ISSN 2398-2969      

Proteinuria

icanis

Introduction

  • Definition: an abnormally increased concentration of protein in urine.
  • Causes: proteinuria may be prerenal, renal (which may be either glomerular or tubular), or postrenal. Glomerular proteinuria is the most important kind. In prerenal proteinuria, the kidneys are presented with an abnormally increased concentration of small proteins in the blood, which are smaller than 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 abnormal 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. Damaged renal tubules may fail to reabsorb filtered protein, leading to tubular proteinuria. In postrenal proteinuria, tissue damage or inflammation beyond the kidney tubules 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. Transient proteinuria is poorly described in dogs but occurs in humans associated with fever or exercise, 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. Massive (or heavy) proteinuria may lead to the nephrotic syndrome (the combination of heavy proteinuria and consequent hypoalbuminemia, hypercholesterolemia and edema or ascites).
  • Signs: prerenal proteinuria may be associated with discolored urine (if the protein is hemoglobin or myoglobin) and clinical signs of the underlying disease (eg myeloma, lymphona). Postrenal 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). Thromboembolic events (leading to lameness, dyspnea, or neurological signs) can occur in up to 25% of dogs. 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 using the urine protein : creatinine ratio (UPCR), serum chemistry profile, and ideally histopathologic examination of a kidney biopsy if proteinuria is glomerular, of high magnitude, or progressive despite standard therapy. In prerenal proteinuria there will be an excessive amount of a protein in the blood. In postrenal 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, antiplatelet drugs, inhibition of the renin-angiotensin-aldosterone system (RAAS), ± immunosuppressive therapy in certain cases.
  • 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 stage 3 or 4 chronic kidney disease, prognosis is poor.

Pathogenesis

Etiology

  • For prerenal proteinuria, intravascular hemolysis (hemoglobinuria Hemoglobinuria), rhabdomyolysis (myoglobinuria Myoglobinuria), and lymphoid malignancies (Bence-Jones proteinuria) are the most important causes.
  • For postrenal proteinuria, idiopathic cystitis Cystitis 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 Amyloidosis in dogs 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 is the most common cause of glomerular proteinuria. Unfortunately, it is usually idiopathic, the source of antigens contributing to the glomerular damage remaining uncertain.

Specific causes of glomerulonephropathy include:

Predisposing factors

General

  • For prerenal proteinuria:
    • Disorders associated with intravascular hemolysis (hemoglobinuria Hemoglobinuria).
    • Severe muscle injury, rhabdomyolysis (myoglobinuria 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 (eg Soft-coated Wheaten terrier) and may prove to be relevant in members of some other breeds with 'sporadic' glomerulopathy.
  • For postrenal 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.

Pathophysiology

  • Proteinuria may be prerenal, renal (which may be either glomerular or tubular), or postrenal. Glomerular proteinuria is the most important origin of proteinuria.
  • In prerenal proteinuria, the kidneys are presented with an abnormally increased concentration of a small protein in the blood, which are smaller than 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 abnormal 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 Amyloidosis is another important cause of glomerular proteinuria.
  • Damaged renal tubules (eg in acute tubular necrossi, Fanconi syndrome or tubulointerstitial nephritis) may fail to absorb filtered protein, leading to tubular proteinuria.
  • In postrenal proteinuria, tissue damage or inflammation beyond the renal tubules 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.
  • In immune-complex glomerulopathy, the most important cause of glomerular proteinuria:
    • 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 Hypoproteinemia, weight loss, ascites, peripheral edema and hypercholesterolemia Hyperlipidemia.
    • 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) progressive chronic kidney disease and associated clinical signs.
    • Loss of antithrombin, platelet hyperactivity, and (sometimes) thrombocytosis → hypercoagulable state → thromboembolic disorders (lungs, CNS, caudal aorta).

