NDT Advance Access originally published online on September 5, 2006
Nephrology Dialysis Transplantation 2007 22(2):660-661; doi:10.1093/ndt/gfl554
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Ciprofloxacin-induced ANCA-negative cutaneous and renal vasculitis—resolution with drug withdrawal
Email: leroy.storsley{at}cdha.nshealth.caSir,
A 50-year-old male with a history of hypertension underwent cystoscopy for gross haematuria. A bladder tumour was resected cystoscopically, and subsequently proved to be benign. He presented one week later with fever, delirium and right-sided flank pain. He was admitted with a diagnosis of urosepsis, and treated with ampicillin and gentamicin intravenously. His clinical condition rapidly improved, and was discharged 4 days later on oral ciprofloxacin.
Ten days after discharge, he developed a skin rash on his legs. The rash was an initially red, palpable purpura that progressed to purplish lesions that ultimately ulcerated. He had no other symptoms suggestive of systemic vasculitis.
The patient was started on a tapering dose of oral prednisone for what was felt to represent a cutaneous vasculitis, and his ciprofloxacin was discontinued after 10 days of therapy. His rash improved significantly, with the ulcerative lesions healing over the course of the next 1 month, and the steroids were discontinued.
Approximately 2 months after the course of ciprofloxacin, and as he was tapering off his steroids, he was noted to have worsening of his hypertension (180/110), which was previously well-controlled. A urinalysis showed >3 g/l protein and >50 RBC/hpf. There was 24.1 g of protein in his 24 h collection. Bloodwork included normal electrolytes, urea 14.8 mmol/l, creatinine 205 µmol/l, albumin 33 g/l, haemoglobin 140 g/l and erythrocyte sedimentation rate 66 mm/h. A CT-guided renal biopsy was performed, and he was subsequently referred to nephrology.
He was assessed in nephrology out-patient clinic 
6 months after his course of ciprofloxacin and 4 months after the proteinuria was diagnosed. His only complaint was fatigue. In addition to quinapril 20 mg OD which he had been on for 5 years, his medications now included methyldopa 250 mg BID, furosemide 40 mg OD, metolazone 2 mg OD, and diltiazem 300 mg OD. His blood pressure was 138/78, pulse 96 and weight 133.2 kg. His rash had completely resolved, with numerous depressed scars on his shins from healed ulcerations. He had oedema up to his knees bilaterally, but the rest of his exam was within normal limits.
Further laboratory investigations at this time included normal electrolytes, creatinine 175 µmol/l, haemoglobin 136, negative hepatitis B and C serology, and negative anti-nuclear antibody, anti-neutrophil cytplasmic antibodies (ANCAs) and anti-glomerular basement antibodies. Complement levels had previously been normal. A repeat 24 h urine collection contained 9.25 g/day protein.
His renal biopsy demonstrated glomeruli with diffuse, global proliferation (Figure 1). While necrosis was not seen, there were occasional crescents present (Figure 2). A moderate cellular infiltrate was seen within the interstitium, and red blood cell casts were seen within tubules. Immunofluorescence showed a trace of finely granular positivity for IgM, kappa and lambda, which was interpreted as being non-specific. There were no electron-dense deposits on electron microscopy.
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A diagnosis of ciprofloxacin-induced vasculitis was made based on the time course of his skin rash and renal biopsy findings.
As he had already received 2 months of steroid therapy (albeit prior to the renal biopsy for his cutaneous vasculitis), it was decided to observe him closely and not to pursue further immunosuppression.
Over the course of the next 6 months, his creatinine gradually improved to 105 mmol/l, and his proteinuria decreased to 340 mg/day. His blood pressure also improved, and his methyl-dopa and diltiazem were discontinued.
Discussion
Ciprofloxacin and the related fluoroquinolones are being used with increasing frequency [1], increasing the possibility for clinicians to encounter an increased number of adverse events related to the use of these drugs.
Ciprofloxacin has long been recognized to cause renal dysfunction [2,3], and the majority of reported cases appear to be due to acute interstitial nephritis [4]. More recently, the occurrence of acute renal failure due to ciprofloxacin crystalluria has been confirmed [5]. There is one previous report of two cases of renal vasculitis associated with ciprofloxacin [6]. One case was ANCA positive and had normal glomeruli but evidence of necrotizing arteritis, while the other case was ANCA negative, with segmental glomerular necrosis and fibrinoid changes. Both were treated with cyclophosphamide and prednisone.
Drug-induced vasculitis has been linked to medications from virtually all pharmacological classes, but the anti-thyroid drugs propylthiouracil and methimazole are probably the most widely reported and best described. A comprehensive review comparing patients with anti-thyroid drug-induced vasculitis (n = 16) to those with idiopathic vasculitis (n = 56), found that drug-related disease had a significantly higher rate of skin involvement (62.5 vs 25%), less renal involvement (19 vs 75%), and were less likely to affect the gastrointestinal or central nervous systems [7]. All cases were ANCA positive, with 94% being P-ANCA or anti-myeloperoxidase (MPO) antibody positive. Treatment consisted primarily of removing the offending drug; corticosteroids were prescribed in three cases and cyclophosphamide in three more. In contrast to idiopathic vasculitis, the patients with drug-related disease fared much better, with no lethal outcomes, no relapses and only one case of chronic renal failure.
The pathogenesis of drug-induced vasculitis is uncertain. It has been proposed that the drug or a metabolite may serve as hapten for the induction of anti-MPO antibodies [6]. The ANCA-negative status of our patient would appear to make this unlikely, although the induction of other as yet undetected antibodies cannot be ruled out.
This case adds to the literature that supports an association between ciprofloxacin use and renal vasculitis. In contrast to the previously reported cases of ciprofloxacin-induced vasculitis, our patient improved without cytotoxic therapy, in keeping with the anti-thyroid drug experience. Clinicians should be aware of the potential for a range of renal side effects related to the use of ciprofloxacin, including renal vasculitis.
Conflict of interest statement. None declared.
1Division of Nephrology
2Department of Pathology
Dalhousie University
Halifax
Nova Scotia
Canada
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