Increased SDMA is a kidney distress call, and veterinarians know exactly where it’s coming from – the kidneys. More technically, SDMA (symmetric dimethylarginine) is a form of amino acid, released into your pet’s circulation during protein degradation, and it’s excreted by the kidneys.3 SDMA increases sooner than previously standard methods of detection (creatinine during your pet’s routine blood work).3 In fact, studies show:
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Monday, December 14, 2015
Any increase in SDMA concentration above the reference interval (greater than 14 µg/dL in cats and adult dogs greater than 16µg/dL in puppies) is considered meaningful.
An elevated SDMA concentration is a reflection of impaired glomerular filtration rate (GFR). Both primary kidney disease
and secondary kidney insults, such as concurrent disease, can cause an elevation in SDMA concentration.
The IDEXX SDMA Test is included with every chemistry panel or as a stand-alone test from IDEXX Reference Laboratories.
To get started with IDEXX Reference Laboratories, call 1-800-667-3411.
The SDMA slide is available to run on your Catalyst One or Catalyst Dx chemistry analyzer.
To order Catalyst SDMA slides, click here.
Kidney disease is common with 1 in 3 cats 25 and 1 in 10 dogs 26 developing some form of kidney disease over their lifetime. Recent studies suggest kidney disease is even more common and until now has been under-recognized. 27 The IDEXX SDMA Test will help to recognize kidney disease in more animals earlier with prevalence increasing with age. As kidney disease advances, creatinine will also be increased.
• Prevalence of increased IDEXX SDMA concentration in dogs
Approximately 11% of dogs have an increased SDMA. Prevalence increases with age with only 7% prevalence in dogs 1–6 and 7–9 years of age, 11% prevalence in dogs 10 and 11 years old, and then prevalence increases with each year of age from 16% in dogs 12 years old up to 42% in dogs 15 years old and older. 8
• Prevalence of increased IDEXX SDMA in cats
Approximately 26% of cats have an increased SDMA. Just like in dogs, prevalence increases with age with 10% prevalence in cats 1–5 years of age, 13% prevalence in cats 6–9 years old, 17% prevalence in cats 10 and 11 years old, 24% prevalence in cats 12 and 13 years old, and then prevalence increases with each year of age from 33% in cats 14 years old up to 67% in cats 18 years old and older. 8
An increased IDEXX SDMA concentration indicates decreased kidney function as a result of acute kidney injury (AKI), chronic kidney disease (CKD), or both and should never be ignored. An IDEXX SDMA concentration above the reference interval requires you to take action to investigate, manage, and monitor using the IDEXX SDMA Test diagnostic algorithm.
Using the IMM approach, first, a complete urinalysis should be performed (if not already).
When the SDMA result is ≥ 20 µg/dL
• Kidney disease is probable and you should act immediately by following the investigate, manage, and monitor (IMM) protocol of the IDEXX SDMA Test diagnostic algorithm, as described below.
When the SDMA result is 15-19 µg/dL
• Determine if there is other evidence of kidney disease including: clinical signs or physical findings increasing creatinine within the reference interval or azotemia urine changes such as inappropriate urine specific gravity, active urine sediment or proteinuria or abnormal kidney imaging. These findings suggest that kidney disease is probable and immediate action be taken using the IMM protocol described below.
• If there is no other evidence of kidney disease, then recheck the SDMA in 2-4 weeks.
• At recheck if the SDMA is persistently increased, then act immediately upon probable kidney disease with the IMM protocol of the IDEXX SDMA Test diagnostic algorithm:
• I — Investigate for an underlying cause of kidney disease, especially more treatable conditions such as infection, obstruction, or exposure to toxins or potentially nephrotoxic drugs, and to look for confounding conditions by assessing hydration status, blood pressure and thyroid status.
• M — Manage or treat any underlying causes or confounding conditions and implementing practices to avoid future insults to the kidneys, such as taking precautions with prescribed drugs and when anesthetizing the patient.
• M — Monitor the patient as indicated based on treatments initiated for any identified underlying diseases or confounding conditions.
If both IDEXX SDMA and creatinine concentrations are within their reference intervals, then kidney disease is unlikely. If both IDEXX SDMA and/or creatinine concentrations are at the upper end of the reference interval, or they have been increasing within the reference interval, early kidney disease cannot be ruled out. A complete urinalysis should be performed to confirm there is no other evidence of kidney disease.
This combination of results is uncommon. Hemolysis, if present, can result in decreased SDMA. SDMA and creatinine can both be affected by biologic and assay variability resulting in fluctuations around the upper end of the reference interval this can be seen with well-managed stable CKD and results will likely align as disease progresses. Creatinine can exceed the reference interval in muscular dogs with normal kidney function. Creatinine can be artifactually increased postprandially. If kidney disease is still suspected, a complete urinalysis should be performed on all patients to evaluate for inappropriate specific gravity, proteinuria or other evidence of kidney disease.
Symmetric dimethylarginine (SDMA) is a methylated arginine amino acid. SDMA, along with its structural biologically active isomer, asymmetric dimethylarginine (ADMA), are derived from intranuclear methylation of L-arginine residues on various regulatory proteins and are released into the cytoplasm after proteolysis. SDMA is excreted by the kidneys, whereas ADMA is largely metabolized.
Three key attributes make the IDEXX SDMA Test more reliable than creatinine.
• Biomarker for kidney function
SDMA is excreted by the kidneys. SDMA more accurately reflects glomerular filtration rate (GFR) in dogs and cats. 1-3,6
• Earlier than creatinine
SDMA increases as early as 25% loss of kidney function, 1-2 making SDMA more reliable in both acute or active kidney injury and chronic kidney disease. 1-3 Creatinine cannot identify kidney issues until almost 75% of kidney function is lost. 2,3
• Specific for kidney function
SDMA is less impacted by extrarenal factors than creatinine, including body condition, advanced age, and disease state. 4,5
SDMA is also not affected by lean body mass, making it more reliable for assessing kidney function in animals with chronic kidney disease or other conditions that result in weight and muscle loss, such as hyperthyroidism. 4,5
No, IDEXX did not discover SDMA. Numerous published studies have evaluated SDMA as a kidney biomarker.
