Hyperaldosteronism:
The Prevalence and Role in Cats
with Chronic Kidney Disease
Drs. J.H.P. Verhoek
Studentno.: 0462284
October 2010- February 2011
Supervisors:
Dr. H.S. Kooistra
Drs. S.C. Djajadiningrat-Laanen
Department of Veterinary Endocrinology,
Faculty of Veterinary Medicine, Utrecht University.
Hyperaldosteronism: The Prevalence and Role in Cats with Chronic Kidney Disease
Drs. J.H.P. Verhoek
Contents
Summary ............................................................................................................. 3
Introduction .......................................................................................................... 4
The adrenal glands ............................................................................................. 4
Renin Angiotensin System and Aldosterone ........................................................... 4
Hyperaldosteronism ............................................................................................ 4
Aim of the study .................................................................................................... 6
Materials and Methods ........................................................................................... 7
Cats ................................................................................................................. 7
Blood pressure measurement .............................................................................. 7
Blood collection and analyses............................................................................... 8
Urine collection and analyses ............................................................................... 8
Eye examination ................................................................................................ 8
Statistics ........................................................................................................... 9
Results ................................................................................................................10
Anamnesis and clinical exam ..............................................................................10
Blood pressure ..................................................................................................10
Blood analyses ..................................................................................................10
Hormone measurements ....................................................................................11
Urine ...............................................................................................................12
Eye examination ...............................................................................................13
Discussion ...........................................................................................................14
References ..........................................................................................................17
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Hyperaldosteronism: The Prevalence and Role in Cats with Chronic Kidney Disease
Drs. J.H.P. Verhoek
Summary
Introduction- The zona glomerulosa of the adrenal glands produces aldosterone. In
primary hyperaldosteronism there is an aldosterone excess due to an adrenocortical
tumor or a non-tumoral adrenocortical hyperplasia. A mineralocorticoid excess causes
increased sodium retention and an increased potassium excretion. This can lead to
muscle weakness or paralysis and acute blindness by ablatio retinae or intraocular
bleeding. It is also associated with slowly progressive renal failure.
Aim of the study- The aim of the research is to demonstrate that hyperaldosteronism is
more common among cats than is assumed and to investigate the prevalence of primary
hyperaldosteronism in cats with chronic renal failure. When the disease is diagnosed in
an early stage a treatment can be started and the renal damage may be limited.
Hypothesis- The prevalence of primary hyperaldosteronism in cats with chronic kidney
disease is approximately 10%.
Animals- Twenty-one cats kept as companion animal have been examined for this study.
After measuring creatinine and thyroxine levels, seven of the twenty-one cats could not
be taken into account in the study because of a creatinine level within the reference
range (indicating no renal failure is present) or thyroxine levels above the upper
reference value (indicating a possible thyroid problem). Therefore fourteen cats were
suitable for measurement of plasma aldosterone concentration (PAC) and plasma renin
concentration (PRA).
Methods- Blood pressure measurements, blood and urine collection and analysis and eye
examinations were performed on the cats.
Results- There were no significant correlations found. Eight of the cats had a blood
pressure >160 mmHg. In six cases the plasma potassium concentration was below the
reference values, six cats had an aldosterone-renin ratio above the reference values. The
specific gravity of the urine was below the reference values in six cats and in two cats
retinal abnormalities were found.
Conclusion- Given the limited number of cats examined, no firm conclusions can be
drawn. It is necessary to obtain more data in order to determine the prevalence of
primary hyperaldosteronism in cats with chronic kidney disease. However, six out of
fourteen cats had an aldosterone-renin ratio above the reference value and may have
primary hyperaldosteronism.
