Primary hyperaldosteronism (PHA) in cats is suggested by clinical signs and an elevated plasma aldosterone-to-renin ratio (ARR), but a test to confirm the diagnosis is lacking.
Primary hyperaldosteronism (PHA) in cats is suggested by clinical signs and an elevated plasma aldosterone-to-renin ratio (ARR), but a test to confirm the diagnosis is lacking.
Fludrocortisone does not suppress urinary aldosterone excretion in cats with PHA, but does so in cats with arterial hypertension because of other causes.
Nineteen client-owned cats with arterial hypertension because of PHA (n = 9) or other causes (n = 10).
Prospective clinical study. The urinary aldosterone-to-creatinine ratio (UACR) was determined in morning urine before, during, and after 4 days of oral fludrocortisone administration in a dose of 0.05 mg/kg q12h. Arterial blood pressure and plasma potassium concentration were measured before and after fludrocortisone administration.
A basal UACR above 46.5 × 10−9, the upper limit of the reference range, was found in 3 cats with PHA. All PHA cats had basal UACRs >7.5 × 10−9. In all non-PHA cats with a basal UACR >7.5 × 10−9, fludrocortisone administration induced >50% suppression. In contrast, fludrocortisone administration resulted in <50% suppression in 6 of the 9 PHA cats. Neither basal UACR, nor UACR after suppression testing, correlated with the etiology of PHA (adenoma, adenocarcinoma, or suspected bilateral hyperplasia of the zona glomerulosa). Fludrocortisone induced hypokalemia in 7 cats, but did not induce or exacerbate arterial hypertension.
Measuring the UACR before and after 4 days of administering fludrocortisone is a practical method of confirming most cases of PHA in cats, and of substantiating the absence of PHA in cats having an ARR within the reference range.
plasma aldosterone-to-renin ratio
plasma aldosterone concentration
plasma renin activity
urinary aldosterone-to-creatinine ratio
Primary hyperaldosteronism (PHA), also termed primary aldosteronism, low-renin hyperaldosteronism, or Conn's syndrome, is the adrenocortical disorder of autonomous hypersecretion of aldosterone. In 1983, nearly 30 years after the first reported case in humans, PHA was first reported to occur in a cat. PHA in cats was initially thought to be rare but the number of reports has risen considerably in the past 15 years.[4-16] Increased awareness of the disease will probably lead to a further increase in recognized cases.
The mineralocorticoid excess in cats with PHA, originating from unilateral or bilateral neoplasia or bilateral hyperplasia of the adrenal zona glomerulosa, can result in systemic arterial hypertension, hypokalemia, or both and has also been associated with progressive loss of kidney function. PHA can be treated surgically or pharmacologically, and hence the hypertension and hypokalemia might be cured or alleviated and the deterioration of kidney function might be retarded. It is thus worth evaluating aldosterone secretion in cats with arterial hypertension, hypokalemia, or chronic kidney disease.
The diagnosis of PHA in cats is currently based on the history, clinical signs, routine laboratory results, and the use of an elevated plasma aldosterone-to-renin ratio (ARR) as a positive screening test. Ideally, the autonomous hypersecretion of aldosterone should be confirmed by a suppression test. In the absence of such a test for PHA in cats, diagnostic imaging is usually employed to detect abnormalities of size or structure of the adrenal gland(s) suggesting adrenal neoplasia and to detect any distant metastases. However, ultrasonographic and CT examinations failed to detect an adrenal adenoma and bilateral hyperplasia of the zona glomerulosa in 4 of 21 cats with histopathologically confirmed PHA.[4, 5, 8-13, 15] The inaccuracy of diagnostic imaging and the lack of other practicable diagnostic methods underscore the need for a reliable confirmatory test for PHA in cats.
In the fludrocortisone suppression test, the mineralocorticoid fludrocortisone promotes sodium and water retention, and thereby induces blood volume expansion. In cats with normal aldosterone regulation this should lead to suppressed renin and aldosterone release. In contrast, cats that are refractory to normal aldosterone regulation expectedly demonstrate a lack of aldosterone suppression. Fludrocortisone suppression of urinary aldosterone excretion was investigated in 15 healthy cats and 1 cat with a confirmed aldosterone-secreting adrenocortical carcinoma. The basal urinary aldosterone-to-creatinine ratio (UACR) in the cat with PHA did not exceed the wide reference range in healthy cats, while fludrocortisone given orally for 4 days in a dose of 0.05 mg/kg BW q12h caused a significant decrease in the UACR in healthy cats, but no decrease in the cat with PHA. The fludrocortisone suppression test was therefore considered promising.