The IDEXX SDMA Test is the only commercially available SDMA test that has been validated for use in dogs and cats. 1,13 The IDEXX SDMA Test is an immunoassay performed on a high-throughput chemistry analyzer at our reference laboratories. In this way, we provide SDMA results as part of our routine chemistry panels alongside creatinine.
Kidney disease is common in dogs and cats, and it is well recognized that traditionally available diagnostic tests detect it late. At IDEXX, we are committed to enhancing the health and well-being of pets by providing veterinarians with tools and diagnostics to support the practice of best medicine. Diagnosing kidney disease early provides opportunities to intervene and improve outcomes by addressing causes and complications. Because SDMA helps veterinarians to more reliably diagnose, stage and treat kidney disease we believed it was important to add it to all routine chemistry panels.
The Catalyst SDMA Test is available to run in-house with any chemistry CLIP or as a standalone test on Catalyst One and Catalyst Dx chemistry analyzers.
The Catalyst SDMA Test is also available in the Catalyst SDMA and Total T4 Kit. This kit includes one SDMA slide and one total T4 slide that share a reagent. This allows for SDMA and total T4 to be run together on the Catalyst Dx Chemistry Analyzer.
SDMA is excreted from the kidneys therefore, as kidney function or GFR decreases, SDMA increases. Studies have shown a very strong correlation between SDMA and GFR (R 2 of 0.82 in cats 9 R 2 of 0.85 in dogs 1 ). A benefit of using SDMA along with creatinine, which typically increases above the reference interval when there is up to a 75% reduction in GFR, 2,3 is that SDMA increases when there is on average a 40% decrease in GFR. 2,3 In some cases, SDMA increases earlier when there is 25% reduction of GFR, representing 25% loss of kidney function. 1,2
Performing a GFR clearance test is the gold standard for measuring GFR and assessing kidney function. However, performing a GFR clearance test is expensive, cumbersome, and not routinely done in practice.
• Creatinine—SDMA is a more reliable and sensitive indicator of kidney function in animals. SDMA increases earlier than creatinine in dogs and cats with both AKI and CKD, 1-3 and unlike creatinine, SDMA is not impacted by lean muscle mass. 4,5 SDMA increases on average with 40% loss of kidney function versus creatinine, 2-3 which does not increase until up to 75% of kidney function is lost. 2,3 Creatinine is a breakdown product of muscle and is therefore impacted by lean body mass, whereas SDMA is not.
• Blood urea nitrogen (BUN)—BUN is also a late marker of kidney dysfunction in contrast to SDMA. In addition, BUN can be influenced by decreased production in liver disease and increases with high-protein meals or gastrointestinal bleeding versus SDMA, which changes only with changes in GFR.
• Urine specific gravity (USG)—Loss of urine concentrating ability progresses with kidney disease and dysfunction, and it is apparent before metabolic wastes such as BUN and creatinine increase. This change occurs with approximately 67% loss of nephron function but is variable. 10 SDMA may increase in patients with early kidney disease that can still concentrate their urine. Natural fluctuations in USG are common in healthy animals and are influenced by how much the animal drinks prior to urine collection. Poor urine concentration is not specific to the kidney and can be influenced by other diseases (e.g., diabetes, liver disease, and Cushing’s disease) versus SDMA, which is influenced by changes in GFR. Finding a persistently increased IDEXX SDMA concentration and inappropriately concentrated urine suggests kidney disease is probable and immediate action should be taken.
• Urine protein:creatinine (UPC)—The UPC ratio is a urine test. It is used to fully quantify protein detected in the urine once transient proteinuria, urinary tract infection, inflammation, or significant hematuria have been ruled out. The UPC ratio may detect kidney disease earlier than creatinine if the primary target of the disease is the glomerulus and with some cases of tubulointerstitial disease. However, it is common for the UPC ratio to remain normal in animals with CKD, especially in early stages when SDMA may be increased. Persistent proteinuria that results in UPC ratios greater than 0.4 in cats and 0.5 in dogs, where prerenal and postrenal proteinuria have been ruled out, are consistent with glomerular or tubulointerstitial CKD, whereas UPC ratios greater than 2.0 are strongly suggestive of glomerular disease. 11 In animals with proteinuria, the UPC ratio should be used to monitor progression and response to treatment.
• Microalbuminuria—Microalbuminuria is a urine test. It is an early marker only in some cases of CKD. Physiologic transient increases are common. It will also be positive with urinary tract inflammation, so additional testing is needed to rule out urinary tract infection, inflammation, or significant hematuria. Once persistence has been established and false positives eliminated, microalbuminuria will be the earliest indicator of glomerular disease. In early glomerular disease when GFR may still be normal, SDMA may also remain normal. Similarly, microalbuminuria may be an early indicator of some but not all tubulointerstitial CKD, and as GFR decreases, SDMA will increase. A positive result for microalbuminuria should always be followed by testing a UPC ratio to determine quantitative value. It is common for the microalbuminuria test and the UPC ratio to be normal, especially in early CKD.
SDMA is a more reliable tool to evaluate kidney function and results should be considered first, before creatinine. However, creatinine is still complementary to SDMA for evaluating kidney function. A complete kidney evaluation should consist of a thorough history, physical examination, and evaluation of a minimum database, including CBC, chemistry profile with the IDEXX SDMA Test and electrolytes, and complete urinalysis.
IDEXX includes the IDEXX SDMA Test in all routine reference laboratory chemistry panels, so creatinine is readily available for comparison. Creatinine is needed for International Renal Interest Society (IRIS) staging of CKD, so it remains important for clinical characterization of CKD patients.
