Early postoperative C-terminal agrin fragment (CAF) serum levels predict graft loss and proteinuria in renal transplant recipients

Dominik Steubl; Anna Vogel; Stefan Hettwer; Susanne Tholen; Peter B. Luppa; Ina-Christine Rondak; Lutz Renders; Uwe Heemann; Marcel Roos

doi:10.1515/cclm-2015-0369

Article

Early postoperative C-terminal agrin fragment (CAF) serum levels predict graft loss and proteinuria in renal transplant recipients

Dominik Steubl , Anna Vogel , Stefan Hettwer , Susanne Tholen , Peter B. Luppa , Ina-Christine Rondak , Lutz Renders , Uwe Heemann and Marcel Roos

Published/Copyright: June 18, 2015

Published by

Become an author with De Gruyter Brill

Submit Manuscript Author Information

From the journal Clinical Chemistry and Laboratory Medicine (CCLM) Volume 54 Issue 1

Abstract

Background: C-terminal agrin fragment (CAF), cleavage product of agrin, was previously correlated with kidney function in renal transplant patients. This article studies the predictive value of CAF for long-term outcomes in renal transplant recipients.

Methods: In this observational cohort study, serum CAF, creatinine and blood-urea-nitrogen (BUN) concentrations and eGFR (CKD-EPI) were assessed 1–3 months after transplantation in 105 patients undergoing kidney transplantation. Cox regression models were used to analyse the predictive value of all parameters concerning all-cause mortality (ACM), graft loss (GL), doubling of creatinine/proteinuria at the end of follow-up.

Results: Median follow-up time was 3.1 years. The mean concentrations were 191.9±152.4 pM for CAF, 176±96.8 μmol/L for creatinine, 12.6±6.2 mmol/L for BUN and 44.9±21.2 mL/min for CKD-EPI formula, respectively. In univariate analysis CAF and BUN concentrations predicted ACM (CAF: HR=1.003, 1.1-fold risk, p=0.043; BUN: HR=1.037, 1.3-fold risk, p=0.006). Concerning GL, CAF (HR=1.006, 3.1-fold risk, p<0.001), creatinine (HR=2.396, 2.6-fold risk, p<0.001), BUN (HR=1.048, 1.7-fold risk, p=0.001) and eGFR (CKD-EPI) (HR=0.941, 0.45-fold risk reduction, p=0.006) showed a statistically significant association. CAF was the only parameter significantly associated with doubling of proteinuria (HR=1.005, 1.7-fold risk, p<0.001). In multiple regression analysis (CAF only) the association remained significant for GL and doubling of proteinuria but not ACM.

Conclusions: Early postoperative serum CAF appears to be a useful tool for the assessment of long-term outcomes in renal transplant recipients. Most importantly it represents a promising predictor for the development of proteinuria.

Keywords: biomarker; C-terminal agrin fragment; graft loss; outcome; proteinuria

Corresponding author: Dr. med. Dominik Steubl, Department of Nephrology, Klinikum rechts der Isar, Ismaninger Straβe 22, 81675 Munich, Germany, Phone: +49 89 41402231, Fax: +49 89 41404878, E-mail: dominik.steubl@lrz.tum.de

Acknowledgments

We thank Dr. Paul Albert, PhD, University of Ottawa for the revision of the manuscript.

Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission. The results presented in this paper have not been published previously in whole or part, except in abstract format.
Research funding: None declared.
Employment or leadership: Stefan Hettwer is currently employed by Neurotune AG, Schlieren, Switzerland. The remaining authors of this manuscript have no conflicts of interest to disclose as described by the journal.
Honorarium: None declared.
Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.

References

1. Lamb KE, Lodhi S, Meier-Kriesche H-U. Long-term renal allograft survival in the United States: a critical reappraisal. Am J Transplant 2011;11:450–62.10.1111/j.1600-6143.2010.03283.xSearch in Google Scholar PubMed

2. Vadivel N, Tullius S, Chandraker A. Chronic allograft nephropathy. Semin Nephrol 2007;27:414–29.10.1016/j.semnephrol.2007.03.004Search in Google Scholar PubMed

3. Meier-Kriesche HU, Schold JD, Kaplan B. Long-term renal allograft survival: have we made significant progress or is it time to rethink our analytic and therapeutic strategies? Am J Transplant 2004;4:1289–95.10.1111/j.1600-6143.2004.00515.xSearch in Google Scholar PubMed

