Canine glomerular disease 10/6/05 5:46 PM Page 469

REVIEW

Canine glomerulonephritis: new

thoughts on proteinuria and treatment
Glomerular disease in the dog is not only a common form of renal allograft. Even though the inclusion crite-
ria were biased against proteinuric disease,
disease but also an important cause of chronic renal failure. The
47 per cent of the dogs studied had
presence of immune complexes in glomerular capillary walls is a glomerular disease (Mathews and others
2000). The magnitude of this problem
major cause of canine glomerular disease and is commonly referred
is emphasised by additional studies that
to as glomerulonephritis. Leakage of plasma proteins, principally have shown the prevalence of glomerular
disease in randomly selected dogs to be as
albumin, across the damaged glomerular capillary walls results
high as 70 per cent (Rouse and Lewis
in persistent proteinuria – the clinicopathological hallmark of 1975, Muller-Peddinghaus and Trautwein
1977).
glomerulonephritis. Recent evidence suggests that, in addition
Most canine glomerular disease is
to being a marker of disease, persistent proteinuria is associated thought to be associated with the presence
of immune complexes in glomerular
with progressive glomerular and tubulointerstitial lesions and
capillary walls (DiBartola and others 1980b,
loss of additional nephrons. Perhaps the best treatment for Jaenke and Allen 1986, Center and others
1987, Cook and Cowgill 1996). However,
glomerulonephritis is the identification and correction of any
structural abnormalities (for example, type
underlying inflammatory, immune-mediated or neoplastic disease IV collagen defects in hereditary nephritis
in Samoyed dogs), haemodynamic abnor-
that results in the deposition or formation of glomerular immune
malities (such as intraglomerular hyperten-
complexes. In cases of idiopathic glomerulonephritis, sion) and glomerular amyloid deposition
are examples of additional types of glomeru-
angiotensin-converting enzyme inhibitors have been shown to
lar disease in dogs.
decrease proteinuria and potentially slow disease progression. This review will focus on immune
complex glomerulonephritis (GN). Persis-
tent proteinuria (principally albuminuria)
G. F. GRAUER
INTRODUCTION with inactive urine sediment has long
Journal of Small Animal Practice (2005) been the clinicopathological hallmark
46, 469-478 Until relatively recently, canine glomerular of glomerular disease in dogs. However,
disease was thought to be uncommon and confirmation of GN requires histological
unimportant. It is now recognised that examination of renal biopsy specimens.
glomerular disease is not only common Use of the UP/C to quantitatively estimate
but can also lead to chronic renal insuffi- proteinuria has greatly facilitated the diag-
ciency or failure in the dog. For example, nosis of GN in veterinary medicine.
in a study of 76 dogs with chronic renal Beyond the diagnostic utility of protein-
disease, 40 (52 per cent) had glomerular uria, pathophysiological consequences of
disease rather than non-glomerular disease persistent proteinuria in dogs may include
as the underlying pathological process decreased plasma oncotic pressure, hyper-
(MacDougall and others 1986). cholesterolaemia, systemic hypertension,
In another study of dogs with naturally hypercoagulability, muscle wasting and
occurring end-stage renal disease that weight loss. The potential for proteinuria
received renal allografts, glomerular disease to be associated with renal disease
was judged to be the underlying pathology progression has also been recognised,
in seven of 15 cases (Mathews and others stimulating a discussion about what level
2000). It is interesting to note that a urine of proteinuria is normal. Development
protein:creatinine ratio (UP/C) of less of canine-specific albumin ELISA technol-
than five was required for a dog to be eligi- ogy that enables the detection of very
Department of Clinical Sciences, ble for transplantation. This helped low concentrations of albumin (micro-
College of Veterinary Medicine,
Kansas State University, exclude underlying glomerular disease, albuminuria) has helped drive this re-
Manhattan, Kansas 66506, USA which might have adversely affected the evaluation.lllll

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Canine glomerular disease 10/6/05 5:46 PM Page 470

Table 1. Diseases associated with

The presence of immune complexes in
glomerular capillary walls often stimulates
glomerular cell proliferation and thicken-
ing of capillary walls, which can lead to
glomerular hyalinisation and sclerosis.
Irreversible damage to the glomerulus
renders the entire nephron unable to
function and, as the disease progresses,
glomerular filtration may be decreased
resulting in azotaemia and renal failure.
General treatment objectives for GN
include attenuation of the proteinuria
and disease progression. Specific treat-
ment objectives include: identification
and elimination of any underlying
disease process that may be producing
antigen-antibody complexes; decreasing
the angiotensin and aldosterone res-
ponse; decreasing the platelet/thrombox-
ane response; and supportive care.
AETIOLOGY AND
PATHOPHYSIOLOGY
Soluble circulating antigen-antibody com-
plexes may be deposited or trapped in the
glomerulus when a mild antigen excess
occurs, or when antigen and antibody
molecules are present in approximately
equal numbers in the plasma. Immune
complexes formed when a large antibody
excess exists tend to be large, insoluble and
glomerulonephritis in dogs
Infectious
Canine adenovirus I
Bacterial endocarditis
Brucellosis
Dirofilariosis
Ehrlichiosis
Leishmaniosis
Pyometra
Borelliosis
of endogenous immunoglobulin or com- Chronic bacterial infections (gingivitis,
plement within the glomerulus using vari- pyoderma)
ous immunological techniques is not Rocky Mountain spotted fever
Trypanosomosis
difficult, but identification of exogenous Septicaemia
antigens within glomerular tissue is rarely Helicobacter*
accomplished. Neoplasia
In contrast to the glomerular deposition Inflammatory
of preformed complexes, immune com- Pancreatitis
plexes may also form in situ in the Systemic lupus erythematosus
Other immune-mediated diseases
glomerular capillary wall. This occurs Prostatitis
when circulating antibodies react with Hepatitis
endogenous glomerular antigens or Inflammatory bowel disease
‘planted’ non-glomerular antigens in the Others
glomerular capillary wall. Hyperadrenocorticism and long-term
high-dose corticosteroids*
Autoimmune GN, the condition in Idiopathic
which antibodies are directed against Familial
endogenous glomerular basement mem- Non-immunological hyperfiltration*
Diabetes mellitus*
brane material, has not been documented
*Uncertain or questionable causes
in dogs with naturally occurring GN.
However, non-glomerular antigens may
localise in the glomerular capillary wall as a
result of electrical charge interaction or affinity for glomerular capillary walls, and
biochemical affinity with the glomerular that heartworm-associated immune com-
capillary wall. When antibodies present in plexes can form in situ within the glomeru-
plasma react with an antigen in situ, a lus (Grauer and others 1989). Soluble
smooth, linear pattern of immune com- Dirofilaria immitis antigens contain carbo-
plexes is often produced. For example, hydrate moieties (Weil and others 1985)
studies of dogs with dirofilariosis have and therefore the adherence of these anti-
shown that heartworm antigens have an gens to the glomerular capillary wall may
Immune complex deposition or in situ formation
➞ ➞

➞➞

rapidly removed from the circulation by

➞

phagocytic cells. Conversely, immune

complexes formed when a large antigen Complement
➞ Endothelial damage ➞ Platelet
excess exists do not readily bind comple-
activation
➞ aggregation
➞ ➞
➞ ➞

ment and have a reduced capacity to pro-

➞
Production of
duce immunological injury. vasoactive substances
Production of Coagulation system
Glomerular deposition of preformed proinflammatory (Ang II, TXB, ET-1) activation
➞ ➞

immune complexes usually results in a molecules

➞

lumpy or granular immunofluorescent or

immunocytochemical pattern along capil- Intraglomerular Fibrin production
lary walls. Several infectious and inflam- Production of hypertension
➞

growth factor and

matory diseases have been associated with
➞
➞

glomerular deposition of immune com-

matrix promoting
substances
➞
plexes (Table 1). However, in many cases Proliferative and/or Ang II Angiotensin II
membranous response TXB Thromboxane
the antigen source or underlying disease resulting in proteinuria ET-1 Endothelin-1
process is not identified, and the glomeru-
lar disease is referred to as idiopathic FIG 1. Proposed glomerular pathophysiology subsequent to immune complex deposition
(Cook and Cowgill 1996). Identification or in situ formation

