Definition

• Urinary protein detected by dipstick analysis, urinary protein:creatinine ratio (UP:C 0.4 in cats or 0.5 in dogs), urinary albumin:creatinine ratio (UA:C probably >30 mg/g), or 24-hour urine protein content (>20 mg/kg). UP:C of 0.2–0.4 in cats and 0.2–0.5 in dogs is borderline.
• Microalbuminuria is the abnormal presence of low concentrations of albumin in the urine (1–30 mg/dL) below the limit of detection of standard urine dipsticks.

Pathophysiology

• Prerenal: greater than normal delivery of low molecular weight plasma proteins to glomeruli.
• Renal, glomerular: excessive loss of larger molecular weight proteins (e.g., albumin) across the GBM secondary to altered permselectivity of glomeruli.
• Renal, tubular: reduced tubular reabsorption of proteins.
• Post-renal: exudation of blood or plasma into lower urinary tract.

Systems Affected

• Renal/Urologic-chronic glomerular proteinuria causes progressive tubular damage resulting in advanced chronic kidney disease (CKD).
• Cardiovascular-systemic hypertension is common with glomerular disease.
• Hemic/Lymphatic/Immune-severe glomerular proteinuria can lead to edema and/or hypercoagulability. Hypercoagulability is brought about by vascular stasis, hyperfibrinogenemia, platelet abnormalities, loss of antithrombic substances, and an increase in procoagulant factors. The pathogenesis of edema involves both inappropriate renal sodium retention and decreased plasma oncotic pressure.

Genetics

Familial nephropathies associated with glomerular proteinuria have been described in several breeds of dogs; in only a few has the mode of inheritance been established: Samoyed (X-linked), English cocker spaniel (autosomal recessive), bull terrier (autosomal dominant), Dalmatian (autosomal dominant), Bernese mountain dog (suspect autosomal recessive), Brittany spaniel (autosomal recessive), Chinese Shar-Pei (suspect autosomal recessive). Doberman pinscher, bullmastiff, Newfoundland, rottweiler, Pembroke Welsh corgi, beagle, English foxhound, soft-coated Wheaten terrier, and others.

Incidence/Prevalence

• In a study of urinalysis data from 500 dogs, the prevalence of proteinuria was approximately 19%.
• The prevalence of microalbuminuria was 25% in 3,041 dogs and 25% 1,243 cats. Prevalence increased with advancing age.

Signalment

Signs

• Vary with underlying cause and severity of proteinuria.
• Patients with glomerular proteinuria are frequently asymptomatic or have signs attributable to underlying diseases.

Causes

Risk Factors

• Chronic inflammatory (e.g., infectious and immune-mediated) and neoplastic diseases can lead to development of glomerulonephritis or amyloidosis. Examples include dirofilariasis, ehrlichiosis, borreliosis, babesiosis, chronic bacterial infections (e.g., endocarditis, pyoderma), pyometra, bartonellosis, FIV, mast cell tumor, lymphosarcoma, hyperadrenocorticism, and systemic lupus erythematosus.
• Systemic hypertension.
• Chronic hyperlipidemia (e.g., miniature schnauzer).
• Multiple myelomas can produce paraproteins resulting in Bence-Jones proteinuria.

Differential Diagnosis

Differentiate prerenal, post-renal, and renal tubular from glomerular causes.

CBC/Biochemistry/Urinalysis

• Urine dipstick and sulfosalicylic acid tests allow qualitative and semiquantitative assessment of urine protein content. Results of both are affected by urine concentration and must be interpreted in context of urine specific gravity. Low urine protein (trace or 1 +) may be normal in a concentrated urine sample.
• The dipstick lacks specificity (dog, 69%; cat, 31%) and sensitivity (dog, 54%; cat, 60%).
• Contamination with quaternary ammonium compounds causes false-positive urine dipstick colorimetric (tetrabromphenol blue) test results. False-positive test results also occur when urine is highly alkaline (pH >8–9) or when the dipstick is immersed in the urine for a prolonged time.
• Low concentrations of Bence-Jones proteins or gamma globulins may not be detected by urine dipsticks.
• SSA turbidometric test results are falsely increased by radiographic contrast media, penicillins, sulfisoxazole, or the urine preservative thymol.
• SSA test results are falsely decreased by very alkaline urine and increased by uncentrifuged urine.
• If proteinuria is detected by these methods, the urine sediment should be evaluated for hematuria, pyuria, and/or bacteriuria. Hematuria alone typically does not increase urine albumin content above the negligible range (i.e., >1 mg/dL) or the UP:C above 0.4 until there is a visible color change in the urine. In a study of the effects of inflammation on urine protein determination, 67% of dogs with varying degrees of pyuria had negligible urine albumin concentrations (<1 mg/dL) and 81% had normal UP:C (<0.4).
• To determine if proteinuria is persistent repeat the urine protein screening test in proteinuric patients that initially have a normal urine sediment or have been treated for urinary tract inflammation or hemorrhage. If proteinuria is transient and the urine sediment is normal, consider functional proteinuria or false-positive test results.
• Although not all animals with glomerular disease are hypoalbuminemic, glomerular proteinuria should be suspected when proteinuria and hypoalbuminemia are concurrent. As disease progresses, clinicopathologic changes consistent with glomerular disease may develop.

