INTERNAL MEDICINE 3B (NEPHROLOGY)

Disturbances in Sodium and Potassium

Department of Medicine

TOPIC OUTLINE Acute hyponatremia can be safely corrected more quickly than chronic
I. Composition of Body Fluids hyponatremia. A severely symptomatic patient with acute hyponatremia is in
II. Sodium Disorders danger from brain edema. In contrast, a symptomatic patient with chronic
a. Hyponatremia hyponatremia is more at risk from rapid correction of hyponatremia.
b. Hypernatremia Diagnostic Approach to Hyponatremia:
III. Potassium Disorders
a. Hypokalemia
b. Hyperkalemia
IV. References
LEGEND
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COMPOSITION OF BODY FLUIDS

 Total-body water- distributed in two major compartments:
o 55–75% is intracellular (K+ and organic phosphate esters)
o 25–45% is extracellular (Na+, Cl-, HCO3): subdivided into two
(ratio of 1:3)
- Intravascular (plasma water)
- Extravascular (interstitial)
 Starling forces determine the fluid movement between the
intravascular and interstitial spaces occurs across the capillary wall
o Capillary hydraulic pressure > Colloid osmotic pressure 
movement of plasma ultrafiltrate into the extravascular space.
o Return of fluid into the intravascular compartment occurs via
lymphatic flow.
 Osmolality- solute or particle concentration of a fluid.
o Expressed as mOsm/kg (NV: 280-295 mOsm/kg).
o Water easily diffuses across most cell membranes to achieve
osmotic equilibrium (ECF osmolality = ICF osmolality).
o Major ECF particles are Na+ (main constituent).
o Solutes that are restricted to the ECF or the ICF determine
the “tonicity” or effective osmolality of that compartment.
o Urea do not contribute to water shifts across most
membranes and are thus known as ineffective osmoles.
Posm = 2 x plasma Na+ [mEq/L) + glucose (mg/dL)/18 + BUN
(mg/dL)/2.8
 Key effectors of osmolality:
o Vasopressin secretion
o Water ingestion
o Renal water transport
SODIUM DISORDERS
 Caused by abnormalities in water homeostasis, leading to changes
in the relative ratio of Na+ to body water.
o Hyperosmolar disorders (hypernatremia)- deficiency of body
water relative to body solute.
o Hypoosmolar disorders (hyponatremia)- excess of body water
relative to body solute.
 Water intake and circulating AVP constitute the two key effectors in
the defense of serum osmolality.
I. HYPONATREMIA (<135mM)
 Occurs in up to 22% of hospitalized patients.
 Almost always the result of an increase in circulating AVP and/or
increased renal sensitivity to AVP + intake of free water
 Subdivided diagnostically into three groups:
o Hypovolemic, euvolemic, and hypervolemic
o Acute (<48 hrs) or Chronic (>48 hrs)
 Pseudohyponatremia- hyponatremia with normal or increased
plasma osmolality accompanied with hyperlipidemia,
hyperproteinemia.
A. HYPOVOLEMIC HYPONATREMIA
 Hypovolemia causes a marked neurohumoral activation, increasing
circulating levels of AVP.
o Increase in circulating AVP helps preserve blood pressure via
vascular and baroreceptor V1A receptors and increases water
reabsorption via renal V2 receptors
o Activation of V2 receptors can lead to hyponatremia in the setting of
increased free water intake.
 Decreased total body water and sodium.
 Gold standard for diagnosis: correction of serum Na+ after hydration
with normal saline,
 Urine Na+ concentration:
o Non-renal loss: <20 mEq/L (good response to IV NSS)
o Renal loss: >20 mEq/L
 Effects of diuretics:
o Thiazides cause hyponatremia via polydipsia and diuretic-induced
volume depletion. Do not inhibit the renal concentrating mechanism,
such that circulating AVP retains a full effect on renal water retention.
o Loop diuretics inhibit Na+-Cl– and K+ absorption by the TALH,
blunting the countercurrent mechanism and reducing the ability to
concentrate the urine.
B. HYPERVOLEMIC HYPONATREMIA
 Patients develop an increase in total-body Na+-Cl– that is accompanied by
a proportionately greater increase in total-body water, leading to a
reduced plasma Na+ concentration.
 Sodium-avid edematous disorders
o Congestive heart failure
o Liver cirrhosis
o Nephrotic syndrome
 Urine Na+ concentration is typically very low (<10 mM), even after
hydration with normal saline; may be obscured by diuretic therapy.
 The degree of hyponatremia provides an indirect index of the associated
neurohumoral activation and is an important prognostic indicator.
C. EUVOLEMIC HYPONATREMIA
 Subclinically volume-expanded (no edema).
o Due to AVP-induced water and Na+-Cl– retention
 SIAD- most frequent cause of euvolemic hyponatremia.
o The generation of hyponatremia in SIAD requires an intake of free
water, with persistent intake at serum osmolalities that are lower than
the usual threshold for thirst.
o Osmotic threshold and osmotic response curves for the sensation of
thirst are shifted downward in patients with SIAD.
o Four distinct patterns of AVP secretion:
- Independent for the most part of the underlying cause.
- Unregulated, erratic AVP secretion with no obvious correlation
between serum osmolality and circulating AVP levels.
- Failure to suppress AVP secretion at lower serum osmolalities
- No detectable circulating AVP
o Serum uric acid is often low (<4 mg/dL).
o Common causes of SIAD:
- Pulmonary disease and CNS diseases
- Small-cell lung carcinoma (75% of malignancy-associated SIAD)
- Selective serotonin reuptake inhibitors (SSRIs)

