Skip to main content
SpringerLink
Log in

Cystatin C Is a Gender-Neutral Glomerular Filtration Rate Biomarker in Patients with Cirrhosis

  • Original Article
  • Published:
Digestive Diseases and Sciences Aims and scope Submit manuscript

Abstract

Background

Lower serum Cr levels in women as compared to men result in underestimation of renal dysfunction and lower model for end-stage liver disease-sodium scores leading to reduced access to liver transplantation in women compared to men with comparable hepatic dysfunction.

Aim

The aim of this study was to determine the gender differences in serum Cr, cystatin C, and other endogenous glomerular filtration rate (GFR) biomarkers, measured and estimated GFR, Cr clearance, and Cr production rates.

Methods

We measured GFR by iothalamate plasma clearance in 103 patients with cirrhosis and assessed gender differences in GFR, Cr clearance and production rate, serum Cr, cystatin C and other endogenous GFR biomarkers including beta-trace protein, beta-2 microglobulin, and dimethylarginines.

Results

Comparison of men and women showed significantly lower values for mean serum Cr (0.97 vs. 0.82 mg/dl, P = 0.023), and Cr production rate (13.37 vs. 11.02 mg/kg/day, P = 0.022). In contrast to the serum Cr and Cr production rate, men and women exhibited no significant differences in the means of serum cystatin C and other GFR biomarkers, measured GFR, GFR estimated using Cr–cystatin C GFR equation for cirrhosis, measured and estimated Cr clearances. After controlling for age, race, weight, height, and GFR, female gender remained associated with lower serum Cr levels (P = 0.003). Serum cystatin C levels were not associated with gender, age, race, weight, height, C-reactive protein, and history of hypothyroidism.

Conclusions

Our results suggest that cystatin C and endogenous GFR biomarkers other than Cr, measured GFR, GFR estimated by Cr–cystatin C GFR equation for cirrhosis, measured and estimated Cr clearance minimized between-gender biases in accounting for renal function in patients with cirrhosis. Therefore, serum cystatin C should be measured as a complementary test to serum Cr when renal function is assessed in patients with cirrhosis, particularly in women and those with sarcopenia.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Cocchetto DM, Tschanz C, Bjornsson TD. Decreased rate of creatinine production in patients with hepatic disease: implications for estimation of creatinine clearance. Therapeutic Drug Monitoring. 1983;5:161–168.

    Article  CAS  PubMed  Google Scholar 

  2. Sherman DS, Fish DN, Teitelbaum I. Assessing renal function in cirrhotic patients: problems and pitfalls. American Journal of Kidney Diseases. 2003;41:269–278.

    Article  CAS  PubMed  Google Scholar 

  3. Papadakis MA, Arieff AI. Unpredictability of clinical evaluation of renal function in cirrhosis—prospective study. American Journal of Medicine. 1987;82:945–952.

    Article  CAS  PubMed  Google Scholar 

  4. Mindikoglu AL, Pappas SC. New developments in hepatorenal syndrome. Clin Gastroenterol Hepatol. 2017. https://doi.org/10.1016/j.cgh.2017.05.041.

  5. Bjornsson TD. Use of serum creatinine concentrations to determine renal function. Clinical Pharmacokinetics. 1979;4:200–222.

    Article  CAS  PubMed  Google Scholar 

  6. Allocation of livers. https://optn.transplant.hrsa.gov/media/1200/optn_policies.pdf#nameddest=Policy_09. Accessed on November 24, 2017.

  7. Kim WR, Biggins SW, Kremers WK, et al. Hyponatremia and mortality among patients on the liver-transplant waiting list. New England Journal of Medicine. 2008;359:1018–1026.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Malinchoc M, Kamath PS, Gordon FD, et al. A model to predict poor survival in patients undergoing transjugular intrahepatic portosystemic shunts. Hepatology. 2000;31:864–871.

    Article  CAS  PubMed  Google Scholar 

  9. Lai JC, Terrault NA, Vittinghoff E, et al. Height contributes to the gender difference in wait-list mortality under the MELD-based liver allocation system. American Journal of Transplantation. 2010;10:2658–2664.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Mindikoglu AL, Regev A, Seliger SL, et al. Gender disparity in liver transplant waiting-list mortality: the importance of kidney function. Liver Transplantation. 2010;16:1147–1157.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Moylan CA, Brady CW, Johnson JL, et al. Disparities in liver transplantation before and after introduction of the MELD score. JAMA. 2008;300:2371–2378.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Myers RP, Shaheen AA, Aspinall AI, et al. Gender, renal function, and outcomes on the liver transplant waiting list: assessment of revised MELD including estimated glomerular filtration rate. Journal of Hepatology. 2011;54:462–470.

