Lecture outline 9/20/2013

9/20/2013
Lecture outline
Review of the Glomerulus
€ Glomerular diseases in dogs
€ Diagnostic approach to proteinuria
€ Treatment recommendations for
protein-losing nephropathy syndromes
€
Susan M. Simmerson, DVM
Internal Medicine
Major points
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Proteinuria is the hallmark of glomerular
disease
Protein-Losing Nephropathy (PLN) and
glomerular disease are synonymous
Many forms of glomerular disease (PLN)
are treatable
Kidney biopsy is an important and feasible
diagnostic test
In some cases favorable prognosis is
contingent upon early detection and
intervention
Glomerulus
€
Functions to maintain normal oncotic
pressure by inhibiting the loss of serum
proteins, especially albumin, into the
urine while allowing water, electrolytes
and waste products to enter into the
tubules for either reabsorption or
excretion into the urine
400,000 - 600,000 corpuscles per
kidney in the dog
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Glomerular blood flow
Glomerulus – Selective Barrier
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Fenestrated endothelium
y 34 nm diameter
y Albumin ~ 36 nm
Afferent arteriole
€ Glomerular tuft
€ Efferent arteriole
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Mesangial cells
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Basement membrane
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Podocytes
y Contractile role to influence GFR
y Negatively charged
y Cover and interdigitate with each other to create
slit-pores
Nephrology and Urology of Small Animals.
Bartges and Polzin; Wiley-Backwell 2011
http://2.bp.blogspot.com/podocyte.jpg
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Juxtaglomerular Apparatus
Distinct region at the vascular pole of
the glomerulus
€ Macula densa
€
Renal
Corpuscule
y Specialized epithelial cells in the Loop of
Henle that detect changes in NaCl
concentration in urinary filtrate
y Signal Renin release from JG cells
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Juxtaglomerular (JG) cells
y Modified smooth muscle cells around the
afferent arteriole
Nephrology and Urology of Small Animals.
Bartges and Polzin; Wiley-Backwell 2011
Three most common forms of
glomerular disease in dogs
1.
2.
3.
Membranoproliferative
glomerulonephritis (MPGN)
Membranous nephropathy (MP)
Amyloidosis
Many of the glomerular diseases in dogs
are believed to develop secondary to
an infectious, neoplastic, or noninfectious inflammatory conditions
Glomerular Diseases in Dogs
Amyloidosis
Focal segmental glomerulosclerosis
Glomerulonephritis
Crescentic (rare)
Membranoproliferative
Proliferative (IgA nephropathy)
Glomerulosclerosis
Hereditary nephritis
Lupus nephritis
Membranous nephropathy
Minimal change glomerulopathy
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Membranoproliferative
Glomerulonephritis
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Membranoproliferative
Glomerulonephritis
Accounts for up to 60% of cases of
glomerular disease in dogs
Rapidly progressive immunologic injury to
the glomerular structure, inlcuding the
mesangium, accompanied by tubular
necrosis and interstitial nephritis
Often fatal
Primary or Secondary
Antigen
y Reported in association with Borrelia burgdorferi
in dogs
Sequella of Antigen-Antibody
Deposition in the Glomerulus
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Activation of complement with infiltration of
neutrophils, T-lymphocytes, and macrophages
Glomerulus responds and releases cytokines
and growth factors
Platelet aggregation
Activation of coagulation cascade
Fibrin formation
Mesangial proliferation
Mesangial matrix production
Inflammatory cell adhesion
Increased vascular permeability
Membranous Glomerulopathy
Less common in dogs and less serious
€ Antigen-Antibody deposition along the
basement membrane
€ Does not involve the mesangium
€ Most common glomerular disease in
cats
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Membranous Glomerulopathy
Amyloidosis
Accounts for up to ¼ of dogs with
glomerular disease
€ Results from deposition of nonfunctional protein or amyloid A
€ Amyloid A is synthesized in the liver in
response to tissue injury
€ Underlying disease process indentified
in ~ 30% of cases
€ Poor prognosis
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www.unckidneycenter.org
Amyloidosis
