Alkaff, Firas F.

Bakker, Stephan J.L.

Berger, Stefan P.

De Borst, Martin H.

Groothof, Dion

Knobbe, Tim J.

Kremer, Daan

Neto, António W.Gomes

Peterson, Sarah

Post, Adrian

Salamah, Sovia

van Londen, Marco

Yerramilli, Murthy

English

Neto, Antonio W.Gomes

Van Londen, Marco

EUR Research Repository

EUR Research Information PortalPlasma symmetric dimethylarginine and kidney graft function in kidney transplantrecipientsPublished in:Nephrology Dialysis TransplantationPublication status and date:Published: 01/09/2024DOI (link to publisher):10.1093/ndt/gfae109Document VersionPublisher's PDF, also known as Version of recordDocument License/Available under:Article 25fa Dutch Copyright ActCitation for the published version (APA):Kremer, D., Salamah, S., Groothof, D., Post, A., Knobbe, T. J., Peterson, S., Neto, A. W. G., Van Londen, M., Yerramilli, M.,Berger, S. P., Alkaff, F. F., TransplantLines Investigators, De Borst, M. H., & Bakker, S. J. L. (2024). Plasma symmetricdimethylarginine and kidney graft function in kidney transplant recipients. Nephrology Dialysis Transplantation, 39(9), 1533-1536. https://doi.org/10.1093/ndt/gfae109Link to publication on the EUR Research Information PortalTerms and Conditions of UseExcept as permitted by the applicable copyright law, you may not reproduce or make this material available to any third partywithout the prior written permission from the copyright holder(s). Copyright law allows the following uses of this materialwithout prior permission:            • you may download, save and print a copy of this material for your personal use only;            • you may share the EUR portal link to this material.In case the material is published with an open access license (e.g. a Creative Commons (CC) license), other uses may beallowed. Please check the terms and conditions of the specific license.Take-down policyIf you believe that this material infringes your copyright and/or any other intellectual property rights, you may request itsremoval by contacting us at the following email address: openaccess.library@eur.nl. Please provide us with all the relevantinformation, including the reasons why you believe any of your rights have been infringed. In case of a legitimate complaint,we will make the material inaccessible and/or remove it from the website.RESEARCHLETTERNephrol Dial Transplant , 2024, 39 , 1533–1536 https://doi.org/10.1093/ndt/gfae109Advance access publication date: 15 May 2024 Plasma symmetric dimethylarginine and kidney graft function in kidney transplant recipients Daan Kremer 1 , Sovia Salamah 1 ,2 , Dion Groothof 1 , Adrian Post 1 , Tim J. Knobbe 1 , António W. Gomes Neto 1 ,Sarah Peterson 3 , Marco van Londen 1 , Murthy Yerramilli 3 , Stefan P. Berger 1 , Firas F. Alkaff 1 ,4 , TransplantLines Investigators 5 ,Martin H. de Borst 1 and Stephan J.L. Bakker 1 1 University of Groningen, University Medical Center Groningen, Department of Internal Medicine, Division of Nephrology, Groningen, The Netherlands 2 Department of Public Health and Preventive Medicine, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia 3 IDEXX Laboratories, Westbrook, ME, USA 4 Division of Pharmacology and Therapy, Department of Anatomy, Histology, and Pharmacology, Faculty of Medicine Universitas Airlangga, Surabaya, Indonesia 5 University Medical Center Groningen, University Medical Center Groningen Transplant Center, Groningen, The Netherlands Correspondence to: Daan Kremer; E-mail: d.kremer@umcg.nl; Firas F. Alkaff; E-mail: f.f.alkaff@umcg.nl, firasfarisialkaff@fk.unair.ac.idTo the Editor, Early identification of kidney transplant recipients (KTRs) at risk of graft failure is essential to provide optimal care. Unfor- tunately, current measures, including creatinine and creatinine- based (estimated) glomerular filtration rate [(e)GFR], have limited utility in the early prediction of graft outcome [1 ]. This limited utility largely results from the muscle mass dependence of crea- tinine [2 , 3 ]. Thus, relying on creatinine-based measures may lead to overestimation of kidney function in patients with low mus- cle mass [4 ], such as KTRs. Consequently, there is a need for al- ternative markers of kidney function that are muscle mass inde- pendent. Plasma symmetric dimethylarginine (SDMA) is a prime candidate. SDMA is produced through the methylation of arginine residues [5 , 6 ]. In the process of proteolysis, SDMA is liberated into the bloodstream, and because it is produced in almost all nucle- ated cells, its circulating levels are considered unrelated to muscle mass [6 ]. Moreover, SDMA is solely cleared by the kidneys, high- lighting its potential use as an endogenous marker of kidney func- tion [7 , 8 ]. These distinctive features, together with its analytical stability [7 ], have led to the widespread use of SDMA as a marker of kidney function in animals such as cats, dogs, horses, rats, tigers and flamingos [6 ]. We hypothesized that SDMA may also be suitable for kidney function estimation in human populations where muscle wasting is prevalent, such as KTRs. We therefore assessed cross-sectional associations of plasma SDMA (IDEXX Laboratories, Westbrook, ME, USA) with creatinine-based GFR estimates and iothalamate- measured GFR (mGFR) [9 , 10 ]. We also assessed prospective asso- ciations of SDMA with graft failure in KTRs. In additional analy- ses, we focused on KTRs with either low or high muscle mass as measured by 24-h urinary creatinine excretion, because we hy- pothesized that SDMA may have particular added value on top of creatinine-based assessment in these patients. We included pa- tients from two independent cohorts of KTRs who were ≥1 year post-transplant and visited the outpatient clinic of the University Medical Center Groningen (UMCG), Groningen, The Netherlands [11 , 12 ]. Both studies were approved by the UMCG institutional re- view board (METc 2008/186 and METc 2014/077) and adhere to the Declarations of Helsinki and Istanbul. All patients provided writ- ten informed consent. More details on study populations, meth- ods and analyses are provided in the Supplementary Methods. Cohort A included 627 KTRs (56% male, age 53 ± 13 years, eGFR 52 ± 21 