Other Laboratory Tests

• Urine protein should be quantified in dogs and cats that have hypoalbuminemia and/or repeatedly positive urine dipstick or SSA tests in absence of LUT hemorrhage or inflammation. In theory, the UP:C, UA:C or 24-hour urine collections can be used for quantification. The UP:C is the preferred for quantification because more is known about use of this test and it is technically easier to perform than 24-hour urine collections.
• Microalbuminuria is detected in dogs using a point of care immunoassay or quantitation using an immunoassay. Microalbuminuria is an early predictor of proteinuria. If microalbuminuria is detected via one of these tests, the test should be repeated in 2–4 weeks. If repeatedly positive, and if the concentration is increasing, the patient may be at risk for glomerular disease.
• Appropriate diagnostic testing should be performed to thoroughly evaluate an animal for an underlying disease when persistent proteinuria is believed to be of glomerular origin.

Imaging

Ultrasound and radiographs may reveal an underlying infectious, inflammatory, or neoplastic disease process or evidence of LUT disease. Ultrasound may provide information about structural changes suggesting primary renal disease (e.g., loss of corticomedullary distinction, hyperechogenicity, and irregular surface margin) or evidence in support of LUT disease.

Diagnostic Procedures

• Blood pressure should be monitored in patients with persistent renal proteinuria.
• Renal biopsy is needed to specifically diagnose the glomerular disease when an underlying disease cannot be identified or proteinuria has persisted for several months following treatment of an underlying disease.

Appropriate Health Care

Most patients with proteinuria can be managed as outpatients. Inpatient care may be required during select diagnostic evaluation (renal biopsy) or when there are complications associated with uremia, thromboembolism or edema in patients with glomerular proteinuria.

Nursing Care

Physical therapy and exercise may limit formation of edema in patients with glomerular proteinuria and hypoalbuminemia. For these patients, cage confinement should be avoided.

Activity

Activity should not be restricted in animals with proteinuria.

Diet

If glomerular disease is suspected, feed a diet formulated for kidney diseases.

Client Education

It is important to determine the cause of persistent proteinuria, which may indicate the presence of kidney disease. Renal proteinuria is a risk factor for progressive kidney disease, thromboembolism, and edema. It is important that all medications are given and the animal is evaluated as prescribed by a veterinarian.

Surgical Considerations

Animals with severe hypoalbuminemia (i.e., <2 g/dL) present unique challenges to anesthesia. Consideration should be given to referral of these patients to a secondary or tertiary care facility if anesthesia and/or surgery are indicated.

Drug(s) Of Choice

An angiotensin-converting enzyme inhibitor should be given to dogs and cats with glomerular proteinuria. Animals that do not have a meaningful reduction in proteinuria (see “Patient Monitoring”) when given a maximal dose of an ACEi can also be given an angiotensin receptor blocker (ARB). An ARB can also be given to those animals that have adverse effects from an ACEi. Use of aldosterone antagonists in management of proteinuria needs further investigation but may be indicated for patients that have increased aldosterone concentrations following treatment with an ACEi or ARB. Animals with concurrent hypertension often require addition of a calcium channel blocker (e.g., amlodipine) or another antihypertensive agent to control both hypertension and proteinuria. Supplementation with n-3 polyunsaturated fatty acid (PUFA) should be considered in dogs, and possibly cats, with glomerular proteinuria when the diet being fed does not have a reduced n-6/n-3 PUFA ratio that approximates 5:1. Dogs with glomerular disease should also be given low-dose aspirin or clopidogrel as thromboprophylaxis.

Contraindications

There are no known contraindications in animals with proteinuria.