Timecourse

  • Hemoglobinuria 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.
  • Postrenal 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

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Treatment

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Outcomes

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Further Reading

Publications

Refereed papers

  • Recent references from PubMed and VetMedResource.
  • Lourenço B et al (2020) Efficacy of telmisartan for the treatment of persistent renal proteinuria in dogs: A double-masked, randomized clinical trial. J Vet Intern Med 34, 2478-2496 PubMed.
  • Littman M P et al (2013) Consensus recommendations for the diagnostic investigation of dogs with suspected glomerular disease. J Vet Intern Med 27 (1), S19-S26 PubMed.
  • Brown S, Elliot J, Francy T, et al (2013) Consensus recommendations for standard therapy of glomerular disease in dogs. J Vet Intern Med 27 (1), S27-S43 PubMed.
  • Pressler B et al (2013) Consensus guidelines for immunosuppressive treatment of dogs with glomerular disease absent a pathologic diagnosis. J Vet Intern Med 27 (1), S55-S59 PubMed.
  • Segev G et al (2013) Consensus recommendations for immunosuppressive treatment of dogs with glomerular disease based on established pathology. J Vet Intern Med 27 (1), S44-S54 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.
  • Nabity M B, Boggess M M, Kashtan C E, Lees G E (2007) Day-to-day variation of the urine protein: creatinine ratio in female dogs with stable glomerular proteinuria caused by X-linked hereditary nephropathy. JVIM 21 (3), 425-430 PubMed.
  • Welles E G, Whatley E M, Hall A S & Wright J C (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.
  • Jacob F, Polzin D J, Osbourne C A, Neaton J D, Kirk C A, Allen T A & Swanson L L (2005) Evaluation of the association between initial proteinuria and morbidity rate or death in dogs wiht naturally occurring chromic renal failure. JAVMA 226 (3), 393-400 PubMed.
  • Lees G E, Brown S A, Elliott J, Grauer G E & Vaden S L (2005) Assessment and management of proteinuria in dogs and cats: 2004 ACVIM Forum Consensus Statement (small animal). JVIM 19 (3), 377-385 PubMed.
  • Burkholder W J, Lees G E, LeBlanc A K, Slater M R, Bauer J E, Kashtan C E, McCracken B A & Hannah S S (2004) Diet modulates proteinuria in heterozygous female dogs with X-linked hereditary nephropathy. JVIM 18 (2), 165-175 PubMed.
  • Zaragoza C, Barrera R, Centeno F, Tapia J A & Mane M C (2004) Canine pyometra: a study of the urinary proteins by SDS-PAGE and Western blot. Theriogenology 61 (7-8), 1259-1272 PubMed.
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  • Grauer G F, Greco D S, Getzy D M, Cowgill L D, Vaden S L, Chew D J, Polzin D J & Barsanti J A (2000) Effects of enalpril versus placebo as a treatment for canine idiopathic glomerulonephritis. JVIM 14 (5), 526-533 PubMed.
  • Littman M P, Dambach D M, Vaden S L & Giger U (2000) Familial protein-losing enteropathy and protein-losing nephropathy in Soft Coated Wheaten Terriers: 222 cases (1983-1997). JVIM 14 (1), 68-80 PubMed.
  • Brown S A, Brown C A, Crowell W A, Barsanti J A, Allen T, Cowell C & Finco D R (1998) Beneficial effects of chronic administration of dietary omega-3 polyunsaturated fatty acids in dogs with renal insufficiency. J Lab Clin Med 131 (5), 447-455 PubMed.
  • Waters C B, Adams L G, Scott-Moncrieff J C, DeNicola D B, Synder P W, White M R & Gasparini M (1997) Effects of glucocorticoid therapy on urine protein-to-creatinine ratios and renal morphology in dogs. JVIM 11 (3), 172-177 PubMed.
  • Cook A K & Cowgill L D (1996) Clinical and pathological features of protein-losing glomerular disease in the dog: a review of 137 cases (1985-1992). JAAHA 32 (4), 313-322 PubMed.
  • Lulich J P, Osbourne C A & Polzin D J (1996) Diagnosis and long-term management of protein-losing glomerulonephropathy. A 5-year case-based approach. Vet Clin North Am. Sm Anim Pract 26 (6), 1401-1416 PubMed.
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