Read the French translation: Les IECA: Pour ou Contre la Prescription?

Introduction

During the 1990s, new knowledge about renal disease progression led to the opinion that pharmacological strategies might provide renoprotection, maintain the quality of life of the patient and increase survival time. Of all the candidate drugs, angiotensin-converting enzyme (ACE) inhibitors appeared to be the most efficient. Their benefit was first demonstrated in rodent models, and then in humans. In small animal medicine, ACE inhibitors were initially developed for the treatment of cardiac diseases. In the early 2000s, these agents were also proposed for the medical management of feline and canine chronic kidney disease (CKD). Their use for this indication is today popular although high quality evidence of their beneficial effect on relevant long-term clinical outcome is lacking. The benefit to risk ratio of ACE inhibitors in CKD depends moreover on the clinical condition of the patient, the stage of the renal disease, and the use of concomitant drugs.

Surrogate Endpoints Supporting the Use of Ace Inhibitors in Canine and Feline CKD

Antiproteinuric Effects

Proteinuria is not only a marker of glomerular damage, but also a major factor in CKD progression. Filtered proteins indeed induce the expression of proinflammatory cytokines and are directly toxic to the tubular epithelial cells. Proteinuria is also a major prognostic indicator in dogs¹ and cats² with CKD. It is associated with development of azotemia in healthy geriatric cats.³ ACE inhibitors appear to have the greatest antiproteinuric effect in patients with CKD.⁴ In canine idiopathic glomerulonephritis, enalapril decreased proteinuria. The mean baseline values for urine protein to creatinine ratio (UPC) were 4.7 and 8.7 in the placebo and enalapril treatment group, respectively. Six months after treatment, the mean values of UPC were 6.6 and 3.7, respectively.⁵ An antiproteinuric effect of benazepril was also evidenced in cats with CKD.^6,7

Effects on Systemic and Glomerular Hypertension

Systemic arterial hypertension is frequent in canine and feline CKD. High systolic blood pressure (SBP) is associated with increased risks of uremic crisis and mortality in dogs.⁸ In cats, unlike dogs, SBP and long term SBP control do not appear to be associated with survival in CKD.^2,9 Nevertheless, as systemic arterial hypertension may cause target organ damage (e.g., ocular lesions), an anti-hypertensive treatment is needed.

ACE inhibitors are mildly hypotensive in dogs. The maximal decrease in blood pressure, observed between 1 and 6 h after administration, generally does not exceed 20 mmHg.⁴ The anti-hypertensive effects of ACE inhibitors in cats are often negligible and amlodipine besylate is preferred as first-line treatment. ACE inhibitors may be added to amlodipine when blood pressure does not return to normal values with amlodipine monotherapy. The advantage of the combination is not only that ACE inhibitors and amlodipine are additive in their anti-hypertensive effect. As shown in normal dogs,¹⁰ amlodipine-induced activation of renin-angiotensin-aldosterone system (RAAS) is also partially negated by ACE inhibition.

Glomerular hypertension is a functional adaptation of the surviving nephron. It increases the filtration capacity of each individual nephron and therefore compensates for the decrease in total GFR resulting from the loss of nephrons. However, the long-term effect of glomerular hypertension is deleterious as stretching of capillaries and mesangial cells leads to glomerular damage and CKD progression. 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 in dogs with experimental CKD is decreased by 30%.¹¹ In cats with induced CKD, benazepril induced an increase in GFR (up to 30%), but did not affect plasma creatinine concentration.¹² In another study in cats with spontaneous CKD, benazepril reduced serum creatinine concentration.¹³ The arteriolar vascular effect, and not the systemic antihypertensive effect, is the primary factor contributing to the decrease in glomerular hypertension.¹²