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Hyperaldosteronism: The Prevalence and Role in Cats with Chronic Kidney Disease
Drs. J.H.P. Verhoek
Introduction
The adrenal glands
The adrenal glands are situated craniomedial to the kidneys and are located in the
retroperitoneum. They are paired endocrine organs, each consisting of a medulla and
cortex. The medulla secretes epinephrine and norepinephrine. In the cortex three zones
can be distinguished: the zona glomerulosa, zona fasciculata and zona reticularis. The
zona glomerulosa produces mineralocorticoids, primarily aldosterone. In the zona
fasciculata glucocorticoids, cortisol and corticosterone, and androgens are produced. The
zona reticularis produces androgens and glucocorticoids.1,2
Renin Angiotensin System and Aldosterone
The renin-angiotensin system (RAS) is a hormonal system that regulates blood pressure
and liquid balance. Angiotensinogen is produced in the liver as a glycoprotein. Renin,
which is released from the juxtaglomerular cells in the kidneys when the blood volume
decreases, splits angiotensinogen into angiotensin I. Angiotensin I is converted into
angiotensin II (ANG II) by the activity of the angiotensin-converting enzyme (ACE),
produced in the lungs. There are two main receptors to which ANG II binds, AT1 and
AT2. The receptors are distributed heterogeneously in the kidney. Through binding AT1
vasoconstriction occurs and aldosterone is secreted by the adrenal cortex.3
Aldosterone binds to the mineralocorticoid receptors of the target organs; the
kidney is one of the most important target organs. Aldosterone stimulates the active
reabsorption of Na+ in the kidney from the tubular urine into the nearby capillaries.
Water is passively absorbed with the Na+. Aldosterone also stimulates the active
secretion of K+ into the urine simultaneously with Na+ reabsorption.2
Hyperaldosteronism
Excessive aldosterone production can be the result of primary or secondary causes.
Secondary hyperaldosteronism develops in response to RAS activation which in turn
continuously stimulates the aldosterone synthesis, in that case both renin and
aldosterone levels are high. Conditions in which this occurs are heart failure, kidney
failure and hepatic dysfunction. Despite the high levels of renin and angiotensin and
consequently high plasma aldosterone levels, the fluid volume remains reduced and the
blood pressure is low-normal. In primary hyperaldosteronism there is a mineralocorticoid
excess, which can have two causes: an adrenocortical tumor, usually unilateral, or a nontumoral bilateral adrenocortical hyperplasia (idiopathic form). Due to autonomous
excessive secretion of aldosterone the renin level is low.1,4,5 Primary hyperaldosteronism
is mostly seen in middle-aged and older cats.6
A mineralocorticoid excess causes increased sodium retention and an increased
potassium excretion. The former can lead to systemic arterial hypertension, and a
potassium deficiency in the body. As a result of the potassium deficiency, muscle
weakness or paralysis may occur. There is also a possibility of developing acute blindness
by ablatio retinae or intraocular bleeding due to an elevated arterial blood pressure. 7
Primary hyperaldosteronism is often associated with slowly progressive renal failure,
most likely because aldosterone promotes thrombosis and fibrosis in the kidney.
Circulating aldosterone may promote vascular fibrosis by binding corticoid receptors in
the cytosol of the vascular fibroblasts or by disrupting the vascular fibrinolytic balance;
the plasminogen activator system. There is also evidence that ANG II plays a role in the
progression of renal disease, by regulating inflammatory and immune cell responses and
thus attracting inflammatory cells to the kidneys. Previous studies show that cats with an
adrenal tumor had less kidney failure compared to the cats with hyperplasia of the
adrenals despite higher PAC levels. Because in hyperplasia the renin is not fully
suppressed it is thought that aldosterone and ANG II both contribute to the kidney
4
Hyperaldosteronism: The Prevalence and Role in Cats with Chronic Kidney Disease
Drs. J.H.P. Verhoek
damage in idiopathic hyperaldosteronism.8 An elevated blood pressure is also associated
with chronic renal failure. Despite extensive studies in humans and animals the exact
cause is still not known.9
The diagnosis of primary hyperaldosteronism is based on de relationship between the
plasma aldosterone concentration (PAC) and the plasma renin activity (PRA), the
increased aldosterone to renin ratio (ARR). An alternative diagnostic approach is
measuring the urinary aldosterone-creatinine ratio (UACR) in combination with the
suppressant fludrocortisone. This test is already used in human medicine to diagnose
primary hyperaldosteronism.10,11 To distinguish between tumoral and non-tumoral
mineralocorticoid excess, diagnostic imaging is necessary.12
Unilateral adrenalectomy is preferred in unilateral primary hyperaldosteronism. In
bilateral adrenocortical disorders a medical treatment with a mineralocorticoid-receptor
antagonist called spironolactone and oral supplementation with K +- gluconate is
possible.1,12
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Hyperaldosteronism: The Prevalence and Role in Cats with Chronic Kidney Disease
Drs. J.H.P. Verhoek
Aim of the study
Angiotensin II and aldosterone contribute to the progression of kidney damage (reported
in laboratory animals and in human). Angiotensin II is considered to be a true pro
inflammatory modulator that contributes to the onset and progression of kidney damage.
