Proteinuria

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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.

Diagnosis

Clinical signs

  • Pigmenturia (sometimes) if preglomerular.
  • Stranguria, pollakiuria, inappropriate urination, discolored urine (if post glomerular).
  • Glomerular proteinuria:
    • Often there are no clinical signs.
    • Sometimes there are signs related to the underlying cause of glomerular damage.
    • Weight loss, muscle wasting.
    • Poor haircoat.
    • Pitting, subcutaneous edema of the distal limbs.
    • Ascites (fluid wave on abdominal ballotment).
    • Abnormal kidney size (large or small) or shape.
    • Signs of uremia     .
    • Dyspnea without obvious abnormalities on auscultation or radiography (pulmonary thromboembolism).

Diagnosis

Differential diagnosis

  • Need to categorize the proteinuria first (preglomerular, glomerular, post glomerular) and then consider differential diagnoses.
  • Membranous glomerulopathy / glomerulonephropathy (sporadic or familial).
  • Glomerular amyloidosis (proteinuria may be very severe).
  • Familial glomerular disease that is not immune complex-mediated or amyloidosis.
  • Renal tubular disease (causes proteinuria that is often not as severe as that caused by glomerular disease).
  • Bacterial urinary tract infection, lower urinary tract neoplasia (rare in cats), urolithiasis (can cause proteinuria, but sediment usually shows clear evidence of inflammation).
  • Genital tract disease (causes proteinuria on free-catch urine samples, but typically not on cystocentesis-derived samples).
  • Severe liver disease (causes hypoalbuminemia, but not heavy proteinuria).
  • Severe gastrointestinal disease (protein-losing enteropathy typically causes hypoalbuminemia and hypoglobulinemia, but not proteinuria).
  • Other causes of abdominal fluid accumulation (abdominal neoplasia, peritonitis     , portal hypertension, abdominal hemorrhage).
  • Right-sided congestive heart failure (ascites)      or severe heartworm disease  [Feline cardiopulmonary dirofilariasis]  (which can also cause glomerulonephritis, to complicate matters).
  • Benign proteinuria caused by a wide range of environmental and metabolic factors.

Outcomes

Prognosis

  • Very variable depending on the underlying cause. Cross references:  multiple myeloma, lymphoma, chronic cystitis, interstitial cystitis, idiopathic cystitis, pyelonephritis.
  • Heavy proteinuria and azotemia at the time of diagnosis are usually considered negative prognostic indicators. However, some patients with heavy proteinuria presumed to be caused by severe glomerular disease make a full recovery, especially if an underlying cause can be detected and eliminated. Even if the cause is not found, some animals respond to therapy and may remain stable for years. Some cases eventually progress to chronic renal failure and need to be managed for that. Advanced chronic kidney disease is a negative prognostic indicator even if (especially when) the proteinuria resolves.
  • The prognosis is generally poor if arterial thromboembolism develops.

Expected response to treatment

  • Diminishing proteinuria as assessed by monitoring serial urine protein: creatinine ratios (improvement noted over several weeks).
  • Systemic hypertension controlled.
  • Alleviation of any concurrent signs such as stranguria, pollakiuria, and discolored urine.

Reasons for treatment failure

  • Incurable underlying cause.
  • Progression to chronic renal failure and uremia.
  • Progressive or uncontrolled proteinuria, hypoalbuminemia     →   intractable edema, ascites or fatal thromboembolism.
  • Uncontrolled hypertension    →    fatal cerebral vascular accident or other complications.
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