ml/min/1.73 m2 ) at 5.3 years (range 1.8–12.0) af- ter transplantation. Cohort B included 764 KTRs (59% male, age 56 ± 13 years, eGFR 51 ± 18 ml/min/1.73 m2 ) at 4.7 years (range 1.0–11.3) after transplantation. Detailed baseline characteristics of cohort A and cohort B are shown in Supplementary Tables S1and S2. Linear regression analyses with plasma SDMA as a depen- dent variable are shown in Supplementary Tables S3 and S4. In cohort A, mGFR was assessed in a subset of 179 KTRs (50% male, age 55 ± 12 years, GFR 56 ± 21 ml/min). Plasma SDMA was more strongly correlated with mGFR {Spearman’s correlation coefficient −0.81 [95% confidence interval (CI) −0.86 to −0.73]} than creati- nine was [Spearman’s correlation coefficient −0.72 (95% CI −0.79 to −0.62)]. This was particularly pronounced in females (Fig. 1 ). In cohort B, mGFR was assessed in a subset of 248 KTRs (62% male, age 56 ± 13 years, mGFR 61 ± 18 ml/min). Here, SDMA correlated more strongly with mGFR than creatinine and eGFR, both in males and females ( Supplementary Fig. S1). During a median follow-up of 5.5 years (IQR 4.9–6.1), 80 pa- tients (13%) from cohort A experienced graft failure. SDMA was strongly associated with graft failure in Cox regression anal- yses [hazard ratio (HR) per standard deviation (SD) 3.31 (95% CI 2.63–4.17)]. The association remained independent of adjust- ment for age, sex, time after transplantation, 24-h urinary pro- tein excretion, human leucocyte antigen class II antibodies and eGFR [adjusted HR per SD 1.93 (95% CI 1.33–2.81)]. Similar re- sults were obtained when adjusting for log2 creatinine instead of eGFR ( Supplementary Table S5). Models including SDMA and eGFR or creatinine as markers of kidney function yielded better model fit than models including only eGFR or creatinine as kidney function markers ( Plikelihood r atio test < .001 for both). The prospec- tive associations of plasma SDMA were replicated in cohort B, showing results that were in line with the findings in cohort A ( Supplementary Table S6). In cohort A, but not cohort B, there was effect modifica- tion by eGFR of the association between SDMA and graft fail- ure ( Pinteraction < .001) in the final model. In stratified analyses, in Received: March 4, 2024; Editorial decision: May 13, 2024© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA. All rights reserved. For permissions, please e-mail: journals.permissions@oup.comDownloaded from https://academic.oup.com/ndt/article/39/9/1533/7674883 by Rijksuniversiteit Groningen user on 18 September 20241534 | Nephrol Dial Transplant, 2024, Vol. 39, No. 9Figure 1: Correlations of mGFR with plasma SDMA and creatinine and eGFR in cohort A. eGFR was calculated using the creatinine-based Chronic Kidney Disease Epidemiology Collaboration equation. Figure 2: Kaplan–Meier curves for death-censored graft survival in groups based on median eGFR and median SDMA concentrations (i.e. 51 ml/min/1.73 m2 and 19.5 μg/dl, respectively). P -values represent significant differences between the groups as assessed using the logrank test. patients with an eGFR below the median (i.e. 51 ml/min/1.73 m2 ), graft failure occurred in 7% of those with plasma SDMA concen- trations below the median compared with 25% among those with plasma SDMA concentrations above the median (Fig. 2 ). Repetition of the Cox regression analyses in 195 patients with relatively high or low muscle mass (i.e. 24-h urinary creati- nine excretion > 1 SD below or above the mean, 56% male, age 53 ± 13 years, eGFR 52 ± 20 ml/min/1.73 m2 ) showed a strong association of plasma SDMA with increased risk of graft failure [adjusted HR per SD 2.21 (95% CI 1.16–4.21)] in the fully adjusted models. In contrast, in this same model, eGFR and creatinine were not at all associated with the risk of graft failure ( P > .5). This study shows that plasma SDMA correlates more strongly with mGFR than creatinine in two large independent cohorts of outpatient KTRs. Moreover, higher SDMA was associated with a higher risk of graft failure, independent of age, sex, 24-h urinary protein excretion and creatinine/eGFR. In line with our hypothe- sis, SDMA but not creatinine/eGFR was strongly associated with graft failure in patients with relatively low or high muscle mass. This highlights the limited value of creatinine in patients with atypical muscle mass, positioning SDMA as a kidney function marker not invalidated by this confounder. The strengths of the current study include the long and complete follow-up in two large cohorts of KTRs with a wide range of kidney functions in whom sarcopenia and muscle wasting are prevalent. Moreover, the availability of gold standard iothalamate mGFR allowed for comparing the correlation of SDMA, creatinine and eGFR with mGFR. A limitation of the current study is the inclusion of primarily Caucasian KTRs from a single centre in The Netherlands. It ap- pears likely that SDMA may have even more added value in pop- ulations from different backgrounds, given the larger variation in Downloaded from https://academic.oup.com/ndt/article/39/9/1533/7674883 by Rijksuniversiteit Groningen user on 18 September 2024D. Kremer et al. | 1535muscle mass, but this should be assessed in future studies. Future studies are needed to compare the observed cross-sectional and prospective associations of SDMA with those of other kidney func- tion markers, such as cystatin C. A potential weakness of cystatin C is that its circulating concentrations may be affected by non- GFR determinants, including fat mass, glucocorticoid exposure, inflammation and thyroid function. Although the current results are encouraging and suggest that SDMA is primarily determined by GFR, other studies are necessary to reveal whether this is true under all circumstances in all subjects and whether there are rel- evant non-GFR determinants to take into account when evaluat- ing SDMA concentrations. If these are absent or differ from the non-GFR determinants of cystatin C, SDMA may have an impor- tant role as an adjunct for assessing kidney function in situations where creatinine and cystatin C are considered unreliable. In conclusion, plasma SDMA was more strongly correlated with mGFR than