Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Implications of augmented renal clearance in critically ill patients

Abstract

Critically ill patients can display markedly abnormal physiological parameters compared with those in ward-based or ambulatory settings. As a function of both the underlying inflammatory state and the interventions provided, these patients manifest substantial changes in their cardiovascular and renal function that are not always immediately discernable using standard diagnostic tests. Impaired renal function is well documented among such individuals; however, even patients with normal serum creatinine concentrations might display elevated glomerular filtration rates, a phenomenon we have termed augmented renal clearance (ARC). This finding has important ramifications for the accurate dosing of renally eliminated drugs, given that most pharmaceutical dosing regimens were validated outside the critical care environment. Empirical approaches to dosing are unlikely to achieve therapeutic drug concentrations in patients with ARC, placing them at risk of suboptimal drug exposure and potential treatment failure. With an increasing appreciation of this phenomenon, alternative dosing strategies will need to be investigated.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: Mechanisms underlying augmented renal clearance.

References

  1. Udy, A. A., Putt, M. T., Shanmugathasan, S., Roberts, J. A. & Lipman, J. Augmented renal clearance in the intensive care unit: an illustrative case series. Int. J. Antimicrob. Agents 35, 606–608 (2010).

    Article  CAS  Google Scholar 

  2. Dellinger, R. P. et al. Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2008. Crit. Care Med. 36, 296–327 (2008).

    Article  Google Scholar 

  3. Stevens, L. A., Coresh, J., Greene, T. & Levey, A. S. Assessing kidney function—measured and estimated glomerular filtration rate. N. Engl. J. Med. 354, 2473–2483 (2006).

    Article  CAS  Google Scholar 

  4. Brown, R. et al. Renal function in critically ill postoperative patients: sequential assessment of creatinine osmolar and free water clearance. Crit. Care Med. 8, 68–72 (1980).

    Article  CAS  Google Scholar 

  5. Claus, B., Colpaert, K., Hoste, E. A., Decruyenaere, J. & De Waele, J. Increased glomerular filtration in the critically ill patient receiving anti-infective treatment. Crit. Care 14 (Suppl. 1), P509 (2010).

    Article  Google Scholar 

  6. Fuster-Lluch, O., Geronimo-Pardo, M., Peyro-Garcia, R. & Lizan-Garcia, M. Glomerular hyperfiltration and albuminuria in critically ill patients. Anaesth. Intensive Care 36, 674–680 (2008).

    Article  CAS  Google Scholar 

  7. Ibrahim, E. H., Sherman, G., Ward, S., Fraser, V. J. & Kollef, M. H. The influence of inadequate antimicrobial treatment of bloodstream infections on patient outcomes in the ICU setting. Chest 118, 146–55 (2000).

    Article  CAS  Google Scholar 

  8. Udy, A. A., Roberts, J. A., Boots, R. J., Paterson, D. L. & Lipman, J. Augmented renal clearance: implications for antibacterial dosing in the critically ill. Clin. Pharmacokinet. 49, 1–16 (2010).

    Article  CAS  Google Scholar 

  9. Tett, S., Moore, S. & Ray, J. Pharmacokinetics and bioavailability of fluconazole in two groups of males with human immunodeficiency virus (HIV) infection compared with those in a group of males without HIV infection. Antimicrob. Agents Chemother. 39, 1835–1841 (1995).

    Article  CAS  Google Scholar 

  10. Tett, S. E., Kirkpatrick, C. M., Gross, A. S. & McLachlan, A. J. Principles and clinical application of assessing alterations in renal elimination pathways. Clin. Pharmacokinet. 42, 1193–1211 (2003).

    Article  Google Scholar 

  11. Hoste, E. A. et al. Assessment of renal function in recently admitted critically ill patients with normal serum creatinine. Nephrol. Dial. Transplant. 20, 747–753 (2005).

