NDT Advance Access published online on May 30, 2008
Nephrology Dialysis Transplantation, doi:10.1093/ndt/gfn281
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Correspondence and offprint requests to: E-mail: Clajus.Christian{at}MH-Hannover.DESir,
We would like to thank Dr Hirschberg and colleagues for their interest in our report, which was aimed to raise awareness of the rare but repeatedly described untoward effects of deferoxamine on renal function. Moreover, we aimed to propose a mechanism by which these untoward effects on renal function could be mediated [2]. In the discussion we stated that a different drug, deferasirox, has ‘been repeatedly shown to cause acute renal failure’ quoting a recent paper by Kontoghiorghes [3]. Dr Hirschberg and colleagues, who, as members of the renal safety board for deferasirox, had detailed knowledge of the post-marketing surveillance data, are ‘very sceptical’ that deferasiox was responsible for these cases of acute renal failure.
We can only refer to data available in the public domain. According to the FDA website, there had been 115 reports of suspected adverse drug reactions in the association with the use of deferasirox from 2 November 2005 to 20 June 2006 (http://www.fda.gov/cder/dsn/2007_fall/nme. htm). Sixteen unduplicated reports described renal adverse events. Seven patients improved after discontinuation of deferasirox. Seven patients had ‘acute renal failure’ with an onset between 5 and 58 days after initiation of the therapy. Dr Hirschberg and colleagues state that ‘the term acute renal failure was inappropriately used in many cases to describe a relatively minor increase in serum creatinine (<2x upper limit of normal) that developed over the course of several weeks’. Unfortunately, there had been no uniformly accepted definition of acute renal failure [4]. However, in a variety of settings, there is accumulating evidence that small increments in serum creatinine are associated with adverse outcomes [4]. Therefore, the term acute kidney injury (increase of creatinine >25 µmol/l over 48 h), which is often superimposed on pre-existing CKD, was recently introduced. This definition will increase the clinical awareness and the detection of injury to the kidney and should, in our view, also be used in the setting of pharmacovigilance. Aside from the FDA information, Vichinsky et al. [5] showed in 132 adult and paediatric patients that deferasirox administration was accompanied in a mild and stable increase of serum creatinine in 36.4% of the patients. Of the 63 patients in that study that received deferoxamine, 22.2% experienced such an increase of serum creatinine. In contrast to deferoxamine, where the mean change in creatinine was 3.06 µmol/l, the mean increase in the deferasirox-treated group was 6.3 µmol/l. Unfortunately, serum creatinine only rises after a substantial loss of glomerular filtration rate and is also influenced by many factors like gender, weight and race. Estimation of glomerular filtration rate, e.g. by measuring cystatin C, would therefore be the preferred way to monitor renal function. Data on proteinuria, another important marker of renal damage, are missing completely.
As vividly illustrated by the post-marketing information of Novartis on deferasirox (14 May 2007), a pro-active approach to potential, even rare side effects of new drugs are in the best interest of the public. A uniform assessment of renal function and renal injury, e.g. by determination of estimated GFR and proteinuria, as proposed in a science advisory of the AHA for the assessment of patients with or at increased risk for cardiovascular disease [1], would provide a better scientific basis for the monitoring of untoward renal effects of new drugs.
Conflict of interest statement: Investigator initiated trials by Dr J. T. Kielstein supported by Novartis, Europe.
1 Department of Nephrology 2 Institute of Pathology 3 Institute for Clinical Pharmacology Hannover Medical School Germany
References
- Brosius FCr, Hostetter TH, Kelepouris E, et al. Detection of chronic kidney disease in patients with or at increased risk of cardiovascular disease: a science advisory from the American Heart Association Kidney and Cardiovascular Disease Council; the Councils on High Blood Pressure Research, Cardiovascular Disease in the Young, and Epidemiology and Prevention; and the Quality of Care and Outcomes Research Interdisciplinary Working Group: developed in collaboration with the National Kidney Foundation. Circulation (2006) 114:1083–1087.
[Abstract/Free Full Text] - Clajus C, Becker JU, Stichtenoth DO, et al. Acute kidney injury due to deferoxamine in a renal transplant patient. Nephrol Dial Transplant (2008) 23:1061–1064.
[Free Full Text] - Kontoghiorghes GJ. Deferasirox: uncertain future following renal failure fatalities, agranulocytosis and other toxicities. Expert Opin Drug Saf (2007) 6:235–239.[CrossRef][Web of Science][Medline]
- Mehta RL, Kellum JA, Shah SV, et al. Acute Kidney Injury Network: report of an initiative to improve outcomes in acute kidney injury. Crit Care (2007) 11:R31.[CrossRef][Medline]
- Vichinsky E, Onyekwere O, Porter J, et al. A randomised comparison of deferasirox versus deferoxamine for the treatment of transfusional iron overload in sickle cell disease. Br J Haematol (2007) 136:501–508.[CrossRef][Web of Science][Medline]
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