4. Meier-Kriesche HU, Schold JD, Srinivas TR, Kaplan B. Lack of improvement in renal allograft survival despite a marked decrease in acute rejection rates over the most recent era. Am J Transplant 2004;4:378–83.10.1111/j.1600-6143.2004.00332.xSearch in Google Scholar PubMed

5. Hariharan S, Mcbride MA, Cherikh WS, Tolleris CB, Bresnahan BA, Johnson CP. Post-transplant renal function in the first year predicts long-term kidney transplant survival. Kidney Int 2002;62:311–8.10.1046/j.1523-1755.2002.00424.xSearch in Google Scholar PubMed

6. Galichon P, Xu-Dubois YC, Finianos S, Hertig A, Rondeau E. Clinical and histological predictors of long-term kidney graft survival. Nephrol Dial Transplant 2013;28:1362–70.10.1093/ndt/gfs606Search in Google Scholar PubMed

7. Kaplan B, Schold J, Meier-Kriesche HU. Poor predictive value of serum creatinine for renal allograft loss. Am J Transplant 2003;3:1560–5.10.1046/j.1600-6135.2003.00275.xSearch in Google Scholar PubMed

8. Lenihan CR, O’Kelly P, Mohan P, Little D, Walshe JJ, Kieran NE, et al. MDRD-estimated GFR at one year post-renal transplant is a predictor of long-term graft function. Ren Fail 2008; 30:345–52.10.1080/08860220801947686Search in Google Scholar PubMed

9. He X, Moore J, Shabir S, Little MA, Cockwell P, Ball S, et al. Comparison of the predictive performance of eGFR formulae for mortality and graft failure in renal transplant recipients. Transplantation 2009;87:384–92.10.1097/TP.0b013e31819004a1Search in Google Scholar PubMed

10. Rodrigo E, Ruiz JC, Fernández-Fresnedo G, Fernández MD, Piñera C, Palomar R, et al. Cystatin C and albuminuria as predictors of long-term allograft outcomes in kidney transplant recipients. Clin Transplant 2013;27:E177–83.10.1111/ctr.12082Search in Google Scholar PubMed

11. Steubl D, Hettwer S, Vrijbloed W, Dahinden P, Wolf P, Luppa P, et al. C-Terminal agrin fragment – a new fast biomarker for kidney function in renal transplant recipients. Am J Nephrol 2013;38:501–8.10.1159/000356969Search in Google Scholar PubMed

12. Steubl D, Hettwer S, Dahinden P, Luppa P, Rondak IC, Regenbogen C, et al. C-terminal agrin fragment (CAF) as a serum biomarker for residual renal function in peritoneal dialysis patients. Int Urol Nephrol 2015;47:391–6.10.1007/s11255-014-0852-5Search in Google Scholar PubMed

13. Drey M, Behnes M, Kob R, Lepiorz D, Hettwer S, Bollheimer C, et al. C-terminal agrin fragment (CAF) reflects renal function in patients suffering from severe sepsis or septic shock. Clin Lab 2015;61:69–76.10.7754/Clin.Lab.2014.140724Search in Google Scholar

14. Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF 3rd, Feldman HI, et al; CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration). A new equation to estimate glomerular filtration rate. Ann Intern Med 2009;150:604–12.10.7326/0003-4819-150-9-200905050-00006Search in Google Scholar PubMed PubMed Central

15. Svensson M, Dahle DO, Mjøen G, Weihrauch G, Scharnagl H, Dobnig H, et al. Osteoprotegerin as a predictor of renal and cardiovascular outcomes in renal transplant recipients: follow-up data from the ALERT study. Nephrol Dial Transplant 2012;27:2571–5.10.1093/ndt/gfr694Search in Google Scholar PubMed

16. Tsai SF, Shu KH, Ho HC, Chen CH, Wu MJ, Wen MC. Doubling of serum creatinine as an outcome after renal transplant – pathological evidence of graft biopsy. Ann Transplant 2013;18:471–81.10.12659/AOT.889098Search in Google Scholar PubMed

17. Available from: http://www.neurotune.com/downloads.html. Accessed 15 November, 2014.Search in Google Scholar

18. R Core Team (2014). R: a language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. Available from: http://www.R-project.org/. Accessed 11 November, 2014.Search in Google Scholar

19. Aalen OO, Johansen S. An empirical transition matrix for non-homogeneous Markov chains based on censored observations. Scand J Stat 1978;5:141–50.Search in Google Scholar