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Table 1.0: Causes of Syndrome of Inappropriate Antiduresis

Malignant Diseases Pulmonary Disorders Disorders of the CNS Drugs Other Causes
o Carcinoma o Infections o Infection o Drugs that stimulate release of o Hereditary (gain-of-
o Lung o Bacterial pneumonia o Encephalitis AVP or enhance its action function mutations in
- Small cell o Viral pneumonia o Meningitis o Chlorpropamide the vasopressin V2
- Mesothelioma o Pulmonary abscess o Brain abscess o SSRIs receptor)
o Oropharynx o Tuberculosis o Rocky Mountain spotted fever o Tricyclic antidepressants o Idiopathic
o Gastrointestinal tract o Aspergillosis o AIDS o Clofibrate o Transient
- Stomach o Asthma o Bleeding and masses o Carbamazepine o Endurance exercise
- Duodenum o Cystic fibrosis - Subdural hematoma o Vincristine o General anesthesia
- Pancreas o Respiratory failure - Subarachnoid hemorrhage o Nicotine o Nausea
o Genitourinary tract associated with positive- - Cerebrovascular accident o Narcotics o Pain
- Ureter pressure breathing - Brain tumors o Antipsychotic drugs o Stress
- Bladder - Head trauma o Ifosfamide
- Prostate - Hydrocephalus o Cyclophosphamide
- Endometrium - Cavernous sinus thrombosis o NSAIDS
o Endocrine thymoma o Other o MDMA (“ecstasy”)
o Lymphomas - Multiple sclerosis o AVP analogues
o Sarcomas - Guillain-Barré syndrome o Desmopressin
o Ewing’s sarcoma - Shy-Drager syndrome o Oxytocin
- Delirium tremens o Vasopressin
- Acute intermittent porphyria

D. LOW SOLUTE INTAKE AND HYPONATREMIA

 Occurs in patients with a very low intake of dietary solutes.
 Beer potomania- occurs in alcoholics whose sole nutrient is beer.
o Beer is very low in protein and salt content (1–2 mM of Na+).
o AVP levels have not been reported in patients with beer
potomania but are expected to be suppressed or rapidly
suppressible with saline hydration.
 Also seen in highly restricted solute intake due to nutrient-
restricted diets (extreme vegetarian diets).
o Resumption of a normal diet and/or saline hydration will also
correct the causative deficit in urinary solute excretion
 Typically present with a very low urine osmolality (<100–200
mOsm/kg) with a urine Na+ concentration that is <10–20 mM.
 Pathophysiology:
o Inadequate dietary intake of solutes.
o Reduced urinary solute excretion limits water excretion such
that hyponatremia ensues after relatively modest polydipsia.
E. CLINICAL FEATURES OF HYPONATREMIA
 Generalized cellular swelling (cerebral edema)
o Consequence of water movement down the osmotic gradient
from the hypotonic ECF to the ICF.
 Symptoms are primarily neurologic
o Initial CNS response to acute hyponatremia: increase in
interstitial pressure  shunting of ECF and solutes from the
interstitial space into the CSF  systemic circulation.
o This is accompanied by an efflux of the major intracellular ions,
Na+, K+, and Cl– from brain cells.
 Acute symptomatic hyponatremia:
o Medical emergency
o Premenopausal women are much more likely than men to
develop encephalopathy and severe neurologic sequelae.
o Early symptoms: nausea, headache, and vomiting.
o Severe complications: seizure activity, brainstem herniation,
coma, and death (normocapneic or hypercapneic
respiratory failure)
o Often has an iatrogenic component
o Causes of acute hyponatremia:
- Iatrogenic
 Postoperative: premenopausal women
 Hypotonic fluids with cause of ↑ vasopressin
 Glycine irrigation: TURP, uterine surgery
 Colonoscopy preparation
- Recent institution of thiazides
- Polydipsia
- MDMA (“ecstasy,” “Molly”) ingestion
- Exercise induced
- Multifactorial, e.g., thiazide and polydipsia
 Chronic hyponatremia
o Less likely to have severe symptoms.
o Subtle gait and cognitive defects, vomiting, nausea, confusion,
seizures (Na < 125 mM)
o Increased risk of falls
o Also increases the risk of bony fractures owing to the
associated neurologic dysfunction.
Chronic hyponatremia results in an efflux of organic osmolytes
from brain cells; this response reduces intracellular osmolality and the
osmotic gradient favoring water entry. This reduction in intracellular
osmolytes is largely complete within 48 h, the time period that clinically
defines chronic hyponatremia; this temporal definition has considerable
relevance for the treatment of hyponatremia.
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 The management of chronic hyponatremia is complicated significantly by
the asymmetry of the cellular response to correction of plasma Na+
concentration.
o Reaccumulation of organic osmolytes by brain cells is attenuated and
delayed as osmolality increases after correction of hyponatremia,
sometimes resulting in:
- Degenerative loss of oligodendrocytes
- Osmotic demyelination syndrome (ODS)
 Classically affect the pons
 Other regions of the brain can also be involved in ODS
 Relowering of plasma Na+ concentration after overly rapid
correction can prevent or attenuate ODS.
o Overly rapid correction of hyponatremia (>8–10 mM in 24 h or 18 mM
in 48 h) is also associated with a disruption in integrity of the blood-
brain barrier, allowing the entry of immune mediators that may
contribute to demyelination.
F. DIAGNOSTIC EVALUATION OF HYPONATREMIA
 Clinical assessment of hyponatremic patients should focus on:
o Volume status
o Underlying cause
o Detailed drug history
 Radiologic imaging may also be appropriate to assess whether patients
have a pulmonary or CNS cause for hyponatremia.
 Laboratory investigations:
o Measurement of serum osmolality to exclude pseudohyponatremia
o Elevated BUN and creatinine can also indicate renal dysfunction as a
potential cause of hyponatremia
o Hyperkalemia may suggest adrenal insufficiency or
hypoaldosteronism.
o Serum glucose (plasma Na+ concentration falls by ~1.6–2.4 mM for
every 100-mg/dL increase in glucose)
o Measurement of serum uric acid
- SIAD-type physiology will typically be hypouricemic
- Volume-depleted patients will often be hyperuricemic.
o Thyroid, adrenal, and pituitary function
o Urine electrolytes
- Urine Na+ concentration: renal vs. non-renal causes
- Urine K+: calculate urine-to-plasma electrolyte ratio (predicts
response to fluid restriction)
o Urine osmolality
- <100 mOsm/kg is suggestive of polydipsia
- >400 mOsm/kg indicates that AVP excess
- Intermediate values are more consistent with multifactorial
pathophysiology (AVP excess with polydipsia)
G. TREATMENT OF HYPONATREMIA
 Treatment or withdrawal of underlying cause
 Considerations:
o Presence/severity of symptoms
o Duration: acute vs. chronic
- Chronic: risk for ODS if plasma Na+ is corrected by > 8-10 mM
within 24 hrs or >18 mM within 48 hours
 Response to intervention is unpredictable.
 Acute symptomatic hyponatremia:
o Hypertonic 3% saline (513 mM)
o Goal: increase plasma Na+ by 1-2 mM/h (total 4-6 mM/h) and to
alleviate severe acute symptoms followed by corrective guidelines for
chronic hyponatremia
o Na+ deficit = 0.6 x BW x (target plasma Na+ - starting plasma Na+)
o Monitor plasma Na+ every 2-4 hours
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 Chronic hyponatremia  Gestational DI- rare complication of late-term pregnancy wherein

