Rosalie Sabina Michiko S. Samonte, MD DPSPSan Beda College of MedicineNovember 2012

Molecules or ions with an electrical chargeImportant determinants of osmolality, state of dehydration and pH of both ECF and ICFEffective osmoles particles that are not equally distributed, cause movements of water and hence determine volume of compartmentsExpressed as mEq/L or mmol/L (SI)1 mEq = 1mmol

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

Extracellular fluid (ECF)Fluid outside the cell. 40% of bodys H20Conduit3 types:Interstitial (28%)- fluid around/between cellsIntravascular(8%)- (plasma) fluid in blood vesselsTranscellular(4%)CSF, Synovial fluid, etc

Normal range: 136-142 mmol/LMajor cation in ECF; determines ECF volumeResponsible for 90-95% of osmotic pressureMaintains water balance, transmits nerve impulses, contracts musclesCritical values: 160 mmol/L

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

Maintains normal concentrations of Na+ & K+2 K+ into cells, 3 Na+ outUses ATP, magnesium and an enzymePrevents cell swelling and creates an electrical charge allowing neuromuscular impulse transmission

Ion Sensitive Electrodes (ISE)May be direct or indirectIndirectDilution of the sampleMost automated analyzersAffected by lipid and protein concentrationsDirectNo dilution of the sampleBlood gas machines

AnalyticalElectrodes are very specificIn the presence of increased amounts of non-aqueous components we get reduced values with indirect methods (pseudohyponatremia)Pre-analyticalDrip-arm sample (Taken from the arm with IV line)Wrong patientGross hemolysis (dilution with intracellular fluid)

The most common electrolyte disorder

Primarily neurologic symptomsHeadache, muscle twitching, altered mental status, stupor, seizures, comaEdema

Artifactual hyponatremiaIn 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/kgIncreased values = alcoholism, aldosteronism, diabetes insipidus, high protein diet, dehydration, hypercalcemia, hyperglycemia, hypernatremia & hyperkalemiaDecreased 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 volumeCauses: 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 developDehydration of neurons with disturbed brain functionOliguria, concentrated urineDry skin, firm rubbery skin turgor, dry mouth, dry mucous membranesHigh body temperatureThirstHypotension related to tachycardia

Major intracellular cationNormal range: 3.8-5.0 mmol/LImportant for protein and glycogen metabolismImportant for cardiac and neuromuscular functionIon selective electrode methodPotassium imbalances are less common, but more dangerous

Na+ / K+ ATPaseAldosterone - 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 lowChanges in pH : Acidosis hyperkalemia (K+ moves out, H+ moves in)Alkalosis hypokalemia (K+ moves in, H+ moves out)

Common vomiting and diarrheaMetabolic alkalosis ( H+ extruded in exchange for K+) Insulin,-2-agonists-stimulates NaK-ATPaseCushing's syndrome mineralocortecoids1 & 2 Aldosteronism - aldosterone Na+ reabsorption; K+ excretion

Skeletal muscle weaknessSmooth muscle of GI constipation, abdominal distension, paralytic ileus, nausea, vomiting, anorexiaCardiac 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 resultWhen 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, paralysisFibrillation, or bradycardia; depends on level of serum K+Electrocardiogram: tall & narrow, peaked T-wavesMuscles irritability progresses to flaccid paralysisConfusion, malaise, nausea, colicky pain, diarrheaOliguria anuriaTerminate in death from ventricular fibrillation

When platelet and leukocytes are elevated (thrombocytosis and leukocytosis)Prolonged tourniquet application; small gauge needleIn vitro hemolysisDelayed processing of specimensNO physiologic consequenceRULE out first in differential diagnosis of hyperkalemia

Major extracellular anionNormal range: 95-103 mmol/LDietary chloride 100% absorbed in the intestine, excreted in urine/sweatHelps maintain electrical neutrality and pHISE

Main usefulness (in terms of lab testing) in calculation of the anion gapAnion gap For every cation, there is always an associated anion. Na+ -main extracellular cation. HCO3- + Cl- are the main extracellular anions AG = Na+ - (HCO3-+ 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/LPathology: HCO3- (base loss)RareCaused by excess aldosterone Na+ and therefore Cl- reabsorption (Cl- follows Na+)Signs and symptoms of acidosis

5th most abundant mineral element in the human bodyNot free in ICF99% is found in crystal form in bones and teeth1% in ECF and soft tissuesSerum (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 contextDiseases 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 pHTourniquet left too long can lower pH falsely elevate resultsISE

