Rosalie Sabina Michiko S.

Samonte, MD DPSP
San Beda College of Medicine
November 2012
Molecules or ions with an electrical charge
Important determinants of osmolality, state
of dehydration and pH of both ECF and ICF
Effective osmoles particles that are not
equally distributed, cause movements of
water and hence determine volume of
compartments
Expressed as mEq/L or mmol/L (SI)
1 mEq = 1mmol


Intracellular fluid
(ICF)
Fluid inside the
cell
Most (60%) of the
bodys H20 is in
the ICF.
Metabolic
activities

Extracellular fluid (ECF)
Fluid outside the cell.
40% of bodys H20
Conduit
3 types:
Interstitial (28%)- fluid
around/between cells
Intravascular(8%)-
(plasma) fluid in
blood vessels
Transcellular(4%)CSF,
Synovial fluid, etc


Normal range: 136-142 mmol/L
Major cation in ECF; determines ECF volume
Responsible for 90-95% of osmotic pressure
Maintains water balance, transmits nerve
impulses, contracts muscles
Critical values: <120 mmol/L, >160 mmol/L


Renin-Angiotensin-Aldosterone System:
promotes Na
+
reabsorption by kidney
Vasopressin (ADH):Released in response to
osmolality and low volume water
reabsorption osmolality
Atrial Natriuretic Peptide (ANP): promotes
renal Na
+
and water loss to BP



Maintains normal concentrations of Na
+
& K
+

2 K
+
into cells, 3 Na
+
out
Uses ATP, magnesium and an enzyme
Prevents cell swelling and creates an
electrical charge allowing neuromuscular
impulse transmission

Ion Sensitive Electrodes (ISE)
May be direct or indirect
Indirect
Dilution of the sample
Most automated analyzers
Affected by lipid and protein concentrations
Direct
No dilution of the sample
Blood gas machines
Analytical
Electrodes are very specific
In the presence of increased amounts of non-
aqueous components we get reduced values with
indirect methods (pseudohyponatremia)
Pre-analytical
Drip-arm sample (Taken from the arm with IV
line)
Wrong patient
Gross hemolysis (dilution with intracellular fluid)

The most common electrolyte disorder
<135 mmol/L
Causes:
1. Shift of H20 from the cell caused by
extracellular solutes (ex. Glucose)
2. Retention of excess H20
3. Loss of Na
+

4. Shift of Na
+
into cells.

Primarily neurologic symptoms
Headache, muscle twitching, altered
mental status, stupor, seizures, coma
Edema

Artifactual hyponatremia
In vitro hemolysis most common

Hemolyzed
Dilution of sample (flame photometer, and
indirect ion-specific electrode method)
Occurs in Hyperglycemia, Hyperproteinemia, &
Hyperlipidemia (occupy volume and displace
water, so that plasma contains less water per unit
volume and less electrolytes per unit volume)
Measured osmolality is NORMAL

Osmolality-a measure of the number of particles
dissolved in a solution (protein, glucose, chloride,
sodium, bicarbonate and urea in the plasma).
Affected by increases or decreases in fluid volume
or by an increase or decrease in blood particles.
** Used to assess the patients fluid status and
identify any ADH abnormalities.
Normal: Adults: 280-295 mmol/kg
Increased values = alcoholism, aldosteronism,
diabetes insipidus, high protein diet, dehydration,
hypercalcemia, hyperglycemia, hypernatremia &
hyperkalemia
Decreased values = fluid overload, liver failure with
ascites, Addison's disease



>145 mmol/L (CRISIS >160 mmol/L)
Always associated with effective
plasma osmolality and reduced cell
volume
Causes:
1. Loss of H20 or reduced intake
2. Gain of Na
+

3. Both
Activity of nerves, muscles (more sensitive, easily
depolarized)
- hyperactivity, restlessness, agitated behavior,
convulsions, muscle tremors, spasms, rigidity,
coma may develop
Dehydration of neurons with disturbed brain
function
Oliguria, concentrated urine
Dry skin, firm rubbery skin turgor, dry mouth, dry
mucous membranes
High body temperature
Thirst
Hypotension related to tachycardia