Antifibrogenic Effects

Activation of the RAAS, and the consequent increased production of angiotensin II, plays a major role in the progression of renal fibrosis. Angiotensin II increases the production of transforming growth factor-β, a powerful fibrogenic cytokine, which is another main factor involved in the pathophysiology of renal diseases.⁴ Treatment with ACE inhibitors has been reported to have beneficial effects on renal structural changes in experimental canine CKD. It blunted the extent of glomerular hypertrophy in uninephrectomised diabetic dogs,¹⁴ induced a transient reduction in glomerular basement membrane splitting in X-linked hereditary nephritis,¹⁵ and decreased glomerular and tubulointerstitial lesions in dogs with induced CKD.¹¹

Clinical Trials with ACE Inhibitors in Canine and Feline CKD

Although ACE inhibitors are antiproteinuric agents, decrease blood pressure, improve glomerular hemodynamics, and limit the development of kidney lesions, these effects are only surrogate endpoints and do not indicate an improvement in the clinical outcome of the treated patient. Therapeutic recommendations should ideally be based on results of randomized, controlled clinical trials. Several clinical trials in human patients have been published in the literature to demonstrate ACEI efficacy in the treatment of various nephropathies. Information available in veterinary nephrology is more limited and less convincing.

Canine CKD

In Samoyed dogs with X-linked hereditary nephritis, enalapril (2 mg/kg, p.o., twice daily), given before the occurrence of proteinuria and clinical signs, delayed development of azotemia, slowed down the increase in proteinuria, and increased survival time by 36% (from 201 to 273 days).¹⁵

In dogs with naturally occurring idiopathic glomerulonephritis, no change in serum creatinine was observed following enalapril treatment (0.5 mg/kg, p.o., q12-24 h, for 6 months). However, an increase of more than 0.2 mg/dL after 6 months of treatment was observed in only three of 16 enalapril-treated dogs, and in 13 of 14 placebo-treated dogs. Enalapril improved the clinical response to treatment.⁵ Similarly, the clinical score was better for dogs with CKD treated with benazepril (0.5 mg/kg, p.o., q 24 h) than for dogs in the placebo group.¹⁶

Feline CKD

The largest prospective, randomized, double-blind, placebo-controlled clinical trial for testing the efficacy of ACE inhibitors in veterinary nephrology was performed with benazepril (0.5-1.0 mg/kg, po, q 24 h for up to 3 years) in 192 cats with CKD. Benazepril induced a reduction in proteinuria. Renal survival time (i.e., the need for parenteral fluid therapy or euthanasia or death of the cat because of renal failure) was not however affected by ACE inhibitor in the whole tested group [637 ± 480 days with benazepril and 520 ± 323 days with placebo (P=0.47)], or in cats with pronounced proteinuria (initial UPC ≥ 1).⁶ In another prospective randomized, double-blind, placebo-controlled clinical trial in 61 cats with naturally occurring CKD, the cumulative survival rate at the end of the study was unaffected by the treatment (88 ± 6% in the benazepril group and 70 ± 13% in the placebo group).⁷

Thus, although most studies showed positive trends and none of them adverse effects on CKD progression, the beneficial effect of ACE inhibitors on survival time in canine and feline patients with CKD remains questionable. Possible explanations could be a lack of statistical power, insufficient duration of the study, inappropriate definition of inclusion criteria, inadequate selection of primary and secondary end-points, and the potential inter-individual variability of clinical response to the treatment. These issues are not specific to ACE inhibitors. Use of most medical treatments in small animal nephrology is therefore supported by generally less convincing evidence (e.g., pathophysiological considerations or expert opinion) than clinical trials.

When to Give or Not to Give ACE Inhibitors in Canine and Feline CKD

Whereas high quality evidence regarding effects on long-term clinical outcome is still lacking, the prescription of ACE inhibitors has become increasingly popular in veterinary nephrology over the last 10 years. The main reason is that the benefit to risk ratio of the treatment with ACE inhibitors is considered to be high, even though the benefit has mainly been demonstrated from surrogate endpoints. The current recommendations for ACE inhibitors prescription in small animal nephrology are most often based on expert opinions.

