Article #3 CE Protein-Losing Nephropathy

Jill Brunker, DVM, DACVIM Oklahoma State University

ABSTRACT: As the quality of veterinary medicine continues to evolve, the longevity of companion animals is increasing.With the development of more diagnostic testing modalities such as , proper interpretation and early intervention have become vital in delaying the progression of renal insufficiency and failure. In addition, detecting protein- uria may indicate the presence of a systemic disease, cuing veterinarians to conduct more diagnostic tests, which may help identify an underlying disease process.

roteinuria is a frequent finding via urinal- selective permeability is accomplished by a bar- ysis in animals with urinary tract disease. rier comprised of fenestrated endothelium, PDetection of small amounts of protein in glomerular basement membrane, and epithelial may indicate early glomerular disease or podocytes. The fenestrations within the endo- the presence of other pathologic processes.1–3 thelium have a diameter of approximately 34 Glomerular disease is a common cause of renal nm and normally function to restrict the loss of insufficiency and failure.4 Protein-losing ne- protein with a diameter equal to or greater than phropathies (PLNs) may be a clinical manifes- the fenestration size. Albumin has an effective tation of systemic diseases. Earlier detection diameter of 36 nm and a molecular weight of may lead to identification and treatment of an 69 kD. In addition to a mechanical barrier, the underlying disease process, thereby delaying, basement membrane is thought to be negatively but rarely halting, development of charged, which would further increase its ability when the glomerulus has been damaged.5,6 to repel negatively charged proteins such as albumin.7 Smaller proteins and solutes with PHYSIOLOGY negative or positive charges are freely filtered The functional unit of a nephron includes the through the glomerulus, but many are generally glomerulus, a tuft of capillaries contained reabsorbed in the tubules or catabolized and within Bowman’s capsule, and the tubules. The therefore may not be detected in urine.7 tubules are divided into the proximal convo- Changes in glomerular hemodynamic proper- luted tubule segment, the loop of Henle, the ties can also damage the glomerular barrier, distal convoluted tubule segment, and the col- resulting in increased protein losses in the urine lecting duct. The glomerulus functions to main- filtrate. Once protein enters the tubules, they tain normal osmotic pressure by inhibiting the have a limited ability for reabsorbtion.7 loss of serum proteins, espe- Send comments/questions via email cially albumin, into the urine PATHOPHYSIOLOGY [email protected] while allowing water, elec- Proteinuria is caused by one of three basic or fax 800-556-3288. trolytes, and waste products to processes8: Visit CompendiumVet.com for enter the tubules for either full-text articles, CE testing, and CE reabsorption from the tubules • Preglomerular (i.e., fever, hypothermia, test answers. or excretion into urine. This strenuous exercise, venous congestion)

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• Glomerular tion; cause relaxation of the mesangial cells, resulting in vasodilation; and have an antiinflammatory effect in the Postglomerular (i.e., hemorrhage or inflammation of • kidneys.13 Conversely, thromboxanes tend to induce the urogenital tract, lack of tubular reabsorption) platelet activation, are chemotactic for neutrophils, and The causes of preglomerular proteinuria usually result in cause mesangial cell contraction and vasoconstriction as mild, transient proteinuria, and most of these causes can well as interfere with mesangial phagocytosis of immune usually be ruled out with a thorough history and physi- complexes, possibly leading to a decreased GFR.12–14 cal examination. Other proteins, such as hemoglobin The causes of glomerulonephritis can be separated and , are freely filtered through the glomeru- into two categories: lus and may be present in urine. These proteins cause Primary (idiopathic) glomerulonephritis—No con- 9 • urine to remain red after centrifugation. Postglomerular current disease is identified. causes are most commonly the result of cystitis, metritis, Secondary glomerulonephritis—Damage to the prostatitis, or neoplasia and usually involve concurrent • glomerulus is the result of an identified systemic dis- inflammatory sediment or .9,10 The other pos- ease. The causes of secondary glomerulonephritis in sibility for postglomerular proteinuria is a lack of tubu- dogs and cats include many infectious diseases, lar reabsorption. A small amount of protein may be inflammatory conditions, neoplasia, heredity, certain present in the ultrafiltrate, but normal tubules degrade drugs, and endocrinopathies (Table 1). and reabsorb this protein.7 The loss of electrolytes and with normal glucosemia may indicate a renal In immune-mediated diseases (secondary to infectious tubular disorder that may accompany proteinuria (Fan- agents, organ/tissue damage), the antigen–antibody coni-like syndrome). complexes within the glomeruli lead to activation of For proteinuria to be glomerular, there has to be dam- complement with infiltration of neutrophils, T lympho- age to the glomeruli, most commonly from glomeru- cytes, and macrophages.14,15 Further destruction occurs lonephritis or amyloidosis. The mesangial cells are secondary to platelet aggregation, activation of the coag-