Major intracellular cation
Normal range: 3.8-5.0 mmol/L
Important for protein and glycogen
metabolism
Important for cardiac and neuromuscular
function
Ion selective electrode method
Potassium imbalances are less common, but
more dangerous


Na
+
/ K
+
ATPase
Aldosterone - causes renal secretion and
excretion of K
+
(opposite the effect of
aldosterone on Na
+
)
Normal kidneys (primary site of overall K
+

regulation) excrete K
+
freely; unable to
conserve K
+
when levels are low
Changes in pH :
Acidosis hyperkalemia (K+ moves out, H+ moves in)
Alkalosis hypokalemia (K+ moves in, H+ moves out)


<3.8 mmol/L (CRISIS <2.5 mmol/L)
Causes:
1. Intracellular shift
2. Reduced intake (rare)
3. Increased loss (Renal loss of K
+
most
common cause of hypokalemia)

Common vomiting and diarrhea
Metabolic alkalosis ( H+ extruded in
exchange for K
+)

Insulin,-2-agonists-stimulates NaK-
ATPase
Cushing's syndrome
mineralocortecoids
1 & 2 Aldosteronism - aldosterone
Na+ reabsorption; K
+
excretion

Skeletal muscle weakness
Smooth muscle of GI constipation, abdominal
distension, paralytic ileus, nausea, vomiting,
anorexia
Cardiac muscle weak contractions, rapid pulse,
irregular contractions (lowered conduction from SA
to AV to bundles & Purkinje fibers)
CNS functions decrease confusion & irritability,
memory impairment, lethargy, apathy, drowsiness,
delirium (impaired conduction of nerve impulses)
Kidneys less responsive to ADH; polyuria,
polydipsia, nocturia result
When severe, ventricular fibrillation, respiratory
paralysis, cardiac arrest

>5.0 mmol/L (CRISIS >6 mmol/L)
Causes:
1. K
+
shifts from cells to ECF
2. Increased intake of K
+

3. Reduced excretion of K
+





ALMOST ALWAYS DUE TO IMPARED RENAL
EXCRETION -Renal failure is most common cause

Muscle irritability, weakness, paralysis
Fibrillation, or bradycardia; depends on level
of serum K+
Electrocardiogram: tall & narrow, peaked T-
waves
Muscles irritability progresses to flaccid
paralysis
Confusion, malaise, nausea, colicky pain,
diarrhea
Oliguria anuria
Terminate in death from ventricular
fibrillation


When platelet and leukocytes are elevated
(thrombocytosis and leukocytosis)
Prolonged tourniquet application; small
gauge needle
In vitro hemolysis
Delayed processing of specimens
NO physiologic consequence
RULE out first in differential diagnosis of
hyperkalemia


Major extracellular anion
Normal range: 95-103 mmol/L
Dietary chloride 100% absorbed in the intestine,
excreted in urine/sweat
Helps maintain electrical neutrality and pH
ISE
Main usefulness (in terms of lab testing) in
calculation of the anion gap
Anion gap For every cation, there is always an
associated anion. Na
+
-main extracellular cation.
HCO
3
-
+ Cl
-
are the main extracellular anions
AG = Na
+
- (HCO
3
-
+ Cl
-
)
(Normal AG: 6-12)


Cl
-
follows Na
+
when aldosterone causes
more Na
+
reabsorption; in the Loop of Henle,
active transport moves Cl
-
into the medulla
and

Na
+
follows they follow each other
>103 mmol/L
Pathology: HCO
3
-
(base loss)
Rare
Caused by excess aldosterone Na
+
and
therefore Cl
-
reabsorption (Cl
-
follows Na
+
)
Signs and symptoms of acidosis
<95 mmol/L
Pathology: HCO
3
-
(base gain)
Causes:
Prolonged vomiting (loss of HCl)
Profuse sweating
Diarrhea
Lack of aldosterone Na
+
loss and Cl
-
and K
+
excretion
Signs and symptoms of alkalosis and hypokalemia

5
th
most abundant mineral element in the human
body
Not free in ICF
99% is found in crystal form in bones and teeth
1% in ECF and soft tissues
Serum (plasma) calcium exists in 3 Forms:
1) Free or ionized-physiologically active- 50%
of Total serum calcium
2) Complexed calcium (bound to anions) 10%
3) Plasma protein-bound (80% bound to
albumin)-40%


