Felis ISSN 2398-2950

Proteinuria

Contributor(s): Larry G Adams, Richard Squires

Introduction

  • Definition: an abnormally increased concentration of protein (often albumin) in urine.
  • Causes: proteinuria may be preglomerular, glomerular or post glomerular. Glomerular proteinuria is the most important kind. In preglomerular proteinuria, the kidneys are presented with an abnormally increased concentration of small proteins in the blood, which are smaller than the effective the glomerular filtration barrier and exceeds the ability of the renal tubules to reabsorb it. This protein may, for example, be free hemoglobin, myoglobin or, in patients with lymphoma or multiple myeloma, immunoglobulin light chains (Bence-Jones protein). In glomerular proteinuria, the glomeruli are damaged and an abnormally large amount of protein leaks through an excessively permeable glomerular filter into the urinary space. For example, in glomerulonephritis, antigen-antibody complexes may be deposited, or may form, in the glomerular capillary basement membranes, damaging them.  Damage to the filtration barrier leads to glomerular proteinuria, sometimes very severe. Glomerular amyloidosis is another important cause of severe glomerular proteinuria.  In post glomerular proteinuria, tissue damage or inflammation beyond the glomeruli is responsible for the increased urinary protein concentration. For example, bacterial urinary tract infection (upper or lower) can lead to passage of proteinaceous inflammatory exudate in the urine. Damaged renal tubules may fail to reabsorb filtered protein, leading to tubular proteinuria. Various endocrinopathies, and a variety of other environmental and metabolic factors can lead to benign proteinuria which is usually mild and may be reversible with treatment of the underlying cause.
  • Severity: proteinuria may be overt (detectable using conventional urine dipsticks) or less severe. Microalbuminuria is the term used to describe an abnormally large amount of albumin in the urine, but not enough to be detectable using a conventional dipstick. It has recently been suggested that microalbuminuria may be a useful early marker for a wide variety of systemic disease states, particularly inflammatory and neoplastic disorders. Massive (or heavy) proteinuria may lead to the nephrotic syndrome (the combination of heavy proteinuria and consequent hypoalbuminemia, hypercholesterolemia and edema or ascites).
  • Signs: preglomerular proteinuria may be associated with discolored urine and clinical signs of the underlying disease. Post glomerular proteinuria is usually associated with abnormally increased frequency of urination, straining, and, again, discolored urine (typically pink or red). Often glomerular proteinuria causes no clinical signs until it is severe. Then it may lead to hypoalbuminemia and sometimes to subcutaneous edema (eg of the distal limbs). Progressive loss of damaged glomeruli may eventually lead to renal failure (with polydipsia/polyuria, inappetence, and vomiting).
  • Diagnosis: urine analysis, including sediment examination, urine protein quantitation, serum chemistry profile, histopathologic examination of a kidney biopsy. In preglomerular proteinuria there will be an excessive amount of a protein in the blood. In post glomerular proteinuria there will usually be evidence in the urine sediment of urinary tract inflammation or hemorrhage. In glomerular proteinuria, there will be excessive albumin in the urine, which may be extreme.
  • Treatment: categorize the proteinuria and then eliminate the underlying cause, if possible. Glomerular proteinuria may be managed using a renal diet, low-dose aspirin, angiotensin-converting enzyme (ACE) inhibition, ± immunosuppressant / immunomodulator therapy.
  • Prognosis: very variable depending upon the underlying cause and the severity. Some cases with glomerular proteinuria progress rapidly despite therapy, others remain stable for prolonged periods. If complicated by thromboembolism (eg pulmonary or caudal aortic) or advanced renal failure, prognosis is poor.
    Follow the diagnostic tree for Proteinuria Proteinuria.

Pathogenesis

Etiology

  • For preglomerular proteinuria, intravascular hemolysis (hemoglobinuria), rhabdomyolysis (myoglobinuria), and lymphoid malignancies (Bence-Jones proteinuria) are the most important causes.
  • For post glomerular proteinuria, idiopathic cystitis Cystitis: bacterial and urolithiasis Urolithiasis are important causes. Bacterial urinary tract infections and urinary tract neoplasia are less common.
  • The molecular basis of some familial glomerulopathies is beginning to be elucidated.
  • Renal amyloidosis in cats is usually caused by accumulation and polymerization of part of the protein serum amyloid A (SAA). SAA is an acute phase reactant, increasing in inflammatory disease states. It has therefore been conjectured that renal amyloidosis may follow chronic inflammatory disorders. However, there is usually no historical or physical examination evidence of extra-renal inflammation in patients with renal amyloidosis.
  • Immune-complex glomerulonephropathy can cause glomerular proteinuria in cats. Unfortunately, it is usually idiopathic, the source of antigens contributing to the glomerular damage remaining uncertain.

