The treatment of proteinuria in dogs with telmisartan | VETgirl Veterinary Continuing Education Podcasts
In this VETgirl online veterinary continuing education podcast, we discuss the use of telmisartan in dogs with proteinuria. Recall that the renin-angiotensin-aldosterone system (RAAS) is a physiological system that plays vital roles in blood pressure (BP) regulation, vascular resistance, fluid balance, and electrolyte regulation. Chronic RAAS activation can worsen urinary protein loss, and two common classes of medications that target this pathway are used for dogs suffering from proteinuria. Perhaps the most familiar are the angiotensin-converting enzyme (ACE) inhibitors, such as enalapril or benazepril. In veterinary medicine, these medications are commonly prescribed for patients suffering from proteinuria. However a second class, angiotensin receptor blockers (ARBs), have become increasingly popular in recent years, which include medications such as losartan and telmisartan. So, Lecavalier et al wanted to evaluate this in a study entitled Treatment of proteinuria in dogs with telmisartan: A retrospective study. In this study, the authors sought to describe telmisartan’s use and efficacy in dogs, and they hypothesized that telmisartan would effectively lower the urine protein-to-creatinine ratio (UPC) in dogs with proteinuria.
This was a retrospective study evaluating different medication protocols in dogs with proteinuria. The investigators evaluated medical records from dogs referred to a private referral hospital over a 2-year period (2017 to 2019). To be included, dogs must have had clinically relevant proteinuria, which was defined as a UPC greater than 0.5 on at least 3 separate occasions, measured at least 2 weeks apart. This was to ensure that the proteinuria was persistent. Additionally, all dogs had a biochemical profile, hematology, urinalysis, urine culture, 4Dx SNAP test, and a BP measurement. Diagnostic imaging and renal biopsies were not required for inclusion, but dogs with a positive 4Dx SNAP test, bacteriuria (based on cytology or culture), pyuria (>6-8 WBC/hpf), or a diagnosis of neoplasia were excluded. Dogs that met all of these criteria were divided into 3 groups based on what therapy they received. These groups were telmisartan alone, telmisartan plus benazepril, or telmisartan plus mycophenolate. Dogs receiving corticosteroids were allowed to be enrolled. Importantly, these treatment decisions were made by the clinician, and were based on the clinician’s assessment of the dog at presentation.
Telmisartan was started at a dose of 0.5 mg/kg once daily in all dogs. The investigators monitored serum creatinine, electrolytes, and BP within 1-2 weeks of starting treatment. The dose was then increased to approximately 1 mg/kg daily as long as the dog was clinically tolerating the medication, and if recheck laboratory values were acceptable. Acceptable laboratory values were considered to be less than 30% increase in creatinine, a serum potassium level less than 6 mmol/L, and a minimum systolic BP of 120 mmHg (Bugbee, Brown). For dogs receiving benazepril, the doses ranged from 0.5-1 mg/kg once daily, and mycophenolate was administered at 10-15 mg/kg twice daily.
In addition to the UPC performed prior to treatment, recheck UPCs, creatinine levels, and potassium levels were then performed at 1, 3, 6, and 12 months after starting therapy. BP was measured when possible. Dogs were not required to have all of those recheck visits performed, but all dogs were required to have a follow-up UPC performed at least 1 month after starting therapy to be included. The authors classified response to treatment as follows: complete (UPC <0.5), partial (UPC >0.5 but reduced by 50% or greater from baseline values), or no response (UPC decreased by less than 50% of starting values). Information for each dog was carefully documented, including signalment, additional medications, and adverse events during the study period.
So, what’d the authors find in this study? In total, 44 dogs fulfilled the necessary inclusion and exclusion criteria and were enrolled in the study. These dogs consisted of 39% spayed females, 52% neutered males, and 9% intact males. The most commonly represented breeds included Yorkshire terrier (7), mixed breed (6), Miniature Schnauzer (4), and Labrador Retriever (4). Several other breeds were included that were represented by 3 or fewer dogs. Of these 44 dogs, 9 dogs had concurrent hyperadrenocorticism, which is relevant given that proteinuria is often observed in dogs with hyperadrenocorticism. Six of these 9 dogs were receiving telmisartan alone, whereas 2 dogs and 1 dog were receiving telmisartan with benazepril or mycophenolate, respectively. Additionally, 6 of the 44 dogs were diagnosed with hypertriglyceridemia and 4 with protein-losing enteropathy. The majority of these dogs were receiving telmisartan alone, with a small number of dogs in the other treatment categories. Medications that dogs in this population were receiving concurrently included trilostane, levothyroxine, bezafibrate, cyanocobalamin, and 14 dogs were receiving a fatty acid supplement. None of the dogs in this study received amlodipine. Additionally, only 6 dogs in this population were being fed a commercial renal diet. The majority of dogs (34) had both abdominal ultrasound and thoracic radiography performed. Prior to treatment, 31 dogs had BP measurements recorded (mean = 159 mmHg, range = 115-205 mmHg). Variable numbers of dogs had BP re-evaluated at each follow-up visit. For instance, after 1 month of therapy, 9 dogs (21%) had a recheck BP performed. In this group, the mean pre- and post-treatment BPs were 165 and 154 mmHg, respectively. Six dogs (14%) were evaluated at the 6-month time point, and in these dogs the mean pre- and post-treatment BPs were 172 and 149 mmHg, respectively.
Now, let’s hear about how these medication strategies performed! In terms of the treatment groups, 75% of dogs in this study (n = 33) were in the telmisartan alone group. Let’s begin with how well telmisartan addressed proteinuria in this group. In these dogs, the average pre-treatment UPC was 5.3. By one month after starting telmisartan, the average UPC was 2.5, representing a 53% decrease. Not too shabby! Remember that not all dogs had follow-up visits at each timepoint, but 19 dogs had recheck visits 3 months after starting treatment. In this group, the average pre-treatment UPC was 4.43, and the average 3-month post-treatment UPC was 2.5, representing a 43% decrease. Of the 15 dogs that had a 6-month visit, a 40% drop in UPC was noted, and of the 10 dogs with a 1-year follow-up, there was a 41% drop in UPC. Another way of looking at this information is that of all dogs in the telmisartan group, 70% had a positive response to treatment by 1 month. In fact, between 60-80% of dogs showed either a complete or partial response to telmisartan in terms of UPC at the other timepoints as well. Wow!
Now, let’s talk about the other treatment groups, starting with telmisartan and benazepril. Only 11% of dogs in the study (n = 5) received this combination. Of these 5 dogs, 3 were started on telmisartan alone, and subsequently had benazepril added into their medication plan. The other 2 were started on benazepril first, but telmisartan was added due to inadequate response to benazepril alone. When looking at this group as a whole, the average UPC prior to treatment was 3.62, and the average UPC value after 1 month of therapy was 2.5. This represents a 31% decrease. Only 2 dogs had a 3-month follow-up, but the UPC only dropped from 5 to 4.4 in these dogs. Neither dog was designated as having a response, meaning that neither had a UPC reduction greater than 50% from baseline. Three dogs had a recheck at 6 months, and only 2 dogs at 12 months. Two of the 3 dogs had a complete response at 6 months, and 1 of the 2 had a complete response at 12 months. The remaining dogs were designated as having no response. Recall that 3 dogs were receiving telmisartan prior to starting benazepril, so it’s also important to note how these pups responded to the telmisartan alone. One had no response to telmisartan, and in fact, the UPC in this pup increased during that time period. The other dog had an incomplete response, and the third dog had demonstrated no response after 1 month of telmisartan. For those reasons, benazepril was added to these pups’ treatment plans.
The final group consisted of 6 dogs (14% of dogs in the study) receiving both telmisartan and mycophenolate. The average UPC of dogs in this group was 9.23 prior to treatment. After 1 month of treatment, the average UPC was 1.85, representing an 80% reduction! In fact, 50% of dogs had a complete response after the first month of therapy, which was more than in the other treatment groups. In the telmisartan alone group, 9% of dogs had a complete response after a month, and in the telmisartan-benazepril group, still only 20% of dogs had a complete response in this first month. Only 3 of the 6 dogs in the telmisartan-mycophenolate group had a 3-month follow-up visit performed. The average UPC dropped from 13.36 pre-treatment to 1.46 at 3 months, representing an 89% reduction. An 89% reduction was also noted in the dogs with a 6-month recheck, and a 92% reduction was observed in the dogs with a 12-month recheck. Note that renal biopsies were not performed in this population, so the authors were unable to confirm immune-mediated pathology in these dogs. Thus, the decision to use an immunosuppressive, mycophenolate, was dependent on the clinician’s clinical judgement. Clearly, these numbers are impressive. However, the authors emphasize that in order to draw firm conclusions from this group, a larger population with control groups and renal histopathology would be necessary.
For those of you familiar with using telmisartan, you know that monitoring of renal values and electrolytes is an important component of patient management. A previously published consensus statement offers fantastic guidance in clinical decision making as you monitor telmisartan use (Brown), and you’ll note that serum creatinine increases by 30% and serum potassium levels > 6 mmol/L are two important thresholds to remember. No dogs in this study had serum potassium levels increase above 6 mmol/L at any point during the study period. However, 14% of dogs were azotemic prior to starting therapy. As noted earlier, not all dogs had values rechecked at each time interval. However, if looking at mean serum creatinine values pre- and post-treatment at each time interval, there was never an increase greater than 30% at any time point. That said, 2 dogs did develop clinically significant azotemia within the first month of starting telmisartan, requiring exclusion from the study. Three dogs developed mild, self-resolving gastrointestinal signs after starting telmisartan. This means that out of the 44 dogs included, 5 dogs (11%) developed an adverse event to telmisartan, the 2 dogs with azotemia and the 3 with gastrointestinal upset.
The authors acknowledge several limitations to this study, which are largely related to its retrospective nature. For instance, dogs had various diagnostic work-ups, rechecks performed at different time intervals, and different comorbidities and medications. These types of factors could influence results, so it is important to remember such limitations. However, with that all said, what can we take away from this VETgirl podcast? Well overall, the results of this study showed that telmisartan did effectively reduce proteinuria in dogs. This is great! While about 70% of dogs treated with only telmisartan demonstrated a complete or partial response within the first month of treatment, other dogs in this group needed longer treatments. Overall, UPCs were lowered by more than 40% over the study period for dogs receiving only telmisartan. Dogs receiving combination therapy also demonstrated variable improvements in proteinuria, but additional prospective studies to better clarify the performance of these drugs within specific disease states will be necessary. The majority of dogs tolerated telmisartan well, with only 5 dogs experiencing adverse events during this study period. This VETgirl will remember to consider telmisartan in tough proteinuria cases! That said, remember that this drug requires close monitoring and may not be the right choice for all patients.
Abbreviations:
ACE – Angiotensin-converting enzyme
ARB – Angiotensin receptor blocker
BP – Blood pressure
RAAS – Renin-angiotensin-aldosterone system
UPC – Urine protein-to-creatinine ratio
References:
Lecavalier J, Fifle L, Javard R. Treatment of proteinuria in dogs with telmisartan: A retrospective study. J Vet Intern Med 2021;1-9.
Bugbee AC, Coleman AE, Wang A, et al. Telmisartan treatment of refractory proteinuria in a dog. J Vet Intern Med. 2014;28:1871-1874.
Brown S, Elliott J, Francey T, et al. Consensus recommendations for standard therapy of glomerular disease in dogs. J Vet Intern Med. 2013;27:S27-S43.10.
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