E. Obare

Comparison of Serum Concentrations of Symmetric Dimethylarginine and Creatinine as Kidney Function Biomarkers in Cats with Chronic Kidney Disease

Background Symmetric dimethylarginine (SDMA) has been shown to be an accurate and precise biomarker for calculating estimated glomerular filtration rate (GFR) in humans, as well as a more sensitive biomarker than serum creatinine concentration (sCr) for assessing renal dysfunction. Objectives The purpose of this retrospective study was to report on the utility of measuring serum SDMA concentrations in cats for detection of chronic kidney disease (CKD) before diagnosis by conventional measurement of sCr. Animals Chronic kidney disease cats (n = 21) included those persistently azotemic for ≥3 months (n = 15), nonazotemic cats with GFR >30% decreased from median GFR of normal cats (n = 4), and nonazotemic cats with calcium oxalate kidney stones (n = 2). Healthy geriatric cats (n = 21) were selected from the same colony. Methods Symmetric dimethylarginine concentrations (liquid chromatography‐mass spectroscopy) and sCr (enzymatic colorimetry) were determined retrospectively from historical data or banked serum samples in azotemic cats or at the time GFR (iohexol clearance) was measured in nonazotemic cats. Results Serum SDMA (r = −0.79) and sCr (r = −0.77) concentrations were significantly correlated to GFR (both P < .0001). Symmetric dimethylarginine became increased before sCr in 17/21 cats (mean, 17.0 months; range, 1.5–48 months). Serum SDMA had higher sensitivity (100%) compared with sCr (17%), but lower specificity (91% versus 100%) and positive predictive value (86% versus 100%). Conclusion and Clinical Importance Using serum SDMA as a biomarker for CKD allows earlier detection of CKD in cats compared with sCr, which may be desirable for initiating renoprotective interventions that slow progression of CKD.

Symmetric Dimethylarginine Assay Validation, Stability, and Evaluation as a Marker for the Early Detection of Chronic Kidney Disease in Dogs

Background Symmetric dimethylarginine (SDMA) is a small molecule formed by methylation of arginine, and released into blood during protein degradation. SDMA is primarily eliminated by renal excretion and is a promising endogenous marker of glomerular filtration rate (GFR). Objectives To validate an assay for SDMA measurement, determine stability of SDMA in blood, and compare SDMA with serum creatinine concentration (sCr) and GFR for early detection of decreasing kidney function in dogs with chronic kidney disease (CKD). Animals Eight male dogs affected with X‐linked hereditary nephropathy and 4 unaffected male littermates. Methods Prospective study validating SDMA measurement using liquid chromatography‐mass spectrometry, assessing stability of SDMA in serum and plasma, and serially determining sCr, SDMA, and GFR (using iohexol clearance) in dogs during progression from preclinical disease to end‐stage renal failure. Correlations were determined using linear regression. Timepoints at which sCr, SDMA, and GFR identified decreased renal function were compared using defined cutoffs, trending in an individual dog, and comparison with unaffected littermates. Results Symmetric dimethylarginine was highly stable in serum and plasma, and the assay demonstrated excellent analytical performance. In unaffected dogs, SDMA remained unchanged whereas in affected dogs, SDMA increased during disease progression, correlating strongly with an increase in sCr (r = 0.95) and decrease in GFR (r = −0.95). Although trending improved sCrs sensitivity, SDMA identified, on average, <20% decrease in GFR, which was earlier than sCr using any comparison method. Conclusions and Clinical Importance Symmetric dimethylarginine is useful for both early identification and monitoring of decreased renal function in dogs with CKD.

