Grand Rounds

1
Grand Rounds

• Dianne E. Kittrell, D.V.M.
• The Animal Medical Center
• New York, NY
• March 19, 2003

2
Gigio Vosilla Signalment
11 Yr, MC, Miniature Poodle No known prior
medical conditions Vaccinated annually No monthly
heartworm of tick preventative Extensive travel
history
3
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.

4
Pertinent History

• Previously healthy animal
• Medical attention provided by RDVM
• Palliative - aimed at controlling blood loss
• CBC, SMA
• Urinalysis, Urine culture

5
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.

6
Initial Problem List

• Epistaxis
• Chronic, intermittent
• Hypoalbuminemia
• Hyperglobulinemia
• Anemia
• Proteinuria
• Lethargy and Inappetance
• Pelvic limb stiffness
• Chronic, progressive

7
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

8
Differential Diagnoses

• Epistaxis
• Neoplasia/Polyps
• (carcinomas, sarcomas)
• Hypertension
• (primary or secondary)

9
Differential Diagnoses

• Hypoalbuminemia
• Physiologic
• dilution
• Decreased production
• Hepatic failure
• Increased loss
• Renal
• Gastrointestinal
• Significant hemorrhage
• catabolism

10
Differential Diagnoses

• Hyperglobulinemia
• Alpha globulins
• alpha-1,alpha-2
• Beta globulins
• beta-1, beta-2
• Gamma globulins
• IgM, IgA, IgG
• Monoclonal
• Polyclonal

11
Differential Diagnoses

• Monoclonal
• Infections
• (Ehrlichiosis, Leishmaniasis, idiopathic)
• Neoplasia
• (Multiple myeloma, macroglobulinemia, lymphoma,
  rare extramedullary plasmacytoma)
• Miscellaneous
• (Cunaneous amyloidosis, plasmacytic
  gastroenteritis)

12
Differential Diagnoses

• Polyclonal
• Infections
• Bacterial (Brucellosis, Pyoderma, Bacterial
  endocarditis)
• Viral
• Fungal (blastomycosis, histoplasmosis,
  coccidioidomycosis)
• Rickettsial (Erlichiosis)
• Parasitic (Dirofilariasis, Demodicosis, Scabies)

13
Differential Diagnoses

• Polyclonal
• Immune-Mediated
• (infectious complex deposition, SLE, GN, IMHA,
  ITP, Polyarthritis, pemphigus complex, Rheumatoid
  arthritis)
• Neoplasia

14
Differential Diagnoses

• Proteinuria
• Pre renal
• Exercise, fever or seizures, hyperproteinemia
• Renal
• Glomerular disease
• Tubular dysfunction
• Post renal
• Lower urinary tract disease

15
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

16
Differential Diagnosis

• Chronic Lameness
• Musculoskeletal disease
• Arthritic changes, luxating patellas, cruciate or
  lateral collateral ligamentous rupture
• Joint disease
• Infectious, immune mediated, inflammatory
• Neurologic deficit

17
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 proteincreatinine ratio free catch
• Bence-Jones proteins
• Cytology of Lymph node aspirates
• Blood pressure Doppler normal _at_ 140mmHg
• Orthopedic exam

18
Initial Therapeutic plan

• Doxycycline
• 10mg/kg/day
• Tetracycline antibiotic
• Bacteriostatic
• Broad spectrum

19
Initial Results Day Two
20
Initial Results - Day Three

• Urine protein/creatinine ratio
• 8.7 (increased)
• Bence-Jones proteins
• positive
• Tick panel E.Canis, RMSF Lyme
• no antibody detected _at_ 125 (negative)
• Lymph nodes cytology
• consistent with hyperplastic lymph nodes.
• Drawer sign present
• suspect chronic cruciate tear
• EPH pending

21
Treatment

• Therapeutic adjustments
• Enalapril (0.5mg/kg/day)
• Low dose aspirin (0.5mg/kg/day)
• Derm Caps
• Canned K/D diet

22
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

23
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.