Circulating aldosterone promotes thrombosis and fibrosis and is considered to be a
promoter of fibroproliferative destruction of the kidney. Thus primary hyperaldosteronism
is associated with the progression of renal disease in cats. Treatment of the excessive
aldosterone secretion could prevent the progression of kidney damage.3,8,13 It is
recommended to consider primary hyperaldosteronism as a differential diagnosis in
middle-aged and older cats with hypokalemic polymyopathy and/ or systemic
hypertension and should no longer be considered a rare condition.6
The aim of the research is to demonstrate that hyperaldosteronism is more
common among cats than is assumed and to investigate the prevalence of primary
hyperaldosteronism in cats with chronic kidney disease. G.P. Rossi et al. (2006) showed
in a prospective study in 1125 hypertensive human patients that the aldosterone to renin
ratio (ARR) was above the reference value in 11.2% of the patients.14
When the disease is diagnosed in an early stage a treatment can be started and the renal
damage may be limited.
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Hyperaldosteronism: The Prevalence and Role in Cats with Chronic Kidney Disease
Drs. J.H.P. Verhoek
Materials and Methods
Cats
21 cats kept as a companion animal have been examined for this study. Before starting
the study the inclusion criteria were determined. The cats had to repeatedly have a
creatinine level above the upper reference value. No underlying conditions, such as
diabetes mellitus or hyperthyroidism should be present. The cats could not be on ACE
inhibitors, or the owner had to temporarily stop giving the medication at least one week
before the examination. The owner also had to withhold food for at least 12 hours before
the appointment in order to prevent interference with the blood values.
After measuring creatinine and thyroxine levels, seven of the twenty-one cats
could not be taken into account in the study because of a creatinine level within the
reference range or thyroxine levels above the upper reference value. Fourteen cats were
suitable for measurement of plasma aldosterone and plasma renin concentration.
Different breeds of cat were included in the study; twelve European shorthair, one
Siamese, one Birman. Eight of these cats were female and six male, all were castrated.
The average age of the cats was fourteen years and five months. The youngest cat was
eight years and one month old, the oldest cat was twenty-one years and six months old
at the time of examination. The mean weight of the cats was 3.70 kg, the lightest cat
was 2.15 kg and the heaviest cat 6.70 kg (Table 1).
Cat
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Breed
ESH
ESH
ESH
Birman
ESH
ESH
ESH
Siamese
ESH
ESH
ESH
ESH
ESH
ESH
Sex
MC
FC
FC
MC
FC
FC
FC
MC
FC
FC
MC
MC
FC
MC
Age
17 yrs 8 mon
16 yrs 8 mon
8 yrs 1 mon
15 yrs 9 mon
12 yrs 8 mon
21 yrs 6 mon
18 yrs 7 mon
13 yrs
9 yrs 9 mon
15 yrs 6 mon
9 yrs 9 mon
10 yrs 8 mon
15 yrs 8 mon
16 yrs 5 mon
Weight (kg)
3.97
3.40
2.15
2.85
3.05
2.75
2.60
4.77
3.05
3.47
6.70
5.70
3.10
4.20
Table 1: breed, sex, age and weight of the cats. ESH= European shorthair, MC=Male Castrate, FC= Female Castrate,
yrs= years, mon= months.