The aim of this study was to evaluate the efficacy and safety of the oral fludrocortisone suppression test to confirm the diagnosis of PHA in cats with arterial hypertension or hypokalemia and arterial hypertension. Changes in urinary aldosterone excretion were monitored from day to day to determine the minimum duration of the test. Adverse effects such as a transient decrease in the plasma potassium concentration or a rise in arterial blood pressure were also documented.
Nineteen client-owned cats presented with arterial hypertension (n = 10) or hypokalemia and arterial hypertension (n = 9) were enrolled in this prospective clinical study, with the informed consent of their owners. Based on the plasma ARR, the arterial hypertension or hypokalemia and arterial hypertension were attributed to PHA in 9 cats (PHA group) and other causes in 10 cats (non-PHA group). Sixteen cats were treated at the Utrecht University Clinic for Companion Animals, The Netherlands. Urine samples before and after suppression were also included from 2 cats referred to the Vetsuisse Faculty of the University of Zurich, Switzerland, and from 1 cat referred to the Faculty of Veterinary Medicine of the Aristotle University of Thessaloniki, Greece. In these 3 cats, the diagnosis of PHA was based on increased PAC and suppressed PRA values, but the values were not included in statistical analyses because they were determined in other laboratories. The results of routine laboratory examinations and systolic blood pressure measurements in these 3 cats were excluded from statistical analysis for the same reason.
The PHA group consisted of 6 neutered females, 2 castrated males, and 1 intact male, with a median age of 13 years (range 8–19 years, n = 8; the age of 1 adopted stray cat was unknown). Eight of the PHA group were domestic shorthair cats and one was a Burmese. At admission, median systolic blood pressure was 193 mmHg (range 160–280 mmHg) and median plasma potassium concentration was 3.1 mmol/L (range 1.8–4.3 mmol/L). All 9 cats were hypertensive, despite antihypertensive medication in 1, and 5 were hypokalemic, with associated muscle weakness in 3, despite oral potassium supplementation in 2. Abdominal ultrasonography revealed an adrenal mass in 7 of the PHA cats and normal-sized adrenal glands in 2. Cytological examination of a fine-needle aspiration biopsy in a PHA cat with unilateral adrenal mass and radiographic findings suggestive of pulmonary metastases indicated an adrenal adenocarcinoma. Histopathologic examination in four different PHA cats revealed an adrenal adenocarcinoma in one and an adrenal adenoma in three, one of which was designated multinodular.
The non-PHA group consisted of 4 neutered females and 6 castrated males, with a median age of 14 years (range 11–16 years). There were 5 domestic shorthair cats, 2 British shorthairs, 1 Persian, and 2 crossbreds. The median systolic blood pressure at admission was 225 mmHg (range 166–283 mmHg) and median plasma potassium concentration was 3.6 mmol/L (range 2.8–4.1 mmol/L). All of the non-PHA cats were hypertensive, despite antihypertensive medication in 3, and 4 were hypokalemic, 1 with muscle weakness despite oral potassium supplementation. Abdominal ultrasonography in the 9 cats revealed an adrenal mass in 1 and postmortem examination showed this to be a benign adrenocortical mass which was immunonegative for neurospecific enolase. Combined with the unremarkable ARR, these findings are consistent with a non-aldosterone-secreting adrenal mass.
Before the fludrocortisone suppression test, an attempt was made to normalize blood pressure with oral amlodipine in 8 PHA and 8 non-PHA cats. One PHA cat and 2 non-PHA cats also received atenolol. Potassium chloride or potassium gluconate was added to the food as required according to the plasma potassium concentration. Other oral medications included benazepril in 3 cats, spironolactone in 1 other, and methimazole in another. Prednisolone was administered to 1 cat to alleviate neurological signs that were found at postmortem examination to have been caused by a meningioma. The medications were continued during the fludrocortisone suppression test, with 2 exceptions: benazepril was withheld for 7 days before the test in one non-PHA cat and both amlodipine and benazepril were withheld for 2 days before the test in a cat with PHA. Another hypokalemic PHA cat received additional intravenous potassium supplementation during the test.
