- ALBUMIN-TO-CREATININE RATIO (ACR)
- Overview
- The albumin-to-creatinine ratio is a urine test used to assess the amount of protein passing through the kidneys into the urine. Normal kidneys typically allow only a small amount of protein to pass into the urine; when larger amounts are present, it is a sign of kidney damage. Albumin is the most abundant protein in the blood and the easiest to detect.
- Albumin-to-creatinine ratio (ACR)
- The albumin-to-creatinine ratio is measured by dividing the concentration of albumin in a urine sample by the concentration of creatinine. The ratio is preferred over the albumin level because it corrects for variations in urine dilution that may occur from dehydration, diuretics, and other things. [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
- 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]
| CRP normal value (mg/L) |
|---|
| 0 - 4.9 |
- SERUM CREATININE, CrCl, AND GFR
- Serum creatinine
- Creatinine, a byproduct of muscle metabolism that passes freely across the glomerulus, is released into the bloodstream and removed by the kidneys at a constant rate throughout the day, producing steady serum concentrations. If the kidneys become damaged, creatinine removal is impaired, and serum levels rise, making it a measure of kidney function. Normal ranges vary by lab, but a level greater than 1.3 mg/dl is typically considered elevated.
- Individual differences in muscle mass described below can also influence creatinine levels
- Age - people tend to lose muscle mass as they age, causing creatinine levels to decline; therefore, serum creatinine levels are not always a good predictor of renal function in elderly patients
- Resistance training - an athlete with large muscle mass may have a higher creatinine level than an average-built person with the same kidney function
- Gender - men generally have more muscle mass than women
- Race - Blacks tend to have more muscle mass than other races
- Diet - low-protein diets can reduce creatinine concentrations [5]
- GFR and CrCl
- The kidney glomerulus, which forms a barrier between circulatory blood and renal tubular fluid, acts as a filter that blocks the passage of proteins and blood cells into the urine while allowing electrolytes and other solutes to pass freely. The glomerular filtration rate (GFR) is the volume of blood the kidneys filter over a minute. It is expressed as millimeters per minute per standardized body surface area, which is 1.73 m2 (ml/min/1.73 m2). In practice, the 1.73 m2 is often omitted.
- GFR can be measured directly, but the process is cumbersome and impractical, so instead it is approximated with the creatinine clearance (CrCl) and estimated glomerular filtration rate (eGFR); in practice, the terms GFR and CrCl are used interchangeably. Both measures are calculated using formulas (see below) that incorporate the patient's age, sex, serum creatinine, and in some cases, weight and race. [5]
| Formulas for calculating GFR and CrCl |
|---|
MDRD formula
|
Cockcroft-Gault Equation
|
CKD-EPI formula
|
CKD-EPI formula (2021)
|
| 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 |
| Albuminuria categories in CKD | ||||
|---|---|---|---|---|
| Category | AER (mg/24 hours) |
ACR (mg/mmol) |
ACR (mg/g) |
Degree |
| A1 | < 30 | < 3 | < 30 | Normal to mild increase |
| A2 | 30 - 300 | 3 - 30 | 30 - 300 | Moderate increase (Microalbuminuria) |
| A3 | > 300 | > 30 | > 300 | Severe increase (Macroalbuminuria) |
- 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]
| 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 |
- 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
| 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 |
- 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)
| Vd and drug distribution | |
|---|---|
| Vd (Liters) | Distribution |
| < 10 |
Intravascular
|
| 10 - 20 |
Extracellular fluid
|
| 25 - 30 |
Intracellular fluid
|
| 40 |
Whole body fluid
|
| > 40 |
Fat tissue
|
- 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.
- BIBLIOGRAPHY
- 1 - PMID 16450016
- 2 - PMID 8151903
- 3 - PMID 10893433
- 4 - PMID 18347777
- 5 - PMID 11904577
- 6 - PMID 21617108
- 7 - PMID 21193625
- 8 - PMID 17276798
- 9 - PMID 16160202
- 10 - PMID 18826876
- 11 - PMID 11106349
- 12 - PMID 15684121
- 13 - PMID 15880505
- 14 - PMID 5904286
- 15 - PMID 9250851
- 16 - PMID 22570462
- 17 - PMID 9347849
- 18 - PMID 17272767
- 19 - PMID 25740799 - MA of BNP trials
- 20 - PMID 18154959 - MA of BNP trials
- 21 - Clin Chem website
- 22 - PMID 24653858 - CRP paper
- 23 - LabCorp website
- 24 - PMID 17548411 - MA on RF
- 25 - PMID 22956589 - BMJ RF study
- 26 - Quest Diagnostics™ website
- 27 - PMID 24340846 - Anti-CCP study
- 28 - PMID 24126457 - ANA paper
- 29 - PMID 18426576 - Practical aspects in the management of hypokalemic periodic paralysis, J Transl Med (2008)
- 30 - PMID 29610508 - ACG Clinical Guideline: Management of Crohn’s Disease in Adults, Am J Gastroenterol (2018)
- 31 - PMID 28455343 - 2017 ACC/AHA/HFSA Focused Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure, Circulation (2017)
- 32 - PMID 30888397 - Evaluating the Erythrocyte Sedimentation Rate, JAMA (2019)
- 33 - PMID 24647050 - KDOQI US Commentary on the 2012 KDIGO Clinical Practice Guideline for the Evaluation and Management of CKD, Am J Kidney Dis (2014)