Relationship between lean body mass and serum renal biomarkers in healthy dogs

Background Symmetric dimethylarginine (SDMA) is an accurate and precise biomarker for estimating glomerular filtration rate (GFR) in humans and cats. Serum creatinine (sCr) also correlates with GFR, but has limitations as a biomarker of renal function because nonrenal factors can influence its concentration. Hypothesis Differences in lean body mass (LBM) influence sCr, but not serum SDMA concentrations. Animals Forty‐one healthy Beagles, mean age 9.9 years (range: 3.1–14.8 years), were studied over a 6 month period. Methods Serum biomarkers of renal function were measured prospectively at baseline, and 1, 3, and 6 months. SDMA concentrations were measured by liquid chromatography‐mass spectroscopy and sCr concentrations by enzymatic colorimetry. Body composition was determined by dual energy x‐ray absorptiometry. Results LBM (P < .001) and age (P = .006) were significant explanatory variables for sCr concentration (R 2 = 0.38), but not SDMA concentration. Time on food was the only significant explanatory variable for SDMA concentration (R 2 = 0.49). SDMA concentrations decreased across time (P < .001). LBM was affected by sex (males > females; P = .02). Mature adult dogs (<8 years) had greater LBM compared with geriatric dogs (≥8 years; P < .001). Conclusion and Clinical Importance sCr concentrations, but not SDMA concentrations, are influenced by LBM, which limits sCr utility as a biomarker for monitoring renal function in dogs with decreased LBM. Reductions in LBM can lower sCr concentration and overestimate GFR. SDMA concentrations, but not sCr concentrations were influenced by time on food. SDMA could have clinical advantages over sCr in monitoring response to nutritional interventions.

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

The purpose of this study was to determine whether feeding cats reduced protein and phosphorus foods with added fish oil, L-carnitine, and medium-chain triglycerides (MCT) altered serum biomarkers of renal function. Thirty-two healthy cats, mean age 14.0 (8.3-19.6) years, were fed control food or one of two experimental foods for 6 months. All foods had similar concentrations of moisture, protein, and fat (approximately 8.0%, 26.5%, and 20.0%, respectively). Both experimental foods contained added fish oil (1.5%) and L-carnitine (500 mg/kg). Experimental-food 2 also contained increased MCT (10.5% from coconut oil), 1.5% added corn oil, and reduced animal fat. Glomerular filtration rate (GFR), serum biochemistries, renal function biomarkers including serum creatinine (sCr) and symmetrical dimethylarginine (SDMA), and plasma metabolomic profiles were measured at baseline, and at 1.5, 3, and 6 months. Body composition was determined by dual-energy X-ray absorptiometry. Although both experimental foods altered plasma fatty acids, carnitine and related metabolites, and lysophospholipid concentrations, there were no changes in renal function biomarkers. There was, however, a benefit in using SDMA versus sCr to assess renal function in older cats with less total lean mass. Compared with cats <12 years, those >15 years had lower total lean mass (P < 0.01), lower GFR (P = 0.04), and lower sCr concentrations (P < 0.01). However, SDMA concentrations (P < 0.01) were higher in older cats. This study shows that in cats, serum SDMA concentration is more highly correlated with GFR than sCr concentration, and, unlike sCr, which declines with age because of muscle wasting, SDMA increases as GFR declines with age.

Relationship between Serum Symmetric Dimethylarginine Concentration and Glomerular Filtration Rate in Cats

Background Direct measurement of glomerular filtration rate (GFR) is the preferred method to assess renal function in cats, but it is not widely used in the diagnosis of chronic kidney disease (CKD). In cats with CKD, symmetric dimethylarginine (SDMA) has been shown to increase and to correlate with plasma creatinine concentrations. Hypothesis In cats, reduced GFR corresponds with increased serum SDMA concentration. Animals The study group consisted of ten client‐owned cats whose GFR had been measured previously. Cats ranged in age from 11.1 to 16.9 years; both azotemic and nonazotemic animals were included. Methods Glomerular filtration rate was determined for each cat by plasma iohexol clearance using the three sample slope‐intercept method, and serum SDMA concentration was measured by liquid chromatography‐mass spectrometry. Results A linear relationship was observed between GFR and the reciprocal of serum SDMA concentration (R 2 = 0.82, P < .001). A similar relationship was found between GFR and the reciprocal of plasma creatinine concentration (R 2 = 0.81, P < .001). Conclusions and Clinical Importance Increased serum SDMA concentrations were observed in cats with reduced renal function as determined by direct measurement of GFR. This finding indicates that SDMA could have clinical applications in the diagnosis of CKD in cats.

Serum Concentrations of Symmetric Dimethylarginine and Creatinine in Dogs with Naturally Occurring Chronic Kidney Disease.

