Doxycycline may reduce the incidence of aneurysms in haemodialysis vascular accesses
Charles Diskin,
Thomas J. Stokes,
Linda M. Dansby,
Lautrec Radcliff and
Thomas B. Carter
Auburn University, Hypertension, Nephrology, Dialysis and Transplantation, Opelika, AL, USA
Correspondence and offprint requests to: Charles Diskin, MD, HNDT, Auburn University, Bldg 21, 121 N. 20th Street, Opelika, AL 36801, USA. Email: hndtsiz{at}bellsouth.net
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Abstract
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Background. Doxycycline can prevent aortic aneurysms through the inhibition of enzymes that degrade vessel walls. We investigated whether haemodialysis patients who had received one or more courses of doxycycline were at less risk for aneurysms in their vascular accesses than those who had received other antibiotics.
Methods. Three hundred and eight patients undergoing chronic maintenance hemodialysis were evaluated for aneurysm formation after exposure to doxycycline or another antibiotic. Conditional forward logistical analysis using Cox proportional hazards test (SPSS) was performed to determine the potential significance of differences of aneurysm formation between the two groups.
Results. Patients who had received doxycycline appeared to be at lower risk than the control group, but the effect was most obvious in those patients with synthetic grafts.
Conclusions. Doxycycline may have the ability to reduce aneurysm formation in haemodialysis vascular accesses and a large prospective study is warranted.
Keywords: aneurysms; antibiotics; haemodialysis; medications; vascular access
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Introduction
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Vascular access continues to be the most vexing problem for haemodialysis patients. Thrombosis is the major complication, but the development of aneurysms can also result in loss of vascular access. We previously reported a preliminary observation on the effects of various medications to reduce the incidence of thrombosis [1], the results of which have been confirmed recently by a more comprehensive and statistically robust study [2]. Here, we would like to issue a preliminary report on the potential use of doxycycline to decrease aneurysm formation.
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Subjects and methods
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Three hundred and eight patients undergoing chronic maintenance haemodialysis were interviewed, examined and their medication charts reviewed. One hundred and thirty patients (Table 1) were found to have received some antibiotic prior to the development of any aneurysm on their haemodialysis access. An aneurysm was defined as a circumscribed dilatation, either fusiform or sacular, of a vascular access <12 cm in length and >200% the diameter of the preceding and following segments of the access. The exact time of the development of an aneurysm was not always known. The documentation in the medication chart and the inspection at the time of the study were, at best, rough approximations of an insidious onset. Seventy-six of the accesses were fistulae while 54 were synthetic grafts. Twenty-six patients received one or more (range: 121) courses of doxycycline (DOX) (100 mg a day for 10 days) for treatment of infections, while 104 patients received courses of another antibiotic (controls) during that time period (Table 2). The DOX patients were then compared with the controls for the development of aneurysms. There was no statistical difference in the age of accesses of the groups (DOX: 40±32 months vs controls: 28±30 months). Similarly, although 88% of the patients were of African-American descent, there were no significant differences between the DOX and control groups in terms of patient age, access age, sex, race and the presence of diabetes mellitus. Conditional forward logistical analysis using Cox proportional hazards test (SPSS) was performed to determine the potential significance of differences of aneurysm formation between the two groups.
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Results
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The hazard risk for aneurysm development increased consistently and significantly (P<0.11) with access age (but not patient age) for all accesses and was not statistically different for grafts or fistulae (Figure 1); however, the risk for the DOX group was significantly lower when compared with controls (P<0.013; Figure 2). The protective effect from the risk of aneurysm formation was most pronounced in grafts (P<0.03; Figure 3), but while also present in fistulae it did not reach statistical significance (P<0.10; Figure 4). Sex, race, patient age, presence of diabetes and patient years on haemodialysis were not independently associated with aneurysm formation. No DOX patient suffered any complication related to the medication.
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Discussion
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Previous studies have shown that aneurysmal degeneration of the aorta is associated with chronic inflammation and degeneration of structural matrix proteins within the aorta wall, due to a demonstrated increase in the activity of matrix metalloproteinases (MMPs) [3]. Doxycycline directly inactivates MMPs by combining with their active zinc site and secondarily inhibits MMPs by binding to inactive calcium sites [4,5]. In a study of treatment of abdominal aneurysms in rats, doxycycline effectively inhibited aneurysmal dilation, even without any significant effect on inflammation [6]. Doxycycline is well tolerated and has been shown to decrease aortic aneurysm growth rates in humans [7]. Haemodialysis accesses are constantly being cannulated, resulting in a chronic state of repair that may predispose them to aneurysm formation. Here, we report that the patients who received doxycycline appeared less likely to develop aneurysms in their vascular accesses when compared with patients who had received other antibiotics during that time interval.
While this may be a promising development, caution must be used in interpreting our results. This was a small retrospective study and the documentation of the time of aneurysm formation in relation to the dosing of the doxycycline may have been inexact, despite the dates being recorded in the medical charts and verified by the patients at interview. Aneurysm formation undoubtedly begins long before it is clinically apparent. Furthermore, an aneurysm may have occurred some time before effort was taken to document it in the medical charts and reliance upon patient memory is treacherous. This is a small study and statistical significance is swayed by only a few aneurysms. Furthermore, even within the DOX group many patients received multiple courses of doxycycline while some received only one. If there is an aneurysm protective effect of doxycycline, how many courses are necessary and at what time interval? Since it has been shown that short-term treatment with subantimicrobial doses of doxycycline is sufficient to inhibit MMPs [8,9], it is not unreasonable that intermittent 10-day antibiotic treatment courses, such as were taken by the DOX patients, may have an effect on aneurysm development. However, we have not begun to address those questions nor have we even established a protective effect; that can only be achieved by a large-scale prospective study, similar to those performed in the investigation of aortic wall aneurysms [46]. Since doxycycline also has an effect on preventing smooth muscle migration, proliferation and intimal hypertrophy [10], similar to the ideal drugs that we hypothesized to prevent access thrombosis [11], perhaps doxycycline should also be included in future studies designed to prevent vascular access thrombosis. Although teeth discoloration, nausea and abdominal bloating have been reported as side effects in previous aortic aneurysm studies in non-uraemic patients, we found doxycycline to be well tolerated and appropriate for investigation in haemodialysis patients. We hope that this brief observation will stimulate future studies to investigate its protective effect on vascular accesses.
Conflict of interest statement. None declared.
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References
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Received for publication: 24. 8.04
Accepted in revised form: 22.12.04