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Serum Cystatin C as a Risk Factor for Supratherapeutic Digoxin Concentration in Elderly Patients with Heart Failure and Chronic Kidney Disease

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Abstract

Background

Digoxin is primarily metabolized by the kidney, and its toxicity is strongly associated with high concentrations, particularly in elderly patients. The purpose of this study was to evaluate the predictive performance of renal function biomarkers for supratherapeutic digoxin concentrations in elderly patients with heart failure (HF) and chronic kidney disease (CKD).

Methods

Data were retrospectively obtained from elderly patient with HF and CKD who received digoxin treatment from January 2022 and December 2022. Logistic regression was used to assess independent risk factors for supratherapeutic concentrations. The predictive performance of serum creatinine, serum cystatin C, and blood urea nitrogen on supratherapeutic concentrations was compared by receiver operating characteristic analysis.

Results

A total of 115 elderly patients with HF and CKD were enrolled in our study. Supratherapeutic concentrations were detected in 49 patients. Logistic regression analysis showed that estimated glomerular filtration rate calculated by serum cystatin C [eGFRCysC, odds ratio (OR): 0.962, P = 0.006], heart rate (OR: 1.024, P = 0.040), and NYHA class (OR: 3.099, P = 0.010) were independent risk factors for supratherapeutic concentration. Cutoff value for eGFRCysC between the two groups was 41 ml/min/1.73m2. Predictive performance of serum cystatin C was further improved in patients with obesity, CKD stage 4–5, and older than 75 years compared with normal weight, CKD stage 3, and aged 60–75-year-old patients.

Conclusions

Serum cystatin C is a sensitive renal function biomarker to predict supratherapeutic digoxin concentration in elderly patients with HF and CKD.

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References

  1. Roger VL. Epidemiology of heart failure. Circ Res. 2013;113(6):646–59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Ambrosy AP, Fonarow GC, Butler J, Chioncel O, Greene SJ, Vaduganathan M, et al. The global health and economic burden of hospitalizations for heart failure: lessons learned from hospitalized heart failure registries. J Am Coll Cardiol. 2014;63(12):1123–33.

    Article  PubMed  Google Scholar 

  3. Uretsky BF, Young JB, Shahidi FE, Yellen LG, Harrison MC, Jolly MK. Randomized study assessing the effect of digoxin withdrawal in patients with mild to moderate chronic congestive heart failure: results of the PROVED trial. PROVED Investigative Group. J Am Coll Cardiol. 1993;22(4):955–62.

  4. Devereux RB. Withdrawal of digoxin from patients with chronic heart failure treated with angiotensin-converting-enzyme inhibitors. N Engl J Med. 1993;329(24):1820.

    CAS  PubMed  Google Scholar 

  5. Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE Jr, Drazner MH, et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2013;62(16):e147-239.

    Article  PubMed  Google Scholar 

  6. Moffett BS, Garner A, Zapata T, Orcutt J, Niu M, Lopez KN. Serum digoxin concentrations and clinical signs and symptoms of digoxin toxicity in the paediatric population. Cardiol Young. 2016;26(3):493–8.

    Article  PubMed  Google Scholar 

  7. Lopes RD, Rordorf R, De Ferrari GM, Leonardi S, Thomas L, Wojdyla DM, et al. Digoxin and mortality in patients with atrial fibrillation. J Am Coll Cardiol. 2018;71(10):1063–74.

    Article  CAS  PubMed  Google Scholar 

  8. Dickstein K, Cohen-Solal A, Filippatos G, McMurray JJ, Ponikowski P, Poole-Wilson PA, et al. ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2008: the Task Force for the diagnosis and treatment of acute and chronic heart failure 2008 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association of the ESC (HFA) and endorsed by the European Society of Intensive Care Medicine (ESICM). Eur J Heart Fail. 2008;10(10):933–89.

  9. GBD Chronic Kidney Disease Collaboration. Global, regional, and national burden of chronic kidney disease, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2020;395(10225):709–33.

    Article  Google Scholar 

  10. Pontremoli R, Borghi C, Perrone FP. Renal protection in chronic heart failure: focus on sacubitril/valsartan. Eur Heart J Cardiovasc Pharmacother. 2021;7(5):445–52.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Webster AC, Nagler EV, Morton RL, Masson P. Chronic kidney disease. Lancet. 2017;389(10075):1238–52.