The IDEXX SDMA Test is a serum test and SDMA is a reliable marker of GFR SDMA increases as kidney function decreases, regardless of underlying cause. It is both sensitive and specific for loss of kidney function. Unlike the IDEXX SDMA Test, the microalbuminuria test and the UPC ratio are urine tests. They detect protein in the urine that can be from anywhere in the urinary tract, so it’s important to eliminate false-positive results, especially with urinary tract infections, other inflammation, or significant hematuria. Transient proteinuria that can also result from physiologic causes, such as strenuous exercise, fever, exposure to extreme cold or heat, and stress, must first be eliminated and persistence demonstrated.
Patients with glomerular disease may develop proteinuria long before a significant change in GFR, so their SDMA may remain normal until disease is more advanced and GFR decreases. However, patients with tubulointerstitial disease may have only mild proteinuria or no proteinuria at all in these cases, SDMA will usually be an earlier indicator of CKD.
The microalbuminuria test detects very small amounts of protein in the urine. A positive microalbuminuria test can result from physiologic or pathologic conditions. Transient physiologic increases can occur with fever, strenuous exercise, seizures, exposure to extreme heat or cold, and stress. Pathologic urinary proteinuria can be from anywhere in the urinary tract therefore, false positives are common, especially with urinary tract inflammation. Only after urinary tract infection, inflammation, significant hematuria, and nonpathologic causes have been ruled out and persistence established can microalbuminuria be considered an early indicator of kidney disease. Microalbuminuria of renal origin occurs with glomerular disease and with some, but not all, tubulointerstitial disease. The IDEXX SDMA Test, on the other hand, is a serum test and SDMA is a biomarker for GFR, increasing only when there is on average a 40% loss of GFR, 2,3 regardless of underlying etiology of the kidney disease.
A published study in cats found the sensitivity of SDMA to be 100% and the specificity to be 91% when compared to the gold standard of GFR. There were 2 “false positives” in this study, but these 2 cats actually did have a 25% reduction in their GFR the GFR cut off to define kidney disease in this study was only a 30% reduction in GFR. 2
No. In the feline study mentioned in Question 2.6, the sensitivity of creatinine, using the reference interval established for their laboratory, was only 17%. However, when the IRIS CKD Stage 1 cut off for creatinine of 1.6 mg/dL (140 µmol/L) was used instead, the sensitivity still only increased to 50%. 2 SDMA is more reliable, as it is better correlated with GFR and is more sensitive than creatinine. At IDEXX, we established our creatinine reference intervals by performing a true reference interval study with clinically healthy dogs and cats following Clinical and Laboratory Standards Institute (CLSI) guidelines. 8
Reference intervals should be established by each laboratory by performing a reference interval study following Clinical and Laboratory Standards Institute (CLSI) guidelines. Measurement of all analytes are affected by the methodology used, including the type of chemistry analyzer and the reagents and calibrators. A universal reference interval for any given analyte across all methodologies is not possible. The IRIS CKD staging guidelines are intended for use after CKD is diagnosed. The diagnosis should be based on all clinical information, evaluation of laboratory results guided by the lab’s provided reference intervals, and other diagnostic information available. Once CKD is diagnosed and kidney function is stable, the patient can be staged using the IRIS guidelines with their suggested cutoffs for creatinine. These IRIS creatinine cutoffs do not replace an individual laboratory’s reference interval, rather they are provided for staging to help guide management of CKD. At IDEXX we established our creatinine reference intervals by performing a true reference interval study of clinically healthy dogs and cats following CLSI guidelines. 8
As a functional biomarker it has not been recognized that SDMA can help localize kidney disease or specify the cause of kidney disease. It increases as GFR decreases, reflecting overall nephron function, which does not appear to be affected by lesion localization or etiology.
SDMA is more reliable than creatinine because it increases earlier than creatinine in dogs and cats with kidney disease 1-3,6 and it is also not impacted by lean body mass like creatinine is. 4,5
Early diagnosis provides the opportunity to take action by doing the following:
• Investigate for an underlying cause of kidney disease, especially more treatable conditions such as infection, obstruction, or exposure to toxins or potentially nephrotoxic drugs, and to look for confounding conditions by assessing hydration status, blood pressure, and thyroid status.
• Manage or treat any underlying causes or confounding conditions and implement practices to avoid future insults to the kidneys, such as taking precautions with prescribed drugs and when anesthetizing the pet.
• Monitor the patient as indicated based on treatments initiated for any identified underlying diseases or confounding conditions.
SDMA correlates with GFR and therefore will increase in acute kidney injury (AKI) or with active disease once there is functional loss of the kidney. Because it increases when there is on average 40% loss of GFR 2,3 and as early as 25% kidney functional loss 1,2 versus creatinine, which is not increased until up to 75% loss of GFR, 2,3 it increases earlier in AKI or when there is an active disease process such as pyelonephritis. By the time an animal presents with clinical signs and has increased creatinine (is azotemic), SDMA will be clearly increased. SDMA might alert to the development of hospital acquired kidney injury or help to confirm toxin exposure when suspected, such as a scenario of possible lily exposure where the cat is hospitalized and being serially monitored for evidence of kidney injury. Demonstrating a significant increase in SDMA would confirm altered GFR, likely due to acute injury from the toxic plant, justifying continued fluid support and hospital care.
The reference interval for dogs and cats is the same: 0–14 µg/dL. Reference intervals were established following the Clinical and Laboratory Standards Institute (CLSI) guidelines for determining reference intervals. Adult (1 year and older) animals characterized as healthy based on history and physical examination were studied. Animals received no medications except for routine heartworm and parasite prophylaxes. Males and females were equally represented and were of various breeds and sizes. 12
In puppies, the IDEXX SDMA Test reference interval has been determined to be slightly higher (0–16 μg/dL) than the adult reference interval (0–14 μg/dL). A majority of puppies (90%) have results that fall within the adult reference interval, and another 6% have a result within the extended puppy reference interval. Reference interval studies are underway for kittens and results should be interpreted in light of other findings.