The most common causes of proteinuria in dogs and cats are glomerulonephritis and amyloidosis. important components of the glomerulus. These cells ulation cascade, and fibrin formation.14,15 The glomeru- are located between two neighboring capillaries and have lus responds to this insult by releasing additional a contractile role, influencing the glomerular filtration cytokines and growth factors, leading to mesangial cell rate (GFR). The mesangial cells also play an important proliferation, mesangial matrix production, inflamma- role in perpetuating the immune response to glomeru- tory cell adhesion, increased vascular permeability, intra- lonephritis. Some vasoactive substances and cytokines glomerular coagulation, and fibrin deposition.15 (e.g., endothelins, angiotensin II, vasopressin, norepi- Damage to the glomerulus occurs when immune com- nephrine, platelet-activating factor, thromboxane A2, his- plexes or amyloid, respectively, is deposited in the capil- tamine) can cause contraction of the mesangial cells, lary walls of the glomerulus.15 The antigen–antibody thereby decreasing GFR. Others, such as atrial natri- complexes may be circulating in the blood and subse- uretic peptide, dopamine, and cAMP, cause relaxation of quently deposited in the glomerulus, or the antigen the mesangial cells. The mesangial cells can also activate becomes embedded within the glomerular capillary wall T lymphocytes, which can further perpetuate the disease and the antibody binds to the antigen in situ.15 Once this process by recruiting other immune cells.11 Prosta- glomerular damage occurs, the selective permeability is glandins (PGs) and thromboxanes play a role in the local lost and protein enters the ultrafiltrate in the renal pathogenesis of glomerulonephritis and are foci for tubules. The proteins themselves increase lysosomal pro- potential treatments.12 Some PGs (i.e., PGE and prosta- cessing to the protein, which is toxic to the tubular cyclin) are beneficial in that they inhibit platelet func- epithelial cells.14,16 As a result, the lysosomes swell and

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Table 1. Causes of Secondary Glomerulonephropathy in Hyaline or protein casts detected Dogs and Cats14,a via urinalysis may suggest exces- sive protein loss with glomerular Causes Dogs Cats disease.6,9 Hyperfiltration with in- Inflammatory creased hydraulic pressure of the Infectious Dirofilariasis FIV remaining nephrons may damage Ehrlichiosis FIP RMSF Mycoplasmal polyarthritis the less affected glomeruli and Borreliosis worsen the proteinuria. If any por- Septicemia tion of the nephron is irreversibly Pyoderma damaged, the entire nephron will Pyometra be lost. Once greater than 66% to Bartonellosis 75% of nephron function is lost, Immune-mediated SLE SLE renal azotemia develops. Some Polyarthritis dogs with PLN retain the ability IMHA to concentrate urine with concur- IMTP rent glomerular azotemia. The Others IBD Pancreatitis degree of proteinuria may decrease Prostatitis Cholangiohepatitis over time as nephrons are lost. Hepatitis Periodontal disease However, this should not be assumed to indicate that the Neoplastic Leukemia Lymphoma glomerular disease and the PLN Transitional cell Leukemia are improving. carcinoma Mast cell tumors In one study,6 amyloidosis was Lymphoma shown to be one of the most com- Bronchogenic carcinoma mon causes of glomerular diseases in dogs, accounting for 23% of Drugs Glucocorticoid excess — Trimethoprim–sulfa dogs with glomerular disease. Amyloidosis results from the de- Hereditary Soft-coated wheaten Abyssinian position of an acute-phase reac- terrier tant fragment, amyloid A. The Doberman pinscher most common type of amyloidosis Beagle in dogs is secondary or reactive. In English cocker spaniel Shar-pei reactive amyloidosis, serum amy- Greyhound loid A is synthesized by the liver Dalmatian in response to tissue injury. Bernese mountain dog Chronic inflammation can result Samoyed in a prolonged increase in serum amyloid A concentration, leading Endocrine Hyperadrenocorticism — to development of reactive amy- loidosis, although other factors Other Systemic Systemic hypertension (e.g., inherited, environmental) aAll differentials are not listed. might be involved.6 In this same IBD = inflammatory bowel disease; IMHA = immune-mediated hemolytic anemia; IMTP = 6 immune-mediated thrombocytopenia; RMSF = Rocky Mountain spotted fever; SLE = sys- study, it was determined that an temic lupus erythematosus underlying disease process was causing amyloidosis in only 32% of cases. Beagles, collies, and rupture, resulting in tubulointerstitial injury, fibrosis, and Walker hounds may be at increased risk of amyloidosis.17 eventual loss of the nephron.14 Protein casts also con- Familial amyloidosis is a rare cause of amyloidosis and tribute to loss of nephrons by obstructing the tubule.16 may occur in beagles, English foxhounds, shar-peis, and

