Adverse Drug Events in Patients with Chronic Kidney Disease Associated with Multiple Drug Interactions and Polypharmacy

  • Julia SommerEmail author
  • Andreas Seeling
  • Harald Rupprecht
Original Research Article


Background and Purpose

Chronic kidney disease (CKD) is associated with adverse drug events due to medication errors and the risks of polypharmacy. The aim of this study was to investigate whether multiple pharmacodynamic interactions are a significant problem in CKD patients to improve medication safety.


The discharge medication of 200 elderly patients with stage 3, 4 and 5/5D CKD was analysed in a retrospective observational study with respect to kidney-related medication errors and multiple pharmacodynamic interactions. The clinical relevance of the most common and hazardous multiple interactions was assessed by evaluating adverse events at the primary or the subsequent hospital stay.


Findings showed that 29.5% of the study cohort were at risk of QTc-interval prolongation in association with their medication combinations and half of them exhibited QTc-interval prolongation. The QTc interval was extended among all patients receiving a combination of two or more drugs with ‘known’ risk of Torsades de pointes. Amiodarone, citalopram and ciprofloxacin turned out to be the most hazardous drugs in this context. Eight percent of the patient population received a regimen of 4–6 potassium-enhancing drugs during their hospital stay, which was not de-escalated in 75.0% in the ambulatory setting. Despite close monitoring in the clinical setting, 37.5% of these patients developed hyperkalaemic episodes during their primary stay and 66.7% during rehospitalization. Of the study cohort, 8.5% received a combination of three drugs with antithrombotic or antiplatelet effects. Of these, 64.7% developed haemorrhagic events with two of them proving fatal.


Multiple pharmacodynamic interactions related to QTc prolongation, hyperkalaemia and haemorrhage are frequently associated with a negative outcome in older adults with CKD and often require recurrent medical treatment or rehospitalization.


Author contributions

JS conceived and designed the investigation and the database for data analysis, collected and interpreted the data, performed the literature research and wrote the paper. HR contributed to the study design, data interpretation and writing of the paper. AS contributed to data interpretation. Each author contributed important intellectual content during manuscript drafting.

Compliance with Ethical Standards


This study was funded by a grant from the Klinikum Bayreuth GmbH and by a grant from the Förderinitiative Pharmazeutische Betreuung e.V. There was no commercial funding for this study.

Conflict of interest

The results presented in this paper have not been published previously in whole or in part. All authors have reported that they have no relationships relevant to the contents of this article to disclose.