    Article  PubMed  Google Scholar 

  13. Cholongitas E, Marelli L, Kerry A, et al. Female liver transplant recipients with the same GFR as male recipients have lower MELD scores—a systematic bias. American Journal of Transplantation. 2007;7:685–692.

    Article  CAS  PubMed  Google Scholar 

  14. Huo SC, Huo TI, Lin HC, et al. Is the corrected-creatinine model for end-stage liver disease a feasible strategy to adjust gender difference in organ allocation for liver transplantation? Transplantation. 2007;84:1406–1412.

    Article  PubMed  Google Scholar 

  15. Mindikoglu AL, Emre SH, Magder LS. Impact of estimated liver volume and liver weight on gender disparity in liver transplantation. Liver Transplantation. 2013;19:89–95.

    Article  PubMed  Google Scholar 

  16. Stevens LA, Levey AS. Measurement of kidney function. Medical Clinics of North America. 2005;89:457–473.

    Article  PubMed  Google Scholar 

  17. Portal AJ, Austin M, Heneghan MA. Novel approaches to assessing renal function in cirrhotic liver disease. Hepatol Res. 2007;37:667–672.

    Article  PubMed  Google Scholar 

  18. Filler G, Bokenkamp A, Hofmann W, et al. Cystatin C as a marker of GFR—history, indications, and future research. Clinical Biochemistry. 2005;38:1–8.

    Article  CAS  PubMed  Google Scholar 

  19. Filler G, Kusserow C, Lopes L, et al. Beta-trace protein as a marker of GFR—history, indications, and future research. Clinical Biochemistry. 2014;47:1188–1194.

    Article  CAS  PubMed  Google Scholar 

  20. Schardijn GH, Statius van Eps LW. Beta 2-microglobulin: its significance in the evaluation of renal function. Kidney International. 1987;32:635–641.

    Article  CAS  PubMed  Google Scholar 

  21. Kielstein JT, Salpeter SR, Bode-Boeger SM, et al. Symmetric dimethylarginine (SDMA) as endogenous marker of renal function—a meta-analysis. Nephrology, Dialysis, Transplantation. 2006;21:2446–2451.

    Article  CAS  PubMed  Google Scholar 

  22. Knight EL, Verhave JC, Spiegelman D, et al. Factors influencing serum cystatin C levels other than renal function and the impact on renal function measurement. Kidney International. 2004;65:1416–1421.

    Article  CAS  PubMed  Google Scholar 

  23. Gerbes AL, Gulberg V, Bilzer M, et al. Evaluation of serum cystatin C concentration as a marker of renal function in patients with cirrhosis of the liver. Gut. 2002;50:106–110.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Mindikoglu AL, Dowling TC, Magder LS, et al. Estimation of glomerular filtration rate in patients with cirrhosis by using new and conventional filtration markers and dimethylarginines. Clinical Gastroenterology and Hepatology. 2016;14:624–632 e2.

    Article  PubMed  Google Scholar 

  25. Orlando R, Mussap M, Plebani M, et al. Diagnostic value of plasma cystatin C as a glomerular filtration marker in decompensated liver cirrhosis. Clinical Chemistry. 2002;48:850–858.

    CAS  PubMed  Google Scholar 

  26. Randers E, Ivarsen P, Erlandsen EJ, et al. Plasma cystatin C as a marker of renal function in patients with liver cirrhosis. Scandinavian Journal of Clinical and Laboratory Investigation. 2002;62:129–134.

    Article  CAS  PubMed  Google Scholar 

  27. Priem F, Althaus H, Birnbaum M, et al. Beta-trace protein in serum: a new marker of glomerular filtration rate in the creatinine-blind range. Clinical Chemistry. 1999;45:567–568.

    CAS  PubMed  Google Scholar 

  28. Inker LA, Tighiouart H, Coresh J, et al. GFR estimation using β-trace protein and β2-microglobulin in CKD. American Journal of Kidney Diseases. 2016;67:40–48.

