Finch

Jepson

Kielstein

Miyagawa

Von Hendy-Willson

English

Braff, J

Obare, E

Yerramilli, M

Elliott, J

RVC Research Online

Relationship between Serum Symmetric DimethylarginineConcentration and Glomerular Filtration Rate in CatsJ. Braff, E. Obare, M. Yerramilli, J. Elliott, and M. YerramilliBackground: Direct measurement of glomerular filtration rate (GFR) is the preferred method to assess renal functionin cats, but it is not widely used in the diagnosis of chronic kidney disease (CKD). In cats with CKD, symmetric dimethy-larginine (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 rangedin 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 threesample slope-intercept method, and serum SDMA concentration was measured by liquid chromatography-massspectrometry.Results: A linear relationship was observed between GFR and the reciprocal of serum SDMA concentration(R2 = 0.82, P < .001). A similar relationship was found between GFR and the reciprocal of plasma creatinine concentra-tion (R2 = 0.81, P < .001).Conclusions and Clinical Importance: Increased serum SDMA concentrations were observed in cats with reduced renalfunction as determined by direct measurement of GFR. This finding indicates that SDMA could have clinical applicationsin the diagnosis of CKD in cats.Key words: Creatinine; Feline; Kidney; Renal.A lthough direct measurement of glomerular filtra-tion rate (GFR) is widely accepted as the goldstandard for measuring renal function in cats, it isinfrequently used in veterinary practice. The require-ment for a bolus injection of contrast agent andthe need for multiple, precisely timed blood samplesmake the testing costly and inconvenient to perform.Because of the infrequent use of direct GFR measure-ment in veterinary practice and the limitations of avail-able markers for renal function, alternate methods thatapproximate GFR have utility in the diagnosis ofchronic kidney disease (CKD) in cats. Measurementsof plasma creatinine concentrations are commonlyused to assist veterinarians in the diagnosis of CKDin cats, and plasma creatinine concentrations increasewhen GFR reduces.1 However, plasma creatinineconcentration is impacted by a number of extrarenalfactors such as muscle mass that can confound accu-rate diagnosis,2 and significant kidney function hasalready been lost by the time creatinine concentra-tions are outside of the reference range for normalcats.3 Urine specific gravity can be helpful in assess-ing kidney function, but urine samples are often notcollected in routine clinical practice despite theirdiagnostic utility.Dimethylated derivatives of arginine, symmetric dimethylarginine (SDMA) and asymmetric dimethylarginine(ADMA) derive from intranuclear methylation ofL-arginine residuals by protein-arginine methyltransfer-ase and are released into circulation after proteolysis.While ADMA is metabolized enzymatically by dimethy-larginine dimethylaminohydrolase, SDMA is mostlyeliminated by renal excretion suggesting SDMA to bean ideal candidate for a surrogate endogenous markerof GFR. A meta-analysis of 18 studies involving 2,136human patients found high correlation of SDMA toboth GFR and serum creatinine and concluded thatSDMA holds considerable potential as a marker ofrenal function.4Plasma SDMA is increased among cats with CKDand correlates with plasma creatinine concentration.5This suggests that SDMA could provide a reliablealternative to creatinine for estimating renal functionin cats. The observed correlation with plasma creati-nine points to an increase in SDMA concentrationamong cats with reduced GFR, but the relationshipbetween SDMA and GFR in cats is yet to be directlyevaluated. The analysis presented in this pilot study isintended to assess the potential of SDMA as a surro-gate marker for GFR in cats.From the IDEXX Laboratories, Inc., Westbrook, ME (Braff,Obare, Yerramilli, Yerramilli); and the Department of ComparativeBiomedical Sciences, Royal Veterinary College, London, UK(Elliott).Corresponding author: M. Yerramilli, IDEXX BiotechnologyGroup, IDEXX Laboratories, Inc., One IDEXX Drive, Westbrook,ME 04092; e-mail: yerramilli-murthy@idexx.com.Submitted February 24, 2014; Revised May 1, 2014;Accepted July 30, 2014.Copyright © 2014 by the American College of Veterinary InternalMedicineDOI: 10.1111/jvim.12446Abbreviations:ADMA asymmetric dimethylarginineCKD chronic