Protein losing kidney disease: What to do (Proceedings)


The disease is a result of immune complexes accumulating within the glomerulus.


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.

Clinical findings

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 will predominate.

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.


If at all possible, the source of antigen-antibody complexes should be identified and treated (heart worm infestation for instance). If this is possible, the complexes can eventually be removed from the kidney once the underlying cause is removed. As such, it is important to work up the patient thoroughly for any potential underlying cause (abscesses, chronic infections, neoplasia).

Unfortunately in most cases of glomerulonephritis a specific underlying cause cannot be identified and only non-specific therapy is available. The goals of therapy are to minimize the loss of protein and deal with the complications of glomerular disease.

Although this is an immune-mediated process, the use of immune suppressive agents to date has not been of benefit. This may because in veterinary medicine we have not been able to subdivide the various forms of glomerular injury sufficiently to find those that are responsive to immune-suppressive therapy. The use of prednisone is likely to be avoided as glomerular injury has been documented with the use of corticosteroids and Cushings disease. A recent study showed no benefit from the use of cyclosporine. Overall at this time in veterinary medicine there is no strong indication for the use of immune-suppressive therapy with glomerular injury unless an underlying disease is present that might respond to such therapy (cancer, SLE).

Minimizing clotting potential may be of benefit in reducing complications of the glomerular disease as well as possibly slowing the progression of the injury within the kidney. Use of anticoagulation (warfarin) is a consideration though very difficult to perform properly and associated with high risk of problems. In addition the predominant problem leading to progression is platelet function which is not influenced by anticoagulation. Aspirin therapy is often used because it reduces platelet function. The ideal dose to use has not been established, though usually a low dose is suggested as appropriate (0.5 to 5 mg/kg SID to BID). The low dose is hoped to decrease platelet activity without significantly affecting prostaglandin production in the kidney (prostacyclin is produced in the kidney and is anti-thrombotic and a vasodilator, aspirin would decrease its production. Whether this is truly of benefit is unknown, it is known that with heart worm disease, the amount of aspirin needed to reduce platelet function increases considerably. Other anti-platelet drugs are available, though not tested to date in clinical veterinary practice.

Use of lower protein diet with salt restriction is indicated. Lower protein levels in the food tend to decrease the amount of protein lost. Albumin levels do need to be monitored to make sure that protein restriction does not exacerbate hypoalbuminemia.

ACE inhibitors should be a part of the therapeutic plan in any animal with glomerulonephritis unless clear contraindications exist. ACE inhibitors will help with hypertension, though additional medications such as a calcium channel blocker (amlodipine) may be needed as well. What has however been shown is that ACE inhibitors prolong life expectancy in dogs with GN. ACE inhibitors also seem to reduce the amount of protein loss independent of their effect on the systemic blood pressure. Monitoring of renal function is vital when using an ACE inhibitor, especially initially, as they can cause acute renal failure. Calcium channel blockers such as amlodipine are very effective at lowering blood pressure and may also lessen the progression of the disease. Many times a combination approach is needed to control blood pressure.

Other therapies have at times been suggested to be of benefit with glomerular injury. The use of fish oil supplements was shown in some studies to be of benefit in humans with glomerulonephritis. This could be modulating inflammation, anti-platelet effects and by effects on eicosanoid production in the kidney.


Etiology and pathophysiology

Amyloid deposition can occur in a variety of ways. In dogs and cats the most common is through the hepatic production of serum amyloid protein A. The excessive production of this protein leads to the deposition of the AA amyloid in various organs, whereby the kidney, spleen and liver seem to be predisposed. This is termed reactive amyloidosis. This can be caused by a specific reaction to chronic infectious or inflammatory diseases. In most cases however the inciting cause is not determined. There does seem to be a breed predisposition in Abyssinian cats and Shar Pei dogs. Depending upon where the amyloid is deposited will determine the clinical signs noted.

Clinical findings

The place where the amyloid is deposited will determine the clinical signs noted. The kidney is a preferred place for amyloid deposition, though usually amyloidosis is a systemic disorder. If deposited in the glomerulus, proteinuria will predominate. If deposited in the medulla, renal failure will be the main sign. Deposition in spleen and liver can lead to fracture of these organs, though this is extremely rare.

Hypertension is a common finding with amyloidosis and can lead to retinal changes including detachment. In Shar Peis, recurring fevers and joint swelling (Shar Pei fever, Swollen Hock Syndrome) may be the main signs. Loss of concentrating ability or proteinuria in a Shar Pei does warrant suspicion of amyloidosis.


The same treatments as indicated for glomerulonephritis are indicated for renal amyloidosis. In contrast to glomerulonephritis there may be more specific therapies for amyloid deposition, thought their value is anecdotal and as yet unproven.

DMSO has been reputed to be of benefit in the preventing further deposition of amyloid in dogs with renal amyloidosis. There have been studies showing both benefit and lack of benefit. A therapeutic trial can be attempted. Colchicine has been suspected of being of benefit in Shar Pei fever. In a similar disease in humans, colchicine limits the number of febrile episodes and prevents renal failure. Whether the same is true for Shar Peis is uncertain. Again a therapeutic trial is well worth it given the likely progression of the disease.

References: available upon request from the author

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