Serum is the preferred specimen, heparinized
plasma acceptable (citrate, oxalate, EDTA
interferes)
Normal = 2.2 to 2.58 mmol/L (Total Calcium)
Methods:
1)Calorimetric w/ metallochromic indicators-widely
used; affected by hemolysis, lipemia, paraproteins
and magnesium.
2)Atomic absorption spectrophotometry (reference
standard)
3) Indirect potentiometry


Free or ionized + Plasma protein-bound
Results must be interpreted in clinical context
Diseases associated with hypoalbuminemia
may falsely lower calcium levels corrected
by:
Total calcium (mg/dL) corrected for hypoalbuminemia
=Total calcium measured + [(Normal albumin-
Patients albumin) x 0.8]
*Normal albumin value of 4.4 is used
Normal = 4.6 to 5.3 mmol/L (Ionized free)
Whole blood, heparinized plasma or serum
collected anaerobically & transported in ice to
prevent loss of CO2, glycolysis and to
stabilize pH
Tourniquet left too long can lower pH
falsely elevate results
ISE

The total Ca++ test- more frequently ordered;
good reflection of the amount of free Ca++ in
the blood since balance between free and
bound is usually stable and predictable.
Easier to perform.
In some, the balance between bound and free
calcium is disturbed ionized calcium may
be necessary.
Ionized calcium : Test of choice in critically ill
patients receiving blood transfusions or IV
fluids, patients undergoing major surgery,
and patients with blood protein abnormalities
like hypoalbuminemia.
Large fluctuations in ionized calcium
bradycardia or tachycardia, tetany, confusion
or even coma.
Critically ill ionized calcium


Skeletal mineralization
Cofactor in blood clotting
Neural transmission
Activates intracellular enzymes (ex. Muscle
contraction)
Excitability of skeletal & cardiac muscles
In glandular synthesis & regulation of endocrine &
exocrine glands
Controls membrane permeability for ions, closes ion
channels
Acid-base balance
Hemodialysis
Myeloma
Renal failure
Cirrhosis
Treatment with thiazide diuretics
Sepsis & other cardiovascular instability
Massive blood transfusion
Regulated by parathormone (PTH) and calcitonin
PTH causes 4 activities that serum Ca
+2
with vitamin D, Ca
+2
uptake in intestines
Ca
+2
excretion by kidneys
release of Ca
+2
from bones (osteoclast activity)
phosphate excretion by kidneys, Ca
+2
is
reabsorbed


Calcitonin causes a serum Ca
+2
Calcitonin deposition of bone by
osteoblasts, removing the needed materials
from the blood
Serum calcium and serum phosphate are
inversely related
If both calcium ions and phosphates are high
in the blood, they are deposited into bone
matrix.

> 4.8 mmol/L (CRISIS >6 mmol/L)
PATHOLOGY: Keeps more ion channels closed
reduced neuromuscular responses (raises
threshold; requires stronger stimulus for
depolarization)
NOTE: There is an INVERSE relationship between Ca
+2

level & cell membrane permeability.
Ca
+2
permeability
Excess Ca
+2
excreted; if urine becomes alkaline, kidney
stones form (calcium dissolves in acid)
NOTE: More Ca
+2
in diet binds oxalate in the gut
lower number of oxalate kidney stones
Causes gastric juice formation

Hyperparathyroidism excess PTH
Complication of cancer (esp. with widespread bone
breakdown displaces Ca
+2
to the blood)
Prolonged immobility: reduced weight bearing =
reduced stress on bones matrix breaks down
Ca
+2
is released
Excess ingestion of vitamin D ( absorption
beyond normal)
Addison's disease (adrenocortical insufficiency)
Multiple myeloma (>20 mEq/L) breakdown


Hypercalcemia may lead to DEATH
Reduction of neuromuscular excitability related
to reduced permeability of cell membranes
- GI (smooth muscle): constipation, anorexia, abdominal
pain, nausea, vomiting
- heart (cardiac muscle): arrhythmias shorter QT
interval, inverted T wave, prolonged systole & force of
contraction
- skeletal muscle: reduced muscle tone, dysphagia
- CNS: sedative effect apathy, depression,
headache, drowsiness, poor memory
IF SEVERE: lethargy, syncope (fainting), disorientation,
hallucinations, coma
-polyuria, polyphagia, weakness

