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Basics ⬇

Basics

Definition

Concurrent proteinuria, hypoalbuminemia, hypercholesterolemia, and third-space fluid accumulation (i.e., ascites, subcutaneous edema, etc.).

Pathophysiology

  • Glomerular disease may result in marked urinary protein loss. Greater than 3.5 g albumin loss per day in humans often results in nephrotic syndrome. Magnitude of hypoalbuminemia and proteinuria required for development of nephrotic syndrome in dogs and cats is unknown; although affected patients usually have very low serum albumin concentrations, not all dogs with very low serum albumin concentrations will develop nephrotic syndrome.
  • Reduced plasma oncotic pressure may result in hyperaldosteronism, which induces sodium and water retention, leading to edema and ascites.
  • Alternatively, non-aldosterone mediated sodium retention, or a hypothetical “vascular permeability factor,” have been suggested as mechanisms whereby glomerular protein loss may increase, along with fluid loss from the systemic vasculature.
  • Hypercholesterolemia is a consequence of decreased catabolism and increased hepatic synthesis of lipoproteins.
  • Other glomerular disease complications frequently diagnosed in dogs with nephrotic syndrome include hypertension, hypercoagulability, muscle wasting, and weight loss.
  • Thromboembolism is a consequence of a generalized pro-coagulative state, due in part to increased platelet number and sensitivity, urinary loss of antithrombin, and increased concentrations of some clotting factors.

Systems Affected

  • Renal/Urologic-persistent proteinuria initially without active urine sediment. With progressive disease and nephron loss, azotemia chronic kidney disease and uremia may occur.
  • Cardiovascular-dependent edema, ascites, hypercholesterolemia/hyperlipidemia, hypertension, hypercoagulability, and thromboembolic disease.

Genetics

Familial glomerular diseases have been reported in several breeds (see Glomerulonephritis and Amyloidosis chapters), but are less likely to result in nephrotic syndrome than non-familial protein-losing nephropathies.

Incidence/Prevalence

  • Nephrotic syndrome is an uncommon complication of glomerular disease, with a median of 0.5 new cases per year diagnosed at 8 veterinary teaching hospitals in 1 study.
  • Nephrotic syndrome has not been associated with histologic subtype of glomerular disease.

Signalment

Species

Dog and cat

Breed Predilections

No breed appears to be at increased risk of the nephrotic syndrome complication with glomerular disease.

Mean Age and Range

Dogs with nephrotic syndrome are typically younger than those with non-nephrotic glomerular disease (mean, 6.2 years vs. 8.4 years at time of initial diagnosis).

Predominant Sex

None recognized

Signs

Historical Findings

  • Pitting subcutaneous edema and/or ascites are the most common presenting complaints.
  • Clinical signs associated with an underlying infectious, inflammatory, or neoplastic disease may be the primary reason for seeking veterinary care. Subtle edema or ascites may then be detected by physical examination or with diagnostic imaging.
  • Rarely, dogs may develop acute dyspnea, severe panting, weakness, or collapse due to pleural or pericardial effusion, pulmonary edema, or pulmonary thromboembolism.

Physical Examination Findings

  • Dependent pitting, subcutaneous edema, or ascites.
  • Complications of hypertension: retinal hemorrhage or detachment, papilledema, arrhythmias and/or murmurs secondary to left ventricular hypertrophy.
  • Dyspnea and/or cyanosis in dogs with pleural effusion or pulmonary thromboembolism.

Causes

  • Glomerular disease may be a consequence of chronic inflammatory conditions (e.g., infection, neoplasia, or immune-mediated diseases).
  • Nephrotic syndrome is unlikely to be solely a consequence of severe proteinuria; additional unidentified factors appear to be necessary.