creatinine. Its independent associations with graft failure in two large cohorts support its potential use as a marker of kidney function, especially in patients with low muscle mass, where creatinine-based assessment of kidney function is less re- liable. SUPPLEMENTARY DATA Supplementary data are available at Nephrology DialysisTransplantation online. FUNDING The TransplantLines Food and Nutrition Biobank and Cohort Study (ClinicalTrials.gov, NCT02811835) was financially supported by Top Institute Food and Nutrition (grant A-1003). The SDMA measurements were kindly performed free of charge by IDEXX Laboratories (Westbrook, ME, USA). The TransplantLines study was supported by a grant from Astellas BV and Chiesi Pharma- ceuticals BV and co-financed by the Dutch Ministry of Economic Affairs and Climate Policy by means of the PPP allowance made available by Top Sector Life Sciences & Health to stimulate public–private partnerships. The funders had no role in the study de- sign, data collection, analysis, reporting or decision to submit for publication. AUTHORS’ CONTRIBUTIONS D.K. and S.S. drafted the manuscript. D.G., A.P., T.J.K., A.W.G.N., S.P., M.v.L., M.Y., S.P.B., M.H.d.B., F.F.A. and S.J.L.B. revised the manuscript. S.P., M.H.d.B., M.Y. and S.J.L.B. conceptualized the project and were involved in funding acquisition. DATA AVAILABILITY STATEMENT Public sharing of individual participant data was not included in the informed consent forms of the TransplantLines Biobank and Cohort Study, but data will be made available to interested re- searchers upon reasonable request after approval by the Trans- plantLines scientific committee, which may be contacted through datarequest.transplantlines@umcg.nl. CONFLICT OF INTEREST STATEMENT S.P. and M.Y. are employed by IDEXX Laboratories. The other au- thors declare no conflicts of interest. The SDMA measurements were performed by IDEXX Laboratories in return for financial support to sustain the TransplantLines Biobank. The co-authors affiliated with IDEXX Laboratories have read and approved the manuscript, but did not influence the manuscript content or the decision to publish. APPENDIX TransplantLines Investigators: Coby Annema, Stefan P Berger, Hans Blokzijl, Frank AJA Bodewes, Marieke T de Boer, Kevin Damman, Martin H de Borst, Arjan Diepstra, Gerard Dijkstra, Ri- anne M Douwes, Caecilia SE Doorenbos, Michele F Eisenga, Michiel E Erasmus, C Tji Gan, Antonio W Gomes Neto, Eelko Hak, Bouke G Hepkema, Marius C van den Heuvel, Frank Klont, Tim J Knobbe, Daan Kremer, Coretta van Leer-Buter, Henri GD Leuvenink, Marco van Londen, Willem S Lexmond, Vincent E de Meijer, Hubert GM Niesters, Gertrude J Nieuwenhuis-Moeke, L Joost van Pelt, Robert A Pol, Robert J Porte, Adelta V Ranchor, Jan Stephan F Sanders, Marion J Siebelink, Riemer JHJA Slart, J Cas Swarte, Daan J Touw, Charlotte A te Velde-Keyzer, Erik AM Verschuuren, Michel J Vos, Rinse K Weersma, Stephan JL Bakker. REFERENCES 1. Naesens M, Lerut E, Emonds MP et al. Proteinuria as a nonin- vasive marker for renal allograft histology and failure: an ob- servational cohort study. J Am Soc Nephrol 2016; 27 :281–92. https://doi.org/10.1681/ASN.20150100622. Baxmann AC, Ahmed MS, Marques NC et al. Influence of muscle mass and physical activity on serum and urinary creatinine and serum cystatin C. Clin J Am Soc Nephrol 2008; 3 :348–54. https://doi.org/10.2215/CJN.028707073. Brosnan JT, da Silva RP, Brosnan ME. The metabolic burden of creatine synthesis. Amino acids 2011; 40 :1325–31. https://link.springer.com/article/10.1007/s00726-011-0853-y4. Groothof D, Post A, Polinder-Bos HA et al. Muscle mass and estimates of renal function: a longitudinal cohort study. J Cachexia Sarcopenia Muscle 2022; 13 :2031–43. https://onlinelibrary.wiley.com/doi/full/10.1002/jcsm.129695. Coyne MJ, Eric Schultze A, McCrann DJ et al. Evaluation of renal injury and function biomarkers, including symmetric dimethylarginine (SDMA), in the rat passive Heymann nephritis (PHN) model. PLoS One 2022; 17 :e0269085. https://journals.plos.org/plosone/article?id=10.1371/journal.pone.02690856. Hall JA, Yerramilli M, Obare E et al. Relationship between lean body mass and serum renal biomarkers in healthy dogs. J Vet Intern Med 2015; 29 :808–14. https://pubmed.ncbi.nlm.nih.gov/25913398/7. Nabity MB, Lees GE, Boggess MM et al. Symmetric dimethy- larginine assay validation, stability, and evaluation as a marker for the early detection of chronic kidney disease in dogs. J Vet Intern Med 2015; 29 :1036–44. https://pubmed.ncbi.nlm.nih.gov/26079532/8. Kielstein JT, Salpeter SR, Bode-Boeger SM et al. Symmet- ric dimethylarginine (SDMA) as endogenous marker of renal function—a meta-analysis. Nephrol Dial Transplant 2006; 21 :2446–51. https://doi.org/10.1093/ndt/gfl2929. Levey AS, Stevens LA, Schmid CH et al. A new equation to esti- mate glomerular filtration rate. Ann Intern Med 2009; 150 :604–12. https://doi.org/10.7326/0003-4819-150-9-200905050-0000610. Tent H, Rook M, Stevens LA et al. Renal function equations be- fore and after living kidney donation: a within-individual com- parison of performance at different levels of renal function. Clin J Am Soc Nephrol 2010; 5 :1960–8. https://pubmed.ncbi.nlm.nih.gov/20616162/Downloaded from https://academic.oup.com/ndt/article/39/9/1533/7674883 by Rijksuniversiteit Groningen user on 18 September 20241536 | Nephrol Dial Transplant, 2024, Vol. 39, No. 911. Eisenga MF, Gomes-Neto AW, Van Londen M et al. Rationale and design of TransplantLines: a prospective cohort study and biobank of solid organ transplant recipients. BMJ Open 2018; 8 :e024502. https://doi.org/10.1136/bmjopen-2018-02450212. van den Berg E, Engberink MF, Brink EJ et al. Dietary pro- tein, blood pressure and renal function in renal transplant recipients. Br J Nutr 2013; 109 :1463–70. https://doi.org/10.1017/S0007114512003455Received: March 4, 2024; Editorial decision: May 13, 2024 © The Author(s) 2024. Published by Oxford University Press on behalf of the ERA. All rights reserved. For permissions, please e-mail: journals.permissions@oup.comDownloaded from https://academic.oup.com/ndt/article/39/9/1533/7674883 by Rijksuniversiteit Groningen user on 18 September 2024