o Prevent ODS (increased risk: alcoholism, hypokalemia) increased activity of a circulating placental protease with
- Increase plasma Na+: “vasopressinase” activity leads to reduced circulating AVP and polyuria,
 < 8-10 mM in 24 hours often accompanied by hypernatremia.
 < 18 mM in 48 hours
o Water deprivation Diagnostic Approach to Hypernatremia:
- U-P electrolyte ratio (urine Na+ + K+/ plasma Na+)
 Ratio > 1: <500 mL/day
 Ratio ~ 1: 500-700 mL/day
 Ratio < 1: <1L/day
 Patients with SIAD:
o Combined therapy with oral furosemide (20 mg BID) and oral
salt tablets
- Furosemide serves to inhibit the renal countercurrent
mechanism and blunt urinary concentrating ability
- Salt tablets counteract diuretic-associated natriuresis.
o Demeclocycline is a potent inhibitor of principal cells and can be
used in patients whose Na+ levels do not increase in response
to furosemide and salt tablets.
- Associated with a reduction in GFR
- It should be avoided in cirrhotic patients
 AVP antagonists- are highly effective in SIAD and in hypervolemic
hyponatremia due to heart failure or cirrhosis
o Augmentation of free water clearance.
o Tolvaptan: oral V2 antagonist
o Conivaptan: IV V1A/V2 antagonist
o Abnormalities in liver function tests have been reported with
chronic tolvaptan therapy (use of this agent should be restricted
to <1–2 months).
 Specific treatments:
o Hypovolemic hyponatremia: isotonic normal saline
o Euvolemic hyponatremia: treat underlying cause
o Hypervolemic hyponatremia: treat CHF, cirrhosis, nephrotic
syndrome
II. HYPERNATREMIA (>145 mM)
 Less common than hyponatremia.
 Associated with mortality rates of as high as 40–60%, mostly due to
the severity of the associated underlying disease processes. C. CLINICAL FEATURES OF HYPERNATREMIA
 Pathophysiology:  Hypernatremia increases osmolality of the ECF (cellular shrinkage).
o Result of a combined water and electrolyte deficit, with losses of  Symptoms are predominantly neurologic.
H2O in excess of Na+. o Altered mental status is the most frequent manifestation
o Less frequently, the ingestion or iatrogenic administration of o Acute hypernatremia may lead to parenchymal or subarachnoid
excess Na+ can be causative (IV hypertonic saline). hemorrhages and/or subdural hematomas
 Elderly individuals with reduced thirst and/or diminished access to o Vascular complications are primarily encountered in pediatric and
fluids are at the highest risk of developing hypernatremia. neonatal patients.
A. NON-RENAL CAUSES OF HYPERNATREMIA  Osmotic damage to muscle membranes can also lead to hypernatremic
rhabdomyolysis.
 Insensible losses of water may increase in the setting of fever,  Chronic hypernatremia are less likely to develop severe neurologic
exercise, heat exposure, severe burns, or mechanical ventilation. compromise but cellular response predisposes these patients to the
o ~ 10 ml/kg per day development of cerebral edema and seizures during overly rapid
o 700 ml in a 70kg person hydration (overcorrection of plasma Na+ concentration by >10 mM/d).
 Diarrhea- most common GI cause of hypernatremia.
D. DIAGNOSTIC EVALUATION OF HYPERNATREMIA
 Osmotic diarrhea and viral gastroenteritides typically generate
stools with Na+ and K+ <100 mM.  History should focus on the presence or absence of thirst, polyuria, and/or
B. RENAL CAUSES OF HYPERNATREMIA an extrarenal source for water loss, such as diarrhea.
 Physical examination
 Osmotic diuresis: o Detailed neurologic exam and an assessment of the ECFV
o Increase in urinary solute excretion and urine osmolality o Patients with a particularly large water deficit and/or a combined
o Hyperglycaemia, excess urea, post-obstructive diuresis, deficit in electrolytes and water may be hypovolemic, with reduced
mannitol JVP and orthostasis.
 Water diuresis: Diabetes insipidus (central or nephrogenic)  Accurate documentation of daily fluid intake and daily urine output.
o Disorder of insufficient AVP secretion or reduced renal  Laboratory investigations:
response to AVP o Serum osmolality: >295 mOsm/kg
o Clinical syndrome characterized by excretion of abnormally - Increase in circulating AVP
large volumes of urine (diabetes) that is dilute (hypotonic) and - Excretion of low volumes (<500 mL/d) of maximally
devoid of taste from dissolved solutes (insipid). concentrated urine
Table 1.1: Difference between Central vs. Nephrogenic DI o Urine with osmolality >800 mOsm/kg
Features Central DI Nephrogenic DI - Extrarenal source of water loss is primarily responsible for the
o Inadequate o Renal resistance to AVP generation of hypernatremia.
secretion and o Genetic or acquired E. TREATMENT OF HYPERNATREMIA
Defect deficient synthesis (hypercalcemia,
of AVP hypokalemia, lithium, or  Correct/withhold underlying cause: drugs, hyperglycemia, hypercalcemia,
ifosfamide) hypokalemia, diarrhea
DDAVP o Good response o No response (no  Administer free water (electrolyte free water)
Response (>50% increase in change in Uosm) o Per orem or by NGT
Uosm) o IV: D5 water, hypotonic saline (1/4 or 1/2 normal saline)
o Thiazides and NSAIDS  Free water deficit: [(Na - 140)/140] x TBW
o IV, intranasal/oral (indomethacin)
o TBW = 50% of body weight in F, 60% in M
Treatment DDVAP o If secondary to lithium:
- Amiloride 2.5-10mg/d
o Administer over 48-72 hours
- Increase water intake o Avoid correction of plasma Na+ by > 10mM/day
o

