Proteinuria

Measurement and interpretation of proteinuria and albuminuria (revised 2016)

Gregory F. Grauer Manhattan, KS, USA

Introduction

Persistent proteinuria with an inactive urine sediment is likely marker of chronic kidney disease (CKD) in dogs and cats.1 Recent evidence also suggests an association between renal proteinuria and progression of CKD in both species: the greater the magnitude of proteinuria, the greater the risk of renal disease progression and mortality.2-5 Importantly, treatments that have attenuated proteinuria in dogs and cats with CKD have also been associated with slowed kidney disease progression and/or improved survival.4-8 For these reasons, screening for renal proteinuria and longitudinal assessment of renal proteinuria have recently received renewed interest.

Proteinuria is a general term that describes the presence of any type of protein in the urine, such as albumin, globulins, and Bence Jones proteins. Proteinuria of renal origin results from two major mechanisms: the first is a loss of selective glomerular filtration resulting in an increased amount of plasma protein in the filtrate; the second is an impaired resorption of the filtered protein. Albumin is the predominate protein in urine in dogs and cats in both health and renal disease.

Normal physiology

The urine of healthy dogs and cats contains only a small amount of albumin (< 1 mg/dl) and other proteins. Type IV collagen within the basement membrane of the glomerular capillary wall restricts the filtration of most plasma proteins, primarily on the basis of molecular weight and size. Albumin (molecular weight 69,000 daltons) and larger proteins are normally not present in large quantities in glomerular filtrate due to this glomerular selective permeability. The negatively charged glomerular capillary wall further impedes the passage of negatively charged proteins like albumin. The initial glomerular filtrate of healthy dogs and cats contains only 2-3 mg/dl of albumin compared with about 4 g/dl found in plasma. Smaller-molecular-weight proteins, as well as those positively charged larger proteins that do pass through the glomerular capillary wall, are almost completely reabsorbed by tubular epithelial cells. Such reabsorbed proteins may be broken down and used by the epithelial cells or returned to the plasma as their constituent amino acids. This reabsorption occurs primarily in proximal convoluted tubules and reduces the concentration of albumin in normal urine to < 1 mg/dl. Reabsorption of protein by tubular epithelial cells, however, has a transport maximum. Tubular proteinuria may occur if that maximum is exceeded (e.g., excessive production of small molecular weight proteins like Bence Jones proteins) or if damage to the tubular epithelial cells (e.g., nephrotoxic damage or chronic tubulointerstitial disease) decreases their reabsorptive capacity.

Detection of proteinuria

The urine dipstick colorimetric test is the usual first-line screening test for the detection of proteinuria/albuminuria, but false-positive reactions are common. Many laboratories confirm positive reactions for protein on the dipstick test with the sulfosalicylic acid (SSA) turbidimetric test. Proteinuria detected by dipstick and/or SSA screening tests and thought to be of renal origin is often confirmed and quantitated using the urine protein/creatinine ratio (UP/C). The dipstick, SSA, and UP/C tests are more sensitive for albumin than for other proteins. There are also species-specific tests that are capable of detecting albumin concentrations as low as 1 mg/dl in canine and feline urine (Heska and Antech quantitative albuminuria assays).

The dipstick colorimetric test for proteinuria is inexpensive, easy to use, and primarily measures albumin, but sensitivity and specificity are relatively low. False-negative results (decreased sensitivity) may occur with Bence Jones proteinuria, low concentrations of albuminuria, and/or dilute or acidic urine. The lower limit of detection for the conventional dipstick test is approximately 30 mg/dl. False-positive results are also common in both species with the dipstick but occur more frequently in cats than in dogs. For example, when 599 canine and 347 feline urine samples (from apparently healthy dogs and cats) were 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 ELISA (Heska Corporation) there were disparate results.9 The sensitivities (≥ trace positive reaction) for conventional urine protein test strips for albuminuria in canine and feline urine were 81% and 90%, respectively, but specificities were only 48% and 11%, respectively.9

