A practical guide to antiproteinuric drugs in dogs

Increases in intraglomerular hydrostatic pressure and up-regulation of the renin-angiotensin-aldosterone system (Figure 1) are beneficial short-term adaptive mechanisms that promote flow across the glomerular filtration barrier and slow the accumulation of uremic toxins in people and animals with kidney disease.1-3 However, persistently increased plasma angiotensin II and aldosterone concentrations and intraglomerular hypertension contribute to the long-term progression of kidney disease by worsening proteinuria and promoting the interstitial fibrosis and mesangial cell proliferation typical of "end-stage kidneys."3-5

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Increased urine protein excretion is the hallmark clinicopathologic abnormality in dogs with protein-losing nephropathies. After the exclusion of preglomerular and postglomerular causes of increased urine protein excretion, such as immunoglobulin-producing neoplasms, hemoglobinuria, renal tubular disease, and any cause of lower urinary tract inflammation (e.g. bacterial infections or urolithiasis), glomerular disease can be presumptively diagnosed if the urine protein:creatinine ratio (UPC) is persistently > 0.5.

1. The renin-angiotensin-aldosterone system and sites of action of antiproteinuric drugs administered to dogs with glomerular disease.

Pharmacologic inhibition of the renin-angiotensin-aldosterone system delays the development of azotemia and prolongs the survival of both people and dogs with glomerulopathies.6-9 Treatment with antiproteinuric drugs is recommended when the UPC ratio is > 2.010; however, the preferred drug class, dosage, and monitoring scheme remain unclear. In this article, I summarize the published support for administering angiotensin-converting enzyme (ACE) inhibitors and angiotensin II-receptor blockers (ARBs) and suggest an evidence-based treatment protocol.

Click here to download an algorithm on administering ACE inhibitors and ARBs to treat proteinuria in dogs with glomerular disease.

ACE INHIBITORS

Inhibition of ACE activity decreases serum concentrations of angiotensin II and aldosterone, thereby reducing both intraglomerular hydrostatic pressure and systemic blood pressure.11,12 ACE inhibition in people with chronic proteinuric nephropathies slows the decline in glomerular filtration rate, delays progression to end-stage renal disease, and prolongs overall survival time, independent of the severity of initial proteinuria.6-8 Administering enalapril or benazepril to dogs with naturally occurring idiopathic glomerular disease9 or azotemic chronic kidney disease of undetermined etiology13 reduces the UPC ratio and stabilizes or improves renal disease, respectively, as compared with dogs receiving placebos.

Enalapril

Enalapril is the ACE inhibitor most commonly prescribed to dogs in the United States. Maximal reduction in proteinuria is desirable, so I recommend initial administration of the maximum recommended dosage (0.5 mg/kg orally b.i.d.) in nonazotemic dogs with serum creatinine concentrations < 3 or 4 mg/dl. However, because ACE inhibitors reduce the glomerular filtration rate, when treating dogs with serum creatinine concentrations between 3 and 5 mg/dl, it is prudent to initiate therapy at a lower dosage (0.25 mg/kg orally b.i.d.) and recheck serum creatinine concentrations within four to seven days. If the azotemia has not worsened, increase the enalapril dosage to the maximum recommended dose (0.5 mg/kg orally b.i.d.) and recheck serum creatinine concentrations again in four to seven days.

Adverse effects of enalapril—and ACE inhibitors, in general—in people include hyperkalemia and gastrointestinal disturbances.14,15 Although these have not been reported in published studies in dogs, I have occasionally noted both of these adverse events in dogs with glomerular disease that have been administered standard dosages of enalapril. Temporarily discontinuing drug administration in dogs with enalapril-associated anorexia and then administering a lower dosage after the appetite returns is usually successful. The dosage can be increased back to the desired total daily dose after two to four weeks.

Alternative ACE inhibitors

Alternative ACE inhibitors that can be considered include benazepril, lisinopril, captopril, ramipril, and quinapril, although there are no studies directly comparing the efficacy of these drugs with enalapril in dogs with naturally occurring disease. All ACE inhibitors except captopril reach therapeutic serum concentrations with half-lives that permit once- or twice-a-day dosing in healthy dogs.16-19 In people, however, tissue-specific differences in lipophilicity and variable-binding affinity to the various ACE inhibitor pro-forms suggests that substituting one ACE inhibitor for another may require validation of each drug.20

Variable effectiveness and recommendation

Indirect evidence as to the variability of the effectiveness of the various ACE inhibitors includes greater reduction in the severity of echocardiographic variables in Cavalier King Charles spaniels with asymptomatic mitral regurgitation treated with quinapril vs. enalapril,21 renal excretion of serum enalaprilat (the active metabolite of enalapril) and possible accumulation in dogs with subnormal glomerular filtration rate vs. hepatic metabolism of benazeprilat,18 and failure of captopril to reduce serum ACE activity in healthy dogs as well as other ACE inhibitors.16 The significance of these differences in dogs with naturally occurring kidney diseases and renal impairment is unknown; however, they imply that substitution of one ACE inhibitor for another may not be without consequences.

