Suspected primary hyperreninism in a cat with malignant renal sarcoma and global renin‐angiotensin‐aldosterone system upregulation

Abstract A 14‐year‐old male castrated domestic medium‐hair cat with diabetes mellitus was evaluated for vomiting, diarrhea, and anorexia. Two weeks before presentation, the cat had been diagnosed with congestive heart failure and started on furosemide. Initial diagnostic testing identified hypokalemia, systemic hypertension, and hypertrophic cardiomyopathy phenotype, and plasma aldosterone concentration was moderately increased. Abdominal ultrasound examination disclosed bilateral adrenomegaly and a right renal mass, and cytology of a needle aspirate of the mass was consistent with malignant neoplasia. The cat was treated with amlodipine and spironolactone. Because of the unusual presentation for hyperaldosteronism, a comprehensive profile of renin‐angiotensin‐aldosterone system (RAAS) peptides was performed. Results from multiple timepoints indicated persistently and markedly increased plasma renin activity and generalized RAAS upregulation. In addition to the lack of adrenal tumor, the markedly increased plasma renin activity was atypical for primary hyperaldosteronism. These clinical findings are suggestive of primary hyperreninism, a condition previously unreported in cats. The concurrent presence of a renal neoplasm suggests the possibility of a renin‐secreting tumor.

to an overall increase in systemic blood pressure and glomerular filtration rate. 1 The activity of the RAAS is related to both renal and cardiovascular status. Although the RAAS is intended to be protective against hypovolemia or hypotension, abnormal activation of this system can be seen with disease processes such as chronic kidney disease (CKD) and cardiac disease. In these instances, excessive RAAS activation can further exacerbate the underlying disease through mechanisms including systemic hypertension, glomerulosclerosis, and myocardial fibrosis. [2][3][4][5] For this reason, RAAS-inhibiting agents, such as ACE or renin inhibitors, frequently are utilized as adjunctive treatments. 1 Beyond the traditional pathway of renin, AngI, ACE, and AngII, recent research has identified additional components of the RAAS.
The discovery of ACE2, as well as multiple alternative downstream angiotensin peptides including angiotensin III (AngIII), angiotensin IV (AngIV), Ang (1)(2)(3)(4)(5)(6)(7), and Ang (1)(2)(3)(4)(5), provides further insight into the complex nature of this system as well as offering potential targets for future research and treatments. 6,7 Interestingly, some of these novel peptides have been shown to have positive systemic effects and antagonize the action of AngII, which may depend not only on the specific peptide, but also on its concentration and the type of receptor that is bound. 7 Some RAAS-inhibiting agents, such as telmisartan, may exert beneficial affects not only by impeding the traditional RAAS, but also by diverting RAAS metabolites to these alternative beneficial pathways. 7,8 In cats, the relative concentrations of such new peptides (as well as possible derangements in the presence of systemic disease) are not well established. Consideration of both classical and alternative RAAS pathways is crucial for the understanding and management of disease.
Comprehensive RAAS profiling has been performed in healthy cats, as well as in cats with cardiomyopathy 8,9 or systemic hypertension. 9 Results of these studies suggest that among cats with cardiomyopathy, RAAS profiles remain unchanged compared to healthy cats during the early and asymptomatic phase. 8 In contrast, cats with more advanced disease and congestive heart failure show significant and nonspecific RAAS upregulation, with the most marked RAAS perturbations occurring in furosemide-treated cats. 9 Among cats with systemic hypertension, untreated cats did not differ from healthy controls, whereas significant nonspecific RAAS upregulation was observed in the subset of cats receiving amlodipine. 9 In this case report, we describe the use of a comprehensive RAAS profile to document markedly increased concentrations of both classical and alternative RAAS aminopeptides (APs) in a cat with hyperaldosteronism, systemic hypertension, congestive heart failure, CKD, and a renal mass, leading to suspicion of hyperreninism secondary to a renin-secreting tumor.  Abbreviations: AngI, angiotensin I; AngII, angiotensin II; AngIII, angiotensin III; AngIV, angiotensin IV; IQR, interquartile range; RAAS, renin-angiotensin-aldosterone system. F I G U R E 2 Cytology of a fine-needle aspirate of the cat's renal mass (Wright's stain, Â60 magnification). Cells displayed atypia with anisokaryosis, prominent nucleoli, and nuclear molding. Cytology was consistent with a malignant neoplasia with a sarcoma considered most likely. Scale bar = 20 μm q12h and blood glucose concentration was monitored regularly q2-4h. The cat ultimately was discharged on 1 unit insulin glargine SC q24h. time because of concern for additive effects on blood pressure. The patient again was evaluated 8 weeks after discharge for recurrence of lethargy, hyporexia, and substantial weight loss. Systolic blood pressure, serum fructosamine concentration, and a repeat total T4 concentration were within normal limits. A serum biochemistry profile disclosed static azotemia and hypokalemia as well as hyperglobulinemia (4.6 g/dL; RI, 2.3-3.8). Further imaging diagnostics (repeat abdominal ultrasound, computed tomography) were declined by the owner.

