Published on November 16, 2007
Grand Rounds: Grand Rounds Dianne E. Kittrell, D.V.M. The Animal Medical Center New York, NY March 19, 2003 “Gigio” Vosilla Signalment: “Gigio” Vosilla Signalment 11 Yr, MC, Miniature Poodle No known prior medical conditions Vaccinated annually No monthly heartworm of tick preventative Extensive travel history Presenting Complaints: Presenting Complaints Epistaxis: Intermittent and bilateral of one month duration Lethargy and inappetence: Two week history of nonspecific clinical abnormalities. Stiff gait: Recent progression of chronic pelvic limb stiffness. Pertinent History: Pertinent History Previously healthy animal Medical attention provided by RDVM: Palliative - aimed at controlling blood loss CBC, SMA Urinalysis, Urine culture Initial Abnormalities: Initial Abnormalities Physical Examination 10.0 LBS Mild weight loss per owners Depressed/quiet Febrile 103 Pale mucous membranes Mild generalized lymphadenomegaly Referral blood work Hypoalbuminemia: 1.9 g/dl Hyperglobulinemia: 9.9 g/dl Non-regenerative anemia: 18.4 % Proteinuria: 3+ - 1.043 spec grav. Initial Problem List: Initial Problem List Epistaxis Chronic, intermittent Hypoalbuminemia Hyperglobulinemia Anemia Proteinuria Lethargy and Inappetance Pelvic limb stiffness Chronic, progressive Differential Diagnoses: Differential Diagnoses Epistaxis Bleeding disorders: Factor deficiency (congenital or acquired), thrombocytopenia/thrombocytopathy (infectious or immune mediated) Infections: Viral, bacterial (rhinosinusitis), fungal (aspergillus spp., cryptococcus), Rickettsial (ehrlichia, RMSF), parasitic Differential Diagnoses: Differential Diagnoses Epistaxis Neoplasia/Polyps (carcinomas, sarcomas) Hypertension (primary or secondary) Differential Diagnoses: Differential Diagnoses Hypoalbuminemia Physiologic dilution Decreased production Hepatic failure Increased loss Renal Gastrointestinal Significant hemorrhage catabolism Differential Diagnoses: Differential Diagnoses Hyperglobulinemia Alpha globulins: alpha-1,alpha-2 Beta globulins: beta-1, beta-2 Gamma globulins: IgM, IgA, IgG Monoclonal Polyclonal Differential Diagnoses: Differential Diagnoses Monoclonal Infections (Ehrlichiosis, Leishmaniasis, idiopathic) Neoplasia (Multiple myeloma, macroglobulinemia, lymphoma, rare extramedullary plasmacytoma) Miscellaneous (Cunaneous amyloidosis, plasmacytic gastroenteritis) Differential Diagnoses: Differential Diagnoses Polyclonal Infections Bacterial: (Brucellosis, Pyoderma, Bacterial endocarditis) Viral Fungal: (blastomycosis, histoplasmosis, coccidioidomycosis) Rickettsial: (Erlichiosis) Parasitic: (Dirofilariasis, Demodicosis, Scabies) Differential Diagnoses: Differential Diagnoses Polyclonal Immune-Mediated: (infectious complex deposition, SLE, GN, IMHA, ITP, Polyarthritis, pemphigus complex, Rheumatoid arthritis) Neoplasia Differential Diagnoses: Differential Diagnoses Proteinuria Pre renal Exercise, fever or seizures, hyperproteinemia Renal Glomerular disease Tubular dysfunction Post renal Lower urinary tract disease Differential Diagnosis: Differential Diagnosis Nonregenerative Anemia Secondary anemia Inflammation Chronic renal failure Chronic hepatic disease Endocrine diseases Infections Ehrlichia Bone Marrow dyscrasias Drug induced hematologic dyscrasias Iron-Deficiency Differential Diagnosis: Differential Diagnosis Chronic Lameness Musculoskeletal disease Arthritic changes, luxating patellas, cruciate or lateral