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Abyssinian cats. With renal amyloidosis in shar-peis and Cutaneous and renal glomerular vasculopathy, also Abyssinians, the amyloid is deposited primarily in the known as Alabama rot, occurs in young adult racing renal medulla; thus proteinuria may not be as marked.14 greyhounds, which usually present with cutaneous, well- Primary or immunoglobulin-associated amyloidosis demarcated ulcers primarily on the extremities.22 Some involves deposition of immunoglobulin light-chain frag- dogs may develop proteinuria and azotemia.22 The cause ments into the tissue and is rare in dogs and cats. Amy- of cutaneous and renal glomerular vasculopathy is loidosis, in general, is uncommon in cats.14 unknown, and the presence of azotemia seems to result in a poorer prognosis.22 HISTORY AND PHYSICAL EXAMINATION Clinical signs of PLN depend on the severity of the DIAGNOSIS glomerular disease.6,17,18 For example, an animal may have The diagnosis of PLN is fairly straightforward based weight loss and a dull, unkempt haircoat or appear clini- on proteinuria without an active sediment or hematuria. cally normal and have a positive microalbuminuria test Because most is excreted after entering the result. Some animals may show predominantly clinical renal tubules, it provides a good estimate of GFR.14 signs of an associated underlying disease. In the later Therefore, if urine creatinine levels are then compared stages of the disease process, these animals may have with the amount of protein in the urine by a urine pro- more obvious abnormalities, such as anorexia, vomiting, tein:creatinine ratio, the amount of proteinuria can be diarrhea, polyuria, polydipsia, and anemia, as typically quantified. The results of the urine protein:creatinine seen with decompensated renal failure. Some dogs with ratio correlate fairly closely with a 24-hour measure- PLN retain the ability to concentrate urine with concur- ment of protein excretion in urine.6,23 A urine protein: rent renal azotemia, assuming pre- or postrenal azotemia creatinine ratio of less than 0.4 to 0.5 is normal in dogs