| CASE DESCRIPTION
Because of the cat's unusual hyperaldosteronism phenotype involving bilateral adrenomegaly (rather than a discrete adrenal mass), as well as the presence of a presumptive malignant renal mass, an AP profile (RAS-Fingerprint, Attoquant Diagnostics, Vienna, Austria) was performed to investigate whether components of the RAAS in addition to aldosterone were dysregulated. Repeated venous blood samples were collected on a single day, 1, 4, and 9 hours after receiving all current medications that morning (furosemide, amlodipine, clopidogrel, spironolactone, and potassium gluconate). Insulin was the only medication administered during the course of sample collection. Within a month after blood sampling for RAAS quantification, the cat's lethargy and weight loss progressed, prompting the owners to elect euthanasia.
Permission for necropsy was declined.

| COMPLETE RAAS PROFILE
The plasma equilibrium concentrations of 6 different RAAS angiotensin peptides, including AngI, AngII, AngIII, AngIV, Ang(1-7), and Ang (1)(2)(3)(4)(5) were quantified by liquid chromatography-mass spectrometry/mass spectroscopy performed at a commercial laboratory using previously validated and described methods. 8,10 Angiotensin-based markers for renin (PRA-S) and angiotensin converting enzyme (ACE-S) were derived from AngII and AngI concentrations by calculating their sum and ratio, respectively, as described by the analytical laboratory. 11,12 The results obtained were compared to RAAS profile results obtained from 34 healthy cats, 17 cats with underlying cardiomyopathy (7 of which received furosemide), and 15 cats with systemic hypertension (7 of which received amlodipine). 9 As shown in Tables 1 and 2, concentrations of RAAS angiotensin peptides in our cat were markedly increased compared to those of healthy cats, and in most cases exceeded the 75% percentile for cats with cardiomyopathy or  can be attributable specifically to hyperaldosteronism, the far more common cause of primary hyperaldosteronism (PA) in cats is unilateral adrenal neoplasia as opposed to the finding of bilateral adrenomegaly in this case. 13,14 Additionally, in cases of PA, the increased aldosterone concentration has an inhibitory effect on renin release, resulting in a decreased PRA. 14 The substantial increase in PRA observed in our case is more consistent with aberrant renin production leading to generalized RAAS upregulation and secondary hyperaldosteronism.
In humans, PRA often is increased secondary to CKD, and renininhibiting agents occasionally are used to manage disease sequelae. 15 By contrast, the available literature in cats with CKD is less clear.
Although earlier studies consistently document secondary hyperaldosteronism, PRA has been found to be low, normal, or high in cats with CKD. 16,17 The presence of concurrent hypertension, as seen in our cat, can decrease PRA in both normal and azotemic cats and can be associated with increased plasma aldosterone concentrations. 17 Plasma renin activity is increased in humans with congested heart failure (CHF), 3  Another study found that despite having increased aldosterone concentrations at baseline, hypertensive cats receiving amlodipine did not have further increases in aldosterone concentration. 17 In humans, most diuretics, including spironolactone and furosemide, lead to an increase in PRA, but in some patients PRA remains unchanged. [22][23][24] Preliminary data suggest that furosemide may further exacerbate RAAS disturbances in cats with cardiomyopathy. 9 Oral potassium supplementation also may increase aldosterone and PRA. 25 Although it is recognized that the cat's medications likely altered its RAAS profile, it is considered highly unlikely that these medications solely led to such marked global dysregulation.
The presence of a malignant renal neoplasm offers a possible etiology for the suspected hyperreninism in our case. In humans, hyperreninism has been associated with renin-producing juxtaglomerular cell tumors (reninomas), and affected patients may present with hypertensive cardiomyopathy and congestive heart failure. 26,27 Although in the present case, histopathology of the renal tumor was unavailable, a reninoma would be expected to result in similar RAAS perturbations.
The persistently increased RAAS activity, independent of the timing of medication administration, also is suggestive of aberrant and autonomous renin production.
Our case report had some limitations. As previously discussed, the concurrent administration of medications that can affect RAAS status likely influenced the results obtained in this case. However, it would be difficult to characterize the RAAS of a hyperreninemic cat without the influence of such medications, because the rarity of this disease entity, combined with the severe systemic sequelae, most T A B L E 3 Plasma equilibrium concentrations of RAAS aminopeptides, calculated PRA-S, and ACE-S from the reported case (average of 3 timepoints) and hypertensive cats receiving amlodipine and cats with cardiomyopathy receiving furosemide RAAS biomarker CM + furosemide (n = 7) SHT + amlodipine (n = 7) Patient