Specific causes of glomerulonephropathy include

  • Infections and infestations (eg FeLV, FIV, FIP, abscesses, dirofilariasis, bacterial cholangiohepatitis, mycoplasmal arthritides).
  • Non-infectious causes of severe inflammation and tissue damage (eg pancreatitis Pancreatitis).
  • Various forms of neoplasia (neo-antigens; lymphoma, leukemia, mast cell tumor).
  • Glomerulonephritis Glomerulonephritis may accompany, and presumably have the same underlying cause as, some other immune-mediated disorders, eg
  • True autoimmune response to native glomerular antigens (not, as yet, confirmed in cats).

Predisposing factors

General

  • For preglomerular proteinuria:
    • Disorders associated with intravascular hemolysis (hemoglobinuria).
    • Severe muscle injury, rhabdomyolysis (myoglobinuria).
    • Lymphoid malignancy (eg plasma cell tumor) or another cause of paraproteinemia.
  • For glomerular proteinuria:
    • An inflammatory, infectious, or neoplastic source of antigens that can contribute to immune complex formation.
    • A familial predisposition to form immune complexes or deposit amyloid in the glomeruli.
    • Altered (ie increased) intestinal permeability has been postulated to play a role in some canine breeds and may prove to be relevant in cats.
  • For post glomerular proteinuria:
    • Factors predisposing to urinary tract inflammation or infection: eg compromised immune function, anatomical defects in the urinary tract, urinary motility disorders, catheterization.
    • Familial tendency to form uroliths.
    • Urinary neoplasia (rare in cats).

Pathophysiology

  • Proteinuria may be preglomerular, glomerular or post glomerular. Glomerular proteinuria is the most important origin of proteinuria.
  • In preglomerular proteinuria, the kidneys are presented with an abnormally increased concentration of a small protein in the blood, which are smaller then the effective glomerular filtration barrier and exceeds the ability of the renal tubules to reabsorb it. This protein may, for example, be free hemoglobin, myoglobin or, in patients with lymphoma or multiple myeloma, immunoglobulin light chains (Bence-Jones protein).
  • In glomerular proteinuria, the glomeruli are damaged and an abnormally large amount of protein leaks through an excessively permeable glomerular filter into the urinary space. For example, in membranous glomerulopathy, antigen-antibody complexes may be deposited, or may form in situ, in or near the glomerular capillary basement membranes, damaging them. Complement-mediated damage to the filtration barrier leads to glomerular proteinuria, sometimes very severe. Renal amyloidosis is another important cause of glomerular proteinuria. However, in Abyssinian cats amyloid deposition in the renal medulla, rather than in the glomeruli, may cause renal failure with little proteinuria. 
  • In post glomerular proteinuria, tissue damage or inflammation beyond the glomeruli is responsible for the excessive urinary protein losses. For example, bacterial urinary tract infection (upper or lower) can lead to passage of proteinaceous inflammatory exudate in the urine. Damaged renal tubules (eg in acute tubular necrosis) may fail to reabsorb filtered protein, leading to tubular proteinuria
  • Various endocrinopathies, and a variety of other environmental and metabolic factors can lead to benign proteinuria which is usually mild and may be reversible with treatment of the underlying cause.
  • In membranous glomerulopathy, the most important cause of glomerular proteinuria in cats:
    • Ag-Ab complexes form in situ or lodge in or near the glomerular capillary basement membranes     →     complement activation    →     glomerular injury    →     leakage of proteins, especially albumin, through the now excessively permeable glomerular filter     →   proteinuria    →     (if severe) hypoalbuminemia, weight loss, ascites, peripheral edema and hypercholesterolemia.
    • Glomerular damage     →   decreased glomerular filtration through affected glomeruli     →   increased glomerular filtration through other, less damaged nephrons     →   hyperfiltration and glomerulosclerosis of remaining nephrons    →     (if sufficiently severe) chronic renal failure.
    • Loss of antithrombin III, platelet hyperactivity, and (sometimes) thrombocytosis    →     hypercoagulable state    →     thromboembolic disorders (lungs, caudal aorta).

