MEDICAL TERMS AND VALUES

• ALBUMIN-TO-CREATININE RATIO (ACR)

• Background
• The albumin-to-creatinine ratio is a urine test that is used to assess the amount of protein that is passing from the kidneys into the urine
• Albumin is the main protein found in the blood, and it is the main protein that passes into the urine when kidney damage is present
• Normal kidneys typically allow a small amount of protein to pass into the urine, but larger amounts are a sign of kidney damage
• Diabetic kidney disease is one of the main causes of albumin in the urine (albuminuria)


• Albumin-to-creatinine ratio (ACR)
• The ACR is measured from a sample of urine
• The ratio is calculated by dividing the amount of albumin in the sample by the amount of creatinine in the sample
• Comparing the amount of albumin to the amount of creatinine corrects for the variations in urine concentration that can occur from factors such as dehydration, diuretics, etc. [6]


• Technique
• The test is best performed on a morning urine sample
• Ideally, the patient should not have eaten within 2 hours of the test
• If a test is positive, it should be repeated in 3 - 6 months
• The diagnosis of proteinuria can be made if 2 out of 3 tests are found to be positive
• In practice, all of these guidelines are rarely followed [6, 7]


• Factors that can affect the test
• Dietary protein intake
• Exercise within 24 hours
• Urinary tract infection
• Fever
• Heart Failure
• Very high blood sugar
• Very high blood pressure [7,8]


• Ranges
• See albuminuria categories in CKD below

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• C-REACTIVE PROTEIN (CRP)

• Overview
• C-Reactive Protein (CRP) is an acute phase reactant meaning it's serum levels rise quickly after an inflammatory process starts
• CRP is made in the liver and released into the bloodstream within a few hours of the start of inflammation (e.g. infection, tissue injury, trauma). CRP has a half-life of 19 hours.
• CRP levels rise faster and decreases more rapidly than the erythrocyte sedimentation rate (ESR) which is also used to detect inflammation. Another characteristic that separates the CRP from the ESR is that the ESR may be elevated in conditions that are noninflammatory where the CRP is typically only elevated in inflammatory conditions. [21,30,32]


• Causes of elevated CRP
• Infection
• Inflammatory conditions (e.g. Rheumatoid arthritis, inflammatory bowel disease, giant cell arteritis)
• Pregnancy
• Cancer
• Medications (e.g. oral contraceptives, estrogens)
• Obesity [21,22]

• Reference [23]

CRP normal value (mg/L)
0 - 4.9

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• GLOMERULAR FILTRATION RATE (GFR) AND CREATININE CLEARANCE (CrCl)

• Overview
• The "glomerulus" is the microscopic, fundamental working unit of the kidney
• The glomerulus serves as a filter/barrier between blood in the circulation and fluid destined for elimination from the body as urine [4]
• The Glomerular Filtration Rate (GFR) is the rate at which blood is filtered by the glomerulus expressed as milliliters per minute (ml/min)


• GFR and CrCL
• Direct measurement of the GFR is tedious and involved
• The serum creatinine level (see creatinine above) provides an indirect way to estimate GFR that is easy and widely available
• The serum creatinine value is plugged into a formula along with other patient variables (age, sex, race, weight), and an estimation of "Creatinine Clearance" is made
• Creatinine Clearance is considered an estimation of the GFR
• In practice, the two terms are used interchangeable [5]

• Formulas
• In adults, there are primarily three formulas that are used to estimate the GFR

• Formula accuracy
• A number of studies have looked at the accuracy of these three formulas
• In general, the MDRD equation performs better than the Cockcroft-Gault equation
• In one study, the MDRD-calculated-GFR was within 30% of the true GFR in 91% of the patients
• In the same study, the Cockcroft-Gault-calculated-GFR was within 30% of the true GFR in 65% of the patients [5]
• Most laboratories estimate GFR with the MDRD formula
• CKD-EPI formula
• Recent studies have shown that the CKD-EPI formula is superior to the MDRD formula in predicting GFR and outcomes associated with GFR [16]
• Most laboratories estimate GFR with the MDRD formula

• ^✝Category 1 if kidney damage is present
• NKF - National Kidney Foundation; KDIGO - Kidney Disease: Improving Global Outcomes
• Reference [33]

