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NDT Advance Access originally published online on April 30, 2007
Nephrology Dialysis Transplantation 2007 22(8):2391-2394; doi:10.1093/ndt/gfm251
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© The Author [2007]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
(Section Editor: A. Meyrier)

An unusual case of acute kidney injury due to vancomycin—lessons learnt from reliance on eGFR

Katherine Barraclough1, Marianne Harris2, Val Montessori2 and Adeera Levin1

1Department of Nephrology and 2Department of Infectious Diseases, St Paul's Hospital, Vancouver, Canada

Correspondence and offprint requests to: Dr Katherine A. Barraclough, Department of Nephrology, St Paul's Hospital, 1081 Burrard Street, Providence Building, 6th Floor, Room 6010A, Vancouver, British Colombia, V6Z1Y6, Canada. Email: arbieb{at}hotmail.com



   Abstract
Top
 Abstract
Introduction
 Case report
 Discussion
 Teaching points
 References
 
We present a case of renal impairment in an emaciated HIV-infected male that initially went unrecognized because of reliance on serum creatinine and estimated glomerular filtration rate (eGFR). Inaccurate vancomycin dosing led to toxic drug levels (66 mg/l), associated with acute and severe worsening of kidney function. This occurred in the context of escalating doses of vancomycin given in the presence of changing kidney function, albeit kidney function that always remained well within the normal range (serum creatinine 29 – 42 µmol/l). In the absence of other plausible explanations, a presumptive diagnosis of vancomycin nephrotoxicity was made. Given the rarity of this diagnosis in the current era, we discuss the pathophysiology of vancomycin nephrotoxicity. We also explore the potential reasons for inaccuracy of GFR prediction equations in the HIV population, and discuss the potential pitfalls associated with application of eGFR or even serum creatinine without appropriate understanding of their limitations. We believe our case highlights a number of important teaching points:

  1. Vancomycin nephrotoxitiy is rare but can occur in the setting of kidney dysfunction.
  2. Current assessment of kidney function using creatinine and eGFR requires awareness of the clinical caveats in which these measures may be misleading.
  3. Acute changes in kidney function, irrespective of the test used, should be contextualized to the individual situation.
  4. Persons with HIV and low muscle mass constitute a specific subgroup in whom assessment of kidney function may be problematic using creatinine.

We support ongoing efforts to develop or refine equations for specific unique and easily identifiable populations.

Keywords: creatinine; estimation equation; glomerular filtration rate; human immunodeficiency virus; nephrotoxicity; vancomycin



   Introduction
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 Abstract
 Introduction
Case report
 Discussion
 Teaching points
 References
 
Vancomycin nephrotoxicity is uncommon [1]. A likely relationship exists between toxicity and serum drug concentration, but the therapeutic to toxic ratio is so wide that incidence in clinical practice is limited [2]. Vancomycin undergoes renal excretion and blood levels increase markedly with decreased renal clearance. Algorithms exist for dosing patients with renal impairment, but these rely on estimation of glomerular filtration rate (eGFR) via prediction equations. These equations have not been validated in the HIV- infected population despite atypical characteristics of this group that may limit applicability. Our case highlights these characteristics and demonstrates the pitfalls of reliance on eGFR in certain populations. This case supports a dose-dependant role of vancomycin in causation of nephrotoxicity.



   Case report
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 Abstract
 Introduction
 Case report
Discussion
 Teaching points
 References
 
A 36 year old Caucasian male presented with shortness of breath and fever. He was HIV and Hepatitis C infected, with a CD4 count of 160/µl (11%). There was no history of opportunistic infection or other AIDS-defining illness. He was homeless and on no prescribed medication.

Examination revealed a confused, emaciated male weighing 40 kg (BMI 13.4). Blood pressure was 130/90. Temperature was 37.9°C. Respiratory rate was 28 and room air oxygen saturation was 95%. There was minimal air entry to the left lung, with middle lobe crepitations. No alternative focus of infection was identified.

Investigations revealed elevated inflammatory markers [ESR 30 mm/h, white blood cell count 16 x 103/µl (16 x 109/l)] and left lung air space opacification with cavitation on chest radiograph. Cerebral CT scan and lumbar puncture were normal. The patient had normal kidney function [serum creatinine 0.3 mg/dl (29 µmol/l) (eGFR >120 ml/min/1.73m2)]. Urinalysis showed no proteinuria, haematuria or infection.

