Strategies for Protein Losing Nephropathy

Melissa S. Wallace, DVM, Dipl. ACVIM

Introduction

There are two major protein losing kidney diseases (i.e. glomerulopathies) in dogs and cats, which are immune complex glomerulonephritis and renal amyloidosis. Glomerulopathies cause significant protein loss through the glomerulus, resulting in nephrotic syndrome. Renal proteinuria, hypoalbuminemia, hypercholesterolemia, and peripheral edema or body cavity effusions characterize nephrotic syndrome. In addition, glomerulopathies usually cause chronic renal failure due to progressive loss of functional nephrons.

Pathogenesis of Glomerulonephritis

Immunologic Mechanisms: The most common type of immune-mediated glomerular disease in dogs and cats is the deposition of preformed antigen:antibody complexes within the glomerulus. When a particular antigen is present in equal or slightly excessive amounts in the circulation as compared to circulating antibodies, the complexes are small enough to escape the reticuloendothelial system and end up being deposited in the glomerulus. This triggers a type III hypersensitivity reaction

Sometimes, antigens can be 'planted' within the glomerular capillary wall due to electrical or other interactions within the GBM. Then circulating antibodies can form complexes with those antigens in situ. This is the situation with the glomerulonephritis that results from heartworm disease in the dog. Truly autoimmune glomerulonephritis, with immune reaction against endogenous GBM antigens, occurs in people and has not been reported in the dog or cat.

Inflammatory Cascade: The immune complexes in the glomerulus activate compliment. Neutrophils, macrophages, platelets and glomerular cells are involved in the inflammatory response. Lymphocytes play a major role in recognizing and responding to the antigens and mesangial cells also activate T-lymphocytes. Eicosanoids, cytokines and growth factors are produced, such as thromboxane, leukotrienes, tumor necrosis factor, platelet derived growth factor, platelet activating factor, interleukins, and others. The coagulation system is activated, and fibrin deposition occurs. Ultimately, the charge selectivity of the GBM is lost, resulting in proteinuria. The inflammatory process damages the glomerulus, resulting in thickening of the GBM, cellular proliferation within the mesangium, hyalinization, sclerosis and glomerular death. The result is chronic renal failure, in addition to the effects of severe proteinuria. As single nephron GFR increases in an attempt to compensate for loss of nephron mass, increased filtration and intraglomerular hypertension will exacerbate proteinuria.

Etiologic Agents Associated with Glomerulonephritis

A laundry list of infectious, inflammatory and neoplastic diseases have been associated with glomerulonephritis in dogs and cats. Why some animals with a particular disease develop GN and others with the same disease do not is a relative mystery, but genetic factors in immune response probably play a role. In many GN patients, a predisposing cause is not found. Some of the more common infectious agents to keep in mind when diagnosing protein losing kidney diseases include: Brucellosis, Ehrlichiosis, Leptospirosis, Borelliosis, chronic bacterial infections, and heartworm disease. Noninfectious causes include inflammatory bowel disease, systemic lupus erythematosis, and hyperadrenocorticism, among others.

Histopathologic Categories of Glomerulonephritis

Glomerulonephritis is diagnosed with renal biopsy. Because an etiologic agent is usually not known, the disease is typically classified by the histopathologic changes. Membranous GN is characterized mostly by thickening of the glomerular basement membrane. Cases with an increased cellularity in the mesangium are referred to as proliferative GN. Cases where both changes are present are classified as membranoproliferative GN. Glomerulosclerosis refers to hyalinization and scarring of the glomeruli. Minimal change disease is suspected when the histopathology is only mildly abnormal in spite of significant proteinuria, and electron microscopy and/or immunofluorescence is necessary for a diagnosis. In companion animals, the histopathologic classification as it relates to prognosis is unclear, other than the more severe and widespread the lesions are, the worse the prognosis.

Immunofluorescence and electron microscopy may add information to the histopathology which will eventually help to better define glomerulonephritis in dogs and cats and correlate these finding with prognosis. These services are often unavailable outside of a teaching or research institution.

Renal Amyloidosis

Amyloidosis is a diverse group of diseases characterized by the deposition of insoluble polymerized proteins extracellularly in tissues. The deposits have a biophysical conformation called a beta-pleated sheet, which imparts distinct staining and optical properties. Amyloid deposits have a homogenous pink appearance on routine histopathology, and stain positively with Congo red.