  1. 1.
    Dorks M, Herget-Rosenthal S, Schmiemann G, Hoffmann F. Polypharmacy and renal failure in nursing home residents: results of the inappropriate medication in patients with renal insufficiency in nursing homes (IMREN) study. Drugs Aging. 2016;33(1):45–51. Scholar
  2. 2.
    Breton G, Froissart M, Janus N, Launay-Vacher V, Berr C, Tzourio C, et al. Inappropriate drug use and mortality in community-dwelling elderly with impaired kidney function—the Three-City population-based study. Nephrol Dial Transplant. 2011;26(9):2852–9. Scholar
  3. 3.
    Chiu YW, Teitelbaum I, Misra M, de Leon EM, Adzize T, Mehrotra R. Pill burden, adherence, hyperphosphatemia, and quality of life in maintenance dialysis patients. Clin J Am Soc Nephrol. 2009;4(6):1089–96. Scholar
  4. 4.
    Fabbietti P, Di Stefano G, Moresi R, Cassetta L, Di Rosa M, Fimognari F, et al. Impact of potentially inappropriate medications and polypharmacy on 3-month readmission among older patients discharged from acute care hospital: a prospective study. Aging Clin Exp Res. 2018;30(8):977–84. Scholar
  5. 5.
    Steinman MA, Miao Y, Boscardin WJ, Komaiko KDR, Schwartz JB. Prescribing quality in older veterans: a multifocal approach. J Gen Intern Med. 2014;29(10):1379–86. Scholar
  6. 6.
    Maher RL, Hanlon J, Hajjar ER. Clinical consequences of polypharmacy in elderly. Expert Opin Drug Saf. 2014;13(1):57–65. Scholar
  7. 7.
    Group KDIGOKCW. KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney Int 2013;Suppl(3):1–150.Google Scholar
  8. 8.
    Rautaharju PM, Surawicz B, Gettes LS, Bailey JJ, Childers R, Deal BJ et al. AHA/ACCF/HRS recommendations for the standardization and interpretation of the electrocardiogram: part IV: the ST segment, T and U waves, and the QT interval: a scientific statement from the American Heart Association Electrocardiography and Arrhythmias Committee, Council on Clinical Cardiology; the American College of Cardiology Foundation; and the Heart Rhythm Society. Endorsed by the International Society for Computerized Electrocardiology. J Am Coll Cardiol. 2009;53(11):982–91. Scholar
  9. 9.
    Oster JR, Singer I, Fishman LM. Heparin-induced aldosterone suppression and hyperkalemia. Am J Med. 1995;98(6):575–86. Scholar
  10. 10.
    Ben Salem C, Badreddine A, Fathallah N, Slim R, Hmouda H. Drug-induced hyperkalemia. Drug Saf. 2014;37(9):677–92. Scholar
  11. 11.
    Aldahl M, Jensen A-SC, Davidsen L, Eriksen MA, Møller Hansen S, Nielsen BJ et al. Associations of serum potassium levels with mortality in chronic heart failure patients. Eur Heart J. 2017;38(38):2890–6. Scholar
  12. 12.
    Iwagami M, Tomlinson LA, Mansfield KE, Douglas IJ, Smeeth L, Nitsch D. Gastrointestinal bleeding risk of selective serotonin reuptake inhibitors by level of kidney function: a population-based cohort study. Br J Clin Pharmacol. 2018;84(9):2142–51. Scholar
  13. 13.
    de Abajo FJ. Effects of selective serotonin reuptake inhibitors on platelet function: mechanisms, clinical outcomes and implications for use in elderly patients. Drugs Aging. 2011;28(5):345–67. Scholar
  14. 14.
    Mehran R, Rao SV, Bhatt DL, Gibson CM, Caixeta A, Eikelboom J, et al. Standardized bleeding definitions for cardiovascular clinical trials: a consensus report from the Bleeding Academic Research Consortium. Circulation. 2011;123(23):2736–47. Scholar
  15. 15.
    O’Shaughnessy M, Allen N, O’Regan J, Payne-Danson E, Mentre L, Davin D, et al. Agreement between renal prescribing references and determination of prescribing appropriateness in hospitalized patients with chronic kidney disease. QJM. 2017;110(10):623–8. Scholar
  16. 16.
    Schachtele S, Tumena T, Gassmann KG, Fromm MF, Maas R. Co-prescription of QT-interval prolonging drugs: an analysis in a large cohort of geriatric patients. PLoS One. 2016;11(5):e0155649. Scholar
  17. 17.
    Meid AD, von Medem A, Heider D, Adler J-B, Günster C, Seidling HM, et al. Investigating the additive interaction of QT-prolonging drugs in older people using claims data. Drug Saf. 2017;40(2):133–44. Scholar