Blood pressure measurement
To determine the systemic arterial blood pressure of the cats, a small area of hair just
above the carpus, at the medial site of the right front leg was shaved. After the shaving a
ten minute acclimation period was maintained in a quiet examination room.15 Sparkes et
al. measured the systolic blood pressure (SBP) of seven cats to investigate the effect of
an acclimation period. The results showed a significance reduction in blood pressure
(from 176 mmHg to 157 mmHg) after a 10 minute acclimation period.16
An ultrasonic Doppler flow detector (Model 811-B, Parks medical electronics), a
three centimetre cuff, and a transducer were used to measure the systolic arterial blood
pressure of the cats. The cuff was placed around the radius and ulna (carpus). The cat’s
position and the position of the cuff had to cause as little stress as possible. The cuff was
held at the level of the right atrium or close to it. The Doppler probe with ultrasonic gel
was held on the shaved area to hear the blood flow in the median artery. The cuff was
then inflated approximately twenty mmHg above the point the flow could no longer be
7
Hyperaldosteronism: The Prevalence and Role in Cats with Chronic Kidney Disease
Drs. J.H.P. Verhoek
heard. Then the cuff was slowly deflated, when the flow was heard again, the value was
read of the manometer connected to the cuff. This value is the systolic arterial blood
pressure. The procedure was repeated several times, the first measurement should not
be taken into account, the average of at least three consecutive values with less than
twenty percent difference was noted as the average systolic arterial blood pressure.15
Hypertension was diagnosed when the systolic arterial blood pressure was >160180 mmHg. More studies are necessary to determine the exact reference value of the
cats’ blood pressure (BP), but based on the data currently available a systolic blood
pressure > 160-180 mmHg, in combination with other clinical signs associated with
hypertension, should be seen as a guideline for diagnosis.15
Blood collection and analyses
8 ml blood samples were collected from the jugular vein. 4 ml was put on ice
immediately after collecting the blood in an EDTA-coated tube. The sample was then
centrifuged for 10 minutes, and plasma was stored at -20 °C until assayed.
1 ml was put in another EDTA-coated tube and 3 ml in a heparin-coated tube at room
temperature. The heparin sample was also centrifuged for 10 minutes and the heparinplasma and EDTA-blood was taken to the UVDL (Universitair Veterinair Diagnostisch
Laboratorium).
ETDA-plasma stored at -20 °C was used to assay plasma aldosterone
concentration (PAC) and plasma renin concentration (PRA) at the nephrology department
of the UMC Utrecht. A radio immuno assay was used to measure both hormone
concentrations.17
The heparin-plasma was used for the assay of sodium, potassium, urea,
creatinine, calcium, phosphate, thyroxine, albumin and fructosamine. Sodium,
potassium, calcium, phosphate and fructosamine were determined with a DxC 600
Beckman Coulter blood gas and electrolyte analyzer. Urea and creatinine were
determined with a Beckman Synchron CX7 using a Beckman-Coulter reagent. Finally,
thyroxine and albumin were determined with the Siemens Immulite® 2000 immunoassay
system, with antigen coupled to beats and (home made) bromocresol green reagent.
EDTA-blood was used to assay hematocrit and reticulocyte with the Siemens ADVIA 120
hematology system.18
Urine collection and analyses
Before examination the owners were asked to collect urine from the cat with Katkor ®, a
non absorbing cat litter that does not change the composition of the urine, at home. The
urine samples had to be less than 24 hours old and had to be kept in the fridge before
analysis. When the owner was not able to collect urine with the Katkor® litter, the
veterinarian collected urine by bladder puncture.
A 3 ml sample was used to determine specific gravity, pH, protein, haemoglobin,
glucose, creatinine, protein to creatinine ratio and sediment. A refractometer was used
for the measurement of the urine specific gravity. The pH, glucose and haemoglobin were
measured using a test strip. Creatinine and total protein level measurement was done
with a Beckman Synchron CX7 chemistry analyzer. For determination of the presence of
sediment the urine was centrifuged for 5 minutes, and then looked at with the use of a
microscope by a laboratory analyst.18
Eye examination
The eyes of the cats were examined with a direct ophthalmoscope (WelchAllyn). The
examination was performed in a darkened room without the use of a mydriatic drug.
First the cornea, anterior chamber, iris, pupil, lens and vitreous humor were examined
using a slit lamp. Then the fundus was examined with an ophthalmoscope. The focus was
on the optic disc, retinal vasculature, tapetum lucidum and tapetum nigrum.
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Hyperaldosteronism: The Prevalence and Role in Cats with Chronic Kidney Disease
Drs. J.H.P. Verhoek
Statistics
The statistical analysis was performed using SPSS 17.0. The data was first checked on
normal distribution, using the Kolmogorov-Smirnov test, in order to calculate the
correlation. The mean and scatter were also calculated. In normally distributed data the
Pearson correlation coefficient was used to calculate the correlation, the Spearman
correlation coefficient was used to calculate the correlation in data that was not normally
distributed. P=0.05 was considered statistically significant.19
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Hyperaldosteronism: The Prevalence and Role in Cats with Chronic Kidney Disease
Drs. J.H.P. Verhoek
Results
Anamnesis and clinical exam
Nine out of fourteen cats had polyuria and polydipsia, four cats showed weight loss.