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Example: 70 kg, female, serum Na+ 155 A. REDISTRIBUTION AND HYPOKALEMIA

TBW: 70 x 0.5 = 35
[155 - 140/ 140] x 35  Na+/K+-ATPase-mediated cellular uptake of K+
Water deficit = 3.75 liters o Insulin
- Iatrogenic hypokalemia in the management of DKA.
POTASSIUM DISORDERS - Endogenous insulin can provoke hypokalemia, hypomagnesemia
 Homeostatic mechanisms maintain plasma K+ concentration and/or hypophosphatemia in malnourished patients given a
between 3.5 and 5.0 mM. carbohydrate load.
 98% of total-body K+ is intracellular (muscle) o β2 -adrenergic activity:
 Entire daily K+ excretion:  Alteration in the activity of endogenous sympathetic NS
o ~90% in the urine - Alcohol withdrawal
o 10% in the stool - Hyperthyroidism
- Acute myocardial infarction
I. HYPOKALEMIA (3.5 mM) - Severe head injury
 Occurs in 20% of hospitalized patients.  β2 agonists: bronchodilators, tocolytics (Ritodrine), theophylline,
 Has adverse effects on cardiac rhythm, blood pressure and or caffeine overingestion
cardiovascular morbidity.  Sympathomimetics: pseudoepinephrine and ephedrine
 Pseudohypokalemia- factitious decrease in serum K due to o Thyroid hormone
increased uptake of K by cells after venipuncture  Hyperthyroidism with periodic attacks of hypokalemic paralysis
o High ambient temperature (thyrotoxic periodic paralysis)
o Profound leucocytosis - More frequent in Asian or Hispanic origin (genetic variation in
Kir2.6 or muscle-specific TH-responsive K+ channel)
Table 1.2: Causes of Hypokalemia - Weakness of the extremities and limb girdles
Decreased Intake - Paralytic episodes occur between 1 and 6 a.m
o Starvation - Signs and symptoms of hyperthyroidism are not invariably
o Clay ingestion
present.
Redistribution into Cells
- Hypokalemia is attributed to both direct and indirect activation
o Acid-base
of the Na+/K+-ATPase
- Metabolic alkalosis
o Hormonal
- High-dose propranolol (3 mg/kg) rapidly reverses the
- Insulin associated hypokalemia, hypophosphatemia, and paralysis.
- Increased β2-adrenergic sympathetic activity: post–myocardial o Alkalosis
infarction, head injury  Familial hypokalemic periodic paralysis- hypokalemic weakness in the
- β2-Adrenergic agonists—bronchodilators, tocolytics absence of thyroid abnormalities
- α-Adrenergic antagonists o Missense mutations of voltage sensor domains within the α1 subunit
- Thyrotoxic periodic paralysis of L-type calcium channels or the skeletal Na+ channel
- Downstream stimulation of Na+/K+-ATPase: theophylline, caffeine o These mutations generate an abnormal gating pore current activated
o Anabolic state by hyperpolarization.
- Vitamin B12 or folic acid administration (red blood cell  Inhibition of passive efflux of K+: barium toxicity
production)
- Granulocyte-macrophage colony-stimulating factor (white blood B. NON-RENAL LOSS OF POTASSIUM
cell production)  Loss of K+ in sweat is typically low
- Total parenteral nutrition
o Except under extremes of physical exertion.
o Other
- Pseudohypokalemia  Vomiting or nasogastric suctioning
- Hypothermia o Hypochloremic alkalosis results in persistent kaliuresis due to
- Familial hypokalemic periodic paralysis secondary hyperaldosteronism and bicarbonaturia.
- Barium toxicity: systemic inhibition of “leak” K+ channels  Diarrhea: non-anion gap acidosis + negative urine anion gap
Increased Loss o Infectious diarrheal disease
o Non-renal o Non-infectious gastrointestinal processes: celiac disease, ileostomy,
- Gastrointestinal loss (diarrhea) villous adenomas, IBD, colonic pseudo-obstruction (Ogilvie’s
- Integumentary loss (sweat) syndrome), VIPomas, and chronic laxative abuse
o Renal
C. RENAL LOSS OF POTASSIUM
- Increased distal flow and distal Na+ delivery:
 Diuretics  Drug-induced hypokalemia:
 Osmotic diuresis o Diuretics- particularly common cause
 Salt-wasting nephropathies - Associated increases in distal tubular Na+ delivery and distal
- Increased secretion of potassium tubular flow rate and secondary hyperaldosteronism.
 Mineralocorticoid excess:
- Thiazides > loop diuretics
 Primary hyperaldosteronism
 Genetic hyperaldosteronism (familial
- Diuretic effect of thiazides is largely due to inhibition of the Na+-
hyperaldosteronism types I/II/III, congenital adrenal Cl– cotransporter NCC in DCT cells
hyperplasias) o High doses of penicillin-related antibiotics (nafcillin, dicloxacillin,
 Secondary hyperaldosteronism (malignant ticarcillin, oxacillin, and carbenicillin)
hypertension, renin-secreting tumors, renal artery - Can increase obligatory K+ excretion by acting as non-
stenosis, hypovolemia) reabsorbable anions in the distal nephron.
 Cushing’s syndrome o Aminoglycosides, amphotericin, foscarnet, cisplatin, and ifosfamide
 Bartter’s syndrome  Hyperaldosteronism: aldosterone activates the ENaC channel in
 Gitelman’s syndrome principal cells via multiple synergistic mechanisms.
 Apparent mineralocorticoid excess: o Primary: genetic or acquired (aldosterone : PRA ration >50)
 Genetic deficiency of 11β-dehydrogenase-2 (syndrome - Congenital adrenal hyperplasia: increases in circulating 11-
of apparent mineralocorticoid excess) deoxycorticosterone  hypertension and hypokalemia
 Inhibition of 11β-dehydrogenase-2 (glycyrrhetinic/  Caused by defects in either steroid 11β-hydroxylase or
glycyrrhizinic acid and/or carbenoxolone; licorice, food
steroid 17α-hydroxylase.
products, drugs)
 Liddle’s syndrome
o Acquired causes:
 Distal delivery of non-reabsorbed anions: - Aldosterone-producing adenomas (APAs) – 60%
 Vomiting - Idiopathic hyperaldosteronism (IHA) due to bilateral adrenal
 Nasogastric suction hyperplasia and adrenal carcinoma– 40%
 Proximal renal tubular acidosis - Primary or unilateral adrenal hyperplasia (PAH)
 Diabetic ketoacidosis o Secondary:
 Glue-sniffing (toluene abuse), - Increased levels of circulating renin and angiotensin II
 Penicillin derivatives (penicillin, nafcillin, dicloxacillin, - Renal artery stenosis is the most frequent cause
ticarcillin, oxacillin, and carbenicillin)
- Magnesium deficiency