The cause of this slight increase in IDEXX SDMA concentration in puppies is unknown at this time, but physiological roles for protein arginine methylation, including signal transduction, mRNA splicing, transcriptional control, DNA repair, and protein translocation, are postulated to be increased in growing animals, resulting in increased SDMA generation.
It has been recognized that on a population basis, median SDMA results appear to be slightly higher (approximately 1 μg/dL) in greyhounds compared to other breeds. Nevertheless, most healthy greyhounds with normal kidney function will have SDMA results within the reference interval. Keep in mind that it is also common for greyhounds to have creatinine concentrations just above the reference interval, which is believed to be a result of their high muscle mass. Therefore, in greyhounds, both creatinine and SDMA concentrations may be near the upper end or just above their respective reference intervals, and the results of both should be evaluated together, along with a complete urinalysis.
The IDEXX SDMA Test has not been validated nor reference intervals established yet for species other than dogs and cats. Projects validating SDMA and establishing reference intervals for other species are ongoing. However, SDMA results will be provided on routine nonspecies-specific chemistry profiles. For species other than dogs and cats, no reference interval will be provided, and the following statement will be given with the IDEXX SDMA Test result: SDMA is a new kidney test for dogs and cats. No information is currently available on how to interpret SDMA in other species.
Any increase in IDEXX SDMA concentration above the reference interval (greater than 14 µg/dL in cats and adult dogs greater than 16µg/dL in puppies) is considered meaningful. Most animals with early kidney disease have a SDMA between the upper end of the reference interval up to 20 µg/dL. Since SDMA increases as kidney function decreases, an SDMA concentration greater than 20 µg/dL is typically seen in more advanced disease, along with an increased creatinine concentration. Less than 1% of all results will be above 50 µg/dL. The linearity of the assay is up to 100 µg/dL.
Renal failure is an outdated term. Current terminology for acute progressive disease is acute kidney injury (AKI). Current terminology for chronic disease is chronic kidney disease (CKD) and the International Renal Interest Society (IRIS) CKD staging system should be used to stage chronic stable disease from stage 1 through stage 4. Please see the IRIS guidelines for more information. SDMA offers another tool for recognition of dogs and cats with early kidney disease. An increased IDEXX SDMA concentration should be investigated, managed, and monitored to determine the probability of kidney disease and whether it is likely due to ongoing kidney injury or part of CKD.
CKD is common in older cats. Lean body mass decreases as cats age. SDMA is not impacted by lean muscle mass like creatinine is, which makes SDMA a more reliable indicator of kidney function in older cats. 4,5 Therefore, not only will SDMA help to detect CKD in older cats, it should be helpful to monitor kidney function in cats with CKD as their disease progresses and they continue to lose muscle mass. SDMA has been incorporated into the International Renal Interest Society (IRIS) guidelines as an adjunct for both diagnosis and staging of CKD. Creatinine can understage CKD in underweight animals and SDMA may help to direct treatment for the appropriate IRIS stage. SDMA may also help to identify an acute or chronic kidney injury that should be investigated and treated.
SDMA correlates well with GFR, increasing when there is on average a 40% loss, 2,3 and as little as 25% loss, of GFR. 1 Reduced urine concentrating ability typically appears when there is, on average, a 67% loss of GFR, but this is variable. Cats with experimentally induced kidney disease, for example, showed poor correlation between maximum urine concentration and GFR, with some azotemic cats retaining concentrating ability despite severe reduction in GFR. 10 Given the lack of correlation between GFR and USG, a linear relationship between SDMA and USG could not be expected.
SDMA will however typically increase before isosthenuria associated with renal dysfunction develops. In many cases of early CKD, where SDMA is increased but creatinine is normal, the dog or cat will have an inappropriate USG (i.e., less than 1.030 for dogs or less than 1.035 for cats). However, in more than 25% of dogs and cats with an increased SDMA, significant urine concentrating ability will still remain because their GFR is only mildly decreased, or because of the variable timing of loss of concentrating ability. In patients with persistently increased SDMA where dehydration has been excluded, kidney disease is probable and should be further investigated, even if appropriate urine concentrating ability is noted.
SDMA can be run on serum (preferred) lithium heparin or EDTA plasma is also acceptable.
Studies have shown that lipemia and icterus do not affect the IDEXX SDMA result. Mild to moderate hemolysis does not impact IDEXX SDMA concentration, 13 but IDEXX Reference Laboratory SDMA Test results may be depressed in markedly hemolyzed specimens. In addition, it is rare that SDMA cannot be measured in specimens with extreme hemolysis and lipemia. However, as with all laboratory testing, quality specimens free of lipemia and hemolysis are preferred to provide the most accurate results. The Catalyst SDMA Test is not impacted by specimen quality.
IDEXX SDMA Test results are included with all routine chemistry panel results with the same turnaround time. The IDEXX SDMA Test does not impact the turnaround time of any routine chemistry panel result. Stand-alone IDEXX SDMA Test results are provided daily.
The Catalyst SDMA Test is available to run on Catalyst One and Catalyst Dx chemistry analyzers. With results available during the patient visit, veterinarians can get real-time answers with one sample, in one run.
SDMA is stable for 4 days at room temperature and 14 days refrigerated. 1 It is also stable for years in specimens that remain frozen and do not undergo freeze thaw cycles. Accordingly, whole blood, serum, or plasma specimens discovered in the centrifuge or on the counter that remained at room temperature for 24 hours or less should be acceptable to submit to IDEXX Reference Laboratories for IDEXX SDMA testing.