collateral ligamentous rupture Joint disease Infectious, immune mediated, inflammatory Neurologic deficit Initial Diagnostic Plan: Initial Diagnostic Plan Submit and Pend: CBC, Serum Chemistry Panel Special Coagulation Panel Serum EPH Tick serology including E Canis, Rocky Mountain Spotted Fever and Lyme Urine protein:creatinine ratio – free catch Bence-Jones proteins Cytology of Lymph node aspirates Blood pressure – Doppler – normal @ 140mmHg Orthopedic exam Initial Therapeutic plan: Initial Therapeutic plan Doxycycline 10mg/kg/day Tetracycline antibiotic Bacteriostatic Broad spectrum Initial Results – Day Two: Initial Results – Day Two Initial Results - Day Three: Initial Results - Day Three Urine protein/creatinine ratio: 8.7 (increased) Bence-Jones proteins: positive Tick panel: E.Canis, RMSF& Lyme: no antibody detected @ 1:25 (negative) Lymph nodes cytology: consistent with hyperplastic lymph nodes. Drawer sign present: suspect chronic cruciate tear ***EPH pending Treatment: Treatment Therapeutic adjustments Enalapril (0.5mg/kg/day) Low dose aspirin (0.5mg/kg/day) Derm Caps Canned K/D diet Probable Differentials: Probable Differentials Myeloma Lethargy & anorexia Hyperglobulinemia monoclonal Bence-Jones proteinuria Non-regenerative anemia Infectious disease Lethargy & anorexia Hyperglobulinemia Monoclonal polyclonal Bence-Jones Proteinuria: possible but not expected Non-regenerative anemia Additional Diagnostics & imaging : New findings: Additional Diagnostics & imaging : New findings Thoracic and abdominal radiographs: normal study Abdominal ultrasound : normal study BMBT : 3 minutes 45 seconds Bone marrow evaluation : normal cellularity and normal activity of all cell series with no evidence of neoplasia. Bone lesions in Myeloma: Bone lesions in Myeloma Myeloma Marrow: Myeloma Marrow Plasma cell infiltration Change of Course & Additional Serology: Change of Course & Additional Serology Serum Electrophoresis: Polyclonal Continue search for infectious diseases Leishmania donovani: negative Heartworm negative Ehrlichia (platys, risticcii, equi) Positive Ehrlichia Risttici 1:5120 Classification of Rickettsiaceae: Classification of Rickettsiaceae Ehrlichia Grouped by Tropism: Ehrlichia Grouped by Tropism Not Absolute… Monocytic Granulocytic Platelet E. ewingii E. equi E. phagocytophila E. canis E. risticii E. chaffeensis E. sennetsu E. muris E. platys Canine Monocytic Ehrlichiosis: Canine Monocytic Ehrlichiosis Clinical Pathology: Typical Picture Anemia (mild to severe, non-regenerative) Thrombocytopenia (mild to moderate) Lymphocytosis Hyperglobulinemia (poly or monoclonal gammopathy) GN signs ( albumin, urine P/C, etc) Bm hypocellularity, plasmacytosis Canine Monocytic Ehrlichiosis: Canine Monocytic Ehrlichiosis Diagnosis: IFA Antibody Titer Morulae (buffy coat) PCR Culture Treatment: Tetracycline's, Chloramphenicol, Imidocarb, Quinolones Corticosteroids IFA (Indirect immunofluorescence assay):: IFA (Indirect immunofluorescence assay): Antibodies in the serum bind to the organisms on a slide and are detected by a fluorescein-labeled conjugate Antibodies reactive with one Ehrlichia species can be cross reactive with other species of Ehrlichia Canine Monocytic Ehrlichiosis: Canine Monocytic Ehrlichiosis Most common form of K9 Ehrlichiosis Organisms infects mononuclear cells Transmission - Rhipicephalus sanguineus (brown dog tick) Acute phase, subclinical carrier phase, and chronic disease phase Can