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 Systemic increases in glucocorticoids
o Cushing’s syndrome: 10%
o Ectopic secretion of ACTH: 60-100%
 Defects in multiple renal tubular transport pathways
o Loss-of-function mutations in subunits of the acidifying H+-
ATPase in alpha-intercalated cells
- Hypokalemic distal renal tubular acidosis
- Non-anion gap acidosis + positive urine anion gap
o Liddle’s syndrome- caused by autosomal dominant gain-in-
function mutations of ENaC subunits.
- Severe hypertension with hypokalemia
- Unresponsive to spironolactone yet sensitive to amiloride.
- More consistent features include: blunted aldosterone
response to ACTH and reduced urinary aldosterone
excretion.
o Hereditary hypokalemic alkalosis
- Bartter’s syndrome: loss of transport function of TALH
 Polyuria and polydipsia due to the reduction in renal
concentrating ability.
 Increase in urinary calcium excretion
 20% are hypomagnesemic
 Marked activation of the RAAS axis.
- Gitelman’s syndrome: loss of transport function of DCT
 Loss-of-function mutations in the thiazide-sensitive Na+-
Cl– cotransporter of the DCT.
 Uniformly hypomagnesemic
 Marked hypocalciuria,
 Chondrocalcinosis- abnormal deposition of calcium
pyrophosphate dihydrate (CPPD) in joint cartilage
 Magnesium depletion- has inhibitory effects on muscle Na+/K+-
ATPase activity, reducing influx into muscle cells and causing a
secondary kaliuresis.
o Also causes exaggerated K+ secretion by the distal nephron
- Attributed to a reduction in the magnesium-dependent,
intracellular block of K+ efflux through the secretory K+
channel of principal cells (ROMK).
o Hypomagnesemic patients are clinically refractory to K+
replacement in the absence of Mg2+ repletion.
D. CLINICAL FEATURES OF HYPOKALEMIA
 Cardiac muscle cells
o Major risk factor for both ventricular and atrial arrhythmias.
o Predisposes to digoxin toxicity by reduced competition between
K+ and digoxin for shared binding sites on cardiac Na+/K+-
ATPase subunits.
o ECG changes: broad flat T waves, ST depression, and QT
prolongation (most marked when serum K+ is <2.7 mmol/L).
o Important precipitant of arrhythmia in patients with additional
genetic or acquired causes of QT prolongation.
 Skeletal muscle cells
o Hyperpolarization of skeletal muscle, thus impairing the
capacity to depolarize and contract
o Weakness and even paralysis may ensue.
o It also causes a skeletal myopathy and predisposes to
rhabdomyolysis.
 Intestinal cells: paralytic effects may cause intestinal ileus.
 Functional renal effects
o Na+-Cl– and HCO3 retention
o Polyuria, phosphaturia, hypocitraturia
o Activation of renal ammoniagenesis.
o Generation of metabolic alkalosis.
o Also predisposes to AKI and can lead to ESRD in patients with
long-standing hypokalemia due to eating disorders and/or
laxative abuse.
E. DIAGNOSTIC EVALUATION OF HYPOKALEMIA
 History: medications and symptoms
 Physical examination: BP, volume status, signs suggestive of
specific hypokalemic disorders (e.g: Cushing’ syndrome,
hyperthyroidism).
 Laboratory examinations:
o Electrolytes, Mg2+, Ca2+, BUN, creatinine, serum osmolality,
CBC, ABG
o Urinary pH, osmolality, creatinine and electrolytes
- Urine K+ < 15: non renal loss
o Other tests: thyroid function tests, PRA, aldosterone, adrenal
vein sampling, genetic testing
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o Transtubular K gradient (TTKG)
Urine K+ x serum osmolality
Serum K+ x urine osmolality
- TTKG <3: non renal loss or redistributive hypokalemia
- TTKG >4: renal potassium wasting
o Urinary K-to-creatinine ratio (> 13 mmol/g: renal loss)
Diagnostic Approach to Hypokalemia:
F. TREATMENT OF HYPOKALEMIA
 Goals of therapy:
o Prevent life-threatening and/or serious chronic consequences
o Replace K+ deficit
o Correct underlying cause and/or mitigate future hypokalemia
 Urgency of therapy depends on:
o Severity of hypokalemia
