Hervé P. Lefebvre, DVM, PhD, DECVPT
UMR 181 Physiopathologie et Toxicologie Experimentales INRA, ENVT and Department of Clinical Sciences, National Veterinary School
The optimal objectives of the medical management of chronic kidney disease (CKD) are to delay the progression of the disease, to maintain the quality of life of the patient and to increase survival time. Angiotensin-converting enzyme (ACE) inhibitors appears to be the most efficient pharmacological agents in such therapeutic strategies. During the 1990s, the benefit of ACE inhibitors was evidenced in human hypertensive and non hypertensive nephropathies. These drugs were shown more recently to be also useful in the management of canine and feline CKD.
Pharmacokinetics and Pharmacodynamics of ACE Inhibitors in Healthy and Renal-impaired Conditions
The oral formulations of all veterinary ACE inhibitors (benazepril, enalapril, imidapril and ramipril) correspond to the pro-drug, i.e., an ester of the active moiety, which is absorbed from the digestive tract. The peak plasma concentration of the pro-drug is observed within 30-40 min for most ACE inhibitors in dogs. After absorption, the pro-drug is metabolized in the liver into its active metabolite. The bioavailability of the pro-drugs benazepril and enalapril in dogs ranges from 20 to 40%. Elimination routes differ between ACE inhibitors. For example, in dogs, enalaprilat is mainly cleared (95%) by the kidney while benazeprilat is cleared by both renal (45%) and hepatic (55%) routes. Renal dysfunction has a limited impact on the concentration profiles of ACE inhibitors (e.g., benazeprilat and ramiprilat) mainly cleared by hepatorenal routes while it increases exposure of ACE inhibitors essentially cleared by the kidneys (e.g., enalaprilat) (Lefebvre et al, 1999; 2006). In dogs with decreased glomerular filtration rate (GFR), overexposure to enalaprilat (up to 405%) but not benazeprilat may occur. In cats, benazeprilat is excreted predominantly (about 85%) by the liver and renal dysfunction does not alter benazeprilat pharmacokinetics (King et al, 2002).
The enzymatic cascade by which angiotensin II is produced consists of renin, which cleaves angiotensinogen to form the decapeptide angiotensin-I. Angiotensin-I is then further cleaved by angiotensin-converting enzyme (ACE) to produce angiotensin II, the physiologically active component of the system. Systemic actions of angiotensin II are mainly hypertensive. Bradykinin, an endogenous vasodilator peptide, is also metabolized by ACE. Inhibition of ACE contributes therefore to vasodilation by decreasing the angiotensin II production and inhibiting the bradykinin catabolism. Angiotensin II increases also water volume through sodium (via aldosterone) and water (via antidiuretic hormone) retention. In renal pathophysiological conditions, it is also responsible for growth and profibrogenic actions, cell proliferation, production of cytokines and extracellular matrix proteins, and renal inflammatory cell infiltration.
A single oral benazepril administration at a dose of 0.5 mg/kg induces a rapid decrease in plasma ACE activity with maximal, and nearly total, inhibition observed one hour after dosing. A progressive return to pre-treatment values begins 16 h after benazepril administration, but the ACE activity is only 14% of the control values at 24 h, and 66% after 72 h (Toutain et al, 2000a). The IC50 of enalaprilat, i.e., the free plasma concentration required to produce 50% of the total inhibition, is increased by 2.6 fold in dogs with subclinical CKD (Toutain et al, 2000b).
Effect of ACE Inhibitors on Glomerular and Systemic Hypertension, and Proteinuria
One of the major beneficial effect of ACE inhibitor is to lower glomerular pressure. Glomerular hypertension is a functional adaptation of the surviving nephron, which increases the filtration capacity of each individual nephron and therefore compensate for the decrease in GFR because of the loss of nephrons. Long-term effect of glomerular hypertension is deleterious as stretching of capillaries and mesangial cells leads to glomerular damage and consequently to progression of CKD. ACE inhibitors lower glomerular pressure by decreasing systemic blood pressure and inhibiting the angiotensin II-induced vasoconstriction of the efferent arteriole. With enalapril, the efferent arteriolar resistance is decreased by 30% (Brown et al, 2003). In cats with experimental CKD, the arteriolar vascular effect and not the systemic antihypertensive effect is the primary factor contributing to the decrease in glomerular hypertension (Brown et al, 2001).
