Medical education
Lessons from practice
Volume 209 - Issue 10
Acute kidney injury in an older patient
Authors: Luke Vlismas, Hannah Coleman, Tom N Lea-Henry and Bobby Chacko
Med J Aust 2018; 209 (10): 434-435. || doi: 10.5694/mja18.00045
Published online: 19 November 2018
Published online: 19 November 2018
Clinicians should be mindful about the potential renal effects of cefepime
Clinical record
A 77-year-old man was admitted for investigation of an acute kidney injury after 5 weeks of intravenous cefepime treatment for malignant otitis externa with temporal bone osteomyelitis. He had a history of hypertension, gout and dyslipidaemia, which had been well controlled for several years with stable doses of hydrochlorothiazide 12.5 mg daily, candesartan 16 mg daily, allopurinol 300 mg daily and atorvastatin 40 mg daily. He had no known previous adverse drug reactions.
Cefepime was initiated at a dose of 6 g daily by continuous intravenous infusion with a plan to complete a total of 6 weeks of therapy. The serum creatinine level remained stable between 79 and 93 μmol/L until 5 weeks into treatment, when it suddenly rose to 270 μmol/L (reference interval, 60–110 μmol/L) (Box 1). The patient had been otherwise asymptomatic, with no episodes of intercurrent illness, diarrhoea, vomiting or medication change. He had remained haemodynamically stable and reported no recent non-steroidal anti-inflammatory drug (NSAID) exposure.
Following admission, hydrochlorothiazide, candesartan and allopurinol were withheld; intravenous cefepime was changed to a renally adjusted dose of oral ciprofloxacin 500 mg daily. He was non-oliguric and euvolaemic, and had no fever, rash or arthralgia. Renal tract ultrasound was unremarkable. Urine microscopy showed no eosinophiluria, sterile pyuria or significant albuminuria. Renal tubular injury was supported by a markedly elevated urinary α1-microglobulin concentration of 258 mg/L (reference interval, < 12 mg/L). Despite cessation of diuretics and candesartan and intravenous hydration, the patient’s renal function continued to deteriorate (Box 1).
Given the rapidly progressive renal impairment and excellent control of the malignant otitis externa, high dose corticosteroids were initiated (prednisolone 100 mg daily), with a presumptive diagnosis of cefepime-induced acute interstitial nephritis (AIN). Allopurinol is also associated with AIN, but as the latency period between drug initiation and onset of renal dysfunction is typically less than 2 months for drug-induced AIN, this was considered unlikely. A renal biopsy performed after 3 days of prednisolone therapy was consistent with partially treated AIN (Box 2).
The patient was discharged on a tapering course of prednisolone (over 3 weeks) and oral ciprofloxacin for a further 3 weeks. At follow-up 3 weeks later, his renal function had normalised with a serum creatinine level of 66 μmol/L. His usual medication regimen was reinitiated without recurrence of the kidney injury.
A local shortage of piperacillin–tazobactam in Australia1 has resulted in an increase (Hunter New England Health District antimicrobial usage data) in the use of cefepime, a broad spectrum fourth-generation cephalosporin that is generally well tolerated and considered renal friendly.2
AIN is a common cause of acute kidney injury; with drug-induced AIN accounting for many of these cases, particularly in older adults, although the true incidence may be underestimated. Antibiotics, NSAIDs and proton pump inhibitors are the most common offending medications.3
In patients with drug-induced AIN, the mean delay between commencing the offending drug and the appearance of renal manifestations is 10 days, although the latent period may be as short as one day after some antibiotics or as long as several months with NSAIDs.4 Acute kidney injury from AIN can be asymptomatic or accompanied by clinical or laboratory findings (Box 3) that, when present, are useful for the clinical diagnosis. Sterile pyuria is a reliable clue, but eosinophiluria is no longer considered a useful diagnostic test.4 Renal biopsy is still needed to confirm diagnosis.
Early recognition of AIN is therefore reliant on clinicians considering the diagnosis when managing patients with acute kidney injury. The absence of a clear precipitating factor for the development of acute tubular necrosis (ischaemic or nephrotoxic), paucity of hypersensitivity manifestations and normal urinary sediment are important features to distinguish acute tubular necrosis from AIN. However, the frequently seen oligosymptomatic presentation of AIN confounds this clinical judgement, placing the onus on a renal biopsy to establish accurate diagnosis. This is important, as there are significant differences in their therapeutic approach.