Arterial blood pressure measurements were performed before any other examination, after a 10-minute acclimatization, using a Doppler flow detector,1 a 5 cm-wide cuff (Babyphon infant2), and a hand-held sphygmomanometer (Precisa N2). The mean value of at least 3 consecutive measurements with less than 20% variation was used. Arterial hypertension was diagnosed if the mean systolic blood pressure was >180 mmHg or was >160 mmHg together with hemorrhage in the anterior chamber, vitreous, retina, or subretinal space, retinal vascular tortuosity, multifocal to complete retinal detachment, or any combination of these signs. The ophthalmic examination was performed in a darkened room using a slit lamp microscope3 and an indirect ophthalmoscope.4
An 8-mL blood sample was obtained by jugular venipuncture for routine laboratory examination and for measurement of PAC and PRA. For the latter measurements, blood was collected into an ice-chilled EDTA-coated tube and kept on ice until centrifuging. The sample was centrifuged for 10 minutes at 2500 × g and plasma was stored at −20°C until further processing. PAC and PRA were measured as described previously, and validated for the cat. The plasma ARR was calculated by dividing the PAC (pmol/L) by the PRA (fmol/L/s). PRA values below the detection limit were set at 40 fmol/L/s in order to allow calculation of the minimum ARR.
Morning urine samples were collected by the owner from the cat's litter box, which had been cleaned, dried, and bedded with a non-absorbent cat litter,4 and were kept refrigerated until processed. A sample for routine urine examination was collected within 24 hours before the examination, or obtained by cystocenthesis. Urinary aldosterone concentration was measured as described previously. The UACR was calculated by dividing the urinary aldosterone concentration (pmol/L) by the urinary creatinine concentration (μmol/L). The percent suppression of the UACR by fludrocortisone was calculated as 100 × (UACR on day 0 − UACR on day ×)/UACR on day 0.
Abdominal ultrasonography was performed with a high-definition digital ultrasound system6 by use of a 7.5 MHz phased-array transducer or an 8.5 MHz broadband curved-array transducer, or both.
Arterial blood pressure and plasma potassium concentration were measured at a median interval of 7 days (range 3–10 days) before the suppression test. Morning urine samples were collected for measurement of the UACR. After collection of the first urine sample (day 0), fludrocortisone acetate7 was administered in a dose of 0.05 mg/kg BW orally twice daily for 4.5 days (days 0–4). The suppression test was performed at home in all Dutch cats and one Swiss cat, and at the respective university clinics in the other Swiss cat and the Greek cat. Urine samples for determination of the UACR were collected every morning (days 1–4) or, in 4 cases, in the morning following the last evening dose only (day 4). After collection of the last urine sample, the last morning dose of fludrocortisone was administered to 10 non-PHA cats and 5 PHA cats and the arterial blood pressure and plasma potassium concentration were measured at about the same time of day as before the suppression test.
Statistical analyses were performed using IBM SPSS Statistics version 126.96.36.199 The Shapiro–Wilk test was used to test the data for normal distribution. Groups were compared using Levene's test for equality of variances and an independent-samples t-test for equality of means for data with a normal distribution, and the Wilcoxon signed rank test for data with a non-Gaussian distribution. P < .05 was considered significant. Data are expressed as median and range.
Plasma aldosterone concentration and ARR were increased in all PHA cats and PRA was suppressed in all but 1 PHA cat, whereas these parameters were within or near the limit of the reference range in non-PHA cats (Fig 1). The plasma potassium concentration in PHA cats was significantly lower (P = .019) than that in non-PHA cats, whereas other parameters did not differ significantly between these 2 groups (Table 1).