The SSA test is performed by mixing equal quantities of urine supernatant and 3-5% SSA in a glass test tube and grading the turbidity resulting from precipitation of protein on a 0 to 4+ scale. In addition to albumin, the SSA test can detect globulins and Bence Jones proteins to a greater extent than the dipstick test. False-positive results may occur if the urine contains radiographic contrast agents, penicillin, cephalosporins, sulfisoxazole, or thymol (a urine preservative), and for other, unknown reasons. The protein content may also be overestimated with the SSA test if uncentrifuged, turbid urine is analyzed. The reported sensitivity of the SSA test is approximately 5 mg/dl. Because of the relatively poor specificity of conventional dipstick analysis, many reference laboratories will confirm a positive dipstick test result for proteinuria using the SSA test. Sensitivities (≥ trace positive reaction) for the SSA test for albuminuria in urine from apparently healthy dogs and cats were 73% and 58%, respectively, but specificities were only 64% and 25%, respectively.9

Based on the above study in canine urine, if the urine dipstick or SSA result is ≥ 2+ there is a high probability that the sample is positive for albumin.9 However, if the dipstick analysis is trace or 1+ positive, a turbidimetric SSA analysis should be performed to confirm the diagnosis of proteinuria. When both tests are performed simultaneously they should be interpreted in series (both tests should be positive in order to consider the sample positive for albuminuria), rather than in parallel fashion, to increase specificity.9 If dipstick and SSA results both fall into the trace to 1+ range, positive results should be confirmed with a more specific assay such as the ELISA based albuminuria test.9

For feline urine samples, both routine-screening tests (dipstick and SSA) performed poorly and appear to be of minimal diagnostic value due to an unacceptable high number of false-positives.9 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.9 Based on these data, urine albumin detection in the feline patient should always be performed with a higher quality assay such as the species-specific albuminuria ELISA.

The sensitivity and specificity of the dipstick and SSA tests for detection of albuminuria has also been evaluated in cats with CKD.10  Inasmuch as cats with CKD might be expected to have higher concentrations of albumin in their urine and/or a greater frequency of albuminuria, these screening tests would likely perform better in the detection of albuminuria. In 239 urine samples from 37 cats with CKD the sensitivity and specificity for a > trace reaction on the dipstick and for a > 5 mg/dl reaction on the SSA were 81%/68% and 63%/96%, respectively.10  A positive urine dipstick (≥ trace) and positive SSA (≥ 5 mg/dL), a positive SSA alone, or ≥ 2+ urine dipstick alone was indicative of albuminuria. In these cases, protein quantification by determining UP/C would be warranted. In the case of a negative urine dipstick result the addition of the SSA test added little diagnostic value.10 

Proteinuria detected by these semi-quantitative, screening methods has historically been interpreted in light of the urine specific gravity and urine sediment. For example, a positive dipstick reading of trace or 1+ proteinuria in hypersthenuric urine has often been attributed to urine concentration rather than abnormal proteinuria. In addition, a positive dipstick reading for protein in the presence of hematuria or pyuria was often attributed to urinary tract hemorrhage or inflammation. However, in both situations this interpretation may not be correct. Given the limits of the conventional dipstick test sensitivity, any positive result for protein regardless of urine concentration may be abnormal (except in the case of false-positive results). Likewise, hematuria and pyuria have an inconsistent effect on urine albumin concentrations: not all dogs with microscopic hematuria and pyuria have albuminuria.11  In cases 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.