Identification and removal of the offending drug is the mainstay of the treatment, but recent studies strongly suggest that early steroid administration (within 7 days after diagnosis) improves the recovery of renal function, decreasing the risk of chronic renal impairment from interstitial fibrosis.4 Oral prednisone (0.5–1 mg/kg/day) tapering off over 4–6 weeks is the accepted practice.4
Diagnosis is typically secured by early kidney biopsy before the initiation of therapy. In this case, however, renal biopsy occurred following initiation of treatment because of initial issues with access to biopsy over a weekend, and strong clinical suspicion. Empirical therapy with nephrologist supervision is reasonable in the elderly, the frail and those in whom renal biopsy would be deemed unsafe.
Drug-induced AIN is thought to result from hapten formation and the development of antigen-initiated, cell-mediated immune response (idiosyncratic delayed hypersensitivity reaction to a foreign antigen).5
In this case, as in the two other reported cases of cefepime-induced AIN,6,7 there was an absence of accompanying clinical features with bland urine sediments. Therefore, not only is a renal biopsy crucial to confirm the diagnosis8 but clinicians must hold a high index of suspicion for this side effect when using cefepime.
This case serves as a reminder for clinicians about the potential renal effects of this drug and mandates monitoring renal function regularly during prolonged courses.Lessons from practice
Acute kidney injury may occur with drugs considered to be safe, such as cefepime.
Acute kidney injury from AIN induced by cefepime may present in the absence of clinical features and with a bland urinary sediment.
Unexplained acute kidney injury warrants investigation with renal biopsy.
The mainstay of managing AIN is the removal of the offending drug and the early initiation of corticosteroid therapy. This approach improves time to recovery and overall renal outcome, although it has not been tested by randomised controlled trials.
Box 2 – Renal biopsy showing acute tubular injury (black arrow) accompanied by interstitial oedema (red arrow), and patchy mixed interstitial inflammatory infiltrate (green arrow) (haematoxylin–eosin stain, original magnification × 40)
Box 3 – Clinical and laboratory features at presentation in patients with drug-induced acute interstitial nephritis4
Clinical or laboratory feature |
Proportion |
||||||||||||||
Acute renal failure |
100% |
||||||||||||||
Acute renal failure requiring dialysis |
40% |
||||||||||||||
Arthralgia |
45% |
||||||||||||||
Fever |
36% |
||||||||||||||
Skin rash |
22% |
||||||||||||||
Eosinophilia (> 500 eosinophils/mm3) |
35% |
||||||||||||||
Microhaematuria |
67% |
||||||||||||||
Gross haematuria |
5% |
||||||||||||||
Leukocyturia |
82% |
||||||||||||||
Non-nephrotic proteinuria |
93% |
||||||||||||||
Competing interests
No relevant disclosures.
References
- Therapeutic Goods Administration. Piperacillin sodium – medicine shortage information. http://apps.tga.gov.au/Prod/msi/Search/Details/piperacillin-sodium (viewed Sept 2018).
- Rutter WC, Cox JN, Martin CA, et al. Nephrotoxicity during vancomycin therapy in combination with piperacillin–tazobactam or cefepime. Antimicrob Agents Chemother 2017; 61: 1-9.
- Muriithi AK, Leung N, Valeri AM, et al. Biopsy-proven acute interstitial nephritis, 1993–2011: a case series. Am J Kidney Dis 2014; 64: 558-566.
- Praga M, Gonzalez E. Acute interstitial nephritis. Kidney Int 2010; 77: 956-961.
- Raghavan R, Eknoyan G. Acute interstitial nephritis – a reappraisal and update. Clin Nephrol 2014; 82: 149-162.
- Mac K, Chavada R, Paull S, Howlin K, Wong J. Cefepime induced acute interstitial nephritis – a case report. BMC Nephrol 2015; 16: 15.
- Alzubaidi M SS, Velez JC. Acute interstitial nephritis with cast formation associated with exposure to cefepime [abstract]. Am J Kidney Dis 2016; 67: A1-A118.
- Perazella MA. Diagnosing drug-induced AIN in the hospitalized patient: a challenge for the clinician. Clin Nephrol 2014; 81: 381-388.
Provenance: Not commissioned; externally peer reviewed.