Damage to the glomerulus occurs when immune complexes or amyloid is deposited into the capillary wall of the glomerulus. is not present. This is known as glomerulotubular imbal- and cats.14 A value greater than 1 should prompt a thor- ance, in which the GFR decreases, resulting in renal ough diagnostic evaluation.15 The urine sample should azotemia, but the tubules are still able to concentrate be obtained by cystocentesis to minimize contamination urine.5,14,19 Therefore, the presence of a concentrated from the urogenital tract. urine sample does not rule out the possibility of signifi- Microalbuminuria indicates that the level or amount cant glomerular disease. Animals with severe PLN can of albumin lost, rather than the molecular size (i.e., <69 also present with clinical signs consistent with nephrotic kD) of the molecule lost, is below the minimal level syndrome, which is characterized by marked proteinuria, detected by commonly used urine assays. Certain resulting in hypoalbuminemia, hypercholesterolemia ELISAs for canine and feline microalbuminuria detect (i.e., increased hepatic production in response to low albumin levels (not other proteins) of 1 to 30 mg/dl in oncotic pressure), and ascites or edema. Nephrotic syn- urine. Microalbuminuria has been shown to occur drome is seen in severe cases of proteinuria and is more before increases in the urine protein:creatinine ratio.1–3 typical of amyloidosis and membranous nephropathy.20 There are presently two commercially available tests for Thromboembolism, hyperlipidemia, and hypertension microalbuminuria (i.e., ERD-Screen Urine Test, Heska may be seen in patients with significant proteinuria.6 The Corp.; VetTest Urine P:C Ratio, IDEXX). In one antithrombolytic protein antithrombin III is approxi- study,24 a commercial, semiquantitative human test strip mately the same size as albumin. The loss of antithrom- (Clinitek Microalbumin, Bayer Corp.) for microalbu- bin III, along with other factors, contributes to the minuria proved to be unreliable for detecting microalbu- propensity for thromboembolism to occur.6,21 Anti- minuria in dogs. In cats, the ERD-Screen Urine Test thrombin III activity has been shown to be abnormal if appears to have a sensitivity of 95% and a specificity of serum albumin levels are below 1.8 mg/dl.6 greater than 99%.25 More studies are needed to deter-

September 2005 COMPENDIUM 690 CE Protein-Losing Nephropathy

mine the significance of microalbuminuria in cats as a A definitive diagnosis requires histologic examination correlation with proteinuria and progression of renal with immunofluorescent microscopy and electron disease.16,25 microscopy of the glomeruli from a biopsy of the renal Although conventional urine strips not specifically cortex.14,21 The renal medulla should be avoided because made for detecting canine and feline albumin can be it is associated with an increased incidence of complica- used, these are semiquantitative and have a substantial tions, such as hemorrhage. The biopsies may suggest the number of false-positive and false-negative results com- underlying cause of glomerular disease and better enable pared with species-specific ELISAs.9,26 Urine strips the veterinarian to institute a more directed treatment detect and measure albumin values of 30 mg/dl9 or plan. Some of the histologic types of glomerulopathies more, whereas the sulfosalicylic acid turbidity test can are amyloidosis, membranoproliferative glomerulone- be used to confirm the presence of proteinuria (values phritis, membranous nephropathy, proliferative glomer- ≥5 mg/dl).9 The sulfosalicylic acid turbidity test is able ulonephritis, hereditary nephritis, minimal change to detect other proteins, such as Tamm-Horsfall and disease, and glomerulosclerosis. Care must be taken in Bence Jones proteins.5,9 The urine concentration and pH selecting patients for renal biopsy, and clinicians should

Although conventional urine strips not specifically made for detecting canine and feline albumin can be used, they are semiquantitative and have a substantial number of false-positive and false-negative results compared with species-specific ELISAs. must also be evaluated when interpreting these tests.5 A weigh the risk versus benefit for each patient; a coag- 3+ result from a sulfosalicylic acid turbidity test is more ulation screen is strongly recommended before biopsy. significant in an isosthenuric urine sample than in a The main question that must be addressed to warrant highly concentrated sample. Inaccurate test results may the risk is whether the histopathologic findings would occur in urine that is highly alkaline, dilute, or turbid.9 substantially alter the treatment plan for the patient. A minimum database for animals with proteinuria Renal biopsies are not warranted for animals that are should include a hemogram, serum biochemistry profile, already in renal failure. Methods of obtaining tissue and urinalysis with culture and sensitivity testing. and interpreting histopathology are not discussed here Because PLN is often a sequela of systemic disease, an (see “Glomerulonephritis in Dogs and Cats: Diagno- aggressive attempt should be made to identify an under- sis and Treatment” in the September 2001 issue of lying cause (Table 1). Diagnostic imaging should include Compendium). radiography of the thorax and abdomen as well as abdominal ultrasonography. Serologic testing for infec- TREATMENT tious diseases and inflammatory processes specific to the Treatment of glomerulopathies should always be geographic location should be conducted. Consideration directed toward treating the underlying systemic disease of immune-mediated diseases and appropriate screening process when identified, symptomatically treating (i.e., antinuclear antibody testing, direct Coombs’ test, azotemia when present, and decreasing the amount of immunoelectrophoresis) may be warranted. Systemic protein lost. Serial urine protein:creatinine ratios are blood pressure monitoring is essential. Careful physical essential for monitoring trends with response to treat- examination is essential to identify potential problems ment or disease progression.21 Treatment of azotemia such as periodontal disease or skin or rectal masses that may include maintaining normal hydration status, ame- may be causing chronic antigenic stimulation (e.g., der- liorating gastrointestinal signs secondary to uremic syn- matitis, parasitism, inflammatory bowel disease). drome, dietary changes, and therapy for acid–base

