Persistent proteinuria with an inactive urine sediment is an established marker of CKD (Lees et al, 2004). Proteinuria results when the normal renal handling of protein malfunctions or is overwhelmed. Normally the small amount of protein that is present in the filtrate is passed through the glomerular capillary wall and reabsorbed by the proximal tubule. The glomerular capillary wall serves an anatomical barrier and the primary mechanism by which proteinuria is prevented. In patients with glomerular disease, permselective properties of the glomerular capillary wall are altered and increased amounts of protein are present in urine. Proteinuria may be caused by physiologic or pathologic conditions. Physiologic or benign proteinuria is usually transient, of low magnitude, and abates when the underlying cause is corrected. Examples of conditions that may cause physiologic proteinuria include strenuous exercise, seizures, fever, exposure to extreme heat or cold, and stress.
Pathologic proteinuria may be classified as urinary or non-urinary in origin. Non-urinary disorders include “prerenal” proteinuria (e.g. production of immunoglobulin light chains (Bence Jones proteins) by neoplastic plasma cells) and genital tract inflammation (e.g., prostatitis or metritis). Pathologic urinary proteinuria may be renal or non-renal in origin. Non-renal proteinuria most frequently occurs in association “post renal” lower urinary tract inflammation or hemorrhage. Clinical signs and urine sediment findings are usually compatible with lower urinary tract disease; pollakiuria, dysuria, stranguria, and/or hematuria and pyuria, hematuria, bacteriuria, and increased numbers of transitional epithelial cells respectively. Renal proteinuria is typically caused by increased glomerular filtration of plasma proteins associated with intraglomerular hypertension, the presence of immune complexes, vascular inflammation in glomerular capillaries, or structural defects in the glomerular basement membrane. A small degree of renal proteinuria may also be caused by decreased reabsorption of filtered plasma proteins due to tubulointerstitial disease. In some cases, tubulointerstitial proteinuria may be accompanied by normoglycemic glucosuria and increased excretion of electrolytes (e.g., Fanconi syndrome and acute tubular damage). Glomerular lesions usually result in more severe proteinuria than tubulointerstitial lesions. Renal proteinuria may also be caused by inflammatory or infiltrative disorders of the kidney (e.g., pyelonephritis, leptospirosis, neoplasia) which are often accompanied by an active urine sediment and ultrasonographic changes in the kidney.
Clinical significance of proteinuria depends on its severity and persistence. In the absence of hyperproteinemia, hematuria and urinary tract inflammation, persistent proteinuria usually indicates kidney disease and severe proteinuria (urine protein-creatinine ratio [UPC] ≥ 2) is generally associated with glomerular disease. The magnitude of proteinuria does not predict reversibility of the underlying disease. However, there is growing evidence linking renal proteinuria and progression of CKD in dogs and cats; the greater the magnitude of proteinuria, the greater the risk for progression of renal disease and possible death (Jacob et al, 2005, Syme et al, 2006, Kuwahara et al, 2006, Jepson et al, 2007, King et al 2007, Jepson et al, 2009, Jepson et al, 2010, Chakrabarti et al, 2012, McLeland et al, 2015). Importantly, treatments that attenuated proteinuria in dogs and cats with CKD also have been associated with slowed progression of CKD, improved survival, or both (Jepson et al, 2007, King et al, 2007, Grauer et al, 2000, Mizutani et al, 2006). For these reasons, screening for renal proteinuria and longitudinal assessment of renal proteinuria is important for prognosis and assessment of response to treatment.
The urine dipstick colorimetric test is the most common first-line screening test for the detection of proteinuria/albuminuria; however, false-positive reactions are common and limit the test’s utility (Grauer et al, 2004, Zateli et al, 2010, Hanzlicek et al, 2012, Mamone et al, 2014). While false-positive results (decreased specificity) are common in both species cats are more frequently affected. However, one recent study suggests one brand of dipsticks (Aution Sticks 10PA Aution Sticks 10EA, ARKRAY, Kyoto, Japan) can be used to screen dogs and cats for persistent proteinuria. In this study of urine from 101 dogs and 50 cats the dipstick UPC correlation with the quantitative method was good in cats (rs=0.89 p < 0.0001) and fair in dogs (rs =0.75 p<0.001) (Defontis et al, 2013). The authors note automated reading of the dipsticks (Aution Eleven reflectometer AE-4020, ARKRAY, Kyoto, Japan) was better than visual reading and is the preferred method for urine dipstick examination when available and positive results should be submitted to a reference laboratory for quantitative measurement. Disparate results were documented in a study of 599 canine and 347 feline urine samples analyzed by conventional urine protein test strip method (Multistix Reagent Strips; Bayer Corporation, or Roche Chemstrip 9; Roche Diagnostic Corporation) and a canine or feline albumin-specific quantitative enzyme-linked immunosorbence assay (ELISA) (Heska Corporation) (Lyon et al, 2010). Based on this study in canine urine, if the urine dipstick or SSA result is ≥2+ there is a high likelihood that the sample is positive for albumin. However, if the dipstick analysis is trace or 1+ positive, a turbidimetric SSA analysis should be performed to confirm the diagnosis of proteinuria. To increase specificity, when the dipstick and SSA tests are performed simultaneously, they should be interpreted in series (both tests should be positive to consider the sample positive for albuminuria), rather than in parallel. If dipstick and SSA results both fall into the trace to 1+ range, positive results should be confirmed with a more specific assay such the ELISA-based test. In these studies of feline urine samples, both routine-screening tests (dipstick and SSA) performed poorly and appear to be of minimal diagnostic value because of an unacceptable high number of false positives (Lyon et al, 2010). For both dipstick and SSA tests, the positive and negative likelihood ratios were close to 1 and the positive and negative predictive values were close to 50%, indicating that neither test provided useful information. Based on these data, some investigators suggest, urine albumin detection in the feline patient should always be performed with a higher quality assay such as the species-specific ELISA (Grauer, 2011). Historically, proteinuria detected by these screening methods has been interpreted in light of urine specific gravity and urine sediment such that a trace or 1+ positive dipstick reading in hypersthenuric urine was attributed to urine concentration rather and abnormal proteinuria. Additionally, positive dipstick reading in the presence of an active urine sediment (hematuria or pyuria) was attributed to urinary tract hemorrhage or inflammation. However, these interpretations may be inaccurate. Except in the case of false-positive results, given the limits of conventional dipstick test sensitivity, any positive result for protein regardless of urine concentration may be abnormal. Additionally, not all dogs with microscopic hematuria and pyuria have albuminuria (Vaden et al, 2004). In patients with gross hematuria and/or microscopic pyuria, the source of the hemorrhage and/or inflammation should be diagnosed and treated before further assessment of the proteinuria.
If the results of the screening tests show persistent proteinuria, urine protein excretion should be quantified to facilitate IRIS staging (Table 37-1b), evaluate the severity of renal lesions and to assess the response to treatment or the progression of disease. Urinary protein is most accurately measured by a quantitative analytical technique rather than by dipstick. Methods used to quantitate proteinuria include UPC and immunoassays for albuminuria. Persistent microalbuminuria is the mildest, and often earliest, detectable form of proteinuria. Microalbuminuria (MA) is defined as concentrations of albumin in the urine that are greater than normal (> 1.0 mg/dL) but below the limit of detection using conventional dipstick urine protein screening methodology (i.e., ≤ 30 mg/ dL).