24
Bone lesions in Myeloma
25
Myeloma Marrow

• Plasma cell infiltration

26
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 15120

27
Classification of Rickettsiaceae
28
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
29
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

30
Canine Monocytic Ehrlichiosis

• Diagnosis
• IFA Antibody Titer
• Morulae (buffy coat)
• PCR
• Culture
• Treatment
• Tetracycline's, Chloramphenicol, Imidocarb,
  Quinolones
• Corticosteroids

31
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

32
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

33
Acute E. canis Infections

• Non-specific findings 8-20 days post bite
• Lethargy
• Fever
• Anorexia
• Weight loss
• Lymphadenopathy
• Laboratory changes (Plt, mild PMN, PCV)

34
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)

35
Protein Losing Nephropathy

• Glomerulonephritis
• Primary
• Secondary
• Amyloidosis
• Glomerulopathy
• Familial

36
Diseases Associated with Glomerulonephritis

• Infectious
• Dirofilaria immitis
• Ehrlichiosis
• RMSF
• Borreliosis
• Leptospirosis
• K9 Adenovirus type 2

• Leishmaniasis
• Brucellosis
• Chronic bacterial infections
• Bacterial endocarditis
• Pyometra

37
Diseases Associated with Glomerulonephritis

• Inflammatory Conditions
• Pancreatitis
• Systemic Lupus Erythematosus
• Immune-mediated hemolytic anemia
• Prostatitis
• Polyarthritis
• Endocrine
• Hyperadrenocorticism
• Diabetes Mellitus
• Neoplasia

38
The Glomerulus

• Small molecules move freely
• Larger molecules are restricted
• Negatively charged particles are restricted
• Albumin is excluded

39
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

40
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

41
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

42
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

43
Pathologic Processes Leading to Glomerular Injury
and Proteinuria
44
Pathways Leading to Progressive Renal Failure
45
Glomerular DiseaseBiochemisry 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

46
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

47
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

48
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

49
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50
Treatment of Glomerular DiseaseReduction 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

51
Treatment of Glomerular DiseaseACE 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 200014526-533

52
Treatment of Glomerular DiseasePrevention of
Thromboembolism

• Low dose aspirin (0.5 mg/kg/day has been used in
  dogs with GN to inhibit platelet aggregation
• Dogs with ATIII lt 70 normal or fibrinogen gt 300
  mg/dl may be at increased risk
• Heparin is of little usefulness when ATIII is low
  (requires ATIII as a cofactor)

53
Specific Treatment forGlomerulonephritis

• Cyclosporine (15 mg/kg po q 24 hr did not have
  beneficial effect in dogs with GN one study
• Armstrong et al. JVIM 19959259-266
• Azathioprine (2.2 mg/kg po q 24 hrs) may be
  helpful in dogs w/ GN
• Corticosteroids for treatment of the underlying
  disease

54
Gigio Vosilla - 2 months from onset

• Weight gain 11.4 lbs (from 10.0 lbs)
• Urine proteincreatinine ratio4.2 (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

55
Gigio Vosilla - 4 months from onset

• Weight Gain 12.3 lbs (from 10 lbs)
• Urine proteincreatinine ratio3.4 (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

56
Gigio Vosilla - 6 months from onset

• Temperature 104 degrees
• Urine culture negative
• Recurrence of generalized lymphadenomegaly
• Depressed
• Blood pressure 130 mmHg

57
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

58
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

59
References

• Codner EC, Maslin WR. Investigation of Renal
  Protein Loss in Dogs with Acute Experimentally
  Induced Ehrlichia Canis Infection. AJVR
  199253294-299
• Grauer GF. CVT Update Canine Glomerulonephritis.
  pp. 851-853
• Harrus S, Bark H, Waner T. Canine Monocytic
  Ehrlichiosis An Update. Compendium 1997194
• 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 199913501-504

60
References

• Frank JR, Breitschwert EB. A retrospective Study
  of Ehrlichiosis in 62 dogs from North Carolina
  and Virginia. J Vet Intern Med 199913194-201
• Grindem CB, Breitschwerdt EB, Perkins PC.
  Platelet-Associated Immunoglobulin (Antiplatelet
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• Varela F, Font X, Valladares JE, Alberola J.
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• Forrester SD, Troy GC. Renal Effects of
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  19992119
• Hurley KJ, Vaden SL. Proteinuria in Dogs and
  Cats A diagnostic approach. Urinary Disorders.
  pp. 937-940

61
References

• Grant DC, Forrester DS. Glomerulonephritis in
  Dogs and Cats Glomerular function,
  pathophysiology, and Clinical Signs. Compendium
  200123739-745
• Grant DC, Forrester, SD. Glomerulonephritis in
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• Hammer AS, Couto CG. Complications of Multiple
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  Seminars in Oncology. 199017210-216

62
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
  200014134-139
• 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
  199657948-956

63
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
  200264321-327
• Breitschwerdt EB, Davidson MG, Hegarty BC, Papich
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