  18. 18.
    De Bruin ML, Langendijk PNJ, Koopmans RP, Wilde AAM, Leufkens HGM, Hoes AW. In-hospital cardiac arrest is associated with use of non-antiarrhythmic QTc-prolonging drugs. Br J Clin Pharmacol. 2007;63(2):216–23. Scholar
  19. 19.
    Haugaa KH, Bos JM, Tarrell RF, Morlan BW, Caraballo PJ, Ackerman MJ. Institution-wide QT alert system identifies patients with a high risk of mortality. Mayo Clin Proc. 2013;88(4):315–25. Scholar
  20. 20.
    Tisdale JE, Jaynes HA, Kingery JR, Mourad NA, Trujillo TN, Overholser BR, et al. Development and validation of a risk score to predict QT interval prolongation in hospitalized patients. Circ Cardiovasc Qual Outcomes. 2013;6(4):479–87. Scholar
  21. 21.
    Vandael E, Vandenberk B, Vandenberghe J, Willems R, Foulon V. Risk factors for QTc-prolongation: systematic review of the evidence. Int J Clin Pharm. 2017;39(1):16–25. Scholar
  22. 22.
    Stewart GA, Gansevoort RT, Mark PB, Rooney E, McDonagh TA, Dargie HJ, et al. Electrocardiographic abnormalities and uremic cardiomyopathy. Kidney Int. 2005;67(1):217–26. Scholar
  23. 23.
    Sherif KA, Abo-Salem E, Panikkath R, Nusrat M, Tuncel M. Cardiac repolarization abnormalities among patients with various stages of chronic kidney disease. Clin Cardiol. 2014;37(7):417–21. Scholar
  24. 24.
    Yu H, Zhang L, Liu J, Liu Y, Kowey PR, Zhang Y, et al. Acquired long QT syndrome in hospitalized patients. Heart Rhythm. 2017;14(7):974–8. Scholar
  25. 25.
    Thomsen RW, Nicolaisen SK, Hasvold P, Garcia-Sanchez R, Pedersen L, Adelborg K, et al. Elevated potassium levels in patients with congestive heart failure: occurrence, risk factors, and clinical outcomes: a Danish population-based cohort study. J Am Heart Assoc. 2018;7(11):e008912. Scholar
  26. 26.
    Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JGF, Coats AJS, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC)Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J. 2016;37(27):2129–200. Scholar
  27. 27.
    Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med. 1999;341(10):709–17. Scholar
  28. 28.
    Pitt B, Remme W, Zannad F, Neaton J, Martinez F, Roniker B, et al. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med. 2003;348(14):1309–21. Scholar
  29. 29.
    Zannad F, McMurray JJ, Krum H, van Veldhuisen DJ, Swedberg K, Shi H, et al. Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med. 2011;364(1):11–21. Scholar
  30. 30.
    Juurlink DN, Mamdani MM, Lee DS, Kopp A, Austin PC, Laupacis A, et al. Rates of hyperkalemia after publication of the randomized aldactone evaluation study. N Engl J Med. 2004;351(6):543–51. Scholar
  31. 31.
    Schiff GD, Aggarwal HC, Kumar S, McNutt RA. Prescribing potassium despite hyperkalemia: medication errors uncovered by linking laboratory and pharmacy information systems. Am J Med. 2000;109(6):494–7. Scholar
  32. 32.
    Packham DK, Rasmussen HS, Lavin PT, El-Shahawy MA, Roger SD, Block G, et al. Sodium zirconium cyclosilicate in hyperkalemia. N Engl J Med. 2015;372(3):222–31. Scholar
  33. 33.
    Weir MR, Bakris GL, Bushinsky DA, Mayo MR, Garza D, Stasiv Y, et al. Patiromer in patients with kidney disease and hyperkalemia receiving RAAS inhibitors. N Engl J Med. 2015;372(3):211–21. Scholar
  34. 34.
    Fishbane S, Ford M, Fukagawa M, McCafferty K, Rastogi A, Spinowitz B et al. A Phase 3b, randomized, double-blind, placebo-controlled study of sodium zirconium cyclosilicate for reducing the incidence of predialysis hyperkalemia. J Am Soc Nephrol. 2019:ASN.2019050450. Scholar
  35. 35.
    Valgimigli M, Bueno H, Byrne RA, Collet JP, Costa F, Jeppsson A, et al. 2017 ESC focused update on dual antiplatelet therapy in coronary artery disease developed in collaboration with EACTS: The Task Force for dual antiplatelet therapy in coronary artery disease of the European Society of Cardiology (ESC) and of the European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J. 2018;39(3):213–60. Scholar
  36. 36.
