Glomerular disease is a well-recognized cause of chronic kidney disease (CKD) in dogs, may produce acute kidney injury in dogs, and is also occasionally seen in cats with CKD. These animals should be staged and substaged as recommended above (see Table: Classification of Stages of Kidney Disease, Substages of Chronic Kidney Disease Based on Arterial Blood Pressure (AP) Measurements and Risk of Target Organ Damage, and Substages of Chronic Kidney Disease Based on Proteinuria). Animals with primary glomerular disease as a cause of CKD may have somewhat different clinical and laboratory abnormalities than those with primary tubulointerstitial disease. Although uncommon, urine specific gravity may be inappropriately high for the degree of renal dysfunction, a condition referred to as glomerulotubular imbalance. Damage to the glomerular basement membrane results in albuminuria, which may lead to hypoalbuminemia. Animals may then exhibit signs related to hypoalbuminemia (eg, peripheral edema, hypercoagulability with thrombosis, hypercholesterolemia) instead of or in addition to uremia.
Secondary glomerulopathies, observed as sequelae of systemic or glomerular hypertension in animals with Stage 3 or 4 CKD, are common. Although the overall prevalence of a primary glomerulopathy as an inciting cause is not known, it is apparently more common in dogs than cats.
Immune-mediated glomerulonephropathy is characterized by deposition or in situ formation of immune complexes in the glomerular capillary wall, which then incite inflammatory changes (see Type III Reactions). In one study of dogs, the mean age of presentation for glomerulonephritis was 4–8 yr; 55% were males, and there was no breed predilection. Immune-mediated glomerulonephritis has been associated with neoplasia, rickettsial diseases, systemic lupus erythematosus (SLE), heartworm disease, pyometra, chronic septicemia, and adenovirus infection, but it is usually idiopathic. Although multifactorial in origin, the glomerular disease associated with hyperadrenocorticism and diabetes mellitus in dogs is rarely attributable to immune complex formation.
In one study of cats with glomerulonephritis, the mean age at presentation was 3–4 yr; 75% were males, and there was no breed predisposition. Primary glomerular disease in cats is most frequently associated with chronic infection by feline leukemia virus (FeLV), feline immunodeficiency virus (FIV), or feline infectious peritonitis (FIP) virus but has also been reported in association with neoplasia and systemic inflammatory diseases. The relatively young age and predilection for males reflects the high prevalence of FeLV infection as a cause in reported feline cases.
Familial glomerulopathies as a primary cause of CKD have been reported in several breeds of dogs, including Bernese Mountain Dogs, English Cocker Spaniels, English Springer Spaniels, Doberman Pinschers, Greyhounds, Lhasa Apsos, Poodles, Rottweilers, Samoyeds, Shih Tzus, and Soft-coated Wheaten Terriers. These are not immune complex diseases, although some are characterized by proteinuria and associated clinical abnormalities that resemble those caused by immune-mediated glomerulonephropathy. Several of these breeds of dogs have genetic defects in collagen structure and function (types III or IV), analogous to hereditary nephropathies in people such as Alport syndrome (hereditary nephritis).
Most cases of amyloidosis (see Amyloidosis) in dogs and cats, including familial amyloidosis in Chinese Shar-Pei and Abyssinian cats, are reactive, or secondary, amyloidosis. In this form of the disease, amyloid A protein is deposited in various tissues after serum levels increase as a result of chronic inflammation. When the kidneys are affected, amyloid deposition in the nonfamilial forms in dogs usually occurs in the glomerulus. However, in Shar-Pei, at least 25% of Abyssinian cats, and in many domestic cats with the nonfamilial form of this disease, amyloid is found primarily in the medullary interstitium, where it interferes with the renal concentrating mechanism and is more likely to produce nonproteinuric CKD than protein-losing glomerular amyloid deposition. In contrast, glomerular amyloidosis usually leads to marked proteinuria. The nonfamilial form of amyloidosis usually affects middle-aged to older dogs and cats. Beagles, Collies, and Walker Hounds are reported to be at increased risk. Animals with the familial form of the disease are usually diagnosed at a younger age.
Glomerulopathy often leads to proteinuria (primarily albuminuria) and can produce hypoproteinemia, ascites, dyspnea (due to pleural effusion or pulmonary edema), and/or peripheral edema, which may be referred to as the nephrotic syndrome. Protein wasting can produce preferential loss of lean body mass that may be apparent on careful physical examination. Severe or chronic glomerular disease is a cause of CKD; most dogs and many cats with glomerular disease eventually develop Stage III or IV disease. Systemic hypertension may be more prevalent in proteinuric CKD and may be seen at any stage.
Proteinuria may result in loss of antithrombin III through the glomerular basement membrane, leading to a hypercoagulable state in dogs. Proteinuria also contributes to mild thrombocytosis and platelet hypersensitivity, which contribute to coagulation abnormalities in affected dogs, generally when plasma albumin levels are ≤1 g/dL. Severe dyspnea secondary to pulmonary thromboembolism or other sequelae of thrombotic disease may be seen in dogs with glomerulonephritis or amyloidosis. It is unclear whether a hypercoagulable state also exists in proteinuric cats, because clinical signs from hypercoagulability have not been reported in cats.