    Article  PubMed  Google Scholar 

  12. Stevens PE, Levin A. Evaluation and management of chronic kidney disease: synopsis of the kidney disease: improving global outcomes 2012 clinical practice guideline. Ann Intern Med. 2013;158(11):825–30.

    Article  PubMed  Google Scholar 

  13. Iisalo E. Clinical pharmacokinetics of digoxin. Clin Pharmacokinet. 1977;2(1):1–16.

    Article  CAS  PubMed  Google Scholar 

  14. Dodder NG, Tai SS, Sniegoski LT, Zhang NF, Welch MJ. Certification of creatinine in a human serum reference material by GC-MS and LC-MS. Clin Chem. 2007;53(9):1694–9.

    Article  CAS  PubMed  Google Scholar 

  15. Grubb A, Blirup-Jensen S, Lindström V, Schmidt C, Althaus H, Zegers I. First certified reference material for cystatin C in human serum ERM-DA471/IFCC. Clin Chem Lab Med. 2010;48(11):1619–21.

    Article  CAS  PubMed  Google Scholar 

  16. Sae-Lim O, Doungngern T, Jaisue S, Cheewatanakornkul S, Arunmanakul P, Anutrakulchai S, et al. Prediction of serum digoxin concentration using estimated glomerular filtration rate in Thai population. Int J Gen Med. 2019;12:455–63.

    Article  PubMed  PubMed Central  Google Scholar 

  17. El-Sarnagawy GN, El Sharkawy SI, Helal NE. Predictive factors for recurrence of serious arrhythmias in patients with acute digoxin poisoning. Cardiovasc Toxicol. 2021;21(10):835–47.

    Article  CAS  PubMed  Google Scholar 

  18. Vamos M, Erath JW, Hohnloser SH. Digoxin-associated mortality: a systematic review and meta-analysis of the literature. Eur Heart J. 2015;36(28):1831–8.

    Article  CAS  PubMed  Google Scholar 

  19. O’Riordan S, Ouldred E, Brice S, Jackson SH, Swift CG. Serum cystatin C is not a better marker of creatinine or digoxin clearance than serum creatinine. Br J Clin Pharmacol. 2002;53(4):398–402.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Nakamura T, Ioroi T, Sakaeda T, Horinouchi M, Hayashi N, Saito K, et al. Serum cystatin C levels to predict serum concentration of digoxin in Japanese patients. Int J Med Sci. 2006;3(3):92–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Hallberg P, Melhus H, Hansson LO, Larsson A. Cystatin C vs creatinine as markers of renal function in patients on digoxin treatment. Ups J Med Sci. 2004;109(3):247–53.

    Article  PubMed  Google Scholar 

  22. Garcia A, Hermida J, Tutor JC. Estimation of the glomerular filtration rate from serum creatinine and cystatin C with regard to therapeutic digoxin monitoring. J Clin Pharmacol. 2007;47(11):1450–5.

    Article  CAS  PubMed  Google Scholar 

  23. Šálek T, Vodička M, Gřiva M. Cystatin C may be better than creatinine for digoxin dosing in older adults with atrial fibrillation. J Clin Lab Anal. 2020;34(10): e23427.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Hojs R, Bevc S, Ekart R, Gorenjak M, Puklavec L. Serum cystatin C as an endogenous marker of renal function in patients with chronic kidney disease. Ren Fail. 2008;30(2):181–6.

    Article  CAS  PubMed  Google Scholar 

  25. Yassine HN, Trenchevska O, Dong Z, Bashawri Y, Koska J, Reaven PD, et al. The association of plasma cystatin C proteoforms with diabetic chronic kidney disease. Proteome Sci. 2016;14:7.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Newman DJ, Cystatin C. Ann Clin Biochem. 2002;39(Pt 2):89–104.

