Recent discoveries advance diagnostics, understanding of CKD

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1 Recent discoveries advance diagnostics, understanding of CKD The discovery and evaluation of biomarkers should hopefully improve our diagnostic capabilities and ultimately management and quality and quantity of life for our patients. November 17, 2017 By Jackie Brown Veterinary Practice News

2 A significant number of animals develop some form of kidney disease during their lifetime (approximately 1 in 3 cats 1 and 1 in 10 dogs 2 ). Kidney disease can be challenging to diagnose and manage, but recent discoveries have led to more diagnostic tools and a greater understanding of this disease. Diagnostic breakthroughs The discovery and evaluation of biomarkers is a hot topic currently and should hopefully improve our diagnostic capabilities and ultimately management

3 and quality and quantity of life for our patients, said Joe Bartges, DVM, Ph.D., DACVIM, DACVN, professor of medicine and nutrition at the University of Georgia College of Veterinary Medicine in Athens, Ga. The development of a new biomarker, symmetric dimethylarginine (SDMA), with more biomarkers being identified and evaluated, has impacted on our ability to detect renal disease earlier than before. According to Jane Robertson, DVM, DACVIM, director of medical affairs at IDEXX Laboratories, studies have shown that SDMA correlates well with glomerular filtration rate, increases earlier than creatinine, and is a more reliable indicator of kidney function in pets with decreased muscle because it isn t impacted by lean muscle mass. 3-7 IDEXX s SDMA Test detects elevated SDMA due to active or acute kidney injury, as well as chronic kidney disease, according to the company. SDMA has been shown to increase when there is on average 40 percent loss of kidney function, as compared to creatinine, which does not increase above the reference interval until up to 75 percent of kidney function is lost, 3,4,5 Dr. Robertson said. Current studies on SDMA are evaluating how having an earlier and more reliable biomarker of kidney function will impact how veterinarians diagnose and manage kidney disease and what the patient benefits are.

4 SDMA indeed is a hot topic, with ongoing research currently investigating its impact on identifying and managing kidney disease in hyperthyroid cats, in dogs with vector-borne disease, and in animals with urinary stones. A large, retrospective data analysis found that dogs with antibodies indicating exposure to Ehrlichia in E. canis-endemic areas and B. burgdorferi in Lymeendemic areas had a 300 percent and 43 percent increased risk of developing CKD, respectively, compared to unexposed dogs, 8 Robertson said. Although finding increased SDMA and/or creatinine is significant, it s not the end of the path to diagnosis, Robertson added. Laboratory results should be evaluated in the context of the patient, she said. Consider the patient s history, including the possibility of exposure to infectious agents or toxins, the clinical presentation and duration of clinical signs. What does the patient s physical examination indicate, and how do the kidneys feel on palpation? Even if some evidence of chronic disease is present, an investigation for confounding conditions, such as dehydration, proteinuria, hypertension, and hyperthyroidism should be performed, and secondly, to look for underlying causes such as kidney or ureteral stones, pyelonephritis, and infectious causes.

5 On the treatment side, although not new, hemodialysis is becoming more widely used and accessible, allowing for the treatment of acute kidney failure (especially for cases of poisoning), as well as managing long-term renal disease in animal patients. The availability of hemodialysis is a mix between universities and private practice, Dr. Bartges said. Most are situated in larger metropolitan areas such as New York, Philadelphia, Baltimore, and Phoenix. The University of California, Davis is even involved in research investigating potential home dialysis machines for animal patients. Management breakthroughs It has long been known that therapeutic diets can positively impact patients with renal disease. The nutritional assessment and management of CKD patients is critical to successful outcome as poor body condition is correlated to poorer prognosis, said Jessica M. Quimby, DVM, Ph.D., DACVIM, associate

6 professor at The Ohio State University s Veterinary Medical Center in Columbus, Ohio. Regular assessment of nutritional status, including weight, body condition score, muscle mass score, and caloric intake is a very important part of management. We find that in general, due to inappetence associated with their disease, most patients are not eating adequate calories, and this, combined with cachexia of CKD, has a detrimental effect. Much research has investigated this important aspect of CKD management. Dr. Quimby herself has evaluated the effects of the appetite stimulants mirtazapine and maropitant on feline renal patients in randomized, placebo-controlled, blinded, clinical studies. Perhaps one of the biggest paradigm shifts I have encountered is the recent evidence that cats with CKD do not appear to have uremic gastritis and neither are they significantly hyperacidic as has been previously thought, Dr. Quimby said. We published a pathology study where we were unable to document uremic gastritis or ulceration in CKD cats, 10 and recently Dr. Katie Tolbert demonstrated, 11 as we suspected, that hyperacidity is also unlikely to play a role. In light of this research, Quimby questions the use of acid-suppressant medications and instead thinks more about central effects of uremia in dysregulating appetite.

