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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 (ESRD), 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 (GFR). (2) These individuals have an increased likelihood of developing renal and 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 (CKD). (3) The number in 2002 is projected to be much higher. The National Kidney Foundation (NKF) 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 and hypertension are leading causes of this massive increase, the current habit of people taking a wide variety of prescription and nonprescription 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.

Urinary protein and albumin as markers of kidney 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 is usually a marker of generalized kidney disease, while albuminuria 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 have shown that finding microalbuminuria is a clear and independent marker for diabetic nephropathy. (6,7) The American Diabetes Association (ADA) 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 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 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) Clinical Practice Guidelines 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 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 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 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 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 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 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)

Conclusion

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, and osteoporosis. There are even new tests that may offer a warning of the likelihood of developing Alzheimer's disease, 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)

Most Patients:

* 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 or microscopic examination

Selected patients:

* Ultrasound of the kidneys

* Serum electrolytes

* Urine concentration (specific gravity or osmolality)

* Urinary acidification (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

* 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.

Children

* Test for CKD using the standard urine protein reagent strip or protein-to-creatinine ratio.

* Orthostatic proteinuria 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.

References:

(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 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. 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 Position Statement Regarding the UKPDS 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 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 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 on the prevalence of stages of diabetic nephropathy defined by urinary albumin / creatinine ratio. J Am Soc Nephrology. 1996;7(6):930-937.

(17.) Pugia MJ, Lott JA, Bierbaum LD, Cast TK. Assay of creatinine using the peroxidase 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 R, Luke KE, Shihabi ZK, et al. Albuminuria and proteinuria in hospitalized patients as measured by quantitative and dipstick methods. J Clin Lab Anal. 2001;15:295-300.

(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.
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Author:Ehrmeyer, Sharon
Publication:Medical Laboratory Observer
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Date:Jan 1, 2003
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