o Rate of decline in serum K+
o Associated clinical factors (cardiac disease, digoxin therapy)
 Management:
o Oral KCl- mainstay of therapy
o Oral/IV potassium phosphate- for combined hypokalemia and
hypophosphatemia
o Potassium bicarbonate or potassium citrate: if with concomitant
metabolic acidosis
o Intravenous KCl
- If unable to use the enteral route
- Presence of severe complications
- Administer in saline solution (NO dextrose!)
 20-40 mmol KCl per liter (peripheral line)
- Severe hypokalemia (K < 2.5 mmol/L) or critically symptomatic
 20 mmol in 100 mL of saline solution through a central vein
(femoral veins: preferred)
o Propranolol 3mg/kg for redistributive hypokalemia secondary to
excessive activity of sympathetic nervous system (TPP, theophylline
overdose, acute head injury)
o Severe redistributive hypokalemia (K+ < 2.5)
- Urgent but cautious replacement
- Risk of rebound hyperkalemia
 Correct hypomagnesemia
 Continuous cardiac telemetry during replacement
 Minimize K+ losses
II. HYPERKALEMIA (>5.5 mM)
 Occurs in up to 10% of hospitalized patients.
 Severe hyperkalemia (>6.0 mM) occurs in ~1%, with a significantly
increased risk of mortality.
 Decrease in renal K+ excretion is the most frequent underlying cause.
 Pseudohyperkalemia- artifactual increase in serum K due to the release
of K+ during or after venepuncture.
o Excessive muscle activity during venipuncture (e.g: fist clenching)
o Increase in cellular elements (thrombocytosis, leukocytosis,
erythrocytosis) causing cellular efflux
o Acute anxiety with respiratory alkalosis (redistributive hyperkalemia)
o Cooling of blood after venipuncture (reduce cellular uptake)
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Table 1.3: Causes of Hyperkalemia
Pseudohyperkalemia
o Cellular efflux; thrombocytosis, erythrocytosis, leukocytosis, in vitro
hemolysis
o Hereditary defects in red cell membrane transport
Intra- to Extracellular Shift
o Acidosis
o Hyperosmolality; radiocontrast, hypertonic dextrose, mannitol
o β2-Adrenergic antagonists (noncardioselective agents)
o Digoxin and related glycosides (yellow oleander, foxglove,
bufadienolide)
o Hyperkalemic periodic paralysis
o Lysine, arginine, and ε-aminocaproic acid (structurally similar,
positively charged)
o Succinylcholine; thermal trauma, neuromuscular injury, disuse
atrophy, mucositis, or prolonged immobilization
o Rapid tumor lysis
Inadequate Excretion
o Inhibition of the renin-angiotensin-aldosterone axis; ↑ risk of
hyperkalemia when used in combination
- Angiotensin-converting enzyme (ACE) inhibitors
- Renin inhibitors; aliskiren (in combination with ACE inhibitors or
angiotensin receptor blockers [ARBs])
- Angiotensin receptor blockers (ARBs)
- Blockade of the mineralocorticoid receptor: spironolactone,
eplerenone, drospirenone
- Blockade of the epithelial sodium channel (ENaC): amiloride,
triamterene, trimethoprim, pentamidine, nafamostat
o Decreased distal delivery
- Congestive heart failure
- Volume depletion
o Hyporeninemic hypoaldosteronism
- Tubulointerstitial diseases: systemic lupus erythematosus (SLE),
sickle cell anemia, obstructive uropathy
- Diabetes, diabetic nephropathy
- Drugs: nonsteroidal anti-inflammatory drugs (NSAIDs),
cyclooxygenase 2 (COX2) inhibitors, β-blockers, cyclosporine,
tacrolimus
- Chronic kidney disease, advanced age
- Pseudohypoaldosteronism type II: defects in WNK1 or WNK4
kinases, Kelch-like 3 (KLHL3), or Cullin 3 (CUL3)
o Renal resistance to mineralocorticoid
- Tubulointerstitial diseases: SLE, amyloidosis, sickle cell anemia,
obstructive uropathy, post–acute tubular necrosis
- Hereditary: pseudohypoaldosteronism type I; defects in the
mineralocorticoid receptor or the epithelial sodium channel
o Advanced renal insufficiency
- Chronic kidney disease
- End-stage renal disease
- Acute oliguric kidney injury
o Primary adrenal insufficiency
- Autoimmune: Addison’s disease, polyglandular endocrinopathy
