SDMA

 

SDMA (symmetric dimethylarginine) is the amino acid, arginine, that contains two methyl groups (dimethyl) in a symmetrical orientation. SDMA is considered a sensitive and early marker (more sensitive than serum creatinine) of declining GFR in dogs and cats (Hokamp and Nabity 2016 review).

Physiology

SDMA is produced by all nucleated cells at a constant rate, with highest concentrations in the brain, and is excreted primarily by the kidneys, with some evidence of liver uptake in humans. It does not appear to be reabsorbed in renal tubules or influenced by many non-renal factors, other than diet (Hokamp and Nabity 2016 review).

Methodology

SDMA testing is currently not offered by Cornell University. The gold standard method is high performance liquid chromatography-mass spectrophotometry, however an immunologic-based assay has been developed and is in current use but is proprietary to IDEXX (Hokamp and Nabity 2016 review).

Units of measurement

SDMA is measured in μg/dL (conventional units) or μmol/L (SI units).

Sample considerations

Sample type

Serum, heparinized plasma

Stability

Stable in canine and feline samples for one week at room temperature, 14 days at 4ºC and over a year frozen at -20 or -80ºC (Hokamp and Nabity 2016 review).

Test interpretation

Studies in dogs and cats to date show a good correlation (around 70-80%) between SDMA and GFR (as measured by inulin or iohexol clearance in some studies) (Hokamp and Nabity 2016 review). SDMA does not appear to be a better marker of GFR than serum creatinine measurement in more recent studies (see below), primarily due to lower specificity, with similar sensitivity.SDMA has moderate individuality suggesting that population reference intervals may be appropriate for use in dogs and cats, whereas creatinine had high individuality, indicating that critical differences should be used for the particular creatinine assay in question (Kopke et al 2018, Prieto et al 2020).

  • Dogs
    • A study of 20 clinically healthy dogs in New Zealand, in which serial measurement of SDMA were performed on 9 different occasions, showed that the mean SDMA concentration was above the reference interval in 4 dogs, with another 11 dogs having individual values that fell above the reference interval. Three of the dogs with mean SDMA higher than upper limit of the reference interval of 14 ug/dL also had high creatinine concentrations, suggesting they did have subclinical renal disease. This was not confirmed by GFR testing. It is difficult to believe that the other 11 dogs with high individual values all had renal disease and the authors posited that the reference interval needed adjusting. In the same study, the authors demonstrated a weak correlation of 0.49 (per figure, in text 0.7) between SMDA and creatinine concentrations (measured using the enzymatic method) with a negative proportional bias between the two assays on a difference or Bland-Altman plot (creatinine increased in relation to values as both concentrations increased) (Kopke et al 2018).
    • In another study of 67 dogs with suspected or confirmed chronic kidney disease and 30 healthy dogs, the overall performance (area under the receiver operating characteristic curve) of SDMA and creatinine were similar. Decreased GFR was determined by plasma volume-based renal scintigraphy. The sensitivity of SDMA and creatinine were similar in this cohort, although specificity was lower for SDMA, which seems to be a common theme (more likely increased in healthy dogs) using cut-offs of 14 ug/dL for SDMA and 1.3 mg/dL for creatinine.(Palender et al 2019).
  • Cats: In a study of 49 clinically healthy cats and cats with chronic kidney disease and diabetes mellitus with normal and abnormal glomerular rate (iohexol clearance, with normal defined as ≥ 1.7 ml/(min kg), SDMA at a cut-off of 14 ug/mL had similar sensitivity (76-94% for SDMA versus 71-88% for creatinine) but lower specificity than creatinine at 1.8 mg/dL (71% for SDMA versus 94-96% for creatinine) for cats with decreased GFR. Increasing the SDMA cut-off to 18 ug/mL, improved specificity at the expense of sensitivity (but still similar to creatinine). The results indicate that SDMA and creatinine perform similarly in this cohort of cats (Brans et al 2021).

Increased serum/plasma SDMA concentrations

A recommended upper limit of a reference interval for dogs and cats is 14 μg/dL (Hokamp and Nabity 2016 review), although newer studies suggest higher cut-offs may be superior (see below). A study in 101 Greyhounds, indicates that healthy animals may have SDMA concentrations that slightly exceed this limit (up to 20 μg/dL) (Liffman et al 2018).