    Article  CAS  Google Scholar 

  12. Cockcroft, D. W. & Gault, M. H. Prediction of creatinine clearance from serum creatinine. Nephron 16, 31–41 (1976).

    Article  CAS  Google Scholar 

  13. Levey, A. S. et al. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann. Intern. Med. 130, 461–470 (1999).

    Article  CAS  Google Scholar 

  14. Martin, J. H. et al. Pitfalls of using estimations of glomerular filtration rate in an intensive care population. Intern. Med. J. doi:10.1111/j.1445–59942010.02160.x.

  15. Herrera-Gutierrez, M. E. et al. Replacement of 24-h creatinine clearance by 2-h creatinine clearance in intensive care unit patients: a single-center study. Intensive Care Med. 33, 1900–1906 (2007).

    Article  CAS  Google Scholar 

  16. Cherry, R. A., Eachempati, S. R., Hydo, L. & Barie, P. S. Accuracy of short-duration creatinine clearance determinations in predicting 24-hour creatinine clearance in critically ill and injured patients. J. Trauma 53, 267–271 (2002).

    Article  CAS  Google Scholar 

  17. Kees, M. G., Hilpert, J. W., Gnewuch, C., Kees, F. & Voegeler, S. Clearance of vancomycin during continuous infusion in intensive care unit patients: correlation with measured and estimated creatinine clearance and serum cystatin C. Int. J. Antimicrob. Agents 36, 545–548 (2010).

    Article  CAS  Google Scholar 

  18. Lipman, J., Wallis, S. C. & Boots, R. J. Cefepime versus cefpirome: the importance of creatinine clearance. Anesth. Analg. 97, 1149–1154 (2003).

    Article  CAS  Google Scholar 

  19. Udy, A. et al. Augmented creatinine clearance in traumatic brain injury. Anesth. Analg. 111, 1505–1510 (2010).

    Article  CAS  Google Scholar 

  20. Sunder-Plassmann, G. & Horl, W. H. A critical appraisal for definition of hyperfiltration. Am. J. Kidney Dis. 43, 396–397 (2004).

    Article  Google Scholar 

  21. Di Giantomasso, D., May, C. N. & Bellomo, R. Vital organ blood flow during hyperdynamic sepsis. Chest 124, 1053–1059 (2003).

    Article  Google Scholar 

  22. Mabie, W. C., DiSessa, T. G., Crocker, L. G., Sibai, B. M. & Arheart, K. L. A longitudinal study of cardiac output in normal human pregnancy. Am. J. Obstet. Gynecol. 170, 849–856 (1994).

    Article  CAS  Google Scholar 

  23. Dunlop, W. Serial changes in renal haemodynamics during normal human pregnancy. Br. J. Obstet. Gynaecol. 88, 1–9 (1981).

    Article  CAS  Google Scholar 

  24. Anderson, G. D. Pregnancy-induced changes in pharmacokinetics: a mechanistic-based approach. Clin. Pharmacokinet. 44, 989–1008 (2005).

    Article  CAS  Google Scholar 

  25. Wan, L., Bellomo, R. & May, C. N. The effects of normal and hypertonic saline on regional blood flow and oxygen delivery. Anesth. Analg. 105, 141–147 (2007).

    Article  CAS  Google Scholar 

  26. Di Giantomasso, D., May, C. N. & Bellomo, R. Norepinephrine and vital organ blood flow during experimental hyperdynamic sepsis. Intensive Care Med. 29, 1774–1781 (2003).

    Article  Google Scholar 

  27. Di Giantomasso, D., Morimatsu, H., Bellomo, R. & May, C. N. Effect of low-dose vasopressin infusion on vital organ blood flow in the conscious normal and septic sheep. Anaesth. Intensive Care 34, 427–433 (2006).

    Article  CAS  Google Scholar 

  28. Castellino, P., Giordano, C., Perna, A. & DeFronzo, R. A. Effects of plasma amino acid and hormone levels on renal hemodynamics in humans. Am. J. Physiol. 255, F444–F449 (1988).

    CAS  PubMed  Google Scholar 

  29. Thomas, D. M., Coles, G. A. & Williams, J. D. What does the renal reserve mean? Kidney Int. 45, 411–416 (1994).

    Article  CAS  Google Scholar 

  30. Bratton, S. L. et al. Guidelines for the management of severe traumatic brain injury. IX. Cerebral perfusion thresholds. J. Neurotrauma 24 (Suppl. 1), S59–S64 (2007).

