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J Vet Intern Med 2008;22:450455

R e n a l Am y l o i d o s i s i n C a t t l e w i t h In a m m a t o r y D i s e a s e s
O.M. Elitok, B. Elitok, and O. Unver
Background: The association of inammatory diseases such as traumatic reticuloperitonitis (TRP), mastitis, metritis, and
pododermatitis with renal amyloidosis in cattle is poorly described.
Hypothesis: Serum amyloid A (SAA) levels are elevated during inammatory diseases, and renal amyloidosis is formed as a
complication.
Animals: This study was conducted with 82 crossbred cattle with mastitis (n 5 18 cows), metritis (n 5 11 cows), TRP (n 5
30 cows), and pododermatitis (n 5 23 : 15 cows and 8 beef cattle). Ten clinically healthy cows served as controls.
Methods: Hematological, urinary, and blood parameters, including SAA, were measured by an automated procedure provided with trade kits. Determination of amyloidal structures was made by histopathological examination of renal biopsy
specimens.
Results: At the end of this trial, amyloidosis was detected in 5 cows displaying typical nephrotic syndrome, with hypoproteinemia and proteinuria in combination with polyuria and weight loss. Furthermore, it was observed that cows with renal
amyloidosis had signicantly higher (P o .01) total leukocyte counts, serum and urine enzyme activities, and urea and creatinine concentrations, with lower serum total protein concentrations, when compared with animals without renal amyloidosis.
Conclusions and Clinical Importance: The incidence of AA amyloidosis in cattle in this study suggests that cattle with
mastitis, metritis, and pododermatitis have a high prevalence of systemic amyloidosis in response to inammation.
Key words: Bovine; Inammation; Renal amyloidosis; Serum amyloid A.

myloidosis is dened as the presence of amyloid, a


brillar proteinaceous material that consists of a
main protein and common elements, in tissues.1,2 With
reference to amyloid protein type, AL amyloid (amyloid
light chain) is associated with immunocyte dyscrasias,
whereas AA amyloid is associated with reactive amyloidosis and chronic inammatory processes.3 Reactive
amyloidosis (AA amyloidosis) is a systemic disorder with
a blood precursor termed acute-phase serum amyloid A
(SAA).4 When the concentration of this molecule is increased, typically as a result of chronic inammation,
certain isoforms of SAA are partially cleaved into fragments that have an increased propensity to form brillar
aggregates (amyloid) that are deposited systemically,
mainly in the kidney, liver, and spleen.5
AA amyloidosis in cattle is the most common form
and is usually associated with chronic inammatory diseases of the mammary gland, joints, and respiratory
system.610 Bacterial infections usually lead to a strong
systemic acute-phase response (APR)11; because of the
strong reaction of mononuclear/phagocytic system cells
to viral infections, APR is generally milder in viral
infections.1215 In this study, mastitis, metritis, pododermatitis, and traumatic reticuloperitonitis (TRP) were of
bacterial origin. Therefore, our objectives were to deter-

From the Food Hygiene and Control Division, Agriculture


Researching Institute, Afyonkarahisar, Turkey (OM Elitok); Department of Internal Medicine, Faculty of Veterinary Medicine,
Afyonkarahisar Kocatepe University, Afyonkarahisar, Turkey (B
Elitok); and Department of Pathology, Faculty of Veterinary Medicine, Dicle University, Diyarbakir, Turkey (Unver).
Corresponding author: Dr Bulent Elitok, Department of Internal
Medicine, Faculty of Veterinary Medicine, Afyon Kocatepe University,
03200-Afyonkarahisar, Turkey; e-mail: elitok1969@hotmail.com.

Submitted May 2, 2007; Revised October 5, 2007; Accepted


January 8, 2008.
Copyright r 2008 by the American College of Veterinary Internal
Medicine
10.1111/j.1939-1676.2008.0059.x

mine the occurrence of renal amyloidosis in kidney


biopsies taken from cattle with mastitis, metritis, pododermatitis, or TRP and to evaluate the clinical and
pathologic features of these lesions.

