Dr Lizzie Youens BSc(Hons) BVSc MRCVS
Chronic kidney disease is common in older cats, with a prevalence of 30-40% in cats over 10 years of age.15 Traditionally, screening for renal disease involves the use of blood creatinine and blood urea nitrogen (BUN) levels, along with a urine assessment. However, many of these markers are well known to only detect this disease at a fairly late stage, with creatinine only rising when up to 75% of renal function has already been lost!
The veterinary immunoassay to measure SDMA (symmetric dimethylarginine) has been proposed as a more sensitive method of detecting renal disease with the ability to detect damage at a much earlier stage.
This sounds promising, but is this SDMA immunoassay as good as it seems? And how does it help you, the veterinarian, when your patient has an elevated SDMA on their wellness exam with no other abnormal biochemical or hematologic abnormalities?
Let’s dive into the specifics around the feline SDMA immunoassay to learn more about the important parameters and other considerations veterinarians should think about before utilizing.
Filtration of the blood and disposal of waste products are the primary functions of the kidneys. The glomerular filtrate is modified by the renal tubules which control fluid volume, electrolytes, and acid-base status. Glomerular filtration rate (GFR) is therefore used as the best overall measure of kidney function. GFR can be assessed in individual animals, for example by using iohexol clearance, but this method is expensive and rarely used in general practice. Instead, surrogate markers of GFR such as creatinine are used to assess function - and now, SDMA.
Symmetric dimethylarginine (SDMA) is an arginine amino acid that contains two methyl groups in a symmetrical orientation. It is produced in intracellular proteins by all nucleated cells at a constant rate and is excreted primarily by the kidneys. SDMA is also used as a biomarker to reflect the glomerular filtration rate (GFR) in people, and more recently in dogs and cats,1 now that a veterinary assay has been developed. An increase in SDMA indicates an impaired glomerular filtration rate, and therefore decreased renal function. It has been reported as a sensitive and early marker for renal disease in cats,2 but its usefulness has also been questioned.3
Serum SDMA is increased in both feline acute kidney injury and chronic kidney disease.14 Before SDMA, veterinarians already had a range of criteria to assess kidney function in cats. As in many things, nothing is perfect, and all of these tests have their drawbacks.
Blood tests for creatinine and blood urea nitrogen (BUN) are commonly utilized. These parameters rise when GFR drops but are fairly late markers of renal dysfunction and are impacted by other factors such as muscle mass, diet, and liver disease.
These tests should be paired with a urinalysis. The urine specific gravity is a useful assessment of the urine concentrating power by the kidneys, but it is privy to natural fluctuations and also impacted by other diseases and factors. The urine protein:creatinine ratio quantifies protein in the urine but can be normal in early renal disease along with false positives being seen with urinary infections.
If a kidney disease diagnosis is made, further diagnostics are performed to determine more information such as a full biochemistry, hematology, urinalysis, blood pressure measurement, and potential diagnostic imaging.
SDMA is a sensitive biomarker for renal function, detecting as little as 25-40% loss.4 Creatinine only rises when up to 75% of renal function is lost, and USG is sensitive to only around 66% loss. This means that SDMA can detect deteriorating renal function earlier than some of the traditional renal tests, as it increases before other parameters such as creatinine. In a study involving 21 cats, SDMA increased earlier than creatinine in cats with chronic kidney disease (CKD) by a mean of 17 months.5
SDMA may also be more reliable than other tests such as BUN and creatinine, as it is not affected by common adjacent conditions and other factors. SDMA is also unaffected by a protein-rich diet6 and changes to lean muscle mass.7 Feline SMDA diagnostics may be particularly helpful when understanding that a large proportion of cats being tested for renal function are geriatric and therefore most affected by muscle loss.
Once GFR persistently decreases to 30-50% of normal function, there is irreversible change to renal function, and progression to kidney failure is inevitable.2 The remaining nephrons have entered a hyperfiltration state, there is activation of the renin-angiotension-aldosterone system, renal fibrosis, and glomerulosclerosis. Detecting kidney disease early in cats should trigger initiation of various management techniques to try and preserve some of this function before irreversible change.