Glomerulosclerosis
End stage lesion in
response to chronic
injury
€ Lesion associated
with diabetic
nephropathy
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y Clinical relevance in
dogs is unknown
stanfordhospital.org
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Hereditary Nephritis
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Hereditary Glomerulopathies
Diverse group of inherited glomerular
diseases that are a result of a genetic
mutation or deletion in basement
membrane collagen
€ Soft-coated
€ Beagle:
Amyloidosis and Membranoproliferative
GN
y English cockers
y Bull Terriers
wheaten terrier:
Proliferative and Sclerosing GN
€ Shar-pei:
y Dalmations
Amyloidosis
y Samoyeds
€ Greyhound:
Glomerular vasculopathy and necrosis
Causes of Secondary
Glomerulonephropathy
Infectious
Immune Mediated
Sequella of Glomerular Damage
Neoplastic
Dirofilariasis
SLE
Leukemia
Ehrlichiosis
Polyarthritis
Transitional cell carcinoma
RMSF
IMHA
Lymphoma
Borreliosis
IMTP
Bronchogenic carcinoma
Septicemia
Pyoderma
Bartonellosis
Pyometra
Inflammatory
Drugs
IBD
Glucocorticoid excess
Prostatitis
Trimethoprim-sulfa
Hepatitis
Periodontal disease
Endocrine
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Proteinuria
y Lysosomal processing of the protein in the
ultrafiltrate
y Toxic to tubular epithelial cells
y Development of progressive azotemia
y Decrease in serum albumin and systemic
oncotic pressure
y Systemic hypertenstion
Hyperadrenocorticism
Other
Systemic hypertension
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Clinical Signs of Glomerular
Disease
Highly variable - May be most
symptomatic for underlying disease
€ Anorexia
€ Vomiting
€ Diarrhea
€ PU/PD
€ Anemia
€ Other signs of systemic vasculitis
€ Thromboembolism
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Diagnostic approach to
proteinuria
Nephrotic Syndrome
Marked proteinuria = Hypoalbuminemia
€ Hypercholesterolemia
€ Peripheral edema or ascites
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www.vet.uga.edu
Minimum Database for
Proteinuric Dogs
Complete blood count
€ Serum chemistry
€ Urinalysis
€ Urine culture and sensitivity
€ Urine protein:creatinine
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Localization of Proteinuria
1.
Pre-Glomerular
y
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Proteinuria without an active UTI or
other lower urinary tract disease
y Dip stick vs Sulfasalicylic acid (SSA)
turbidity test
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Glomerular
2.
3.
Hemoglobinuria, myoglobinuria, fever,
venous congestion
Usually transient
Diagnosis of PLN
Urine protein:creatinine (UPC) > 0.5
○ UPC > 1 should prompt diagnostic workup
Post-Glomerular
y
Tubular damage, hemorrhage or
inflammation of the lower urinary tract
Microalbuminuria
Screening for Underlying Disease
Specific for albumin in the urine
€ Can detect 1 – 30 mg/dL
€ Microalbuminuria shown to occur before
increased in UPC
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Tick panels
y Lyme disease
○ C6 Snap or Quantitative C6
y 4DX
○ Lyme snap
○ E-canis
○ Dirofilaria
○ Anaplasma
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Others
y Autoimmune testing (ANA, Combs, RH factor,
etc)
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Imaging
Chest or abdominal radiographs
screening for underlying disease
€ Abdominal ultrasound to image the
kidneys
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Diagnosis of Glomerular Disease
€Kidney
Biopsy
y Ultrasound guided TruCut
y 20 minute procedure under light anesthesia
y Most of the time kidneys appear normal
y In severe cases may see hyperechoic
cortices or medullary rim sign
Kidney Biopsy
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Patient selection is key
y Stable patient
y Non-coagulopathic patient
y Controlled hypertension
y Caution with severely azotemic patient
Diagnosis of Glomerular Disease
€ Kidney
Biopsy
~ $500
y Definitive diagnosis
y Prognostic
y Guides treatment
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Texas Veterinary Renal Pathology
Service
Light
Microscopy
Texas Veterinary Renal Pathology
Service
Electron
Microscopy
Texas Veterinary Renal Pathology
Service
Immunofluorescence
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Treatment of Glomerular Disease
Identification and elimination of
causative or associated antigens