Plasma symmetric dimethylarginine and kidney graft function in kidney transplant recipients

ARTS repository - University of Groningen

   University of GroningenPlasma symmetric dimethylarginine and kidney graft function in kidney transplant recipientsTransplantLines Investigators; Kremer, Daan; Salamah, Sovia; Groothof, Dion; Post, Adrian;Knobbe, Tim J.; Neto, António W.Gomes; Peterson, Sarah; van Londen, Marco; Yerramilli,MurthyPublished in:Nephrology Dialysis TransplantationDOI:10.1093/ndt/gfae109IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.Document VersionPublisher's PDF, also known as Version of recordPublication date:2024Link to publication in University of Groningen/UMCG research databaseCitation for published version (APA):TransplantLines Investigators, Kremer, D., Salamah, S., Groothof, D., Post, A., Knobbe, T. J., Neto, A. W.G., Peterson, S., van Londen, M., Yerramilli, M., Berger, S. P., Alkaff, F. F., De Borst, M. H., & Bakker, S. J.L. (2024). Plasma symmetric dimethylarginine and kidney graft function in kidney transplant recipients.Nephrology Dialysis Transplantation, 39(9), 1533-1536. https://doi.org/10.1093/ndt/gfae109CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license.More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne-amendment.Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.Download date: 08-05-2025RESEARCHLETTERNephrol Dial Transplant , 2024, 39 , 1533–1536 https://doi.org/10.1093/ndt/gfae109Advance access publication date: 15 May 2024 Plasma symmetric dimethylarginine and kidney graft function in kidney transplant recipients Daan Kremer 1 , Sovia Salamah 1 ,2 , Dion Groothof 1 , Adrian Post 1 , Tim J. Knobbe 1 , António W. Gomes Neto 1 ,Sarah Peterson 3 , Marco van Londen 1 , Murthy Yerramilli 3 , Stefan P. Berger 1 , Firas F. Alkaff 1 ,4 , TransplantLines Investigators 5 ,Martin H. de Borst 1 and Stephan J.L. Bakker 1 1 University of Groningen, University Medical Center Groningen, Department of Internal Medicine, Division of Nephrology, Groningen, The Netherlands 2 Department of Public Health and Preventive Medicine, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia 3 IDEXX Laboratories, Westbrook, ME, USA 4 Division of Pharmacology and Therapy, Department of Anatomy, Histology, and Pharmacology, Faculty of Medicine Universitas Airlangga, Surabaya, Indonesia 5 University Medical Center Groningen, University Medical Center Groningen Transplant Center, Groningen, The Netherlands Correspondence to: Daan Kremer; E-mail: d.kremer@umcg.nl; Firas F. Alkaff; E-mail: f.f.alkaff@umcg.nl, firasfarisialkaff@fk.unair.ac.idTo the Editor, Early identification of kidney transplant recipients (KTRs) at risk of graft failure is essential to provide optimal care. Unfor- tunately, current measures, including creatinine and creatinine- based (estimated) glomerular filtration rate [(e)GFR], have limited utility in the early prediction of graft outcome [1 ]. This limited utility largely results from the muscle mass dependence of crea- tinine [2 , 3 ]. Thus, relying on creatinine-based measures may lead to overestimation of kidney function in patients with low mus- cle mass [4 ], such as KTRs. Consequently, there is a need for al- ternative markers of kidney function that are muscle mass inde- pendent. Plasma symmetric dimethylarginine (SDMA) is a prime candidate. SDMA is produced through the methylation of arginine residues [5 , 6 ]. In the process of proteolysis, SDMA is liberated into the bloodstream, and because it is produced in almost all nucle- ated cells, its circulating levels are considered unrelated to muscle mass [6 ]. Moreover, SDMA is solely cleared by the kidneys, high- lighting its potential use as an endogenous marker of kidney func- tion [7 , 8 ]. These distinctive features, together with its analytical stability [7 ], have led to the widespread use of SDMA as a marker of kidney function in animals such as cats, dogs, horses, rats, tigers and flamingos [6 ]. We hypothesized that SDMA may also be suitable for kidney function estimation in human populations where muscle wasting is prevalent, such as KTRs. We therefore assessed cross-sectional associations of plasma SDMA (IDEXX Laboratories, Westbrook, ME, USA) with creatinine-based GFR estimates and iothalamate- measured GFR (mGFR) [9 , 10 ]. We also assessed prospective asso- ciations of SDMA with graft failure in KTRs. In additional analy- ses, we focused on KTRs with either low or high muscle mass as measured by 24-h urinary creatinine excretion, because we hy- pothesized that SDMA may have particular added value on top of creatinine-based assessment in these patients. We included pa- tients from two independent cohorts of KTRs who were ≥1 year post-transplant and visited the outpatient clinic of the University Medical Center Groningen (UMCG), Groningen, The Netherlands [11 , 12 ]. Both studies were approved by the UMCG institutional re- view board (METc 2008/186 and METc 2014/077) and adhere to the Declarations of Helsinki and Istanbul. All patients provided writ- ten informed consent. More details on study populations, meth- ods and analyses are provided in the Supplementary Methods. Cohort A included 627 KTRs (56% male, age 53 ± 13 years, eGFR 52 ± 21 ml/min/1.73 m2 ) at 5.3 years (range 1.8–12.0) af- ter transplantation. Cohort B included 764 KTRs (59% male, age 56 ± 13 years, eGFR 51 ± 18 ml/min/1.73 m2 ) at 4.7 years (range 1.0–11.3) after transplantation. Detailed baseline characteristics of cohort A and cohort B are shown in Supplementary Tables S1and S2. Linear regression analyses with plasma SDMA as a depen- dent variable are shown in Supplementary Tables S3 and S4. In cohort A, mGFR was assessed in a subset of 179 KTRs (50% male, age 55 ± 12 years, GFR 56 ± 21 ml/min). Plasma SDMA was more strongly correlated with mGFR {Spearman’s correlation coefficient −0.81 [95% confidence