Treatment of proteinuria in dogs with telmisartan: A retrospective study

Abstract Background Use of telmisartan for the treatment of proteinuria in dogs has not been thoroughly investigated. Hypothesis/Objectives Telmisartan can be effective for the treatment of proteinuria in dogs. Animals Forty‐four client‐owned dogs with proteinuria. Methods Retrospective study. Dogs diagnosed with clinically relevant proteinuria (nonazotemic dogs with a urine protein‐to‐creatinine ratio [UPC] ≥2 and azotemic dogs with UPC ≥0.5) were separated into 3 groups: telmisartan alone, with benazepril, or with mycophenolate. The UPC was recorded before treatment and at subsequent follow‐ups (1, 3, 6, and 12 months, as available). Response to treatment was categorized as complete (UPC ˂0.5), partial (UPC decreased by ≥50% but still ≥0.5), or no response (UPC decreased by <50%). Serum creatinine and potassium concentrations and arterial pressure also were recorded. Results In the telmisartan group, treatment response (UPC ˂0.5 or decreased by ≥50%) was observed in 70%, 68%, 80%, and 60% of dogs at 1, 3, 6, and 12 months follow‐up, respectively. No significant changes were noted in serum creatinine or potassium concentrations, or in arterial blood pressure at all follow‐up times. Adverse effects consisted of mild self‐limiting gastrointestinal signs in 5 dogs. Two dogs developed clinically relevant azotemia that required discontinuation of the treatment before the first follow‐up. Conclusions and Clinical Importance Telmisartan can be considered for treatment of proteinuria in dogs, alone or in combination with other treatments for proteinuria.

electrolyte balance as well as systemic vascular resistance. 4,5 However, chronic activation of the RAAS results in increased glomerular filtration rate, which in turn can exacerbate proteinuria. Persistent proteinuria further damages nephrons and contributes to progression of kidney disease. 6,7 Treatment of proteinuria includes treatment of underlying diseases when present, as well as immunosuppression, if warranted. Feeding a diet supplemented with omega-3 fatty acids, antithrombotic treatment and medications that decrease the vasoconstrictive effect of angiotensin II on the efferent glomerular arteriole system, such as angiotensin-converting enzyme inhibitors (ACEi), angiotensin receptor blockers (ARBs), or aldosterone antagonists, also are recommended. 1,8,9 Angiotensin-converting enzyme inhibitors, such as benazepril or enalapril, have been used in veterinary medicine to treat systemic hypertension and proteinuria. 7,10,11 Recently, ARBs, such as telmisartan and losartan, have been used to treat systemic hypertension in cats and dogs . 6,11,12 Losartan has been used in dogs, 13 but dogs seem to be unable to metabolize it to the active metabolite that is responsible for much of the therapeutic effect in people. 14 By selectively blocking the angiotensin II type 1 receptor (AT1) receptor, ARBs allow the angiotensin II type 2 receptor (AT2) to remain available for activation by angiotensin II. The AT2 receptors appear to have renoprotective effects such as vasodilatation, natriuresis, and inhibition of inappropriate cell growth. Therefore, specific AT1 blockade could offer potential benefits. 15 A meta-analysis of 20 reports of randomized trials including over 25 000 human patients identified significant improvement in proteinuria and albuminuria as well as prevention of disease progression with telmisartan use. 16 Two recent prospective, multicenter, placebo-controlled blinded studies showed the safety and efficacy of telmisartan in hypertensive cats, 6,12 and a case report of refractory proteinuria in a dog showed successful treatment after introduction of telmisartan. 17 Recently, a double-masked randomized clinical trial indicated the efficacy of telmisartan in proteinuric dogs with chronic kidney disease, including a more rapid response compared with enalapril. 18 Limited data, however, are available on use of telmisartan in dogs.
Our primary objective was to describe the use of telmisartan to treat proteinuria in dogs, with the hypothesis that a decrease in the urine protein-to-creatinine ratio (UPC) would be observed after treatment.
F I G U R E 1 Flow diagram illustrating case selection and overview of study 2 | MATERIALS AND METHODS