|Parameter (Units)||Non-PHA||PHA||Reference Range|
|Sodium (mmol/L)||150.5 (145–153) ||151 (147–155) ||146–158|
|Potassium (mmol/L)||3.65 (3.1–4.6) ||2.85 (1.8–3.7) ||3.4–5.2|
|Urea (mmol/L)||11.2 (8.8–14.7) ||13 (7.5–16.2) ||6.1–12.8|
|Creatinine (μmol/L)||161 (113–227) ||157.5 (100–198) ||76–164|
|Calcium (mmol/L)||2.575 (2.43–2.83) ||2.625 (2.38–2.70) ||2.36–2.86|
|Phosphate (mmol/L)||1.2 (0.99–1.66) ||1.15 (1.05–1.37) ||0.89–2.05|
|Albumin (g/L)||27 (22–40) ||25 (22–26) ||25–34|
|Total thyroxine (nmol/L)||21 (16–56) ||17 (14–38) ||15–45|
|Fructosamine (μmol/L)||204 (166–241) ||188 (179–303) ||156–240|
|Hematocrit (L/L)||0.34 (0.27–0.38) ||0.36 (0.35–0.38) ||0.28–0.47|
|Specific gravity||1.030 (1.020–1.046) ||1.025 (1.016–1.040) ||>1.020|
|Protein-to-creatinine ratio||0.24 (0.1–0.95) ||0.19 (0.1–0.25) ||<0.4|
The basal UACR was significantly higher (P < .01) in the PHA cats than in the non-PHA cats (Table 2). There was a significant difference (P < .01) between UACR before and after fludrocortisone administration in the non-PHA cats, but not in the PHA cats.
|Time||UACR (×10−9)||Systolic Blood Pressure (mmHg)||Plasma Potassium Concentration (mmol/L)|
|Non-PHA||6.25 (2.5–17.2)||2.8 (0.7–7.3)||149 (130–283) ||146 (126–263) ||3.8 (3.3–4.6) ||3.3 (2.7–4.9) |
|PHA||18.2 (10.6–135)||20.9 (4.7–156)||141 (122–151) ||142 (123–144) ||3.45 (3.1–3.6) ||3.25 (2.6–4.1) |
In all non-PHA cats, the basal UACR was within the reference range of <46.5 × 10−9, whereas the basal UACR exceeded the reference range in 3 PHA cats (Fig 2). All PHA cats had basal UACRs >7.5 × 10−9. After 4 days of fludrocortisone administration, the UACR was suppressed in all non-PHA cats by a median of 62.5% (range 33–76%). In contrast, the UACR was suppressed in only 4 of the 9 PHA cats, at a maximum of 70%. The suppression in the non-PHA cats did not differ significantly (P = .11) from the median suppression of 78% (range 44–97%) reported in 15 healthy cats. Also, the suppressed UACR values on day 4 in non-PHA cats were not significantly different (P = .39) from those reported in healthy cats.
Suppression of the UACR by fludrocortisone was not related to the etiology of PHA. The UACR was suppressed in 2 cats with adrenocortical adenoma but increased in the third, suppressed in only 1 of 2 cats with an adrenocortical carcinoma, and suppressed in only 1 of 2 cats with PHA and normal-sized adrenal glands by ultrasonography, suggestive of bilateral hyperplasia of the zona glomerulosa.
In most non-PHA cats, the UACR was increased on individual days of fludrocortisone administration before eventually being suppressed (Fig 3). In comparison with the non-PHA cats, the 5 with PHA had only mild fluctuations in day-to-day suppression.
Valid measurements of pre- and postsuppression systolic blood pressure were obtained in 8 non-PHA and 3 PHA cats, and measurements of plasma potassium concentration in 9 non-PHA and 4 PHA cats (Table 2). Neither systolic blood pressure nor plasma potassium concentration before and after fludrocortisone suppression differed significantly in either group. Any increments in systolic pressure during the fludrocortisone suppression test were <10% of the pretest value, and did not result in systolic arterial pressures >160 mmHg. Plasma potassium concentration decreased in 6 non-PHA and 2 PHA cats, by a median of 0.65 mmol/L (range 0.5–1.7 mmol/L), and reached values below the reference range in 7 cats. This was associated with muscle weakness in 1 PHA cat.
