Glomerulonephritis remains an important cause of renal disease in dogs

Q: How does one diagnose and manage dogs with glomerulonephritis?

A: Dr. Shelly L. Vaden at the 21st American College of Veterinary Internal Medicine Forum in Charlotte, North Carolina, gave a lecture on diagnosis and treatment of glomerulopathy in dogs. Some relevant points in this lecture are provided.

Johnny D. Hoskins, DVM, Ph.D., Dipl. ACVIM

Glomerular disease is an important cause of renal disease in dogs. The incidence of some forms of glomerular disease may increase with age. There are both immunologic and non-immunologic mechanisms of glomerular injury that can lead to the various forms of glomerular disease. Glomerulonephritis is generally considered to be the most commonly occurring glomerular disease in dogs and is the result of immunologic glomerular injury. Immune-complexes that have become deposited in the glomerulus or have formed in-situ initiate glomerular damage.

Cell-mediated immune mechanisms also take part in the pathogenesis of glomerular inflammation. Once glomerular damage is initiated, the activation of complement, the coagulation cascade and resident cells, influx of neutrophils, monocytes and platelets, release of proteolytic enzymes, synthesis of cytokines or other growth factors, generation of proinflammatory lipid mediators and alteration of hemodynamic factors contribute to glomerular injury.

It can be very difficult to differentiate non-immunologically from immunologically mediated glomerular diseases with the limited diagnostic techniques that are generally used in the evaluation of proteinuric dogs.

In general, there is no gender predisposition for glomerular disease in dogs; however, the clinical manifestations of X-linked hereditary nephritis are more severe in affected male dogs. Glomerular disease can develop in any age dog but appear to be more common in middle-aged to older dogs.

There are several breeds of dogs known to have familial glomerular diseases; some of these diseases are manifested at an early age (Bernese Mountain dog, Bull Terrier, Cocker Spaniel (especially English), Dalmatian, Doberman Pinscher, Newfoundland, Chinese Shar-pei, Soft-Coated Wheaten Terrier).

Dogs with glomerulopathies may be asymptomatic, may have non-specific signs of disease (weight loss, lethargy), or may present with signs consistent with chronic renal failure or uremia (polyuria, polydipsia, anorexia, vomiting, malodorous breath). Signs of fluid retention (abdominal enlargement consistent with ascites, subcutaneous edema) or thromboembolism (dyspnea, decreased or absent peripheral pulse, loss of limb function) will occasionally be the primary complaint at presentation. Other dogs may have non-specific evidence of systemic disease such as poor body condition or poor hair coat. Dogs with advanced disease may have oral ulcerations and pale mucous membranes.

Proteinuria says glomerular disease

Historically, a urine protein: creatinine ratio (UPC) >1 in a urine sample that is free of macroscopic hematuria or inflammation has been considered abnormal. However, the UPC in healthy dogs probably does not exceed 0.5. There is no magic value of UPC that is diagnostic for any one disease. Dogs with amyloidosis, in general, have the highest UPCs while those with tubulointerstitial disease have normal values or values that are in the lower part of the abnormal range.

Dogs with glomerulonephritis can have UPCs as low as 1 or in excess of 40. Microalbuminuria is detected prior to increases in UPC, and the magnitude of microalbuminuria increased over time in dogs that eventually developed overt proteinuria as detected by increased UPC.

A dog with persistent microalbuminuria of increasing magnitude should be assessed as having an injurious process to the glomerular filtration barrier and may eventually develop overt proteinuria.

Isosthenuria is a variable finding in dogs with glomerulopathies; the urine concentrating ability remains intact in many dogs. In dogs with glomerular disease, casts, if present, are most often hyaline but can be granular, waxy or fatty. Other abnormal findings may include hypoproteinemia due to hypoalbuminemia, hypercholesterolemia, azotemia, hyperphosphatemia and nonregenerative anemia.

Thrombocytosis is common. Antithrombin III activity is predictably decreased in dogs that have a serum albumin of less than 2.0-2.5 g/dl. Probable risk factors for thromboembolism in dogs include serum albumin <2.0 g/dl and antithrombin III <70 percent of normal.