470 JOURNAL OF SMALL ANIMAL PRACTICE • VOL 46 • OCTOBER 2005

Canine glomerular disease 10/6/05 5:46 PM Page 471

FIG 2. Advanced membranoproliferative

glomerulonephritis. The large glomerulus
shows hypercellularity with prominent focal
accumulations of mesangial matrix material
and thickened glomerular capillary walls.
Adhesions to the Bowman’s capsule and
periglomerular fibrosis are also present. The
small glomerulus is irreversibly damaged and
obsolescent. A hyaline cast is present in a
tubule (arrow). Periodic acid-Schiff.
200.
Reprinted with permission (Grauer 1991)

be caused by a carbohydrate-glycoprotein
interaction.
The immune-mediated pathophysiol-
ogy associated with either deposition or
in situ formation of immune complexes
stresses the importance of identification
and correction of any underlying or con-
current disease process.
The glomerulus provides a unique envi-
ronment for injurious immune complexes
to stimulate production of bioactive medi-
ators like proinflammatory cytokines,
vasoactive substances, growth factors,
and extracellular matrix proteins and pro-
teases, which can contribute to the injury
(Johnson 1997) (Fig 1). These substances
may be produced by endogenous glomeru-
lar cells or by recruited platelets, macro-
phages and neutrophils. For example,
activation of the renin-angiotensin-
aldosterone system (RAAS) can have
haemodynamic and non-haemodynamic
effects on the kidneys (Hilgers and Mann
1996). The main haemodynamic effect is
vasoconstriction of the efferent glomerular
arteriole, resulting in intraglomerular
hypertension. This increased hydrostatic
pressure within the glomerular capillaries
helps drive glomerular proteinuria. Angio-
tensin and aldosterone are also proinflam-
matory and can stimulate glomerular cell
proliferation and fibrogenesis.
In addition to the RAAS, several factors,
including activation of the complement
system, platelet aggregation, activation
of the coagulation system and fibrin
deposition, also contribute to glomerular
damage (Vassalli and McCluskey 1964,
Henson 1971, Kincaid-Smith 1972, Clark
and others 1976). Platelet activation and
aggregation occur secondarily to endothe-
lial damage or antigen-antibody inter-
thickening of the glomerular basement
membrane and, if the injury persists,
hyalinisation and sclerosis (Fig 2). In cases
where identification and correction of an
underlying disease process is not possible,
treatment is focused on decreasing this
glomerular response to immune complexes
(for example, angiotensin and platelet
antagonists).ll
Once a glomerulus has been irreversibly
damaged by GN, the entire nephron
becomes non-functional. Fibrosis and scar-
ring of irreversibly damaged nephrons may
give the appearance of interstitial inflam-
mation, and for many years renal intersti-
tial inflammation or ‘chronic interstitial
nephritis’ was thought to be the primary
lesion that caused chronic renal insuffi-
ciency or failure in dogs. As more and
more nephrons become involved, glom-
erular filtration as a whole decreases.
Remaining viable nephrons compensate
for the decrease in nephron numbers with
increased individual glomerular filtration
rates (Fig 3). This ‘hyperfiltration’, cou-
pled with systemic hypertension and high
dietary protein, if present, may contribute
Decreased number of
nephrons
➞
➞
to glomerular hyalinisation and sclerosis
(Brenner and others 1982). Although it
has not been documented in dogs with
naturally occurring GN, hyperfiltration
and proteinuria in remnant nephrons may
result in progressive nephron loss indepen-
dent of the previously discussed immune-
mediated GN.
There is increasing evidence in labora-
tory animals and humans that proteinuria
can cause glomerular and tubular damage,
and result in progressive nephron loss.
Plasma proteins that have crossed the
glomerular capillary wall can accumulate
within the glomerular tuft and stimulate
mesangial cell proliferation and increased
production of mesangial matrix (Jerums
and others 1997). In addition, excessive
amounts of protein in glomerular filtrate
can be toxic to human tubular epithelial
cells and can lead to interstitial inflamma-
tion, fibrosis and cell death (Tang and
others 1999). Proximal tubular cells nor-
mally resorb protein from the glomerular
filtrate by endocytosis. Albumin and other
proteins accumulate in lysosomes and are
then degraded into amino acids. In pro-
➞➞ Systemic hypertension

action (Hayslett 1984). Platelets, in turn,

exacerbate glomerular damage by releasing
vasoactive and inflammatory substances,
and by the facilitation of the coagulation
Renal vasodilatation
Intraglomerular
hypertension
➞ Proteinuria
➞

Glomerular hyperfiltration
cascade. They are also capable of releasing
➞
➞

growth-stimulating factors that promote FIG 3. Proposed

proliferation of vascular endothelial cells pathogenesis of
nephron loss in Glomerular cell proliferation Protein depletion
(Hayslett 1984). The glomerulus responds progressive renal Glomerulosclerosis Weight loss
to this injury by cellular proliferation, disease

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Canine glomerular disease 10/6/05 5:46 PM Page 472

Table 2. Signs associated with different manifestations of glomerular disease

Manifestation Clinical signs Clinicopathological findings

Mild to moderate proteinuria* Lethargy, mild weight loss, Serum albumin (1·5-3·0 mg/dl)
decreased muscle mass
Marked proteinuria Severe muscle wasting Serum albumin (<1·5 mg/dl)
(>3·5 g/day) Weight gain may occur, as a hypercholesterolaemia
result of oedema or ascites
Renal failure Depression, anorexia, nausea, Azotaemia, isosthenuria or
vomiting, weight loss, minimally concentrated urine,
teinuric conditions, excessive lysosomal polyuria-polydipsia hyperphosphataemia,
non-regenerative anaemia
processing can result in swelling and rup- Pulmonary thromboembolism Acute dyspnoea or severe Hypoxaemia, normal or low PCO2,
ture of lysosomes, causing enzymatic dam- panting fibrinogen (>300 mg/dl),
age to the cytoplasm (Olbricht and others antithrombin III (<70 per cent of
normal)
1986). Retinal haemorrhage and/or Acute blindness Systolic blood pressure
Tubular injury may also occur as a con- detachment >180 mmHg
sequence of proteinaceous casts obstruct- *Microalbuminuria may precede proteinuria and therefore be an early diagnostic tool
ing the tubules (Bertani and others 1986). PCO2 Carbon dioxide in the blood