Stages of kidney disease
GFR (ml/min)	Degree of kidney disease	NKF / KDIGO stages
≥ 90	Normal	G1✝
60 - 89	Mild	G2
45 - 59	Moderate	G3a
30 - 44	Moderate	G3b
15 - 29	Severe	G4
< 15	Kidney failure	G5

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• ERYTHROCYTE SEDIMENTATION RATE (ESR)

• Overview
• The ESR test measures how fast red blood cells separate from plasma and settle at the bottom of a tube of anticoagulated blood
• Results are reported in millimeters of clear plasma that are present at the top portion of the tube after one hour
• There are three primary factors that affect how fast RBCs settle
• Spatial interference - conditions that increase or decrease the presence of RBCs and other cells (e.g. anemia, polycythemia, leukocytosis) can affect how fast RBCs settle. RBC size can also affect settling with microcytosis increasing the rate and macrocytosis decreasing the rate.
• RBC electrical charge - under normal conditions, RBCs have a negative charge that causes them to repel each other. This repelling effect slows settling. Inflammatory markers such as fibrinogen have a large positive charge. If fibrinogen levels are elevated, they can blunt the negative charge that repels RBCs and increase the rate of settling.
• Blood viscosity - factors that affect the thickness of blood will affect the rate of settling (e.g. hypoalbuminemia, hyperbilirubinemia, increased immunoglobulins, hypercholesterolemia).


• Diagnostic value
• An elevated ESR may be an indicator that inflammation is present somewhere in the body. The main drawback to the ESR is that it is nonspecific, and a number of noninflammatory processes can elevate the ESR (see below).
• One characteristic that separates the ESR from another inflammatory marker, the C-reactive protein, is that the ESR may be elevated in conditions that are noninflammatory where the C-reactive protein is typically only elevated in inflammatory conditions. [21,32]


• Factors that may increase the ESR
• Infection
• Inflammatory conditions (e.g. rheumatoid arthritis, inflammatory bowel disease, giant cell arteritis)
• Anemia
• RBC microcytosis
• Pregnancy
• Advanced age
• Immune disorders (e.g. multiple myeloma, Waldenstrom's macroglobulinemia)
• Menstruation
• Medications (e.g. oral contraceptives, methyldopa, theophylline)
• Hypoalbuminemia
• Vitamin A
• Fatty liver
• Obesity [21,32]


• Factors that may decrease the ESR
• Polycythemia
• RBC macrocytosis
• Leukocytosis
• Sickle cells
• Hypofibrinogenemia (e.g. disseminated intravascular coagulation, liver failure)
• Hyperbilirubinemia
• Hypercholesterolemia [32]

• Reference [23]

Normal ESR values by age and sex
Patient population	ESR (mm/hr)
Male 0 - 50 years	0 - 15
Male ≥ 50 years	0 - 30
Female 0 - 50 years	0 - 32
Female ≥ 50 years	0 - 40

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• IRON STUDIES

• Iron studies are reviewed here - Iron review

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• MODIFIED RANKIN SCALE

• Overview
• The modified Rankin scale is used to measure disability in stroke patients
• It is widely used as an outcome measure in stroke treatment trials. It has also been incorporated into guidelines for certain stroke treatments (e.g. endovascular treatment)
• The definition for each Rankin score is given in the table below

• Reference [18]

Grade (Rankin score)	Symptoms
0	No symptoms at all
1	No significant disability: despite symptoms, able to carry out all usual duties and activities
2	Slight disability: unable to perform all previous activities but able to look after own affairs without assistance
3	Moderate disability: requiring some help but able to walk without assistance
4	Moderately severe disability: unable to walk without assistance and unable to attend to own bodily needs without assistance
5	Severe disability: bedridden, incontinent and requiring constant nursing care and attention
6	Death

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• SERUM CREATININE (SCr)

• Physiology
• Creatinine is a byproduct of muscle metabolism
• Creatinine is released into the bloodstream at a steady rate throughout the day
• The kidneys filter creatinine from the blood and excrete it into the urine
• The constant dumping of creatinine into the blood by muscle and removal of creatinine from the blood by the kidneys creates a steady concentration of creatinine in the blood [3]