20. Schnuelle P, Lorenz D, Trede M, Van Der Woude FJ. Impact of renal cadaveric transplantation on survival in end-stage renal failure: evidence for reduced mortality risk compared with hemodialysis during long-term follow-up. J Am Soc Nephrol 1998;9:2135–41.10.1681/ASN.V9112135Search in Google Scholar PubMed

21. Arend SM, Mallat MJ, Westendorp RJ, Van Der Woude FJ, van Es LA. Patient survival after renal transplantation; more than 25 years follow-up. Nephrol Dial Transplant 1997;12:1672–9.10.1093/ndt/12.8.1672Search in Google Scholar PubMed

22. CTS, Collaborative Transplant Study. CTS-K-11101-0814 2012. CTS, Collaborative Transplant Study 2012. Ref. Type: electronic citation.Search in Google Scholar

23. Fitzsimmons W, Thompson D, Hariharan S, Van Veldhuisen P. Serum creatinine as a surrogate endpoint for graft loss in kidney transplantation: validation efforts from multicentre trials. Am J Transplant 2002;2:272.Search in Google Scholar

24. Tejani A, Stablein D, Ho P. Calculated creatinine clearance (CCC) as the most promising candidate surrogate end point for clinical trials. Am J Transplant 2002;2:256.Search in Google Scholar

25. Kasiske BL, Israni AK, Snyder JJ, Skeans MA; Patient Outcomes in Renal Transplantation (PORT) Investigators. The relationship between kidney function and long-term graft survival after kidney transplant. Am J Kidney Dis. 2011;57:466–75.10.1053/j.ajkd.2010.10.054Search in Google Scholar PubMed

26. Oh SW, Kim S, Na KY, Kim KW, Chae DW, Chin HJ. Glomerular filtration rate and proteinuria: association with mortality and renal progression in a prospective cohort of a community-based elderly population. PLoS One 2014;9:e94120.10.1371/journal.pone.0094120Search in Google Scholar PubMed PubMed Central

27. Shabir S, Halimi JM, Cherukuri A, Ball S, Ferro C, Lipkin G, et al. Predicting 5-year risk of kidney transplant failure: a prediction instrument using data available at 1 year posttransplantation. Am J Kidney Dis 2014;63:643–51.10.1053/j.ajkd.2013.10.059Search in Google Scholar PubMed

28. Martínez Esteban D, Jironda Gallegos C, Cabello Diaz M, Frias P, López Jiménez V, Gutierrez de la Fuente C, et al. Creatinine clearance and proteinuria as early markers of kidney graft survival. Transplant Proc 2010;42:2880–2.10.1016/j.transproceed.2010.08.022Search in Google Scholar PubMed

29. Knoll GA. Proteinuria in kidney transplant recipients: prevalence, prognosis, and evidence-based management. Am J Kidney Dis 2009;54:1131–44.10.1053/j.ajkd.2009.06.031Search in Google Scholar PubMed

30. Fernández-Fresnedo G, Plaza JJ, Sánchez-Plumed J, Sanz-Guajardo A, Palomar-Fontanet R, Arias M. Proteinuria: a new marker of long-term graft and patient survival in kidney transplantation. Nephrol Dial Transplant 2004;19 (Suppl. 3):iii47–51.10.1093/ndt/gfh1015Search in Google Scholar PubMed

31. Sancho Calabuig A, Pallardó Mateu LM, Avila Bernabeu AI, Gavela Martínez E, Beltrán Catalán S, Crespo Albiach JF. Very low-grade proteinuria at 3 months posttransplantation is an earlier marker of graft survival. Transplant Proc 2009;41:2122–5.10.1016/j.transproceed.2009.06.137Search in Google Scholar PubMed

32. Sancho A, Gavela E, Avila A, Morales A, Fernández-Nájera JE, Crespo JF, et al. Risk factors and prognosis for proteinuria in renal transplant recipients. Transplant Proc 2007;39:2145–7.10.1016/j.transproceed.2007.07.005Search in Google Scholar PubMed

33. Ponticelli C. The pros and the cons of mTOR inhibitors in kidney transplantation. Expert Rev Clin Immunol 2014;10:295–305.10.1586/1744666X.2014.872562Search in Google Scholar PubMed

Received: 2015-4-18

Accepted: 2015-5-20

Published Online: 2015-6-18

Published in Print: 2016-1-1

You are currently not able to access this content.

Articles in the same Issue

https://doi.org/10.1515/cclm-2015-0369

Keywords for this article

biomarker; C-terminal agrin fragment; graft loss; outcome; proteinuria