Kidney Function Tests
Kidney function tests are a cadre of tests that are used to screen for and manage renal disease. Tests commonly used for this purpose are plasma creatinine, blood urea nitrogen (BUN), electrolytes, and routine urinalysis. Additional laboratory tests are performed to evaluate abnormal renal function and help differentiate between causes. The most commonly used follow-up tests are creatinine clearance, plasma and urine osmolality, and urine sodium.
Renal function tests are used to screen for renal disease, to differentiate the cause of renal disease, and to determine the extent of renal dysfunction. These tests attempt to define the clinical state of renal dysfunction and not the process of injury. The latter is determined primarily by a combination of clinical data and biopsy to determine the histological pattern of injury.
A complete history should be taken prior to kidney function tests to assess the patient's symptoms and food and drug intake. A wide variety of prescription and over-the-counter medications can affect blood and urine kidney function test results, as can some food and beverages. Renal function tests are performed on both blood and urine. Blood samples are collected by venipuncture from a vein in the crease of the arm. The nurse or phlebotomist performing the procedure should observe universal precautions for the prevention of transmission of blood-borne pathogens. The creatinine clearance test requires a timed urine sample. Explicit written instruction must accompany the explanation of how to collect this sample. It is imperative that the patient empty his or her bladder at the start of the test and not include this urine in the collection. It is equally important that all urine produced during the time of the test be saved and refrigerated, and that the bladder be emptied completely and this urine added to the collection at the end of the test.
The kidneys are a pair of organs located in the back of the abdominal cavity on either side of the vertebral column. Their purpose is to filter the blood and remove wastes and excess water. They also selectively reabsorb compounds that have been filtered, thus conserving essential nutrients, electrolytes, amino acids and other biomolecules. Approximately one-quarter of the cardiac output, 1200 mL of blood per minute are received by the kidneys. Each kidney is made up of functional micro-scopic units called nephrons. Each nephron contains a capillary tuft, the glomerulus and a tubule. Blood flows into the kidneys, and engorges the capillary tufts. Water and small solutes pass through the vessel walls forming a filtrate of the plasma which enters the underlying space, Bowman's capsule. The walls of the capsule form a tubule that traverses the kidney. Blood leaves the glomerular capillaries through an efferent arteriole which forms a capillary network, the vasa recta, that follows the path of the tubules. The cells of the renal tubule modify the filtrate along its length ultimately forming urine that passes out of the body. The tubule is responsible for two processes, reabsorption and secretion. Reabsorption is
When kidney function becomes compromised by disease, the processes of glomerular filtration and tubular reabsorption and secretion become affected to different extents. This can result in retention of waste products that are incompletely filtered, loss of essential solutes that are not reabsorbed, and failure of the tubules to respond to hormonal control of electrolyte and water balance. Blood and urine biochemistry tests reflect the extent of this dys-function and are used to characterize the clinical state of the patient. Fortunately, the kidneys have a large reserve capacity, and a significant amount of damage must be incurred before kidney function tests become significantly abnormal.
There are several renal states that can be categorized by renal function test results, but the two major ones are acute and chronic renal failure. Renal failure is a term used to describe a loss of renal function characterized by uremia, the retention of nitrogenous wastes in the blood. The acute form is rapid in onset and often reversible. It can occur as three different states, termed prerenal, renal (intrarenal), and postrenal failure. Prerenal failure results from decreased blood flow to the kidneys, and its most common cause is congestive heart failure. Renal failure results from injury to the glomerulus and the tubules. The most common causes are glomerulonephritis which is mediated by autoantibodies that damage the glomerulus and obstruct the tubules; pyelonephritis which is caused by a bacterial infection of the interstitium; and tubular damage caused by drugs, heavy metals, and viral infections. Post renal failure is caused by obstruction below the kidneys. This can result from urinary tract stones, tumors, or anatomic obstruction as in benign prostatic hypertrophy. The chronic form is characterized by slow onset without accompanying symptoms in its early stage. Chronic renal failure often follows episodes of acute renal failure, and it is not reversible. Chronic renal failure is most commonly a sequalae to acute glomerulonephritis or pyelonephritis which together account for more than half the cases. Other causes of chronic renal failure are chronic diseases such as diabetes mellitus, renal vascular disease (e.g., atherosclerosis of the renal vessels), hypertension, polycystic kidney disease, drug damage, and kidney stones. Kidneys from patients with chronic renal failure will appear smaller than average and a biopsy of the kidney will demonstrate scarring of the tubules.