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Additional Therapies for Protein-Losing Nephropathy in Small Animalsa • Elimination or treatment of concurrent disease — ACE inhibitors Enalapril (0.5 mg/kg q12–24h) Benazepril (0.5 mg/kg q12–24h) Lisinopril (0.7 mg/kg/day) — Aspirin Dogs (0.5 mg/kg q12–24h) Cats (0.5 mg/kg q48h) — Low-protein diets Dogs (2–3 g/kg/day) Cats (4 g/kg/day) • Omega-3 PUFAs • Supportive care — Antihypertensive medications (i.e., ACE inhibitors and/or amlodipine) and a sodium-restricted diet — Diuretics as needed for ascites/edema (i.e., furosemide and/or spironolactone) — Paracentesis for severe accumulations of body cavity effusions • Immunosuppressive treatment — Controversial; use with caution aAll medications are not included. disturbances, electrolyte abnormalities, systemic blood pressure, and endocrinopathies resulting from renal disease. Additional treatments of PLN (see box on this page) may include angiotensin-converting enzyme (ACE) inhibitors, low-dose aspirin, a low-protein diet, and omega-3 polyunsaturated fatty acids (PUFAs). Specific therapies for amyloidosis have proven to be ineffective. If amyloidosis is diagnosed before renal failure, especially in shar-peis, colchicine may be helpful (see box on page 693). Colchicine reduces serum amyloid A protein release from hepatocytes and may reduce a mediator called amyloid-enhancing factor.27 Anecdotal success has been reported with dimethyl sulfoxide, which is thought to help by act- ing as an antiinflammatory in both the liver and kidneys27 (see box on page 693). ACE inhibitors, such as enalapril maleate, have been shown to signifi- cantly decrease the amount of proteinuria by causing vasodilation of the renal arterioles, primarily the efferent arteriole.28 This reduces the hydraulic pressure across the glomerulus; thus less protein is “forced” out of the glomerulus into the ultrafiltrate in the tubule.28 Enalapril might have addi- tional beneficial effects5,14,21,28: • Reducing loss of glomerular heparan sulfate (helping maintain negative charge) • Decreasing the size of the glomerular capillary endothelial pores • Improving lipoprotein metabolism