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 mineralizationCofactor in blood clottingNeural transmissionActivates intracellular enzymes (ex. Muscle contraction)Excitability of skeletal & cardiac musclesIn glandular synthesis & regulation of endocrine & exocrine glandsControls membrane permeability for ions, closes ion channels

Acid-base balanceHemodialysisMyelomaRenal failureCirrhosisTreatment with thiazide diureticsSepsis & other cardiovascular instabilityMassive blood transfusion

Regulated by parathormone (PTH) and calcitoninPTH causes 4 activities that serum Ca+2with 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+2Calcitonin deposition of bone by osteoblasts, removing the needed materials from the bloodSerum calcium and serum phosphate are inversely relatedIf 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 stonesCauses gastric juice formation

Hyperparathyroidism excess PTHComplication 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 releasedExcess ingestion of vitamin D ( absorption beyond normal)Addison's disease (adrenocortical insufficiency)Multiple myeloma (>20 mEq/L) breakdown

Hypercalcemia may lead to DEATHReduction 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 memoryIF 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 fracturesIncreased 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/musclesCAUSES:HypoparathyroidismImpaired absorption of calcium from GIDiarrhea excessive loss of intestinal secretionsMassive 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 functionNormal: 125 mL/minBest overall indicator of kidney functionSteady-state levels of substances eliminated by glomerular filtrationMeasurement of clearance of suitable markers

Urea final end product of protein metabolismProduction rate depends on dietary protein intake.Freely filtered by the glomerulus but tends to be reabsorbed and return to the bloodstreamBlood 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 hypoperfusionRenal: acute tubular necrosisPostrenal: obstruction of urinary flowIncreased protein catabolism:Increased dietary protein intakeGI bleeding (blood digested and protein absorbed)Severe stress

Reduced dietary intake of proteinAnabolism during recovery from illnessSevere liver diseaseOverhydration

Isotope dilution mass spectrometry-gold standardColorimetric methodEnzymatic method hydrolysis of urea by urease, producing ammonia and CO2. Measurement of ammonia is most often used

Amino acid waste product of protein metabolismEndogenous 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 tubulesSome tubular excretionNormal range: 53-136 micromoles/L (adult) 27-53 micromoles/L (children)

More sensitive and specific testProduction rate more constant than ureaDoes not undergo significant tubular reabsorption

Reduced renal functionUrinary tract obstructionIncreased total muscle massMuscle trauma or rhabdomyolysisDrugs ex. Cimetidine, trimethoprim, triamterene, amilioride and probenecid block tubular secretion of creatinine.

Scant muscle mass frail elderly and childrenSome 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 valuesCreatinine 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 xV 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 glomerulusGlomerulus = sole route of excretion from the body (no tubular secretion or reabsorption) Non-toxic and easily measurable

Property

Urea

Creatinine

Inulin

99mTcDTPA

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 StandardPlant 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 periodBlood sample taken within the period of collectionProblems: COMPLETE urine collection is essential for the accurate determination of creatinine clearanceIncreased in pregnancyIncreased with exerciseGFR as reflected by creatinine clearance declines by 10% per decade after age 50 Reference range : 90-120 mL/min for young adultsNOT widely done any more, due to the difficulty in assuring a complete urine collection

Cockroft-GaultModification 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, henceOverestimates 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 concentrationSimplified MDRD formula: 4 variable s( serum creatinine, age, race, sex)Isotope dilution mass spectrometry (IDMS)-traceable MDRD equation:

eGFR (mL/min/1.73 m2) = 175 (Scr)-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 formulaBoth 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 measurementsUseful in chronic states where creatinine production=amount excreted in urineARF: Crea using 24-hr urine collection is more useful in determining CC

Cysteine proteinase inhibitor C (MW13000)Small size high pI = freely filtered at glomerulusConstant production rate by all nucleated cellsNo known extra-renal excretion routesNot influenced by muscle mass, diet or subjects sexDifficult and expensive

Constant component of HLA class I antigensProduced at a constant rate by B lymphocytesFreely filtered at glomerulus and almost completely reabsorbed and metabolized by proximal tubular cellsIn 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 creatinineCostly

A low-molecular-weight glycoprotein freely filtered through the glomerular basement membrane with minimal non-renal eliminationLevels are increased with renal diseaseStudies show BTP is less sensitive than Cystatin-C

Mannopyranosyl-L-tryptophan (MPT)Filtered by the glomerulus freely and not reabsorbedMeasured only by high-performance liquid chromatography (HPLC); time-consuming and expensiveNot 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 bothCommon in hospitalized patientsMortality 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)

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