Increased glomerular permeability to

plasma proteins allows tubular cell contact
with transferrin, complement and lipo-
proteins. Transferrin increases iron uptake
by epithelial cells. Once inside the cell the
iron ions catalyse the formation of reactive
oxygen species that can cause peroxidative
injury (Alfrey and others 1989). Comple-
ment proteins can be activated on the
brush border of proximal tubular cells,
resulting in insertion of a membrane attack
complex followed by cytoskeletal damage
and cytolysis (Camussi 1994). Resorbed
lipoproteins can release lipid moieties
that can accumulate into lipid droplets or
be oxidised to toxic radicals (Ong and
Moorhead 1994). All of these processes
can irreversibly damage the proximal
tubule and interstitium and result in
nephron loss.
Exposure to plasma proteins at the api-
cal surface of the tubular cell results in a
basolateral release of growth factors,
fibronectin and monocyte chemoattrac-
tant protein-1 (MCP-1) (Harris and others
1996). This process may also induce exces-
sive tubular expression of transforming
growth factor-
1 (TGF-
1) that can result
in the interstitial inflammation and scar-
ring typical of end-stage kidney disease
(Remuzzi 1995).
Another mediator of tubulointerstitial
damage related to excessive tubular cell
protein resorption is the upregulation
of tubular-derived endothelin-1 (ET-1)
(Benigni and others 1995). Tubular ET-1
formed in response to increasing concentra-
tions of albumin presented to the proximal
tubular epithelium is secreted towards
the basolateral cellular compartment and
accumulates in the interstitium causing
ischaemia. ET-1 also binds to receptors on
interstitial fibroblasts, causing interstitial cel-
lular proliferation and extracellular matrix
production (Benigni and others 1995).
Based on this evidence in other species,
it is possible that proteinuria is not only
a marker of glomerular disease in the dog,
but also a mediator of progressive renal
injury. Attenuating proteinuria should be
a major treatment objective in dogs with
GN.
CLINICAL SIGNS
The clinical signs associated with mild to
moderate urinary protein loss are usually
non-specific and include weight loss and
lethargy. However, if protein loss is severe
(serum albumin concentration of less than
10 to 15 g/l), oedema and/or ascites often
occur (Table 2). If the glomerular disease
process causes loss of greater than three-
quarters of the nephrons, renal failure and
resultant azotaemia, polydipsia, polyuria,
anorexia, nausea and vomiting may occur.
Occasionally, clinical signs associated with
an underlying infectious, inflammatory or
neoplastic disease may be the reason why
owners seek veterinary care. Rarely, dogs
may be presented with acute dyspnoea or
severe panting caused by a pulmonary
thromboembolism.
Persistent proteinuria may lead to clini-
cal signs of the nephrotic syndrome that
is a combination of proteinuria, hypo-
albuminaemia, ascites or oedema, and
hypercholesterolaemia. Classically, a com-
bination of decreased plasma oncotic pres-
sure and hyperaldosterone activity, causing
sodium retention, was thought to be the
cause of ascites and oedema. It has been
hypothesised that intrarenal mechanisms,
independent of aldosterone, may con-
tribute to sodium retention (Brown and
others 1982). The hypercholesterolaemia
associated with the nephrotic syndrome
probably occurs because of a combination
of decreased catabolism of proteins and
lipoproteins, and increased hepatic syn-
thesis of proteins and lipoproteins
(Wheeler and others 1989). This results
in the accumulation of cholesterol-rich
lipoproteins with large molecular weights,
which are not as easily lost through the
damaged capillary wall as the proteins
with smaller molecular weights, such as
albumin.
In addition to these clinical signs, sys-
temic hypertension and hypercoagulability
are frequent complications in dogs with
nephrotic syndrome. Hypertension proba-
bly occurs because of a combination of
activation of the RAAS and decreased renal
production of vasodilators, coupled with
increased responsiveness to normal vaso-
pressor mechanisms. Systemic hyper-
tension has been commonly associated
with immune-mediated GN, glomerulo-
sclerosis and amyloidosis and, in one study,
84 per cent of dogs with glomerular disease
were found to be hypertensive (Cowgill
1991). Retinal changes, including haemor-
rhage, detachment and papilloedema, can
be consequences of systemic hypertension
and, rarely, blindness may be the present-
ing sign in hypertensive dogs. Blood pres-
sure measurement should be included in
evaluating and managing glomerular
disease as it is probable that controlling
systemic hypertension will attenuate the
disease’s progression.
Hypercoagulability and thrombo-
embolism associated with nephrotic

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Canine glomerular disease 10/6/05 5:46 PM Page 473

Positive dipstick result for proteinuria

➞ ➞ ➞ ➞ ➞
Evaluate results in light of urine sediment findings

Confirm positive results with SSA or ERD

syndrome occur secondarily to several

abnormalities in the clotting system. In Confirm proteinuria is persistent
addition to a mild thrombocytosis, a
hypoalbuminaemia-related platelet hyper-
sensitivity has been found to increase Obtain UP/C
platelet adhesion and aggregation

➞
proportionately to the magnitude of
hypoalbuminaemia (Green and others
UP/C=<0·5, UP/C=<0·5 to 2·0, UP/C=>2·0,
1985). Loss of antithrombin III in may be normal, most likely renal most likely
urine also contributes to hypercoagula- transient or early proteinuria, either glomerular
➞

bility (Green and Kabel 1982). Anti- renal proteinuria glomerular or tubular proteinuria

➞
thrombin III works in concert with

➞ ➞
heparin to inhibit serine proteases (clotting Recheck in two
to four weeks Reassess patient’s history,
factors II, IX, X, XI and XII) and normally
PE, complete MDB, ‘antigen
plays a vital role in modulating thrombin hunt’, blood pressure
and fibrin production.

Finally, altered fibrinolysis and increases
in the concentration of clotting factors
with large molecular weights may lead to
a relative increase in clotting factors
compared with regulatory proteins. The
pulmonary arterial system is the most
common location for a thromboembolus
to lodge. Dogs with pulmonary throm-
boembolisms are usually dyspnoeic and
hypoxic, with few pulmonary paren-
chymal radiographic abnormalities. Treat-
ment of pulmonary thromboembolism is
difficult, often expensive and frequently
unrewarding. Therefore, early prophylac-
tic treatment is important.
➞➞ ➞
Abnormalities
➞ No abnormalities
Pursue further diagnostics and Continue to monitor
appropriate treatment proteinuria
Determine the need to treat
versus continued monitoring
and investigation, based on
the magnitude of the
proteinuria and whether or
not it increases over time
FIG 4. Brief algorithm for the diagnosis of proteinuria. SSA Sulfosalicylic acid, ERD Heska’s Early
Renal Damage point-of-care microalbuminuria assay, UP/C Urine protein:creatinine ratio,
PE Physical examination, MDB Minimum database (complete blood count, serum biochemistry
profile and complete urinalysis)

DIAGNOSIS
Detecting and quantifying
proteinuria
Proteinuria is routinely detected by semi-
quantitative methods including the urine
dipstick colorimetric test and the sulfosali-
cylic acid (SSA) turbidometric test. Ideally,
these screening tests are performed concur-
rently as the SSA test has increased sensitiv-
ity for proteinuria and the dipstick method
often lacks specificity, which can result in
false positives (Grauer and others 2004).
Proteinuria detected by these screening
methods has historically been interpreted
in the light of urine specific gravity and the
urine sediment findings. For example, in a
hypersthenuric animal a positive dipstick
result of trace or +1 proteinuria has often
been attributed to urine concentration
rather than abnormal proteinuria. Simi-
larly, a positive dipstick reading for protein-
uria in the presence of haematuria or pyuria
was often attributed to urinary tract haem-
orrhage or inflammation.
In both examples, the traditional inter-
pretation may not be correct. Given the
limits of conventional dipstick sensitivity
(greater than 0·30 g/l), any positive result
for proteinuria, regardless of urine con-
centration, may be abnormal. Likewise,
haematuria and pyuria have an inconsis-
tent effect on urine albumin concentra-
tions; not all dogs with haematuria and
pyuria have albuminuria (Vaden and
others 2002).
One of the hallmarks of glomerular
proteinuria is persistence. Persistent pro-
teinuria was recently defined in a con-
sensus statement commissioned by the
American College of Veterinary Internal
Medicine as three positive urinalyses each
separated by at least two weeks. If the
results of screening tests for proteinuria
are persistently positive, urine protein
excretion should be quantified (Fig 4).
This helps evaluate the severity of renal
lesions and assess response to treatment or
progression of disease.
Although 24-hour collection of urine
and measurement of urine protein excre-
tion in mg/kg/day has been the gold stan-
dard for quantitating proteinuria, such
collections require the use of a metabolism