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• Slowing glomerular mesangial growth and proliferation Additional Therapies for Amyloidosis in Small Animals • Inhibiting bradykinin degradation • Colchicinea (0.025 mg/kg q12–24 PO or The usual starting dose of enalapril is 0.5 mg/kg/day. If 0.01–0.03 mg/kg/day) the urine protein:creatinine ratio does not decrease within • Dimethyl sulfoxide (300 mg/kg/day PO or dilute 2 to 4 weeks, the dose frequency should be increased to 90% solution 1:4 in sterile water and administer every 12 hours. When receiving ACE inhibitors, patients 20–80 mg/kg SCb three times/wk) should be monitored for potential deterioration in renal a status, such as increasing azotemia; thus baseline blood May cause gastrointestinal distress; side effects may be tolerable at lower doses. urea nitrogen and creatinine concentrations should be bMay cause local irritation. obtained before therapy and repeated within 7 days.5 Patients unable to tolerate ACE inhibitors often have a decreased appetite. Enalapril is cleared predominately by is the result of chronic inflammation or an immune- the kidneys, and a 33% reduced enalapril dose is sug- mediated disease. Prednisolone may actually induce gested for dogs and cats with mild renal impairment glomerular disease and increase proteinuria.18,35,36 If cor- (i.e., azotemia).29 Conversely, dogs with renal insuffi- ticosteroids are used, they should be administered with ciency can adequately clear benazepril,29,30 possibly mak- caution, including judicious serial monitoring of the ing it a better choice of ACE inhibitor in animals, urine protein:creatinine ratio to detect increasing values. especially cats, with renal insufficiency.31,32 However, nei- Certain types of glomerulonephritis, identified only ther may prove effective in cats with proteinuria second- through histopathology (e.g., primary membranous ary to systemic hypertension.33 nephropathy of minimal change disease), have shown Aspirin therapy is directed at decreasing platelet improvement with steroids.14 Cyclosporine has been aggregation and may decrease the probability of throm- shown to be of no benefit, but future studies are needed boembolism.5 At normal doses, aspirin blocks the regarding use of immunosuppressive drugs in treating cyclooxygenase pathway, including both thromboxane various glomerular diseases.37 and PG production. At a much lower dosage of 0.5 mg/kg q12–24h (q48h for cats), aspirin irreversibly PROGNOSIS blocks thromboxane production by platelets without The prognosis for patients with PLN is variable and decreasing the beneficial effects of PGI2 (i.e., prostacy- depends on the severity and extent of both renal disease clin) production.13,14,21 By blocking thromboxane pro- and any underlying systemic disease as well as response duction, adverse effects of thromboxanes, such as to treatment.6 If azotemia is present at the time of diag- platelet aggregation within the glomerulus and mesan- nosis, the average time until death for dogs is less than 3 gial cell contraction slowing GFR, are decreased.12–14 In months.18 Poor prognostic indicators in humans include the future, alternative treatment modalities may include concurrent azotemia, severe proteinuria, systemic hyper- thromboxane synthase inhibitors, which have shown tension, and marked tubulointerstitial lesions; this is promise in decreasing the amount of proteinuria in dogs probably true in animals, as well.14 with experimentally induced glomerulonephritis.5,12 Through renoprotective effects and by reducing REFERENCES hypertriglyceridemia and lowering systemic blood pres- 1. Lees GE, Jensen WA, Simpson DF, et al: Persistent precedes sure in humans, omega-3 PUFAs have also proven to be onset of overt proteinuria in male dogs with X-linked hereditary nephropathy [abstract]. J Vet Intern Med 16:353, 2002. 14,34 beneficial in chronic renal disease. Commercial renal 2. Grauer GF, Oberhauser EB, Basaraba RJ, et al: Development of microalbumin- diets for dogs usually contain a higher ratio of omega-3 uria in dogs with heartworm disease [abstract]. J Vet Intern Med 16:352, 2002. PUFA and also have the benefit of phosphorus, sodium, 3. Vaden SL, Jensen WA, Longhofer S, Simpson DF: Longitudinal study of 14 microalbuminuria in soft-coated wheaten terriers [abstract]. J Vet Intern Med and protein restriction. Decreasing the amount of 15:300, 2001. dietary protein may decrease the amount of proteinuria 4. Macdougall DF, Cook T, Steward AP, Cattell V: Canine chronic renal dis- and is an important component of treatment.21 ease: Prevalence and types of glomerulonephritis in the dog. Int 29:1144–1151, 1986. Using immunosuppressive drugs to treat glomeru- 5. Grant DC, Forrester SD: Glomerulonephritis in dogs and cats: Diagnosis lonephritis is controversial. Immunosuppressive drugs and treatment. Compend Contin Educ Pract Vet 23(9):798–804, 2001. are indicated if the inciting cause of glomerular disease 6. Cook AK, Cowgill LD: Clinical and pathological features of protein-losing