Risk Factors

See “Causes”

Diagnosis ⬆ ⬇

Diagnosis

Differential Diagnosis

Proteinuria

  • Often due to inflammatory post-glomerular urinary tract disease (e.g., bacterial cystitis/pyelonephritis, urolithiasis, tubular renal failure, or lower urinary tract neoplasia). Inflammation of the urinary tract is usually (but not always) associated with active urine sediment.
  • Hyperglobulinemia may be associated with proteinuria, and may be more likely discovered when urinalysis includes the sulfosalicylic acid turbidimetric test (Bumin test).
  • Protein-losing nephropathies typically result in inactive urine sediment (although hyaline casts may be present); renal biopsy is the only accurate way to distinguish the various types of glomerular disease.

Hypoalbuminemia

Decreased albumin production (severe liver disease) and gastrointestinal albumin loss (protein-losing enteropathies) must be distinguished from hypoalbuminemia secondary to glomerular disease.

CBC/Biochemistry/Urinalysis

  • Persistent, significant proteinuria with inactive urine sediment.
  • Hypoalbuminemia and hypercholesterolemia are by definition essential components of the nephrotic syndrome.
  • Renal failure may occur with advanced disease. Azotemia may precede loss of urine concentrating ability.

Other Laboratory Tests

Urine Protein:Creatinine Ratio

  • Confirms and quantifies the severity of proteinuria.
  • Magnitude of proteinuria can be used to assess response to therapy or progression of disease.

Protein Electrophoresis

Urine and serum protein electrophoresis may identify pre-glomerular proteinuria in patients with monoclonal gammopathies or urinary immunoglobulin light chains (Bence-Jones proteins).

Imaging

  • Radiography-loss of abdominal detail due to ascites is the most common abnormality. Pleural effusion (uncommon), pulmonary edema, or pericardial effusion (very uncommon) may be present.
  • Abdominal ultrasonography-usually confirms large volume of peritoneal and retroperitoneal fluid. Mild renomegaly may be observed with glomerular diseases.

Diagnostic Procedures

Renal biopsy is indicated if significant and persistent proteinuria with inactive urine sediment exists. Microscopic evaluation of renal tissue will establish subtype of glomerular disease and help in formulating a prognosis. Consider renal biopsy only after less-invasive tests (CBC, serum biochemistry profile, urinalysis, quantitation of proteinuria) are completed and blood clotting ability has been assessed.

Treatment ⬆ ⬇

Treatment

Appropriate Health Care

  • Most dogs and cats can be treated as outpatients.
  • Severely azotemic or hypertensive patients, or patients with thromboembolic disease, may require hospitalization.

Nursing Care

  • Abdominocentesis-reserve for patients with respiratory distress or abdominal discomfort caused by ascites. Excessive fluid removal will promote further fluid accumulation and contribute to electrolyte abnormalities.
  • Plasma transfusion is not indicated for routine treatment of hypoalbuminemia. Very large volumes of plasma are required to significantly increase serum albumin concentration, and transfused proteins have relatively short half-lives.
  • Intravenous human albumin can be used in patients with life-threatening complications due to fluid accumulation (e.g., pulmonary edema; pleural effusion).
  • Use of low-sodium, “maintenance”-type fluids (e.g., 0.45% NaCl) for all crystalloid needs may minimize extravascular fluid accumulation in hospitalized animals.
  • Intravenous synthetic colloids frequently exacerbate fluid extravasation in patients with nephrotic syndrome. There is a faster return to baseline oncotic pressure in nephrotic patients than in healthy animals after colloidal fluid administration, likely due to increased urinary loss and accumulation within interstitial tissues. These fluids should therefore be limited to patients with immediate, life-threatening needs for oncotic pressure support.

Activity

Activity restriction may decrease likelihood of thromboembolic disease; conversely, increased activity in humans with nephrotic syndrome promotes fluid mobilization and lymphatic uptake.

Diet

  • Sodium-reduced, high-quality, low-quantity protein diets are currently recommended. Prescription “renal diets” meet these criteria.
  • Normal or high dietary protein may contribute to renal disease progression by exacerbating glomerular hyperfiltration, proteinuria, and glomerulosclerosis.