The kidneys may look normal on abdominal radiography or appear small and irregular. Some dogs may have enlarged kidneys. Similar changes in shape and size can be seen by ultrasound but increased echogenicity of the cortex and loss of corticomedullary distinction may also be noted.

The renal pelvis may be mildly dilated if polyuria is present or fluids are being given. The kidneys may appear normal by ultrasound. During radiographic or ultrasonographic evaluation of the abdomen, attention should also be given to other organs in search of another disease process. Thoracic radiographs should also be evaluated in middle to advanced age dogs.

Hypertension is common in dogs with glomerulopathies. Uncontrolled hypertension is a risk factor for progressive renal injury. Every dog with persistent proteinuria should have blood pressure measured on a regular basis (every three to six months). Renal biopsy provides a definitive diagnosis of glomerular disease but may not be needed if treatment of a potential underlying disease leads to resolution of the proteinuria. When renal biopsies are required in the diagnostic evaluation of dogs with glomerular disease, tissue specimens should be submitted for light microscopy.

Management considerations

The management of dogs with glomerulopathies includes treatment of potentially underlying disease processes, reduction of proteinuria and management of uremia and other complications of generalized renal failure. Most glomerulopathies in dogs develop secondary to a systemic infectious, inflammatory or neoplastic disease process. The initial step in the management of a persistently proteinuric dog is to treat any potentially underlying diseases. The dog should be subsequently evaluated for resolving proteinuria. Because uncontrolled proteinuria leads to progressive tubulointerstitial damage, a reduction in proteinuria may slow the progression of glomerular disease.

The use of angiotensin-converting enzyme (ACE) inhibitors to reduce proteinuria in dogs with glomerulopathies is now considered the standard of care. Typically benazepril (0.25-0.5 mg/kg PO) is given once daily. If there is not a reduction in proteinuria after four to six weeks of administration, the frequency can be increased to twice daily or double the ACE inhibitor's dosage. Adequate blood pressure control of hypertensive dogs may also lead to a reduction in proteinuria and slow the progression of disease. Because ACE inhibitors are relatively weak antihypertensive agents, additional antihypertensive agents (amlodipine, 0.05-0.1 mg/kg q24h PO) may be needed if hypertension persists (systolic blood pressure >170 mmHg) after the initiation of ACE inhibitor administration. Low dose aspirin (0.5 to 5.0 mg/kg PO q12h) is often administered to prevent thromboembolism in at-risk dogs and may have the added benefit of attenuating progressive glomerular injury through inhibition of platelet cyclooxygenase.

Immunosuppressive drugs

The use of immunosuppressive drugs is generally limited to dogs that have developed glomerulonephritis secondary to a steroid-responsive disease, such as systemic lupus erythematosus. Corticosteroids may exacerbate proteinuria and cause additional glomerular lesions; they should be used only with caution and close monitoring. The starting dose of prednisolone is 2.2 mg/kg daily PO with subsequent tapering to 1-2 mg/kg q48h or the lowest dose needed to maintain effect. Alternatively, azathioprine (2 mg/kg PO q24 hours for 10-14 days then q48h), cyclophosphamide (50 mg/m2 PO q24h for three to four days each week) or chlorambucil (2 mg/m2 PO q48h) can be used. Cyclosporine is probably not beneficial in dogs with glomerulonephritis.

The UPC, urinalysis, body weight, body condition score, and serum albumin and creatinine concentrations should be evaluated monthly whenever modifications in the therapeutic plan are being made every three to six months if the dog's clinical signs are stable and therapeutic changes are not being made. Because slight day-to-day variation can occur, the UPC may be evaluated by repeat measurement (at least two to three) over a period of days. Systemic blood pressure should be measured at least every three to six months, and more frequently if hypertension is unregulated. If the dog no longer has the ability to produce concentrated urine, a urine sample should be submitted for bacterial culture and susceptibility testing every six months. Because histologic lesions do not necessarily resolve even though renal function may improve, repeat biopsies are generally not needed. A reduction in proteinuria (ideally of >50 percent) as measured by the UPC without an increase in serum creatinine concentration indicates improvement or response to medical therapy.