Timecourse

  • Hemoglobinuria and myoglobinuria are usually associated with acute, short-lived disorders. Bence-Jones proteinuria may be present for weeks or months before it is detected.
  • Post glomerular proteinuria is usually detected fairly quickly because of associated straining, increased frequency of urination, inappropriate urination, and (sometimes) discolored urine.
  • The time course of glomerular proteinuria is much more variable. The disease may progress rapidly or remain stable (and sometimes, presumably, undetected) for years.

Diagnosis

This article is available in full to registered subscribers

Sign up now to purchase a 30 day trial, or Login

Treatment

This article is available in full to registered subscribers

Sign up now to purchase a 30 day trial, or Login

Outcomes

This article is available in full to registered subscribers

Sign up now to purchase a 30 day trial, or Login

Further Reading

Publications

Refereed papers

  • Recent references from PubMed and VetMedResource.
  • Syme H M (2009) Proteinuria in cats. Prognostic marker or mediator?​ J Feline Med Surg 11 (3), 211-218 PubMed.
  • White J D, Norris J M, Bosward K L et al (2008) Persistent haematuria and proteinuria due to glomerular disese in related Abyssinian cats. J Feline Med Surg 10 (3), 219-229 PubMed.
  • Grauer G F (2007) Measurement, interpretation, and implications of proteinuria and albuminuria. Vet Clin North Am Small Anim Pract 37 (2), 283-295 PubMed.
  • Whittemore J C, Miyoshi Z, Jensen W A et al (2007) Association of microalbuminuria and the urine albumin-to-creatinine ratio with systemic disease in cats.  JAVMA 230 (8), 1165-1169 PubMed.
  • Elliott J & Syme H M (2006) Proteinuria in chronic kidney disease in cats - prognostic marker or therapeutic target? JVIM 20 (5), 1052-1053 PubMed.
  • Kuwahara Y, Ohba Y, Kitoh K et al (2006) Association of laboratory data and death within one month in cats with chronic renal failure. JSAP 47 (8), 446-450 PubMed.
  • Langston C E & Reine N J (2006) Hyperthyroidism and the kidney. Clinical techniques in Small Animal Practice 21 (1), 17-21 PubMed.
  • Mardell E J & Sparkes A H (2006) Evaluation of a commercial in-house test kit for the semi-quantitative assessment of microalbuminuria in cats. J Feline Med Surg (4), 269-278 PubMed
  • Syme H M, Markwell P J, Pfeiffer D et al (2006) Survival of cats with naturally occurring chronic renal failure is related to severity of proteinuria. JVIM 20 (3), 528-535 PubMed.
  • Welles E G, Whatley E M, Hall A S et al (2006) Comparison of Multistix PRO dipsticks with other biochemical assays for determining urine protein (UP), urine creatinine (UC) and UP:UC ratio in dogs and cats. Vet Clin Pathol 35 (1), 31-36 PubMed.
  • White J D, Norris J M, Baral R M et al (2006) Naturally-occurring chronic renal disease in Australian cats: a prospective study of 184 cases. Aus Vet J 84 (6), 188-194 PubMed.
  • Lees G E, Brown S A, Elliott J et al (2005) Assessment and management of proteinuria in dogs and cats: 2004 ACVIM Forum Consensus Statement (small animal). JVIM 19 (3), 377-385 PubMed.
  • Lees G E (2004) Early diagnosis of renal disease and renal failure. Veterinary Clinics of North America. Small Animal Practice 34 (4), 867-885 PubMed.
  • Osborne C A, Bartges J W, Polzin D J et al (1996) Percutaneous needle biopsy of the kidney. Indications, applications, technique, and complications. Vet Clin North Am Small Anim Pract 26 (6), 1461-1504 PubMed.
  • Arthur J E, Lucke V M, Newby T J et al (1986) The long term prognosis of feline idiopathic membranous glomerulonephritis. JAAHA 22 (6), 731-737 VetMedResource.
  • Nash A S, Wright N G, Spencer A J et al (1979) Membranous nephropathy in the cat; a clinical and pathological study. Vet Rec 105 (4), 71-77 PubMed.


ADDED