Using a creatinine ratio in urinalysis to improve the reliability of protein and albumin results. (Clinical Issues).
There are currently more than 300,000 people in the U.S. who are on renal dialysis with end-stage renal disease End-stage renal disease (ESRD)
Total kidney failure; chronic kidney failure is diagnosed as ESRD when kidney function falls to 5-10% of capacity.
Mentioned in: Chronic Kidney Failure
end-stage renal disease (ESRD ESRD end-stage renal disease.
End-stage renal disease; chronic or permanent kidney failure.
Mentioned in: Dialysis, Kidney
ESRD End-stage renal disease, see there ), and this number is doubling every 10 years. (1)0 A major part of this is related to the dramatic increase in the incidence of diabetes, the leading cause of ESRD in North America. The National Health and Nutrition Examination Survey has found that almost 8 million Americans have a greater than 50 percent reduction in their glomerular filtration rate glomerular filtration rate
n. Abbr. GFR
The volume of water filtered out of the plasma through glomerular capillary walls into Bowman's capsules per unit of time. (GFR GFR - Grim File Reaper ). (2) These individuals have an increased likelihood of developing renal and cardiovascular disease Cardiovascular disease
Disease that affects the heart and blood vessels.
Mentioned in: Lipoproteins Test
cardiovascular disease . The key to reducing the impact of these changes is early detection and treatment.
In 1990, A.R. Nissenson et al. estimated that approximately 9.1 million Americans had chronic kidney disease Chronic kidney disease (CKD), also know as chronic renal disease, is a progressive loss of renal function over a period of months or years through five stages. Each stage is a progression through an abnormally low and progressively worse glomerular filtration rate, which is (CKD See count-key-data. ). (3) The number in 2002 is projected to be much higher. The National Kidney Foundation Not to be confused with American Kidney Fund.
The National Kidney Foundation, Inc. (NKF) is a major voluntary health organization in the United States. Its mission is to prevent kidney and urinary tract diseases, improve the health and well-being of individuals and (NKF NKF National Kidney Foundation
NKF Norges Kampsportforbund
NKF Norges Klatreforbund (Norway)
NKF Norges Kofferttenking Forbund ) estimates that there are 20 million Americans with diseases of the kidney and urinary tact, with an additional 20 million currently undiagnosed. (4) While diabetes mellitus diabetes mellitus
Disorder of insufficient production of or reduced sensitivity to insulin. Insulin, synthesized in the islets of Langerhans (see Langerhans, islets of), is necessary to metabolize glucose. In diabetes, blood sugar levels increase (hyperglycemia). and hypertension are leading causes of this massive increase, the current habit of people taking a wide variety of prescription and nonprescription non·pre·scrip·tion
Sold legally without a physician's prescription; over-the-counter. medications may also contribute to the problem. Most of these medications are excreted through the kidneys, and in many cases, they are known to cause kidney damage kidney damage Kidney injury Nephrology A structural or functional compromise in renal function due to external–eg, athletic, occupational, or other trauma, resulting in bruising or hemorrhage, which can be profuse and life threatening Etiology Vascular .
Urinary protein and albumin as markers of kidney disease Kidney Disease Definition
Kidney disease is a general term for any damage that reduces the functioning of the kidney. Kidney disease is also called renal disease.
Urine testing has been used to help identify disease in humans for centuries. It has proven to be an ideal test medium for many analytes because the test is noninvasive, and in most cases, the results are available within minutes. While there are a number of markers that are currently being looked at to detect early kidney changes, the only test that is widely available, at a reasonable cost, is the urine protein test. Persistent increased proteinuria proteinuria /pro·tein·uria/ (-ur´e-ah) an excess of serum proteins in the urine, as in renal disease or after strenuous exercise.proteinu´ric
1. is usually a marker of generalized kidney disease, while albuminuria albuminuria /al·bu·min·uria/ (al-bu?mi-nu´re-ah) presence in the urine of serum albumin, the most common kind of proteinuria.albuminu´ric
n. has been found to be an even better marker of chronic kidney disease. (5) The currently used reagent strips (see Table 1) measure several common urinary proteins, although they are most sensitive to albumin.
