Clinical evaluation of plasma aldosterone concentration and eplerenone treatment in cats and dogs with chronic kidney disease

慢性腎臓病の猫と犬における血漿アルドステロン濃度およびエプレレノン治療の臨床学的評価

Clinical evaluation of plasma aldosterone concentration and eplerenone treatment in cats and dogs with chronic kidney disease

Degree Grantors Yamaguchi University

Aldosterone is a steroid hormone synthesized in the adrenal cortex and is part of the renin-angiotensin-aldosterone system (RAAS). It accelerates renal sodium retention and elimination of potassium through its action on the mineralocorticoid receptor (MR), and has a major role in regulating body fluid volume and blood pressure. Excessive secretion of aldosterone and activation of the MR cause cardiovascular inflammation, fibrosis and remodeling, and tubulointerstitial fibrosis and glomerular injury in the kidney. There are several reports on plasma aldosterone concentration (PAC) in healthy, chronic kidney disease (CKD), systemic hypertension, and chronic heart failure in cats and dogs. Measurement of urinary aldosterone/creatinine ratio has also been reported in cats and dogs. However, it has been suggested that measuring aldosterone in feline urine using the available methodology has limited or no utility in investigating feline hypertension associated with CKD. It may be important to evaluate PAC in cats and dogs with CKD associated with the activation of RAAS.
On the other hand, angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers suppress the RAAS during hypertensive, renal, and cardiac diseases in cats. The Randomized Aldactone Evaluation Study in humans showed that the aldosterone antagonist, spironolactone, reduced the mortality of patients with chronic heart failure who received ACEI and loop diuretics. Spironolactone also reportedly reduced the mortality rate in cats with congestive heart failure secondary to cardiomyopathy. Another selective aldosterone antagonist, eplerenone, not only antagonizes MR but also blocks the nongenomic effects of aldosterone in vascular tissues not susceptible to spironolactone. These effects of eplerenone may be more effective than spironolactone in treating hypertension due to vasoconstriction. Although eplerenone reduces mortality and hospitalization in human patients with chronic heart failure, there are no available reports on eplerenone’s use in feline practice.
Since elevated PAC is a risk factor for kidney injury in humans, and MR antagonists are beneficial in rodent models of CKD and human patients, it was hypothesized that if an elevated PAC is detectable in the early stages of the disease in cats, the use of eplerenone may prolong lifespan. However, the relationship between PAC and the survival time in cats and dogs with CKD has not been investigated. Therefore, this study aimed to investigate PAC in cats and dogs with CKD, and evaluate the influence of high PAC on the survival time of CKD animals and the effect of treatment with eplerenone in CKD cats with high PAC.
In chapter 1, PAC in cats with CKD was investigated retrospectively, and the survival time of cats with high PAC was evaluated. Furthermore, the effect of treatment with eplerenone on survival time in CKD cats with high PAC was examined prospectively. The eplerenone study was conducted including both cats with CKD only and CKD cats complicated cardiac disease or systemic hypertension. The PAC was measured retrospectively in blood samples obtained from 156 client-owned cats that visited a veterinary hospital. The cats were designated into 2 groups: clinically healthy (n = 101) and CKD (n = 55). The PAC was measured by solid-phase radioimmunoassay. Median (minimum–maximum) PAC in healthy cats was 97 (10–416) pg/mL and the upper limit (95th percentile) was 243 pg/mL. In the CKD group, PAC [126 (10–981) pg/mL] was significantly higher than in the clinically healthy group. In the CKD group as classified by the International Renal Interest Society (IRIS) stage, the PACs were higher in IRIS stage 2 than in the healthy group. Similarly, PACs in IRIS stage 3 and 4 cats were higher than in the healthy group. In cats with CKD, the survival time of those with high PAC (n = 16) (> 243 pg/mL) was significantly shorter than that of those (n = 39) with normal PAC. In cats with high PAC and CKD, eplerenone administration (2.5 to 5 mg/kg body weight; n = 8) prolonged significantly the survival compared to cats not receiving eplerenone (n = 18). These results indicated that PAC could be a prognostic marker of CKD in cats and that eplerenone may prolong the survival in cats with CKD and high PAC complicated with cardiac disease or hypertension.
In chapter 2, PAC in dogs with CKD was investigated retrospectively, and the survival time of CKD dogs with high PAC was evaluated. PAC was measured in blood samples obtained from 145 client-owned dogs. The dogs were divided into two groups: clinically healthy (n = 106) and CKD (n = 39). In clinically healthy group, median (minimum–maximum) PAC was 56 (10–250) pg/mL, and the upper limit (95th percentile) was 182 pg/mL. PAC (median 69 pg/mL; range 10–553 pg/mL) in CKD group was significantly higher than in the healthy group. In the CKD group as classified by IRIS stage, PAC (median 97 pg/mL) in IRIS stage 2 and 3 was significantly higher than in the healthy group. A significant positive correlation between PAC and IRIS stage was observed in CKD dogs, suggesting that the lower survival rate in high PAC group may be related to severity of CKD. In dogs with CKD, the survival time of those with high PAC (n = 10) (> 182 pg/mL) was significantly shorter than that of those with normal PAC (n = 24). These results suggested that high PAC might indicate shorter survival time in dogs with CKD.
In conclusion, this study revealed that both cats and dogs with CKD had significantly higher PAC than clinically healthy animals. In CKD, the survival time of cats and dogs with high PAC was significantly shorter than those with normal PAC. The use of eplerenone also significantly prolonged the survival of cats with high PAC in CKD complicated with cardiac disease or hypertension. This study proposes PAC as a prognostic marker of cats or dogs with CKD. Eplerenone may be useful in prolonging cats’ survival with high PAC in CKD complicated with cardiac disease or hypertension. However, further study on PAC level in CKD progression and treatment response in a larger population may be required. This study provided new information on the relationship between PAC and the survival of cats or dogs with CKD, and the effect of eplerenone treatment for the survival time of cats with high PAC and CKD.

Creators 甲斐 みちの