Detecting renal disease early is important not only to impose management strategies to slow progression, but also to detect treatable conditions such as infections and trigger diagnosis of concurrent diseases such as feline hyperthyroidism.
SDMA was traditionally measured using a liquid chromatography-mass spectroscopy (LC-MS) technique, but there is now an immunologic-based assay. The veterinary immunoassay for SDMA has been found to have fairly high levels of dispersion of at least 40%, meaning a measured result of 14 μg/dl represents a range of possible results from 8 μg/dl to 20 μg/dl.8 Care should therefore be taken to not to over-analyze small changes to SDMA results, as there may be both analyzer and biological variability.
The specificity of feline SDMA has also been questioned, along with its apparent superiority to creatinine. In a study of 49 cats,13 SDMA had a similar sensitivity to creatinine (76-94% SDMA compared to 71-88% creatinine), but SDMA had a lower specificity (71% versus 94-96% for creatinine). The study concluded that SDMA was a reliable biomarker for decreased GFR but could not confirm that it is any better than creatinine.
Now we know the ins and outs of the SDMA test, how can we apply this knowledge practically? Here are some situations in which SDMA may be of use.
Given its ability to detect renal dysfunction before other, more traditional markers, SDMA can be a useful addition to a wellness exam. Early detection of kidney dysfunction should lead to appropriate steps being taken to protect remaining function, such as dietary management and optimizing hydration.
Renal disease and hyperthyroidism are both common in older cats and are often seen as co-morbidities. However, hyperthyroidism can mask renal disease via its effect on GFR. Having a more sensitive test for renal function may be helpful in these cases.
Chronic kidney disease has some implications for anesthetic safety. Awareness of renal function allows for educated decisions to be made.
Is measuring SDMA actually helpful? This test will only make a difference to patients if veterinarians act differently based on the result. When the SDMA test is used, it is looking for impairment of the GFR, which should lead to action. Patients with impaired GFR should be investigated for an underlying cause or concurrent condition. They should be treated appropriately (including for proteinuria and hypertension), and then monitored for any deterioration in function.
The International Renal Interest Society (IRIS) has adapted staging guidelines17 to include SDMA, assessing that SDMA may be able to detect earlier levels of dysfunction and may be particularly useful to assess patients with poor muscle condition. For example, a cat with a creatinine of <1.6 mg/dl, who would be a Stage 1 based on this level would be upgraded to a Stage 2 if SDMA was persistently >18 µg/dl. Similarly, a cat with SDMA of >25 µg/dl would cause a traditionally Stage 2 cat (creatinine between 1.6 and 2.8 mg/dl) to be treated as a Stage 3. It is worth noting that the IRIS guidelines state that the abnormal SDMA level should be proven to be persistent - i.e., repeatable over two measurements, 2-4 weeks apart.
Algorithms for interpreting SDMA results are available online and on diagnostic reports.16 In essence, an SDMA result of ≥20 μg/dL should automatically trigger concern for a disease process — either primary renal function or reflecting another disease process which is affecting the kidneys. However, an SDMA result of 15–19 μg/dL is less easily interpreted. If there is other evidence that kidney function is affected, such as through urinalysis or blood azotaemia, then the patient should be treated as if a reduced GFR is present. However, if there are no other signs of kidney disease, it may be more appropriate to monitor and recheck SDMA in 2-4 weeks. If SDMA remains persistently elevated, the patient should be treated as having a degree of renal dysfunction.
It is also worth noting that any cause of decreased GFR can alter SDMA. This includes pre-renal causes such as dehydration, hypotension/shock, anesthesia and cardiac disease as well as renal and post-renal causes. It will also alter with any other disease processes which affect the kidneys, such as hyperthyroidism, vector-borne disease, hypertension, sepsis and cancer.9-12 If the SDMA is raised in a patient, a full health assessment should be performed rather than primary kidney disease assumed.
SDMA appears to have higher sensitivity for detection of early renal disease in cats. However, its specificity and factors affecting specificity have not been tested using any large-scale prospective studies. It should be considered a useful addition to a renal panel involving other tests such as creatinine and urinalysis, and it may aid in early detection of disease.