In dogs and cats the type of amyloidosis that is usually diagnosed is Systemic Reactive Amyloidosis. This is caused by deposition of amyloid A protein, which is an amino terminal fragment of an acute phase reactant called serum amyloid A protein (SAA). The liver, in response to tissue injury in the body, synthesizes this acute-phase reactant. Prolonged increased concentrations of SAA in circulation plus other factors predispose some animals to deposition of the amyloid A protein into tissues such as the kidney. Familial predilections are recognized in Shar pei dogs and Abyssinian cats, which may have amyloid deposits in many organs. Other predisposing causes may be systemic inflammatory, infectious or neoplastic diseases. Usually, no predisposing cause is found.

Renal amyloidosis is characterized by severe proteinuria and progressive renal failure. In a certain subset of Shar pei dogs and in Abyssinian cats, amyloid deposition appears to be more interstitial than glomerular, so the proteinuria may be less severe. The prognosis for renal amyloidosis is poor to grave, especially if renal failure is present at the time of diagnosis.

The Clinical Syndrome of Protein Losing Nephropathy

Signalment

•  Canine GN - no age or sex predilection. Familial GN is reported in the Doberman pinscher, Rottweiler, Samoyed, Greyhound, Bernese Mountain Dog, Soft-coated Wheaten terrier, and Beagle.

•  Amyloid - familial in Abyssinian cats and Shar pei dogs, which usually show clinical signs at < 5 years of age. There may be a gender predisposition (more females). For idiopathic amyloidosis, age is usually > 5 years with no sex predilection. Beagles may be at increased risk.

History

•  Clinical signs are usually those of chronic renal failure and uremia, and consist of anorexia, lethargy, weight loss, polyuria, polydipsia, vomiting, halitosis and a poor haircoat.

•  Shar pei dogs may have historical "Shar pei fever", a waxing and waning inflammatory disease characterized by high fever and tibiotarsal joint inflammation. A cause and effect relationship to amyloidosis is suspected.

•  Nephrotic syndrome usually has no historical signs until peripheral edema and/or body cavity effusions are apparent.

•  Signs of thromboembolic disease may be present, the most common being pulmonary thromboembolism, resulting in acute dyspnea and tachypnea.

Physical Examination

•  PE may reveal an unthrifty animal, sometimes with uremic halitosis and/or oral ulcers, and peripheral edema and/or ascites. In some cases the P.E. is normal.

•  Retinal detachment and/or hemorrhage may be seen with secondary hypertension

Laboratory Findings

•  The biochemistry profile will usually reveal hypoalbuminemia (with a normal serum globulin) and hypercholesterolemia. If the animal is in renal failure, azotemia will be present. Hyperphosphatemia is an advanced change.

•  The urinalysis shows proteinuria, and the urine specific gravity will not always be isosthenuric as in typical of chronic renal failure. The amount of proteinuria that is considered normal depends on the urine concentration. Because the disease is more glomerular than tubular, loss of urine concentrating ability may be partially spared. Hematuria and/or inflammation in the sediment make proteinuria difficult to accurately interpret, as it could be from pyelonephritis or lower urinary tract disease. Casts may be present in cases of renal proteinuria, and are usually hyaline or granular.

•  The complete blood count will usually be normal, but mild to moderate anemia may be present as with any chronic renal disease. A leukocytosis may be seen if an underlying systemic inflammatory disease is present.

•  Urine protein:creatinine ratio: A 24-hour urine collection for measurement of renal protein loss is the gold standard, but urine protein:creatinine ratio does a good job of approximating it, because it stays constant in spite of changing urine volumes. Interpretation: Canine UP:UC < 0.5 = normal; UP:UC > 0.5 = suspicious; UP:UC > 1.0 = abnormal. Feline UP:UC > 0.5 = abnormal. Cases of GN or amyloid usually have UP:UC > 3.0.

•  The urine culture is usually negative unless the glomerulonephritis is secondary to chronic pyelonephritis (rare), or a secondary kidney infection has occurred.

Imaging

•  Survey abdominal radiographs are part of the minimum database. A chest radiograph to look for systemic disease (heartworm disease, mycotic infection, neoplasia, etc.) is indicated.

•  Ultrasound changes may be absent, or consistent with chronic renal disease.