interval (CI) −0.86 to −0.73]} than creati- nine was [Spearman’s correlation coefficient −0.72 (95% CI −0.79 to −0.62)]. This was particularly pronounced in females (Fig. 1 ). In cohort B, mGFR was assessed in a subset of 248 KTRs (62% male, age 56 ± 13 years, mGFR 61 ± 18 ml/min). Here, SDMA correlated more strongly with mGFR than creatinine and eGFR, both in males and females ( Supplementary Fig. S1). During a median follow-up of 5.5 years (IQR 4.9–6.1), 80 pa- tients (13%) from cohort A experienced graft failure. SDMA was strongly associated with graft failure in Cox regression anal- yses [hazard ratio (HR) per standard deviation (SD) 3.31 (95% CI 2.63–4.17)]. The association remained independent of adjust- ment for age, sex, time after transplantation, 24-h urinary pro- tein excretion, human leucocyte antigen class II antibodies and eGFR [adjusted HR per SD 1.93 (95% CI 1.33–2.81)]. Similar re- sults were obtained when adjusting for log2 creatinine instead of eGFR ( Supplementary Table S5). Models including SDMA and eGFR or creatinine as markers of kidney function yielded better model fit than models including only eGFR or creatinine as kidney function markers ( Plikelihood r atio test < .001 for both). The prospec- tive associations of plasma SDMA were replicated in cohort B, showing results that were in line with the findings in cohort A ( Supplementary Table S6). In cohort A, but not cohort B, there was effect modifica- tion by eGFR of the association between SDMA and graft fail- ure ( Pinteraction < .001) in the final model. In stratified analyses, in Received: March 4, 2024; Editorial decision: May 13, 2024© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA. All rights reserved. For permissions, please e-mail: journals.permissions@oup.comDownloaded from https://academic.oup.com/ndt/article/39/9/1533/7674883 by Rijksuniversiteit Groningen user on 18 September 20241534 | Nephrol Dial Transplant, 2024, Vol. 39, No. 9Figure 1: Correlations of mGFR with plasma SDMA and creatinine and eGFR in cohort A. eGFR was calculated using the creatinine-based Chronic Kidney Disease Epidemiology Collaboration equation. Figure 2: Kaplan–Meier curves for death-censored graft survival in groups based on median eGFR and median SDMA concentrations (i.e. 51 ml/min/1.73 m2 and 19.5 μg/dl, respectively). P -values represent significant differences between the groups as assessed using the logrank test. patients with an eGFR below the median (i.e. 51 ml/min/1.73 m2 ), graft failure occurred in 7% of those with plasma SDMA concen- trations below the median compared with 25% among those with plasma SDMA concentrations above the median (Fig. 2 ). Repetition of the Cox regression analyses in 195 patients with relatively high or low muscle mass (i.e. 24-h urinary creati- nine excretion > 1 SD below or above the mean, 56% male, age 53 ± 13 years, eGFR 52 ± 20 ml/min/1.73 m2 ) showed a strong association of plasma SDMA with increased risk of graft failure [adjusted HR per SD 2.21 (95% CI 1.16–4.21)] in the fully adjusted models. In contrast, in this same model, eGFR and creatinine were not at all associated with the risk of graft failure ( P > .5). This study shows that plasma SDMA correlates more strongly with mGFR than creatinine in two large independent cohorts of outpatient KTRs. Moreover, higher SDMA was associated with a higher risk of graft failure, independent of age, sex, 24-h urinary protein excretion and creatinine/eGFR. In line with our hypothe- sis, SDMA but not creatinine/eGFR was strongly associated with graft failure in patients with relatively low or high muscle mass. This highlights the limited value of creatinine in patients with atypical muscle mass, positioning SDMA as a kidney function marker not invalidated by this confounder. The strengths of the current study include the long and complete follow-up in two large cohorts of KTRs with a wide range of kidney functions in whom sarcopenia and muscle wasting are prevalent. Moreover, the availability of gold standard iothalamate mGFR allowed for comparing the correlation of SDMA, creatinine and eGFR with mGFR. A limitation of the current study is the inclusion of primarily Caucasian KTRs from a single centre in The Netherlands. It ap- pears likely that SDMA may have even more added value in pop- ulations from different backgrounds, given the larger variation in Downloaded from https://academic.oup.com/ndt/article/39/9/1533/7674883 by Rijksuniversiteit Groningen user on 18 September 2024D. Kremer et al. | 1535muscle mass, but this should be assessed in future studies. Future studies are needed to compare the observed cross-sectional and prospective associations of SDMA with those of other kidney func- tion markers, such as cystatin C. A potential weakness of cystatin C is that its circulating concentrations may be affected by non- GFR determinants, including fat mass, glucocorticoid exposure, inflammation and thyroid function. Although the current results are encouraging and suggest that SDMA is primarily determined by GFR, other studies are necessary to reveal whether this is true under all circumstances in all subjects and whether there are rel- evant non-GFR determinants to take into account when evaluat- ing SDMA concentrations. If these are absent or differ from the non-GFR determinants of cystatin C, SDMA may have an impor- tant role as an adjunct for assessing kidney function in situations where creatinine and cystatin C are considered unreliable. In conclusion, plasma SDMA was more strongly correlated with mGFR than creatinine. Its independent associations with graft failure in two large cohorts support its potential use as a marker of kidney function, especially in patients with low muscle mass, where creatinine-based assessment of kidney function is less re- liable. SUPPLEMENTARY DATA Supplementary data are available at Nephrology