus, constipation
y Skeletal muscles: weakness,
rhabdomyolysis, cramps, decreased
DTR
y

Intake

Intake

Renal
Polyuria (nephrogenic DI)
Ammonia production in PT
Metabolic alkalosis
y Interstitial fibrosis, intrarenal
vasoconstriction, renal cyst formation
y
y

Loss:
- Renal Loss
- Nonrenal Loss: GI, skin

Loss:
- Renal Excretion
- Nonrenal Loss

Endocrine
y
y

glucose tolerance
Aldosterone

Hepatic encephalopathy

|
|
|

HYPERKALEMIA
Cardiac
Neuromuscular
Endocrine

EKG FINDINGS IN
DYSKALEMIAS

CAUSES OF HYPOKALEMIA
| Pseudohypokalemia
| Transcellular
| Decreased
|K

K redistribution
K intake

loss

Renal
y Non-renal
y

POTASSIUM INFLUX

HYPOKALEMIA

Transcellular
shift

Hypokalemia

[K+]

< 20mmol/day
Urine
Poor Intake
GI Loss

Spurious

|
|
|

Urine [K+] > 20 mmol/day

|
|
|

Metabolic Acidosis
RTA
Ketoacidosis
Ureterosigmoidostomy

Metabolic Alkalosis
with Hypertension
Mineralocorticoid
Glucocorticoid

Metabolic Alkalosis
with Normotension
Vomiting, NG suction
Diuretics
Posthypercapnia
Mg Depletion
Bartters and Gitelmans
Syndromes

HYPOKALEMIC PERIODIC
PARALYSIS
|

Occurrence

|
|
|
|
|

HYPOKALEMIC PERIODIC
PARALYSIS
|

Age of presentation: childhood to third decade of life

| Clinical presentation
Episode of hypokalemia and muscle weakness, typically
persist for 6-24 hr
y Normal serum K and strength between attack
y Hypokalemia between paralytic episodes suggests
secondary causes

Precipitating factors
y

Sporadic
y AD (2/3) with reduced penetration in women
y

Extracellular alkalosis
Excess Insulin
Stress-induced catecholamine release
-adrenergic agonists
Dobutamine, dopamine
Theophyllin
Chloroquine, hydroxychloroquine intoxication
Barium Intoxication
Toluene Intoxication
Acute anabolic state
TPN in malnourished patients
Treatment of pernicious anemia
Periodic Paralysis
y Hereditary
y Thyrotoxic

y
y

Carbohydrate ingestion
Emotional stress
Overexertion

Molecular basis
y

Mutation in ion channels of the skeletal muscle sacrolemma

|

|
|

Dihydropyridine-sensitive receptor 1-subunit gene (CACNA1S)

1-sodium channel gene (SCN4A)
ATP-sensitive K channel (KATP)

Treatment
y
y

Acute: KCl administration

Prevention: low Na, low carbohydrate diet, avoidance of
overexertion, carbonic anhydrase inhibitors

THYROTOXIC PERIODIC
PARALYSIS

CAUSES OF POTASSIUM
DEPLETION

Asian and Latin-American men in the third decade of

life
| Negative family history
|

Precipitating factors: exercise, carbohydrate ingestion,

alcohol consumption

Hypophosphatemia and mild hypomagnesemia are

often present.
| S/S of hyperthyroidism may be subtle or absent
|

Treatment: KCl and -blocker may abbreviate the

duration of paralytic attack

Extrarenal
Renal
(urine K+ <20 mmol/day) (urine K+ >20 mmol/day)
|
|
|

Inadequate intake
Copious perspiration
Gastrointestinal losses
y Vomiting or NG suction
y Diarrhea
y Laxative abuse
y Villous adenoma
y Intestinal fistula
y Cation exchange resin

UFosm

UK / PK
Uosm/Posm

PK
|

UK = ?