Over the years, the significance of even low levels of albumin, "microalbuminuria" (defined as an albumin level of 5-160 mg/L), has been clearly identified in individuals with diabetes mellitus. (1) Long-term studies in both Type 1 and Type 2 diabetes type 2 diabetes
See diabetes mellitus. have shown that finding microalbuminuria is a clear and independent marker for diabetic nephropathy diabetic nephropathy (nfro´p . (6,7) The American Diabetes Association The American Diabetes Association, or the ADA, is an American health organization providing diabetes research, information and advocacy. Founded in 1940, the American Diabetes Association conducts programs in all 50 states and the District of Columbia, reaching hundreds of (ADA Ada, city, United States
Ada (ā`ə), city (1990 pop. 15,820), seat of Pontotoc co., S central Okla.; inc. 1904. It is a large cattle market and the center of a rich oil and ranch area. ) and other diabetes organizations all recommend yearly testing of all individuals with diabetes for microalbuminuria. (8) If a positive finding is obtained, aggressive management of both the patient's blood glucose blood glucose Diabetology The principal sugar produced by the body from food–especially carbohydrates, but also from proteins and fats; glucose is the body's major source of energy, is transported to cells via the circulation and used by cells in the presence and blood pressure is indicated to reduce the potential for kidney and widespread vascular damage.
The NKF has published various position papers and practice testing guidelines for kidney disease. "Considerable evidence, accrued over the past decade, indicates that the presence of even relatively small amounts of protein or albumin in the urine is an important early sign of kidney disease and is a strong predictor of an increased risk for cardiovascular mortality and morbidity in certain high-risk groups within the general population." (4) The NKF recommends that a "spots" urine, tested for either protein or albumin and compared to the urine creatinine, is the most convenient and reliable test method for identifying proteinuria or albuminuria. Figures 1 and 2 show diagnostic testing Diagnostic testing
Testing performed to determine if someone is affected with a particular disease.
Mentioned in: Von Willebrand Disease algorithms developed by the NKF that include either a protein-to-creatinine ratio, or an albumin-to-creatinine ratio, depending on whether the individual is at risk for CKD or not. The ADA also recognizes the importance of regular testing of the urine of all individuals with diabetes for proteinuria, albuminuria and microalbum inuria, and using the urinary protein- (or albumin-) to-creatinine ratio, as an early indicator of diabetic kidney disease. (8,9)
Measuring proteinuria and albuminuria to creatinine ratios
The NKF has recently published its Kidney Disease Outcomes Quality Initiative (K/DOQI K/DOQI Kidney Disease Outcomes Quality Initiative ) Clinical Practice Guidelines clinical practice guidelines Clinical policies, practice guidelines, practice parameters, practice policies Medtalk Systematically developed statements to assist practitioner and Pt decisions about appropriate health care for specific clinical circumstances. See Psychology. for Chronic Kidney Disease. (1) In these guidelines, the NKF recommends that proteinuria needs to be regularly monitored in patients at risk for kidney disease. The particular test required (either albumin for adults or total protein for children) is based on the population being tested. If a positive initial test is obtained, a quantitative protein- or albumin-to-creatinine ratio should be performed within three months. The NKF has also published guidelines for the Clinical Evaluation clinical evaluation Medtalk An evaluation of whether a Pt has symptoms of a disease, is responding to treatment, or is having adverse reactions to therapy of Patients at increased risk of CKD (Figure 3) and guidelines for the assessment of proteinuria to identify CKD (Figure 4).
Using a randomly collected (spot) urine sample is the biggest drawback for assessing proteinuria, due to its variation in protein concentration over time. For instance, a sample might show a "trace" reaction for protein (150-250 mg/dL) in concentrated urine from an individual without disease. Conversely, a "trace" reaction in dilute urine is most likely to be clinically significant. To eliminate this uncertainty, a 24-hour (24-h) urine sample was collected to accurately determine the urine protein excretion. This is tedious and inconvenient for the patient, as well as being a costly process for the laboratory. A significant number of samples are improperly collected, either rendering the results useless, which requires a fresh collection, or giving erroneous results. Studies have looked at 8-h (overnight) urine collections as an alternative to the 24-h collections. (5) This did not appear to offer any advantages. In the clinical laboratory, urine creatinine levels have been used to confirm the reliability of a 24-h urine sample for decades. It has now been shown that calculating a protein- (or albumin-) to-creatinine ratio on a random urine sample provides a more reliable, quicker and less expensive option.