Hypertension is a frequent finding in dogs and cats with advanced stage of CKD. ACE inhibitors are generally mildly hypotensive in dogs. The maximal decrease in blood pressure is observed between 1 and 6 h following dosing, but the change does not exceed 20 mmHg (Lefebvre et al, 2004). In cats, the anti-hypertensive effect of ACE inhibitors is generally negligible, and amlodipine besylate is preferred. ACE inhibitors may be added to amlodipine when blood pressure does not return to normal values with amlodipine monotherapy.
ACE inhibitors also appear to have the greatest antiproteinuric effects in patients with CKD. Proteinuria is not only a marker of glomerular damage but also a major factor in the progression of CKD. Filtered proteins induce the expression of proinflammatory cytokines and are directly toxic to the tubular epithelial cells. Proteinuria is also a prognostic indicator in CKD in dogs (Jacob et al, 2005) and cats (Syme et al, 2006). In canine idiopathic glomerulonephritis, a randomized, blinded, placebo-controlled trial was performed to assess the effect of enalapril. The initial dose of enalapril was 0.5 mg/kg PO q24h but was increased to 0.5 mg/kg q12h after 30 days of treatment if the UPC remained at >50% of the baseline value. Enalapril induced a decrease in proteinuria. The mean values at baseline for UPC were 4.7 and 8.7 in the placebo and enalapril treatment group, respectively. At six months after treatment, the mean values of UPC were 6.6 and 3.7, respectively (Grauer et al, 2000). Similarly, antiproteinuric effect of benazepril was evidenced in cats with CKD (King et al, 2006).
Effect of ACE Inhibitors on the Progression of CKD
The first controlled study of an ACE inhibitor in the treatment of a naturally occurring renal disease in dogs was performed in Samoyed-cross male pups with X-linked hereditary nephritis (Grodecki et al, 1997). Enalapril was administered continuously orally q12h at a dose of 2 mg/kg from the age of 4 weeks, i.e., at an asymptomatic stage of the disease. Enalapril treatment induced a decrease in proteinuria, and decreased glomerular basement membrane splitting. The increase in serum creatinine concentration was delayed. The effective renal plasma flow was lower in untreated animals. Treatment increased the survival time by 36%. In dogs with experimental renal failure, enalapril (0.5 mg/kg PO q12h) decreased glomerular and tubular interstitial lesion scores (Brown et al, 2003). In dogs with naturally occurring CKD, no change in serum creatinine was observed following enalapril treatment. However, an increase of more than 0.2 mg/dL after 6 months of treatment was observed in only 3/16 enalapril-treated dogs, and in 13/14 placebo-treated dogs. Enalapril improved also the response to treatment (Grauer et al, 2000).
In cats, a double-blind, parallel-group, prospective, randomized clinical trial was recently published. A total of 192 cats with CKD with an initial plasma creatinine concentration >2 mg/dL and USG <1.025 were recruited. Cats were administered daily placebo or benazepril (0.5-1.0 mg/kg q24 h) for up to 1,119 days. A significant decrease in proteinuria was observed. Benazepril also increased appetite in cats with initial UPC > or equal to 1. No significant effect on survival times however was observed. No difference between benazepril and placebo treated groups was observed for the incidence of adverse events for any organ system (King et al, 2006). Similar results were obtained in another trial (Mituzani et al, 2006). In cats with polycystic kidney disease, enalapril (0.5 mg/kg, PO, q24h) given for 1 week did not significantly alter GFR or ERPF, but these animals did not show detectable abnormalities in renal function (Miller et al, 1999). In cats with experimental CKD, benazepril induced a significant increase in GFR but did not affect plasma creatinine concentration (Brown et al, 2001).
Potential Adverse Effects of ACE Inhibitors in Small Animals with CKD
The benefit to risk ratio of the treatment with ACE inhibitors is high as adverse effects of ACE inhibitors are rare and occur in specific conditions.
ACE inhibitors are contraindicated in pregnant animals and neonates, as renal RAAS plays indeed a pivotal role in nephrogenesis and renal development. One potential issue is the age at which treatment with ACE inhibitors of congenital renal disease can be initiated. In dogs, it was shown that initiation of enalapril treatment in puppies at 4 months of age did not induce any adverse effects (Grodecki et al, 1997).
ACE inhibitors can induce hypotension. Although ACE inhibitors are mildly hypotensive agents in dogs and cats, they are contraindicated in animals with pre-existing hypotension, hypovolemia, hyponatremia and acute renal failure.
ACE inhibitors may cause acute renal failure, especially when the renal perfusion is decreased (e.g., severe dehydration). In such conditions, glomerular filtration is maintained by angiotensin II-induced constriction of the efferent arteriole. The risk of plasma electrolyte alterations, especially hyperkalemia, is also very limited.
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