Precautions

Drugs highly bound to albumin may have an altered effect if hypoalbuminemia is present. The use of warfarin as an anticoagulant should be avoided. With hypoalbuminemia or azotemia, higher doses of furosemide may be required to mobilize edema effectively; however, they should be used with extreme caution.

Possible Interactions

There are no known important drug interactions in dogs with proteinuria other than the previously mentioned concern with highly protein-bound drugs.

Alternative Drugs

An ARB is an alternative to an ACEi.

Patient Monitoring

• The UP:C, urinalysis, systemic arterial blood pressure and serum albumin, creatinine and potassium concentrations should be monitored at least quarterly in all dogs and cats being treated for glomerular disease.
• Use the UP:C to assess progression of glomerular disease. Response to treatment should be evaluated for several months after resolution of any underlying disease. In general, a reduction of a UP:C to <0.5 (dog) or <0.2 (cat) without inappropriate worsening of renal function is considered a therapeutic success. However, this ideal target is often not achieved and a reduction in UP:C of 50% or greater is the recommended alternate target.
• Monitor serum creatinine concurrently. Reduced proteinuria or reduced albuminuria that is concurrent to a rising serum creatinine may reflect deteriorating renal function.
• Because UP:Cs may vary, two to five serial assessments may be needed to evaluate response to treatment or progression in patients with glomerular proteinuria. Alternatively, the UP:C can be measured in a sample that has been pooled by adding equal aliquots of 2 to 3 samples that have been collected and refrigerated over a 48-hour time period.
• When given an ACEi or an ARB, dogs with stage 1 or 2 CKD can have an increase in serum creatinine of up to 30% without warranting a change in treatment. Worsening of renal function in dogs with stage 3 or 4 CKD should be avoided. During therapy the serum potassium concentration should not be allowed to exceed 6 mmol/L and the systolic blood pressure should not be <120 mmHg.

Prevention/Avoidance

Adult dogs and cats should have annual urinalyses including determination of urine protein. Repeat the tests in 2–4 weeks if proteinuria is detected. Patients with persistent proteinuria or microalbuminuria of glomerular origin should be evaluated more thoroughly for underlying causes of glomerular injury. Potential underlying causes should be eliminated or managed. If proteinuria persists, potential underlying causes have been managed appropriately or underlying causes were not identified, and the patient is in CKD stage 1, 2, or 3, the dog or cat should be evaluated via renal biopsy and managed appropriately.

Possible Complications

• Edema
• Thromboembolism
• Systemic hypertension
• Progressive kidney disease
• Poor wound healing

Expected Course and Prognosis

• Vary with the cause of proteinuria.
• Post-renal and prerenal proteinuria should resolve following resolution of inciting causes.
• Most diseases associated with renal tubular proteinuria are progressive.
• Although glomerular diseases are often progressive, the rate of progression varies and spontaneous remissions have been reported. Animals with persistent glomerular proteinuria may develop renal tubular damage resulting in advanced CKD and eventual uremia and death. Some dogs die shortly after the initial detection of proteinuria, while others remain alive for years. Dogs with nephrotic syndrome and/or azotemia may have a shorter survival.

Associated Conditions

Heavy proteinuria can be associated with hypoalbuminemia, hypoglobulinemia (rare), hypercholesterolemia, low antithrombin III, thrombocytosis, hyperfibrinogenemia, edema, thromboembolism, and systemic hypertension.

Age-Related Factors

Familial glomerular diseases should be considered in young animals with glomerular range proteinruia.

Zoonotic Potential

Proteinuria does not have a zoonotic potential. However, glomerular proteinuria can occur with a variety of infectious diseases, some of which could have a zoonotic potential.

Pregnancy/Fertility/Breeding

Some drugs used in the treatment of diseases associated with proteinuria may be contraindicated in pregnancy.

Synonyms

None

See Also

• Amyloidosis
• Azotemia and Uremia
• Glomerulonephritis
• Hematuria
• Hypoalbuminemia
• Nephrotic Syndrome
• Pyuria

Abbreviations

• ACEi = angiotensin converting enzyme inhibitor
• ARB = antiotensin receptor blocker
• CKD = chronic kidney disease
• FIV = feline immunodeficiency virus
• GBM = glomerular basement membrane
• LUT = lower urinary tract
• PUFA = polyunsaturated fatty acid
• SSA = sulfosalicylic acid
• UA:C = urinary albumin:creatinine ratio
• UP:C = urine protein:creatinine ratio

Author Shelly L. Vaden

Consulting Editor Carl A. Osborne

Client Education Handout Available Online