NDT Advance Access originally published online on March 1, 2005
Nephrology Dialysis Transplantation 2005 20(5):959-961; doi:10.1093/ndt/gfh694
© The Author [2005]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oupjournals.org
Original Article
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: 1–21) 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 [4–6]. 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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- Diskin CJ, Stokes TJ, Thomas SG et al. An analysis of the effect of routine medications on hemodialysis vascular access survival. Nephron 1998; 78: 365–368[CrossRef][Web of Science][Medline]
- Saran R, Dykstra DM, Wolfe RA, Gillespie B, Held P, Young EW. Association between vascular access failure and the use of specific drugs: the Dialysis Outcomes and Practice Patterns Study (DOPPS). Am J Kidney Dis 2002; 40: 1255–1263[CrossRef][Web of Science][Medline]
- Baxter BT, Pearce WH, Waltke EA et al. Prolonged administration of doxycycline in patients with small asymptomatic abdominal aortic aneurysms: report of a prospective multicenter trial. J Vasc Surg 2002; 36: 1–12[Web of Science][Medline]
- Sorsa T, Ding Y, Salo T et al. Effect of tetracycline on neutrophil, salivary and gingival collagenases. Ann NY Acad Sci 1994; 732: 112–131[Web of Science][Medline]
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- Lee HM, Ciancio SG, Tuter G, Ryan ME, Komaroff E, Golub LM. Subantimicrobial dose doxycycline efficacy as a matrix metalloproteinase inhibitor in chronic periodontitis patients is enhanced when combined with a non-steroidal anti-inflammatory drug. Periodontol 2004; 75: 453–463
- Brown DL, Desai KK, Vakili BA, Nouneh C, Lee HM, Golub LM. Clinical and biochemical results of the metalloproteinase inhibition with subantimicrobial doses of doxycycline to prevent acute coronary syndromes (MIDAS) pilot trial. Arterioscler Thromb Vasc Biol 2004; 24: 733–738[Abstract/Free Full Text]
- Islam MM, Franco CD, Courtman DW, Bendeck MP. A nonantibiotic chemically modified tetracycline (CMT-3) inhibits intimal thickening. Am J Pathol 2003; 163: 1557–1566[Abstract/Free Full Text]
- Diskin CJ, Stokes TJ, Pennell A. Pharmacologic intervention to prevent vascular access thrombosis. Nephron 1993; 64: 1–26[Web of Science][Medline]
Received for publication: 24. 8.04
Accepted in revised form: 22.12.04
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Abstract
Introduction