Basal UACR values in cats with PHA overlapped with those in cats with arterial hypertension or hypokalemia and arterial hypertension because of other causes, but basal UACR was >7.5 × 10−9 in all cats with PHA and above the reference range only in individual cats with PHA. In other words, an elevated basal UACR pointed to PHA and a basal UACR <7.5 × 10−9 excluded PHA. For UACR values between 7.5 × 10−9 and the upper limit of the reference range, the fludrocortisone suppression test was required for differentiation. As in healthy cats, 4 days of oral fludrocortisone administration induced >50% suppression in all non-PHA cats with basal UACRs >7.5 × 10−9. In contrast, fludrocortisone administration resulted in <50% suppression in 6 of the 9 PHA cats. Applying the criteria for both basal UACR and fludrocortisone suppression test results, ie, a basal UACR <7.5 × 10−9 excludes PHA, a basal UACR above the reference range points to PHA and, in cats with a basal UACR between 7.5 × 10−9 and 46.5 × 10−9, >50% suppression of the UACR excludes PHA, correctly indicated non-PHA in all cats in which ARR was not elevated and correctly indicated PHA in 7 of the 9 cats in which ARR was elevated.
Multinodular disease of the zona glomerulosa was confirmed in one and suspected in 1 other PHA cat with a basal UACR within the reference range and a >50% suppression after fludrocortisone administration. The former had a unilateral multinodular adrenocortical adenoma confirmed histologically and the latter had adrenals of normal size by ultrasonography, suggesting that bilateral hyperplasia of the zona glomerulosa caused the elevated ARR. Multinodular disease of the zona glomerulosa might have rendered these cats still partially susceptible to normal aldosterone regulation, which could explain the fludrocortisone suppression test results. In another PHA cat with normal-sized adrenals on ultrasonography, however, the basal UACR was elevated and not suppressed by fludrocortisone. These 3 cases support the impression of considerable individual variation in both the level and the autonomy of aldosterone secretion in cats with multinodular disease of the zona glomerulosa.
Considerable individual variation in both the basal UACR and suppression was found in cases of zona glomerulosa neoplasia. This indicates that neither an elevated basal UACR nor a specific level of suppression can be used to predict the etiology (adenoma, adenocarcinoma, or suspected bilateral hyperplasia of the zona glomerulosa) of PHA.
Mild day-to-day fluctuations in UACR, presumably mirroring daily fluctuations in aldosterone secretion, were noted in almost all cats throughout the fludrocortisone suppression test. The nearly 5-fold increase in the UACR in 1 cat on day 2 of fludrocortisone administration is unexplained.
Fludrocortisone can have adverse effects because of activation of mineralocorticoid receptors in the distal nephron. Enhanced sodium and water resorption and potassium excretion can potentially lead to arterial hypertension, hypokalemia, or both. This could be of concern in cats prone to, or affected by, arterial hypertension or hypokalemia. In 7 of the 11 cats in which systolic blood pressure was measured before and after the suppression test, fludrocortisone had little or no effect. The small changes observed probably represented normal fluctuations. Changes in plasma potassium concentration were also mild in most of the cats but decreases >1 mmol/L did occur in 3 and hypokalemia was induced or exacerbated in 7 cats, leading to muscle weakness in 1. Daily measurements of plasma potassium are therefore advisable to optimize potassium supplementation during the test period.
The minimum duration of the fludrocortisone suppression test can be derived from Figure 3. Maximum suppression of UACR was achieved after a minimum of 3 days in 9 of the 10 non-PHA cats, but in 1 cat marked suppression did not occur until day 4. Hence, a duration of 4 days would seem advisable, as is used in humans.
Guidelines for the test in humans include insuring that the patients are potassium-replete and that medications that markedly affect the ARR, such as spironolactone, are discontinued for at least 4 weeks. Furthermore, if hypertension can be controlled with relatively non-interfering medications such as nondihydropyridine calcium channel antagonists and alpha-adrenergic blockers, it is also advisable to withdraw beta-adrenergic blockers, dihydropyridine calcium channel antagonists, and angiotensin-converting enzyme inhibitors for at least 2 weeks before testing, although these guidelines are currently under debate. Unfortunately, most cats with PHA have severe arterial hypertension, and this is best controlled using a dihydropyridine calcium channel antagonist (eg, amlodipine), either alone or in combination with a beta-adrenergic blocker or an angiotensin-converting enzyme inhibitor. Although these guidelines were followed in 2 initial cats of our study (1 of which was already permanently blind because of complications of arterial hypertension), it was then decided to aim for a stable arterial pressure within the reference range before starting the test, in order to preserve or try to restore vision, and reduce the risk of further hypertension-induced damage to organs such as the heart, kidneys, and brain. Therefore, most cats of our study received amlodipine, and some also received atenolol. Although it is unknown whether these medications affected suppression test results, any such effects should have occurred in both PHA and non-PHA cats.