A number of studies have been conducted to determine the relative reliability of performing a protein- or albumin-to-creatinine ratio on a random urine sample as an alternative to using a 24-h sample. The protein-(or albumin-) to-creatinine ratio correlates to the 24-h total urine protein and significantly improves the reliability of the test results from random urine.(10,11) A comparison of 24-h total urine protein or albumin results, with untimed, random urines tested for protein-to-creatinine ratios, found that the results correlated very well (r=0.97). (12) A study comparing the albumin-excretion rate to the albumin-to-creatinine ratio on a random sample found that the two results were essentially equal, without the time and trouble involved in collecting an accurate 24-h sample. (13) In renal transplant renal transplant Transplantation of a kidney from a living donor or cadaver to a recipient with ESRD Indications–children Congenital kidney/GU tract malformations–42%; focal segmental glomerulosclerosis-12% and others; 31% of children were ≤ age 5 patients, it was shown that the protein-to-creatinine ratio on a random urine sample was a useful and convenient screening and longitudinal test for proteinuria (as compared to the 24-h total urine protei pro·te·i
Plural of proteus. n). (14)
Laboratories have been performing quantitative protein-(albumin-) to-creatinine ratios for some years. However, the cost and difficulty of measuring protein (or albumin) and creatinine in a routine urinalysis precluded the regular use of ratios. New routine urinalysis reagent strips are now available that measure both the total protein and albumin and allow for the determination of the creatinine ratio. These can be used as a first-line test to identify urine samples that required more specific quantification. (15) Various studies have confirmed the performance of the reagent strip and shown that the number of false-positive and false-negative protein test results was significantly reduced by using the ratio. (16) Concentrated and dilute random urine samples give unacceptable numbers of false-positive and false-negative results, respectively, that are corrected for, (or at least identified) if a ratio to the creatinine level is calculated. While these routine reagent strips are not quantitative, the semiquant itative results are usually all that is required for clinical decision making. If quantitation is required, there are now a number of easy-to-use test systems available for rapid quantitation of either protein- (or albumin-) to the urine creatinine level.
The future of urine testing for proteinuria
A new creatinine test Creatinine Test Definition
Creatine is an important compound produced by the body. It combines with phosphorus to make a high—energy phosphate compound in the body. Creatine phosphate is used in skeletal muscle contraction. pad has been included on the new Bayer Multistix PRO and Clinitek Microalbumin Reagent Strips for urinalysis, to provide protein- or albumin-to-creatinine ratios, as a means of improving strip results with correlation to actual analyte excretion rates. The ratio allows for the use of single-voided, spot specimens in the discrimination of normal and abnormal levels of protein. (17) The ratio can either be determined visually by comparing the results of the protein and creatinine to a chart in the product insert, or automatically calculated if the strip is "read" using a reagent strip reader. As of the fall of 2002, Bayer was the only company to offer such a product as part of a routine urine reagent strip (Table 1). Other products may be available in the future.
