Protein Losing Kidney Disease: What To Do
Dr. Anthony Carr, DACVIM (internal medicine) Associate Professor
ETIOLOGY AND PATHOPHYSIOLOGY:
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. THERAPY:
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:
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. THERAPY:
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.
TAKE HOME MESSAGE:
Glomerular disease can be a significant cause of morbidity and mortality in dogs and cats. A urinalysis should be a common part of medical testing including as a pre-surgical screen. It is also indicated in those diseases known to be associated with glomerular injury including diabetes, Cushings, tick-borne illnesses, neoplasia, heart worm infestation and immune-mediated diseases. In breeds predisposed to amyloidosis screening programs should be considered. What treatment is absolutely correct has yet to be established but certainly some therapeutic interventions in regard to diet, use of ACE inhibitors and control of hypertension do hold promise to extend the life expectancy of affected pets.