DialysisTransplantation online. FUNDING The TransplantLines Food and Nutrition Biobank and Cohort Study (ClinicalTrials.gov, NCT02811835) was financially supported by Top Institute Food and Nutrition (grant A-1003). The SDMA measurements were kindly performed free of charge by IDEXX Laboratories (Westbrook, ME, USA). The TransplantLines study was supported by a grant from Astellas BV and Chiesi Pharma- ceuticals BV and co-financed by the Dutch Ministry of Economic Affairs and Climate Policy by means of the PPP allowance made available by Top Sector Life Sciences & Health to stimulate public–private partnerships. The funders had no role in the study de- sign, data collection, analysis, reporting or decision to submit for publication. AUTHORS’ CONTRIBUTIONS D.K. and S.S. drafted the manuscript. D.G., A.P., T.J.K., A.W.G.N., S.P., M.v.L., M.Y., S.P.B., M.H.d.B., F.F.A. and S.J.L.B. revised the manuscript. S.P., M.H.d.B., M.Y. and S.J.L.B. conceptualized the project and were involved in funding acquisition. DATA AVAILABILITY STATEMENT Public sharing of individual participant data was not included in the informed consent forms of the TransplantLines Biobank and Cohort Study, but data will be made available to interested re- searchers upon reasonable request after approval by the Trans- plantLines scientific committee, which may be contacted through datarequest.transplantlines@umcg.nl. CONFLICT OF INTEREST STATEMENT S.P. and M.Y. are employed by IDEXX Laboratories. The other au- thors declare no conflicts of interest. The SDMA measurements were performed by IDEXX Laboratories in return for financial support to sustain the TransplantLines Biobank. The co-authors affiliated with IDEXX Laboratories have read and approved the manuscript, but did not influence the manuscript content or the decision to publish. APPENDIX TransplantLines Investigators: Coby Annema, Stefan P Berger, Hans Blokzijl, Frank AJA Bodewes, Marieke T de Boer, Kevin Damman, Martin H de Borst, Arjan Diepstra, Gerard Dijkstra, Ri- anne M Douwes, Caecilia SE Doorenbos, Michele F Eisenga, Michiel E Erasmus, C Tji Gan, Antonio W Gomes Neto, Eelko Hak, Bouke G Hepkema, Marius C van den Heuvel, Frank Klont, Tim J Knobbe, Daan Kremer, Coretta van Leer-Buter, Henri GD Leuvenink, Marco van Londen, Willem S Lexmond, Vincent E de Meijer, Hubert GM Niesters, Gertrude J Nieuwenhuis-Moeke, L Joost van Pelt, Robert A Pol, Robert J Porte, Adelta V Ranchor, Jan Stephan F Sanders, Marion J Siebelink, Riemer JHJA Slart, J Cas Swarte, Daan J Touw, Charlotte A te Velde-Keyzer, Erik AM Verschuuren, Michel J Vos, Rinse K Weersma, Stephan JL Bakker. REFERENCES 1. Naesens M, Lerut E, Emonds MP et al. Proteinuria as a nonin- vasive marker for renal allograft histology and failure: an ob- servational cohort study. J Am Soc Nephrol 2016; 27 :281–92. https://doi.org/10.1681/ASN.20150100622. Baxmann AC, Ahmed MS, Marques NC et al. Influence of muscle mass and physical activity on serum and urinary creatinine and serum cystatin C. Clin J Am Soc Nephrol 2008; 3 :348–54. https://doi.org/10.2215/CJN.028707073. Brosnan JT, da Silva RP, Brosnan ME. The metabolic burden of creatine synthesis. Amino acids 2011; 40 :1325–31. https://link.springer.com/article/10.1007/s00726-011-0853-y4. Groothof D, Post A, Polinder-Bos HA et al. Muscle mass and estimates of renal function: a longitudinal cohort study. J Cachexia Sarcopenia Muscle 2022; 13 :2031–43. https://onlinelibrary.wiley.com/doi/full/10.1002/jcsm.129695. Coyne MJ, Eric Schultze A, McCrann DJ et al. Evaluation of renal injury and function biomarkers, including symmetric dimethylarginine (SDMA), in the rat passive Heymann nephritis (PHN) model. PLoS One 2022; 17 :e0269085. https://journals.plos.org/plosone/article?id=10.1371/journal.pone.02690856. Hall JA, Yerramilli M, Obare E et al. Relationship between lean body mass and serum renal biomarkers in healthy dogs. J Vet Intern Med 2015; 29 :808–14. https://pubmed.ncbi.nlm.nih.gov/25913398/7. Nabity MB, Lees GE, Boggess MM et al. Symmetric dimethy- larginine assay validation, stability, and evaluation as a marker for the early detection of chronic kidney disease in dogs. J Vet Intern Med 2015; 29 :1036–44. https://pubmed.ncbi.nlm.nih.gov/26079532/8. Kielstein JT, Salpeter SR, Bode-Boeger SM et al. Symmet- ric dimethylarginine (SDMA) as endogenous marker of renal function—a meta-analysis. Nephrol Dial Transplant 2006; 21 :2446–51. https://doi.org/10.1093/ndt/gfl2929. Levey AS, Stevens LA, Schmid CH et al. A new equation to esti- mate glomerular filtration rate. Ann Intern Med 2009; 150 :604–12. https://doi.org/10.7326/0003-4819-150-9-200905050-0000610. Tent H, Rook M, Stevens LA et al. Renal function equations be- fore and after living kidney donation: a within-individual com- parison of performance at different levels of renal function. Clin J Am Soc Nephrol 2010; 5 :1960–8. https://pubmed.ncbi.nlm.nih.gov/20616162/Downloaded from https://academic.oup.com/ndt/article/39/9/1533/7674883 by Rijksuniversiteit Groningen user on 18 September 20241536 | Nephrol Dial Transplant, 2024, Vol. 39, No. 911. Eisenga MF, Gomes-Neto AW, Van Londen M et al. Rationale and design of TransplantLines: a prospective cohort study and biobank of solid organ transplant recipients. BMJ Open 2018; 8 :e024502. https://doi.org/10.1136/bmjopen-2018-02450212. van den Berg E, Engberink MF, Brink EJ et al. Dietary pro- tein, blood pressure and renal function in renal transplant recipients. Br J Nutr 2013; 109 :1463–70. https://doi.org/10.1017/S0007114512003455Received: March 4, 2024; Editorial decision: May 13, 2024 © The Author(s) 2024. Published by Oxford University Press on behalf of the ERA. All rights reserved. For permissions, please e-mail: journals.permissions@oup.comDownloaded from https://academic.oup.com/ndt/article/39/9/1533/7674883 by Rijksuniversiteit Groningen user on 18 September 2024