Material and Methods


Animals and Clinical Variables
This study was conducted on 82 crossbred cattle with mastitis
(n 5 18 cows), metritis (n 5 11 cows), TRP (n 5 30 cows), and
pododermatitis (n 5 23 : 15 cows and 8 beef cattle). Ten clinically
healthy cows served as controls. According to their owners, the animals in the present study had shown signs of the diseases for at least
12 days. It was determined that the mean illness period was 420
days. Thus, the animals in the present study were assigned to chronic inammatory periods according to their medical history and
results of laboratory tests. Clinical variables recorded for all animals included rectal temperature by an electronic thermometer,
heart and respiratory rates for 1 minute, and the number of rumen
contractions by auscultation for 5 minutes with a stethoscope.
Weight loss was determined according to appearance of animals
and measurement of body weight, whereas polyuria and polydipsia
were dened according to the owners calls and our observations
during the study period. The presence of ascites in cattle was determined by physical examination (ie, palpation of an abdominal site
and auscultation of the other site of the abdomen). In addition,
mastitis was detected by the California mastitis test of milk samples
and rectal examination for metritis along with monitoring for assessment of systemic and local clinical signs. All cows in this study
were in their 2nd or 3rd lactation.

Blood Sampling and Hematologic and Blood Serum


Analysis
Blood samples for CBC and serum were taken from the jugular
veins before kidney biopsy. Hematologic parameters were determined by an automated procedure,a with differential white cell
counts calculated from blood smears. Additionally, the blood samples were allowed to clot at 37 1C, and the serum samples
were extracted and stored at 20 1C until the analyses were performed. Serum samples were analyzed for glucose (GLU), urea,
creatinine, and total protein (TP) concentrations, and aspartate

Renal Amyloidosis in Cattle

451

Results

aminotransferase (AST), g-glutamyl transferase (GGT), and alkaline phosphatase (ALP) activities were measured by standard
methods with commercial kits supplied by Roche Diagnosticsb in
the Roche/Hitachi 917 Clinical Chemistry Analyzer. SAA concentrations were measured by an enzyme-linked immunosorbent assay
(ELISA) with a Multispecies SAA ELISA kit according to directions supplied by the manufacturer.c

Clinical Variables
Common clinical ndings were anorexia, polyuria
(16%), polydipsia (20%), diarrhea (13%), and weight
loss (100%) (Table 1). The mean baseline temperatures
for all study groups were signicantly higher compared
with the control group (P o .01). Although baseline respiration and heart rate for the 4 study groups and control
group were not different (P 4 .1), animals with mastitis,
TRP, metritis, and pododermatitis had signicantly
decreased rumen motility compared with the control
group (P o .01).

Urinary Examinations
Sterile urine samples were collected via a urinary catheter and
used immediately for analytical tests. Urine samples were analyzed
for GLU, urea, creatinine, and TP concentrations, and AST, GGT,
ALP activities were measured by standard methods with commercial kits supplied from Roche Diagnostics in the Roche/Hitachi 917
Clinical Chemistry Analyzer. Additionally, urinary sediment and
strip testd measurements were evaluated.

Hematological Findings

Histopathology

Striking hematological ndings were leukocytosis


and lymphopenia (Table 2). The higher total leukocyte
count and lymphocyte rate were detected in mastitis
and TRP groups (P o .01) when compared with other
groups, whereas the number of neutrophils was
lower. Although the PCV values for the study groups
were signicantly lower (P o .01) than those of the control group, these values remained within reference
ranges.

Before the quantitative examinations were carried out, all control


specimens were histologically examined by a pathologist and were
found to be normal renal tissue. A total of 92 renal biopsy specimens
(including control group animals) were collected via percutaneous
kidney biopsy with a 14G tru-cut biopsy needle without ultrasound
guidance. To assess the immediate effects of percutaneous kidney
biopsy, 8 cows were examined clinically and in terms of laboratory
ndings daily for 7 days. No life-threatening complications or clinically or laboratory detectable abnormalities were observed, and all
cattle survived after kidney biopsy at the end of 7 days.
Biopsy specimens from kidneys were embedded in parafn; sections were cut precisely at 4 mm and stained with hematoxylin and
eosin. In addition, Congo red staining was carried out and examined
by ordinary and polarized light microscopy.