Albumin is normally present in urine at concentrations of less than 30 mg albumin/g creatinine (< 3.4 mg/mmol). The upper reference limit for albumin in urine is approximately [less than or equal to] 30 mg/day. Albumin-to-creatinine ratio results of 30-300 mg/g (3.4-33.9 mg/mmol) are indicative of incipient nephropathy nephropathy /ne·phrop·a·thy/ (ne-frop´ah-the) disease of the kidneys.nephropath´ic
analgesic nephropathy in high-risk groups. Increased albumin-to-creatinine ratio results of [greater than or equal to] 80 mg/g ([greater than or equal to]9 mg/mmol) are indicative of nephropathy in a generally healthy population. Clinical proteinuria clinical proteinuria Lab medicine Urinary protein excretion > 0.5 g/24 hr, a level detectable by ordinary dipstick testing; CP corresponds to an albumin excretion of > 300 mg/24 hr; CP is a typical finding in early DM. See Diabetes mellitus. is indicated at a ratio result of 300 mg/g (33.9 mg/mmol) or greater. (17)
The new Multistix PRO urinalysis reagent strips measure the creatinine and allow estimations of significant albuminuria at [greater than or equal to]80 mg/g (9 mg/mmol) and significant proteinuria at [greater than or equal to]300 mg/g (33.9 mg/mmol). The creatinine reaction is based on the peroxidase-like activity of copper-creatinine complexes. (18) By factoring the test result to the creatinine value, concentrated urine samples that contain only a small amount of protein may be correctly identified as being normal, while a dilute sample with a small amount of protein may be identified as being abnormal. These new test strips have been extensively evaluated against both currents reagent strip methods and standard laboratory quantitative methods. (19-21) The Clinitek Microalbumin strip allows an estimation of microalbuminuria at 30 mg/g (3.4 mg/mmol) or above. Specimens with creatinine concentrations of 10 mg/dL (880[micro] mol/L) are too dilute to accurately determine the ratio result. The Multistix PRO stri p also makes estimations of inadequate specimens when the urine is too dilute. Repeat testing on a new specimen is recommended in these cases. (17)
Urinalysis has been used to assist the physician in making a diagnosis and in the management of patients for millennia. One of the most significant tests of kidney disease has always been the finding of proteinuria, but in many cases, due to the wide variation in the concentration of the urine sample, the results obtained were misleading or wrong. By comparing the protein, or albumin, results to the creatinine concentration of the urine sample, these variations are corrected. For example: If the urine is concentrated, a level of protein (or albumin) that is within normal limits might show a "trace" reaction. The ratio result would show that the level was normal. On the other hand, a dilute urine might show only a very small amount of protein or albumin when the amount being excreted is abnormal. The third situation that can occur is when a urine is so dilute that most of the results are of limited value. In this case, the very low creatinine value would indicate that a fresh, first-morning sample should be te sted to ensure that nothing of significance is missed.
Today, there are many tests being run on urine samples, such as drug screening, pregnancy tests, and tests for cancer markers, sexually transmitted diseases Sexually transmitted diseases
Infections that are acquired and transmitted by sexual contact. Although virtually any infection may be transmitted during intimate contact, the term sexually transmitted disease is restricted to conditions that are largely , and osteoporosis. There are even new tests that may offer a warning of the likelihood of developing Alzheimer's disease Alzheimer's disease (ăls`hī'mərz, ôls–), degenerative disease of nerve cells in the cerebral cortex that leads to atrophy of the brain and senile dementia. , and undoubtedly, more tests will be on the way. In all cases, it is important to be able to improve the reliability of the test result. One such way is to calculate the ratio of the test result to the creatinine level.
[FIGURE 1 OMITTED]
[FIGURE 2 OMITTED]
Table 1 Comparison of commonly used reagent strips Reagent Strips Specific Alubmin Measures Sensitivity (mg/dl) Creatinine Multistix PRO 10LS 8-15 Yes Multistix 10 SG No No Clinitek Microalbumin 2-4 Yes Chemstrip 10 UA No No Micral 2 No ImmunoDip Microalbumin 1.2-1.8 No Reagent Strips Protein Albumin-to-Creatinine Sensitivity (mg/dl) Ratio Limit (mg/g) Multistix PRO 10LS 30 80 Multistix 10 SG 15-30 N/A Clinitek Microalbumin N/A 30 Chemstrip 10 UA 18 N/A Micral N/A N/A ImmunoDip Microalbumin N/A N/A Reagent Strips Protein-to-Creatinine Result from Ratio Limit (mg/g) Instrument Reading Multistix PRO 10LS 300 Yes Multistix 10 SG N/A Yes Clinitek Microalbumin N/A Yes Chemstrip 10 UA N/A Yes Micral N/A No ImmunoDip Microalbumin N/A No Multistix, Multistix PRO, and Clinitek are trademarks of Bayer Corporation (Medfield, MA 02052), Chemstrip 10UA and Micral are trademarks of Roche Diagnostics (Indianapolis, IN 46256), ImmunoDip is a trademark of Diagnostic Chemicals Limited (Oxford, CT 06478)
Figure 3: NKF testing protocol recommendations for clinical evaluation of patients at increased risk of CKD (1)
* Blood pressure measurement
* Serum creatinine to estimate GFR
* Protein or albumin in a first morning or random urine sample, followed up with a quantitative protein- or albumin-creatinine ratio for all positives.