Seven of the cats vomited approximately once a week, one cat vomited almost every
day. In three cats the owner noticed that they were coughing occasionally. In six cats the
owner noticed muscle weakness.
General physical examination: in three cats one or more lymph nodes were
enlarged. In one cat the thyroid gland was possibly slightly enlarged. On palpation of the
kidneys no abnormalities were found.
Blood pressure
The fourteen cats in this study had a mean systolic arterial blood pressure of 177 mmHg
(2479/14). The highest blood pressure measured was 240 mmHg and the lowest was
132 mmHg (=scatter). 50% (7/14) of all examined cats had a systolic arterial blood
pressure above 180 mmHg. One of the cats had an average BP between 160 mmHg and
180 mmHg (167 mmHg) (Table 2). There was no significant correlation between ARR and
blood pressure and no significant correlation between the creatinine level and blood
pressure.
Cat
1
2*
3
4
5*
6*
7*
8
9
10
11
12*
13*
14
Blood pressure (mmHg)
195
132
192
202
209
146
202
167
145
212
154
240
135
148
Table 2: Systolic arterial blood pressure, *= cats with an ARR above the upper reference value.
Blood analyses
All of the cats had a creatinine value above the upper reference value (Table 3). The
average plasma creatinine value was 195.4 µmol/L. The highest value measured was 321
µmol/L and the lowest 167 µmol/L, reference values: 76-164 µmol/L. Three of fourteen
cats (21.4%) had a urea value higher than the upper reference value. The average urea
value was 11.4 mmol/L, with a scatter of 7.1-20.1 mmol/L, reference values: 6.1-12.8
mmol/L.
Six cats showed hypokalaemia, the average potassium value was 3.58 mmol/L,
scatter: 3.0-4.6 mmol/L, reference values: 3.4-5.2 mmol/L. There was no significant
correlation between plasma creatinine concentration and plasma potassium
concentration. All cats had a sodium value within the reference values (146-158
mmol/L), with an average of 151.1 mmol/L, scatter 147-155 mmol/L. The average
phosphate concentration was 1.18 mmol/L, scatter 0.89-1.55 mmol/L, reference values:
0.89-2.05 mmol/L, i.e. all cats had a phosphate value within the reference. Two cats had
10
Hyperaldosteronism: The Prevalence and Role in Cats with Chronic Kidney Disease
Drs. J.H.P. Verhoek
a calcium value at or below the lower reference value, the average calcium value was
2.57 mmol/L, the highest value was 2.70 mmol/L and the lowest was 2.21 mmol/L,
reference values: 2.36-2.86 mmol/L. Fructosamine average was 203.8 µmol/L, scatter:
144-254 µmol/L, reference values: 156-240 µmol/L. One cat had a concentration below
the lower limit of the reference value and one cat had a concentration above the upper
reference value.
The lowest hematocrit (Ht) value was 0.19 L/L, the highest 0.38 L/L, with an
average of 0.30 L/L, reference values: 0.28-0.47 L/L. The blood had coagulated in one
sample so determination of Ht was not possible for that cat. In three of the cases the Ht
was below the reference value, they had a regenerative anaemia, the reticulocytes were
0.1% or higher (0.1, 0.4, 0.4%). The average Ht was 0.16% with a scatter of 0.0-1.3%.
The average thyroxine value was 25.6 nmol/L, with a scatter of 16-50 nmol/L.
Reference values: 15-45 nmol/L, so one of the cats had a slightly increased thyroxine
level. Six cats had an albumin level below the lower limit of the reference value (25-34
g/L), the average value was 24.6 g/L, with a scatter of 20-27 g/L.