The patient was empirically treated with cefotaxime (1g i.v. tid). Bronchoalveolar lavage was performed and methicillin-resistant Staphylococcus aureus (MRSA) was cultured. Vancomycin (1g i.v. bid) was added. Despite persistently negative blood cultures and no vegetation on transthoracic echocardiogram, it was presumed that the cavitating MRSA pneumonia was secondary to septic emboli. Six weeks of vancomycin was considered necessary. Sulfamethoxazole–Trimethoprim (400/80 mg p.o. daily) was commenced as prophylaxis against pneumocystis carinii.

One day after commencement of antibiotics, the patient remained febrile. Vancomycin trough levels were subtherapeutic (6mg/l) (Figure 1) and dose was increased to 1g i.v. tid. The fever settled. Serum creatinine was 0.4 mg/dl (31 µmol/l).


Figure 1
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  		Fig. 1. Evolution of residual concentrations of vancomycin and serum creatinine levels. To convert serum creatinine in mg/dl to µmol/l, multiply by 88.4.

 
Two days later, serum creatinine was 0.5 mg/dl (42 µmol/l) (~30% change from baseline). No adjustment of vancomycin dosing occurred. Four days later, serum creatinine had risen to 1.4 mg/dl (123 µmol/l) (eGFR 55 ml/min/1.73 m2). Vancomycin level was in the toxic range (66 mg/l). The patient appeared clinically stable and adequately hydrated. Kidney ultrasound showed no obstruction and urinalysis was unremarkable. Technetium 99m MAG3 scan showed normal perfusion, but delayed transit and poor excretion of tracer bilaterally. Sulfamethoxazole–Trimethoprim was discontinued despite an absence of urinary eosinophils. Serum creatinine peaked at 1.9mg/dl (166 µmol/l) (eGFR 41 ml/min/1.73 m2). Vancomycin dose frequency was reduced to 1g i.v. q48h.

The patient remained in hospital to complete 6 weeks of vancomycin therapy. Serum creatinine slowly improved to 0.8 mg/dl (70 µmol/l) and remained at this level at discharge. Notably, this was greater than two times the admission value and if sustained would represent a 50% reduction in baseline kidney function.



   Discussion
Top
 Abstract
 Introduction
 Case report
 Discussion
Teaching points
 References
 
We present the unusual occurrence of acute kidney injury due to vancomycin. The case illustrates the potential pitfalls associated with the use of eGFR and creatinine in the HIV and other identifiable populations.

Vancomycin is an antibiotic in clinical use predominantly for MRSA treatment. Initially a nosocomial pathogen, MRSA is now an increasingly prevalent community pathogen. HIV disease is a recognized risk factor for MRSA community carriage [3].

Vancomycin is excreted by glomerular filtration, 80–90% as unchanged drug. The mean elimination half-life from plasma is 4–6 h with normal renal function, compared with 7.5 days in anephric patients [1]. Vancomycin nephrotoxicity is thought to be uncommon due to a particularly high toxic to therapeutic ratio. It principally manifests as increases in serum creatinine concentration, although interstitial nephritis has been reported [4,5]. Most reports of nephrotoxicity have been associated with early, relatively impure, vancomycin formulations [1] and the incidence with current formulations remains unclear. Many with presumed vancomycin nephrotoxicity have pre-existing renal dysfunction or are receiving other nephrotoxic agents, making the role of vancomycin unclear. Thus, reported incidence rates range between 0% and 44% [6]. The relationship between serum concentration and nephrotoxicity also remains unclear. A dose-dependent effect is suggested, with all reported cases occurring at levels above 39 mg/l [2].

Our patient developed renal failure in association with vancomycin levels substantially above the therapeutic range (10–15 mg/l). The level of 66 mg/l is higher than that previously reported [2,7]. Given no other plausible explanation, it is reasonable to assume the major contributor to be vancomycin.

More importantly, the risk of toxicity went unrecognized. This patient's low muscle mass ensured a substantial reduction in creatinine generation, resulting in GFR overestimation. The rise in serum creatinine from 29 to 42 µmol/l represented near total loss of glomerular filtration, not identified because both creatinine and eGFR remained within the ‘normal’ range.