Background Serum concentrations of symmetric dimethylarginine (SDMA) detected chronic kidney disease (CKD) in cats an average of 17.0 months before serum creatinine (Cr) concentrations increased above the reference interval. Objectives To report on the utility of measuring serum SDMA concentrations in dogs for detection of CKD before diagnosis by measurement of serum Cr. Animals CKD dogs (n = 19) included those persistently azotemic for ≥3 months (n = 5), dogs that were azotemic at the time of death (n = 4), and nonazotemic dogs (n = 10). CKD dogs were compared with healthy control dogs (n = 20). Methods Retrospective study, whereby serum Cr concentrations were determined by enzymatic colorimetry and serum SDMA concentrations were determined by liquid chromatography‐mass spectrometry in dogs with necropsy confirmed CKD. Results Serum SDMA increased before serum Cr in 17 of 19 dogs (mean, 9.8 months; range, 2.2–27.0 months). Duration of elevations in serum SDMA concentrations before the dog developed azotemia (N = 1) or before the dog died (N = 1) was not determined. Serum SDMA and Cr concentrations were linearly related (r = 0.84; P < .001). Serum SDMA (r = −0.80) and serum Cr (r = −0.89) concentrations were significantly related to glomerular filtration rate (both P < .001). Conclusion and Clinical Importance Using serum SDMA as a biomarker for CKD allows earlier detection of kidney dysfunction in dogs than does measurement of serum Cr. Earlier detection might be desirable for initiating renoprotective interventions that slow progression of kidney disease.

Plasma Symmetric Dimethylarginine Concentration in Dogs with Acute Kidney Injury and Chronic Kidney Disease

Background 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. Hypothesis/objectives SDMA would correctly identify dogs with renal disease but would not be able to differentiate between AKI and CKD. Animals Eighteen healthy control dogs, 48 dogs with AKI, and 29 dogs with CKD. Methods 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. Results 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 < .0001) or CKD (P < .0001) in comparison with healthy dogs. Median SDMA/creatinine ratio in dogs with AKI and CKD was 6.5 (1.7–20.9) and 10 (2.4–33.9) (P = .0004), respectively. Although there was overlap of the SDMA/creatinine ratio in dogs with AKI or CKD, it was significantly higher in dogs with CKD compared to dogs with AKI (P = .0004). Conclusions and Clinical Importance In this population, SDMA was suitable for identifying dogs affected by AKI or CKD, but could not differentiate between them.

Positive Impact of Nutritional Interventions on Serum Symmetric Dimethylarginine and Creatinine Concentrations in Client-Owned Geriatric Dogs

A prospective study was conducted in client-owned geriatric dogs to evaluate the short-term effects of a test food on serum symmetric dimethylarginine (SDMA) and creatinine (Cr) concentrations. Test food contained functional lipids (fish oil), antioxidants (lipoic acid, vitamins C and E), L-carnitine, botanicals (fruits and vegetables), controlled sodium concentration, and high quality protein sources (high bioavailability and an ideal amino acid composition). Dogs (n = 210) were fed either test food or owner’s-choice foods (non-nutritionally controlled cohort). Dogs were included based on age and body weight: small (6.8 to 11.4 kg) and medium dogs (11.5 to 22.7 kg) were ≥ 9 years, whereas dogs >22.7 kg were ≥ 7 years at baseline. At baseline, all dogs had to have serum Cr concentrations within the reference interval and be free of chronic disease. Renal function biomarkers and urinalysis results at baseline, and after consuming test food or owner’s-choice foods for 3 and 6 months, were evaluated. Only dogs consuming test food showed significant decreases in serum SDMA and Cr concentrations (both P ≤ 0.05) across time. At baseline or during the 6-month feeding trial, 18 dogs (8.6%) had increased serum SDMA, but normal serum Cr, consistent with IRIS Stage 1 chronic kidney disease. This included 9 dogs fed test food and 9 dogs fed owner’s-choice foods. Compared with baseline, after feeding 9 dogs test food for 6 months, serum SDMA decreased in 8 dogs and increased in 1 dog. After feeding 9 dogs owner’s-choice foods for 6 months, serum SDMA decreased in 4 dogs and increased in 4 dogs (remained stable in 1 dog). The decreases in serum SDMA and Cr concentrations were significant (both P = 0.03) only for dogs fed test food. These results suggest that nonazotemic dogs with elevated serum SDMA (early renal insufficiency) when fed a test food designed to promote healthy aging are more likely to demonstrate improved renal function compared with dogs fed owner’s-choice foods.