    Hansen ML, Sorensen R, Clausen MT, Fog-Petersen ML, Raunso J, Gadsboll N, et al. Risk of bleeding with single, dual, or triple therapy with warfarin, aspirin, and clopidogrel in patients with atrial fibrillation. Arch Intern Med. 2010;170(16):1433–41. Scholar
  37. 37.
    Lamberts M, Olesen JB, Ruwald MH, Hansen CM, Karasoy D, Kristensen SL, et al. Bleeding after initiation of multiple antithrombotic drugs, including triple therapy, in atrial fibrillation patients following myocardial infarction and coronary intervention: a nationwide cohort study. Circulation. 2012;126(10):1185–93. Scholar
  38. 38.
    Dewilde WJM, Oirbans T, Verheugt FWA, Kelder JC, De Smet BJGL, Herrman JP, et al. Use of clopidogrel with or without aspirin in patients taking oral anticoagulant therapy and undergoing percutaneous coronary intervention: an open-label, randomised, controlled trial. Lancet. 2013;381(9872):1107–15. Scholar
  39. 39.
    Bonde AN, Lip GY, Kamper AL, Fosbol EL, Staerk L, Carlson N, et al. Renal function and the risk of stroke and bleeding in patients with atrial fibrillation: an observational cohort study. Stroke. 2016;47(11):2707–13. Scholar
  40. 40.
    Dahal K, Kunwar S, Rijal J, Schulman P, Lee J. Stroke, major bleeding, and mortality outcomes in warfarin users with atrial fibrillation and chronic kidney disease: a meta-analysis of observational studies. Chest. 2016;149(4):951–9. Scholar
  41. 41.
    Cannon CP, Bhatt DL, Oldgren J, Lip GYH, Ellis SG, Kimura T, et al. Dual antithrombotic therapy with dabigatran after PCI in atrial fibrillation. N Engl J Med. 2017;377(16):1513–24. Scholar
  42. 42.
    Gibson CM, Pinto DS, Chi G, Arbetter D, Yee M, Mehran R, et al. Recurrent hospitalization among patients with atrial fibrillation undergoing intracoronary stenting treated with 2 treatment strategies of rivaroxaban or a dose-adjusted oral vitamin K antagonist treatment strategy. Circulation. 2017;135(4):323–33. Scholar
  43. 43.
    Lopes RD, Heizer G, Aronson R, Vora AN, Massaro T, Mehran R, et al. Antithrombotic therapy after acute coronary syndrome or PCI in atrial fibrillation. N Engl J Med. 2019;380(16):1509–24. Scholar
  44. 44.
    Roldan V, Marin F, Manzano-Fernandez S, Gallego P, Vilchez JA, Valdes M, et al. The HAS-BLED score has better prediction accuracy for major bleeding than CHADS2 or CHA2DS2-VASc scores in anticoagulated patients with atrial fibrillation. J Am Coll Cardiol. 2013;62(23):2199–204. Scholar
  45. 45.
    Labos C, Dasgupta K, Nedjar H, Turecki G, Rahme E. Risk of bleeding associated with combined use of selective serotonin reuptake inhibitors and antiplatelet therapy following acute myocardial infarction. CMAJ. 2011;183(16):1835–43. Scholar
  46. 46.
    Straus SMJM, Kors JA, De Bruin ML, van der Hooft CS, Hofman A, Heeringa J, et al. Prolonged QTc interval and risk of sudden cardiac death in a population of older adults. J Am Coll Cardiol. 2006;47(2):362–7. Scholar
  47. 47.
    Zhang Y, Post WS, Dalal D, Blasco-Colmenares E, Tomaselli GF, Guallar E. QT-interval duration and mortality rate: results from the third national health and nutrition examination survey. JAMA Intern Med. 2011;171(19):1727–33. Scholar
  48. 48.
    Collins AJ, Pitt B, Reaven N, Funk S, McGaughey K, Wilson D, et al. Association of serum potassium with all-cause mortality in patients with and without heart failure, chronic kidney disease, and/or diabetes. Am J Nephrol. 2017;46(3):213–21. Scholar
  49. 49.
    Sood P, Kumar G, Nanchal R, Sakhuja A, Ahmad S, Ali M, et al. Chronic kidney disease and end-stage renal disease predict higher risk of mortality in patients with primary upper gastrointestinal bleeding. Am J Nephrol. 2012;35(3):216–24. Scholar

Copyright information

© Springer Nature Switzerland AG 2020

Authors and Affiliations

  1. 1.Department of PharmacyKlinikum Bayreuth GmbHBayreuthGermany
  2. 2.Institute of PharmacyFriedrich-Schiller-Universität JenaJenaGermany
  3. 3.Department of NephrologyKlinikum Bayreuth GmbHBayreuthGermany
  4. 4.KfH Dialysis CentreBayreuthGermany

Personalised recommendations