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Glomerulopathy (glomerulonephritis) (GN) 

Glomerulopathy is a disease characterized by structural or functional changes which occur initially and primarily in the glomeruli. Although the disease begins in the glomeruli, as time progresses, if the glomerular disease is not reversed, the tubular portions of the nephron will also show signs of disease.

The term glomerulonephritis is analogous to dermatitis or enteritis in that an anatomical area is specified but the cause of the abnormality is not implied. Because glomerular lesions in many patients are not associated with an inflammatory response, the less specific term, glomerulopathy, provides a more accurate collective description of glomerular disease than does glomerulonephritis.

GN may be a primary disease involving only the kidneys or GN may be a manifestation of a systemic immune mediated, infectious or neoplastic disease such as:

  • systemic lupus erythematosus
  • pyometra
  • dirofilariasis
  • neoplasia
  • diabetes mellitus
  • ehrlichiosis
  • feline leukemia virus infections
  • adverse drug reactions (e.g. gold salts, penicillamine)
  • or many many others...

Any infection of low pathogenicity that does not kill the host and in which organisms (bacteria, parasites, viruses, protozoa) their antigens or altered host antigens are present in circulation for relatively long periods of time have the potential to cause immune complex GN.

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Filtration barrier

The filtration barrier is the barrier which prevents molecules from crossing from blood in the glomerular capillary (cap) into glomerular filtrate (us = urinary space) and is comprised of:

  • fenestrated endothelial cells (end)
  • 3 layered basement membrane (gbm)
  • foot processes of visceral epithelial cells named podocytes (e)
  • slit pores

For a substance to pass from the lumen of the glomerular capillary (cap) to the urinary space (us) which is contiguous with the tubular lumen, it must be small enough to pass through each of the above components of the filtration barrier. The entire filtration barrier is coated with a negatively charged substance called sialoprotein. The sialoprotein repels negatively charged substances and attracts positively charged substances. The cutoff to pass the barrier is ~70,000 molecular weight units. Negatively charged molecules are repelled to some degree by silaoprotein and positively charged molecules are attracted by sialoprotein. Therefore the charge of the molecule in addition to the molecular weight will determine whether the molecule passes through the filtration barrier. For a frame of reference, albumin is about 65,000 molecular weight units.

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Pathogenesis of GN

GN is most often caused by the deposition of immune complexes in the glomerulus, a type III hypersensitivity reaction. Soluble circulating complexes of antigen and antibody lodge in the filtration barrier of the glomerulus. The antigen is not related to glomerular antigens. There are two other types of GN, anti-glomerular basement membrane GN and in-situ immune complex GN, which may occur, but they are rare compared to immune complex GN. Anti-glomerular basement membrane (GBM) GN is caused by the development of antibody against the basement membrane of the glomerulus. Anti - GBM GN has been experimentally induced in dogs and horses. There are few, if any, spontaneous cases. In-situ immune complex GN occurs when an antigen becomes lodged in the filtration barrier and then circulating antibody reacts with the fixed antigen inciting an immune response.

Immune complexes vary in size depending upon the ratio of antigen to antibody. If an animal is exposed to a large antigen load and has limited antibody formation, the immune complexes which form in this situation of antigen excess, are low in molecular weight, do not bind complement, and do not result in immune injury. Additionally if the animal cannot mount a strong antibody response, it may die of that disease before sufficient time has elapsed to form immune complex disease.

Conversely, if the animal mounts a vigorous immune response, the large antibody excess results in large immune complexes which do not circulate. These immune complexes are removed by phagocytosis and do not cause immune injury. The vigorous antibody response results in elimination of the antigen (elimination of the disease) and the animal does not develop immune complex GN.

The final situation is one in which the animal has a slight to moderate antigen excess over antibodies. In this situation, the immune complexes that form are "just the right size" to freely circulate, bind complement, and induce immune injury. Immune complexes of this size are formed by animals unable to mount a vigorous antibody response to clear an antigen, therefore the antigen and associated antibodies stay in circulation for long periods of time.

Even within the category of immune complexes formed in the face of slight to moderate antigen excess, there is some variability in size and that variability can influence the site of deposition of immune complexes in the glomerulus and subsequently influence the clinical signs which develop. Immune complexes can deposit in a subendothelial, subepithelial location or within the mesangium.

gbm_norm.jpg (32531 bytes)

 

This schematic represents the "normal" appearance of the glomerular filtration barrier. To enter urine, a substance must move from the capillary lumen to the urinary space, traversing all barriers between those two points.