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glomerular disease in the dog: A review of 137 cases (1985–1992). JAAHA 32. King JN, Strehlau G, Wernsing J, Brown SA: Effect of renal insufficiency on 32:313–322, 1996. the pharmacokinetics and pharmacodynamics of benazepril in cats. J Vet 7. Russo LM, Bakris GL, Comper WD: Renal handling of albumin: A critical Pharmacol Ther 25(5):371–378, 2002. review of basic concepts and perspective. Am J Kidney Dis 39:899–919, 2002. 33. Steele JL, Henik RA, Stepien RL: Effects of angiotensin converting enzyme 8. Gary AT, Cohn LA, Kerl ME, et al: The effects of exercise on microalbu- inhibition on plasma aldosterone concentration, plasma renin activity, and minuria in dogs. J Vet Intern Med 17:435–436, 2003. blood pressure in spontaneously hypertensive cats with chronic renal disease. 3:157–166, 2002. 9. Grauer GF: Proteinuria, in Ettinger SJ, Feldman EC: Textbook of Veterinary J Vet Ther Internal Medicine. St. Louis, Elsevier Saunders, 2005, pp 114–116. 34. Brown SA, Brown CA, Crowell WA, et al: Beneficial effects of chronic 10. Vaden SL, Pressler BM: Urinary tract inflammation has a variable effect on administration of dietary omega-3 polyunsaturated fatty acids in dogs with renal insufficiency. 131(5):447–455, 1998. urine albumin concentrations [abstract]. J Vet Intern Med 16:378, 2002. J Lab Clin Med 11. Merkel F, Marx M, Netzer KO, Weber M: T cell involvement in glomerular 35. Lees GE, Willard MD, Dziezyc J: Glomerular proteinuria is rapidly but reversibly increased by short-term prednisone administration in heterozygous injury. Kidney Blood Press Res 19:298, 1996. (carrier) female dogs with X-linked hereditary nephropathy [abstract]. J Vet 12. Grauer GF, Frisbie DD, Longhofer SL, Cooley AJ: Effects of a thromboxane Intern Med 16:352, 2002. synthetase inhibitor on established immune complex glomerulonephritis in 36. Waters CB: Effects of glucocorticoid therapy on urine protein-to-creatinine dogs. Am J Vet Res 53:808–813, 1992. ratios and renal morphology in dogs. J Vet Intern Med 11:172–177, 1997. 13. Rachear D, Feldman B, Farver T, et al: The effect of three different dosages 37. Vaden SL, Breitschwerdt EB, Armstrong JP, et al: The effects of cyclosporine of acetylsalicylic acid on canine platelet aggregation. JAAHA 24:23–26, 1988. versus standard care in dogs with naturally occurring glomerulonephritis. J 14. Vaden SL: Glomerular diseases, in Ettinger SJ, Feldman EC: Textbook of Vet- Vet Int Med 9:259–266, 1995. erinary Internal Medicine. St. Louis, Elsevier Saunders, 2005, pp 1786–1799. 15. Grant DC, Forrester SD: Glomerulonephritis in dogs and cats: Glomerular function, pathophysiology, and clinical signs. Compend Contin Educ Pract Vet 23(8):739–740, 2001. 16. Polzin DJ, Osborne CA, Ross S: Chronic , in Ettinger SJ, ARTICLE #3 CE TEST Feldman EC (eds): Textbook of Veterinary Internal Medicine. St. Louis, Else- This article qualifies for 2 contact hours of continuing CE vier Saunders, 2005, pp 854–855. education credit from the Auburn University College of 17. DiBartola SP, Tarr MJ, Parker AT, et al: Clinicopathologic findings in dogs with renal amyloidosis: 59 cases (1976–1986). JAVMA 195:358–364, 1989. Veterinary Medicine. Subscribers may purchase individual 18. Center SA, Smith CA, Wilkinson E, et al: Clinicopathologic, renal immuno- CE tests or sign up for our annual CE program. Those fluorescent, and light microscopic features of glomerulonephritis in the dog: who wish to apply this credit to fulfill state relicensure 41 cases (1975–1985). JAVMA 190:81–90, 1987. requirements should consult their respective state 19. Willard MD, Krehbiel JD, Schmidt GM, et al: Serum and urine protein abnormalities associated with lymphocytic leukemia and glomerulonephritis authorities regarding the applicability of this program. in a dog. JAAHA 17:381–386, 1981. To participate, fill out the test form inserted at the end 20. Biewenga WJ, Gruys E: Proteinuria in the dog: A clinicopathological study of this issue or take CE tests online and get real-time in 51 proteinuric dogs. Res Vet Sci 41:257–264, 1986. scores at CompendiumVet.com. 21. Grauer GF: CVT update: Canine glomerulonephritis, in Bonagura JD (ed): Kirk’s Current Veterinary Therapy XIII. Philadelphia, WB Saunders, 2000, pp 851–853. 1. A normal glomerulus has fenestrations in the 22. Cowan LA, Hertzke DM: Cutaneous and renal glomerulopathy of grey- basement membrane approximately the same hound dogs, in Bonagura JD (ed): Kirk’s Current Veterinary Therapy XIII. diameter as Philadelphia, WB Saunders, 2000, pp 845–855. 23. Grauer GF, Thomas CB, Eicker SW: Estimation of quantitative proteinuria a. albumin. d. electrolytes. in the dog, using the urine protein-to-creatinine ratio from a random, voided b. urea. e. creatinine. sample. Am J Vet Res 46(10):2116–2119, 1985. c. globulins. 24. Pressler BM, Vaden SL, Jensen WA, Simpson D: Detection of canine microalbuminuria using semiquantitative test strips designed for use with human urine. Vet Clin Pathol 31(2):56–60, 2002. 2. Which is not considered a cause of postglomeru- 25. Langston C: Microalbuminuria in cats. JAAHA 40:251–254, 2004. lar proteinuria? 26. Jensen WA, Grauer GF, Andrews J, et al: Prevalence of microalbuminuria in a. d. metritis dogs [abstract]. J Vet Intern Med 15:300, 2001. b. prostatitis e. cystitis 27. Pressler BM, Vaden SL: Managing renal amyloidosis in dogs and cats. Vet c. urinary tract infection Med 98(4):320–332, 2003. 28. Grauer GF, Greco DS, Getzy DM, et al: Effects of enalapril versus placebo as a treatment for canine idiopathic glomerulonephritis. J Vet Intern Med 3. Which does not typically result in contraction of 14:526–533, 2000. the mesangial cells? 29. Lefebvre HP, Laroute V, Concordet D, Toutain PL: Effects of renal impair- a. dopamine d. platelet-activating factor ment on the disposition of orally administered enalapril, benazepril and their b. angiotensin II e. thromboxanes active metabolites. J Vet Intern Med 13:21–27, 1999. 30. Kitagawa H, Eguchi T, Kitoh K, et al: Plasma concentrations of an c. endothelins angiotensin-converting enzyme inhibitor, benazepril, and its active metabo- lite, benazeprilat, after repeated administrations of benazepril in dogs with 4. Which is most consistent with a diagnosis of experimental kidney impairment. J Vet Med Sci 62(2):179–185, 2000. glomerulotubular imbalance in dogs with PLN? 31. Brown SA, Brown CA, Jacobs G, et al: Effects of the angiotensin converting enzyme inhibitor benazepril in cats with induced renal insufficiency. Am J Vet a. renal azotemia with the inability to concentrate urine Res 62(3):375–383, 2001. b. renal azotemia with the ability to concentrate urine

