Now, more than ever before, it is critical to test indiviudals for proteinuria to detect those at increased risk because there are effective interventions that can help delay the progression of kidney disease to kidney failure. Also, identification of proteinuric individuals, who are at increased risk for cardiovascular events, allows for the early institution of preventative and intensive therapies to manage co-existent risk factors (hypertension, hyperglycemia, dyslipidemia, smoking), which improve the benefit/risk ratio of interventional strategies.^2,5,6 Thus, it is now imperative to incorporate testing for proteinuria in office practice for early detection and its quantitation to evaluate the effectiveness of therapeutic interventions.

The normal rate of protein excretion in healthy adults is less than 150 mg/day, of which less than 30 mg is albumin while the rest comprises different proteins and glycoproteins originating from tubular epithelial cells. Proteinuria that results from glomerular injury is predominantly albumin, which has a molecular weight that is just above that of the glomerular ultafiltration barrier and constitutes the major component of plasma proteins that leak into urine. Glomerular leakage of protein is the major pathologic form of proteinuria encountered clinically. Other types of proteinuria, tubular or overflow, are less common and have not been shown to be associated with cardiovascular outcomes that have come to be associated with glomerular proteinuria, an indicator of microvascular injury.⁷

Since glomerular proteinuria is reversibly increased in certain clinical conditions (exercise, fever, sleep apnea) the diagnosis of persistent proteinuria should be established from repeat testing, two or more weeks after its initial detection. Also, assessment of the amount of protein excreted is essential since it correlates directly with the magnitude of risk and its reduction constitutes a measure of therapeutic efficacy. For the quantification of proteinuria, there is now convincing evidence that the urine protein to creatinine or albumin to creatinine ratio in a spot urine sample accurately predicts the level of protein excretion.⁸  In the clinical use of this simpler approach to quantification, the importance of sampling time has been examined. First morning specimens minimize the circadian changes in protein excretion, and appear to most closely reflect the 24-hour excretion. However, in controlled studies of morning versus random spot urine samples the differences found have been minor and within the expected biologic range of measurements.⁹  This is important as it circumvents the need for a return visit by the patient to provide a morning specimen.

NKF-K/DOQI Recommendations on Proteinuria Assessment The recently published National Kidney Foundation-Kidney Disease Outcomes Quality Initiative (K/DOQI) Clinical Practice Guidelines for Chronic Kidney Disease: Evaluation, Classification and Stratification¹⁰ (www.kdoqi.org) recommend that: “All individuals should be assessed, as part of routine health encounters, to determine whether they are at increased risk of developing kidney disease, based on clinical and sociodemographic factors”; and that: “Individuals at increased risk of developing chronic kidney disease should undergo testing for markers of kidney damage”, specifically for proteinuria.

The potential clinical factors for an increased risk, which are recommended to be queried at routine health encounters, are: diabetes, hypertension, autoimmune diseases, urinary tract infection, urinary stones, lower urinary tract obstruction, cancer, family history of chronic kidney disease, reduction in kidney mass, exposure to nephrotoxins, and low birth weight. The sociodemographic factors recommended for query are: older age, ethnic minority status (African American, American Indian, Hispanic), exposure to chemical or environmental hazard, and low income or education. A positive answer to any of these factors places an individual in the increased risk category and necessitates testing for proteinuria.

Timed Urine Collections Versus Untimed (“spot”) Urine Samples

For quantification of proteinuria the K/DOQI guidelines recommend that: “Under most circumstances, untimed (spot) urine samples should be used to detect and monitor proteinuria”; that: “It is usually not necessary to a obtain timed urine collection (overnight or 24-hour) for these evaluations”; that: “First morning specimens are preferred, but random specimens are acceptable if first morning specimens are not available”; that: “In most cases, screening with urine dipsticks are acceptable for detecting proteinuria: standard dipsticks are acceptable for detecting increased total urine protein, and albumin-specific dipsticks are acceptable for detecting albuminuria”; that :  “Patients who test positive should undergo confirmation by a quantitative measurement (protein to creatinine or albumin to creatinine ratio) within 3 months”; and that: “Two or more positive quantitative tests temporarily spaced by 1 or 2 weeks should be diagnosed as persistent proteinuria.”

The algorithm proposed in these guidelines for proteinuria testing constitutes a reasonable and efficient approach to the detection and follow-up of proteinuria. The differentiation of testing for protein or albumin from the presence or absence of risk factors circumvents the use of the less sensitive dipstick, which detects protein at concentrations of 10-20 mg/dl, in those at increased risk and calls for the direct testing for albuminuria, which detects modest increments in albumin of 3-4 mg/dl (so-called microalbuminuria), in those who stand to benefit most from early detection. The quantification after the initial positive dipstick test circumvents the agony of waiting for results and the added office visit that would be necessary if another dipstick were repeated before progressing to the quantification, which reflects the level of increased risk and is necessary for the subsequent evaluation of therapy from reduction in the amount of proteinuria.

It is anticipated that the adoption and implementation of such a methodical approach to the detection of proteinuria would allow for early detection and institution of interventional measures that have been shown to be effective in reducing proteinuria, retarding the progression of kidney disease, and improving cardiovascular mortality and morbidity, with the consequent of improvement of outcomes for all individuals at increased risk.

REFERENCES                                                            

1)      Keane WF, Eknoyan G. Proteinuria, albuminuria, risk, assessment, detection and elimination (PARADE). A position paper of the National Kidney Foundation. Am J Kidney Dis 1999; 33:1004-1010.

2)      Grimm RH Jr, Sandsen KH, Kasiske B, Keane WM, Wahi M. Proteinuria is a risk factor for mortality over 10 years of follow up. MRFIT Research Group. Multiple Risk Factor Intervention Trial. Kidney Int 1997; 63:S10-S14 (suppl 63).

3)      Peterson JC, Adler S, Burkart JM, Greene T, HebertLA, Hunsicker LG, Hing AJ, Klahr S, Massry SG, Seifert JL. Blood pressure control, proteinuria and the progression of renal disease. The Modification of Diet in Renal Disease Study. Ann Intern Med 1995; 123:754-762.

4)      Mutner P, He J, Harmon L, Loria C, Whelton P. Renal insufficiency and subsequent death resulting from cardiovascular disease in the United States. J Am Soc Nephrol 2002; 13:745-753.

5)      Gerstein HC, Mann JF, Yi Q, Zinman D, Dinneen SF, Hoogwerf B, Halle JP, Rashkow A, Joyce C, Nawaz S, Yusuf S. Albuminuria and risk of cardiovascular events, death and heart failure in diabetic and nondiabetic individuals. JAMA 2001; 286:421-426.

6)      Keane WF. Proteinuria: Its clinical importance and role in progressive renal disease. Am J Kidney Dis 35: S97-S105 (suppl 1).

7)      Mann, J. F. E., Gerstein, H. C., Yi, Q.-L., Lonn, E. M., Hoogwerf, B. J., Rashkow, A., Yusuf, S. Development of Renal Disease in People at High Cardiovascular Risk: Results of the HOPE Randomized Study. J Am Soc Nephrol 2003; 14:641-647

8)      Schwab SS, Christensen RL, Dougherty K, Klahr S. Quantification of proteinuria by the use of protein-to-creatine ratios in a single voided urine. Arch Int Med 1987; 147:845-848.

9)  Chitalia VC, Kothari J, Wells EJ, Livesey JH, Robson RA, Searle M, Lynn KL. Cost-benefit analysis and prediction of 24-hour proteinuria from the spot urine protein-creatinine ratio. Clin Nephrol 2001; 55:436-447.