Rapid Diagnosis of Proteinuria and Albuminuria: Current Methods and Clinical Applications
Importance and Significance of Proteinuria
Proteinuria is evaluated to diagnose kidney damage caused by various diseases. In addition, proteinuria is closely associated with the development and progression of chronic kidney disease (CKD). Proteinuria and albuminuria have been established as independent risk factors for cardiovascular disease, end-stage kidney disease, and mortality [1–7]. Therefore, proteinuria should be regarded as a marker of existing kidney damage that directly contributes to the pathogenesis of renal, cardiovascular, and vascular diseases. Accordingly, this laboratory marker, identified using various diagnostic methods, is used to assess the risk of CKD and monitor the progression of kidney diseases associated with proteinuria [8].
Definition of Proteinuria
An adult excretes an average of approximately 80 mg of protein in the urine per day. Urinary protein excretion of less than 150 mg/day is considered normal. In the absence of kidney damage, approximately 15% of urinary protein consists of albumin, whereas the remaining 85% comprises other serum and urinary proteins, including beta-2 microglobulin and uromodulin (Tamm-Horsfall protein).
Albuminuria refers to the excretion of any amount of albumin in the urine. It is a marker of kidney damage, reflecting increased glomerular permeability.
Albuminuria Classification
The term microalbuminuria is partly misleading and has caused considerable confusion [10]. Therefore, the 2013 KDIGO guidelines recommend abandoning the term microalbuminuria [9]. These recommendations propose three categories of albuminuria:
A1 – urine albumin-to-creatinine ratio (ACR)
A3 – ACR >300 mg/g.
By determining the albuminuria category and calculating the glomerular filtration rate (GFR), kidney damage in CKD can be assessed. The presence of A2 or A3 albuminuria significantly increases the risk of CKD. This risk remains high even in individuals with a GFR >90 mL/min/1.73 m². Nephrotic-range proteinuria is characterized by specific signs and symptoms, including hypoalbuminemia, edema, and hypercholesterolemia.
Types of Proteinuria
Proteinuria may be either physiological or pathological. Physiological proteinuria resolves spontaneously without evidence of other kidney damage. In contrast, pathological proteinuria is usually persistent and associated with kidney disease.
Proteinuria is classified according to its underlying cause (etiology) and the site of kidney damage. Isolated proteinuria is defined by the presence of urinary protein without other signs of kidney damage (such as hematuria or other abnormal urinary findings) and in the absence of diseases known to cause proteinuria. Pathological proteinuria is classified as glomerular (caused by damage to the glomerular basement membrane resulting in increased permeability), tubular (caused by impaired tubular reabsorption of low-molecular-weight proteins), or overflow proteinuria (when the plasma concentration of a specific protein exceeds the kidney's tubular reabsorptive capacity). Overflow proteinuria occurs in multiple myeloma, light-chain disease, hemoglobinuria, and myoglobinuria.
Postrenal proteinuria results from diseases affecting the urinary tract epithelium. When glomerular proteinuria is suspected, it is important to determine not only the amount of urinary protein excreted but also the type of protein or proteins passing through the glomerular basement membrane, as this information is valuable for establishing an accurate diagnosis and prognosis. In cases of selective proteinuria, only medium-molecular-weight proteins are excreted in the urine (-->
Diagnosis of Proteinuria
Clinical practice guidelines recommend replacing the traditional 24-hour urine collection for protein quantification with measurement of the urine protein-to-creatinine ratio (PCR) or the urine albumin-to-creatinine ratio (ACR) [9,11]. The ACR is the preferred diagnostic tool for detecting kidney damage caused by hypertension and diabetes because these conditions primarily affect the glomeruli and promote albuminuria. When excretion of a specific protein is suspected, such as in multiple myeloma, disease-specific laboratory tests should be performed.
Proteinuria is most commonly detected using conventional urine dipstick tests (performed at the bedside or in outpatient settings with visual or automated interpretation) or by laboratory-based urinalysis [12]. Although laboratory testing offers greater diagnostic accuracy, urine dipsticks are less expensive because they require no specialized equipment, personnel, or sample transportation, making them well suited for screening purposes.
Benefits of Diagnostic Strips for Evaluating Proteinuria
Principles of Urine Dipstick Testing
Urine dipsticks are routinely used as part of standard urinalysis. Owing to their affordability and ease of use, dipstick testing is widely employed in everyday clinical practice. Urinalysis should be performed while wearing appropriate medical gloves and protective eyewear. The dipstick is briefly immersed in a fresh urine sample and immediately removed.
Urine dipsticks can assess multiple urinary parameters simultaneously. Some chemical reactions require up to two minutes to develop fully; therefore, it is essential to follow the manufacturer's instructions and interpret the results only after the recommended reading time has elapsed. Failure to do so may result in inaccurate interpretation.
The protein content of a urine sample can be assessed qualitatively (protein present or absent) or semi-quantitatively (estimating protein concentration within predefined reference ranges). Dipsticks contain buffer indicators that change color after interacting with urinary proteins. This method is particularly sensitive to albumin because albumin contains numerous amino groups capable of binding hydrogen ions [13]. Dipsticks are capable of detecting albumin concentrations of approximately 10–20 mg/dL [14]. The concentration of the urine sample influences the test results, and low-level proteinuria may be reported as "trace" or "1+".
Limitations of Diagnostic Strips
Because of their affordability, urine dipsticks are increasingly used in clinical practice. However, this diagnostic method has several limitations. First, dipsticks are designed to detect only normal and pathological ranges of proteinuria. Second, current dipsticks can distinguish only whether urinary protein concentrations fall within the range of 20–300 mg/dL or exceed 300 mg/dL. For greater diagnostic accuracy, quantitative laboratory methods should be used [15].
False-Positive Results
False-positive results may occur in concentrated or alkaline urine (pH >8), hematuria, highly pigmented urine, or when urine samples are contaminated with ammonia-containing compounds, detergents, or antiseptics [16].
False-Negative Results
False-negative results may occur in highly dilute urine (specific gravity <1.005) or when proteins other than albumin are excreted in the urine [14]. False-negative results may also result from improper testing technique, such as leaving the dipstick immersed in the urine sample for too long, which washes away the strip's buffer system.
Interpretation of Dipstick Results
Most urine dipsticks allow semi-quantitative measurement of total urinary protein. However, this method does not accurately detect low or moderate levels of proteinuria. In addition, dipstick testing does not account for urine concentration. For many years, it was believed that the reproducibility of dipstick results was independent of the individual performing the test [17]. However, more recent studies have shown that manual interpretation results in a higher frequency of inaccurate readings (both underestimation and overestimation of urinary protein concentration) than interpretation using an automated urine dipstick analyzer [9,14,18].
Semi-automatic reflectance analysis tools also more accurately determine the protein concentration in a urine sample...
Prepared according to Matthias A. Cassia, , Federico E. Pozzi, Sara Bascapè, et al. Proteinuria and Albuminuria at Point of Care. Nephrology@Point of Care. October 5, 2016.
Dr. Justas Simonavičius
Lithuanian University of Health Sciences, Faculty of Medicine
More information in the publication "Kidney and Cardiovascular Diseases", 2018.