Calcium in fluids precipitates more easily
renal calculi (kidney stones)
Loss from bone weakens it pathogenic
fractures
Increased gastric juice formation may lead to
gastric ulcer formation

< 4 mmol/L (CRISIS < 3.5 mmol/L)
Pathology: Excessive membrane permeability
excess irritability, over-excitation nerves/muscles
CAUSES:
Hypoparathyroidism
Impaired absorption of calcium from GI
Diarrhea excessive loss of intestinal secretions
Massive blood transfusions (esp. in newborn)
Malignancy

Increased neuromuscular irritability related to
increase permeability of cell membranes;
depolarization is easier
- muscle twitches, cramps, spasms, convulsions
- laryngospasm
- nervous: numbness, tingling of lips, fingers, toes,
irritability
- cardiac dysrrhythmia, cardiac arrest
- prolonged QT interval, reduced force of systole

Glomerular Filtration Rate (GFR)- global
measure of renal function
Normal: 125 mL/min
Best overall indicator of kidney function
Steady-state levels of substances eliminated by
glomerular filtration
Measurement of clearance of suitable markers
Urea final end product of protein metabolism
Production rate depends on dietary protein
intake.
Freely filtered by the glomerulus but tends to be
reabsorbed and return to the bloodstream
Blood urea levels are quite sensitive indicators of
renal disease, becoming elevated when renal
function drops to around 25-50% of normal.
Normal 2.9-8.9 mmol/L

States associated with elevated levels of urea in blood are
referred to as uremia or azotemia.
Renal causes of urea plasma elevations:
Prerenal: renal hypoperfusion
Renal: acute tubular necrosis
Postrenal: obstruction of urinary flow
Increased protein catabolism:
Increased dietary protein intake
GI bleeding (blood digested and protein absorbed)
Severe stress
Reduced dietary intake of protein
Anabolism during recovery from illness
Severe liver disease
Overhydration
Isotope dilution mass spectrometry-gold
standard
Colorimetric method
Enzymatic method hydrolysis of urea by
urease, producing ammonia and CO2.
Measurement of ammonia is most often used
Amino acid waste product of protein metabolism
Endogenous creatinine produced is proportional to
muscle mass the production varies with age and
sex
Dietary fluctuations of creatinine intake cause only
minor variation in daily creatinine excretion of the
same person.



Not bound to plasma proteins, hence freely
filtered by the glomerulus; Not reabsorbed
by the tubules
Some tubular excretion
Normal range: 53-136 micromoles/L (adult)
27-53 micromoles/L (children)

More sensitive and specific test
Production rate more constant than urea
Does not undergo significant tubular
reabsorption
Reduced renal function
Urinary tract obstruction
Increased total muscle mass
Muscle trauma or rhabdomyolysis
Drugs ex. Cimetidine, trimethoprim,
triamterene, amilioride and probenecid block
tubular secretion of creatinine.
Scant muscle mass frail elderly and children
Some muscular dystrophies

Some tubular secretion (10-20% of total). In
chronic renal failure, may rise up to 40%
(underestimation of renal dysfunction)
Extrarenal elimination by creatinases in the
GIT by intestinal flora.
Jaffe reaction (Alkaline picrate method)-
glucose, protein, acetoacetate, pyruvate, uric
acid, fructose, ascorbic acid and cephalosporins
falsely elevate the result.
Kinetic or autoanalyzer assay-bilirubin
decreases creatinine values
Creatinine Imidohydrolase- generally very
accurate but is also affected by flucytosine and
severe hyperglycemia.
Isotope dilution mass spectrometry-gold
standard


Clearance = (U x V)/P
Where U is the urinary concentration of substance x
V is the rate of urine formation (mL/min)
P is the plasma concentration of substance x
Units = volume/unit time (mL/min)
If clearance = GFR, then substance x should
have the following properties:
Freely filtered by glomerulus
Glomerulus = sole route of excretion from the
body (no tubular secretion or reabsorption)
Non-toxic and easily measurable