JOURNAL OF SMALL ANIMAL PRACTICE • VOL 46 • OCTOBER 2005 473

Canine glomerular disease 10/6/05 5:46 PM
cage, or indwelling or repeated urinary
catheterisation, making the procedure
cumbersome and expensive. The UP/C in
spot urine samples from dogs has been
shown to accurately reflect the quantity
of protein excreted in the urine over a
24-hour period (White and others 1984,
Grauer and others 1985, McCaw and
others 1985).
Most studies have shown that normal
urine protein excretion in dogs is less than
10 to 15 mg/kg/day (Barsanti and Finco
1979, DiBartola and others 1980a,
Biewenga and others 1983, White and
others 1984, Center and others 1985,
Grauer and others 1985), and that normal
UP/Cs are less than 0·2 to 0·3.
The initially recommended normal val-
ues for canine UP/Cs of less than 1·0 were
likely to have been conservative and have
recently been lowered. Today ratios of
less than 0·5 are considered normal and
it is likely that the definition of normal
will continue to decrease with time. For
example, even the very low single nephron
proteinuria that occurs secondarily to
intraglomerular hypertension in hyper-
trophied nephrons in chronic renal disease
is abnormal compared with what fre-
quently would be considered normal
whole-body or whole-kidney proteinuria.ll
Whenever possible, it is recommended
that more than one UP/C, separated by at
least 24 hours, be used to establish baseline
proteinuria in individual patients. Renal
proteinuria of either tubular or glomeru-
lar origin is indicated by a ratio greater
than 0·5. A ratio greater than 2·0 is strong
evidence of glomerular disease.
Microalbuminuria
Recently a point-of-care immunoassay for
the detection of low levels of albumin
(microalbuminuria) in the urine of dogs
has become commercially available (ERD-
HealthScreen; Heska). Microalbuminuria
is usually defined as a urine albumin con-
centration of between 0·01 and 0·30 g/l.
These are abnormal concentrations too
small to be routinely detected by standard
dipstick screening tests. It is interesting to
474
Page 474
note that microalbuminuria has been
shown to be an accurate predictor of subse-
quent renal diseases in humans with both
systemic hypertension and diabetes melli-
tus, and it has also been observed in
humans with systemic diseases that are
associated with glomerulopathy (Gosling
1995, Bianchi and others 1999, Pinto-
Sietsma and others 2000, Weir 2002).
The prevalence of microalbuminuria in
dogs has been evaluated in several studies.
In 86 dogs whose owners were not seeking
veterinary care the prevalence of micro-
albuminuria was 19 per cent (Jensen and
others 2001). However, the prevalence was
higher (36 per cent) in 159 dogs whose
owners were seeking veterinary care for
routine health screening, elective proce-
dures and evaluation of health problems at
a veterinary teaching hospital (Jensen and
others 2001). In dogs evaluated at another
veterinary teaching hospital for health
problems, the prevalence of micro-
albuminuria was 30 per cent, although
it was more rigidly defined as albumin
levels of between 2 and 20 mg/dl (Pressler
and others 2001). In 3041 dogs owned
by staff from over 350 veterinary clinics,
the prevalence of microalbuminuria was
25 per cent (Radecki and others 2003).
Although the health status of this study
population of dogs was not reported, a
statistically significant correlation was
found between increasing age and micro-
albuminuria. The increasing prevalence
of glomerular lesions in dogs as they
age tends to corroborate the age-related
prevalence of microalbuminuria (Rouse
and Lewis 1975, Muller-Peddinghaus and
Trautwein 1977).
Based on recent studies, microalbumin-
uria appears to be a good indicator of early
renal disease in dogs, particularly those dis-
eases that involve the glomerulus. Albu-
minuria was evaluated in 36 male dogs
with X-linked hereditary nephropathy.
This is a rapidly progressive glomerular
disease occurring secondarily to a defect in
type IV collagen, which is a structural
component of the glomerular basement
membrane (Lees and others 2002a). In
JOURNAL OF SMALL ANIMAL PRACTICE
these dogs, lesions in the glomerular base-
ment membrane became apparent by
eight weeks of age. Persistent microalbu-
minuria was detected between eight and
23 weeks of age, up to 16 weeks before
the onset of overt proteinuria, which
occurred at 14 to 30 weeks of age. It was
concluded that microalbuminuria was a
reliable early marker of developing
nephropathy.
In 12 healthy dogs that were experi-
mentally infected with D immitis L3 larvae
and longitudinally evaluated, all developed
microalbuminuria. Of all the samples
collected over the 14 to 23 month post-
infection period of study, 82 per cent were
positive for microalbuminuria (Grauer
and others 2002). The onset of microalbu-
minuria corresponded to the onset of
antigenaemia. The magnitude of microal-
buminuria increased over time and it
preceded the development of overt pro-
teinuria, as measured by UP/C. At the
end of the study, there was histological
evidence of glomerular disease by light
microscopy (n=11) or electron microscopy
(n=12).
The prevalence of microalbuminuria in
20 soft-coated wheaten terriers, genetically
at risk of developing protein-losing
enteropathy and nephropathy, was 76 per
cent (Vaden and others 2001). The magni-
tude of microalbuminuria increased over
time and 43 per cent of the dogs with
microalbuminuria eventually developed
abnormal UP/Cs. The observation that
persistent microalbuminuria develops in
dogs with this type of protein-losing
nephropathy at approximately the same
time that mesangial hypercellularity and
segmental glomerular sclerosis occur is of
interest. Concurrent inflammatory bowel
disease may account for microalbuminuria
in some of the dogs that did not progress
to overt proteinuria.
Other conditions have been reported in
dogs with microalbuminuria, including
infectious, inflammatory, neoplastic, meta-
bolic and cardiovascular disease (Pressler
and others 2001, Whittemore and others
2003). Results of an ongoing study of
• VOL 46 • OCTOBER 2005
Canine glomerular disease 10/6/05 5:46 PM
microalbuminuria in dogs with lympho-
sarcoma and osteosarcoma demon-
strated that urine albumin concentrations
were significantly increased in these ani-
mals, even though UP/Cs may not be
increased above the reference range
(Pressler and others 2003). However, urine
albumin concentrations did not con-
sistently decrease with decreased tumour
burden.
The prevalence of microalbuminuria in
dogs admitted to intensive care units is
higher than in other reported patient pop-
ulations and appears to vary with different
classifications of disease (Pressler and
others 2001, Whittemore and others
2003). As has been reported in humans
with acute inflammatory conditions, tran-
sient microalbuminuria occurred in some
of these dogs. A large percentage of ani-
mals that were euthanased or died had
microalbuminuria suggesting that, as in
humans, its presence may be a negative
prognostic indicator.
Further study is necessary to determine