7 Consequentially, appetite stimulants and anti-emetic or anti-nausea medications may be a more appropriate strategy for management, in addition to identifying and correcting other factors that may affect appetite such as anemia, dehydration, and hypokalemia, she said. We have spent a significant amount of time studying medical management of appetite including mirtazapine and maropitant. 8,9 We have demonstrated that both are beneficial for the management of poor appetite and weight in CKD. Additionally, we demonstrated that transdermal mirtazapine is able to reach therapeutic serum concentrations and increased appetite and weight in placebo controlled studies in normal and CKD cats. Robertson s own cat has seen remarkable improvement thanks to transdermal mirtazapine. Digger is 16-year old, domestic shorthair with CKD, and he has always been a picky eater, she said. He was feral when I got him and near impossible to medicate. The use of transdermal mirtazapine has resulted in Digger not only eating the renal therapeutic diet, but he has also gained some weight. Also of interest on the drug front are angiotensin receptor blockers, which are currently are being evaluated for the treatment of renal disease. These work on the renin-angiotensin-aldosterone system by impairing interaction of angiotensin-ii with its receptor, Bartges said. These have potential to

8 improve our management of particularly proteinuric renal disease. Focus on quality of life Quimby reminds us that without a cure, management requires making recommendations from the various therapies available while evaluating the patient s quality of life. Discussion of various therapies, how they will work for this particular patient, and the balance between quantity and quality of life is important, she said. For this reason, evidence-based therapies are important so that treatments can be ranked and justified based on their likelihood to improve patient outcome. References 1 Lulich JP, Osborne CA, O Brien TD, Polzin DJ. Feline renal failure: questions, answers, questions. Compend Contin Educ Pract Vet. 1992;14(2): Brown SA. Renal dysfunction in small animals. The Merck Veterinary Manual website. Accessed at mrkmnls.co/1ijiaol. 3 Nabity MB, Lees GE, Boggess M, et al. Symmetric dimethylarginine assay validation, stability, and evaluation as a marker for early detection of chronic kidney disease in dogs. J Vet Intern Med. 2015;29(4):

9 4 Hall JA, Yerramilli M, Obare E, Yerramilli M, Jewell DE. Comparison of serum concentrations of symmetric dimethylarginine and creatinine as kidney function biomarkers in cats with chronic kidney disease. J Vet Intern Med. 2014;28(6): Hall JA, Yerramilli M, Obare E, Yerramilli M, Almes K, Jewell DE. Serum concentrations of symmetric dimethylarginine and creatinine in dogs with naturally occurring chronic kidney disease. J Vet Intern Med. 2016;30(3): Hall JA, Yerramilli M, Obare E, Yerramilli M, Yu S, Jewell DE. Comparison of serum concentrations of symmetric dimethylarginine and creatinine as kidney function biomarkers in healthy geriatric cats fed reduced protein foods enriched with fish oil, L-carnitine, and medium-chain triglycerides. Vet J. 2014; 202(3): Hall JA, Yerramilli M, Obare M, Yerramilli M, Melendez LD, Jewel DE. Relationship between lean body mass and serum renal biomarkers in healthy dogs. J Vet Intern Med. 2015;29(3): Data on file at IDEXX Laboratories Inc. Westbrook, Maine USA. 9 Quimby JM, Lunn KF. Mirtazapine as an appetite stimulant and anti-emetic in cats with

10 chronic kidney disease: A masked placebocontrolled crossover clinical trial. Vet J. 2013; 197: Quimby JM, Brock WT, Moses K, Bolotin D, Patricelli K. Chronic use of maropitant for the management of vomiting and inappetence in cats with chronic kidney disease: a blinded, placebocontrolled clinical trial. J Feline Med Surg. 2015; 17: bit.ly/2josem4 12 ACVIM Forum 2017; 12. bit.ly/2xusndt