Property Urea Creatinine Inulin
99m
TcDTPA
Not Protein
Bound
Yes Yes Yes Yes
Freely
Filtered
Yes Yes Yes Yes
No secretion
or absorbtion
Flow related
reabsorption
Some
secretion
Yes Yes
Constant
endogenous
production
rate
No Yes No No
Easily
Assayed
Yes Yes No No
Gold Standard
Plant polysaccharide (exogenous)
Complex procedure, expensive and not
readily available

Volume of blood plasma that is cleared of creatinine per unit
time
Useful measure for approximating GFR
Total amount of creatinine excreted in urine in a 24 hour
period
Blood sample taken within the period of collection
Problems:
COMPLETE urine collection is essential for the accurate
determination of creatinine clearance
Increased in pregnancy
Increased with exercise
GFR as reflected by creatinine clearance declines by 10% per
decade after age 50
Reference range : 90-120 mL/min for young adults
NOT widely done any more, due to the difficulty in
assuring a complete urine collection

Cockroft-Gault
Modification of Diet in Renal Disease (MDRD)
eCCr = [(140-Age) x IBW)] / 72 x SCr), x 0.85 if
female
IBW is calculated by the ff formula:
:IBW=50 kg + 2.3 kg for each inch over 5 ft.
:IBW=45.5 + 2.3 kg for each inch over 5 ft.
Advantage: reduces variability of serum
creatinine estimates of the GFR caused by
differences in creatinine production due to
difference in muscle mass based on sex and age

Disadvantages:
Does not take into account the differences in
creatinine production due to variation in muscle
mass caused by disease states, hence
Overestimates GFR in pxs with low muscle mass
in relation to body weight (obese, edematous or
chronically debilitated).
Does not take into account variations caused by
extrarenal elimination and tubular secretion
Original formula for eGFR using 6 variables : age,
sex, race, BUN, SCr (serum creatinine) and albumin
concentration
Simplified MDRD formula: 4 variable s( serum
creatinine, age, race, sex)
Isotope dilution mass spectrometry (IDMS)-
traceable MDRD equation:

eGFR (mL/min/1.73 m
2
) = 175 (S
cr
)
-1.154
(Age)
-0.203

(0.742 if female) (1.212 if African American)
*Scr in mg/dL


Same errors resulting from variations in
creatinine production rate caused by diseased
states are NOT eliminated by either formula
Both not applicable to GFR measurements in
children (Modified Schwartz Formula)
eGFR from all the formulas not very accurate but
are still more accurate than those from direct
measurements
Useful in chronic states where creatinine
production=amount excreted in urine
ARF: Crea using 24-hr urine collection is more
useful in determining CC
Cysteine proteinase inhibitor C (MW13000)
Small size high pI = freely filtered at
glomerulus
Constant production rate by all nucleated
cells
No known extra-renal excretion routes
Not influenced by muscle mass, diet or
subjects sex
Difficult and expensive
Constant component of HLA class I antigens
Produced at a constant rate by B lymphocytes
Freely filtered at glomerulus and almost
completely reabsorbed and metabolized by
proximal tubular cells
In the absence of neoplastic or immune
conditions that elevate its production, it is a
more precise and reproducible measure of renal
function than BUN or creatinine
Costly
A low-molecular-weight glycoprotein freely
filtered through the glomerular basement
membrane with minimal non-renal
elimination
Levels are increased with renal disease
Studies show BTP is less sensitive than
Cystatin-C
Mannopyranosyl-L-tryptophan (MPT)
Filtered by the glomerulus freely and not
reabsorbed
Measured only by high-performance liquid
chromatography (HPLC); time-consuming
and expensive
Not affected by muscle mass; effect of
dietary intake on serum concentration is
unknown.
Acute Kidney Injury (formerly known as acute renal
failure) - a syndrome characterised by the rapid loss
of the kidney's excretory function and typically
diagnosed by accumulation urea and creatinine or
decreased urine output, or both
Common in hospitalized patients
Mortality ranging from 10%-80%
Need for biomarkers that help detect AKI before
changes in serum creatinine are noted
4 most promising biomarkers :
Kidney Injury Molecule -1 (KIM-1)
Neutrophil Gelatinase-Associated Lipocalin
(NGAL)
Interleukin-18 (IL-18)
Fatty Acid-Binding Protein (FABP)