  • Physiologic
    • Foals have higher SDMA than adult horses, up to 100 ug/ml between birth and 4 days of age (Siwinska et al 2020, Bozorgmanesh et al 2021). Concentrations are still higher in foals at 20 days of age versus adult horses (up to 27 ug/ml) (Bozorgmanesh et al 2021).
  • Pathophysiologic: As indicated above, measurement of SDMA is currently being used as a sensitive and early marker of decreased GFR in dogs and cats (Hokamp and Nabity 2016 review), but it does appear less specific, depending on the cut-off used.
    • Non-azotemic dogs: Creatinine concentrations correlated better to GFR (based on iohexol clearance) than SDMA in 119 non-azotemic dogs. Using a cut-off of 14 ug/dL, SDMA concentrations were high in 50% of dogs without any defects in GFR, indicating a 50% false positivity rate. The most common diseases in the dogs with false increases in SDMA were psychogenic polydipsia and dermatopathy, but it is unclear how the latter is related to SDMA concentrations. The optimal SDMA concentration in this study was 18 ug/dL, which had a sensitivity and specificity of 90% and 83%, respectively, for detecting a 40% decrease in GFR (McKenna et al 2020).
    • Renal disease
      • Acute kidney injury (AKI) and chronic kidney disease (CKD) in dogs: In one study of 48 dogs with AKI and 29 dogs with CKD, SDMA concentrations (measured by HPLC) were higher in all, but one dog each with AKI or CKD, versus 18 healthy dogs. All dogs with AKI had high creatinine concentrations (>1.8 mg/dL, reference interval of 0.6-1.4 mg/dL), with some having a normal urea nitrogen concentration, and all dogs with CKD had urea nitrogen concentrations >53 mg/dL(reference interval of 20-59 mg/dL, which is far higher than our interval for urea nitrogen in dogs), with some having normal creatinine. All healthy dogs had normal creatinine (<1.3 mg/dL) but some had urea nitrogen concentrations as high as 75 mg/dL (Dahlem et al 2017).  This data indicates SDMA may be normal in some dogs with renal disease. In a prospective study of 67 dogs with chronic kidney disease (IRIS stage 1-3 mostly), creatinine (at 1.3 mg/dL) and SDMA (at 14 ug/dL) showed similar sensitivity and specificity and correlation to GFR measurements, versus cystatin C (0.5 mg/L), which was as sensitive but less specific for a low GFR (defined conservatively as <30.8 ml/min/L). However, none of the dogs in IRIS stage had a GFR below this value (Pelander et al 2019). This data suggests that creatinine and SDMA perform equally for diagnosis of CKD, but using them sequentially may help identify false negative results. 
      • Acute kidney injury in horses: Horses with acute kidney injury (defined as an acute onset of azotemia) had higher SDMA than adult clinically healthy horses (Siwinska et al 2020).
    • Thyroid dysfunction
      • Azotemia post treatment for hyperthyroidism in cats: In a study of 242 hyperthyroid non-azotemic cats, 42 cats became azotemic after radioactive iodine therapy, with azotemia being defined by high serum creatinine concentrations (>2.0 mg/d). The SDMA concentration was high in 19 of the 42 cats with creatinine within reference intervals before radioactive iodine treatment but in three of these cats, the SDMA normalized after treatment. The cause of the high SDMA in these cats is not known, but this suggests that high SDMA concentrations do not always mean renal dysfunction or that the renal dysfunction was transient. This study did show that SDMA was more sensitive than creatinine for picking up changes in GFR in cats with hyperthyroidism, although a USG <1.035, and both SDMA and creatinine concentrations independently predicted renal azotemia post radioactive iodine treatment in this cohort of cats. Many cats with hyperthyroidism had low SDMA (<10 ug/dL), which was attributed to the increased GFR in this syndrome (Peterson et al 2018).
      • Hypothyroidism in cats: In the above study, cats that developed azotemia after radioactive iodine therapy were more likely to be hypothyroid, suggesting hypothyroidism may cause decreased GFR and increased SDMA concentrations. However hypothyroidism is quite rare in cats (except for those treated with radioactive iodine) so it would be difficult to test this theory (Peterson et al). 

 

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