   University of GroningenPlasma symmetric dimethylarginine and kidney graft function in kidney transplant recipientsTransplantLines Investigators; Kremer, Daan; Salamah, Sovia; Groothof, Dion; Post, Adrian;Knobbe, Tim J.; Neto, António W.Gomes; Peterson, Sarah; van Londen, Marco; Yerramilli,MurthyPublished in:Nephrology Dialysis TransplantationDOI:10.1093/ndt/gfae109IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.Document VersionPublisher's PDF, also known as Version of recordPublication date:2024Link to publication in University of Groningen/UMCG research databaseCitation for published version (APA):TransplantLines Investigators, Kremer, D., Salamah, S., Groothof, D., Post, A., Knobbe, T. J., Neto, A. W.G., Peterson, S., van Londen, M., Yerramilli, M., Berger, S. P., Alkaff, F. F., De Borst, M. H., & Bakker, S. J.L. (2024). Plasma symmetric dimethylarginine and kidney graft function in kidney transplant recipients.Nephrology Dialysis Transplantation, 39(9), 1533-1536. https://doi.org/10.1093/ndt/gfae109CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license.More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne-amendment.Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.Download date: 24-12-2024RESEARCHLETTERNephrol Dial Transplant , 2024, 39 , 1533–1536 https://doi.org/10.1093/ndt/gfae109Advance access publication date: 15 May 2024 Plasma symmetric dimethylarginine and kidney graft function in kidney transplant recipients Daan Kremer 1 , Sovia Salamah 1 ,2 , Dion Groothof 1 , Adrian Post 1 , Tim J. Knobbe 1 , António W. Gomes Neto 1 ,Sarah Peterson 3 , Marco van Londen 1 , Murthy Yerramilli 3 , Stefan P. Berger 1 , Firas F. Alkaff 1 ,4 , TransplantLines Investigators 5 ,Martin H. de Borst 1 and Stephan J.L. Bakker 1 1 University of Groningen, University Medical Center Groningen, Department of Internal Medicine, Division of Nephrology, Groningen, The Netherlands 2 Department of Public Health and Preventive Medicine, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia 3 IDEXX Laboratories, Westbrook, ME, USA 4 Division of Pharmacology and Therapy, Department of Anatomy, Histology, and Pharmacology, Faculty of Medicine Universitas Airlangga, Surabaya, Indonesia 5 University Medical Center Groningen, University Medical Center Groningen Transplant Center, Groningen, The Netherlands Correspondence to: Daan Kremer; E-mail: d.kremer@umcg.nl; Firas F. Alkaff; E-mail: f.f.alkaff@umcg.nl, firasfarisialkaff@fk.unair.ac.idTo the Editor, Early identification of kidney transplant recipients (KTRs) at risk of graft failure is essential to provide optimal care. Unfor- tunately, current measures, including creatinine and creatinine- based (estimated) glomerular filtration rate [(e)GFR], have limited utility in the early prediction of graft outcome [1 ]. This limited utility largely results from the muscle mass dependence of crea- tinine [2 , 3 ]. Thus, relying on creatinine-based measures may lead to overestimation of kidney function in patients with low mus- cle mass [4 ], such as KTRs. Consequently, there is a need for al- ternative markers of kidney function that are muscle mass inde- pendent. Plasma symmetric dimethylarginine (SDMA) is a prime candidate. SDMA is produced through the methylation of arginine residues [5 , 6 ]. In the process of proteolysis, SDMA is liberated into the bloodstream, and because it is produced in almost all nucle- ated cells, its circulating levels are considered unrelated to muscle mass [6 ]. Moreover, SDMA is solely cleared by the kidneys, high- lighting its potential use as an endogenous marker of kidney func- tion [7 , 8 ]. These distinctive features, together with its analytical stability [7 ], have led to the widespread use of SDMA as a marker of kidney function in animals such as cats, dogs, horses, rats, tigers and flamingos [6 ]. We hypothesized that SDMA may also be suitable for kidney function estimation in human populations where muscle wasting is prevalent, such as KTRs. We therefore assessed cross-sectional associations of plasma SDMA (IDEXX Laboratories, Westbrook, ME, USA) with creatinine-based GFR estimates and iothalamate- measured GFR (mGFR) [9 , 10 ]. We also assessed prospective asso- ciations of SDMA with graft failure in KTRs. In additional analy- ses, we focused on KTRs with either low or high muscle mass as measured by 24-h urinary creatinine excretion, because we hy- pothesized that SDMA may have particular added value on top of creatinine-based assessment in these patients. We included pa- tients from two independent cohorts of KTRs who were ≥1 year post-transplant and visited the outpatient clinic of the University Medical Center Groningen (UMCG), Groningen, The Netherlands [11 , 12 ]. Both studies were approved by the UMCG institutional re- view board (METc 2008/186 and METc 2014/077) and adhere to the Declarations of Helsinki and Istanbul. All patients provided writ- ten informed consent. More details on study populations, meth- ods and analyses are provided in the Supplementary Methods. Cohort A included 627 KTRs (56% male, age 53 ± 13 years, eGFR 52 ± 21 ml/min/1.73 m2 ) at 5.3 years (range 1.8–12.0) af- ter transplantation. Cohort B included 764 KTRs (59% male, age 56 ± 13 years, eGFR 51 ± 18 ml/min/1.73 m2 ) at 4.7 years (range 1.0–11.3) after transplantation. Detailed baseline characteristics of cohort A and cohort B are shown in Supplementary Tables S1and S2. Linear regression analyses with plasma SDMA as a depen- dent variable are shown in Supplementary Tables S3 and S4. In cohort A, mGFR was assessed in a subset of 179 KTRs (50% male, age 55 ± 12 years, GFR 56 ± 21 ml/min). Plasma SDMA was more strongly correlated with mGFR {Spearman’s correlation coefficient −0.81 [95% confidence interval (CI) −0.86 to −0.73]} than creati- nine was [Spearman’s correlation coefficient −0.72 (95% CI −0.79 to −0.62)]. This was particularly pronounced in females (Fig. 1 ). In cohort B, mGFR was assessed in a subset of 248 KTRs (62% male, age 56 ± 13 years, mGFR 61 ± 18 ml/min). Here, SDMA correlated more strongly with mGFR than creatinine and eGFR, both in males and females ( Supplementary Fig. S1). During a median follow-up of 5.5 years (IQR 4.9–6.1), 80 pa- tients (13%) from cohort A experienced graft failure. SDMA was strongly associated with graft failure in Cox regression anal- yses [hazard ratio (HR) per standard deviation (SD) 3.31 (95% CI 2.63–4.17)]. The association remained independent of adjust- ment for age, sex, time after transplantation, 24-h urinary pro- tein excretion, human leucocyte antigen class II antibodies and eGFR [adjusted HR per SD 1.93 (95% CI 1.33–2.81)]. Similar re- sults were obtained when adjusting for log2 creatinine instead of eGFR ( Supplementary Table S5). Models including SDMA and eGFR or creatinine as markers of kidney function yielded better model fit than models including only eGFR or creatinine as kidney function markers ( Plikelihood r atio test < .001 for both). The prospec- tive associations of plasma SDMA were replicated in cohort B, showing results that were in line with the findings in cohort A ( Supplementary Table S6). In cohort A, but not cohort B, there was effect modifica- tion by eGFR of the association between SDMA and graft fail- ure ( Pinteraction < .001) in the final model. In stratified analyses, in Received: March 4, 2024; Editorial decision: May 13, 2024© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA. All rights reserved. For permissions, please e-mail: journals.permissions@oup.comDownloaded from https://academic.oup.com/ndt/article/39/9/1533/7674883 by Rijksuniversiteit Groningen user on 18 September 20241534 | Nephrol Dial Transplant, 2024, Vol. 39, No. 9Figure 1: Correlations of mGFR with plasma SDMA and creatinine and eGFR in cohort A. eGFR was calculated using the creatinine-based Chronic Kidney Disease Epidemiology Collaboration equation. Figure 2: Kaplan–Meier curves for death-censored graft survival in groups based on median eGFR and median SDMA concentrations (i.e. 51 ml/min/1.73 m2 and 19.5 μg/dl, respectively). P -values represent significant differences between the groups as assessed using the logrank test. patients with an eGFR below the median (i.e. 51 ml/min/1.73 m2 ), graft failure occurred in 7% of those with plasma SDMA concen- trations below the median compared with 25% among those with plasma SDMA concentrations above the median (Fig. 2 ). Repetition of the Cox regression analyses in 195 patients with relatively high or low muscle mass (i.e. 24-h urinary creati- nine excretion > 1 SD below or above the mean, 56% male, age 53 ± 13 years, eGFR 52 ± 20 ml/min/1.73 m2 ) showed a strong association of plasma SDMA with increased risk of graft failure [adjusted HR per SD 2.21 (95% CI 1.16–4.21)] in the fully adjusted models. In contrast, in this same model, eGFR and creatinine