Uosm = Posm

Vomitting/gastric suction
Diuretics
Intrinsic renal diseases
Mineralocorticoid excess
Disorders mimicking aldosterone
excess

TTKG > 2 Renal loss

TTKG < 1 Extrarenal loss

Hyperkalemia
y
y

TTKG > 7-9 Potassium gain

TTKG < 5 Renal potassium retention

Water
(ADH)

Unreliable when Uosm < Posm

or UNa < 25 mEq/L
UK

Uosm

MECHANISMS OF RENAL K+ LOSS

RENAL POTASSIUM LOSS

|

Distal flow rate

Distal sodium delivery
Negative transepithelial
(transtubular) potential difference
Mineralocorticoid activity

Renal tubular acidosis

Chloride depletion

Hypokalemia
y

TTKG =

TALH

Metabolic acidosis
Ureterosigmoidostomy, DKA,

INTERPRETATION OF
TTKG

TRANSTUBULAR POTASSIUM
GRADIENT
(TTKG)
UFK

Drugs
Mg depletion
Inhibit Na+ absorption at

Drug-associated hypokalemia
y
y
y
y
y
y
y

Thiazide and loop diuretics

Penicillin analogue-carbenicillin, ticarcillin
Amphotericin B-directly increase collecting duct K
secretion
Aminoglycosides-unknown mechanism, may
associated with hypomagnesemia
Cisplatin, ifosfamide
Toluene intoxication
Chinese herbal medicine

RENAL POTASSIUM LOSS

|

Intrinsic renal diseases

y
y
y
y
y
y
y
y

Diuretic phase of ATN

Interstitial nephritis
Postobstructive diuresis
Salt-wasting nephropathy
Lysozymuria in leukemic patients
RTA
Bartters and Gitelmans syndrome
Liddles syndrome

MINERALOCORTICOID
EXCESS
|

Primary hyperaldosteronism
Adrenal adenoma (Conns syndrome)
Idiopathic hyperplasia
y Adrenal carcinoma
y
y

Secondary hyperaldosteronism

Glucocorticoid-remediable aldosteronism
(Familial hyperaldosteronism type I)

MONOGENEIC
MINERALOCORTICOID
HYPERTENSION

HT + hypokalemia + metabolic alkalosis

Plasma renin activity
High
Secondary
hyperaldosteronism

Low
Serum aldosterone concentration
Low

Exclude licorice, AME,

Liddles syndrome, DOC
excess

GLUCOCORTICOID-REMEDIABLE
ALDOSTERONISM (GRA)
|
|

AD, hypertension in childhood

Aldosterone synthase is regulated by ACTH

High levels of hybrid steroids (18-hydroxycortisol,

18-oxocortisol)
| Improved by dexamethasone
|

Normal or high
Primary
hyperaldosteronism
GRA

DISORDERS MIMICKING
ALDOSTERONE EXCESS
|
|
|

Cushing syndrome
Liddles syndrome
Apparent mineralocorticoid excess syndrome
(AME)

Drug: licorice (glycyrrhetinic acid),

carbenoxolone, gossypol
| Congenital adrenal hyperplasia (CAH)
|

y
y

11 -hydroxylase deficiency
17 -hydroxylase deficiency

LIDDLES SYNDROME
AD, teenage and adult
Missense mutations in the and subunits of
ENaC
| Suppression of renin and aldosterone
|
|

Urinary mineralocorticoid metabolites are

normal

Treatment: sodium restriction, K replacement,

amiloride or triamterene

APPARENT MINERALOCORTICOID
EXCESS SYNDROME (AME)
AR
| 11 -hydroxy steroid dehydrogenase type II deficiency
| Low renin, low aldosterone

HYPOKALEMIA WITH
HYPERTENSION
AND METABOLIC ALKALOSIS
Disease

Serum
aldosterone

Plasma
renin

Serum
cortisol

Response to
glucocorticoids

Primary
aldosteronism

No

Secondary
aldosteronism

No

GRA

Yes

AME

Yes

No

11-hydroxylase,
17-hydroxylase
deficiency

Yes

Cushings syndrome

No

Increased ratio of tetrahydrocortisol plus

allotetrahydrocortisol/tetrahydrocortisone in urine
| Treatment: dexamethasone
| Acquired form: licorice, carbenoxolone, gossypol
|

BARTTERS SYNDROME
Hypokalemia, metabolic alkalosis, increased UNa,
UK, UCl
| Normal blood pressure
| AR or sporadic, Neonatal or childhood
| Elevated plasma renin and aldosterone activities
| Increased PGE2 production
| Hypercalciuria and nephrocalcinosis
|

Mild hypermagnesiuria and hypomagnesemia

(25%)