- Infectious: HIV, cytomegalovirus, tuberculosis, disseminated
fungal infection
- Infiltrative: amyloidosis, malignancy, metastatic cancer
- Drug-associated: heparin, low-molecular-weight heparin
- Hereditary: adrenal hypoplasia congenita, congenital lipoid
adrenal hyperplasia, aldosterone synthase deficiency
- Adrenal hemorrhage or infarction, including in antiphospholipid
syndrome
A. EXCESS POTASSIUM INTAKE
 Excessive intake of K+ is a rare cause, given the adaptive capacity
to increase renal secretion.
 Dietary intake can have a major effect in susceptible patients
o Diabetics with hyporeninemic hypoaldosteronism
o Chronic kidney disease
 Drugs that impact on the renin-angiotensin-aldosterone axis are
also a major cause of hyperkalemia.
o Over-replacement
o K+ containing medications
Table 1.4: Foods with High K+ Content
Highest Content (>1000mg [25mmol]/100g)
o Dried figs
o Molasses
o Seaweeds
Very High Content (>500mg [12.5mmol]/100g)
o Dried fruits (dates, prunes)
o Nuts
o Avocados
o Bran cereals
o Wheat germ
o Lima beans
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High Content (>250mg [6.2mmol]/100g)
o Vegetables: spinach, tomatoes, broccoli. winter spinach, beets, carrots,
cauliflower, potatoes
o Fruits: bananas, cantaloupe, kiwis, oranges, mangoes
o Meats: ground beef, steak, pork, veal, lamb
A. REDISTRIBUTION AND HYPERKALEMIA
 Efflux of intracellular K+ and hyperkalemia
o Acidemia is associated with cellular uptake of H+ and an associated
efflux of K+ (this effective K+-H+ exchange serves to help maintain
extracellular pH)
- Limited to non–anion gap causes of metabolic acidosis and lesser
respiratory causes of acidosis
- Hyperkalemia due to an acidosis-induced shift of K+ from the cells
into the ECF does not occur in the anion gap acidoses lactic
acidosis and ketoacidosis.
o Solvent drag effect: water moves out of cells along the osmotic
gradient
- Hypertonic mannitol, hypertonic saline, and IVIg
- Diabetics are also prone to osmotic hyperkalemia in response to
IV hypertonic glucose, when given without adequate insulin.
o Inhibition of Na+/K+-ATPase and impairs the uptake of K+
- Digoxin inhibits Na+/K+-ATPase and impairs the uptake of K+ by
skeletal muscle.
- Fluoride poisoning is typically associated with hyperkalemia.
o Succinylcholine depolarizes muscle cells, causing an efflux of K+
through AChRs.
o Severe tissue necrosis:
- Acute tumor lysis syndrome
- Rhabdomyolysis
 Familial Hyperkalemic Periodic Paralysis (HYPP)
o Develop myopathic weakness during hyperkalemia induced by
increased K intake or rest after heavy exercise
o Autosomal dominant mutations in the SCN4A gene
 Inadequate excretion
o Primary hypoaldosteronism may be genetic or acquired.
- Addison’s disease
- Polyglandular endocrinopathy
o HIV- most important infectious cause of adrenal insufficiency.
B. RENAL DISEASE AND HYPERKALEMIA
 CKD and ESRD- associated deficit or absence of functioning nephrons.
 Oliguric AKI- decreased distal tubular flow rate and Na+ delivery.
 Tubulointerstitial disease
o Hyperkalemia out of proportion to GFR
o Amyloidosis, sickle cell anemia, interstitial nephritis, and obstructive
uropathy
C. MEDICATION-ASSOCIATED HYPERKALEMIA
 Inhibition of some component of the RAA axis:
o Renin inhibitors: hyporeninemic hypoaldosteronism
- NSAIDs, COX2 inhibitors, cyclosporine, tacrolimus
o ACE inhibitors, ARB
o MLR inhibitor: Yasmin-28 (OCP), spironolactone
 Inhibition of ENaC activity:
o amiloride, trimethoprim (TMP), pentamidine, nafamostat
 Most drugs that affect the renin-angiotensin-aldosterone axis also block
the local adrenal response to hyperkalemia, thus attenuating the direct
stimulation of aldosterone release by increased plasma K+ concentration.
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D. CLINICAL FEATURES OF HYPERKALEMIA  Immediate antagonism of the cardiac effect of hyperkalemia