Thus, I recommend enalapril as my ACE inhibitor of choice in dogs with glomerulopathies, as it was the drug evaluated in the previously mentioned study reporting effects in animals with naturally occurring glomerular disease.9 Anecdotal reports suggest that alternative ACE inhibitors are also effective, but I reserve them for administration to dogs that develop refractory enalapril-associated side effects.

Dosage

Published dosages of ACE inhibitors are based on the pharmacodynamic endpoint of plasma ACE activity reduction in healthy dogs to 25% of baseline.16 Although this dosage is appropriate for initial dosage establishment, prospective clinical trials in people now suggest that higher ACE inhibitor dosages that aim to maximally reduce the UPC ratio or plasma angiotensin II concentration may further improve patient survival times.

In people with diabetic nephropathy, doubling their lisinopril dosage further decreases the UPC ratio from 66% to 72% below baseline values. Likewise, patients with nondiabetic glomerular disease receiving standard vs. up-titrated dosage of benazepril to minimize proteinuria had a 37.5% vs. 52.5% decrease in UPC ratio below baseline22,23; blood pressure and rate of glomerular filtration rate decline were both reduced with higher drug dosages.

Dogs administered > 0.5 mg/kg twice a day enalapril or > 0.5 mg/kg daily benazepril anecdotally may have reductions in UPC ratio beyond that achieved with standard dosages; however, no controlled studies have evaluated whether this decrease in UPC ratio is associated with delay in onset of azotemia or increased survival. Additionally, ACE inhibitors may induce or exacerbate azotemia in both people and dogs24-27; whether higher drug dosages increase the risk of this uncommon adverse effect is unknown.

Nonresponders and aldosterone escape

Up to 50% of people with proteinuric nephropathies fail to respond appropriately to initial ACE inhibitor therapy, defined as a reduction in the UPC ratio of ≥ 50%.28-30 Additionally, proteinuria will increase to pretreatment concentrations within 1.5 to three years in 50% of the one-half of all patients initially classified as ACE inhibitor responders.28-30 These nonresponders have increases in serum angiotensin II and aldosterone concentrations that parallel their increase in UPC ratio and, thus, are assumed to have lost most renoprotective benefits of ACE inhibitor therapy. This phenomenon of aldosterone escape presumptively occurs secondary to up-regulated ACE or other kinase cleavage of angiotensin I to angiotensin II or increased metabolism of excretion of ACE inhibitor.

ARBs

ARBs are competitive antagonists of angiotensin II. However, unlike ACE inhibitors, aldosterone escape does not blunt ARB-induced renin-angiotensin-aldosterone system blockade and reduction of the UPC ratio.

This class of drugs is commonly prescribed as first-line therapy in people with glomerular disease and appears to be equally effective as ACE inhibitors at reducing the severity of proteinuria, mean arterial blood pressure, and glomerular filtration rate decline.31,32 Available ARBs include losartan, irbesartan, olmesartan, candesartan, valsartan, azilsartan, and telmisartan. In people, these drugs vary in maximum achievable decreases in mean arterial pressure or reduction of the UPC ratio, with telmisartan in particular having more potent antiproteinuric effects than losartan has.33

Animal studies

Published information on ARB administration in dogs is limited to pharmacokinetic studies in healthy animals and effects on renal and systemic hemodynamics in animals with experimentally induced renal disease. Losartan has low oral bioavailability, and after gastrointestinal absorption, it undergoes enterohepatic recirculation and eventual biliary excretion.34 Intraglomerular hydrostatic pressure, systemic blood pressure, and end-organ damage are reduced in dogs with experimentally induced renal disease administered ARBs.35,36

Adjunctive administration

Based on the recognized benefits of ARB therapy in people with proteinuric nephropathies, many veterinary nephrologists consider adjunctive administration of these drugs to dogs with persistent proteinuria despite treatment with ACE inhibitors. First-line therapy with ARBs is not recommended as of yet, as it is still unknown whether long-term prognosis worsens, improves, or does not change in affected animals.

The generic formulation of losartan is affordable by most owners and has been used by many veterinary nephrologists as an adjunctive treatment in dogs with refractory proteinuria. An initial losartan dosage (0.125 to 0.25 mg/kg b.i.d.) can be administered as an adjunct to an ACE inhibitor (continued at the standard dosage discussed above) for four to seven days, followed by measurement of the serum creatinine concentration to confirm that azotemia has not markedly worsened. The losartan dosage can then be titrated up in a step-wise fashion, based on continued reduction of the UPC ratio, to a maximum of 0.5 to 2 mg/kg b.i.d., rechecking the serum creatinine concentration and UPC ratio after each dosage adjustment.

Reversible gastrointestinal side effects have anecdotally occurred in some dogs, although it is unclear whether this is due to concurrent use of losartan with an ACE inhibitor or due to the ARB alone. In people, concurrent use of ACE inhibitors and ARBs increases the risk of severe hyperkalemia.

Because of the limited literature regarding ARB therapy in dogs, I encourage you to discuss with a specialist whether administering an ARB in a particular patient may be indicated.

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Barrak Pressler, DVM, PhD, DACVIM

Department of Veterinary Clinical Sciences

College of Veterinary Medicine

The Ohio State University

Columbus, OH 43210