€ Reduction of the glomerular response to
injury
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Antiproteinuric Drugs
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Ace Inhibitors
y Vasodilate efferent arteriol decreasing
intraglomerlular pressure
○ Enalapril
○ Benazapril
○ Lisinopril
y Aldosterone escape can render them ineffective
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Angiotensin II Receptor blockers
y Directly block receptor
○ Losartan
○ Irbesartan
y Aldosterone escape does not blunt RAAS blockade
Treatment of Glomerular Disease
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Antiproteinuric drugs indicated when
UPC > 2
y Creatinine < 3 mg/dL - Enalapril 0.5 mg/kg
PO BID
y Creatinine 3-5 mg/dL – Enalapril 0.25 mg/kg
Ace Inhibitor Dosage Adjustments
Minimum increase in Creat – no change
in enalapril dose
€ > 30% increase in Creat – discontinue
enalapril
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PO BID
y Creatinine > 5 mg/dL – Consider Benazepril
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Recheck UPC in 3-4 weeks
instead 0.25-0.5 mg/kg PO q 24H
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Recheck serum creatinine in ~ 1 week
Lees, GE, Brown SA, ElliottJ, et al. Assessment and management of proteinuria in dogs and cats:
2004 ACVIM Consensus Statement (small animal). J. Vet Int Med 2005; 19:377-385
Lees, GE, Brown SA, ElliottJ, et al. Assessment and management of proteinuria in dogs and cats:
2004 ACVIM Consensus Statement (small animal). J. Vet Int Med 2005; 19:377-385
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Ace Inhibitor Dosage Adjustments
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UPC > 0.5 –
y increase enalapril by 0.25 mg/kg BID to a
maximum of 1 mg/kg BID
y Consider adjunct therapy with losartan
0.125-0.25 mg/kg BID titrated up to a
maximum of 2 mg/kg BID
Antihypertensives
Ace inhibitors and ARB’s minimally
reduce hypertension
€ Amlodipine first line therapy
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y 0.1-0.4 mg/kg PO q 24H
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Hydralazine – refractory hypertension
y Unpredictable
y 0.5-2 mg/kg PO q 12H titrated to effect
y Can also be given IV
Lees, GE, Brown SA, ElliottJ, et al. Assessment and management of proteinuria in dogs and cats:
2004 ACVIM Consensus Statement (small animal). J. Vet Int Med 2005; 19:377-385
Antithrombotic therapy
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Dogs with PLN are predisposed to
thromboembolism
y Aspirin
○ 0.5 mg/kg PO SID-BID
y Clopidogrel
○ No evidence to support it’s use
○ 3-5 mg/kg PO q 24H
Omega III Fatty Acids
Fish oils PO q D
€ Antiinflammatory effect
€ Reduces hypertriglyeceridemia and
lowering systemic blood pressure in
people
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Immunosuppression
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Controversial
Indicated if the inciting cause is chronic
underlying inflammation or immune
mediated disease
Corticosteroids administered with caution
Cyclosporine has been shown to be
ineffective
Mycophenolate or Azathioprine anecdotally
used particularly in cases of Lyme nephritis
Nutritional Therapy
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Prescription kidney diet if they will eat it
y Modified protein content
y Sodium restriction
Fluid Therapy in Glomerular
Disease
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BE CAREFUL
y It is very easy to fluid overload these dogs
y Reduced oncotic pressure from
hypoalbuminemia
y Concurrent hypertension
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Crystalloids IV to replace dehydration
deficit and ongoing losses
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Conservative use of colloid therapy
(Hetastarch)
y Consider lower sodium crystalloids
Prognosis for PLN
Depends upon the severity and extent of
renal damage and reversibility of
underlying disease
€ If azotemia persists at the time of
diagnosis, time of death for dogs in less
than 3 months
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Take Home Point:
Glomerular disease is common in
canine patients
€ Early recognition and treatment of
disease prior to development of
azotemia improves prognosis
€ Consider a kidney biopsy – is feasible
and yields useful information to guide
therapy
€
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