    Article  Google Scholar 

  31. Sen, J. et al. Triple-H therapy in the management of aneurysmal subarachnoid haemorrhage. Lancet Neurol. 2, 614–621 (2003).

    Article  Google Scholar 

  32. Papp, A., Uusaro, A., Parviainen, I., Hartikainen, J. & Ruokonen, E. Myocardial function and haemodynamics in extensive burn trauma: evaluation by clinical signs, invasive monitoring, echocardiography and cytokine concentrations. A prospective clinical study. Acta Anaesthesiol. Scand. 47, 1257–1263 (2003).

    Article  CAS  Google Scholar 

  33. Barton, R. G. et al. Resuscitation of thermally injured patients with oxygen transport criteria as goals of therapy. J. Burn Care Rehabil. 18, 1–9 (1997).

    Article  CAS  Google Scholar 

  34. Latenser, B. A. Critical care of the burn patient: the first 48 hours. Crit. Care Med. 37, 2819–2826 (2009).

    Article  CAS  Google Scholar 

  35. Palmieri, T., Lavrentieva, A. & Greenhalgh, D. G. Acute kidney injury in critically ill burn patients. Risk factors, progression and impact on mortality. Burns 36, 205–211 (2010).

    Article  Google Scholar 

  36. Loirat, P. et al. Increased glomerular filtration rate in patients with major burns and its effect on the pharmacokinetics of tobramycin. N. Engl. J. Med. 299, 915–919 (1978).

    Article  CAS  Google Scholar 

  37. Conil, J. M. et al. Assessment of renal function in clinical practice at the bedside of burn patients. Br. J. Clin. Pharmacol. 63, 583–594 (2007).

    Article  CAS  Google Scholar 

  38. Rey, E., Treluyer, J. M. & Pons, G. Drug disposition in cystic fibrosis. Clin. Pharmacokinet. 35, 313–329 (1998).

    Article  CAS  Google Scholar 

  39. Hedman, A., Alvan, G., Strandvik, B. & Arvidsson, A. Increased renal clearance of cefsulodin due to higher glomerular filtration rate in cystic fibrosis. Clin. Pharmacokinet. 18, 168–175 (1990).

    Article  CAS  Google Scholar 

  40. Jusko, W. J., Mosovich, L. L., Gerbracht, L. M., Mattar, M. E. & Yaffe, S. J. Enhanced renal excretion of dicloxacillin in patients with cystic fibrosis. Pediatrics 56, 1038–1044 (1975).

    CAS  PubMed  Google Scholar 

  41. Wang, J. P. et al. Disposition of drugs in cystic fibrosis. IV. Mechanisms for enhanced renal clearance of ticarcillin. Clin. Pharmacol. Ther. 54, 293–302 (1993).

    Article  CAS  Google Scholar 

  42. Lamoth, F. et al. Reassessment of recommended imipenem doses in febrile neutropenic patients with hematological malignancies. Antimicrob. Agents Chemother. 53, 785–787 (2009).

    Article  CAS  Google Scholar 

  43. Lortholary, O. et al. Pharmacodynamics and pharmacokinetics of antibacterial drugs in the management of febrile neutropenia. Lancet Infect. Dis. 8, 612–620 (2008).

    Article  CAS  Google Scholar 

  44. Pea, F., Furlanut, M. & Viale, P. Is antimicrobial underexposure due to glomerular hyperfiltration a possible cause of increased mortality rate from bacterial infections in critically ill patients? Anaesth. Intensive Care 37, 323–324 (2009).

    CAS  PubMed  Google Scholar 

  45. Roberts, J. A. & Lipman, J. Pharmacokinetic issues for antibiotics in the critically ill patient. Crit. Care Med. 37, 840–851 (2009).

    Article  CAS  Google Scholar 

  46. del Mar Fernandez de Gatta Garcia, M., Revilla, N., Calvo, M. V., Dominguez-Gil, A. & Sanchez Navarro, A. Pharmacokinetic/pharmacodynamic analysis of vancomycin in ICU patients. Intensive Care Med. 33, 279–285 (2007).