The two schematics below represent "extremes" of consequences of immune complex deposition in the glomerular filtration barrier. In reality, most cases of immune complex disease fall somewhere in between these two circumstances.

gbm2.jpg (33095 bytes)

 

Within the category of "just the right size immune complexes" formed in the face of a slight to moderate antigen excess, the larger the complex the shorter distance it will travel before it gets "stuck" in the glomerular filtration barrier. The shortest distance the immune complexes can travel is to get lodged just below the endothelial cells (subendothelial deposition). This is represented by the pink band of material in this schematic. Because the immune complexes are still in close contact with the contents of the capillary lumen and blood in the capillary lumen is the vehicle which brings in inflammatory cells, immune complexes in this location incite a greater inflammatory response than those which become embedded deeper in the filtration barrier. The immune complexes bind and activate complement which enhances the migration of WBC to the site. The WBCs release proteolytic enzymes from lysosomes which cause damage to the glomerulus. This damage may result in the filtration barrier being damaged and allowing more protein to leave the capillary lumen and enter glomerular filtrate (proteinuria) or the damage to the glomerulus may be so great that blood flow through the glomerular capillaries is reduced which in turn decreases GFR resulting in azotemia. The microscopic appearance of the glomerulus is that of increased cellularity. This is called proliferative GN.

gbm3.jpg (25373 bytes)

 

If the immune complexes are a little smaller, 300,000 - 500,000 molecular weight units, they tend to move further across the filtration barrier before getting "stuck" often just below the visceral epithelial cells (subepithelial) or within the GBM itself. The immune complexes are represented by the pink band in this schematic. When the immune complexes are deposited in this location they give the appearance that the GBM is thickened and the appearance is called membranous GN. Although complement is still fixed and WBC are attracted to the location of the immune complexes, less of an inflammatory response is evoked and the animal is proteinuric due to damage to the filtration barrier but is less likely to have reduced blood flow in the glomerular capillaries and therefore less likely to be azotemic.

The schematics above represent "extremes" of consequences of immune complex deposition in the glomerular filtration barrier with resultant azotemia or proteinuria. In reality, most cases of immune complex disease fall somewhere in between these two circumstances and are called membranoproliferative because some features of each of the above two descriptions are present. Therefore patients with glomerular disease can be just proteinuric, proteinuric and azotemic or azotemic without proteinuria. A patient may progress over time. As azotemia develops and progresses, the magnitude of proteinuria may decrease.

After immune complexes lodge, complement is fixed and activated resulting in chemotaxis of inflammatory cells, and release of lysosomal proteases which lead to glomerular damage. Platelets adhere to the damaged endothelium and activate the coagulation cascade leading to deposition of fibrin in the glomerulus. Cell mediated immunity also plays role in immune injury to the glomerulus.

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The morphologic classification of GN includes:

  • Proliferative GN is characterized by cellular swelling or proliferation of parietal epithelial cells, visceral epithelial cells, endothelial cells, or mesangial cells as well as leukocyte exudation. Proliferative changes are active lesions, and potentially can be reversed. Proliferation of parietal epithelial cells is called crescents and in humans is usually irreversible. Similar information about crescent formation in dogs and cats is not known. Animals with proliferative GN may have proteinuria and/or decreased GFR (azotemia).
  • Membranous GN is a thickening of the basement membrane.   Proteinuria is the most prominent sign of membranous GN.
  • Membranoproliferative is a combination of proliferative and membranous.
  • Sclerosis is an end stage appearance and is irreversible. The other morphologic types may progress to sclerosis.

The lesions may be distributed diffusely through both kidneys or may be focal.  Within an individual glomerulus the lesions may be segmental, global, or located in the mesangium.

Clinical presentations  The signalment of animals which develop GN is highly variable reflecting the many different causes of GN. Animals which develop GN as a consequence of an infectious process are usually younger than those that develop GN as a consequence of neoplasia. There is no sex predisposition. The owner complaint and findings on physical examination are also quite variable and may be due to the primary disease, due to GN (ascites, pleural effusion, peripheral edema, thrombosis) or reflect the development of renal failure (signs of uremia and/or hypertension).

Laboratory findings are also variable, reflecting the primary disease, GN or renal failure. The CBC may be normal or disclose inflammation or anemia of chronic inflammation or renal disease.  Serum chemistries may be normal, reflect renal disease (azotemia, hyperphosphatemia) or show evidence of nephrotic syndrome (reduced albumin and increased cholesterol). Urinalysis may show proteinuria, isosthenuria, or rarely hematuria.

