PVM urology/nephrology specialist studies novel diagnostic methods for early identification of kidney diseases as a key to saving lives of pets.
Urinary tract health problems are commonly encountered in small animal veterinary practice (www.vet.purdue.edu/urology). While various advanced diagnostics, treatment plans and therapeutic strategies are available to treat these issues, challenges still exist in early identification of Acute Kidney Injuries (AKI) and Chronic Kidney Disease (CKD). Often in cats and dogs, renal disease is not detected until it has reached later stages and caused a degree of kidney failure. New methods that help with early detection of these problems hold promise for reducing mortality and improving survival time and quality of life in these patients.
Dr. Sarah Steinbach, assistant professor of small animal internal medicine and director of the Purdue Veterinary Hemodialysis Service, is a specialist in the field of veterinary nephrology and urology. Originally from Stein am Rhein, Switzerland, Dr. Steinbach obtained her veterinary degree from the Vetsuisse Faculty University of Bern, Switzerland. “When I was a student I was deeply impressed by the ability to perform hemodialysis in our patients with kidney disease at the University of Bern,” Dr. Steinbach said. “I had great mentors there and fell in love with everything related to the kidney – I knew already back then that I wanted to become a veterinary nephrologist. I am very passionate about veterinary nephrology and urology and love that we are able to provide state of the art care for our furry patients here at Purdue.”
During the first year of her career at Purdue, Dr. Steinbach was instrumental in establishing the Purdue Veterinary Hemodialysis Service. Hemodialysis is a form of blood purification that can be used in animals with kidney disease. This method removes accumulated toxins from the blood that normally are cleared by kidneys when they are functioning properly. Her research focuses on identifying novel biomarkers for CKD and AKI and using minimally invasive techniques to better quantify renal function in pets with kidney disease.
New Diagnostic Approaches
One of the common methods currently used to diagnose kidney disease involves assessing increases in serum creatinine concentration and blood urea nitrogen (BUN). Unfortunately, creatinine concentration is influenced by many factors, including age, breed, gender, total muscle mass, cancer and other diseases, which makes it a less sensitive marker for analyzing variations in kidney function. Furthermore, creatinine levels will not differ from standard or control values until 75% of renal function is lost. By then, in many cases, the damage to kidneys is irreversible, resulting in poor prognosis.
Glomerular Filtration Rate (GFR) is a measure that tells how well the blood is filtered by the kidneys and accurately reflects renal or kidney function. Therefore, determining GFR by either measuring surrogate markers or directly assessing GFR through a so-called clearance procedure (efficiency with which a selective substance or molecule is cleared by kidneys) is helpful in evaluating animals with kidney disease. Measurement of GFR through clearance procedures is currently the gold standard in testing kidney function in humans and pets. The conventional methods for assessment of GFR, however, are inconvenient and cumbersome as they involve multiple timed blood and/or urine samples. Especially in small pets such as cats, this process can be very difficult to follow.
“Less invasive and more accurate methods of assessing kidney function in veterinary medicine are warranted,” Dr. Steinbach said. In an earlier study that was published in PLoS ONE titled “A pilot study to assess the feasibility of transcutaneous GFR measurement using fluorescence-labelled sinistrin in dogs and cats,” Dr. Steinbach and her colleagues used the fluorescence labelled marker fluorescein-isothiocyanate-labelled sinistrin (FITC-S) to assess kidney function transdermally. FITC-S is solely eliminated by kidneys and therefore can be used as a marker for GFR. Instead of blood and urine sampling, fluorescence emitted by the marker is captured by a transcutaneous device called a non-invasive clearance device (NIC kidney device) which is placed on the skin of an animal (Fig 1). This device allows for measuring the kidney’s elimination of FITC-S by detecting the fluorescence signal through the skin of pets that are awake and freely moving (Fig 2). Dr. Steinbach and her colleagues were able to conclude that this method is feasible, noninvasive, provides real time results and is well tolerated by animals. In addition, they were able to identify the optimal dosage of the fluorescent marker FITC-S and the best location for placing the device in cats and dogs, i.e. the ventral abdomen and lateral chest wall, respectively (Fig 3). Dr. Steinbach is continuing her work to assess this promising methodology for establishing standard or reference values and evaluating the consistency of the measurement values under the varying physical and health conditions of small animals. A recent study, “Transcutaneous glomerular filtration rate measurement in a canine animal model of chronic kidney disease,” co-authored by Dr. Steinbach, has already shown promise in a canine model of chronic kidney disease.
