Glomerulonephritis

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.

Diagnosis

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.