kidney diseaseDDAH dimethylarginine dimethylaminohydrolaseGFR glomerular filtration rateHPLC high performance liquid chromatographyLC-MS liquid chromatography-mass spectrometryPRMT protein-arginine methyltransferaseSDMA symmetric dimethylarginineJ Vet Intern Med 2014;28:1699–1701Materials and MethodsTen client-owned cats were included in this study retrospec-tively from a group of 89 cats in which GFR had been previouslymeasured and the data published.6 Cats were selected in order torepresent a range of GFR and creatinine values from the groupof 89 cats included in the original study. Four of the cats selectedhad plasma creatinine concentrations above the laboratory refer-ence range, but no concurrent medical disorders were identifiedbased on the recorded history, physical examination or clinico-pathologic data, which included routine plasma biochemistry, uri-nalysis and packed cell volume determination. The remaining sixcats had plasma creatinine concentrations within the laboratoryreference range but varied from well within to bordering on theupper limit of the reference range (2 mg/dL). These cats were alldeemed healthy based on their recorded history, physical exami-nation and clinicopathologic data.Glomerular filtration rate had been determined by plasma ioh-exol clearance in each cat using the three sample slope-interceptmethod as previously described.6,7 Serum SDMA concentrationswere measured on previously frozen samples (stored at 80°C)collected during the iohexol clearance test using liquid chroma-tography-mass spectrometry as described below.Sample analysis for SDMA was performed using API4000coupled with Shimadzu Nexera high performance liquid chroma-tography (HPLC) system. Acetonitrile extracts of serum (10 lL)were injected into HPLC equipped with a Waters XBridge C185 lm 4.6 9 30 mm column and eluted using 0.1% formic acidand 0.5 mM perfloroheptanoic acid in water (Mobile phase A)and acetonitrile with 0.1% formic acid (Mobile phase B) with aflow rate of 1 mL/min and column temperature of 20°C.The estimation of SDMA concentration was accomplishedusing the standard curve obtained from 9 calibrator solutionsranging from 1.56 to 100 lg/dL. Calibrators were derived from asynthetic SDMA stock solution (1 mg/mL in water) and dilutedin charcoal stripped serum. The calibrator samples were preparedusing the same protocol described for the feline serum samples.The response of the MS/MS detection for all of the samples islinear and quantitation is within the calibration curve with a cor-relation coefficient greater than 0.999.Results from the analyses described above are presented asmedian values with associated ranges. Initial data analysis wasconducted using Excel software, and additional statistical analysiswas performed using SAS software.a,b Linear regression analyseswere used to assess the relationships between GFR and 1/SDMA,GFR and 1/creatinine, and creatinine and SDMA. Coefficients ofdetermination (R2) were calculated to evaluate fit, and P values≤.05 were considered significant. Although good linear fits werefound for GFR with SDMA and GFR with creatinine (R2 = 0.88and R2 = 0.79, respectively), the reciprocals of SDMA and creati-nine (1/SDMA and 1/creatinine) were selected because the reci-procal of creatinine has a better linear relationship with GFRacross a broad range of plasma creatinine concentrations.cResultsThe 10 cats included in this study, three males andseven females, ranged in age from 11.1 to 16.9 yearswith a median age of 13.2 years. All were domesticshorthairs except for one Persian cross and one Tif-fany. GFR for these cats ranged from 0.54 to2.37 mL/min/kg with a median value of 1.56 mL/min/kg. The median serum SDMA concentration was11.9 lg/dL with concentrations ranging from 6.9 to20.2 lg/dL, whereas the median plasma creatinineconcentration was determined to be 1.71 mg/dL withconcentrations ranging from 1.20 to 3.27 mg/dL.Urine specific gravity for these cats was between 1.018and 1.080 with a median value of 1.050.Glomerular filtration rate and the reciprocal of serumSDMA concentration among these cats was found toexhibit a linear relationship (R2 = 0.82, P < .001). Thehighest SDMA values occurred in cats with GFRs of0.00.51.01.52.02.53.00.00 0.05 0.10 0.15 0.20GFR (mL/min/kg)[Serum SDMA (µg/dL)]-1Fig 1. Relationship between glomerular filtration rate (GFR)and