Cat Urea
(mmol/l)
1
11.9
2
10.3
3
15.9
4
20.1
5
10.6
6
9.0
7
14.2
8
8.5
9
12.3
10 12.7
11 7.1
12 9.0
13 9.0
14 9.0
Creatinine
(µmol/l)
194
211
252
321
169
198
198
223
252
183
170
220
175
167
Na+
(mmol/l)
152
153
148
147
154
151
152
155
152
147
151
151
150
152
K+
(mmol/l)
4.5
3.6
3.5
3.3
3.6
3.0
3.3
4.6
3.8
3.4
3.2
3.6
3.1
3.6
Albumin
(hep) (g/L)
26
26
26
24
27
26
26
24
24
20
27
26
23
20
Ht (L/L)
RETI
0.36
0.23
0.32
0.19
0.32
0.28
*
0.33
0.31
0.32
0.29
0.38
0.36
0.25
0.3
0.1
0.2
0.4
0.0
0.1
*
0.2
0.2
0.1
0.1
0.2
0.0
0.4
(%)
Table 3: Urea, creatinine, sodium, potassium, albumin, hematocrit and reticulocyte values in the blood. *=
blood coagulated.
Hormone measurements
Six out of 14 cats in this study had an aldosterone-renin ratio above the upper reference
values. The reference values for plasma aldosterone concentration (PAC) are 110-540
pmol/L, for plasma renin activity (PRA): 60-630 fmol/L and for aldosterone-renin ratio
(ARR): 0.3-3.8 x10-9.17
The average ARR of the six cats was 9.4 x10-9, with a scatter of 4.13 x10-9-22.15
-9
x10 (Table 4). Cat number 2 and 6 had a PAC and PRA within the reference values, cat
number 5 and 13 had a PAC within the reference values and a PRA below the lower limit
of the reference values, cat number 7 and 12 had a PAC above the upper limit of the
reference values and a PRA below the lower limit of the reference values.
The average ARR of all cats was 4.76 x10-9, the lowest ARR measured was 0.38 x10-9
and the highest 22.15 x10-9. Cat number 3 had an ARR within the reference values but
the PAC was above the upper limit of the reference values. The average PAC was 345.7
pmol/L with a scatter of 90-890 pmol/L. Cat number 1 and 4 had an ARR within the
reference values but the PRA was above the upper limit of the reference values. The
average PRA was 181.8 fmol/L, with a scatter of <40-690 fmol/L. There was no
11
Hyperaldosteronism: The Prevalence and Role in Cats with Chronic Kidney Disease
Drs. J.H.P. Verhoek
significant correlation between the ARR and potassium concentration and no significant
correlation between the ARR and creatinine concentration.
Cat
1
2*
3
4
5*
6*
7*
8
9
10
11
12*
13*
14
PAC
(pmol/L)
260
330
660
450
220
290
890
140
290
90
90
610
210
310
PRA
(fmol/L)
690
80
200
680
<40
70
<40
130
310
55
130
<40
<40
200
ARR (x 10-9)
0.38
4.13
3.30
0.66
5.50
4.14
22.15
1.08
0.94
1.64
0.69
15.25
5.25
1.55
Table 4: Blood values. PAC= plasma aldosterone concentration, PRA= plasma aldosterone activity, ARR=
aldosterone-renin ratio. *= cats with an ARR above the upper reference value.
Urine
In two cats the owners failed to collect urine and they did not give permission to perform
a bladder puncture. In ten cats the owners did manage to collect urine with Katkor®
litter, and in two cats the veterinarian performed cystocentesis to collect urine.
Six cats had a specific gravity (s.g.) at or below the lower limit of reference
values, the average s.g. was 1.028, with a scatter of 0.015-0.045 (reference value:
1.020-1.045). One cat had a total protein concentration above the reference value, the
average total protein level in the urine was 0.36 g/L, with a scatter of 0.10-1.34 g/L,
reference value: <0.56 g/L. In one case there was a total protein-creatinine ratio above
the reference value (<0.4), the average protein-creatinine ratio was 0.27, with a scatter
of 0.09-1.64 (Table 5). There is no significant correlation between the specific gravity of
the urine and the plasma creatinine concentration.
Cat
1
2
3
4
5
6
7
8
9
10
11
14
Specific
gravity (s.g.)
1.016
1.019
1.031
1.015
1.045
1.015
1.033
1.045
1.020
1.020
1.044
1.037
Protein
(g/L)
0.10
0.12
0.33
1.34
0.34
0.14
0.48
0.31
0.21
0.22
0.35
0.36
Creatinine
(µmol/L)
7813
12159
15510
7224
22864
7247
14925
29381
11274
12791
33573
19410
Proteincreatinine ratio
0.11
0.09
0.19
1.64
0.13
0.17
0.28
0.09
0.16
0.15
0.09
0.16
Table 5: results urine samples.