Detection of albuminuria

Albuminuria can be measured by quantitative immunoassays at reference laboratories (Antech Diagnostics and Heska Corporation). 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). Urine albumin concentrations above 30 mg/dl are referred to as overt albuminuria. Urine albumin concentrations can be adjusted for differences in urine concentration by dividing by urine creatinine concentrations. For example, a urine albumin/creatinine ratio > 0.03 is considered abnormal in people. Alternatively, urine can be diluted to a standard concentration by using the urine specific gravity (e.g., 1.010), prior to assay. In one study of dogs, normalizing urine albumin concentrations to a 1.010 specific gravity yielded similar results to the urine albumin/creatinine ratio.12 

Indications for use of MA tests include:1

  • when conventional screening tests for proteinuria produce equivocal or conflicting results or false-positive results are suspected.
  • when conventional screening tests for proteinuria are negative in apparently healthy, older dogs and cats and a more sensitive screening test is desired.
  • when conventional screening tests for proteinuria are negative in apparently healthy, young dogs and cats that have a familial risk for developing proteinuric renal disease and a more sensitive screening test is desired.
  • when conventional screening tests for proteinuria are negative in dogs and cats with chronic illnesses that are often associated with proteinuria renal disease and a more sensitive screening test is desired.
  • when previous MA tests were positive (longitudinal monitoring).

Interpretation and follow-up of MA testing is critical. Like other tests for proteinuria, MA tests can be affected by lower urinary tract inflammation and therefore assessment of patient history and urine sediment changes is important. A negative MA result is a useful finding because it obviates any concern about albuminuria until the next testing interval. A positive test result is more complex and needs to be confirmed with follow-up testing approximately 7-10 days later. If the second test is negative, the initial positive test was likely due to transient benign or physiologic albuminuria that is unlikely to have any long-term consequence for the patient. If follow-up tests continue to be positive, more frequent monitoring and further investigation is indicated to verify whether proteinuria is persistent and show any changes in its severity. Increases in magnitude of MA are likely indicative of active, ongoing renal injury, and should prompt further investigation to detect any infectious, inflammatory, or neoplastic disease that might be the underlying cause of renal disease.

Causes of albuminuria

Persistent albuminuria in humans reflects the presence of intraglomerular hypertension and/or generalized vascular damage and endothelial cell dysfunction.13  It is interesting to note that the presence of low level albuminuria has been shown to be an accurate predictor of subsequent renal disease in human beings with both systemic hypertension and diabetes mellitus and has also been observed in patients with systemic diseases that are associated with glomerulopathy.14-18 Importantly, early detection of albuminuria and institution of appropriate treatment has slowed the progression of kidney disease in people.19

A limited number of studies in dogs suggest that low-level albuminuria is a good indicator of early renal disease.12,20,21 In addition to primary kidney disease, other conditions have been reported in dogs with albuminuria, including infectious, inflammatory, neoplastic, metabolic and cardiovascular disease.22,23 Results of a study of albuminuria in dogs with lymphosarcoma and osteosarcoma demonstrated that urine albumin concentrations were significantly increased in dogs with these tumors, even though UP/Cs may not be increased above the reference range.24 Urine albumin concentrations did not, however, consistently decrease with decreased tumor burden.

The prevalence of low-level albuminuria in dogs admitted for intensive care is higher than for other reported patient populations and appears to vary with different classifications of disease.22,23 As reported in people with acute inflammatory conditions, transient albuminuria occurred in some of these dogs. A large percentage of dogs that were euthanized or died had albuminuria, suggesting that, as in people, its presence may be a negative prognostic indicator. Short-term prednisone administration has been shown to cause a substantial but reversible increase in the magnitude of proteinuria/albuminuria in heterozygous, or carrier, female dogs with X-linked hereditary nephropathy.25 Finally, a moderate amount of exercise (treadmill work for 20 minutes) did not affect albuminuria in dogs.26

Localization of proteinuria

When proteinuria/albuminuria is detected by screening tests, it is important to try to identify its source. Proteinuria may be caused by physiologic or pathologic conditions. Physiologic or benign proteinuria is often transient and abates when the underlying cause is corrected. Examples of conditions that may cause physiologic proteinuria are strenuous exercise, seizures, fever, exposure to extreme heat or cold, and stress. The mechanism of physiologic proteinuria is not completely understood, but transient renal vasoconstriction, ischemia, and congestion may be involved. Decreased physical activity may also affect urine protein excretion in dogs: one study showed that urinary protein loss was higher in dogs confined to cages than in dogs with normal activity levels.27