The Importance of Biomarkers
Another approach to diagnosing kidney disease involves reliable biomarkers of kidney function or kidney injury. These biomarkers can help in diagnosing kidney disease earlier, guiding treatment and improving prognoses. An earlier study of the renal injury biomarker NGAL by Dr. Steinbach, entitled, “Plasma and urine neutrophil gelatinase-associate lipocalin (NGAL) in dogs with acute kidney injury and chronic kidney disease,” was published in the Journal of Veterinary Internal Medicine. This study showed that NGAL could be used to differentiate dogs with AKI from those with CKD. However, this test is currently not commercially available for use in a clinical patient. Therefore Dr. Steinbach studied the application of a new biomarker, symmetric imethylarginine (SDMA) that is primarily eliminated by kidneys and, therefore, serves as a good measure of renal function in dogs. Earlier studies on both humans and animals showed that this marker is superior to creatinine as an accurate and consistent measure of kidney function and a means for early detection of kidney disease. IDEXX Reference Laboratories from West Brooke, Maine, developed an immunoassay for SDMA called the IDEXX SDMA test. Using this test in dogs, Dr. Steinbach was able to conclude that plasma concentration of SDMA is a suitable marker to diagnose AKI and CKD in dogs. However, as she expected, this marker did not differentiate between AKI and CKD. Her article “Plasma symmetric dimethylarginine concentration in dogs with acute kidney injury and chronic kidney disease” was published in the Journal of Veterinary Internal Medicine.
Further research would be helpful in seeing how this biomarker could provide information about the prognoses for animals with kidney disease, especially in cats with hyperthyroidism. As an endocrine disorder, hyperthyroidism is characterized by increased production of the hormone thyroxine and is commonly diagnosed in older cats. Increased levels of thyroxine increases renal function and can mask the symptoms of an existing renal disease. Dr. Steinbach is preparing for a clinical trial with the goal of using the NIC Kidney device, along with SDMA as a complimentary biomarker, to study the efficacy of these markers together in detecting kidney disease in hyperthyroid cats.
Besides SDMA and NGAL, there are many other biomarkers, which might not only be useful in evaluating animals with kidney disease, but also in treating animals with urinary tract infections. For example, NGAL has been identified not only as a biomarker of renal injury, but also as a marker for urinary tract infections. Common among humans as well as small animals, urinary tract infections are treated with antibiotics. Given the increase in bacterial antibiotic resistance, treatment is becoming more challenging. Dr. Steinbach is pursuing research to identify novel biomarkers that can distinguish infection from inflammation and thereby identify true infections in cases that currently defy such diagnosis. Dr. Steinbach said, “Asymptomatic or subclinical bacteriuria is an example in which bacteria are found in urine samples but without any symptoms of true infection and treatment in such cases is often not clinically beneficial.” Use of biomarkers that can differentiate between a true infection and subclinical bacteriuria would be helpful and decrease unnecessary use of antibiotics. NGAL has been shown to be elevated in non-azotemic (not showing increase in BUN and creatinine levels) dogs with urinary tract infections (Daure et al. 2013). “Dr. Caroline Aldridge, one of our Small Animal Internal Medicine Residents, and I are currently looking at NGAL and other potentially helpful biomarkers in dogs with and without urinary tract infections,” Dr. Steinbach said.
Hopefully this work will lead to further improvement in the care and treatment of patients with kidney disease or urinary tract infections.