Etiology and Pathophysiology
The disease is a result of immune complexes accumulating within the glomerulus. This can occur either because pre-formed immune-complexes
are deposited in the glomerulus (trapping) or because immune-complexes are actually formed in the glomerulus. In the latter
situation circulating antibodies are attracted to the glomerulus because of antigen located in the glomerulus (planted). The
immune-complexes draw in inflammatory cells, which then sustain an immune response that can eventually lead to destruction
of the glomerulus. It is seen not infrequently in dogs, it is rare in cats.
The destruction of the glomerulus is a complex event. With antigen-antibody complexes being present, a variety of inflammatory
reactions occur including complement activation, homing and migration of white blood cells, and activation of the coagulation
system. Platelet activation is also considered of primary importance as the platelets release substances that further increase
inflammation and cause the development of "scar tissue" through hyalin formation and sclerosis. Initially the damage manifests
as abnormal protein loss because the barrier function of the glomerular capillary is lost (size and charge dependent barrier).
Smaller proteins are lost preferentially, albumin being the one that is of most importance. The sieve never becomes leaky
enough to allow large proteins such as globulins to go across. Once damage is extensive enough the glomerulus becomes non-functional
and then tubular function is lost. Once glomerular injury is widespread enough with a sufficient number of nephrons being
damaged, azotemia can occur as tubular function is lost. It is important to remember that significant glomerular injury can
be present without azotemia being noted.
Proteinuria is of course the hallmark of glomerular involvement. When protein is found in the urine it must first be decided
if it is a clinically significant amount. The same dipstick reaction could indicate significantly different amounts of protein
loss depending upon how concentrated the urine is. The definitive way to determine if protein loss is significant is with
the urine protein to urine creatinine ratio. With this ratio it is possible to get an objective number with regard to the
degree of proteinuria, so that it is a good way to follow up on the case. This no longer holds true however when azotemia
occurs as then GFR is significantly decreased and less protein will be lost (fewer places for it to filter out). A complete
urinalysis is of course needed to rule out other sources of "non-glomerular" protein such as through inflammation or blood
contamination. The UP:UC only holds true if the sediment is "benign", that is few to none WBC and few RBCs are present. In
some cases an infection or inflammatory lesion located downstream from the glomerulus could still be the cause. At times,
a urine culture may be indicated to rule out cystitis, especially if the urine specific gravity is low. An electrophoresis
should be informative in these cases as with inflammation serum "weeps" into the urine in a pattern very similar to serum
whereas with glomerular injury smaller proteins will be preferentially found.
In theory proteinuria can occur in ways other than glomerular injury and urogenital inflammation. Small amounts of protein
can be lost with tubular dysfunction (Fanconi syndrome) though this usually is not of great significance. With abnormally
large amounts of certain proteins in the blood stream some glomerular protein leakage can occur (so called pre-glomerular
or glomerular overload proteinuria). A good example is with Bence-Jones proteinuria as can occur with multiple myeloma (will
see a monoclonal spike in the urine protein as well). It will also be seen with hemoglobinuria secondary to massive hemolysis
or myoglobin with massive muscle breakdown.
Definitive diagnosis is with renal biopsy. This allows differentiation between amyloidosis and glomerulonephritis. A variety
of morphologic patterns may be seen with glomerular pathology (membranous, membranoproliferative, etc.), although to date
it does not appear that in veterinary medicine the differentiation is of prognostic or therapeutic importance.
Glomerular disease can be associated with minimal clinical signs. Weight loss, PU/PD, lethargy will often be present. With
significant protein loss other signs will develop including edema or ascites. At times the underlying disease will be the
main reason the animal is brought for examination. Once glomerular disease has progressed sufficiently, signs of renal failure
With severe protein loss we see development of changes typical for the nephrotic syndrome. These typical changes include proteinuria,
hypoalbuminemia, hypercholesterolemia, and edema, whereby the latter is relatively infrequently seen. Total protein can be
normal as globulin fraction increases from the chronic inflammation so that this is not the most reliable screening test.
The increase in cholesterol is probably related to generalized activation of the liver to produce more albumin.
In association with glomerular diseases we see an increased tendency towards thrombosis. Studies have shown that 20% of dogs
with protein losing kidney diseases had some form of thrombotic complication. With thrombosis (PTE; pulmonary thromboembolism
usually), mortality is extremely high. The increased clotting tendency has been associated with increased Antithrombin III
loss, although this is not the only explanation. AT III is roughly the same size as albumin so that it is lost preferentially.
AT III works to prevent coagulation by inactivating thrombin. Other causes of hypercoagulability include increased platelet
number, platelet reactivity, and an increase in pro-coagulatory proteins. Typical for PTE is severe hypoxia with minimal radiographic
changes. Other studies used in people for definitive diagnosis of a PTE are usually not applicable to veterinary patients.
Hypertension is a very common problem associated with glomerular disease and almost always present in dogs. The process by
which this occurs is rather complex. The hypertension itself may in fact lead to progression of the glomerular injury.