if microalbuminuria is an accurate predic-
tor of overt proteinuria and various addi-
tional types of renal disease in dogs. If
microalbuminuria does predict overt pro-
teinuria and/or renal disease, this early
detection tool should increase the ability to
alter disease progression.
Biopsies indicated by persistent
proteinuria
If persistent proteinuria of renal origin is
identified, a renal biopsy is indicated.
Histopathological evaluation of renal tis-
sue will help to establish a diagnosis (for
example, GN versus amyloidosis or
glomerulosclerosis) and form a prognosis.
However, renal biopsy should be con-
sidered only after less invasive tests (com-
plete blood count, serum biochemistry
profile, urinalysis, quantitation of protein-
uria, and abdominal radiographs or renal
ultrasonography) have been conducted
and an assessment of blood clotting ability
has been performed.
Renal biopsies can be obtained percuta-
neously using the keyhole technique or by
JOURNAL OF SMALL ANIMAL PRACTICE • VOL 46 • OCTOBER 2005
Page 475
laparoscopic (Grauer and others 1983) or TREATMENT
ultrasonographic guidance (Hager and
others 1985). Frequently, the best way to Even though GN is a major cause of
obtain a renal biopsy is by laparotomy chronic renal disease in the dog, its treat-
in which both kidneys can be visualised, ment has received substantially less atten-
postbiopsy haemorrhage can be accurately tion in veterinary medicine than has
assessed and treated, and adequacy of the the treatment of chronic renal failure.
biopsy specimen is assured. A biopsy of As immune complexes usually initiate
the cortical region of the kidney should GN, primary treatment objectives
be obtained to assure an adequate num- include identification and elimination of
ber of glomeruli in the specimen, and causative/associated antigens, and reduc-
to avoid the major vessels and renal tion of the glomerular response to the
nerves in the medullary region. Most immune complexes.
animals will exhibit microscopic haem- Eliminating the source of antigenic
aturia for one to three days postbiopsy, and stimulation is the treatment of choice for
overt haematuria is not uncommon. Severe GN. For example, proteinuria associated
haemorrhage occurs in less than with dirofilariosis in dogs often improves
3 per cent of cases (Jeraj and others 1982) or resolves after successful treatment of the
and is almost always caused by poor parasitic infection. Unfortunately, elimina-
technique. tion of the antigen source is often not
Consultation with the histopathology possible because the antigen source or
laboratory before the biopsy is important underlying disease may not be identified or
to ensure appropriate fixatives are used. may be impossible to eliminate (for exam-
Special stains, thin sections, immuno- ple, neoplasia). In a recent retrospective
fluorescent and/or immunocytochemical study of 106 dogs with GN, 43 per cent
staining, and electron microscopy should had no identifiable concurrent disease or
be used to maximise the information disorder and 19 per cent had neoplasia
gained from the biopsy specimen. (Cook and Cowgill 1996). Infection, poly-
Table 3. Treatment guidelines for glomerulonephritis
Identify and correct any underlying disease processes*
Immunosuppressive treatment†
Haemodynamic/antiproteinuric treatment (angiotensin-converting enzyme inhibitors)*
Antiplatelet-hypercoagulability treatment
Aspirin 0·5 mg/kg every 12 to 24 hours*
Coumadin – titrate dose based on prothrombin time
Supportive care
Dietary: sodium reduced, high quality/low quantity protein, with n-3 fatty acid
supplementation*
Hypertension:
Dietary sodium reduction
Angiotensin-converting enzyme inhibition (eg, enalapril 0·5 mg/kg every 12 to 24 hours)*
Oedema/ascites:
Dietary sodium reduction
Cage rest
Furosemide 1 to 2 mg/kg as needed if necessary. Caution: volume contraction and reduced
glomerular filtration rate may result
Paracentesis for patients with tense ascites and/or respiratory distress
Plasma transfusions†
*Denotes treatments thought most important by the author
†Controversial treatments or treatments with questionable efficacy
475
Canine glomerular disease 10/6/05 5:46 PM
arthritis, hepatitis, hyperadrenocorticism
and immune-mediated anaemia are addi-
tional commonly identified concurrent
medical problems (Cook and Cowgill
1996).
Immunosuppressive agents
Based on results in humans, immunosup-
pressive drugs have been recommended in
dogs with GN. Despite widespread use of
immunosuppressive agents, there has been
only one controlled veterinary clinical trial
assessing the effects of immunosuppressive
therapy. Ciclosporin treatment was found
to be of no benefit in reducing proteinuria
associated with idiopathic GN in dogs
(Vaden and others 1995).
The association between hyperadreno-
corticism or long-term exogenous cortico-
steroid administration and GN and
thromboembolism in the dog, as well as
the lack of consistent therapeutic response
to corticosteroids, raises questions about
the use of corticosteroids in dogs with GN.
In a retrospective study of dogs with natu-
rally occurring GN, treatment with corti-
costeroids appeared to be detrimental,
leading to azotaemia and worsening of
proteinuria (Center and others 1987).
Similarly, prednisone increased the UP/C
from 1·5 to 5·6 in carrier female dogs with
X-linked hereditary nephropathy (Lees
and others 2002b). Consequently, the
routine use of corticosteroids to treat GN
in dogs is not recommended. However,
treatment with corticosteroids would be
indicated if the underlying disease process
was known to be steroid-responsive (for
example, systemic lupus erythematosus).lll
Reducing glomerular response
to immune complexes
Alternatively, treatment may be aimed at
decreasing the glomerular response to the
presence of immune complexes. Increased
urinary excretion of thromboxane has been
detected in dogs with experimentally
induced GN (Longhofer and others 1991,
Grauer and others 1992a). Thromboxane is
thought to arise primarily from platelets
attracted to the glomerulus in immune
476
Page 476
complex disease. Furthermore, platelet sur-
vival is decreased in several types of GN in
human patients, and platelet depletion
attenuates the disease. These findings sug-
gest that platelets and thromboxane have an
important role in the pathogenesis of GN.ll
Thromboxane synthetase inhibitors
decreased proteinuria, glomerular cell pro-
liferation, neutrophil infiltration and fib-
rin deposition in dogs with experimental
GN (Longhofer and others 1991, Grauer
and others 1992a). In the absence of spe-
cific thromboxane synthetase inhibitors,
aspirin may be a valuable substitute
(Grauer and others 1992b). Appropriate
dosage is important if non-specific cyclo-
oxygenase inhibitors such as aspirin are
used to decrease glomerular inflammation
and platelet aggregation. An extremely low
dosage of aspirin (0·5 mg/kg orally, once or
twice daily) may selectively inhibit platelet
cyclo-oxygenase without preventing the
beneficial effects of prostacyclin formation
(vasodilation, inhibition of platelet aggre-