the reciprocal of serum symmetric dimethylarginine (SDMA)for 10 cats selected to represent a range of GFR and plasma cre-atinine values (R2 = 0.82, P < .001).0.00.51.01.52.02.53.00.00 0.20 0.40 0.60 0.80 1.00GFR (mL/min/kg)[Plasma Creatinine (mg/dL)]-1Fig 2. Relationship between glomerular filtration rate (GFR)and the reciprocal of plasma creatinine for 10 cats selected torepresent a range of GFR and plasma creatinine values(R2 = 0.81, P < .001).0.00.51.01.52.02.53.03.50 5 10 15 20 25Plasma Creatinine (mg/dL)Serum SDMA (µg/dL)Fig 3. Relationship between creatinine and serum symmetricdimethylarginine (SDMA) for 10 cats selected to represent arange of glomerular filtration rate (GFR) and plasma creatininevalues (R2 = 0.73, P = .0017).1700 Braff et alless than 1 mL/min/kg (see Fig 1). The relationshipbetween GFR and the reciprocal of plasma creatinineconcentration was observed to be similar (R2 = 0.81,P < .001) (see Fig 2). Consistent with previous find-ings,5 a linear correlation existed between SDMA andplasma creatinine (R2 = 0.73, P = .0017) (see Fig 3).DiscussionResults from this analysis are consistent with ourhypothesis that serum SDMA concentration isincreased in cats with reduced GFR. In this group ofcats, SDMA performs as well as creatinine in terms ofits relationship with GFR with the reciprocal of bothexhibiting linear relationships with GFR over a rangeof GFR values (see Figs 1, 2).Increased serum SDMA concentration among catswith compromised renal function, as determined bydirect measurement of GFR, indicates that SDMAcould have utility in assessing renal function and as asurrogate endogenous marker for GFR in cats. Thisfinding, taken in combination with the correlationbetween SDMA and creatinine,5 underscores the needto examine a larger number of cats across the full rangeof GFRs to fully evaluate the relationship betweenSDMA and GFR. Given the known limitations of cre-atinine, particularly its sensitivity to muscle mass andbody composition,2 more reliable markers of renal func-tion in cats would greatly facilitate early and accuratediagnosis of CKD. Future studies are needed in orderto identify clinical factors that might influence the rela-tionship between GFR and SDMA and to assess thepotential utility of SDMA in diagnosing CKD in cats.Footnotesa Microsoft Office Excel 2007; Microsoft Corporation, Redmond,WAb SAS 9.3; SAS Institute Inc., Cary, NCc Finch NC, Brodbelt D, Syme H, Elliott J. Prediction Formulaefor Fat Free Mass (FFM) and Estimated Glomerular FiltrationRate (eGFR) In Cats. Royal Veterinary College, London, UK(ECVIM abstract 2010)AcknowledgmentConflict of Interest Declaration: J. Braff, E. Obare,Maha Yerramilli, and Murthy Yerramilli are currentlyemployed by IDEXX Laboratories, Inc. J. Elliott hasserved on an advisory board and received travel reim-bursement from IDEXX Laboratories, Inc. within thepast 3 years.References1. Sox EM, Chiotti R, Goldstein RE. Use of gadoliniumdiethylene triamine penta-acetic acid, as measured by ELISA, inthe determination of glomerular filtration rates in cats. J FelineMed Surg 2010;12:738–745.2. Miyagawa Y, Takemura N, Hirose H. Assessments of fac-tors that affect glomerular filtration rate and indirect markers ofrenal function in dogs and cats. J Vet Med Sci 2010;72:1129–1136.3. Von Hendy-Willson VE, Pressler BM. An overview of glo-merular filtration rate testing in dogs and cats. Vet J2011;188:156–165.4. Kielstein JT, Salpeter SR, Bode-Boeger SM, et al. Symmet-ric dimethylarginine (SDMA) as endogenous marker of renalfunction—A meta-analysis. Nephrol Dial Transplant 2006;21:2446–2451.5. Jepson RE, Syme HM, Vallance C, et al. Plasma asymmet-ric dimethylarginine, symmetric dimethylarginine, L-arginine, andnitrite/nitrate concentrations in cats with chronic kidney diseaseand hypertension. J Vet Intern Med 2008;22:317–324.6. Finch NC, Heiene R, Elliott J, et al. A single samplemethod for estimating glomerular filtration rate in cats. J VetIntern Med 2013;27:782–790.7. Finch NC, Syme HM, Elliott J, et al. Glomerular filtrationrate estimation by use of a correction formula for slope-interceptplasma iohexol clearance in cats. Am J Vet Res 2011;72:1652–1659.SDMA and GFR in Cats 1701

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

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

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