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Hyperaldosteronism: The Prevalence and Role in Cats with Chronic Kidney Disease
Drs. J.H.P. Verhoek
Eye examination
Two of the cats had abnormal retinal vasculature. In one of the cats the vessels in the
right eye were dilated more than expected and more tortuous, the dorsal vessel of the
left eye was also dilated, whereas the lateral vessel was too thin. In the other cat not all
vessels could be viewed because the papilla lay against the tapetum nigrum in both eyes.
In the right eye the dorsal vessel was more tortuous than expected. None of the cats had
an ablatio retinae or intraocular bleedings. There was no significant correlation between
the blood pressure and eye abnormalities.
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Hyperaldosteronism: The Prevalence and Role in Cats with Chronic Kidney Disease
Drs. J.H.P. Verhoek
Discussion
Primary hyperaldosteronism is associated with the progression of renal disease in cats. 13
The aim of this study was to investigate the prevalence of primary hyperaldosteronism in
cats with chronic kidney disease. The assumption is that the prevalence of primary
hyperaldosteronism in cats with chronic kidney disease is approximately 10%,
comparable with the prevalence of primary aldosteronism in humans with systemic
hypertension.14
The indirect Doppler blood pressure measurement is a relatively simple and inexpensive
method for use in veterinary practice to determine the systolic arterial blood pressure of
cats. It is important to maintain an acclimation period in a quiet examination room and
the person that performs the measurement has to be experienced in handling cats and
the equipment. When using the Doppler it is important that the position of the cuff and
the position of the cat are not causing stress or discomfort and the cuff must be held at
or close to the position of the atrium at the time of measurement.15 The blood pressure
in this study, measured with an ultrasonic Doppler device, was above the reference
values in 8 out of 14 cats (57%). Because of my relative inexperience with the Doppler
and because some cats were very resistant it was not always possible to carry out the
measurements the optimal way. There are few reference values for Doppler blood
pressure measurement in conscious cats, more research is necessary to improve
reliability.15
50% (3/6) of the cats with an aldosterone-renin ratio (ARR) above the reference
values also had a blood pressure above 180 mmHg. Two of the cats that did not have
hypertension but did have an ARR above the reference value were treated with an ACE
inhibitor before participating in the study. However, the treatment was temporarily
stopped one week prior to the examination, therefore this cannot explain the normal
blood pressure. One of the cats was also treated with atenolol. Atenolol is a selective
beta1-adrenoceptor antagonist, which is used in cats to reduce the heart rate and lower
the blood pressure. When the initial antihypertensive therapy does not provide sufficient
reduction in blood pressure, atenolol is useful as an adjunctive therapy. 9 The third cat did
not receive any medication prior to the examination.
In eight cases the blood pressure was too high but the ARR was within the
reference values in five cats (62.5%). Cat number 1 was treated with a calcium channel
blocker (amlodipine) to decrease the blood pressure therefore the dose should be
adjusted. Cats number 3, 4, 8 and 10 did not receive any drugs. The hypertension in
these cats is most likely caused by chronic renal failure.9 Stiles et al. found a prevalence
of hypertension in cats with chronic renal failure of 65%, a BP>160 mmHg was the
definition of hypertension in their study. In another study by Syme et al. a prevalence of
19.4% was found, their definition of hypertension was a BP>175 mmHg, measured on
multiple occasions.20
There was no significant correlation between the ARR and the BP or between the
plasma creatinine concentration and the BP.
Six of the cats showed some signs of muscle weakness and six of the cats were
hypokalemic. Four of six cats with muscle weakness also had a plasma potassium
concentration below the reference values. In two cats with a potassium level below the
reference values the owners did not notice muscle weakness. Fardella et al. (2000)
examined human patients with essential hypertension, and primary hyperaldosteronism
was diagnosed in 9.5%, none of them were hypokalemic.21 Gordon et al. (1993) found
that only in the more severe cases hypokalemia was present, most patients with primary
hyperaldosteronism are normokalemic.22 DiBartola et al. (1987) found hypokalemia in
approximately 30% of cats with chronic renal failure.23
14
Hyperaldosteronism: The Prevalence and Role in Cats with Chronic Kidney Disease
Drs. J.H.P. Verhoek
There was no significant correlation between the plasma creatinine concentration
and the plasma potassium concentration.
