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
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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
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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 repeled to some degree by silaoprotein and
positively charged molecules are attracted by sialoprotein. Theferfore 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 variabilty in size and that
variabilty 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 loaction or within the mesangium.
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| 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. |
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| 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 embeded 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. |
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| 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. Athough 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 cresents and in humans is usually irreversible. Similar information about cresent
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 prominant 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 refelecting 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 (azotmia, 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 isostenuria. 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 (proteinura and azotemia) and tubular function (abilty 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.
 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.
 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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Diagnosis: The
diagnosis of GN is by interpretation of the entire clinical picture (history, physical
exam and laboaratory work). A biopsy may provide additional information. Biopsy will
differentiate GN from amyloidosis and can yield information
about the potentail 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
microsopic 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 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.
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.
Department of Veterinary Clinical Sciences
College of Veterinary Medicine
Washington State University
Pullman, WA 99164-7060
Telephone 509-335-0711
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College of Veterinary Medicine,
Washington State University, Pullman, WA,
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Copyright 1995-2001 Washington State University
Revised February 19, 2004
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