Pathologic proteinuria may be caused by urinary or non-urinary abnormalities. Non-urinary disorders associated with proteinuria often involve the production of small-molecular-weight proteins (dysproteinemias) that are filtered by the glomeruli and subsequently overwhelm the reabsorptive capacity of proximal tubules. An example of this "pre-renal" proteinuria is the production of immunoglobulin light chains (Bence Jones proteins) by neoplastic plasma cells. Genital tract inflammation (e.g., prostatitis or metritis) can also result in pathologic non-urinary proteinuria. Obtaining urine samples via cystocentesis reduces the potential for urine contamination with protein from the lower urinary tract.

Pathologic urinary proteinuria may be renal or non-renal in origin. Non-renal proteinuria most frequently occurs in association with lower urinary tract inflammation or hemorrhage (also referred to as post-renal proteinuria). Changes observed in the urine sediment are usually compatible with the underlying inflammation (e.g., pyuria, hematuria, bacteriuria, increased numbers of transitional epithelial cells). On the other hand, renal proteinuria is most often caused by increased glomerular filtration of plasma proteins associated with intraglomerular hypertension or the presence of immune complexes, amyloid, or vascular inflammation in glomerular capillaries. 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 that associated with 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.

Monitoring renal proteinuria

Transient renal proteinuria/albuminuria is likely of little consequence and does not warrant treatment. On the other hand, persistent proteinuria/albuminuria with an inactive sediment strongly suggests the presence of CKD. Persistent proteinuria/albuminuria can be defined as positive test results on ≥ three occasions, ≥ two weeks apart. Because persistent proteinuria/albuminuria can be constant or increase or decrease in magnitude over time, monitoring should utilize quantitative methods to determine disease trends and/or response to treatment. Changes in the magnitude of proteinuria should always be interpreted in light of the patient's blood creatinine concentration since proteinuria may decrease in progressive renal disease as the number of functional nephrons decrease. Decreasing proteinuria in the face of a stable blood creatinine suggests improving renal function, whereas decreasing proteinuria with increasing blood creatinine suggests disease progression.

Quantitation of proteinuria

If the results of the screening tests show persistent proteinuria, urine protein excretion should be quantified. This helps to evaluate the severity of renal lesions and to assess the response to treatment or the progression of disease. Methods used to quantitate proteinuria include UP/C and immunoassays for albuminuria, the latter expressed as either urine albumin/creatinine ratio or as mg/dl in urine diluted to a standard specific gravity (e.g., 1.010). Albumin ≥ 30 mg/dl in 1.010 diluted urine will usually result in UP/C ≥ 0.4 in cats and 0.5 in dogs. The UP/Cs and urine albumin/creatinine ratios from spot urine samples accurately reflect the quantity of protein/albumin excreted in the urine over a 24-hour period.28 Because 24-hour urine collection is difficult, spot sampling has greatly facilitated recognition of proteinuric renal diseases in veterinary medicine. Most studies have shown that normal urine protein excretion in dogs and cats is < 10 mg/kg/24 hours and that normal UP/Cs are < 0.2. UP/Cs of 0.2 - 0.5 in dogs and 0.2 - 0.4 in cats are considered borderline proteinuria.1 Persistent proteinuria that results in UP/Cs > 0.4 in cats and > 0.5 in dogs, where pre- and post-renal proteinuria have been ruled out, are consistent with glomerular or tubulointerstitial CKD, whereas UP/Cs > 2.0 are strongly suggestive of glomerular disease.1 It is possible that the definition of “normal” will continue to change with additional research. It is interesting to note that, while the UP/C was a specific test for canine and feline albuminuria when compared to the species-specific quantitative immunoassay, the cut-off value of 0.2 for UP/C resulted in an unacceptable number of false negatives.9Therefore, the UP/C is not recommended as a routine screening test for urine albumin in apparently healthy dogs or cats, especially for low levels of albuminuria.9 In cats with CKD, the single best test for the detection of albuminuria was the UP/C (when ≥ 0.2 was considered positive) in which either a negative or positive test result provided useful information.