Nutritional Interventions that Slow the Age-Associated Decline in Renal Function in a Canine Geriatric Model for Elderly Humans.

ObjectiveTo determine the effects of feeding traditional and renal protective foods (RPF) supplemented with functional food bioactives on glomerular filtration rate (GFR), lean body percent (LB%), and selected circulating biomarker and metabolite concentrations in a geriatric dog model.DesignRandomized block design and cross-sectional study. Setting: Hill’s Pet Nutrition, Inc. dog colony.ParticipantsEighty-one geriatric dogs (mean age, 10.4; range, 7.9-14.2 years) and 30 mature-adult dogs (mean age, 5.0; range, 3.3-6.9 years).InterventionGeriatric dogs were fed one of three foods (n = 27 per group) for 6 months: a traditional RPF (control) that was energy dense and mildly protein-restricted, or control food supplemented with increasing amounts of functional food bioactives: fish oil, lipoic acid, fruits and vegetables, and higher quality protein sources [functional foods one (FF1) and two (FF2)]. Geriatric dogs were compared before and after the feeding trial with mature adult dogs.MeasurementsRenal function was assessed by GFR, LB% was determined by dual energy x-ray absorptiometry, and circulating biomarkers and metabolites were measured in blood.ResultsBefore the feeding trial, GFR (+28.2%), LB% (+18.6%), and serum total protein (+10.0%) were higher in mature versus healthy geriatric dogs (all P<0.001). Geriatric dogs consuming all three foods increased (P<0.001) GFR over time; group averages ranged from 13.0–16.9%. Dogs fed the highest supplemented level of bioactives (FF2) had lower (P<0.001) symmetric dimethylarginine (SDMA) concentrations (-14.3%). Feeding functional foods did not alter body weight, but increased (P<0.001) serum protein concentration (+6.7%).ConclusionSupplementation with functional food bioactives can temporarily reverse the age-associated decline in renal function and serum total protein.

Serum concentrations of symmetric dimethylarginine and creatinine in cats with kidney stones

Serum concentrations of symmetric dimethylarginine (SDMA) correlate with renal function in cats and SDMA has been shown to be a more reliable and earlier marker for chronic kidney disease (CKD) compared with serum creatinine (Cr). Calcium oxalate uroliths tend to develop in mid-to-older aged cats and kidney stones may cause a reduction in renal function with increased SDMA, but normal serum Cr. The purpose of this retrospective study was to determine if cats with kidney stones had increased serum SDMA concentrations, and whether SDMA increased earlier than serum creatinine concentrations. Cats in the colony with kidney stones diagnosed between August 2010 and December 2015 (n = 43) were compared with healthy geriatric cats (n = 21) without kidney stones. Serum SDMA concentrations were determined by liquid chromatography-mass spectrometry and serum Cr concentrations were determined by enzymatic colorimetry. Cats with kidney stones were diagnosed antemortem by radiographic imaging (n = 12) or by postmortem necropsy (n = 31). Retrospectively, serum SDMA was found to be increased above the upper reference limit in 39 of 43 cats with kidney stones. Serum Cr was increased above the upper reference limit in 18 of 43 cats; 6 of these 18 cats had terminal azotemia only. The mean time that serum SDMA was increased before serum Cr was increased was 26.9 months (range 0 to 60 months). Kidney stones were composed of calcium oxalate in 30 of 34 cats. The lifespan for cats with kidney stones (mean, 12.5 years; range, 6.1 to 18.1 years) was shorter (P < 0.001) than for control cats (mean, 15.2 years; range, 13.0 to 17.2 years), suggesting that non-obstructive kidney stones have an effect on mortality rate or rate of CKD progression. In conclusion, if SDMA concentrations are elevated in mid-to-older aged cats, further imaging studies are warranted to check for the presence of kidney stones.