Glomerular tubular [GT] imbalance is a term that emphasizes the dynamic nature of GN. GN may progress to renal failure in some animals. Renal failure is characterized by azotemia and isosthenuria. During the evolution of GN to azotemic renal failure, some animals will be proteinuric and azotemic but still have a concentrated urine specific gravity. This is glomerular tubular [GT] imbalance; an imbalance between glomerular function (proteinuria and azotemia) and tubular function (ability to concentrate). As GN progresses further the animal will become isosthenuric as well.   As GFR decreases markedly less protein is filtered and subsequently proteinuria is less severe.

ns.jpg (32194 bytes)

A syndrome is a group of clinical signs. The nephrotic syndrome includes the signs of   proteinuria, hypoalbuminemia, hyperlipidemia/hypercholesterolemia and edema/ascites. Albumin provides 75% of the colloidal oncotic pressure of blood. Albumin is a small molecule so is readily lost in the urine of patients with glomerular damage resulting in reduced oncotic pressure and the development of edema. The location of edema varies between species; cats are more likely to develop hydrothorax, whereas dogs develop ascites and subcutaneous edema. The loss of fluid from blood vessels leads to hypovolemia and activates the renin-angiotensin system and antidiuretic hormone which promote retention of sodium and water which may result in hypertension. The liver attempts to synthesize more albumin and due to the "turn on" of activity also produces increased amounts of lipoprotein carriers of lipids (triglycerides and cholesterol) which increase in the blood. Lipiduria (lipid in urine) is due to increased turnover of lipid laden renal epithelial cells.

thrombus.jpg (26802 bytes)

Animals with GN may be hypercoagulable and develop thrombosis. The signs of thrombosis are determined by location of the thrombus. A thrombus in the pulmonary vessels results in dyspnea; in the aorta results in rear limb dysfunction, and in the mesenteric artery results in abdominal pain. Pulmonary artery thrombosis is the most common site.

The hypercoagulable state can be due to several factors including an increase in clotting factors, altered platelet function (hypoalbuminemia contributes to platelet hypersensitivity), increased lipids, uremic vasculitis, dehydration, loss of antithrombin III , and increased globulins. Antithrombin III is a naturally occurring anti

 

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DiagnosisThe diagnosis of GN is by interpretation of the entire clinical picture (history, physical exam and laboratory work). A biopsy may provide additional information. Biopsy will differentiate GN from amyloidosis and can yield information about the potential for reversibility (e.g. sclerosis is irreversible). Some patients with GN will have normal renal biopsies at the light microscopic level. If available, consider processing biopsy samples for electron microscopy and immunofluorescence as well as light microscopic analysis.

Therapy: Therapy for immune complex GN may include removal of antigens, correction of immunologic disturbances, inhibition of inflammation, and inhibition of coagulation. Identify and eliminate any predisposing infectious, inflammatory, or neoplastic disease. Inhibition of inflammation with immunosuppressive therapy (corticosteroids, cyclophosphamide or cyclosporin) is controversial. It is not documented in all cases of GN that the immune system is hyperactive.  Treatment of GN with immunosuppressive agents yields mixed results, some animals will get worse.

The treatment of GN in people may include inhibition of coagulation with antiplatelet drugs (aspirin, indomethacin, dipyridamole) but there is limited experience in veterinary medicine with this treatment.  Dogs with antithrombin III concentrations < 70% of normal and fibrinogen concentrations greater than 300 mg/dl are at greater risk to develop thrombosis and may be candidates for anticoagulant therapy, usually with low dose aspirin.

The administration of angiotensin converting enzyme inhibitors (ACE) reduces the magnitude of proteinuria in humans. Enalapril has shown some success in proteinuric dogs. The use of benazepril in proteinuric cats is under investigation.

Inhibition of prostaglandins by the use of thromboxane synthetase inhibitors, cyclo oxygenase inhibitors or diets rich in eicosapentaenoic acid (fish oil, polyunsaturated fatty acids) may have some impact on the magnitude of proteinuria.

Supportive and symptomatic therapy depends upon the signs displayed by the patient:

  • proteinuric only,
  • proteinuric and edematous,
  • proteinuric and edematous and uremic
  • proteinuric and edematous and uremic and oliguric

All animals with GN should have unlimited access to water and avoidance of stress. Restriction of dietary protein may reduce the amount of protein lost in the urine. Restriction of salt intake is indicated if the patient is edematous. Diuretics should be used sparingly to avoid dehydration  Avoid additional immunogenic stresses including  Fresh plasma or blood transfusions can precipitate a thrombotic event. Immunogenic drugs (e.g., trimethoprim/sulfa) may augment immune mediated phenomena and should be avoided.

Treatments should be initiated sequentially rather than all at once and the animals response monitored based on clinical signs and serial urine protein/ creatinine (UPC) ratios. A reduction in (UPC) is a positive response to treatment unless azotemia is increasing, in which case the reduction of UPC is attributable to worsening of renal function with less glomerular filtrate being made.

The prognosis of GN is unpredictable. Signs may regress spontaneously then reoccur. Biopsy findings may predict potential reversibility. Minor inflammatory changes are potentially reversible while proliferation of parietal epithelial cells (crescents) and glomerular atrophy are irreversible lesions. Necrosis, cellular proliferation, and presence of inflammatory cells indicates an active lesion that may resolve or may progress to irreversible lesions.

North Carolina State University  Research Page on protein-losing enteropathy and/or protein-losing nephropathy in related soft-coated wheaten terriers.

 


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