Blood Serum Variables


The highest values for creatinine, urea, and serum
enzymes were detected in mastitis and TRP groups,
whereas mean TP concentration was signicantly
lower (P o .01) in those groups compared with the
other groups and the controls (Table 3). Serum urea
and creatinine concentrations in collaboration with AST,
GGT, and ALP enzyme activities gave signicantly
higher rates (P o .01) during the trial, and these values
were above the reference range. However, serum TP and

Statistical Analysis
Statistical analysis was performed using the Statistical Package
for the Social Sciences (SPSS) v. 11.0 for Windows, and data are
listed as the meanSE. For statistical comparisons, Duncan tests
were performed and P values  0.01 were considered statistically
signicant.

Table 1. Clinical variables for the animals with TRP, mastitis, metritis, and pododermatitis and the cattle with renal
amyloidosis.
X  SD
Parameters
Temperature (C1)
Pulsation (minutes)
Respiration (minutes)
Rumen contractions (5 minutes)
Subcutaneous edema
Weakness
Inappetence
Polyuria
Polydypsia
Diarrhea
Dehydration
Ascites
Dyspnea

Control,
n 5 10

TRP,
n 5 30

Mastitis,
n 5 18

Metritis,
n 5 11

Pododermatitis,
n 5 23

Cattle with Renal


Amyloidosis, n 5 5

37.4  0.2b
66  2e
16  2f
9  3a
(
)
(
)
(
)
(
)
(
)
(
)
(
)
(
)
(
)

38.6  0.1a
68  4d
20  4e
5  2b
(
)
(11 ), n 5 30
(11 ), n 5 30
(11 ), n 5 5
(11 ), n 5 6
(1
), n 5 4
(1
), n 5 5
(
)
(1
), n 5 24

38.4  0.4a
71  6bc
23  3c
6  2b
(
)
(11 ), n 5 16
(11 ), n 5 18
(11 ), n 5 5
(11 ), n 5 5
(1
), n 5 4
(1
), n 5 5
(
)
(1
), n 5 6

38.1  0.2a
72  4b
25  2b
5  1b
(
)
(11 ), n 5 11
(11 ), n 5 11
(11 ), n 5 1
(11 ), n 5 3
(1
), n 5 3
(1
), n 5 3
(
)
(1
), n 5 5

38.3  0.1a
70  3c
21  3d
6  2b
(
)
(11 ), n 5 23
(11 ), n 5 23
(11 ), n 5 1
(11 ), n 5 1
(1
), n 5 1
(1
), n 5 2
(
)
(1
), n 5 12

38.4  0.0a
74  4a
26  2a
4  1c
(
)
(11 ), n 5 5
(111), n 5 5
(111), n 5 5
(111), n 5 5
(1
), n 5 5
(11 ), n 5 5
(
)
(1
), n 5 5

The superscript upper key letters were statically signicant (P o .01).


(
), absent; (1
), mild; (11 ), moderate; (111), severe.
TRP, traumatic reticuloperitonitis.

612
510
2446
1012
2040
4060
410
02
01

Reference Range
7.2  1.0b
7.3  1.2e
32.2  2.4b
8.2  0.4a
32  3a
60  2c
6  3a
2  1a
00

Control, n 5 10
4.8  1.2d
9.6  1.4c
30.4  3.2c
6.6  0.2b
20  4d
78  8a
2  0b
0  0b
00

TRP, n 5 30
4.4  1.1e
10.2  1.2b
30.6  2.0c
6.6  0.6b
28  2b
72  1b
0  0c
0  0b
00

Mastitis, n 5 18
5.2  1.0c
9.1  1.6b
30.8  2.6c
6.8  0.2b
26  2bc
73  2b
1  0c
0  0b
00

Metritis, n 5 11
5.1  1.4c
9.0  1.0d
30.2  1.8c
6.8  0.0b
24  4c
73  1b
3  0b
0  0b
00

Pododermatitis, n 5 23
8.0  1.2a
14.3  1.1a
48.2  1.8a
14.2  0.2b
20  3c
78  1b
1  0c
0  0b
00