Liddles syndrome

GITELMANS SYNDROME
Hypokalemia, metabolic alkalosis, increased
UNa, UK, UCl
| Normal blood pressure
| AR, childhood or early adulthood
| Elevated plasma renin and aldosterone activities
| Normal PGE2 production
| Hypocalciuria and no nephrocalcinosis
| Marked hypermagnesiuria and hypomagnesemia
| Occasional weakness, cramps, or tetany
|

TREATMENT OF
HYPOKALEMIA
Indications for emergency treatment

TREATMENT OF
HYPOKALEMIA
Emergency treatment
y
y
y
y
y
y
y

Parenteral supplement
Concentration <60 mEq/L
Avoid hypertonic dextrose solution
Rate: < 60 mEq/h with EKG monitoring and < 10 mEq/h
without EKG monitoring
Vein with high blood flow for more concentrated solution
Avoid subclavian or jugular vein or central venous catheter
Frequent monitoring

1)

Cardiac arrhythmias and digitalis

toxicity

2)

Severe muscle weakness and

rhabdomyolysis

3)

Hepatic encephalopathy

4)

Severe hypokalemia (< 2-2.5 mmol/L)

TREATMENT OF
HYPOKALEMIA
Emergency treatment
In metabolic acidosis: correct K deficit to safer level before
administering HCO3
y In Cl-responsive metabolic alkalosis: correct K deficit before
overly volume expansion
y

TREATMENT OF HYPOKALEMIA

DYSKALEMIAS

Non Emergency
Potassium rich diet (70-120 mEq/day)
serum [K+] 0.27 K+ deficit 100 mmol
Oral supplement
K citrate, KHCO3, K gluconate, KCl,
K phosphate
30-60 mEq/day
KCl cap: irritate gastric mucosa
Microencapsulated and sustained release
form of KCl: fewer GI side effects

Transcellular Shift

Intake

Loss:
- Renal Loss
- Nonrenal Loss: GI, skin

Transcellular Shift

Intake

Loss:
- Renal Excretion
- Nonrenal Loss

CAUSES OF HYPERKALEMIA
Transcellular
shift

Hyperkalemia

Spurious

Pseudohyperkalemia
y

GFR > 10 ml/min

Low Aldosterone
Primary Adrenal Disease
Hyporeninemic
Hypoaldosteronism
Drugs:
- NSAIDs
- ACE inhibitors
- AT1-receptor antagonists
- Heparin
- Cyclosporin

Normal or High Aldosterone

Acquired Disease:
- Lupus nephritis
- Amyloidosis
- Obstructive nephropathy
Hereditary:
- Pseudohypoaldosteronism
Drugs:
- K-Sparing diuretics
- Trimethoprim

CAUSES OF HYPERKALEMIA
|

Reduced urinary K secretion

y

Primary decrease in distal delivery (renal failure)

|
|

ARF
CKD: GFR < 5 ml/min

Primary decrease in mineralocorticoid activity

y Distal tubular defect
y

Low GFR
Renal Failure

y
|
|

Prolonged tourniquet
Thrombocytosis, leukocytosis: heparinized blood
Familial pseudohyperkalemia: symptomless genetic disorder of
red blood cell membrane permeability (AD)

Excessive dietary intake

Increased K release from cell
y
y
y
y
y
y
y

Pseudohyperkalemia
Metabolic acidosis
Insulin deficiency, hyperglycemia, and hyperosmolality
Increase tissue catabolism
-adrenergic blockade
Exercise
Others: digitalis overdose, succinylcholine, arginine
hydrochloride, hyperkalemic periodic paralysis

INTERPRETATION OF
TTKG

| Hyperkalemia
y
y

TTKG > 7-9 Potassium gain

TTKG < 5 Renal potassium retention

HYPERKALEMIC PERIODIC
PARALYSIS
Mutations in the Na channel SCN4A gene
| In contrast to familial hypokalemic periodic paralysis,
patients with hyperkalemic periodic paralysis are
characterized
|

Younger age of onset (< 10 yr vs. 5 - 20 yr)

Greater frequency of attacks that tend to be of shorter
duration (< 24 h vs. > 24 h)
y Fasting increases the risk of attack
y K administration can precipitate weakness
y
y