occur in any season due in part to chronicity Acute E. canis Infections: Acute E. canis Infections Non-specific findings: 8-20 days post bite Lethargy Fever Anorexia Weight loss Lymphadenopathy Laboratory changes (Plt, mild PMN, PCV) Chronic E. canis Infections: Chronic E. canis Infections Clinical signs: Bleeding disorders (60%) Anorexia (34%) Lethargy (31%) Weight loss (24%) Polyarthritis Neurologic abnormalities (16%) Ocular lesions (16%) Lymphadenopathy; splenomegaly; hepatomegaly (20%) Protein Losing Nephropathy: Protein Losing Nephropathy Glomerulonephritis Primary Secondary Amyloidosis Glomerulopathy Familial Diseases Associated with Glomerulonephritis: Diseases Associated with Glomerulonephritis Infectious Dirofilaria immitis Ehrlichiosis RMSF Borreliosis Leptospirosis K9 Adenovirus type 2 Leishmaniasis Brucellosis Chronic bacterial infections Bacterial endocarditis Pyometra Diseases Associated with Glomerulonephritis: Diseases Associated with Glomerulonephritis Inflammatory Conditions Pancreatitis Systemic Lupus Erythematosus Immune-mediated hemolytic anemia Prostatitis Polyarthritis Endocrine Hyperadrenocorticism Diabetes Mellitus Neoplasia The Glomerulus: The Glomerulus Small molecules move freely Larger molecules are restricted Negatively charged particles are restricted Albumin is excluded Histologic Classification &Familial Glomerular Diseases: Histologic Classification & Familial Glomerular Diseases Membranoproliferative Soft-coated wheaten terriers (often assoc w/PLE) Bernease mountain dogs (often assoc w/ borreliosis) CIII deficiency in Brittany spaniels Basement membrane disorders Autosomal recessive in English cocker spaniels X linked dominant in Samoyeds Suspected in Doberman Pinchers & Bull terriers Pathophysiology: Pathophysiology Preformed circulating antigen-antibody complexes are deposited within the glomeruli Antigen is trapped in the glomerular capillary wall, and circulating antibodies form complexes with them Sodium Retention: Sodium Retention Urinary loss of albumin causes hypoalbuminemia Decreased oncotic pressure causes loss of water and electrolytes from vascular space Decreased circulating volume stimulated the RAS Aldosterone stimulates renal retention of sodium and water Decreased oncotic pressure prevents retention of water in vascular space Sodium Retention: Sodium Retention Aldosterone concentrations can be normal or low in nephrotic syndrome and ace inhibitors may not prevent sodium retention Patients with nephrotic syndrome have blunted ANP response Primary intrarenal sodium retention in distal nephron (independent of aldosterone) leads to ECF expansion and edema Pathologic Processes Leading to Glomerular Injury and Proteinuria: Pathologic Processes Leading to Glomerular Injury and Proteinuria Pathways Leading to Progressive Renal Failure: Pathways Leading to Progressive Renal Failure Glomerular Disease:Biochemisry Findings: Glomerular Disease:Biochemisry Findings Lab abnormalities of CRF Azotemia Hyperphosphatemia Metabolic acidosis Hypoalbuminemia Up to 70% of dogs with amyloidosis Up to 60% of dogs with GN Hypercholesterolemia Up to 90% of dogs with amyloidosis Up to 60 % of dogs with GN *decrease Upr/Ucr in azotemic dogs with declining GFR is NOT a sign of improvement Complications: Thromboembolism in Nephrotc Syndrome: Complications: Thromboembolism in Nephrotc Syndrome Hypercoagulable state Mild thrombocytosis, Increased platelet adhesion and aggregation Loss