* RBCs and WBCs by dipstick dipstick /dip·stick/ (dip´stik) a strip of cellulose chemically impregnated to render it sensitive to protein, glucose, or other substances in the urine. or microscopic examination
* Ultrasound of the kidneys
* Serum electrolytes
* Urine concentration (specific gravity specific gravity, ratio of the weight of a given volume of a substance to the weight of an equal volume of some reference substance, or, equivalently, the ratio of the masses of equal volumes of the two substances. or osmolality osmolality /os·mo·lal·i·ty/ (oz?mo-lal´it-e) the concentration of a solution in terms of osmoles of solute per kilogram of solvent.
* Urinary acidification acidification
a technology used by processors to preserve foods by adding acids (such as acetic, citric, phosphoric, propionic and lactic acid) and thereby reduce the risk of growth of harmful bacteria. (pH)
Figure 4: NKF K/DOQI and the NKF-PARADE guidelines for assessment of proteinuria to identify CKD (1)
Children and Adults
* Under most circumstances, spot urines should be used to detect and monitor proteinuria in adults and children.
* It is usually not necessary for a 24-h sample to be collected.
* First morning samples are preferred, but random samples are acceptable.
* Routine reagent strips are fine for proteinuria.
* Albumin-specific strips are acceptable for albuminuria.
* All positive results need to be confirmed with a quantitative assay, protein- (or albumin-) to-creatinine ratio.
* Adults at risk for CKD need to be tested for urine albumin, using an albumin specific reagent strip or an albumin-to-creatinine ratio.
* For monitoring adults with chronic kidney disease, measure the albumin-to-creatinine ratio or the protein-to-creatinine ratio (if the albumin-to-creatinine ratio is high [>500 to 1000 mg/g)). When the level of albumin exceeds the 500-1000 mg/g level, total protein is a superior indicator of developing kidney disease.
* Test for CKD using the standard urine protein reagent strip or protein-to-creatinine ratio.
* Orthostatic proteinuria orthostatic proteinuria
Nonpathological proteinuria usually occurring between the ages of 10 and 20, and manifested when the individual stands erect but disappears when the person lies down. can be excluded by testing a first morning sample.
* To monitor individuals with CKD, use the protein-to-creatinine ratio on a spot urine.
* For children with diabetes, the same guidelines apply, with the addition of the need to screen and monitor post-pubertal children with diabetes of five or more years' duration.
(1.) NKF K/DOQI Guidelines 2000. Available at www.kidney.org. Accessed October 10, 2002.
(2.) Jones CA, Francis ME, Eberhardt MS, Chavers B, Cresh J, Engelgau M, et al. microalbuminuria in the US population: third National Health and Nutrition Examination Survey. Am J Kidney Dis. 2002; 39(3):445-459.
(3.) Nissenson AR, Pereira BJ, Collins AJ, Steiberg EP. Prevalence and characteristics of individuals with chronic kidney disease in a large health maintenance organization. Am J Kidney Dis. 2001;37(6):11777-1183.
(4.) Keane WF, Eknoyan G. Proteinuria, Albuminuria, Risk, Assessment, Detection, Elimination (PARADE): A Position Paper of the National Kidney Foundation. Am J Kidney Dis. 1999; 33(5):1004-1010. Available at www.kidney.org. Accessed October 10, 2002.
(5.) Ruggenenti P, Gaspari F, Perna A, Remuzzi G. Cross-sectional longitudinal study longitudinal study
a chronological study in epidemiology which attempts to establish a relationship between an antecedent cause and a subsequent effect. See also cohort study. of spot morning urine protein:creatinine ratio, 24-hour urine excretion rate, glomerular filtration rate, and end-stage renal failure in chronic renal disease in patients without diabetes. BMJ BMJ n abbr (= British Medical Journal) → vom BMA herausgegebene Zeitschrift . 1998; 316:504-509.
(6.) The Diabetes Control and Complication Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin dependent diabetes mellitus. N Engl J Med. 1993;42:1555-1558.
(7.) Gerstin HC, Hanna A, Rowe R, Leiter L, MacGregor A. CDA (1) (Compact Disc Audio) The compact disc file extension that is seen on the computer in Explorer or some other file manager. CDA files are actually pointers to the locations of the individual tracks on the CD medium. See CD-DA. Position Statement Regarding the UKPDS UKPDS UK Prospective Diabetes Study and Revision of Diabetes Clinical Practice Guidelines Accounting for the UKPDS Results. C J Diabetes Care. 1995;23:15-17.