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c. prerenal azotemia with the ability to concentrate urine c. hemorrhage d. postrenal azotemia with the ability to concentrate d. high urine alkalinity urine e. all of the above e. none of the above 8. A minimum database for animals with protein- 5. Which is not typically a component of nephrotic uria should not include a syndrome? a. hemogram. a. proteinuria b. serum biochemistry. b. hypogammaglobulinemia c. urinalysis with culture and sensitivity testing. c. hypoalbuminemia d. urine protein:creatinine ratio. d. hypercholesterolemia e. biopsy of the renal medulla. e. ascites 9. Which is not a possible treatment option for 6. Which diagnostic test has the greatest sensitivity PLN? when detecting levels of albumin less than 30 a. enalapril d. omega-3 fatty acids mg/dl in urine? b. a high-protein diet e. none of the above a. a species-specific ELISA c. low-dose aspirin b. a sulfosalicylic acid turbidity test c. commercial human urine test strips 10. Which can result in glomerulonephritis in dogs? d. a urine protein:creatinine ratio a. rickettsial diseases e. none of the above b. trimethoprim–sulfa antibiotics c. polyarthritis 7. Which can cause inaccurate results when evalu- d. heartworm disease ating for glomerular proteinuria? e. all of the above a. a very diluted urine sample b. active urinary sediment