of ATIII in urine (normally acts with heparin to inhibit factors II, IX, X, XII) Urinary loss of lower MW factors (IX XI, XII) Increased Plasma concentration of higher MW factors (II, V, VII, VIII, X) – (increased hepatic synthesis) Thromboembolism occurs in 15-25% of dogs with nephrotic syndrome Complications: Hypertension in Nephrotic Syndrome: Complications: Hypertension in Nephrotic Syndrome Primary intrarenal mechanism for sodium retention Activation of RAS Impaired release of renal vasodilator substance Hypertension occurs in 50-85% of dogs with glomerular disease Controlling hypertension may slow progression of renal disease Complications: Hyperlipidemia in Nephrotic syndrome: Complications: Hyperlipidemia in Nephrotic syndrome Increased hepatic synthesis and decreased peripheral catabolism of lipotroteins caused by hypoalbuminemia and urinary loss of lipid regulatory factors Plasma cholesterol and triglyceride concentrations directly proportional to the degree of renal azotemia Treatment of Glomerular Disease:Reduction of Thromboxanes: Treatment of Glomerular Disease: Reduction of Thromboxanes Effect of Dietary n-3 fatty acid supplementation Omega-3 polyunsaturated fatty acids (fish oil) may suppress glomerular inflammation by decreasing thromboxane synthesis Thromboxane synthetase inhibitors can reduce proteinuria in dogs with experimental GN Treatment of Glomerular Disease:ACE Inhibitors: Treatment of Glomerular Disease: ACE Inhibitors Decrease glomerular capillary hydrostatic pressure (and proteinuria) by decreasing post-glomerular arteriolar restance In a study of dogs with GN; 0.5 mg/kg po q 12-24 hrs reduces proteinuria, reduced blood pressure and may have slowed progression of renal disease. Grauer, Greco, Getzy. JVIM 2000;14:526-533 Treatment of Glomerular Disease:Prevention of Thromboembolism: Treatment of Glomerular Disease: Prevention of Thromboembolism Low dose aspirin (0.5 mg/kg/day has been used in dogs with GN to inhibit platelet aggregation Dogs with ATIII < 70% normal or fibrinogen > 300 mg/dl may be at increased risk Heparin is of little usefulness when ATIII is low (requires ATIII as a cofactor) Specific Treatment forGlomerulonephritis: Specific Treatment for Glomerulonephritis Cyclosporine (15 mg/kg po q 24 hr did not have beneficial effect in dogs with GN one study Armstrong et al. JVIM 1995;9:259-266 Azathioprine (2.2 mg/kg po q 24 hrs) may be helpful in dogs w/ GN Corticosteroids for treatment of the underlying disease Gigio Vosilla - 2 months from onset: Gigio Vosilla - 2 months from onset Weight gain: 11.4 lbs (from 10.0 lbs) Urine protein:creatinine ratio:4.2 (from 8.7) Albumin: 2 g/dl (from 1.5 g/dl) Globulins: 7.7 g/dl (from 10.1) Initiated prednisone therapy 10 mg/day x 14 days; 7.5 mg/day x 14 days; 5 mg/day continually Gigio Vosilla - 4 months from onset: Gigio Vosilla - 4 months from onset Weight Gain: 12.3 lbs (from 10 lbs) Urine protein:creatinine ratio:3.4 (from 8.7) Albumin: 2.0g/dl (from 1.5 g/dl) Globulin: 6.2 g/dl (from 10.1 g/dl) Packed cell volume: 20g/dl Ehrlichia Risticii IFA: Negative Gigio Vosilla - 6 months from onset: Gigio Vosilla - 6 months from onset Temperature: 104 degrees Urine culture negative Recurrence of generalized lymphadenomegaly Depressed Blood pressure: 130 mmHg Gigio Vosilla - 7 months from onset: Gigio Vosilla - 7 months from onset Presented acutely vomiting and depressed Non-ambulatory/joint effusion palpable Progressive anemia: 