were not at all associated with the risk of graft failure ( P > .5). This study shows that plasma SDMA correlates more strongly with mGFR than creatinine in two large independent cohorts of outpatient KTRs. Moreover, higher SDMA was associated with a higher risk of graft failure, independent of age, sex, 24-h urinary protein excretion and creatinine/eGFR. In line with our hypothe- sis, SDMA but not creatinine/eGFR was strongly associated with graft failure in patients with relatively low or high muscle mass. This highlights the limited value of creatinine in patients with atypical muscle mass, positioning SDMA as a kidney function marker not invalidated by this confounder. The strengths of the current study include the long and complete follow-up in two large cohorts of KTRs with a wide range of kidney functions in whom sarcopenia and muscle wasting are prevalent. Moreover, the availability of gold standard iothalamate mGFR allowed for comparing the correlation of SDMA, creatinine and eGFR with mGFR. A limitation of the current study is the inclusion of primarily Caucasian KTRs from a single centre in The Netherlands. It ap- pears likely that SDMA may have even more added value in pop- ulations from different backgrounds, given the larger variation in Downloaded from https://academic.oup.com/ndt/article/39/9/1533/7674883 by Rijksuniversiteit Groningen user on 18 September 2024D. Kremer et al. | 1535muscle mass, but this should be assessed in future studies. Future studies are needed to compare the observed cross-sectional and prospective associations of SDMA with those of other kidney func- tion markers, such as cystatin C. A potential weakness of cystatin C is that its circulating concentrations may be affected by non- GFR determinants, including fat mass, glucocorticoid exposure, inflammation and thyroid function. Although the current results are encouraging and suggest that SDMA is primarily determined by GFR, other studies are necessary to reveal whether this is true under all circumstances in all subjects and whether there are rel- evant non-GFR determinants to take into account when evaluat- ing SDMA concentrations. If these are absent or differ from the non-GFR determinants of cystatin C, SDMA may have an impor- tant role as an adjunct for assessing kidney function in situations where creatinine and cystatin C are considered unreliable. In conclusion, plasma SDMA was more strongly correlated with mGFR than creatinine. Its independent associations with graft failure in two large cohorts support its potential use as a marker of kidney function, especially in patients with low muscle mass, where creatinine-based assessment of kidney function is less re- liable. SUPPLEMENTARY DATA Supplementary data are available at Nephrology DialysisTransplantation online. FUNDING The TransplantLines Food and Nutrition Biobank and Cohort Study (ClinicalTrials.gov, NCT02811835) was financially supported by Top Institute Food and Nutrition (grant A-1003). The SDMA measurements were kindly performed free of charge by IDEXX Laboratories (Westbrook, ME, USA). The TransplantLines study was supported by a grant from Astellas BV and Chiesi Pharma- ceuticals BV and co-financed by the Dutch Ministry of Economic Affairs and Climate Policy by means of the PPP allowance made available by Top Sector Life Sciences & Health to stimulate public–private partnerships. The funders had no role in the study de- sign, data collection, analysis, reporting or decision to submit for publication. AUTHORS’ CONTRIBUTIONS D.K. and S.S. drafted the manuscript. D.G., A.P., T.J.K., A.W.G.N., S.P., M.v.L., M.Y., S.P.B., M.H.d.B., F.F.A. and S.J.L.B. revised the manuscript. S.P., M.H.d.B., M.Y. and S.J.L.B. conceptualized the project and were involved in funding acquisition. DATA AVAILABILITY STATEMENT Public sharing of individual participant data was not included in the informed consent forms of the TransplantLines Biobank and Cohort Study, but data will be made available to interested re- searchers upon reasonable request after approval by the Trans- plantLines scientific committee, which may be contacted through datarequest.transplantlines@umcg.nl. CONFLICT OF INTEREST STATEMENT S.P. and M.Y. are employed by IDEXX Laboratories. The other au- thors declare no conflicts of interest. The SDMA measurements were performed by IDEXX Laboratories in return for financial support to sustain the TransplantLines Biobank. The co-authors affiliated with IDEXX Laboratories have read and approved the manuscript, but did not influence the manuscript content or the decision to publish. APPENDIX TransplantLines Investigators: Coby Annema, Stefan P Berger, Hans Blokzijl, Frank AJA Bodewes, Marieke T de Boer, Kevin Damman, Martin H de Borst, Arjan Diepstra, Gerard Dijkstra, Ri- anne M Douwes, Caecilia SE Doorenbos, Michele F Eisenga, Michiel E Erasmus, C Tji Gan, Antonio W Gomes Neto, Eelko Hak, Bouke G Hepkema, Marius C van den Heuvel, Frank Klont, Tim J Knobbe, Daan Kremer, Coretta van Leer-Buter, Henri GD Leuvenink, Marco van Londen, Willem S Lexmond, Vincent E de Meijer, Hubert GM Niesters, Gertrude J Nieuwenhuis-Moeke, L Joost van Pelt, Robert A Pol, Robert J Porte, Adelta V Ranchor, Jan Stephan F Sanders, Marion J Siebelink, Riemer JHJA Slart, J Cas Swarte, Daan J Touw, Charlotte A te Velde-Keyzer, Erik AM Verschuuren, Michel J Vos, Rinse K Weersma, Stephan JL Bakker. REFERENCES 1. Naesens M, Lerut E, Emonds MP et al. Proteinuria as a nonin- vasive marker for renal allograft histology and failure: an ob- servational cohort study. J Am Soc Nephrol 2016; 27 :281–92. https://doi.org/10.1681/ASN.20150100622. Baxmann AC, Ahmed MS, Marques NC et al. Influence of muscle mass and physical activity on serum and urinary creatinine and serum cystatin C. Clin J Am Soc Nephrol 2008; 3 :348–54. https://doi.org/10.2215/CJN.028707073. Brosnan JT, da Silva RP, Brosnan ME. The metabolic burden of creatine synthesis. Amino acids 2011; 40 :1325–31. https://link.springer.com/article/10.1007/s00726-011-0853-y4. Groothof D, Post A, Polinder-Bos HA et al. Muscle mass and estimates of renal function: a longitudinal cohort study. J Cachexia Sarcopenia Muscle 2022; 13 :2031–43. https://onlinelibrary.wiley.com/doi/full/10.1002/jcsm.129695. Coyne MJ, Eric Schultze A, McCrann DJ et al. Evaluation of renal injury and function biomarkers, including symmetric dimethylarginine (SDMA), in the rat passive Heymann nephritis (PHN) model. PLoS One 2022; 17 :e0269085. https://journals.plos.org/plosone/article?id=10.1371/journal.pone.02690856. Hall JA, Yerramilli M, Obare E et al. Relationship between lean body mass and serum renal biomarkers in healthy dogs. J Vet Intern Med 2015; 29 :808–14. https://pubmed.ncbi.nlm.nih.gov/25913398/7. Nabity MB, Lees GE, Boggess MM et al. Symmetric dimethy- larginine assay validation, stability, and evaluation as a marker for the early detection of chronic kidney disease in dogs. J Vet Intern Med 2015; 29 :1036–44. https://pubmed.ncbi.nlm.nih.gov/26079532/8. Kielstein JT, Salpeter SR, Bode-Boeger SM et al. Symmet- ric dimethylarginine (SDMA) as endogenous marker of renal function—a meta-analysis. Nephrol Dial Transplant 2006; 21 :2446–51. https://doi.org/10.1093/ndt/gfl2929. Levey AS, Stevens LA, Schmid CH et al. A new equation to esti- mate glomerular filtration rate. Ann Intern Med 2009; 150 :604–12. https://doi.org/10.7326/0003-4819-150-9-200905050-0000610. Tent H, Rook M, Stevens LA et al. Renal function equations be- fore and after living kidney donation: a within-individual com- parison of performance at different levels of renal function. Clin J Am Soc Nephrol 2010; 5 :1960–8. https://pubmed.ncbi.nlm.nih.gov/20616162/Downloaded from https://academic.oup.com/ndt/article/39/9/1533/7674883 by Rijksuniversiteit Groningen user on 18 September 20241536 | Nephrol Dial Transplant, 2024, Vol. 39, No. 911. Eisenga MF, Gomes-Neto AW, Van Londen M et al. Rationale and design of TransplantLines: a prospective cohort study and biobank of solid organ transplant recipients. BMJ Open 2018; 8 :e024502. https://doi.org/10.1136/bmjopen-2018-02450212. van den Berg E, Engberink MF, Brink EJ et al. Dietary pro- tein, blood pressure and renal function in renal transplant recipients. Br J Nutr 2013; 109 :1463–70. https://doi.org/10.1017/S0007114512003455Received: March 4, 2024; Editorial decision: May 13, 2024 © The Author(s) 2024. Published by Oxford University Press on behalf of the ERA. All rights reserved. For permissions, please e-mail: journals.permissions@oup.comDownloaded from https://academic.oup.com/ndt/article/39/9/1533/7674883 by Rijksuniversiteit Groningen user on 18 September 2024

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Plasma symmetric dimethylarginine and kidney graft function in kidney transplant recipients

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