o Intravenous calcium- raises action potential threshold and reduces
 Medical emergency due to its effects on the heart. excitability without changing the resting membrane potential
 Cardiac arrhythmias associated with hyperkalemia: - 10 mL of 10% calcium gluconate IV over 2-3 minutes with cardiac
o Sinus bradycardia monitoring
o Sinus arrest - Onset: within 1-3 minutes
o Slow idioventricular rhythms - Duration of action: 30-60 minutes
o Ventricular tachycardia  Rapid reduction in plasma K+ concentration by redistribution into cells
o Ventricular fibrillation o 10 unit regular insulin IV followed immediately by 50ml of 50%
o Asystole dextrose
Table 1.5: Electrocardiographic Changes in Hyperkalemia - Glucose >/= 200-250 mg/dl: insulin without glucose
Severity Serum K+ Level ECG Changes - Onset: 10-20 minutes
o Affects repolarization phase of - Peak: 30-60 minutes
Mild 5.5-.65 cardiac action potential - Duration: 4-6 hours
o Changes in T-wave morphology: o B2 agonists (Albuterol)- additive with insulin plus glucose therapy
Tall peaked T wave - 10-20 mg of nebulized albuterol in 4ml of normal saline, inhaled in
o Depressed intracardiac over 10 minutes
conduction - Onset: 30 minutes
Moderate 6.5-7.5 o Progressive prolongation of the - Peak: 90 minutes
PR and QRS intervals - Duration: 2-6 hours
o Loss of P waves o Intravenous bicarbonate- no role in acute treatment of hyperkalemia
7.0-8.0 o Progressive widening of the QRS - Drop in K+ after 4-6 hours of infusion
Severe complex - Should be infused in isotonic or hypotonic fluid (150 mEq in 1L of
>8.0 o Sine wave pattern: impending D5W)
ventricular fibrillation or asystole  Removal of K+
 Secondary hyperkalemic paralysis o Cation exchange resin [sodium polystyrene sulfonate (SPS)]
o Ascending paralysis - Exchanges Na+ for K+ in the gastrointestinal tract and increases
o The presentation may include diaphragmatic paralysis and fecal excretion of K+
respiratory failure. - Delayed onset of efficacy: up to 24 hours
 Hyperkalemia per se can contribute to metabolic acidosis. - 15-30 grams of powder every 4-6 hours
o Competition between K+ and NH4+ for reabsorption by the TALH - Side effect: intestinal necrosis
and subsequent countercurrent multiplication o Intravenous saline- in hypovolemic patients with oliguria
o Reduced medullary gradient for NH3 /NH4 excretion by the distal o Loop and thiazide diuretics
nephron. - In volume-replete or hypervolemic patients with sufficient renal
function
E. DIAGNOSTIC EVALUATION OF HYPERKALEMIA
- May be combined with intravenous saline or isotonic bicarbonate
 History and PE: medications, diet and dietary supplements, risk o Hemodialysis- most effective and reliable method for K+ removal
factors for kidney failure, reduction in urine output, blood pressure,
and volume status.
 Laboratory: electrolytes, BUN and creatinine, serum osmolality,
magnesium, calcium, CBC, urinary pH, osmolality, creatinine and
electrolytes.
o TTKG: >7-8: hyperkalemia
Diagnostic Approach to Hypokalemia:

F. TREATMENT OF HYPERKALEMIA
 Urgent management if:
o With ECG changes
o Significant hyperkalemia (K >/= 6.5 mM)
 Hospital admission, continuous cardiac monitoring, immediate
treatment. REFERENCES
1. Powerpoint 2022
2. Jameson, J. L., & Loscalzo, J. (2018). Harrison's principles of internal medicine (20th
edition.). New York: McGraw Hill Education.

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