Spironolactone was considered essential during the fludrocortisone suppression test in a cat with an adrenocortical adenoma, in which normokalemia could not be achieved by oral potassium supplements alone. The short-term administration of spironolactone is unlikely to have contributed to the extremely high basal UACR of 135 × 10−9 found in this cat, but might have falsely lowered the suppression rate by competing with fludrocortisone for the mineralocorticoid receptor.
A confirmative test should be safe and practical in order to facilitate its wide application. A test based on suppression of urinary aldosterone excretion rather than ARR achieves this, since urine can be collected easily and non-invasively, and aldosterone is sufficiently stable to allow sample shipping without the temperature constraints for PRA preservation. The aldosterone level in a morning urine sample also reflects aldosterone secretion over a long interval rather than at a single point in time. The UACR before and after suppression might even be an alternative to the ARR in situations in which PRA measurement is not practicable.
In summary, PHA should be considered in any cat with hypokalemia, arterial hypertension, chronic kidney disease, or all, and other potential causes should be excluded. Following a positive screening test, ie, an elevated ARR, the oral fludrocortisone suppression test can be used to confirm the diagnosis. Diagnostic imaging techniques such as ultrasonography and computed tomography should be used to determine the laterality of the excessive aldosterone production.
The oral fludrocortisone suppression test appears to be reliable to exclude the diagnosis of PHA in cats with an ARR within the reference range. In addition, it confirms most cases of PHA, although it does not identify all those with multinodular disease of the zona glomerulosa. Our findings suggest that the fludrocortisone suppression test should be performed in cats with a basal UACR between 7.5 × 10−9 and 46.5 × 10−9, and that suppression <50% indicates inappropriate aldosterone secretion. Neither an elevated basal UACR nor a specific level of suppression can be used to predict the etiology (adenoma, adenocarcinoma, or bilateral hyperplasia of the zona glomerulosa) of PHA. Arterial normotension and normokalemia should be established before the fludrocortisone suppression test is undertaken and it can be necessary to monitor plasma potassium concentration during the test.
The authors thank the owners of the cats for their kind participation in the study, and Drs Annemarie Bulten, Mara Broere, Willemijn Ekkenbus, Anke de Jonge, Kristel de Munnik, and Jennifer Verhoek for their help in collecting the data. The authors are grateful to Dr Christos Koutinas and Dr Nektarios Soubasis from Aristotle University, Thessaloniki, Greece, and Dr Barbara Willi from the University of Zurich, Switzerland, for submitting urine samples and kindly supplying clinical data of cats suspected of having PHA. The study was financed by grants from The Netherlands Association for Companion Animal Medicine of the Royal Netherlands Veterinary Association and Stichting Diergeneeskundig Onderzoek Gezelschapsdieren. Non-absorbing cat litter was provided by Rein Vet Products, Utrecht, The Netherlands.
Urinary aldosterone-to-creatinine ratio values of 1 PHA cat were included in an earlier publication. History and pictures of 2 cats with PHA were used in another publication. One PHA cat was presented by Dr E. Kolia at the Second Veterinary Forum of the Hellenic Companion Animal Veterinary Society (Thessaloniki, Greece, 2011). No other parts of this study have been reported at any meeting.
Conflict of Interest Declaration: Authors disclose no conflict of interest.
Parks Model 811-B ultrasonic Doppler flow detector; Parks Medical Electronics Inc, Aloha, OR
Rudolf Riester GmbH & Co.KG, Jungingen, Germany
Kowa SL-15; Kowa Europe GmbH, Duesseldorf, Germany
Heine Video OMEGA 2C; Heine Optotechnik, Herrsching, Germany
Katkor; Rein Vet Products, Utrecht, The Netherlands
ATL Ultramark HDI 3,000; Philips, Eindhoven, The Netherlands; HD11 XE, Philips
Florinef acetate; Bristol-Myers Squibb BV, Woerden, The Netherlands
IBM Corporation, Armonk, NY