(8.) American Diabetes Association: Clinical Practice Recommendations 1997. Diabetes Care. 1997;20(S1).
(9.) American Diabetes Association. Available at www.diabetes.org. Accessed October 10, 2002.
(10.) Rodriguez-Thompson D, Lieberman ES. Use of a random urinary protein-to-creatinine ratio for the diagnosis of significant proteinuria during pregnancy. Am J Obstet Gynecol. 2001; 85(4):808-811.
(11.) Ramos JG, Martins-Costa SH, Mathias MM, Guerin YL, Barros EG: Urinary protein/creatinine ratio in hypertensive hypertensive /hy·per·ten·sive/ (-ten´siv)
1. characterized by increased tension or pressure.
2. an agent that causes hypertension.
3. a person with hypertension. pregnant women. Hypertens Pregnancy. 1999; 18(3):209-218.
(12.) Lemann J Jr, Doumas BT. Proteinuria in health and disease assessed by measuring the urinary protein/creatinine ratio. Clin Chem. 1987; 23(2 Pt 1)297-299.
(13.) Yamaguchi T, Kadono K. Clinical evaluation of the albumin/creatinine ratio in Outpatients with diabetes. Nippon Jinzo Gakkzi Shi. 1991; 33(3):283-293. (Abstract in English, article in Japanese)
(14.) Torng S, Rigatto C, Rush DN, Nickerson P, Jefferey JR. The urine protein to creatinine ratio (P/C) as a predictor of 24-hour urine protein excretion in renal transplant patients. Transplantation. 2002;72(8):1453-1456.
(15.) Wallace JF, Pugia MJ, Lott JA, Luke, KE, Shihabi ZK, Sheehan M, Bucksa JM. Multisite evaluation of a new dipstick for albumin, protein and creatinine. J Clin Lab Anal. 2001;25(5):231-235.
(16.) Fogarty DG, Hanna LS, Wantman M, Warren JH, Krolewski AS, Rich SS. Urinary albumin excretion in families with type 2 diabetes is heritable her·i·ta·ble
1. Capable of being passed from one generation to the next; hereditary.
2. Capable of inheriting or taking by inheritance. and genetically correlated to blood pressure. Kidney Int. 2000;57(1(:250-257.
(17.) Warram JH, Gearin G, Laffel L, Krolewski AS. Effect of duration of Type I diabetes Type I diabetes
Also called juvenile diabetes. Type I diabetes typically begins early in life. Affected individuals have a primary insulin deficiency and must take insulin injections.
Mentioned in: Diabetic Ketoacidosis on the prevalence of stages of diabetic nephropathy defined by urinary albumin / creatinine ratio. J Am Soc Nephrology nephrology
Branch of medicine dealing with kidney function and diseases. An understanding of kidney physiology is important not only in treating kidney disease but in knowing the effect of drugs, diet, and hypertension on kidney disease, and vice versa. . 1996;7(6):930-937.
(17.) Pugia MJ, Lott JA, Bierbaum LD, Cast TK. Assay of creatinine using the peroxidase peroxidase /per·ox·i·dase/ (per-ok´si-das) any of a group of iron-porphyrin enzymes that catalyze the oxidation of some organic substrates in the presence of hydrogen peroxide.
n. activity of copper-creatinine complexes. Clin Biochem. 2000;33:53-73.
(18.) Pugia MJ, Lott JA, JA Profitt, TK Cast, J. High-sensitivity dye binding assay for albumin in urine. Clin Chem 1999;45, (Suppl A150): 532.
(19.) Pugia MJ, Wallace JF, Lott JA, Sommer Sommer is a surname, from the German and Danish word for the season "summer".
It may refer to:
(20.) Pugia MJ, Lott JA, Luke KE, Shihabi ZK, Wians FH, Phillips L. Comparison of instrument-read reagent strips for albumin and creatinine in urine with visual results and quantitative methods. J Clin Lab Anal. 1998;12:280-284.
Dr. Sharon Ehrmeyer is a professor of pathology and laboratory medicine at the University of Wisconsin Medical School in Madison, WI.