Six out of 14 examined cats (43%) had an aldosterone-renin ratio above the reference
values, which means that they may have primary hyperaldosteronism. Cats number 2
and 6 had a PAC and PRA within the reference values, cats number 5 and 13 had a PAC
within the reference values and a PRA below the lower limit of the reference values, cat
number 7 and 12 had a PAC above the upper limit of the reference values and a PRA
below the lower limit of the reference values. Cat number 3 had an ARR within the
reference values but the PAC was above the upper limit of the reference values. Cat
number 1 and 4 had an ARR within the reference values but the PRA was above the
upper limit of the reference values.
The zona glomerulosa is stimulated by potassium to secrete aldosterone, so the
aldosterone levels can be lower than expected in hypokalemic cats. Low PRA levels in
combination with high-normal or PAC levels above the upper reference values indicate
aldosterone synthesis with little or no stimulation of the RAS.8
There was no significant correlation between the ARR and potassium
concentration and no significant correlation between the ARR and creatinine
concentration.
The method used to measure aldosterone and renin has some practical disadvantages.
The amount of blood needed for the determination (4ml) is large and the necessity to put
the plasma on ice or in a freezer (-20 °C) immediately after collecting the blood is not
very practical. Also, the PRA determination takes time and the reference values have a
high interlaboratory variation. Furthermore, because of fluctuations in PAC and PRA, a
single ARR within the normal limits is not conclusive, and multiple measurements may be
necessary. An additional diagnostic test that may be useful in the diagnosis is the
fludrocortisone suppression test (FST). The test uses the suppressant fludrocortisone.
This suppressant reduces the urinary aldosterone-creatinine ratio (UACR) in healthy
individuals but it has little or no effect on individuals with primary hyperaldosteronism.
Administration of the fludrocortisone (0.05 mg/kg bodyweight) to healthy cats decreased
the UACR with an average of 78%.11
50% of the cats had a specific gravity below the reference values, indicating renal
insufficiency. In dogs wide fluctuations in s.g. have been reported, but not in healthy
cats. However it is recommended to take urine samples at different times for 2-3 days
for determination of s.g.24 There is no significant correlation between the specific gravity
of the urine and the plasma creatinine concentration.
Two of the cats had mild abnormalities of the retinal vasculature. Ocular lesions are
reported in cats with systolic BP values of 168 mmHg or higher and there is even more
risk of ocular injury when the BP exceeds 180 mmHg, although prevalence values vary
across many studies.15 There was no significant correlation between the blood pressure
and eye abnormalities. Due to lack of experience of the investigator, abnormalities may
have been missed. An eye examination by a veterinary ophthalmologist is recommended
in hypertensive patients.
When primary hyperaldosteronism is diagnosed with PAC and PRA measurements and
possibly with the use of the FST, diagnostic imaging is necessary to distinguish between
tumoral and non-tumoral mineralocorticoid excess.12 Adrenalectomy is preferred in
unilateral primary hyperaldosteronism. In bilateral disorders a medical treatment with a
mineralocorticoid-receptor antagonist (spironolactone) and oral supplementation with K +gluconate is possible.1,12 Aldosterone plays an important role in chronic kidney disease by
promoting thrombosis and fibrosis in the kidney.8 In a rat model, Rocha et al. showed a
15
Hyperaldosteronism: The Prevalence and Role in Cats with Chronic Kidney Disease
Drs. J.H.P. Verhoek
decrease in urinary protein excretion in rats treated with an aldosterone-receptor blocker
(spironolactone) as well as fewer nephrosclerotic lesions on histological examination.25
Given the limited number of cats examined, no firm conclusions can be drawn. It is
necessary to obtain more data in order to determine the prevalence of primary
hyperaldosteronism in cats with chronic kidney disease. However, six out of fourteen cats
had an aldosterone-renin ratio above the reference value and may have primary
hyperaldosteronism.
16
Hyperaldosteronism: The Prevalence and Role in Cats with Chronic Kidney Disease
Drs. J.H.P. Verhoek
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