    Article  CAS  PubMed  Google Scholar 

  29. Priem F, Althaus H, Jung K, et al. Beta-trace protein is not better than cystatin C as an indicator of reduced glomerular filtration rate. Clinical Chemistry. 2001;47:2181.

    CAS  PubMed  Google Scholar 

  30. Siroen MP, van der Sijp JR, Teerlink T, et al. The human liver clears both asymmetric and symmetric dimethylarginine. Hepatology. 2005;41:559–565.

    Article  CAS  PubMed  Google Scholar 

  31. Lluch P, Mauricio MD, Vila JM, et al. Accumulation of symmetric dimethylarginine in hepatorenal syndrome. Exp Biol Med (Maywood). 2006;231:70–75.

    Article  CAS  Google Scholar 

  32. Mindikoglu AL, Dowling TC, Wong-You-Cheong JJ, et al. A pilot study to evaluate renal hemodynamics in cirrhosis by simultaneous glomerular filtration rate, renal plasma flow, renal resistive indices and biomarkers measurements. American Journal of Nephrology. 2014;39:543–552.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Mookerjee RP, Malaki M, Davies NA, et al. Increasing dimethylarginine levels are associated with adverse clinical outcome in severe alcoholic hepatitis. Hepatology. 2007;45:62–71.

    Article  CAS  PubMed  Google Scholar 

  34. Mindikoglu AL, Dowling TC, Weir MR, et al. Performance of chronic kidney disease epidemiology collaboration creatinine-cystatin C equation for estimating kidney function in cirrhosis. Hepatology. 2014;59:1532–1542.

    Article  CAS  PubMed  Google Scholar 

  35. DuBois D, DuBois EF. A formula to estimate the approximate surface area if height and weight be known. Arch Int Med. 1916;17:863–871.

    Article  CAS  Google Scholar 

  36. Myers GL, Miller WG, Coresh J, et al. Recommendations for improving serum creatinine measurement: a report from the Laboratory Working Group of the National Kidney Disease Education Program. Clinical Chemistry. 2006;52:5–18.

    Article  CAS  PubMed  Google Scholar 

  37. SAS software. http://www.Sas.Com/. The data analysis for this paper was generated using SAS software, Version 9.2 of the SAS System for Windows. Copyright © 2002-2008 SAS Institute Inc. SAS and all other SAS Institute Inc. product or service names are registered trademarks or trademarks of SAS Institute Inc., Cary, NC, USA.

  38. Mitch WE, Walser M. A proposed mechanism for reduced creatinine excretion in severe chronic renal failure. Nephron. 1978;21:248–254.

    Article  CAS  PubMed  Google Scholar 

  39. Inker LA, Schmid CH, Tighiouart H, et al. Estimating glomerular filtration rate from serum creatinine and cystatin C. New England Journal of Medicine. 2012;367:20–29.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Kasitanon N, Fine DM, Haas M, et al. Estimating renal function in lupus nephritis: comparison of the Modification of Diet in Renal Disease and Cockcroft Gault equations. Lupus. 2007;16:887–895.

    Article  CAS  PubMed  Google Scholar 

  41. McNemar Q. Note on the sampling error of the difference between correlated proportions or percentages. Psychometrika. 1947;12:153–157.

    Article  CAS  PubMed  Google Scholar 

  42. Markwardt D, Holdt L, Steib C, et al. Plasma cystatin C is a predictor of renal dysfunction, acute-on-chronic liver failure, and mortality in patients with acutely decompensated liver cirrhosis. Hepatology. 2017;66:1232–1241.

    Article  CAS  PubMed  Google Scholar 

  43. Finkenstedt A, Dorn L, Edlinger M, et al. Cystatin C is a strong predictor of survival in patients with cirrhosis: is a cystatin C-based MELD better? Liver Int. 2012;32:1211–1216.

    Article  CAS  PubMed  Google Scholar 

  44. Bandaranayake N, Ankrah-Tetteh T, Wijeratne S, et al. Intra-individual variation in creatinine and cystatin C. Clinical Chemistry and Laboratory Medicine. 2007;45:1237–1239.

    Article  CAS  PubMed  Google Scholar 

  45. Delanaye P, Cavalier E, Depas G, et al. New data on the intraindividual variation of cystatin C. Nephron Clin Pract. 2008;108:c246–c248.

    Article  CAS  PubMed  Google Scholar 

  46. Fricker M, Wiesli P, Brandle M, et al. Impact of thyroid dysfunction on serum cystatin C. Kidney International. 2003;63:1944–1947.