Because SDMA is a stable analyte, it is acceptable to add on an IDEXX SDMA Test to serum or plasma specimens being held at the reference laboratory or to submit specimens used for in-house diagnostic testing. It is best to interpret an IDEXX SDMA Test result first along with a paired creatinine result and a complete urinalysis.
Persistently increased SDMA in a hydrated patient is specific for kidney disease. SDMA correlates strongly with GFR and increases when GFR is reduced. Therefore, if GFR is reduced with prerenal or postrenal azotemia, then SDMA will increase accordingly.
IDEXX SDMA is a reliable marker for kidney disease, that is both sensitive and specific, increasing on average when there is a 40% reduction in GFR due to cancer or other conditions. Cancer patients with increased SDMA should be carefully managed since structural kidney disease is often present that results in CKD. In addition, cancer patients have increased risk of acute kidney injury from the disease and/or its treatment. Dogs and cats with cancer often have concurrent reductions in GFR, attributed to such documented conditions as neoplastic kidney infiltration, susceptibility to volume depletion, tumor lysis syndrome, obstruction, and sepsis, or to nephrotoxicity from cancer chemotherapy drugs. Early kidney dysfunction will be under diagnosed with creatinine since it only increases with significant reduction of GFR, up to 75%. In addition, many cancer- related factors can impact creatinine’s ability to identify loss of kidney function. Creatinine may be less reliable in cancer due to reduced production from cancer cachexia, reduced protein intake, and possibly the chemotherapeutics themselves, so many cancer patients need biopsy to confirm kidney disease. 14-17 SDMA is not affected by many of the extrarenal factors that impact creatinine.
Rarely, a veterinary cancer patient may have a marked increase in IDEXX SDMA that is disproportionate to other kidney markers, and is not associated with expected clinical signs of severely reduced excretory function. Mechanisms other than alterations in GFR are believed to be responsible for the increased SDMA in these patients. One theory being studied actively at IDEXX is that infiltrating cancer cells change the selectivity of the kidney’s glomerular basement membrane via a novel enzymatic pathway, 18 preventing filtration of the cationic SDMA molecule, while nonpolar creatinine is left unchanged. This creates a large differential between IDEXX SDMA and creatinine. Histopathologic evaluation of 19 veterinary cancer patients with increased SDMA confirmed that all had structural kidney damage due to neoplastic infiltration. 18
If dehydration results in a prerenal azotemia reflecting a reduction in GFR, then SDMA should also increase.
SDMA correlates strongly with GFR. Therefore, if GFR is normal in an animal with an endocrinopathy, IDEXX SDMA will also be normal. IDEXX has evaluated SDMA in several dogs with confirmed hyperadrenocorticism and hyposthenuria or isosthenuria, and SDMA was well within the reference interval. In animals evaluated with confirmed diabetes mellitus and no evidence of kidney disease, SDMA results have also been normal. 8 Finding an increased IDEXX SDMA in patients with these endocrine diseases would indicate concurrent kidney disease.
Because SDMA increases early in CKD when there is on average a 40% loss 2,3 and as early as a 25% loss of GFR, 1,2 it is unlikely that an animal with a normal SDMA would have PU/PD or loss of urine concentrating ability associated with renal tubular dysfunction and nephron loss. Typically, PU/PD of renal tubular dysfunction appears when there is a more significant reduction in GFR, on average with 67% loss of GFR, and USG becomes inappropriate (less than 1.030 for dogs, less than 1.035 for cats). 10
In animals with a secondary nephrogenic diabetes insipidus (DI) caused by pyometra, bacteremia, glucocorticoids, or other metabolic diseases, IDEXX SDMA concentrations would be expected to be normal because their GFR would remain normal. In these animals, their inappropriately concentrated urine that is hyposthenuric to isosthenuric is a result of tubular resistance to antidiuretic hormone. However, a patient with pyelonephritis could have aspects of nephrogenic DI, as well as nephron loss from inflammation, so IDEXX SDMA concentration could be normal or increased, depending on the extent that the GFR is affected.
No, SDMA is specific for kidney function and reliably reflects GFR. SDMA does not increase due to pancreatitis alone, and there is no correlation between SDMA and the Spec cPL and Spec fPL tests, which are sensitive markers for canine and feline pancreatitis, respectively. In well-characterized cats with IBD, SDMA only correlated with GFR and not the magnitude of gastrointestinal disease. 8 In human studies, SDMA is not impacted by acute inflammatory response, 19 hepatic disease, 20,21 stroke, or cardiovascular disease 22,23 unless there is concurrent compromise of kidney function. Demonstrating an increased SDMA in a stable patient with IBD, pancreatitis, or other systemic illness suggests alterations in GFR as a result of kidney disease.
Untreated hyperthyroid cats have increased glomerular filtration rate (GFR) and loss of muscle mass secondary to their hyperthyroidism, which can hide underlying CKD. 7 The IDEXX SDMA Test is a more reliable indicator of kidney function than creatinine in hyperthyroidism because unlike creatinine, the IDEXX SDMA Test is not affected by lean body mass and appears to be only slightly blunted by hyperfiltration. 8
The IDEXX SDMA Test often helps to predict the impact of thyroid treatment on kidney function and to identify which cats will become azotemic after treatment of hyperthyroidism. In a recent study, prior to hyperthyroid treatment, the IDEXX SDMA Test was increased in about half of the cats that had a normal creatinine before hyperthyroid treatment but become azotemic after thyroid treatment. 8 Therefore, while a normal pretreatment SDMA concentration does not rule out the possibility of a hyperthyroid cat developing azotemia, it is much more reliable than creatinine for identifying hyperthyroid cats with kidney disease so that appropriate precautions can be taken.
This has not been studied specifically in animals, but it has been confirmed that there is no correlation in dogs and cats between SDMA and serum arginine concentrations. 8 In addition, in pregnant women with preeclampsia receiving prolonged supplementation with L-arginine, there was no impact on serum SDMA concentrations. 24
Urine changes consistent with kidney disease include but are not limited to:
• Inappropriate urine concentration—USG less than 1.030 for dogs, USG less than 1.035 for cats.
• Proteinuria—While small amounts of protein may normally be found in the urine, proteinuria can indicate both renal and nonrenal disease. If significant proteinuria is detected and there is an inactive sediment, a urine protein:creatinine (UPC) ratio should be performed for protein quantification for accurate assessment and monitoring.
• Glucosuria (without hyperglycemia)—Persistent renal glucosuria may suggest tubular injury from renal infection, as with pyelonephritis or leptospirosis, exposure to potential toxins (e.g., jerky treats or heavy metals), or less commonly congenital renal glucosuria.
• Active urine sediment—Presence of pyuria and bacteriuria in a sterilely acquired specimen would be suggestive of urinary tract infection, and a urine culture and MIC susceptibility should be considered. The significance of hematuria, crystals, and epithelial cells would depend on the method of urine collection and storage. Significance of casts depends on type of cast and number present.
Leptospirosis is a common cause of acute kidney injury and liver disease associated with vasculitis. Less commonly, it may contribute to chronic inflammatory disease when patients are minimally symptomatic. Testing for chronic leptospiral infection will likely have the highest yield in patients that have not been vaccinated regularly for leptospirosis and that have interactions with wildlife or access to infected water sources and may also have a history of febrile illness. Complete urinalysis findings might include glucosuria, proteinuria, granular casts, hematuria, and pyuria. It is recommended to test for both antigen with the Leptospira spp. RealPCR Test on whole blood and urine as well as test for antibodies with the Leptospira spp. Antibody by ELISA on serum. The potential for zoonosis and disease progression justifies testing for leptospirosis in patients with acute or chronic kidney disease.
Testing for Lyme disease with a SNAP 4Dx Plus Test is appropriate for all dogs with proteinuria. Lyme nephritis may present as acute, stable, or progressive protein-losing nephropathy. Acute signs of illness are nonspecific and may include vomiting, anorexia, and lethargy. Some dogs may display more subtle or chronic signs, progressing slowly over weeks to months. Urinalyses show proteinuria with variable urine concentration, hematuria, pyuria, bilirubinuria, and glucosuria. Early recognition and treatment of Lyme nephritis might allow for successful treatment of this often fatal complication of Lyme infection.
Testing for common infectious diseases associated with glomerulonephritis using the SNAP 4Dx Plus Test is supported by diagnostic recommendations developed by IRIS. 28 The SNAP 4Dx Plus Test screens for six vector-borne diseases, including Lyme disease, heartworm, Ehrlichia canis, Ehrlichia ewingii, Anaplasma phagocytophilum, and Anaplasma platys.
Testing for retrovirus infection is recommended by the American Association of Feline Practitioners for all sick cats, irrespective of life style, prior history, or previous viral status. 29 FeLV is a specific risk factor for glomerulonephritis (GN) both FeLV and FIV increase the risk for lymphoma and myeloproliferative disorders that may also contribute to GN. Heartworm infection can cause GN. The SNAP FeLV Antigen and FIV Antibody by ELISA with Heartworm profile (available at IDEXX Reference Laboratories) screens for heartworm, FeLV and FIV.
Renal imaging is recommended to identify the presence of urinary calculi, pyelonephritis, renal neoplasia or dysplasia, glomerulonephritis, or other structural abnormalities that could be contributing to kidney disease. Management of urinary calculi and treatment of pyelonephritis is indicated to improve outcome. Radiography and abdominal sonography offer the most powerful combination to indicate kidney size and architecture.
It may be helpful to point out that a urinalysis is a very inexpensive test, relative to the potential information gained, with a low cost/high benefit ratio. A complete urinalysis should be part of the minimum database for all routine preventive healthcare screens and in sick dogs and cats. Patients with kidney disease may have few clinical signs, but the urinalysis can still provide support for the presence of kidney disease and possibly help determine the cause.
Inappropriately concentrated urine is one of the most consistent findings when kidney function is reduced by about 67%, 10 when SDMA would typically be increased, and before azotemia has developed. Identifying proteinuria in absence of inflammation or significant hematuria would indicate a UPC. The presence of pyuria with or without bacteriuria would suggest a urine culture and MIC susceptibility be performed. Identifying crystalluria or presence of casts might also lead to additional diagnostics being performed. Often the challenge can be just collecting the urine. For dogs, you might request that the pet owner drop off a first morning’s urine specimen in a clean or sterile container. For cats, the owner might bring a specimen from a clean litter box, or it may be more practical to simply palpate the bladder and isolate it for collection of a urine specimen by cystocentesis ultrasound guidance should not be necessary routinely.
The IRIS CKD Guidelines now include SDMA. SDMA has been recognized by IRIS, a multinational board of 15 independent veterinarians with particular interest in veterinary nephrology, as a valuable tool to help detect dogs and cats with IRIS CKD Stage 1 disease and to help correctly stage CKD in underweight patients. The following interpretive comments for the diagnostic and therapeutic utilization of SDMA were incorporated into the 2015 IRIS CKD Guidelines.
SDMA correlates very well to GFR. Therefore, if a drug improves GFR, SDMA should decrease, e.g. a diuretic. If a drug reduces GFR, then SDMA should increase, e.g. a sedative that causes hypotension.
The IDEXX SDMA Test is a sensitive kidney function test that helps to identify kidney disease in dogs and cats. If acute kidney injury is identified, then the underlying cause should be treated appropriately. If CKD has been diagnosed and SDMA and creatinine remain increased but stable, the animal should be staged using the IRIS CKD guidelines. Then follow your clinical experience with management of early kidney disease and utilize the current IRIS treatment guidelines to help determine appropriate treatment.
Dietary therapy is a key component for management of CKD in dogs and cats. Kidney therapeutic diets have controlled amounts of protein and are phosphorus-restricted, nonacidifying, and often supplemented with antioxidants and omega-3 fatty acids.
When deciding the appropriate time to begin feeding a kidney therapeutic diet to a patient with CKD, follow your clinical experience and utilize the current IRIS CKD treatment guidelines. According to the IRIS treatment guidelines, it is appropriate to start a renal therapeutic diet when dogs and cats are in IRIS CKD Stage 1 if they have persistent renal proteinuria (UPC ratio greater than 0.4 in cats and 0.5 in dogs) or are in IRIS CKD Stage 2.
For nonproteinuric, IRIS CKD Stage 1 dogs and cats, there is emerging evidence that feeding a renal supportive diet can be beneficial. Two recently published studies showed that dogs and cats with early CKD benefitted from eating a kidney friendly diet. 30,31 Subjects fed a food designed to promote healthy aging were more likely to demonstrate improved or stable kidney function respectively compared to pets fed owner’s choice food. Another recent study found that dogs with IRIS CKD stage 1 fed a renal therapeutic food for 1 year readily accepted the food and their kidney function improved. 32
Starting a kidney therapeutic diet at the earliest appropriate time is ideal because transitioning to a new food should be more successful when the patient’s appetite is still good. Maintaining body weight and muscle is essential to successful management of CKD, and this is achieved primarily by adequate caloric intake.
Yes, there are 2 widely accepted published studies in cats where cats with IRIS CKD stage 2 or 3 disease were either fed a maintenance diet or a renal diet. In one study, the cats fed the renal diet survived 2.4 times longer than the cats on the maintenance diet (on average 633 days versus 264 days). 33 In the other study, cats were followed for 2 years during which none of the cats fed a renal diet had a uremic crisis (severe illness secondary to kidney disease) or died from their kidney disease, whereas for cats fed a maintenance diet, 26% of them had a uremic crisis and 22% of them died of kidney disease. 34 A similar study in dogs found dogs fed renal diet had a 75% reduced risk for having a uremic crisis, and at the end of the 2-year study, 65% of dogs fed maintenance diet had died from kidney disease, compared with 33% of dogs fed a renal diet. Dogs fed the renal diet lived at least 13 months longer than the dogs fed the maintenance diet. 35
SDMA correlates strongly with GFR. Dogs and cats demonstrate measured alterations in GFR depending on the diet fed, and SDMA will be impacted accordingly. However, unlike BUN, it is not expected that SDMA will be impacted by protein content of the diet or gastrointestinal bleeding independent of GFR.
NSAIDs, other potentially nephrotoxic drugs, and drugs primarily eliminated by renal excretion should be discontinued if possible, or only used cautiously in animals with altered kidney function.
If NSAIDs are needed to sustain quality of life in a patient with CKD, then they should be used very cautiously. NSAIDs should never be used in patients with AKI. Pet owners should be clearly and specifically educated about NSAIDs that are prescribed.
If using NSAIDs in patients with CKD, ideally: 36
• Use other pain management strategies first, to include opioids, weight loss, and nutraceuticals.
• Use the least effective dose or use them intermittently.
• Avoid other risk factors when NSAIDs are in use, such as general anesthesia, salt restriction, diuretic use, dehydration, and others.
• Select an NSAID with a low risk of gastrointestinal toxicity to avoid causing dehydration secondary to gastrointestinal disturbance.
• Monitor for changes in liver activity and kidney function after initiating NSAID therapy and before and after each dose adjustment with blood testing and complete urinalysis.
• Discontinue NSAID use if toxicity is suspected or confirmed.
If the IDEXX SDMA concentration is increased on a preanesthetic screen for an elective procedure, then it is recommended to follow the IDEXX SDMA Test diagnostic algorithm to determine if kidney disease is probable and what investigation, management, and monitoring is recommended. If an underlying disease or confounding factor is identified, the patient should first be treated appropriately and stabilized prior to anesthesia. If anesthesia is necessary for an emergency procedure or after kidney disease is diagnosed, then the anesthetic protocol should be adjusted to support the kidneys to prevent kidney insult and preserve kidney function.
Hypovolemia, hypotension, dehydration, hypoproteinemia (low colloid oncotic pressure), and acid-base and electrolyte abnormalities should be corrected before anesthesia is administered. The goal is to ensure adequate oxygen delivery to the kidneys. This is done by focusing on maintaining circulation and oxygen carrying capacity by providing intravenous fluids and supplemental oxygen before and during anesthesia and upon recovery. Blood pressure, heart rate and rhythm, oxygenation, and ventilation should be monitored closely and active warming devices should be used to maintain body temperature. If needed, narcotics should be used for pain management. 37
See section 5 (What should I do if the IDEXX SDMA concentration is increased?) for more. A pet with an increased IDEXX SDMA concentration should be monitored as indicated based on treatments initiated for any identified underlying diseases or confounding conditions. If the patient is stable and no underlying or confounding disease identified, initial recheck in 2-4 weeks based on the SDMA algorithm is recommended. At this initial recheck, if the IDEXX SDMA concentration has returned to normal, then kidney function has likely returned to normal or at least improved, and future rechecks will depend on clinical status and any treatments initiated. If the SDMA concentration remains increased but stable, CKD can be diagnosed and staged based on the International Renal Interest Society (IRIS) guidelines and treated appropriately. If the SDMA concentration continues to increase, then ongoing, active kidney injury is likely and additional diagnostics should be considered to determine the cause and guide treatment.