Creatinine is the metabolic product of skeletal muscle creatine phosphate [8], produced in direct proportion to muscle mass. Mean creatinine generation varies with age, gender, race and body size because of differential muscle mass and metabolism. It also undergoes proximal tubular and extra-renal excretion (through skin and faeces), making it imperfect for GFR measurement.

The Kidney Disease Outcomes and Quality Initiative guidelines advise against its use alone, to assess kidney function [9]. They also advise against timed (24 h) collections, with collection inaccuracies making these no more reliable than estimation equations in most patients [9]. Similarly, the guidelines caution against their use in special populations: severely malnourished individuals are specifically named.

Estimation equations are recommended as the preferred method of GFR assessment [9]. Clinical laboratories are advised to report eGFR in addition to serum creatinine. Commonly used equations such as the Modified Diet in Renal Disease (MDRD) equation [10] and Cockcroft–Gault [11] variably account for the effects of sex, age, body size and ethnicity on serum creatinine. The hope is that more accurate assessment of kidney function will detect kidney disease earlier and allow for more targeted interventions stratified by CKD stage [9].

However, these formulae have limitations. They are unreliable in acute kidney injury [12]. While an acute drop in GFR signifies important changes, the relative change is more important than the actual GFR number, a subtlety under appreciated by non-nephrologists. Another limitation includes their derivation from fairly narrow populations. Subjects enrolled in the MDRD study [10] were primarily white, with non-diabetic kidney disease and a mean GFR of 40 ml/min per 1.73 m2. MDRD has been validated in non-hospitalized patients with CKD, regardless of diagnosis, but is less accurate in those with GFR >60 ml/min, those <18 or >70 years, Asians, unusual body mass, pregnant patients and possibly in transplant recipients [13–16].

Estimation equations have not been validated in the HIV population. The decreased reliability seen with extremes of muscle mass is relevant to the malnourished HIV-infected individual. Highly Active Antiretroviral Therapy (HAART) is known to induce mitochondrial dysfunction [17] and HIV is known to infect renal epithelial cells [18]. Thus, both HAART and the HIV virus itself may further effect creatinine generation or excretion and interfere with any creatinine based GFR estimation.

Accurate assessment of GFR in the HIV population is of paramount importance. HAART involves complex drug regimens often with significant side effects and potential interactions. Many anti-retroviral drugs undergo renal elimination [19]. The HIV infected population also has high exposure to anti-infective and chemotherapeutic agents, many of which undergo renal excretion. To properly predict the effects of parent drugs and metabolites and to dose adjust to ensure efficacy and safety, accurate assessment of GFR is required.

Furthermore, many different forms of renal disease are being reported in this population. Reduced eGFR and proteinuria are associated with mortality and adverse outcomes [20]. Accurate kidney function assessment will help to better identify and manage this high-risk group.

Vancomycin nephrotoxicity is uncommon. Our case is unique in that we believe its occurrence to be related to reliance on serum creatinine and eGFR. We support the need for ongoing development and refinement of equations to more appropriately estimate kidney function in specific, identifiable populations. In the meantime, we encourage education of clinicians and pharmacists as to the limitations of eGFR and any creatinine- based equation in specific clinical situations.



   Teaching points
Top
 Abstract
 Introduction
 Case report
 Discussion
 Teaching points
References
 

  1. Vancomycin nephrotoxicity is a rare diagnosis in the current era. A dose-dependent effect is probable. Renal impairment increases risk because of impaired drug excretion.
  2. Serum creatinine is an imperfect measure of GFR and should not be used alone to assess kidney function. eGFR is also imperfect. It was designed as an estimate measure, to allow better clinical decision making. It is not an exact representation of GFR. It is inaccurate in acute kidney injury and in specific unique and identifiable populations.
  3. Cautious interpretation of conventional measures of kidney function is required in certain settings. As laboratory reporting and subsequent clinical application of estimation equations continues to increase, health care providers need to be aware of pitfalls associated with its use. Application should always be appropriate to the clinical context and patient specific.
  4. Malnourished HIV-infected individuals are at particular risk for mis-diagnosis because of low muscle mass with subsequent reduced creatinine generation. Other HIV or HAART-related factors may further affect validity of creatinine-based GFR estimation. Care is required when assessing kidney function and prescribing medications in this population.

Conflict of interest statement. None declared.