    Article  CAS  PubMed  Google Scholar 

  47. Wiesli P, Schwegler B, Spinas GA, et al. Serum cystatin C is sensitive to small changes in thyroid function. Clinica Chimica Acta. 2003;338:87–90.

    Article  CAS  Google Scholar 

  48. Bjarnadottir M, Grubb A, Olafsson I. Promoter-mediated, dexamethasone-induced increase in cystatin C production by HeLa cells. Scandinavian Journal of Clinical and Laboratory Investigation. 1995;55:617–623.

    Article  CAS  PubMed  Google Scholar 

  49. Bokenkamp A, van Wijk JA, Lentze MJ, et al. Effect of corticosteroid therapy on serum cystatin C and beta2-microglobulin concentrations. Clinical Chemistry. 2002;48:1123–1126.

    CAS  PubMed  Google Scholar 

  50. Risch L, Herklotz R, Blumberg A, et al. Effects of glucocorticoid immunosuppression on serum cystatin C concentrations in renal transplant patients. Clinical Chemistry. 2001;47:2055–2059.

    CAS  PubMed  Google Scholar 

  51. Bokenkamp A. Kidney function itself, and not cystatin C, is correlated with height and weight. Kidney International. 2005;67:777–778. (author reply 778–779).

    Article  PubMed  Google Scholar 

  52. Stevens LA, Levey AS. Measured GFR as a confirmatory test for estimated GFR. Journal of the American Society of Nephrology. 2009;20:2305–2313.

    Article  PubMed  Google Scholar 

  53. Kassirer JP. Clinical evaluation of kidney function—glomerular function. New England Journal of Medicine. 1971;285:385–389.

    Article  CAS  PubMed  Google Scholar 

  54. Levey AS, Coresh J, Greene T, et al. Expressing the Modification of Diet in Renal Disease Study equation for estimating glomerular filtration rate with standardized serum creatinine values. Clinical Chemistry. 2007;53:766–772.

    Article  CAS  PubMed  Google Scholar 

  55. De Souza V, Hadj-Aissa A, Dolomanova O, et al. Creatinine- versus cystatine C-based equations in assessing the renal function of candidates for liver transplantation with cirrhosis. Hepatology. 2014;59:1522–1531.

    Article  PubMed  Google Scholar 

  56. Francoz C, Nadim MK, Baron A, et al. Glomerular filtration rate equations for liver-kidney transplantation in patients with cirrhosis: validation of current recommendations. Hepatology. 2014;59:1514–1521.

    Article  PubMed  Google Scholar 

  57. Francoz C, Prie D, Abdelrazek W, et al. Inaccuracies of creatinine and creatinine-based equations in candidates for liver transplantation with low creatinine: impact on the model for end-stage liver disease score. Liver Transplantation. 2010;16:1169–1177.

    Article  PubMed  Google Scholar 

  58. Larsson A, Malm J, Grubb A, et al. Calculation of glomerular filtration rate expressed in mL/min from plasma cystatin C values in mg/L. Scandinavian Journal of Clinical and Laboratory Investigation. 2004;64:25–30.

    Article  CAS  PubMed  Google Scholar 

  59. Levey AS, Stevens LA, Schmid CH, et al. A new equation to estimate glomerular filtration rate. Annals of Internal Medicine. 2009;150:604–612.

    Article  PubMed  PubMed Central  Google Scholar 

  60. Cholongitas E, Ioannidou M, Goulis I, et al. Comparison of creatinine and cystatin formulae with 51 Chromium-ethylenediaminetetraacetic acid glomerular filtration rate in patients with decompensated cirrhosis. Journal of Gastroenterology and Hepatology. 2017;32:191–198.

    Article  CAS  PubMed  Google Scholar 

  61. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976;16:31–41.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors thank Heather L. Rebuck, MT (ASCP), CLS (NCA) and Sharon Y. Huang, MT for analysis of blood samples at the University of Maryland School of Medicine, Department of Pathology, Clinical Core Research Laboratory and University of Maryland General Clinical Research Center Staff.