| Case selection
Our study was a retrospective study. Electronic medical records of dogs presented at a private referral hospital (DMV Veterinary Center, Montreal, Canada) between 2017 and 2019 were reviewed. Dogs diagnosed with clinically relevant proteinuria that required treatment were included in the study. Dogs were divided into 3 groups depending on the treatment received: telmisartan alone, telmisartan with an ACEi (benazepril), and telmisartan with mycophenolate ( Figure 1 Telmisartan was started at a dosage of 0.5 mg/kg PO q24h in all dogs. One to 2 weeks after initiating treatment, serum creatinine concentration (SCr), serum electrolyte concentrations, and systemic blood pressure were re-evaluated. Telmisartan was increased to a target dosage of 1 mg/kg PO q24h if it was well tolerated by the dog and laboratory results remained within acceptable limits (<30% increase in SCr from baseline, serum potassium concentration < 6 mmol/L, and systolic blood pressure > 120 mm Hg). 17 As for benazepril and mycophenolate, recommended dosages were used (0.5-1 mg/kg PO q24h for benazepril and 10-15 mg/kg PO q12h for mycophenolate). 19 Adjustments were made based on the ACVIM Consensus Statement Recommendations for Standard Therapy of Glomerular Disease in dogs. 9 Urine protein-to-creatinine ratio was determined before treatment and then at subsequent follow-ups as available (1, 3, 6, and 12 months after beginning treatment). When possible, pooled urine samples were used for UPC determination, but otherwise a voided International Renal Interest Society (IRIS) guidelines and categories by target organ damage (TOD) were followed. 11 Response to treatment was rated as complete (UPC <0.5), partial (UPC ≥0.5 but decreased by ≥50%), or no response (UPC decreased by <50%). Treatment protocol and whether telmisartan was used alone or in combination with another drug, was clinician-dependent and influenced by the clinical presentation. Dogs were required to have follow-up of their UPC at least 1 month after the start of treatment to be included in the study.
Breed, age, sex, concurrent conditions, and concurrent medications were recorded for each dog. Adverse effects, as reported by the owners, were defined according to product prescribing information (ie, diarrhea, vomiting, lack of appetite, and decreased activity level). 20 Dogs concurrently receiving corticosteroids were included; dogs diagnosed with neoplasia were excluded.   (1), and American Cocker Spaniel (1). The most common concurrent conditions were hyperadrenocorticism (9), hypertriglyceridemia (6), and proteinlosing enteropathy (4). Concurrent medications received included trilostane, levothyroxine, bezafibrate, and cyanocobalamin. Of the 9 dogs being treated for hyperadrenocorticism, 6 were receiving telmisartan, 2 were receiving telmisartan with benazepril, and 1 was receiving telmisartan with mycophenolate. Of the 6 dogs being treated for hypertriglyceridemia, 4 were receiving telmisartan, and 1 each telmisartan with benazepril and telmisartan with mycophenolate. Of the 4 dogs being treated for protein-losing enteropathy, 3 were receiving telmisartan, and 1 received telmisartan with mycophenolate. Of the dogs included in the study, 6 were being fed a commercial renal diet and 14 were receiving a polyunsaturated fatty acid supplement.
One dog had a complete response, 1 had a partial response, and

| Adverse effects
Of 44 dogs, 5 (11%) were reported to have adverse effects after introduction of telmisartan. These consisted of mild gastrointestinal signs (anorexia and diarrhea), which were self-limiting. Two dogs developed F I G U R E 4 Systemic blood pressure measurements over time at 1, 3, 6, and 12 month in dogs being treated with telmisartan for proteinuria clinically relevant azotemia (increase in SCr >30%) that required discontinuation of the treatment before the 1-month follow-up; these dogs subsequently were excluded.