POSSIBLE POTASSIUM
SOURCES
| Endogenous
y

Rhabdomyolysis, hemolysis, tumor lysis, hematoma

reabsorption, GI bleeding, prolonged fasting

| Exogenous
y

Food, salt substitute (13 mEq/g), potassium citrate,

potassium oral supplements, fluoride-rish water,
water softeners, stored blood (1 U of blood stored for
10 or more days contains ~ 30 mEq/L), Drugs
(potassium penicillin), parenteral replacement, renal
allograft preservation solution, potassium cardioplegia
in cardiac surgery

HYPOALDOSTERONISM
| Aldosterone

deficiency

Primary
Primary adrenal insufficiency
Congenital adrenal hyperplasia
| Isolated aldosterone deficiency
| Heparin, ACEI, AT1-RA
|
|

Hyporeninemic hypoaldosteronism
Renal diseases: DN, GN, HIV, Obstructive
uropathy
| NSAIDS, cyclosporine
|

| Aldosterone

PRIMARY ADRENAL
INSUFFICIENCY
| Aldosterone

and cortisol deficiency

Hypoaldosteronism: hyperkalemia and

normal AG metabolic acidosis
y Cortisol deficiency: hyponatremia
y

| Frequently

due to autoimmune
destruction of adrenal cortex
y Autoantibodies to 21-hydroxylase

resistance

ALDOSTERONE RESISTANCE
| Aldosterone

receptor defects:
spironolactone
| ENaC defects: amiloride, triamterene,
trimethoprim, pentamidine
| Pseudohypoaldosteronism-type 1 (AD and
AR) and type 2 (AD)
| Distal tubular defect

PSEUDOHYPOALDOSTERONISM
TYPE 1

Pseudohypoaldosteronism type 2
Gordon syndrome, familial hyperkalemic HT

WNK4 , WNK1
mutation

AD
AR

K channel

Cl-

Volume depletion, hyperkalemia, metabolic acidosis,

high PRA, high aldosterone

Hypertension, hyperkalemia, metabolic acidosis,

low PRA, low aldosterone

EKG change (emergency)?

10 ?

Membrane antagonism K shift to ICF

IV calcium gluconate Insulin + glucose
2-Adrenergic agonist
NaHCO3?

High urine [K]

Furosemide
NaCl
Urea

GI
Cathartics

Low urine [K]

Mineralocorticoid
NaHCO3
Acetazolamide

TREATMENT OF
HYPERKALEMIA
Mild asymptomatic hyperkalemia
| Decreased
y

Moderate to severe or symptomatic

hyperkalemia

Dietary K+ < 50 mEq/day

| Avoid
y

the exogenous potassium load

TREATMENT OF
HYPERKALEMIA

drugs that cause hyperkalemia

Potassium-sparing diuretics
ACEIs, NSAIDs

| Loop

diuretics volume expansion

| Cation exchange resins by GI route
| Treatment of acidemia

ECG change

K > 6.5 mEq/L

Sudden rise combined with continuous cellular lysis

or the presence of drugs that impair K homeostasis

Antagonizing cardiac effects : IV calcium salts

Promoting rapid intracellular shifting of potassium :

Insulin and glucose, sodium bicarbonate, 2-agonists

Removing potassium rapidly : dialysis

TREATMENT OF
HYPERKALEMIA
Onset

Duration

Antagonise
membrane effects

Mechanism

Calcium

Therapy

Calcium gluconate, 10%

solution, 10 mL i.v. over 10 min

1-3 min

30-60 min

Cellular potassium
uptake

Insulin

Regular insulin 10 U i.v., with

dextrose, 50%, 50 mL if plasma
glucose < 250 mg/dL

30 min

4-6 h

2-agonists

Nebulized albuterol, 10 mg

30 min

2-4 h

NaHCO3

Sodium bicarbonate, 7.5%

solution, 50-100 mL iv. over 1530 min

510 min

2h

Calcium
polystyrene
sulfonate

Kalimate, 60 g p.o., in 20%

sorbitol,
or
Kaate, 60 g in 250 mL water, per
retention enema

1-2 h

4-6 h

Furosemide

40 250 mg IV

Hemodialysis

Potassium removal

Dose

30-60 min

Suparoek Jittikanont

Diuresis
Immediate

HYPONATREMIA &
HYPERNATREMIA

Until dialysis
completed

Renal division
Chiang Mai University

HYPO & HYPERNATREMIA

Osmolality = solute or particle concentration of a fluid
(mEq/kg)
2%
(3.5 5.5 mmol/L)

