Introduction

Dogs and cats may normally have small amounts of protein in their urine; however, the term “proteinuria” usually refers to the presence of an abnormal amount of protein in the urine. The term “microalbuminuria” refers to the presence of albumin in the urine in a concentration of 1–30 mg/dL, which is considered abnormal, but is below the detection limit of the urine dipstick. A persistently high magnitude proteinuria is usually an indicator of chronic kidney disease (CKD); however, it may be a secondary consequence of infectious, inflammatory, metabolic or neoplastic disorders. Proteinuria is also a prognostic marker and is associated with a more rapid progression of CKD, a higher frequency of uremic crises as well as an increased mortality rate.^1,2 Thus, early detection of proteinuric animals will allow close monitoring as well as early therapeutic intervention, which may decrease the magnitude of proteinuria and the disease progression rate of these patients. Screening for proteinuria should be performed in any animal diagnosed with CKD or with any other disease known to be associated with proteinuria.

Methods of Detection and Interpretation of Test Results

The urine dipstick colorimetric test is the most commonly used method to screen for proteinuria. The urine dipstick is more sensitive to albumin compared to other proteins, and its lower detection limit is 30 mg/dL. Interpretation of any result should be done in light of the urine specific gravity. A positive result in highly concentrated urine reflects a smaller degree of protein loss compared to the same amount of protein in diluted urine; thus, the latter is more alarming. Both false positive and false negative results occur using the urine dipstick. Once persistent proteinuria has been confirmed or when a high magnitude proteinuria is suspected, it should be quantified using urine to creatinine ratio (UPC). Its results are used as a guideline for diagnostic investigation, therapeutic intervention, and monitoring response to therapy. Urine protein to creatinine ratio < 0.2 in dogs and cats is considered normal, and a ratio between 0.2–0.4 in cats and 0.2–0.5 in dogs is considered borderline proteinuria.

The Origin of Proteinuria

Once proteinuria has been documented, its origin should be identified as a first step towards the diagnosis of the underlying disease. Proteinuria can be classified as urinary system or extra-urinary system in origin.

Extra-urinary system proteinuria may result from either prerenal or post-urinary system (i.e., genital system) conditions. Prerenal proteinuria results from presence of excessive amounts of either normal (e.g., hemoglobin, myoglobin) or abnormal (e.g., Bence Jones) blood proteins, which can be freely filtered through the glomerulus. Thus, prerenal proteinuria can occur with normal kidney structure and function and treatment is aimed at identifying and eliminating the underlying disease. Urinary system proteinuria can be classified as renal (functional or pathological) or post-renal. Functional renal proteinuria represents a transient change in the permselectivity characteristics of the glomerulus, and thus should not be treated. Pathological renal proteinuria may result from glomerular (decreased permselectivity), tubular (decreased reabsorption) or interstitial (exudation of proteins to the urinary space) abnormalities. Glomerular proteinuria is the most common cause of persistent high magnitude proteinuria. It requires close monitoring, and often warrants diagnostic workup and therapeutic intervention. Post-renal proteinuria relates to the entry of proteins into the urine from the renal pelvis, ureters, urinary bladder, or urethra, and results from disorders along the urinary excretory system (e.g., infection, urolithiasis, neoplasia).

Diagnostic Approach

The diagnostic workup is directed towards the detection of the origin of proteinuria and the underlying disease and includes complete history and physical examination as well as diagnostic tests such as arterial blood pressure measurement, complete blood count, serum chemistry, urinalysis and urine culture, serologic testing and PCR for infectious diseases, diagnostic imaging, and kidney biopsy. Initially, post-renal proteinuria is excluded by evaluating the urine sediment for presence of inflammation and hemorrhage. Then, extra-urinary system causes are excluded. Post-urinary (genital system) proteinuria is easily excluded by performing urinalysis on urine obtained by cystocentesis, and prerenal proteinuria is ruled out by evaluating the plasma protein concentration and excluding dysproteinemia and presence of specific proteins in the urine (e.g., hemoglobinuria, myoglobinuria and Bence Jones proteins). Glomerular proteinuria can be of any magnitude, but is particularly suspected when persistent high magnitude (UPC ≥ 2) proteinuria is present, and after ruling out extra-renal and post-renal causes. Glomerular proteinuria can be diagnosed by obtaining a kidney biopsy which can additionally help in subcategorizing the disease, using light microscopy, electron microscopy and immunofluorescence.