Based on longitudinal testing results in dogs with X-linked hereditary nephropathy, the UP/C must change by at least 35% at high UP/C values (near 12) and 80% at low UP/C values (near 0.5) to demonstrate a significant difference between serial values.29 One measurement was found to reliably estimate the UP/C when the values were < 4, but two or more determinations were necessary to reliably estimate the UP/C when values were higher than 4.29

Importance of renal proteinuria

Proteinuria has been found with other abnormalities as a sequela to partial renal ablation in dogs and cats. Glomerular capillary hypertension, glomerular enlargement, and proteinuria have been documented in dogs with the remnant kidney model of renal failure.30 In cats with the remnant kidney model of CKD, increases in single-nephron glomerular filtration rate occur in association with glomerular hypertrophy, increasing intraglomerular pressures, hyperfiltration, mesangial matrix expansion, and proteinuria.31

Of clinical importance is the association of proteinuria with negative outcomes in dogs and cats with naturally occurring CKD. In affected dogs, the relative risk of uremic crises and mortality was approximately three times greater in dogs with UP/C > 1.0 (n = 25), compared with that in dogs with UP/C < 1.0 (n = 20). In this study, the risk of an adverse outcome was approximately 1.5 times greater for every 1-unit increase in UP/C, and the decline in renal function was greater in dogs with higher UP/C.2 Similarly, relatively mild proteinuria (UP/C > 0.4) appears to be a negative predictor of survival in affected cats. Increasing proteinuria was associated with increasing serum creatinine concentrations and increasing systolic blood pressure (presumably related to glomerular hyperfiltration), and UP/C, age, and serum creatinine concentration (but not blood pressure) were independently associated with mortality.3 Shorter survival also was associated with an increased UP/C as an independent risk factor in another study of cats with naturally occurring CKD.5

Even in patients without azotemia, the development of proteinuria has been linked with negative clinical outcomes. Development of proteinuria was associated with increased risk of mortality due to all causes in cats with normal renal function when proteinuria was first detected. 32 Proteinuria (measured as UP/C; before and after treatment as well as the change in UP/C) was also the only variable related to survival in 141 client-owned cats with naturally occurring systemic hypertension. In these cats, amlodipine treatment decreased both blood pressure and proteinuria.4 In addition, proteinuria was found to be significantly associated with development of azotemia in a prospective, longitudinal cohort study of 95 cats aged 9 years and older (median age = 13).33 When non-azotemic cats were followed for 12 months or until death or azotemia developed, 29/95 (30.5%) developed azotemia (serum creatinine concentration > 2.0 mg/dl), which correlated with the finding of proteinuria (median UP/C, 0.19 in azotemic cats vs. 0.14 in non-azotemic).

Lastly, proteinuria has been associated with progression of CKD in affected cats. In 59 cats with CKD (serum creatinine concentrations > 2.0 mg/dl, urine specific gravity < 1.035, and history and clinical signs compatible with CKD vs. acute kidney injury), the UP/C was positively correlated with both renal interstitial fibrosis score and maximal glomerular volume. Of the 59 cats, 34 (58%) were classified as proteinuric.34 In another study, when cats with CKD surviving > 1 month (n = 34) were compared with cats with CKD surviving < 1 month (n = 16), UP/C was significantly higher in the non-surviving group. In the surviving group, UP/C was the only clinicopathologic variable that exhibited a consistent alteration (increase) in relation to first-visit data and was most likely to be associated with mortality.35 In a third study, a 0.1-unit increase in UP/C was associated with a 24% increase in risk of progression of CKD in client-owned cats. When cats with stable CKD (n=112) were compared with cats with progressive CKD (n=101), median UP/C in the progressive group were higher, compared with that for the stable group (0.27 vs. 0.14, respectively).36

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