ATP-ase

Na+
97% (135-145 mmol/L)

Tonicity = effective osmolality = concentration of solute

or particle that restricted to that compartment (ICF or
ECF)
ECF osmolality = ICF osmolality
[Na+, Cl-, HCO3-]EC = [K+, organic phosphate esters]IC

TBosm = ECosm = ICosm

TBosm = Posm
Posm = (2PNa + glucose/18 + BUN/2.8)
Posm 2PNa
TBosm = (2Na+e + 2K+e)/TBW
Posm = TBosm
2PNa = 2(Na+e + K+e)/TBW

BODY FLUID COMPOSITION

ECF
1/3 of TBW
Plasma
of ECF

Interstitial
fluid
of ECF

ICF
2/3 of TBW

PNa = (Na+e + K+e)/TBW

Posm or PNa = water metabolism

Total body water = 50 - 60% body weight

Thirst
- Effective osmolality (295)
- BP
- ECF volume
- Habit

AVP, ADH
- Hypertonicity
- Effective circulating (arterial) volume
- Nausea
- Pain
- Stress
- Hypoglycemia
- Pregnancy
- Numerous drugs

ADH effect

Glucose 100 mg/dl : PNa 1.4

Plasma protein 1 mg/dl : PNa 0.25
TG 100 mg/dl : PNa 2

CAUSE OF SIADH

SIADH
Hypoosmolality hyponatremia
Uosm > 100
| UNa > 40
| Normovolemia
| Normal PK and acid-base
| Hypouricemia
| Normal adrenal and thyroid function
|
|

CLINICAL FEATURES
|

Neurologic
Severity : rapidity of onset and absolute decrease in
PNa
y Asymptomatic, nausea, malaise, headache, lethargy,
confusion, obtundation, stupor, seizures, and coma
y

< 48 h

> 48 h

MANAGEMENT OF HYPONATREMIA
Correct PNa

1.

y
y

Restrict water intake

Promote water loss

Correct underlying condition

2.

Rate of correction

y
y
y
y

Symptomatic? Chronic?
0.5-1 mEq/L/hr
12 mEq/24 hr
18 mEq/48 hr

RISK FACTOR FOR DEVELOPMENT

OF
Cerebral Edema
|

Postoperative
menstruant females
Elderly females on
thiazide diuretics

Children

Psychogenic polydipsia

Hypoxemia

Osmotic Demyelination
|

Alcoholism

Malnutrition

Burns

Severe potassium
depletion

Elderly women on
thiazide diuretics

MANAGEMENT OF
HYPONATREMIA
|

Hypovolemic hyponatremia
Stuporous to coma or seizure hypertonic saline (3% NaCl,
Na+ 514 mEq/L)
y Asymptomatic or drowsiness isotonic saline
y Na+ required = 0.5 - 0.6 x BW x (desired PNa - current PNa)
y

Euvolemic hyponatremia
Water restriction, increase salt, urea, or protein intake,
furosemide
y Vasopressin antagonist
y

Hypervolemic hyponatremia
y

Salt and water restriction, correct potassium depletion,

furosemide, dialysis

HYPERNATREMIA
|
|

|
|

PNa > 145 mmol/L

Loss of water or Na gain
Hyperosmolality contracted ICF volume
Subarachnoid or intracerebral hemorrhage

Altered mental status, weakness, neuromuscular

irritability, focal neurologic deficits, and
occasionally coma or seizures
| Polyuria or thirst
| Patient with CDI tend to prefer ice-cold water
|

MANAGEMENT OF
HYPERNATREMIA
|

Stop ongoing water loss: treating the underlying

cause

Correct the water deficit

Water deficit (L)

= 0.5-0.6 x BW x [1-(current PNa/140)]
| Fluid therapy = water deficit + ongoing losses
| Over at least 48 - 72 h
|

PNa 0.5 mmol/L per h and 12 mmol/L over the first

24 h

hypovolemic

Total body
sodium

euvolemic

hypervolemic

TBW

ECF