Treatment of Proteinuria

Therapy of proteinuria should be directed towards elimination of any underlying disease and decreasing the magnitude of proteinuria. Successful therapy of the underlying disease may resolve proteinuria; however, some patients will remain proteinuric due to the presence of irreversible damage. When proteinuria persists after elimination of the underlying disease or when the latter neither can be identified nor be eliminated, therapy is merely symptomatic. Treatment goals include decreasing the magnitude of proteinuria to the reference range to minimize progressive kidney damage, as well as preventing and treating the secondary consequences of the protein loss (e.g., thromboembolism).

Azotemic patients require therapeutic intervention at a lower magnitude of proteinuria compared to non-azotemic patients. Current guidelines recommend treating non-azotemic patients when UPC ratio is ≥ 2.0, while azotemic dogs and cats are to be treated when UPC ≥ 0.5 and UPC ≥ 0.4, respectively.

Standard Therapy

Dietary modification, angiotensin converting enzyme inhibition (ACEi) and angiotensin receptor blockade (ARBs) are the mainstay of therapy. Protein restriction is one of the dietary modifications recommended for patients with protein losing nephropathy. Even though counterintuitive, increasing dietary protein amounts is associated with increased albuminuria and may result in decreased serum albumin concentration. ACEi and ARBs decrease the efferent glomerular arteriolar resistance, resulting in decreased glomerular transcapillary hydraulic pressure. Administration of ACEi and ARBs should be exercised with caution, especially in severely and acutely azotemic patients. Low dose aspirin (0.5 mg/kg, PO, q 12–24 h) may also decrease proteinuria in dogs. It has been shown that glomerular damage may be prevented by thromboxane release inhibition, thus preventing platelet aggregation and neutrophil chemotaxis. An additional potential advantage of low dose aspirin therapy is decreasing the risk of thromboembolism, especially in animals with a decreased hypoantithrombinemia.

Immunosuppression

When a kidney biopsy is obtained and there is evidence for immune complex deposition, immunosuppression should be initiated. Empirical application of immunosuppressive/anti-inflammatory therapy should be considered for animals with severe, persistent, or progressive glomerular disease in which there is renal biopsy supported evidence of an immune pathogenesis and no identified contraindication to immunosuppressive therapy. For diseases associated with profound proteinuria, attendant hypoalbuminemia, nephrotic syndrome, and/or rapidly progressive azotemia, single drug or combination therapy consisting of rapidly acting immunosuppressive drugs is recommended.

Based on preliminary, uncontrolled clinical experience with mycophenolate and its low rate of serious complications, mycophenolate is recommended for therapy of dogs with glomerular disease of an apparent immune pathogenesis. Short-term administration of glucocorticoids may be recommended in fulminate cases where immediate immunosuppression is required if their use is adjusted to minimize their adverse effects. However, on the basis of current practice perceptions and anecdotal experience, the use of glucocorticoid therapy should be tapered to the minimally effective dose as quickly as possible due to predictable side effects.³

Monitoring of Proteinuria

When the degree of proteinuria is mild and therapeutic intervention is not indicated, periodic monitoring should include urinalysis, UPC ratio, and serum creatinine and albumin concentration at least every 3–6 months. When therapy is applied, closer monitoring should be performed. In high-risk patients serum creatinine should be monitored 3–5 days after initiation of ACEi/ARBs to identify a significant decrease in glomerular filtration rate. Urinary protein to creatinine ratio should be monitored periodically and therapy should be adjusted. Due to day to day variation, not every change in UPC ratio would be considered significant. At least a 35% or 80% change should be demonstrated when the UPC ratio is high (around 12) or low (around 0.5), respectively. In animals with progressive kidney disease, the magnitude of proteinuria may decrease in late stages of the disease due to a reduction in the number of remaining nephrons through which protein loss can occur.

References

1.  Jacob F, Polzin DJ, Osborne CA, Neaton JD, Kirk CA, Allen TA, et al. Evaluation of the association between initial proteinuria and morbidity rate or death in dogs with naturally occurring chronic renal failure. J Am Vet Med Assoc. 2005;226(3):393–400.

2.  Syme HM, Markwell PJ, Pfeiffer D, Elliott J. Survival of cats with naturally occurring chronic renal failure is related to severity of proteinuria. J Vet Intern Med. 2006;20(3):528–535.

3.  Segev G, Cowgill LD, Heiene R, Labato MA, Polzin DJ. Consensus recommendations for immunosuppressive treatment of dogs with glomerular disease based on established pathology. J Vet Intern Med. 2013;Suppl 1:S44–S54.