    Article  CAS  PubMed  Google Scholar 

  27. Deo R, Shlipak MG, Ix JH, Ali S, Schiller NB, Whooley MA. Association of cystatin C with ischemia in patients with coronary heart disease. Clin Cardiol. 2009;32(11):E18-22.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Einwoegerer CF, Domingueti CP. Association between increased levels of cystatin c and the development of cardiovascular events or mortality: a systematic review and meta-analysis. Arq Bras Cardiol. 2018;111(6):796–807.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Vigil A, Condés E, Vigil L, Gallar P, Oliet A, Ortega O, et al. Cystatin C as a predictor of mortality and cardiovascular events in a population with chronic kidney disease. Int J Nephrol. 2014;2014: 127943.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Ruan ZB, Zhu L, Yin YG, Chen GC. Cystatin C, N-terminal probrain natriuretic peptides and outcomes in acute heart failure with acute kidney injury in a 12-month follow-up: Insights into the cardiorenal syndrome. J Res Med Sci. 2014;19(5):404–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. White CA, Akbari A, Allen C, Day AG, Norman PA, Holland D, et al. Simultaneous glomerular filtration rate determination using inulin, iohexol, and (99m)Tc-DTPA demonstrates the need for customized measurement protocols. Kidney Int. 2021;99(4):957–66.

    Article  CAS  PubMed  Google Scholar 

  32. Heymsfield SB, Arteaga C, McManus C, Smith J, Moffitt S. Measurement of muscle mass in humans: validity of the 24-hour urinary creatinine method. Am J Clin Nutr. 1983;37(3):478–94.

    Article  CAS  PubMed  Google Scholar 

  33. Jang HC. How to diagnose sarcopenia in Korean older adults? Ann Geriatr Med Res. 2018;22(2):73–9.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Wilkinson DJ, Piasecki M, Atherton PJ. The age-related loss of skeletal muscle mass and function: measurement and physiology of muscle fibre atrophy and muscle fibre loss in humans. Ageing Res Rev. 2018;47:123–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Ivey-Miranda JB, Inker LA, Griffin M, Rao V, Maulion C, Turner JM, et al. Cystatin c and muscle mass in patients with heart failure. J Card Fail. 2021;27(1):48–56.

    Article  PubMed  Google Scholar 

  36. Nankivell BJ, Nankivell LFJ, Elder GJ, Gruenewald SM. How unmeasured muscle mass affects estimated GFR and diagnostic inaccuracy. EClinicalMedicine. 2020;29–30: 100662.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Soveri I, Berg UB, Björk J, Elinder CG, Grubb A, Mejare I, et al. Measuring GFR: a systematic review. Am J Kidney Dis. 2014;64(3):411–24.

    Article  PubMed  Google Scholar 

  38. Levey AS, Titan SM, Powe NR, Coresh J, Inker LA. Kidney disease, race, and GFR estimation. Clin J Am Soc Nephrol. 2020;15(8):1203–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Dharnidharka VR, Kwon C, Stevens G. Serum cystatin C is superior to serum creatinine as a marker of kidney function: a meta-analysis. Am J Kidney Dis. 2002;40(2):221–6.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Pharmacy, The First Affiliated Hospital of Guangxi Medical University, No. 6 Shuangyong Road, Nanning, 530021, Guangxi, People’s Republic of China

    Jie-Jiu Lu & Tao-Tao Liu

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  1. Jie-Jiu Lu
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  2. Tao-Tao Liu
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Corresponding author

Correspondence to Tao-Tao Liu.

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Funding

The authors did not receive any funding for the development of this study.

Conflicts of interest

JJL and TTL declare no conflicts of interest in relation to this article.

Ethics approval

This study was approved by the Institutional Ethics Committee from the First Affiliated Hospital of Guangxi Medical University (no. 2022-KY-E-298).

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Not applicable.

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Not applicable.

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Not applicable.

Author contributions

J.J.L. and T.T.L. were involved in conception and design of the study. J.J.L. collected data and provided analysis. J.J.L. and T.T.L. wrote the first draft of the manuscript, and all authors gave final approval of the manuscript to be published.

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Lu, JJ., Liu, TT. Serum Cystatin C as a Risk Factor for Supratherapeutic Digoxin Concentration in Elderly Patients with Heart Failure and Chronic Kidney Disease. Am J Cardiovasc Drugs 24, 303–311 (2024). https://doi.org/10.1007/s40256-024-00629-5

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