Client Education

  • If the underlying cause cannot be identified and corrected, glomerular disease usually progresses to azotemic chronic kidney disease.
  • Renal biopsy is required to differentiate between the various subtypes of glomerular disease and to optimize treatment protocols.
  • Once azotemia and uremia develop, prognosis is poor due to rapid progression of renal failure.
  • Nephrotic syndrome is associated with shortened survival time. In one study, median survival time of 61 dogs with nephrotic syndrome was 12.5 days (range, 0–2,783 days), as compared to 104.5 day (range, 0–3,124 days) median survival time of 99 dogs with non-nephrotic glomerular disease.

Medications ⬆ ⬇

Medications

Drug(s)

See Glomerulonephritis chapter for general treatment recommendations.

Edema and Ascites

  • Dietary sodium reduction.
  • Reserve abdominocentesis and diuretics for patients with respiratory distress or abdominal discomfort. Overzealous diuretic use may result in dehydration and acute renal decompensation.
  • Patients who require maintenance diuretic therapy for severe, persistent extravascular fluid accumulation should be treated with an aldosterone antagonist (spironolactone 1–2 mg/kg PO q12h), and supplemented with low doses of loop diuretics (i.e., furosemide 0.5–2 mg/kg PO q8–12h) as needed.
  • Plasma or albumin transfusions provide only temporary benefit, and are not recommended when the risk of therapy outweighs any potential benefit.

Proteinuria

  • Angiotensin converting enzyme (ACE) inhibitors (e.g., enalapril 0.5 mg/kg PO q12h) decrease severity of proteinuria (see Glomerulonephritis chapter). Because proteinuria is toxic to renal tubules, ACE-inhibitor therapy should be initiated at the time of diagnosis, unless severe azotemia is present.
  • Asprin (0.5 mg/kg PO q12h) decreases thromboembolism risk and should be initiated when serum albumin decreases below 2.0–2.5 g/dL.

Precautions

  • Dose adjustment of highly protein-bound drugs (e.g., aspirin) may be needed.
  • Use ACE inhibitors with caution in patients with serum creatinine >5.0 mg/dL.
  • Diuretics should be used with extreme caution in patients with nephrotic syndrome because of the risk of causing or worsening azotemia.

Possible Interactions

See “Precautions”

Follow-Up ⬆ ⬇

Follow-Up

Patient Monitoring

Urinary protein:creatinine ratio; serum urea nitrogen, creatinine, albumin, and electrolyte concentrations; blood pressure; and body weight. Ideally, recheck examinations should be scheduled 1, 3, 6, 9, and 12 months after initiation of treatment.

Possible Complications

  • See Glomerulonephritis chapter for discussion of glomerular disease complications unassociated with nephrotic syndrome.
  • Complications more likely to develop in nephrotic (vs. non-nephrotic) dogs and cats with glomerular disease include:
    • Arterial or venous thrombosis (e.g., pulmonary thromboembolism)
    • Electrolyte disturbances, particularly with repeated abdominocenteses or high doses of diuretics
    • Faster progression to azotemia and uremia, and decreased median survival time.

Miscellaneous ⬆

Miscellaneous

Associated Conditions

  • Amyloidosis
  • Glomerulonephritis
  • Glomerulopathy
  • Hypercoagulability
  • Hypertension

Pregnancy/Fertility/Breeding

Likely high risk in those patients with severe hypoalbuminemia and/or hypertension.

Abbreviations

  • ACE = angiotensin converting enzyme
  • RBC = red blood cell
  • WBC = white blood cell

Author Barrak M. Pressler

Consulting Editor Carl A. Osborne

Acknowledgment The author and editors acknowledge the prior contribution of Gregory F. Grauer.

Client Education Handout Available Online

Suggested Reading

Cook AK, Cowgill LD. Clinical and pathologic features of protein-losing glomerular disease in the dog: A review of 137 cases (1985–1992). J Am Anim Hosp Assoc 1996, 32:313–322.

Klosterman ES, Moore GE, de Brito Galvao JF, et al. Comparison of signalment, clinicopathologic findings, histologic diagnosis, and prognosis in dogs with glomerular disease with or without nephrotic syndrome. J Vet Intern Med 2011, 25:206–214.