• Kidney disease
• If the kidneys become diseased or damaged, they do not filter creatinine as effectively, and the equilibrium between muscle dumping and kidney removal will shift
• The change in equilibrium will cause a rise in the serum concentration of creatinine
• Creatinine concentration in the serum provides a measure of kidney function


• Variables that affect creatinine
• Because creatinine comes from muscle, its concentration is proportional to muscle mass
• Factors that can affect muscle mass include:
• Age - people tend to lose muscle mass as they age
• Resistance training - athletes may have more muscle mass and higher creatinine levels
• Gender - men generally have more muscle mass than women
• Race - African-Americans tend to have more muscle mass than whites
• Diet - people who eat less protein may have lower creatinine concentrations [5]


• Values
• Serum Creatinine (SCr) levels vary by a person's age, sex, race, weight, and muscle mass, therefore it is not possible to ascribe "normal" values that apply to everyone
• A more accurate estimate of kidney function is derived by using the serum creatinine in formulas that take these variables into account (see glomerular filtration rate for more)
• The values presented here are general measures

Serum creatinine (mg/dl)	Range
≤ 1.2	Normal
1.3 - 1.5	Mild-to-moderate elevation
> 1.5	Significant elevation

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• VOLUME OF DISTRIBUTION (Vd)

• Definition
• The volume of distribution is a pharmacological measure that reflects how a drug is distributed in the human body
• In simple terms, it is the volume of fluid that a specific amount of drug would have to be dissolved in in order to achieve the observed concentration
• Volume of distribution is calculated with the following formula:


• Vd = A / C
• where:
• A = amount of drug in body (bioavailable dose)
• C = concentration of drug in plasma


• Volume of distribution is typically expressed as liters and standardized to a 70 kg person


• Interpretation
• Because the Vd is inversely related to the concentration of the drug in plasma, drugs that stay in the plasma (high plasma concentration) will have a lower Vd and drugs that pass from plasma into other body compartments (lower plasma concentrations) will have a higher Vd
• After a drug is absorbed from the intestines or infused intravenously, there are primarily 5 body compartments in which it can distribute itself.

Five bodily compartments for drug distribution
Compartment	Estimated volume (Based on body weight)
Intravascular fluid	0.08 L/kg
Extracellular fluid	0.20 L/kg
Intracellular fluid	0.40 L/kg
Whole body fluid (extracellular + intracellular)	0.60 L/kg (men and children) 0.50 L/kg (women and elderly men) 0.45 L/kg (elderly women)
Body fat	0.2 - 0.35 L/kg

• If a drug stays primarily in the circulation (intravascular), its volume of distribution will usually be < 10 L
• If a drug distributes throughout fluid but cannot cross cell membranes, then its volume of distribution will be around 10 - 20 L
• If a drug is able to cross cell membranes (intracellular) and accumulate in tissues, then its volume of distribution will be 25 - 30 L
• If a drug distributes in whole body fluid, then its volume of distribution will be around 40 liters
• If a drug is very lipophilic and accumulates in fat, then its volume of distribution may exceed body weight, and in some cases, quite substantially (e.g. chloroquine has a volume of distribution of 13,000 L)

• Reference: Pharmaceutical Calculations, 9th ed. Stoklosa, Ansel (1991)

Vd and drug distribution
Vd (Liters)	Distribution
< 10	Intravascular Drugs that are large molecules Drugs that are highly protein-bound (e.g. warfarin)
10 - 20	Extracellular fluid Drugs with low lipid solubility that cannot cross cell membranes
25 - 30	Intracellular fluid Drugs that can cross cell membranes Drugs that are actively transported across cell membranes
40	Whole body fluid Drugs that pass freely across cell membranes (e.g. alcohol, caffeine)
> 40	Fat tissue Lipophilic drugs that accumulate in fat (e.g. chloroquine, amiodarone)

• Clinical use
• The Vd is most often used to estimate the required dose of a drug in order to achieve a desired plasma concentration (Drug dose = Desired concentration X Vd)
• The Vd is also important to consider when plasma concentrations are closely associated with a drug's therapeutic effect. Highly lipophilic drugs (large Vd) may have altered pharmacokinetics in obese patients. Abnormal fluid accumulation (e.g. ascites, edema) can also change the pharmacokinetics of certain drugs.

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