13% Albumin: 2.5 g/dl Globulin: 5.4 g/dl Azotemic: Bun/Creat: 124/4.8 Plan: Bone Marrow, Joint tap, diuresis, and blood transfusion Forgotten Diagnostics: Forgotten Diagnostics Measurement of serum hyperviscosity Erythrocyte sedimentation rate Follow up inappropriate Serial monitoring of EPH The hyperglobulinemia associated with CME does not correlate with the antibody titers to ehrlichia Anti-Ehrlichia antibody titers may persist for months to years after treatment A progressive decrease in the gammaglobulin concentrations is associated with elimination of the parastite References: References Codner EC, Maslin WR. Investigation of Renal Protein Loss in Dogs with Acute Experimentally Induced Ehrlichia Canis Infection. AJVR 1992;53:294-299 Grauer GF. CVT Update: Canine Glomerulonephritis. pp. 851-853 Harrus S, Bark H, Waner T. Canine Monocytic Ehrlichiosis: An Update. Compendium 1997;19:4 Green CE, Neer TM. Infectious Diseases of the Dog and Cat. Ch. 28; pp. 139-154 Neer TM, Eddlestone SM, Gaunt SD, Corstvet RE. Efficacy of Enrofloxacin for the Treatment of Experimentally Induced Ehrlichia canis Infection. JVIM 1999;13:501-504 References: References Frank JR, Breitschwert EB. A retrospective Study of Ehrlichiosis in 62 dogs from North Carolina and Virginia. J Vet Intern Med 1999;13:194-201 Grindem CB, Breitschwerdt EB, Perkins PC. Platelet-Associated Immunoglobulin (Antiplatelet Antibody) in Canine Rocky Mountain Spotted Fever and Ehrlichiosis. JAHA Jan 1999, vol.35:56-61 Varela F, Font X, Valladares JE, Alberola J. Thrombocytopathia and Light-chain Proteinuria in a Dog Naturally Infected with Ehrlichia Canis. J Vet Intern Med 1997;11:309-311 Forrester SD, Troy GC. Renal Effects of Nonsteroidal Antiinflammatory Drugs. Compendium 1999;21:19 Hurley KJ, Vaden SL. Proteinuria in Dogs and Cats: A diagnostic approach. Urinary Disorders. pp. 937-940 References: References Grant DC, Forrester DS. Glomerulonephritis in Dogs and Cats: Glomerular function, pathophysiology, and Clinical Signs. Compendium 2001;23:739-745 Grant DC, Forrester, SD. Glomerulonephritis in Dogs and Cats: Diagnosis and Treatment. Compendium 2001;23:798-804 Hammer AS, Couto CG. Complications of Multiple Myeloma. JAAHA 1994;30:9-14 Petterson WP, Caldwell CW,Doll DC. Hyperviscosity Syndromes and Coagulopathies. Seminars in Oncology. 1990;17:210-216 References: References Sainz A, Tesouro MA, Amusategui I, Rodriquez F, Mazzucchelli F, Rodriquez M. Prospective Comparative Study of 3 Treatment Protocols Using Doxycycline or Imidocarb Dipropionate in Dogs with Naturally Occurring Ehrlichiosis. JVIM 2000;14:134-139 Grauer GF, Greco DS, Behrend EN, Fettmen MJ, Mani I, Getzy DM, Reinhart GA. Effects of Dietary n-3 Fatty Acid Supplementation Versus Thromboxane Synthetase Inhibition on Gentamicin-Induced Nephrotoxicosis in Healthy Male Dogs. AJVR 1996;57:948-956 References: References Brown SA, Finco DR, Brown, CA, Crowell WA, Alva R, Ericsson GF, Cooper T. Evaluation of the Effects of Inhibition of Angiotensin Converting Enzyme with Enalapril in Dogs with Induced Chronic Renal Insufficiency. AJVR 2002;64:321-327 Breitschwerdt EB, Davidson MG, Hegarty BC, Papich MG, Grindem CB. Prednisolone at Anti-Inflammatory or Immunosuppressive Dosages in Conjunction with Doxycycline does not Potentiate the Severity of Rickettsia rickettsii Infection in Dogs. Antimicrobial Agents and Chemotherapy 1997;141-147
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