Because SDMA correlates specifically with GFR, the IDEXX SDMA concentration will decrease if kidney function improves with treatment and will increase if kidney function is worsening in spite of treatment. Generally, similar trends to BUN and creatinine should be expected. However, BUN is more affected by prerenal factors such as diet and hydration, so changes in BUN may be less specific and harder to interpret during treatment. IDEXX SDMA and creatinine are significantly influenced by diet only if GFR changes but not independent of GFR like BUN. IDEXX SDMA, in contrast to creatinine concentrations, is not affected by changes in lean body mass 4,5 so it is a more reliable and sensitive indicator of kidney function as patients lose lean muscle mass, a common scenario in patients with advanced CKD. Therefore, the IDEXX SDMA concentration is helpful in monitoring CKD patients, especially those with muscle wasting.
SDMA has been incorporated into the International Renal Interest Society (IRIS) Guidelines for assistance with diagnosing chronic kidney disease and for guiding management. Since creatinine can understage CKD in underweight animals, SDMA can ensure that pets are treated for the appropriate stage of disease. Please see the IRIS guidelines for more information.
SDMA, like creatinine and GFR, has a biologic variability of 15%–20% from measurement to measurement in the same patient over a week or more. 1 Therefore, changes need to be greater than this to indicate a true change and significant difference. For example, with 20% biologic variability, an initial SDMA result of 14 µg/dL could recheck anywhere from 11–17 µg/dL based on biologic variability alone, just like a creatinine of 1.5 mg/dL (133 µmol/L) could vary from 1.2–1.8 mg/dL (106–159 µmol/L).
If your patient is clinically stable, with no obvious clinical differences, and no treatments or diet changes have been implemented, but the IDEXX SDMA is within the reference interval on recheck and the measured change is less than 20%, then the change is likely due to inherent biologic variability in renal function. SDMA, like creatinine and GFR, can change 15%–20% from measurement to measurement in the same patient over a week or more. 1
If no urinary abnormalities or other evidence of kidney disease were found previously in the complete workup, then kidney function has likely returned to normal. Monitor any confounding conditions or underlying diseases as needed. Consider a recheck of the patient and kidney function in 4–6 months, or sooner if there are new clinical signs of kidney disease.
If there were urinary abnormalities seen previously or other evidence of kidney disease, then kidney disease is still probable, and it is appropriate to monitor according to the original plan. If no active urinary problem was identified, then the patient likely has stable CKD, and you can continue with conservative monitoring, rechecking in 2–3 months, sooner if progressive signs of illness or urinary abnormality appear.
Determine if the patient is losing weight. SDMA is not impacted by changes in lean body mass whereas creatinine is. 4,5 In an older or underweight animal, SDMA is a more reliable and sensitive indicator of kidney function than creatinine. 1-3 Changes in SDMA up to 20% are potentially consistent with biologic variability 1 greater changes are more likely to indicate a true progression in kidney disease.
A complete physical examination (including determination of body weight and body muscle condition scores), careful history (including access to potentially nephrotoxic medications or substances), and a complete urinalysis (if not already performed) are recommended to try to determine if there is ongoing, active kidney injury and the cause of progression. This investigation may also identify an underlying or confounding disease that was not previously recognized.
Symmetric dimethylarginine (SDMA) is considered a biomarker for early detection of renal dysfunction in human patients with acute kidney injury (AKI). At present, no studies exist analyzing the relevance of SDMA in dogs with AKI.
SDMA would correctly identify dogs with renal disease but would not be able to differentiate between AKI and CKD.
Eighteen healthy control dogs, 48 dogs with AKI, and 29 dogs with CKD.
Prospective study. Dogs with kidney disease were categorized as having AKI or CKD according to the history, clinical signs, laboratory findings, and results of diagnostic imaging. Plasma SDMA concentration was measured by IDEXX Laboratories. SDMA/creatinine ratio was calculated in dogs with AKI or CKD.
Median SDMA concentrations were 8.5 μg/dL (6–12 μg/dL), 39.5 μg/dL (8–>100 μg/dL), and 35 μg/dL (12–>100 μg/dL), in healthy, AKI, and CKD, respectively. SDMA concentrations were significantly higher in dogs with AKI (P
In this population, SDMA was suitable for identifying dogs affected by AKI or CKD, but could not differentiate between them.
Despite the availability of intensive care treatments, AKI has a high fatality rate. 1-4 Early recognition and intervention is a necessity to effectively treat dogs with AKI, as in contrast to CKD, AKI is reversible. 5 Therefore markers for early detection of kidney injury are needed.
At present, renal disease is mainly diagnosed based on an elevation of serum creatinine concentration. Creatinine concentration can be affected by age, sex, muscle mass, and hydration status. A loss of about 75% of renal function is considered necessary for serum creatinine concentration to rise above the upper reference interval. 6 Creatinine is usually considered an insensitive marker to reliably diagnose AKI, although sensitivity might be improved by applying the most recent AKI grading criteria from the International Renal Interest Society (IRIS).1 1 IRIS grading of AKI. International Renal Interest Society website. Iris‐kidney.com/guidelines/grading. html. 2013, © 2016 International Renal Interest Society (IRIS)
The use of special biomarkers to recognize ongoing kidney injury facilitates the differentiation of AKI from CKD in human medicine and allows an early detection of kidney damage. 7 Because of their simple determination, these markers even seem to be superior to the gold standard of clearance methods for determining glomerular filtration rate (GFR). 8-10
Symmetric dimethylarginine (SDMA) is a relatively newly discovered renal biomarker. SDMA is primarily eliminated by renal excretion. Therefore, it is an endogenous marker of GFR. It is not influenced by muscle mass, which is an advantage in comparison with creatinine. 11 So far, SDMA has been used successfully to diagnose CKD in dogs and cats. 12-16
SDMA is an important biomarker for early detection of renal dysfunction in human nephrology studies about patients with AKI. 17-19 However, we are not aware of data on SDMA for dogs with AKI.
The aims of this study were to report SDMA concentration in dogs with AKI and to investigate whether SDMA might be a suitable biomarker to differentiate AKI from CKD. Secondly, we aimed to assess whether SDMA might have prognostic value in dogs with AKI.
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