| DISCUSSION
The purpose of our retrospective study was to describe the use of telmisartan in dogs to treat proteinuria in various clinical situations.
A previous study in cats with chronic kidney disease showed that telmisartan was at least as effective as benazepril and significantly decreased proteinuria after treatment, and a recently published clinical trial on telmisartan use in dogs showed similar results in comparison with enalapril. 18,20 Our study also showed a substantial decrease in proteinuria compared to baseline in dogs treated with telmisartan.
In the group of dogs treated only with telmisartan, most showed a therapeutic response over the course of the study, and a posttreatment UPC <0.5 or a decrease of ≥50% from baseline. 9 Some dogs showed complete response early in the course of treatment whereas others achieved a response later on. At the 1-month follow-up, 70% of dogs showed a favorable response, with 9% having a complete response and 61% having a partial response. Results were similar at subsequent follow-ups, with 68%, 80%, and 60% of dogs showing favorable response to treatment at 3-, 6-, and 12-month follow-ups, respectively. The average decrease over the study period was 41%, which is similar to what is reported in human medical literature.
Human patients experienced an average decrease of 35% in UPC over a 3.4-year period, but most of the decrease occurred in the first 6 months of treatment. 21,22 Most improvement seems to occur after treatment is first introduced, and that the UPC results then remain stable over time. A prospective study of longer duration would be needed to investigate if this trend also applies to dogs.
In the dogs that received both telmisartan and benazepril, 1 dog achieved complete response even though the dog had failed to show a clinically relevant response after receiving benazepril for the previous 15 months. Because this dog had been treated with an ACEi for a long period of time, an ACE escape mechanism (alternate pathway for angiotensin II generation) could have prevented further response before introduction of an ARB. 23 The ARBs are not affected by the ACE escape mechanism, which may explain the continued decrease in proteinuria in this animal. 20 Over time, inhibition of angiotensin converting enzyme decreases with the use of ACEi, allowing plasma concentrations of angiotensin II to increase. This could explain why higher doses of ACEi are sometimes needed and why combination with an ARB can improve the therapeutic response. 24 The 3 dogs that previously received telmisartan failed to show improvement when benazepril was added as combination treatment.
Because specific receptor blockade by telmisartan already was present, the added inhibition of angiotensin converting enzyme by benazepril might have failed to provide further blockade and hence the lack of response. Combination treatment with an ARB and an ACEi is thought to offer more complete blockade of the RAAS compared to monotherapy, and studies in people have suggested a potential combined effect in treating proteinuria. 21,22,25,26 A meta-analysis of people with diabetic nephropathy showed that combination treatment significantly decreased proteinuria compared to monotherapy. 27 However, more recently, studies in people have found that optimal RAAS blockade may be desired over complete blockade, thus minimizing potential adverse effects encountered with complete blockade commonly observed with combined treatment. [20][21][22][23][24][25][26][27][28][29][30][31] A recently published clinical trial in dogs showed that 31% of dogs developed significant increases in SCr requiring hospitalization for treatment, further supporting this argument. 18 Blockade at the angiotensin-II receptors by ARBs could offer a potential benefit over the use of ACEi, especially in dogs refractory to treatment, as was observed in a recent clinical trial. 18 We also cannot exclude that the 2 dogs in our study that had complete response with combination treatment after introduction of telmisartan could have had a similar response had the ACEi been gradually withdrawn or discontinued, as previously described in a case report. 17 Six dogs were treated with both telmisartan and mycophenolate, and a partial or complete response was observed for most of these dogs at the follow-up visits. This combined treatment was generally well tolerated with no clinically important adverse effects reported for dogs in this group. Although a potential underlying immune-mediated process was suspected in these cases, no specific UPC result indicates a specific renal disease. 32 A recent study evaluating dogs with focal segmental glomerulosclerosis confirmed by histopathology showed a median UPC of 5.9 with UPCs ranging from 1.4 to 22, and suggesting that the severity of proteinuria cannot be correlated with an immunemediated cause. 33 Although an immunosuppressive treatment proto- col has yet to be thoroughly investigated in dogs, treatment is recommended in cases in which biopsy results are suggestive of immunopathogenesis, or if azotemia is progressive, severe hypoalbuminemia is present and a lack of response to standard treatment occurs in the absence of a histopathological diagnosis. [34][35][36][37] The use of the immunosuppressive drug mycophenolate in our study might have been responsible for the positive response observed in these dogs. However, a previous prospective clinical trial did show a favorable response in dogs treated with enalapril for idiopathic glomerulonephritis. 10 It is therefore possible that telmisartan could pro-  38,39 For that reason, we routinely recommend follow-up 1 to 2 weeks after initiation of treatment to ensure it is well tolerated by the dog and before increasing the dose into the target range.
In our study, a small percentage of dogs (5/44; 11%) also developed some mild gastrointestinal signs after introduction of telmisartan. These signs were self-limiting and did not preclude continuation of treatment. These signs included anorexia and diarrhea, which also have been reported in cats. 19  Thirty-one dogs (71%) had their blood pressure evaluated before treatment, and mean systolic blood pressure was in the low TOD category (140-159 mm Hg). 11 Blood pressure remained in an acceptable range (>120 mm Hg) 18 for all dogs at the various follow-ups. Not all dogs had blood pressure measurements noted in their records at each follow-up for different reasons (eg, lack of dog compliance, financial restrictions, incomplete medical records). Telmisartan is approved for treatment of hypertension in cats 6 and its use in human patients also has shown it to be an effective antihypertensive agent. 42 A clinical trial evaluating the efficacy of telmisartan in dogs with renal proteinuria showed a more significant decrease in systolic blood pressure compared to dogs treated with enalapril. 18 Additional studies would be necessary to evaluate if telmisartan also could be used to treat hypertension in dogs.
Our study had several limitations because of its retrospective nature. Not all dogs had complete standardized diagnostic evaluations (no imaging performed in some dogs and no renal biopsies were performed) and therefore potential underlying causes of proteinuria may have been missed. Some dogs were not evaluated at each recommended follow-up interval, which could have affected overall results. Method of urine collection varied among dogs. Previous studies have shown that, for most dogs, overall results are similar regardless of the method used, but samples collected in the hospital could yield higher results. 43 Different devices were used to evaluate systemic blood pressure which could have introduced substantial variability. Furthermore, because many dogs had various concurrent diseases, these could have affected the severity of proteinuria. 1 Some dogs also were receiving concurrent medications, special diets and supplements to manage these conditions and could have shown improvement over time as their medical condition was better controlled. Some dogs also were being treated concurrently for proteinlosing enteropathy and required corticosteroid treatment that also could have affected the extent of proteinuria.
The aim of our study was to describe the use of telmisartan for treatment of proteinuria in dogs in various clinical situations. Our results show that most dogs experienced a decrease in the severity of proteinuria after initiation of telmisartan and the drug overall was well tolerated.
Because of the different disease processes present in the dogs and different concurrent treatments, the decrease in proteinuria cannot be attributed to telmisartan alone for all dogs. Additional standardized prospective studies are needed to further validate our findings.

ACKNOWLEDGMENT
No funding was received for this study.