Regardless of the cause, most persons with acute renal failure are characterized by three common laboratory findings: reduced creatinine clearance, azotemia (excessive nitrogen compounds in the blood), and hyperkalemia (excessive potassium in the blood). Creatinine is a waste product of muscle metabolism. It is produced at a constant rate and filtered freely by the glomeruli without reabsorption. Therefore, creatinine levels in the blood are increased when there is reduced glomerular filtration. Although specific for glomerular disease, plasma creatinine is not a sensitive test, and about 60% of the renal capacity is usually lost before levels become abnormal. A more sensitive indicator of glomerular dysfunction is the creatinine clearance test. This test measures the ratio of urine to plasma creatinine. As plasma levels rise, urine levels fall causing the ratio to decrease before plasma creatinine becomes definitively abnormal.
CREATININE CLEARANCE TEST. The creatinine clearance is defined as the volume of plasma that contains the same amount of creatinine as is excreted in the urine in one minute. Because the tubules do not reabsorb creatinine, all of the creatinine filtered by the glomeruli in a given amount of time is excreted in the urine. This test is an estimate of the glomerular filtration rate. The test is performed by measuring creatinine in a timed urine specimen—a cumulative sample collected over a four, 12, or 24-hour hour period. Determination of the plasma creatinine is also required to calculate the urine clearance. The clearance formula is U/P x V x 1.73/A. "U" is the urine creatinine in gm/dL; "P" is the plasma creatinine in mg/dL; and "V" is the volume of urine produced per minute. This is usually calculated by dividing the volume of urine produced per day by 1440 minutes per day. "A" is the person's body surface area expressed in square meters, and 1.73 is the average body surface area in square meters. During the test, the patient must be well hydrated because under conditions of slow filtrate flow the tubules will secrete some creatinine causing an over-estimate of clearance. Creatinine can be measured by a colormetric method called the Jaffe reaction or by a coupled enzymatic reaction. The Jaffe reaction is performed by mixing a plasma or diluted urine sample with a solution of sodium hydroxide and saturated picric acid. At an
Azotemia is the accumulation of nitrogenous (azo) waste products in the blood as a consequence of renal failure. The azo compounds routinely measured are creatinine, urea, and uric acid. While an increase of plasma urea or uric acid is not specific for renal disease, both compounds are retained whenever there is a reduction in the glomerular filtration rate. Of the two compounds, urea is the more sensitive, and urea levels can be used with creatinine to help differentiate prerenal and renal failure.
BLOOD UREA NITROGEN (BUN) TEST. Historically, urea concentration has been expressed as the concentration of nitrogen derived from urea, called the BUN. This test is performed by an enzymatic-ultraviolet photometric method using the enzyme urease. The enzyme catalyzes the hydrolysis of urea by water forming ammonia and carbon dioxide. A coupling enzyme, glutamate dehydrogenase, catalyzes the formation of glutamate from alpha-ketoglutamate and ammonia. In this reaction NADPH is converted to NADP+ which causes a decrease in the absorbance of 340 nm light. The rate of absorbance decrease is proportional to the urea nitrogen concentration of the sample. Urea is freely filtered by the glomerulus but is reabsorbed by the tubules to a variable extent depending upon the movement of filtrate through the tubule. When filtrate flow is slow, 40% or more of the filtered urea can be reabsorbed. For this reason, BUN levels increase much more than creatinine in prerenal failure. In prerenal failure, the kidney is not damaged, but glomerular filtration is reduced because of insufficient blood flow to the glomeruli. This results in increased retention of all three azo compounds. However, poor renal blood flow is a stimulus for ADH secretion that promotes water and urea reabsorption. Since the tubules are undamaged, they reabsorb a maximal amount of urea. This causes the ratio of plasma BUN to creatinine to increase dramatically. The reabsorption of BUN is impaired in renal failure caused by renal damage because the tubules are impaired. Ratios in prerenal failure are approximately 20:1, twice that seen in renal failure caused by damaged kidneys.
Electolyte disturbances are common to all forms of renal failure. Potassium is filtered by the glomerulus and partly reabsorbed in the proximal tubule. A significant amount of potassium is secreted by the collecting tubule in response to aldosterone. Therefore, when the kidneys receive insufficient blood flow potassium is incompletely filtered. When the tubules are damaged, potassium levels rise further because the exchange of potassium for sodium is impaired.
Plasma potassium levels must be maintained within a very narrow range to avoid cardiac arrhythmia. Elevated plasma potassium is the single most important (life-threatening) consequence of renal failure. Plasma potassium is the criterion used to determine the need for dialysis and the frequency and duration of treatment. Urine sodium is very useful in helping to differentiate prerenal from renal failure. In prerenal failure, the daily excretion of sodium is lower than normal because the kidneys attempt to reabsorb sodium in order to restore blood flow. However, in renal failure, daily urine sodium loss is increased owing to tubular failure. Urinary sodium is about twofold higher in intrarenal failure than in prerenal failure.
There are a variety of urine tests that assess kidney function. A simple, inexpensive screening test, routine urinalysis, is often the first test administered when kidney problems are suspected. A first-morning or randomly voided urine sample is examined visually for color and clarity, and a series of up to ten dry reagent strip biochemical tests are performed. Protein, blood, leukocytes, and specific gravity are four tests that are often abnormal in persons with renal failure. Glomerular damage causes albumin and red blood cells to pass through the basement membrane and enter the filtrate in Bowman's space. Leukocytes migrate to the site of injury and enter the filtrate through glomerular lesions and by passing between the tubular cells. Tubular failure disables the concentrating and diluting capacity of the kidneys and the urine produced is consistently of the same specific gravity as the plasma (1.010). Glucose and pH are also useful because a high percentage of diabetics develop renovascular disease, and renal failure results in acidosis (hydrogen ion retention) with concomitant failure to acidify the urine. While these findings can occur in severe lower urinary tract disease, the renal origin of the cells can often be confirmed by microscopic analysis of urinary sediment. In renal injury, stasis, protein, and obstruction of the tubules by cells cause the precipitation of mucoproteins in the tubules. When these are washed out by urine flow, they can be seen using the microscope, and are called casts. The finding of cellular casts in the urinary sediment, identifies the kidney as the source of the cells. Experienced technologists can often distinguish glomerular bleeding from bleeding below the kidney because the former causes characteristic abnormalities in red blood cell structure (dysmorphic cells). Furthermore, the presence of cells and casts signifies renal damage and
rules out prerenal failure as the cause of abnormal biochemistry results.
Glomerulonephritis is the most common cause of intrarenal failure. Urinary sediment in this condition displays large numbers of both red and white blood cells, and usually a predominance of red blood cell casts. Pyleonephritis, the second most common renal disease is characterized by a predomonance of white blood cells and white blood cell casts. Bacteria are usually abundant in the sediment signaling the causative infection.
Postrenal failure may also result in abnormal sediment. The presence of large numbers of crystals in association with biochemical evidence of worsening renal function and hematuria may alert the clinician to the presence of a urinary tract stone. The presence of large numbers of abnormal (cancerous) transitional epithelial cells may be shed into the urine by a bladder tumor and seen in the urine microscopic exam. In such cases, an imaging test, the intravenous pyelogram, is often performed in order to identify the size, location, and possible cause of the obstruction.
OSMOLALITY. Urine osmolality is a measure of the number of dissolved particles in urine. It is a more precise measurement than specific gravity for evaluating the ability of the kidneys to concentrate or dilute the urine. Kidneys that are functioning normally will excrete water in relation to the amount consumed. Those with failing kidneys may not be able to concentrate urine. Solutes will equilibrate by passive diffusion in the tubule and the osmolality will be the same as plasma, approximately 290 mOsm/Kg water. The test may be done on a urine sample collected first thing in the morning as water deprivation overnight should concentrate the urine; multiple timed samples, or on a cumulative sample collected over a 24-hour period. In addition, the ratio of urine to plasma osmolality is another useful way to differentiate prerenal and intrarenal failure. In prerenal failure the kidneys attempt to restore blood volume by reabsorbing sodium. This raises the plasma osmolality causing release of
The acute and chronic forms of renal failure display some distinguishing characteristics. In chronic renal failure, the tubules become scarred causing water loss. This results in polyruria (increased urine volume) as opposed to oliguria (low urine volume) seen in acute renal failure. Scarring also results in salt wasting causing the serum potassium to be lower than seen in acute renal failure. The urinary sediment shows heavy proteinuria, hematuria (red blood cells) and abundant casts. The casts are usually broad and waxy, which are unique characteristics of end-stage renal failure.
OTHER BLOOD TESTS. Measurement of the blood levels of other analytes regulated or affected in part by the kidneys can be useful in evaluating kidney function and in managing conditions such as osteomalacia and renal acidosis that are secondary to renal disease. These include bicarbonate, calcium, magnesium, phosphorus, plasma renin activity, and parathyroid hormone.
Patients will be given specific instructions for collection of urine samples, depending on the test to be performed. During routine urinalysis, the patient will be given a sealed cup to urinate into. Nurses stress that the patient obtain a "clean catch" by initiating urination and placing the sample cup in the urine stream after a few seconds. This prevents the collection of the initial urine which may contain bacteria that are present in the lower urethra or on the skin. Some timed urine tests require an extended collection period of up to 24 hours, during which time the patient collects all urine voided and transfers it to a specimen container. Refrigeration and/or preservatives are typically required to maintain the integrity of such urine specimens. Certain dietary and/or medication restrictions may be imposed for some of the blood and urine tests. The patient may also be instructed to avoid exercise for a period of time before a test to prevent changes in creatinine.
If medication was discontinued prior to a kidney function test, it may be resumed once the test is completed.
Complications for these tests are minimal, but may include slight bleeding from a venipuncture site, hematoma (accumulation of blood under a puncture site), or fainting or feeling light-headed after venipuncture. In addition, suspension of medication or dietary changes imposed in preparation for some blood or urine tests may trigger side-effects in some individuals.
Normal values for many tests are determined by the patient's age and sex. Reference values can also vary by laboratory, but are generally within the ranges that follow.
- Creatinine clearance. For a 24-hour urine collection, normal results are 90-139 mL/min for adult males less than 40 years old, and 80-125 mL/min for adult females less than 40 years old. For people over 40, values decrease by 6.5 mL/min for each decade of life.
- Urine osmolality. With restricted fluid intake (concentration testing), osmolality should be greater than 800 mOsm/kg of water. With increased fluid intake (dilution testing), osmolality should be less than 100 mOSm/kg in at least one of the specimens collected. A 24-hour urine osmolality should average 300-900 mOsm/Kg. A random urine osmolality should average 500-800 mOsm/Kg.
- Urine protein. A 24-hour urine collection should contain no more than 150 mg of protein.
- Urine sodium. A 24-hour urine sodium should be within 75-200 mmol/day.
- Blood urea nitrogen (BUN) should average 8-20 mg/dL.
- Creatinine should be 0.8-1.2 mg/dL for males, and 0.6-0.9 mg/dL for females.
- Uric acid levels for males should be 3.5-7.2 mg/dL and for females 2.6-6.0 mg/dL.
Low clearance values for creatinine indicate diminished ability of the kidneys to filter waste products from the blood and excrete them in the urine. As clearance levels decrease, blood levels of creatinine, urea, and uric acid increase. Since it can be affected by other factors, an elevated BUN, by itself, is suggestive, but not diagnostic, for kidney dysfunction. An abnormally elevated plasma creatinine is a more specific indicator of kidney disease than is BUN.
Inability of the kidneys to concentrate the urine in response to restricted fluid intake, or to dilute the urine in response to increased fluid intake during osmolality testing indicates decreased tubular function. Because the kidneys normally excrete almost no protein in the urine, its persistent presence, in amounts that exceed the normal 24-hour urine value, usually indicates glomerular or tubular injury. These can be distinguished by urine protein electrophoresis. This procedure separates proteins in an electric field based upon their charge. Albuminuria is characteristic of glomerular disease, while urinary excretion of alpha-1 and beta-2 microglobulins is characteristic of tubular damage. Proteinuria of tubular origin is caused by drugs, heavy metals, or viral infection of the kidneys. Urine protein electrophoresis also detects monoclonal immunoglobulin light chains (multiple myeloma and related conditions) and immunoglobulin fragments (systemic autoimmune diseases), which are nonrenal causes of proteinuria.
Health care team roles
Kidney function tests are ordered and interpreted by a physician. Blood samples are collected by a nurse or phlebotomist. Nurses should educate the patient on why the tests are being done and how to collect timed urine samples. In addition, patients with kidney disease may be advised to change their diets. A dietitian may be consulted.
Some kidney problems are the result of another disease process such as diabetes or high blood pressure. Clinicians should take the time to inform patients about how their disease or its treatment will alter kidney function and the different measures they can take to help prevent these changes.
Blood urea nitrogen (BUN)—The nitrogen portion of urea in the bloodstream. Urea is a waste product of protein metabolism in the body.
Creatinine—The metabolized by-product of creatine, an organic compound that assists the body in producing muscle contractions. Creatinine is found in the bloodstream and in muscle tissue. It is removed from the blood by the kidneys and excreted in the urine.
Creatinine clearance rate—The clearance of creatinine from the plasma compared to its appearance in the urine. Since there is no reabsorption of creatinine, this measurement can estimate glomerular filtration rate.
Diuretic—A drug that increases the excretion of salt and water, increasing the output of urine.
Glomerular filtration rate—The rate in millimeters per minute at which plasma is filtered through the glomerular membrane.
Hematuria—The presence of blood in the urine.
Nephrologist—A doctor specializing in kidney disease.
Nephron—The functional unit of the kidney.
Oliguria—The formation of very small amounts of urine.
Osmolality—A measurement of urine concentration that depends on the number of particles dissolved in it. Values are expressed as milliosmols per kilogram (mOsm/kg) of water.
Polyuria—The formation of very large amounts of urine.
Proteinuria—The presence of protein in the urine often caused by damage to the glomerular membrane.
Renal—Pertaining to the kidney
Specific gravity—The ratio of the weight of a body fluid when compared to water.
Urea—A by-product of protein metabolism that is formed in the liver. Because urea contains ammonia, which is toxic to the body, it must be quickly filtered from the blood by the kidneys and excreted in the urine.
Uric acid—A product of purine breakdown that is excreted by the kidney. High levels of uric acid, caused by various diseases, can cause the formation of kidney stones.
Urine—A fluid containing water and dissolved substances excreted by the kidney.
Brenner, Barry M. and Floyd C. Rector Jr., eds. The Kidney, 6th Edition. Philadelphia, PA: W.B. Saunders Company, 1999.
Burtis, Carl A. and Edward R. Ashwood. Tietz Textbook of Clinical Chemistry. Philadelphia, PA: W.B. Saunders Company, 1999.
Kaplan, Lawrence A. and Amadeo J. Pesce. Clinical Chemistry Theory, Analysis and Correlation. St. Louis: Mosby Publishers, 1996.
National Kidney Foundation (NKF). 30 East 33rd Street, New York, NY 10016. (800)622-9020. <http://www.kidney.org>.
Jane E. Phillips, PhD