gation).
Low-dose aspirin is easily administered
on an outpatient basis and does not require
extensive monitoring, as does treatment
with coumadin (Bristol-Myers Squibb).
Because fibrin accumulation within the
glomerulus is a frequent and irreversible
consequence of GN, anticoagulant treat-
ment may serve a dual purpose.
Angiotensin-converting enzyme
inhibitors
There is a growing body of evidence indi-
cating that angiotensin-converting enzyme
inhibitors (ACEIs) reduce protein excre-
tion and disease progression in dogs with
GN. In dogs with unilateral nephrectomy
and experimentally induced diabetes
mellitus, ACEI administration reduced
glomerular transcapillary hydraulic pres-
sure and glomerular cell hypertrophy, as
well as proteinuria (Brown and others
1993). In another study, ACEI treatment
of Samoyed dogs with X-linked hereditary
nephritis decreased proteinuria, improved
renal excretory function, decreased glom-
erular basement membrane splitting and
JOURNAL OF SMALL ANIMAL PRACTICE
prolonged survival compared with control
dogs (Grodecki and others 1997).
Recently, a double-blinded, multicen-
tre, prospective clinical trial assessed the
effects of enalapril versus standard care in
dogs with naturally occurring, idiopathic
GN (Grauer and others 2000). Twenty-
nine adult dogs with membranous (n=16)
and membranoproliferative (n=13) GN
were identified. Dogs were randomly
assigned to receive either enalapril (n=16,
0·5 mg/kg orally, once to twice daily) or a
placebo (n=14) for six months (one dog
was treated first with the placebo and then
with enalapril). All dogs were treated with
low-dose aspirin (0·5 to 5 mg/kg orally,
once to twice daily) and fed a prescription
diet (Canine k/d; Hills). After six months
of treatment the change in UP/C from
baseline was different between groups. The
enalapril treatment group had significantly
reduced UP/Cs. When data were adjusted
for changes in glomerular filtration rate
(UP/C
stable serum creatinine [SrCr]) a
similar significant reduction was noted.
The change in systolic blood pressure after
six months of treatment was also signifi-
cantly different between groups. Response
to treatment was categorised as: improve-
ment (>50 per cent reduction in UP/C
with stable SrCr); no progression (<50 per
cent reduction in UP/C with stable SrCr);
and progression (>50 per cent increase in
UP/C and/or SrCr or euthanasia due to
renal failure). The response to treatment
was significantly better in dogs treated
with enalapril compared with those given a
placebo (Grauer and others 2000).
Treatment with ACEIs probably
decreases proteinuria and preserves renal
function associated with glomerular dis-
ease by several mechanisms. In dogs,
administration of lisinopril decreases effer-
ent glomerular arteriolar resistance, which
results in decreased glomerular transcapil-
lary hydraulic pressure and decreased pro-
teinuria (Brown and others 1993). In rats,
administration of enalapril prevents the
loss of glomerular heparan sulfate, which
can occur with glomerular disease (Reddi
and others 1991).
• VOL 46 • OCTOBER 2005
Canine glomerular disease 10/6/05 5:46 PM
Administration of ACEIs is also
thought to attenuate proteinuria in
humans by decreasing the size of glomeru-
lar capillary endothelial cell pores (Wieg-
mann and others 1992). In addition, the
antiproteinuric and renal protective effects
of ACEIs may be associated with improved
lipoprotein metabolism (Keilani and
others 1993). Decreased production of
angiotensin and aldosterone may also
result in decreased renal fibrosis (Epstein
2001). Administration of ACEIs in dogs
slows glomerular mesangial cell growth
and proliferation, which can alter the per-
meability of the glomerular capillary wall
and lead to glomerulosclerosis (Brown and
others 1993).
Supportive therapies
Supportive therapy is important in the
management of dogs with GN and should
be aimed at alleviating systemic hyper-
tension, decreasing oedema/ascites and
reducing the tendency for thromboem-
bolism to occur. If hypertension is not
controlled with dietary sodium reduction
alone, vasodilator therapy should be con-
sidered. ACEIs are recommended as the
first line of defence for hypertensive dogs
with proteinuria.
Cage rest and dietary sodium restriction
should be the primary treatment consider-
ations for animals with oedema and/or
ascites. Paracentesis and diuretics should
be reserved for those dogs and cats with
respiratory distress and abdominal dis-
comfort. Overzealous use of diuretics
may cause dehydration and acute renal
decompensation. Plasma transfusions will
provide only temporary benefit.
In the past, dietary protein supple-
mentation has been recommended to off-
set the effects of proteinuria, and reduce
oedema and ascites. However, recent stud-
ies involving proteinuric heterozygous
female dogs with X-linked nephropathy
suggest that reduced dietary protein results
in reduced proteinuria (Burkholder and
others 2004). N-3 fatty acid supplementa-
tion may also be beneficial. In dogs with
surgically reduced remnant kidneys,
JOURNAL OF SMALL ANIMAL PRACTICE • VOL 46 • OCTOBER 2005
Page 477
dietary supplementation with fish oil
reduced proteinuria, intraglomerular pres-
sures and glomerular lesions, and main-
tained the glomerular filtration rate
(Brown and others 1998).
PROGNOSIS
The prognosis for dogs with GN is variable
and is best made based on a combination
of the severity of dysfunction (the mag-
nitude of proteinuria and presence or
absence of azotaemia), the response to
therapy and the assessment of renal
histology.
Clinical experience suggests the disease
is progressive in many cases. Well con-
trolled prospective clinical trials evaluating
the efficacy of additional treatment regi-
mens, such as aldosterone antagonists
and angiotensin receptor blockers, will
undoubtedly provide valuable information
and increase vets’ ability to treat this
disease.
A major factor confounding the inter-
pretation of studies designed to assess the
efficacy of GN treatments is the variable
biological behaviour of different types of
GN. In humans, for example, proliferative
and membranoproliferative GN have a
poor prognosis when compared with
membranous GN (Bohle and others
1992). Until results of such trials become
available, ACEIs show the most promise
for the treatment of canine GN when an
underlying disease process cannot be
identified and corrected.
References
ALFREY, A. C., FROMENT, D. H. & HAMMOND, W. S. (1989)
Role of iron in tubulointerstitial injury in nephrotoxic
serum nephritis. Kidney International 36, 753-759
BARSANTI, J. A. & FINCO, D. R. (1979) Protein concentra-
tion in urine of normal dogs. American Journal of
Veterinary Research 40, 1583-1588
BENIGNI, A., ZOJA, C. & REMUZZI, G. (1995) Biology of dis-
ease: the renal toxicity of sustained glomerular pro-
tein traffic. Laboratory Investigation 73, 461-468
BERTANI, T., CUTILLO, F., ZOJA, C., BROGGINI, M. & REMUZZI,
G. (1986) Tubulointerstitial lesions mediate renal
damage in adriamycin glomerulopathy. Kidney Inter-
national 30, 488-496
BIANCHI, S., BIGAZZI, R. & CAMPESE, V. M. (1999) Micro-
albuminuria in essential hypertension: significance,
pathophysiology and therapeutic implications.
American Journal of Kidney Disease 6, 973-995
BIEWENGA, W. I., GRUYS, E. & HENDRIKS, H. I. (1983) Uri-
nary protein loss in the dog: nephrological study of
29 dogs without signs of renal disease. Research
in Veterinary Science 33, 366-374
BOHLE, A., WEHRMANN, M., BOGENSHUTZ, O., BATZ, C., VOGL,
W., SCHMITT, H., MULLER, C. A. & MULLER, G. A. (1992)
The long-term prognosis of the primary glomeru-
lonephritides. A morphological and clinical analysis
of 1747 cases. Pathology, Research and Practice
188, 908-924
BRENNER, B. M., MEYER, T. W. & HOSTETTER, T. H. (1982)
Dietary protein intake and the progressive nature of
kidney disease: the role of hemodynamically medi-
ated glomerular injury in the pathogenesis of pro-
gressive glomerular sclerosis in aging, renal
ablation, and intrinsic renal disease. New England
Journal of Medicine 307, 652-659
BROWN, E. A., MARKANDU, N. D., ROULSTON, I. E., JONES,
B. E., SQUIRES, M. & MACGREGOR, G. A. (1982) Is the
renin-angiotensin-aldosterone system involved in
the sodium retention in the nephrotic syndrome?
Nephron 32, 102-107
BROWN, S. A., BROWN, C. A., CROWELL, W. A., BARSANTI,
J. A., ALLEN, T., COWELL, C. & FINCO, D. R. (1998) Ben-
eficial effects of chronic administration of dietary
n-3 polyunsaturated fatty acids in dogs with renal
insufficiency. Journal of Laboratory Clinical Medicine
131, 447-455
BROWN, S. A., WALTON, C. L., CRAWFORD, P. & BAKRIS, G. L.
(1993) Long-term effects of antihypertensive regi-
mens on renal hemodynamics and proteinuria.
Kidney International 43, 1210-1218
BURKHOLDER, W. J., LEES, G. E., LEBLANC, A. K., SLATER,
M. R., BAUER, J. E., KASHTAN, C. E., MCCRACKEN, B. A.
& HANNAH, S. S. (2004) Diet modulates proteinuria in
heterozygous female dogs with X-linked hereditary
nephropathy. Journal of Veterinary Internal Medicine
18, 165-175
CAMUSSI, G. (1994) Alternative pathway activation of
complement by cultured human proximal tubular
epithelial cells. Kidney International 45, 451-460
CENTER, S. A., SMITH, C. A., WILKINSON, E., ERB, H. N. &
LEWIS, R. M. (1987) Clinicopathologic, renal immuno-
fluorescent, and light microscopic features of GN
in the dog: 41 cases (1975-1985). Journal of the
American Veterinary Medical Association 190, 81-90
CENTER, S. A., WILKINSON, E., SMITH, C. A., ERB, H. N. &
LEWIS, R. M. (1985) 24-hour urine protein/creatinine
ratio in dogs with protein losing nephropathies. Jour-
nal of the American Veterinary Medical Association
187, 820-824
CLARK, W. F., FRIESEN, M., LINTON, A. L. & LINDSAY, R. M.
(1976) The platelet as a mediator of tissue damage
in immune complex GN. Clinical Nephrology 6,
287-289
COOK, A. K. & COWGILL, L. D. (1996) Clinical and patho-
logic features of protein-losing glomerular disease in
the dog: a review of 137 cases. Journal of the Amer-
ican Animal Hospital Association 32, 313-322
COWGILL, L. D. (1991) Clinical significance, diagnosis
and management of systemic hypertension in dogs
and cats. In: Managing Renal Disease and Hyper-
tension. Hill’s Pet Products and Harmon Smith.
pp 35-44
DIBARTOLA, S. P., CHEW, D. J. & JACOBS, G. (1980a) Quan-
titative urinalysis including 24-hour protein excretion
in the dog. Journal of the American Animal Hospital
Association 16, 537-546
DIBARTOLA, S. P., SPAULDING, G. L., CHEW, D. J. & LEWIS,
R. M. (1980b) Urinary protein excretion and
immunopathologic findings in dogs with glomerular
disease. Journal of the American Veterinary Medical
Association 177, 73-77
EPSTEIN, M. (2001) Aldosterone as a mediator of
progressive renal disease: pathogenic and clinical
477
Canine glomerular disease 10/6/05 5:46 PM
implications. American Journal of Kidney Disease
37, 677-688
GOSLING, P. (1995) Microalbuminuria: a marker of sys-
temic disease. British Journal of Hospital Medicine
54, 285-290
GRAUER, G. F. (1991) Glomerular disease and protein-
uria. In: Small Animal Medicine. Ed D. G. Allen.
Lippincott Williams & Wilkins, Philadelphia. pp 615-
623
GRAUER, G. F., CULHAM, C. A., DUBIELZIG, R. R., LONGHOFER,
S. L. & GRIEVE, R. B. (1989) Experimental Dirofilaria
immitis-associated GN induced in part by in situ for-
mation of immune complexes in the glomerular cap-
illary wall. Journal of Parasitology 75, 585-593
GRAUER, G. F., FRISBIE, D. D., LONGHOFER, S. L. & COOLEY,
A. J. (1992a) Effects of a thromboxane synthetase
inhibitor on established immune complex GN in
dogs. American Journal of Veterinary Research 53,
808-813
GRAUER, G. F., GRECO, D. S., GETZY, D. M., COWGILL, L. D.,
VADEN, S. L., CHEW, D. J., POLZIN, D. J. & BARSANTI,
J. A. (2000) Effects of enalapril vs placebo as a
treatment for canine idiopathic glomerulonephritis.
Journal of Veterinary Internal Medicine 14, 526-533
GRAUER, G. F., MOORE, L. E., SMITH, A. R. & JENSEN, W. A.
(2004) Comparison of conventional urine protein
test strips and a quantitative ELISA for the detection
of canine and feline albuminuria. Journal of Veteri-
nary Internal Medicine 18, 418-419
GRAUER, G. F., OBERHAUSER, E. B. & BASARABA, R. J. (2002)
Development of microalbuminuria in dogs with
heartworm disease. Journal of Veterinary Internal
Medicine 16, 352
GRAUER, G. F., ROSE, B. J., TOOLAN, L., THRALL, M. A. &
COLGAR, S. P. (1992b) Comparison of the effects of
low-dose aspirin and specific thromboxane syn-
thetase inhibition on whole blood platelet aggrega-
tion ATP secretion in healthy dogs. American Journal
of Veterinary Research 53, 1631-1635
GRAUER, G. F., THOMAS, C. B. & EICKER, S. W. (1985) Esti-
mation of quantitative proteinuria in the dog, using
the urine protein-to-creatinine ratio from a random,
voided sample. American Journal of Veterinary
Research 46, 2116-2119
GRAUER, G. F., TWEDT, D. C. & MERO, K. N. (1983) Evalu-
ation of laparoscopy for obtaining renal biopsy spec-
imens from dogs and cats. Journal of the American
Veterinary Medical Association 183, 677-679
GREEN, R. A. & KABEL, A. L. (1982) Hypercoagulable
state in three dogs with nephrotic syndrome: role of
acquired antithrombin III deficiency. Journal of the
American Veterinary Medical Association 181, 914-
917
GREEN, R. A., RUSSO, E. A., GREENE, R. T. & KABEL, A. L.
(1985) Hypoalbuminemia-related platelet hypersen-
sitivity in two dogs with nephrotic syndrome. Jour-
nal of the American Veterinary Medical Association
186, 485-488
GRODECKI, K. M., GAINS, M. J., BAUMAL, R., OSMOND, D. H.,
COTTER, B., VALLI, V. E. & JACOBS, R. M. (1997) Treat-
ment of X-linked hereditary nephritis in Samoyed
dogs with angiotensin converting enzyme (ACE)
inhibitor. Journal of Comparative Pathology 117,
209-225
HAGER, D. A., NYLAND, T. G. & FISHER, P. (1985) Ultra-
sound-guided biopsy of the canine liver, kidney and
prostate. Veterinary Radiology 26, 82-88
HARRIS, K. P., BURTON, C. & WALLS, J. (1996) Proteinuria:
a mediator of interstitial fibrosis? Contributions to
Nephrology 118, 173-179
HAYSLETT, I. P. (1984) Role of platelets in glomerulo-
nephritis. New England Journal of Medicine 310,
1457-1458
HENSON, P. M. (1971) Interaction of cells with
immune complexes: adherence, release of con-
stituents, and tissue injury. Journal of Experimental
© British Small Animal Veterinary Association. All rights reserved
Page 478
Medicine 134, 114s-135s
HILGERS, K. F. & MANN, J. F. E. (1996) Role of
angiotensin II in glomerular injury: lessons from
experimental and clinical studies. Kidney and Blood
Pressure Research 19, 254-262
JAENKE, R. S. & ALLEN, T. A. (1986) Membranous
nephropathy in the dog. Veterinary Pathology 23,
718-733
JENSEN, W. A., GRAUER, G. F., ANDREWS, J. & SIMPSON, D.
(2001) Prevalence of microalbuminuria in dogs. Jour-
nal of Veterinary Internal Medicine 15, 300
JERAJ, K., OSBORNE, C. A. & STEVENS, J. B. (1982) Evalu-
ation of renal biopsy in 197 dogs and cats. Journal
of the American Veterinary Medical Association 181,
367-369
JERUMS, G., PANAGIOTOPOULOS, S., TSALAMANDRIS, C., ALLEN,
T. J., GILBERT, R. E. & COMPER, W. D. (1997) Why is
proteinuria such an important risk factor for pro-
gression in clinical trials? Kidney International 52,
S87-S92
JOHNSON, R. J. (1997) Cytokines, growth factors and
renal injury: where do we go now? Kidney Interna-
tional 52, S2-S6
KEILANI, T., SCHLUETER, W. A., LEVIN, M. L. & BATLLE, D. C.
(1993) Improvement of lipid abnormalities associ-
ated with proteinuria using fosinopril, an angiotensin-
converting enzyme inhibitor. Annals of Internal
Medicine 118, 246-254
KINCAID-SMITH, P. (1972) Coagulation and renal disease.
Kidney International 2, 183-190
LEES, G. E., JENSEN, W. A., SIMPSON, D. F. & KASHTAN,
C. E. (2002a) Persistent albuminuria precedes on-
set of overt proteinuria in male dogs with X-linked
hereditary nephropathy. Journal of Veterinary
Internal Medicine 16, 353
LEES, G. E., WILLARD, M. D. & DZIEZUC, J. (2002b)
Glomerular proteinuria is rapidly but reversibly
increased by short-term prednisone administration
in heterozygous (carrier) female dogs with X-linked
hereditary nephropathy. Journal of Veterinary Inter-
nal Medicine 16, 352
LONGHOFER, S. L., FRISBIE, D. D., JOHNSON, H. C., CULHAM,
C. A., COOLEY, A. J., SCHULTZ, K. T. & GRAUER, G. F.
(1991) Effects of a thromboxane synthetase
inhibitor on immune complex GN. American Journal
of Veterinary Research 52, 480-487
MCCAW, D. L., KNAPP, D. W. & HEWET, J. E. (1985) Effect
of collection and exercise restriction on the predic-
tion of urine protein excretion, using urine pro-
tein/creatinine ratio in dogs. American Journal of
Veterinary Research 46, 1665-1669
MACDOUGALL, D. F., COOK, T., STEWARD, A. P. & CATTELL, V.
(1986) Canine chronic renal disease: prevalence
and types of GN in the dog. Kidney International 29,
1144-1151
MATHEWS, K. A., HOLMBERG, D. L. & MILLER, C. W. (2000)
Kidney transplantation in dogs with naturally occur-
ring end-stage renal disease. Journal of the Ameri-
can Animal Hospital Association 36, 294-301
MULLER-PEDDINGHAUS, R. & TRAUTWEIN, G. (1977) Sponta-
neous GN in dogs 1. Classification and immuno-
pathology. Veterinary Pathology 14, 1-13
OLBRICHT, C. J., CANNON, J. K., GARG, L. C. & TISHER, C. C.
(1986) Activities of cathepsin B and L in isolated
nephron segments from proteinuric and nonprotein-
uric rats. American Journal of Physiology 250,
F1055-F1062
ONG, A. & MOORHEAD, J. (1994) Tubular lipidosis: epiphe-
nomenon or pathogenetic lesion in human renal dis-
ease. Kidney International 45, 753-762
PINTO-SIETSMA, S. J., JANSSEN, W. M. T., HILLEGE, H. L.,
NAVIS, G., DE ZEEUW, D. & DE JONG, P. E. (2000) Urinary
albumin excretion is associated with renal functional
abnormalities in a nondiabetic population. Journal
of the American Society of Nephrology 10, 1882-
1888
PRESSLER, B. M., PROULX, D. A. & WILLIAMS, L. E. (2003)
Urine albumin concentration is increased in dogs
with lymphoma or osteosarcoma. Journal of Veteri-
nary Internal Medicine 17, 404
PRESSLER, B. M., VADEN, S. L. & JENSEN, W. A. (2001)
Prevalence of microalbuminuria in dogs evaluated at
a referral veterinary hospital. Journal of Veterinary
Internal Medicine 15, 300
RADECKI, S., DONNELLY, R., JENSEN, W. A. & STINCHCOMB,
D. T. (2003) Effect of age and breed on the
prevalence of microalbuminuria in dogs. Journal of
Veterinary Internal Medicine 17, 406
REDDI, A. S., RAMAMURTHI, R., MILLER, M., DHUPER, S. &
LASKER, N. (1991) Enalapril improves albuminuria by
preventing glomerular loss of heparan sulfate in
diabetic rats. Biochemical Medicine and Metabolic
Biology 45, 119-131
REMUZZI, G. (1995) Abnormal protein traffic through the
glomerular barrier induces proximal tubular cell dys-
function and causes renal injury. Current Opinion in
Nephrology and Hypertension 4, 339-342
ROUSE, B. T. & LEWIS, R. J. (1975) Canine glomerulo-
nephritis: prevalence in dogs submitted at random
for euthanasia. Canadian Journal of Comparative
Medicine 39, 365-370
TANG, S., SHEERIN, N. S., ZHOU, W., BROWN, Z. & SACKS,
S. H. (1999) Apical proteins stimulate complement
synthesis by cultured human proximal tubular
epithelial cells. Journal of the American Society of
Nephrology 10, 69-76
VADEN, S. L., BREITSCHWERDT, E. B., ARMSTRONG, P. J.,
CORREA, M. T., BROWN, C., POLZIN, D. J., BRACE, J. J.,
DIBARTOLA, S. P., BARSANTI, J. A., CROWELL, W., et al
(1995) The effects of cyclosporin versus standard
care in dogs with naturally occurring glomeru-
lonephritis. Journal of Veterinary Internal Medicine
9, 259-266
VADEN, S. L., JENSEN, W. A., LONGHOFER, S. L. & SIMPSON,
D. F. (2001) Longitudinal study of microalbuminuria
in soft-coated wheaten terriers. Journal of Veterinary
Internal Medicine 15, 300
VADEN, S. L., PRESSLER, B. M. & LAPPIN, M. R. (2002)
Urinary tract inflammation has a variable effect on
urine albumin concentrations. Journal of Veterinary
Internal Medicine 16, 378
VASSALLI, P. & MCCLUSKEY, R. T. (1964) The pathogenetic
role of fibrin deposition in immunologically induced
GN. Annals of the New York Academy of Sciences
116, 1052-1062
WEIL, G. I., MALANE, M. S. & POWERS, K. G. (1985)
Monoclonal antibodies to parasite antigens found in
the serum of Dirofilaria immitis-infected dogs. Jour-
nal of Immunology 134, 1185-1191
WEIR, M. R. (2002) Microalbuminuria as a cardio-
vascular and renal risk factor in patients with type
2 diabetes. American Journal of Clinical Procedures
3, 7-14
WHEELER, D. C., VARGHESE, Z. & MOORHEAD, I. F. (1989)
Hyperlipidemia in nephrotic syndrome. American
Journal of Nephrology 9, S78-S84
WHITE, J. V., OLIVIER, B. & REIMAN, K. (1984) Use of pro-
tein-to-creatinine ratio in a single urine specimen for
quantitative estimation of canine proteinuria. Jour-
nal of the American Veterinary Medical Association
185, 882-885
WHITTEMORE, J. C., JENSEN, W. A., PRAUSE, L. & RADECKI,
S. (2003) Comparison of microalbuminuria, urine
dipstick and urine protein creatinine ratio results
in clinically ill dogs. Journal of Veterinary Internal
Medicine 17, 437
WIEGMANN, T. B., HERRON, K. G., CHONKO, A. M.,
MACDOUGALL, M. L. & MOORE, W. V. (1992) Effects
of angiotensin-converting enzyme inhibition on
renal function and albuminuria in normotensive
type I diabetic patients. Diabetes 41, 62-67