Blood Pressure

•  There is a high incidence of hypertension in dogs with glomerulopathies. This is likely to be true of cats as well.

Renal biopsy

•  A renal biopsy is the only way to definitively diagnose glomerulonephritis as opposed to amyloidosis.

•  Prognosis may be at least somewhat ascertained, and treatment modalities may differ.

•  If possible, save a sample for electron microscopy, and also request that immunofluorescence be done.

Antigen Search

•  If glomerulonephritis is diagnosed or highly suspected, serologic studies to look for an underlying infectious disease are warranted. Which diseases to test for depend on the geographical area and travel history of the animal.

•  Considerations for dogs are; Ehrlichiosis, Borreliosis, Rocky Mountain spotted fever, Leptospirosis, and Brucellosis.

•  Cats should be screened for viral diseases such as FIV and FeLV.

Therapy of Glomerulonephritis

•  Treat the underlying cause if it can be found.

•  Reduce proteinuria

i.  Feed moderately protein-restricted diets with high biological value to reduce proteinuria.

ii.  If hypoalbuminemia worsens, give supplemental protein, usually as hard-boiled egg whites (albumin). Each large egg white provides 6 grams of protein.

iii.  Angiotensin converting enzyme inhibitors (e.g. enalopril) have been shown to reduce proteinuria in GN. Give enalopril at 0.5 mg/kg SID to BID PO. Monitor azotemia and UP:UC ratio. If renal failure is severe, consider benazepril instead.

•  Reduce inflammatory mediators

i.  Administering immunosuppressive drugs such as corticosteroids, cyclosporin, azathioprine and/or chlorambucil has met with limited, anecdotal success. In general, these are probably not indicated in the types of GN we recognize in dogs, because they seem not to reliably help, and the side effects are significant.

ii.  Cats may have a more favorable outcome with steroids, and less side effects.

iii.  Minimal change disease is a steroid-responsive disease in people and should probably be treated with steroids in the dog, but it is very rare.

iv.  Because platelets are felt to be primary mediators in the inflammatory response within the glomerulus, antiplatelet drugs such as aspirin may be helpful. Give 0.5 - 5 mg/kg/day for the dog.

•  Reduce thromboembolic tendency

i.  Give aspirin, as above.

ii.  If ATIII is low, consider plasma transfusion (this is a temporary measure).

iii.  Treatment with coumadin to prevent thromboembolism may be beneficial. It is difficult in dogs and cats due to the monitoring required and the risk of exacerbating uremic G.I. bleeding.

•  Manage the uremic syndrome as for chronic renal failure.

•  Fluid therapy

i.  Avoid parenteral fluids in animals with severe hypoalbuminemia unless the animal has become dehydrated or is uremic.

ii.  Fluid therapy in dogs and cats with nephrotic syndrome is difficult to manage, because they are prone to developing peripheral edema, ascites, pleural effusion and pulmonary edema. Monitor physical examination and body weight frequently during fluid administration.

iii.  Fluid therapy is more effective and safer if a combination of colloids and crystalloids are given, instead of just crystalloids. When using colloids, reduce the crystalloid dose by 40 - 60%. A useful colloid for diuresis of nephrotic animals is hydroxyethylstarch at 10 - 20 ml/kg/day as a constant rate infusion. Monitoring colloid oncotic pressure is ideal if possible.

•  Prevent and treat hypertension

i.  Moderate salt restriction may help to control hypertension and accumulation of fluid in body cavities and tissues.

ii.  Systemic hypertension is a common consequence of renal failure, and seems especially common with glomerulopathies.

iii.  Treat hypertension if systolic blood pressure is > 170 mm Hg with angiotensin converting enzyme inhibitors (as above). If inadequate response is seen, add amlodipine.

Therapy of Amyloidosis

•  If the amyloidosis is diagnosed early (i.e. prior to renal failure), especially in the Shar pei, colchicine may be helpful, although this has not been proven. Colchicine works by reducing SAA protein release from hepatocytes, and may reduce a mediator called amyloid enhancing factor. Colchicine may cause G.I. side effects.

•  Dimethylsulfoxide (DMSO) has also had anecdotal success, and is thought to help by acting as an anti-inflammatory in both the liver (where SAA comes from) and in the kidney. Side effects are bad breath, anorexia, nausea, pain on SQ administration if not diluted, and cataracts.