   References
Top
 Abstract
 Introduction
 Case report
 Discussion
 Teaching points
 References
 

  1. Bailie GR, Neal D. Vancomycin ototoxicity and nephrotoxicity. A review. Medical Toxicology & Adverse Drug Experience (1988) 3:376–386.
  2. Frimat L. Renal failure due to vancomycin alone. Nephrology Dialysis Transplantation (1995) 10:550–551.[Free Full Text]
  3. Mathews WC, Caperna JC, Barber RE, et al. Incidence of and risk factors for clinically significant methicillin-resistant Staphylococcus aureus infection in a cohort of HIV-infected adults. J Acquir Immune Defic Syndr (2005) 40:155–160.[CrossRef][Web of Science][Medline]
  4. Wai AO, Lo AM, Abdo A, Marra F. Vancomycin-induced acute interstitial nephritis. [Case Reports. Journal Article]. Annals of Pharmacotherapy (1998) 32:1160–1164.[Abstract]
  5. Codding CE, Ramseyer L, Allon M, et al. Tubulointerstitial nephritis due to vancomycin. Am J Kidney Dis (1989) 14:512–515.[Web of Science][Medline]
  6. Vance Bryan K, Rotschafer JC, Gilliland SS, et al. A comparative assessment of vancomycin associated nephrotoxicity in the young versus the elderly hospitalized patient. J antimicrobial chemotherapy (1994) 33:811–821.[Abstract/Free Full Text]
  7. Mellor JA, Kingdom J, Cafferkey M, et al. Vancomycin toxicity: a prospective study. J Antimicrob Chemother (1985) 17:773–780.
  8. Ledger S. Laboratory assessment of kidney function. [Journal Article]. Cannt Journal (2006) 16:34–37.[Medline]
  9. K/DOQI Clinical practice guidelines for Chronic Kidney Disease: evaluation, classification, and stratification. Am J Kidney Dis (2003) 39:S1–S266.[CrossRef][Web of Science]
  10. Levey AS, Bosch JP, Lewis JB, et al. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Ann Intern Med (1999) 130:461–470.[Abstract/Free Full Text]
  11. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron (1976) 16:31–41.[Web of Science][Medline]
  12. Rule AD, Bergstralh EJ, Slezak JM, Bergert J, Larson TS. Glomerular filtration rate estimated by cystatin C among different clinical presentations. Kidney Int (2006) 69:399–405.[CrossRef][Web of Science][Medline]
  13. Bostom AG, Kronenberg F, Ritz E. Predictive performance of renal function equations for patients with chronic kidney disease and normal serum creatinine levels. J Am Soc Nephrol (2002) 13:2140.[Abstract/Free Full Text]
  14. Froissart M, Rossert J, Jacquot C, et al. Predictive performance of the MDRD and Cockcroft–Gault equations for estimating renal function. J Am Soc Nephrol (2005) 16:763.[Abstract/Free Full Text]
  15. Gaspari F, Ferrari S, Stucchi N, et al. Performance of different prediction equations for estimating renal function in kidney transplantation. Am J Transplant (2004) 4:1826.[CrossRef][Web of Science][Medline]
  16. Coresh J, Astor BC, Greene T, et al. Prevalence of chronic kidney disease and decreased kidney function in the adult US population: Third National Health and Nutrition Examination Survey. Am J Kidney Dis (2003) 41:1.[Web of Science][Medline]
  17. Carr A, Cooper DA. Adverse effects of antiretroviral therapy. Lancet (2000) 356:1423–1430.[CrossRef][Web of Science][Medline]
  18. Rappaport J, Kopp JB, Klotman PE. Host virus interactions and the molecular regulation of HIV-1: Role in the pathogenesis of HIV-associated nephropathy. Kidney Int (1994) 46:16.[Web of Science][Medline]
  19. Jayasekara D, Aweeka FT, Rodriguez R, et al. Antiviral therapy for HIV patients with renal insufficiency. J Acquir Immune Defic Syndr (1999) 21:384–395.[CrossRef][Web of Science][Medline]
  20. Szczech LA, Hoover DR, Feldman JG, et al. Association between renal disease and outcomes among HIV-infected women receiving or not receiving antiretroviral therapy. Clin Infect Dis (2004) 39:1199.[CrossRef][Web of Science][Medline]
Received for publication: 28. 3.07
Accepted in revised form: 2. 4.07


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