Cattle with Renal Amyloidosis, n 5 5

88.40176.8
6775
3036
2030
78132
1319
0488
Variable
2.57.5

Creatinine (mmol/L)
TP (g/L)
AB (g/L)
Urea (mmol/L)
AST (U/L)
GGT (U/L)
ALP (U/L)
SAA (mg/mL)
Glucose (mmol/L)

96.4  15.6
70  1.6a
32.3  1.4a
8.5  0.8e
88.2  12.2d
17.1  0.4d
236.6  22.3e
17.2  1.3c
3.1  0.4a

Control, n 5 10
368.41  16.1
58.3  2.4c
22.4  1.3d
16.8  1.4b
184.3  21.6b
43.3  5.5b
681.3  34.6b
68.4  1.6b
1.9  0.2b

TRP, n 5 30
382.41  12.3
54.1  1.6d
19.4  1.6e
14.6.4  1.1c
188.4  18.5b
44.1  3.4b
677.7  31.2b
68.3  1.7b
2.0  0.0b

Mastitis, n 5 18

353.28  21.4
63.4  3.8b
25.3  1.8c
11.2  1.8d
156.2  14.8c
38.1  3.6c
644.6  45.2c
66.4  2.0b
2.0  0.0b

Metritis, n 5 11

355.41  18.2
64.2  1.1b
29.3  2.1b
11.4  1.3d
152.8  17.2c
36.2  2.4c
629.4  28.6d
66.2  1.8b
1.9  0.3b

Pododermatitis, n 5 23

856.33  48.4a
34.3  1.8e
18.9  0.7f
41.4  2.7a
356.4  35.8a
104.3  4.6a
985.6  64.3a
79.4  2.0a
1.6  0.2c

Cattle with Renal Amyloidosis, n 5 5

The superscript letters were statically signicant (P o .01).


TRP, traumatic reticuloperitonitis; TP, total protein; AST, aspartate aminotransferase; GGT, g-glutamyl transferase; ALP, alkaline phosphatase; SAA, serum amyloid A.

Reference Range

Parameters

X  SD

Table 3. Metabolic prole for the animals with TRP, mastitis, metritis, and pododermatitis and the cattle with renal amyloidosis.

The superscript letters were statically signicant (P o .01).


TRP, traumatic reticuloperitonitis.

Erythrocyte (106/mm3)
Total leukocyte (103/mm3)
PVC (%)
Hemoglobin (g/dL)
% Neutrophil
%Lymphocyte
%Eosinophil
%Monocyte
%Basophil

Parameters

X  SD

Table 2. Hematological ndings for the animals with TRP, mastitis, metritis, and pododermatitis and the cattle with renal amyloidosis.

452
Elitok et al

Renal Amyloidosis in Cattle

453

Table 4. Urinary variables for the animals with TRP, mastitis, metritis, and pododermatitis and the cattle with renal
amyloidosis.
X  SD
Control,
n 5 10

Parameters
Polyuria
Granular cast
Crystals
Pyuria
TP (g/L)
Urea (mmol/L)
GGT (U/L)
ALP (U/L)
AST (U/L)
Creatinine (mmol/L)
Specic gravity

(
(
(

)
)
)

0.0d
2.1  0.3e
0.4  0.01e
0.1  0.04f
0.4  0.01d
0.0e
1.030b

TRP,
n 5 30

Mastitis,
n 5 18

Metritis,
n 5 11

Pododermatitis,
n 5 23

Cattle with Renal


Amyloidosis, n 5 5

(1
)
(1
)
(1
)
(1
)
16.9  1.bc
6.6  0.9b
18.6  1.3c
136.4  12.6b
36.4  1.3b
44.1  4.3c
1.010d

(1
)
(1
)
(1
)
(1
)
17.6  1.3b
6.2  0.5c
21.4  2.0b
126.3  11.0c
38.3  2.0b
48.4  5.2b
1.010d

(1
)
(1
)
(1
)
(1
)
15.4  1.2c
6.0  0.6cd
13.1  1.2d
110.0  14.1d
28.0  1.1c
36.6  6.0d
1.020c

(1
)
(1
)
(1
)
(1
)
14.8  1.3c
5.8  0.5d
14.1  1.1d
100.8  14.6e
26.3  0.8c
37.1  3.0d
1.020c

(11 )
(11 )
(11 )
(111)
28.3  2.2a
14.8  1.5a
56.4  1.8a
323.4  32.1a
264.8  44.6a
87.8  6.7a
1.050a

The superscript upper key letters were statistically signicant (P o .01).


(
), absent; (1
), mild; (11 ), moderate; (111), severe.
TRP, traumatic reticuloperitonitis; TP, total protein; AST, aspartate aminotransferase; GGT, g-glutamyl transferase; ALP, alkaline
phosphatase.

GLU concentrations were signicantly lower (P o .01)


compared with the control group. No differences were
observed among the study groups, whereas the SAA
levels in study groups were signicantly higher than the
levels among control group animals.

Urinary Findings
Proteinuria and lower urine specic gravity values
were the most prominent signs of urinalysis in this trial.
Additionally, higher urinary urea and creatinine concentrations along with higher enzyme activities for GGT,
AST, and ALP were determined as the other conspicuous
signs. In the dipstick examination of urine samples, proteinuria (1
), pyuria (1
), and casts were
determined for the study groups (Table 4).

Cows with Renal Amyloidosis


At the end of this trial, 5 cows in which amyloid was
detected had nephrotic syndrome with hypoproteinemia
and proteinuria in combination with polyuria and weight
loss. The hematological parameters, including erythrocyte count and hematocrit percentage, were increased.
Furthermore, cows with renal amyloidosis had higher
(P o .01) total leukocyte count, serum and urine enzyme
activities, and urea and creatinine concentrations, with
lower serum TP concentration when compared with animals without renal amyloidosis in the study groups. No
differences were observed in SAA concentrations among
the study groups, whereas SAA levels in animals with renal amyloidosis were signicantly higher than in control
group animals.

Histopathological Findings
All the animals survived for 1 week after performing
percutaneous kidney biopsy, and none of them showed
untoward adverse effects during the study. Two cows
from the TRP group and one from the pododermatitis
group were shown to have renal amyloidosis. Lesions
were most notable in the glomeruli (Table 2), where amyloid was present in capillary walls and mesangium
in 5 of 82 animals (6%). A periglomerular mononuclear
cell interstitial inltrate was occasionally noted around
the most severely damaged glomeruli, and inammatory
cells consisted predominantly of lymphocytes and plasma cells (Fig 1). Although amyloid deposits were
hypocellular, a periglomerular mononuclear cell interstitial inltrate was occasionally noted around the most
severely damaged glomeruli. Other lesions detected
in histopathology in the present study are listed in
Table 5.

Fig 1. Renal amyloidosis. Glomerular amyloid depositions


(arrows), Congo red,  40.

454

Elitok et al

Table 5. Histopathological ndings in animals with TRP, mastitis, metritis, and pododermatitis and the cattle with
renal amyloidosis.
Control,
n 5 10

Parameters
Glomerulo-tubulonephrosis
Tubuler degeneration and necrose
Glomerular atrophy and degeneration
Chronic glomerulonephritis
Thickening of basal membrane
Periglomerular lymphohystiyociter inltration
Desquamation of tubulus epithel
Amyloidosis
Glomerular amyloid degeneration

TRP,
n 5 30

Mastitis,
n 5 18

Metritis,
n 5 11

Pododermatitis,
n 5 23

Cattle with Renal


Amyloidosis, n 5 5

18 (111)
12 (111)
9 (11)
8 (11)
2 (11)
15 (11)
3 (11)
2
2 (111)

4 (111)
4 (111)
14 (11)
10 (111)
10 (1)
10 (111)
4 (111)
2
2 (111)

5 (11)
3 (1)
1 (1)
1 (1)
3 (1)
6 (1)
1 (11)
( )
( )

13 (111)
8 (11)
7 (1)
3 (11)
4 (11)
8 (111)
2 (11)
1
1 (111)

5 (111)
5 (111)
5 (111)
5 (111)
5 (111)
5 (111)
5 (111)
5 (111)
5 (111)

Arabic numerals show the number of animals and marks in the parentheses emphasize severity of the lesions: ( ), absent; (1), mild; (11),
moderate; (111), severe.
The amount of amyloid in the kidney as detected by Congo red stain was rated as 1, mild deposition; 11, moderate deposition; 111,
extreme deposition. Furthermore, other lesions detected in histopathology in the present study are scored according to severity of the lesions
as 1, mild; 11, moderate; 111, severe.
TRP, traumatic reticuloperitonitis.

Discussion
This study was undertaken to obtain epidemiological
information about secondary amyloidosis in Turkey,
with a special focus on etiological distribution. This is a
comprehensive pathologic study of AA amyloidosis in
cattle with mastitis, TRP, metritis, and pododermatitis.
Amyloid deposits were found in glomeruli by microscopic examination of the kidneys, and with Congo red
staining renal amyloidosis was conrmed, as previously
reported incidentally in cows.1620 It has been reported
that only in the most advanced cases, with the glomerulus
being in a terminal stage, was a mononuclear cell interstitial inltrate noted.6,7 In this study, we found that the
amyloid deposits were located only within the glomeruli
and that inammatory cells consisted predominantly of
lymphocytes and plasma cells, as has been previously
found in cattle and in dogs.16,18,21
AA amyloidosis characteristically develops in humans
and animals as a consequence of long-standing, chronic
infectious or inammatory processes. It has also been
described in a few cases of bovine spongiform encephalopathy.2224 In the present study, the animals suffered
from mastitis, TRP, metritis, and pododermatitis that
had been caused predominantly by bacterial agents. Bacterial origins have previously been reported in cases of
chronic suppurative pneumonias of domestic and wild
small ruminants.17,20,25,26 However, both medical histories and the laboratory results in this study indicated that
all diseases were in a chronic stage.
In this study, it was determined that SAA levels in
mastitis and TRP groups were higher than in the other
groups. Similar ndings for mastitis were previously reported by Gronlund et al.27 Acute-phase proteins such as
SAA have been identied as markers of inammation in
cattle because they are produced by the liver in response
to proinammatory cytokines.8,28 Additionally, numerous reports on the use of acute-phase protein responses
to predict severity or chronicity of cattle diseases
have been published.2932 Viral infections generally lead

to weak acute-phase reactions,32 a fact that has been


used in human clinical medicine to discriminate between
viral and bacterial infections.33 Although no reports
have been previously published on the induction of
SAA after the occurrence of mastitis, metritis, TRP,
or pododermatitis in cattle, the SAA concentrations
here are within reference ranges previously reported
for and acute-phase concentrations in cattle after
various experimental bacterial infections and aseptic
inammations.11,19,30
Some authors34 have questioned the efcacy of SAA as
a diagnostic tool because it may be elevated under stressful situations. For this purpose, Alsemgeest et al35 tested
this hypothesis using 2 stress levels created by housing
groups of 5 cows on different types of oors, videotaping the animals, and assessing stress. Plasma SAA
concentrations were elevated in cattle housed on
oors associated with the highest levels of physical
stress. In our study, 60% of cows had recently calved,
and this condition may have had an effect on the level of
SAA.
Clinically, AA amyloidosis is characterized by the development of a kidney disease with nephrotic syndrome
and chronic renal failure, often resulting in early
death.6,10,18 In the present study, besides diarrhea, the
chief nding was a nephrotic-like syndrome, in that there
was edema, hypoproteinemia, proteinuria, and low urine
specic gravity, which have also been reported by other
authors.26,28,36,37 White blood cell counts were consistently and persistently increased in study groups.
Furthermore, elevated urea and creatinine concentrations along with increased GGT, AST, and ALP enzyme
activities were noted in both blood serum and urine. Urinary GGT can be used as a marker of renal disease and is
often associated with urine ALP. These data indicated
chronic renal injury.3,28,37
The incidence of AA amyloidosis (6%) in cattle in this
study suggests that cattle with mastitis, metritis, and
pododermatitis have a high prevalence of systemic amyloidosis in response to inammation.

Renal Amyloidosis in Cattle

Footnotes
a

Sysmex, Norderstedt-Hamburg, Germany


D-68298, Mannheim, Germany
c
Biosource, Camarillo, CA
d
Combur 10 Merck, Haar-Munich, Germany
b

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