    Article  CAS  Google Scholar 

  47. Joukhadar, C. et al. Plasma and tissue pharmacokinetics of cefpirome in patients with sepsis. Crit. Care Med. 30, 1478–1482 (2002).

    Article  CAS  Google Scholar 

  48. Kitzes-Cohen, R., Farin, D., Piva, G. & De Myttenaere-Bursztein, S. A. Pharmacokinetics and pharmacodynamics of meropenem in critically ill patients. Int. J. Antimicrob. Agents 19, 105–110 (2002).

    Article  CAS  Google Scholar 

  49. Conil, J. M. et al. Influence of renal function on trough serum concentrations of piperacillin in intensive care unit patients. Intensive Care Med. 32, 2063–2066 (2006).

    Article  CAS  Google Scholar 

  50. Roberts, J. A., Kruger, P., Paterson, D. L. & Lipman, J. Antibiotic resistance—what's dosing got to do with it? Crit. Care Med. 36, 2433–2440 (2008).

    Article  CAS  Google Scholar 

  51. Roberts, J. A., Webb, S., Paterson, D., Ho, K. M. & Lipman, J. A systematic review on clinical benefits of continuous administration of beta-lactam antibiotics. Crit. Care Med. 37, 2071–2078 (2009).

    Article  CAS  Google Scholar 

  52. Wysocki, M. et al. Continuous versus intermittent infusion of vancomycin in severe Staphylococcal infections: prospective multicenter randomized study. Antimicrob. Agents Chemother. 45, 2460–2467 (2001).

    Article  CAS  Google Scholar 

  53. Conil, J. M. et al. Tobramycin disposition in ICU patients receiving a once daily regimen: population approach and dosage simulations. Br. J. Clin. Pharmacol. 71, 61–71 (2011).

    Article  CAS  Google Scholar 

  54. Lugo, G. & Castaneda-Hernandez, G. Relationship between hemodynamic and vital support measures and pharmacokinetic variability of amikacin in critically ill patients with sepsis. Crit. Care Med. 25, 806–811 (1997).

    Article  CAS  Google Scholar 

  55. Geerts, W. H. et al. Prevention of venous thromboembolism: American College of Chest Physicians evidence-based clinical practice guidelines (8th Edition). Chest 133 (6 Suppl.), 381S–453S (2008).

    Article  CAS  Google Scholar 

  56. Robinson, S. et al. Enoxaparin, effective dosage for intensive care patients: double-blinded, randomised clinical trial. Crit. Care 14, R41 (2010).

    Article  Google Scholar 

Download references

Acknowledgements

The authors' work is supported in part by a grant from the National Health and Medical Research Council, Australia (NHMRC Project grant number 519702). A. A. Udy is supported by a Royal Brisbane and Women's Hospital Research Scholarship. J. A. Roberts is supported in part by the National Health and Medical Research Council, Australia (Australian Based Health Professional Research Fellowship grant number 569917).

Author information

Authors and Affiliations

Authors

Contributions

J. Lipman, J. A. Roberts and A. A. Udy contributed equally to discussion of the article content and reviewing/editing the manuscript before submission. A. A. Udy researched data for the article and wrote the initial draft.

Corresponding author

Correspondence to Andrew A. Udy.

Ethics declarations

Competing interests

J. A. Roberts has acted as a consultant to AstraZeneca, and is a member of advisory boards with AstraZeneca, Janssen-Cilag and Johnson and Johnson. Dr. Roberts has also received unrestricted grant funding from Astra-Zeneca, Janssen-Cilag and Novartis, and is listed in the Speakers bureau with Astra-Zeneca. J. Lipman has acted as a consultant for AstraZeneca, Janssen-Cilag, and Wyeth Australia. He has received grant/research support from AstraZeneca. A. A. Udy declares no competing interests.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Udy, A., Roberts, J. & Lipman, J. Implications of augmented renal clearance in critically ill patients. Nat Rev Nephrol 7, 539–543 (2011). https://doi.org/10.1038/nrneph.2011.92

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrneph.2011.92

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing