Urinary Aldosterone/Creatinine Ratio After Fludrocortisone Suppression Consistent with PHA in a Cat

Introduction

Feline primary hyperaldosteronism (PHA) is a rarely diagnosed endocrinopathy that is mainly caused by unilateral or bilateral adrenal micro- and macroadenomas or micronodular hyperplasia of the zona glomerulosa together with hypokalemia and systemic hypertension as its laboratory and clinical hallmarks.¹ The diagnosis of PHA is usually straightforward, even though chronic renal failure and activation of the renin-angiotensin-aldosterone system may mimic its clinicopathological abnormalities. To differentiate primary from secondary hyperaldosteronism, dynamic testing, such as the urine aldosterone/creatinine ratio (UACR) before and after suppression with fludrocortisone acetate, has recently been suggested as an alternative to the aldosterone/renin ratio (ARR).² To the study authors' knowledge, this is the second reported case in which this test has been performed.

Case Report

A 9 yr old castrated male domestic shorthair was admitted to the Companion Animal Clinic of the Faculty of Veterinary Medicine, Aristotle University of Thessaloniki because of progressive weight loss despite normal appetite and occasional lethargy. The cat lived in a shelter with several other cats, was not routinely vaccinated and dewormed, and was fed a commercial dry food as well as homemade food. Prior problems included a right femoral fracture after a fall and a persistent cough that responded well to doxycycline treatment. On clinical examination, the cat was in poor body condition (body weight was 3.1 kg), had an accumulation of dental plaque, a grade 4/6 holosystolic murmur over the heart apex, and a small right kidney on abdominal palpation. Complete blood cell count revealed a neutrophilic leukocytosis, and routine biochemical parameters (including plasma potassium and creatinine concentrations) were within normal limits (Table 1). Urinalysis revealed an appropriate specific gravity and sediment; however, the urinary protein/creatinine ratio was 2.3 (reference range, <0.3). Urine bacterial culture was negative. On thoracic and abdominal radiographs, the only abnormal finding was a mild interstitial pattern in the caudal lung fields. Left ventricular free wall and interventricular septum hypertrophy was documented on echocardiography without left atrial enlargement or other abnormalities. Abdominal ultrasonography showed a small right kidney with increased echogenicity and adrenal glands that were normal in size and echogenicity (Table 1). Arterial blood pressure was measured using the coccygeal artery, a Doppler device, and appropriate cuff in a stress-free environment and was 280–300 mm Hg on repeated measurements.³ Based on the elevated blood pressure, a fundoscopic exam was performed that revealed partial retinal detachment in the left eye. A tentative diagnosis of hypertensive hypertrophic cardiomyopathy, hypertensive retinopathy, and chronic kidney disease [CKD; International Renal Interest Society (IRIS) stage I] were made. Additional test results included normal plasma total thyroxin concentration and an increased plasma aldosterone concentration (PAC) of 651 pmol/L (reference range, 195–390 pmol/L).

Table 1 Clinical, Biochemical, and Ultrasonographic Findings in a Cat Suspected of Primary Hyperaldosteronism After Measurement of the Urine Aldosterone/Creatinine Ratio and Fludrocortisone Suppression Test

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The cat was treated with oral amlodipine^a at a dose of 0.625 mg q 24 hr, benazepril^b at a dose of 0.5 mg/kg q 24 hr, and a palatable diet^c low in Na. Successive measurements of systolic blood pressure revealed persistent hypertension (170–250 mm Hg). To investigate the presence of PHA, antihypertensive treatment was withheld for 2 days before PAC and plasma renin activity (PRA) were measured. PAC was increased (879 pmol/L), and PRA was within the reference range (1.85 ng/mL/hr; reference range, 0.28–2.96 ng/mL/hr), resulting in an increased plasma ARR.

Urinalysis revealed a normalization of the urine protein/creatinine ratio. At the same time, and in order to establish an etiological diagnosis, the UACR was determined both before and after oral administration of fludrocortisone acetate as described previously.² The cat was hospitalized. On the first day, a urine sample was obtained by cystocentesis before the daily administration of fludrocortisone acetate^d at a dose of 0.05 mg/kg q 12 hr for 4 consecutive days. Intermittent blood pressure monitoring documented a persistent, but moderate, systemic arterial hypertension (<220 mm Hg); however, the cat was alert and stable during the test period, and fundoscopic examination during that time did not reveal any changes. On the fifth day, a second morning urine sample was obtained and the UACR was measured. The basal UACR was 92.6 × 10⁻⁹ (reference range, <46.5 × 10⁻⁹) and the UACR after fludrocortisone administration was 155.8 × 10⁻⁹ (reference range, <6 × 10⁻⁹).² The increased basal ratio and the complete lack of suppression that is otherwise expected from normal adrenal glands strongly supported the hypothesis of PHA. Antihypertensive therapy was reinstituted; however, while waiting for the results of the suppression test, the cat died suddenly at home. A necropsy was declined by the owner.

Discussion

PHA is typically regarded as a rare disorder but should probably be considered an underdiagnosed endocrinopathy in cats. PHA is mainly characterized by systemic arterial hypertension and/or hypokalemia.¹ It is caused by either uni- or bilateral neoplasia or hyperplasia of the zona glomerulosa tissue, resulting in increased aldosterone production and release into the circulation, which is the main pathophysiological mechanism behind systemic hypertension and potassium wasting.⁴ However, as in the case described herein, hypokalemia may not be a consistent finding.^4,5 Also, arterial hypertension is not present in all cats with PHA.^4,5 In addition, systemic arterial pressure is not measured on a regular basis by most veterinarians, and arterial hypertension may therefore be overlooked.¹ PHA may both mimic and induce CKD, creating a conundrum as to whether CKD precedes arterial hypertension or is the result of systemic hypertension and PHA.^1,5

Although increased PAC can be indicative of PHA, it may also result from excessive activation of the renin-angiotensin system as in secondary hyperaldosteronism. Conversely, concurrent hypokalemia should decrease PAC.^4,5 PAC should therefore always be interpreted in the light of PRA and plasma potassium concentration. Suppressed PRA, by itself, is not always diagnostic for PHA because renin can also be either normal or low in cats with CKD and secondary hypertension.^6,7 On the other hand, in human and feline patients with PHA and/or CKD with secondary hypertension, renin has been found to be normal or increased.^5,8–10 For those reasons, stand-alone measurement of either PAC or PRA may raise the index of suspicion but cannot offer a definitive diagnosis. Laboratory sensitivity is another factor that may affect PAC and PRA measurements.^11–13

Measurement of the aldosterone concentration in urine collected during a 24 hr period has been used to assess mineralocorticoid status in humans.¹⁴ Because that method is almost inapplicable in veterinary patients, the single-sample UACR has been suggested instead.¹⁵ That said, the UACR did not differ significantly between normal, normotensive, and hypertensive azotemic cats, probably because of the very low aldosterone levels in feline urine.¹⁶ Even though that test was not applied to PHA cases and the results of the study of Syme et al. (2007) were not compared to PAC, the stand-alone measurement of urine aldosterone concentration apparently lacks sensitivity.¹⁵ That assumption is further supported by finding a basal UACR within the reference range in a cat with confirmed PHA.² In the cat described herein, however, the UACR did exceed the reference range, suggesting PHA.

In human patients with PHA, the fludrocortisone suppression test (FST) is used as a confirmatory test, even though the need to go beyond the ARR to diagnose the disease has been challenged.¹⁶ In the FST, aldosterone is measured in plasma before and after 4 days of fludrocortisone administration. The use of the FST by measuring UACR is a novel approach to reach a diagnosis of PHA noninvasively in cats.² In contrast to oral salt loading, oral fludrocortisone acetate (at a dose of 0.05 mg/kg q 12 hr) resulted in significant aldosterone suppression in 15 healthy cats.² In that same study, one cat with PHA had increased UACR after suppression, similar to the case described herein. Even though larger feline populations are required to validate this method as a confirmatory test for PHA, the fact is it bypasses the measurement of renin activity (which can be affected by the laboratory method applied, concurrent medications, Na status, and renal function), lowers the cost, and increases the reliability of the method. Its diagnostic sensitivity could theoretically be limited by the minimal excretion of aldosterone in the feline urine compared to humans.¹⁵

Even though the discontinuation of antihypertensive drugs for the duration of the suppression test and the possibility of fludrocortisone-induced side effects are a concern when performing the FST in humans, the clinical condition of the cat described in this report remained stable throughout the test period.^16,17 Because both dihydropyridines and angiotensin-converting enzyme inhibitors can lower PAC, they may influence the results of this dynamic test.^7,18 However, there are no data regarding the effect of those drugs on aldosterone secretion in cats with PHA. In this case, the 2 day washout period was suboptimal because, in humans, discontinuation of dihydropyridines and angiotensin-converting enzyme inhibitors is suggested to be of at least 2 wk duration.¹⁹ That seems to suggest that their effect was present throughout the duration of the FST, but UACR values were increased nonetheless. Therefore, altering the medication status, especially in the setting of hypertensive target-organ pathology, is not warranted until substantiated by potential future studies.

A definitive diagnosis of PHA was not possible in this case because a postmortem examination that could have possibly verified a microadenoma or hyperplasia of the zona glomerulosa was not performed. Abdominal ultrasonography, which was unremarkable in the described cat, in conjunction with either computed tomography or MRI, has been used in previous cases to assess the adrenal glands for unilateral or bilateral masses.²⁰ However, diagnostic imaging techniques are not always accurate in establishing the etiology of PHA in cats.¹

Conclusion

Proteinuria and systemic hypertension on admission is compatible with an underlying IRIS stage I CKD with arterial hypertension in the cat described in this report. It is unknown whether CKD was the result of PHA or if the severe hypertension can be solely explained by the concurrent IRIS stage I renal failure. However, the high PAC on admission and the results of the fludrocortisone suppression test are highly suggestive of PHA.