The "optimal" target categories for ACE inhibitors are proteinuric IRIS stage II and III CKD. Presence of systemic hypertension in such patients can be a further indication for treatment with ACE inhibitors (monotherapy or combination with amlodipine according to the severity of hypertension). The patient should be in stable clinical conditions and normohydrated when the treatment is initiated. In unstable conditions (e.g., patients requiring fluid therapy), oral medications are generally inappropriate and clinical response to treatment may be equivocal. Treatment should be initiated, sometimes after a period of some weeks, following discharge from the hospital once the patient has recovered. ACE inhibitors are contraindicated in dehydrated patients as they may cause acute renal failure when renal perfusion is decreased. Decision to initiate an ACE inhibitor treatment can be based on values of urine protein to creatinine ratio (UPC), according to the ACVIM guidelines.¹⁷ In IRIS stage II and III, treatment can be initiated when UPC ≥ 0.5 in dogs and UPC ≥ 0.4 in cats.¹⁷ Proteinuria should then be monitored to assess the anti-proteinuric effect of the treatment. Use of ACE inhibitors in stage I (i.e., non azotemic patients) is only recommended in the case of persistent renal proteinuria and UPC ≥ 2.¹⁷ Prescription of ACE inhibitor in IRIS stage IV is also not recommended as such patients are generally unstable and dehydrated. Moreover, the focus of therapy becomes the medical management of uremic complications.¹⁸ In non proteinuric CKD patients, further investigations are needed to document the relevance of treatment with ACE inhibitor.

Adverse effects of ACE inhibitors are rare. Renal safety of ACE inhibitors was an early concern, but their impact on renal function in adult normohydrated animals is minimal. The risk of hyperkalemia is very limited. ACE inhibitors are contraindicated in pregnant animals and neonates, as renal RAAS indeed plays a pivotal role in nephrogenesis and renal development. 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.⁴ Drug interactions mentioned in the literature include potential adverse effects of dual therapy with NSAIDs and ACEI. This interaction is clinically relevant as osteoarthritis and CKD can occur concomitantly in the same patient. COX inhibition induces a vasoconstriction of the afferent arteriole while ACE inhibitors, by blocking angiotensin II synthesis, induce vasodilation of the efferent arteriole. The drop in glomerular capillary pressure may lead to a decrease in GFR, and consequently to acute renal failure. Nevertheless, the contraindication for use of NSAIDs in a patient treated with ACE inhibitor is only relative in IRIS stage II and III, but a very careful monitoring of renal function is recommended when such a dual therapy is initiated.⁴

References

1.  Jacob F, et al. J Am Vet Med Assoc 2005;226:393.

2.  Syme HM, et al. J Vet Intern Med 2006;20:5;28.

3.  Jepson RE, et al J Vet Intern Med 2009;23:806.

4.  Lefebvre HP, et al. J Vet Pharmacol Ther 2004;27:265.

5.  Grauer GF, et al. J Vet Intern Med 2000;14:526.

6.  King JN, et al. J Vet Intern Med 2006;20:1054.

7.  Mizutani H, et al. J Vet Intern Med 2006;20:1074. y

8.  Jacob F, et al. J Am Vet Med Assoc 2003;222:322.

9.  Jepson RE, et al. J Vet Intern Med 2007;21:402.

10. Atkins CE, et al. J Vet Pharmacol Ther 2007;30:394.

11. Brown SA, et al. Am J Vet Res 2003;64:321.

12. Brown SA, et al. Am J Vet Res 2001;62:375

13. Watanabe T, et al. J Vet Med Sci 2007;69:1015.

14. Brown SA, et al. Kidney Int 1993;43:1210.

15. Grodeki KM, et al. J Comp Path 1997;117:209.

16. Tenhünfeld J, et al. J Am Vet Med Assoc 2009;213:1031.

17. Lees GE, et al. J Vet Intern Med 2005;19:377.

18. Brown SA. 2007 BSAVA Manual of Canine and Feline Nephrology and Urology, 2^nd ed: 223.