The BUN, creatinine, and phosphorus concentrations are usually increased, although the degree varies with the stage of CKD at the time of diagnosis. Animals should be staged and substaged on the basis of measurements of blood pressure (see Table: Substages of Chronic Kidney Disease Based on Arterial Blood Pressure (AP) Measurements and Risk of Target Organ Damage), proteinuria (see Table: Substages of Chronic Kidney Disease Based on Proteinuria), and serum creatinine (see Table: Classification of Stages of Kidney Disease). Marked proteinuria with edema may be seen in the presence or absence of azotemia. Physical findings are usually nonspecific except that ascites, pleural effusion, and/or peripheral, pitting, nonpainful, subcutaneous edema are evident in some animals (75% of cats and 15% of dogs). Although uncommon, urine specific gravity may be inappropriately high for the degree of renal dysfunction. A urine protein:creatinine ratio >2 suggests a glomerular origin. If the sediment examination eliminates inflammatory urinary tract disease and hemorrhage as the source of proteinuria, then the degree of increase may help distinguish tubular proteinuria (typical ratio value of 0.5–2), glomerulonephritis (typical ratio value of 0.5–15), and glomerular amyloidosis (typical ratio value of 0.5–40). However, substantial overlap exists in these ranges, and a variety of glomerulopathies such as focal segmental glomerulosclerosis in dogs have yet to be well characterized. Further, the ratio tends to be low in the initial stages of a glomerulopathy, increases in severity as the disease progresses, and then decreases terminally as GFR falls to very low levels in late Stage 4 disease.
Renal biopsy is required to determine the type of glomerular disease. Membranous glomerulonephritis is reported most frequently in cats; there is a roughly equal distribution of histologic findings in dogs, with glomerular amyloidosis; focal segmental glomerulosclerosis; and membranous, proliferative, and membranoproliferative glomerulonephritis all represented. The degree of proteinuria does not always correlate with the severity of the histologic lesions or the degree of azotemia. Systemic hypertension develops in an unusually large proportion of animals with protein-losing glomerulonephritis; therefore, blood pressure should be determined in all animals with evidence of glomerular disease.
A careful search should be made for an inciting disease process. Abdominal and thoracic radiographs, ultrasonography, and specialized serologic tests can exclude various inflammatory, infectious, and neoplastic diseases. In dogs with glomerulonephritis, this includes tests for SLE (eg, antinuclear antibody titer and LE prep) and appropriate antigen or antibody screening tests for other infectious agents and heartworm disease; in cats, tests for infection with FeLV, FIV, FIP, SLE, and heartworm disease should be included.
There are six basic principles for treatment of glomerulonephropathies: 1) If a cause of immune complex disease can be identified, it should be treated. 2) Manifestations of the nephrotic syndrome, if present, should initially be managed by therapies designed to reduce proteinuria. This includes a renal diet low in protein and salt and subsequently, if needed, judicious use of diuretics. 3) Antithrombotics (eg, aspirin) should be considered for hypoalbuminemic (plasma albumin <1 g/dL) dogs but not cats, as well as for dogs with low serum levels of antithrombin III (<30% of normal). In dogs with marked proteinuria and serum albumin <2 g/dL, low-dose aspirin therapy (2.5–5 mg/kg/day, PO) is appropriate, unless melena is present or gastric ulceration is suspected. However, aspirin is bound to plasma proteins and is eliminated via the kidneys, so the lower end of the dosage range should be used in hypoalbuminemic dogs. 4) Because proteinuria may promote interstitial fibrosis, treatment to limit glomerular loss of protein is warranted and may include dietary protein restriction, n-3 polyunsaturated fatty acid supplementation, and administration of an angiotensin-receptor blocker (eg, telmisartan 1 mg/kg/day, PO) or angiotensin-converting enzyme inhibitor (eg, benazepril or enalapril, 0.5 mg/kg, PO, once daily in cats and bid in dogs). 5) Efforts to reduce the magnitude and consequences of glomerular immune complex deposition should be considered, especially in animals with biopsy-confirmed glomerular inflammation and no known primary antigenic stimulus. Immunosuppressive drugs (eg, mycophenolate, azathioprine, cyclophosphamide, cyclosporine) can be used in dogs with glomerulonephritis, although results are variable. For amyloidosis, dimethylsulfoxide and colchicine have been tried, without consistent results. These anti-inflammatory drugs should be administered only on a trial basis with owner consent. Corticosteroids seem to be beneficial only in mild glomerulopathy; they may worsen proteinuria in other glomerulopathies and should be avoided in animals with amyloidosis, because they are reported to enhance amyloid deposition. 6) Manifestations of CKD should be monitored and managed in accordance with the stage of disease (see Chronic Kidney Disease).
Although one study found that mean survival time of dogs with glomerulonephritis was 87 days, the prognosis with early diagnosis and appropriate therapy is much better. In a recent study of dogs with glomerulonephritis, those receiving a placebo medication survived beyond the entire 6-mo duration of the study. The prognosis for animals with amyloidosis is guarded but variable, with reported mean survival times ranging from 49 days to 20 mo.