Author’s contribution

Ayse L. Mindikoglu, M.D., M.P.H. designed and conducted the study, drafted the manuscript, analyzed data, and performed critical review of the manuscript for important intellectual content. Laurence S. Magder, Ph.D., M.P.H. analyzed data, critically reviewed, and revised the manuscript for important intellectual content. Robert H. Christenson, Ph.D. conducted cystatin C and all other GFR biomarker measurements and critically reviewed the manuscript for important intellectual content. Thomas C. Dowling, Pharm.D., Ph.D. conducted GFR measurement analysis and critically reviewed the manuscript for important intellectual content. All other authors critically reviewed the manuscript for important intellectual content.

Funding

The project described was supported by award 5 K23 DK089008-05 from the National Institutes of Health (NIH) National Institute of Diabetes and Digestive and Kidney Diseases (to Ayse L. Mindikoglu, M.D., M.P.H.) and its contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Institute of Diabetes and Digestive and Kidney Diseases or the NIH. This work was also supported in part by the University of Maryland School of Medicine, Department of Medicine funds, University of Maryland Clinical Translational Science Institute, the University of Maryland General Clinical Research Center, and Public Health Service Award P30 DK056338, which funds the Texas Medical Center Digestive Disease Center and its contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Institute of Diabetes and Digestive and Kidney Diseases or the NIH.

Author information

Authors and Affiliations

  1. Division of Abdominal Transplantation, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, 6620 Main Street, Suite 1450, Houston, TX, 77030, USA

    Ayse L. Mindikoglu, Abbas Rana, John A. Goss, Saira A. Khaderi & John M. Vierling

  2. Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine, Houston, TX, USA

    Ayse L. Mindikoglu, Antone R. Opekun & John M. Vierling

  3. Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA

    Antone R. Opekun

  4. Section of Nephrology, Department of Medicine, Baylor College of Medicine, Houston, TX, USA

    William E. Mitch

  5. Division of Biostatistics and Bioinformatics, Department of Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, MD, USA

    Laurence S. Magder

  6. Department of Pathology, University of Maryland School of Medicine, Baltimore, MD, USA

    Robert H. Christenson

  7. College of Pharmacy, Ferris State University, Grand Rapids, MI, USA

    Thomas C. Dowling

  8. Division of Nephrology, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA

    Matthew R. Weir & Stephen L. Seliger

  9. Department of Medicine, Howard University College of Medicine, Washington, DC, USA

    Charles D. Howell

  10. Division of Gastroenterology and Hepatology and VA Maryland Health Care System, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA

    Jean-Pierre Raufman

Authors
  1. Ayse L. Mindikoglu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Antone R. Opekun
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. William E. Mitch
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Laurence S. Magder
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Robert H. Christenson
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Thomas C. Dowling
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Matthew R. Weir
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Stephen L. Seliger
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Charles D. Howell
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Jean-Pierre Raufman
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Abbas Rana
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. John A. Goss
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Saira A. Khaderi
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. John M. Vierling
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ayse L. Mindikoglu.

Ethics declarations

Conflict of interest

Ayse L. Mindikoglu, M.D., M.P.H. A provisional patent application (Serial No: 62/442,479) is filed with the US patent office on 01/05/2017 (Metabolomic Markers to Predict Mortality in Patients with Cirrhosis). A second provisional patent application (Serial No. 62/586,966) is filed with the US Patent and Trademark Office on November 16, 2017, entitled “Metabolomic Biomarkers of Hepatorenal Dysfunction and Mortality in Patients with Cirrhosis.” John M. Vierling, M.D. received research grant support from Mallinckrodt for studies of terlipressin in hepatorenal syndrome.

Meeting material

Mindikoglu AL, Opekun AR, Mitch WE, Magder LS, Christenson RH, Dowling TC, Weir MR, Seliger SL, Howell CD, Raufman, JP, Rana A, Goss JA, Sussman NL, Vierling JM. Serum Creatinine in Female Patients with Cirrhosis Unfairly Bias Liver Transplant Wait List Ranking: Implications for Elimination of Gender Disparities in Access to Orthotopic Liver Transplantation. Gastroenterology 2017;152:5, S1120 (Abstract selected as a Poster of Distinction for presentation during Digestive Disease Week® at McCormick Place in Chicago, IL, May 6–9, 2017).

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Mindikoglu, A.L., Opekun, A.R., Mitch, W.E. et al. Cystatin C Is a Gender-Neutral Glomerular Filtration Rate Biomarker in Patients with Cirrhosis. Dig Dis Sci 63, 665–675 (2018). https://doi.org/10.1007/s10620-017-4897-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10620-017-4897-z

Keywords

Search

Navigation