NDT Advance Access originally published online on January 23, 2006
Nephrology Dialysis Transplantation 2006 21(4):865-868; doi:10.1093/ndt/gfk039
© The Author [2006]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Editorial Review
Does obesity play a role in the pathogenesis of calcific uraemic arteriolopathy?
David T. Janigan1 and
David J. Hirsch2
1 Departments of Pathology and Laboratory Medicine, Queen Elizabeth II Health Sciences Centre and 2 Dalhousie University School of Medicine, Halifax, Nova Scotia, Canada
Correspondence and offprint requests to: Dr David Hirsch, Dickson 5081, 5820 University Ave, QEII Health Sciences Centre, Halifax, Nova Scotia B3H 1V8, Canada. Email: David.Hirsch{at}cdha.nshealth.ca
Keywords: uraemia; calciphylaxis; obesity
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Introduction
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Calcific uremic arteriolopathy (CUA) [
1] refers to calcification
of the media of small terminal arteries and arterioles and associated
fibrotic intimal thickening and lumen narrowing, thereby increasing
the risk of ischaemic necrosis. As the term suggests, CUA is
reported in patients with chronic kidney disease (CKD) ‘nearly
exclusively’ [
2]. Identical clinical and pathologic features
have developed with hyperphosphataemia from other causes [
3–7].
CUA develops silently [1,5,8], sometime presenting only with subcutaneous plaques and/or nodules. But with ischaemic complications it presents acutely with foci with discoloured skin progressing to necrosis and deep ulcers; hereafter designated complicated CUA. Once mistakenly likened to an allergic reaction by Selye (and therefore inappropriately termed ‘calciphylaxis’ [9]), complicated CUA is uncommon but is recognized increasingly in dialysis patients and renal transplant patients [3,8]. The lesions have appeared in ‘proximal’ body areas – abdominal wall, thighs, flanks, buttocks and breasts – and are generally more devastating than ‘distal’ ones localizing mainly in the lower legs [1,5,9–12]. Both may coexist [5].
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The association of proximal lesions with obesity
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Complicated CUA has been reported in a distinctive subgroup:
at least 69 obese and overweight patients, mostly female, with
proximal lesions [
3–6,
8–34] and, when specified,
corresponding to sites of greatest adiposity [
1,
3,
9–12].
Two case-controlled studies [
10,
13] revealed obesity to be a
significant risk factor (another study [
35] based on different
calculations did not).
Our early clinical-pathological experiences with 10 patients [3,4,6,16,17] suggested excessive adipose tissue accumulations may underlie the selection of proximal sites [5].
Recent experiences with an additional 9 patients (unpublished) fortify this notion, which is now based on (a) 17 females, 14 moderately to morbidly obese and 2 overweight, and 2 males, 1 morbidly obese. All obese and overweight patients had proximal lesions, mostly extensive, and distal lesions, mostly limited. This quantitative distribution was reversed in the two non-obese patients; (b) histologic and X-ray studies of tissue samples from all 19 (numerous biopsies and/or debridements, amputated legs from three and five autopsies). Collectively, these revealed calcification of the subcutaneous septa and arterioles that surround adipose tissue lobules, most evident in sites of greatest adiposity, whether or not ulcerated (Figures 1–3
). There were also sometimes lobules with calcified foci without overlying skin necrosis.
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Fig. 1. Ulcerated area (top, far right) with adjacent intact skin to the left. There is perilobular calcification of septa and arterioles in both ulcerated and non-ulcerated parts. The diffuse opacities on the right represent calcification of infarcted adipose tissue. Small, barely evident calcified foci are to the left.
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Fig. 2. Non-ulcerated specimen with non-infarcted subcutis. The skin (top) is slightly folded over, an artefact. In addition to the perilobular calcifications there are small calcific foci in lobules, upper right (Reprinted from ‘Massive necrosis of fat and skin as complication of obesity' — CMAJ 15-Mar-89; Vol. 140, Page(s) 665–668 by permission of the publisher. © 1989 CMA Media Inc).
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Fig. 3. Non-ulcerated, non-necrotic specimen with skin at top and partially calcified deep fascia at bottom right. There is marked septal calcification outlining elongated, distorted lobules. (The apparent calcification of intact skin at top right is an artefact due to its retraction below the cut surface).
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Relevance of the calcified septal–arteriolar tandem
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Anatomically, under the skin fibro-elastic septa extend from
the deep fascia through the subcutis to the dermis and,
en route,
both divide the subcutaneous adipose tissue into lobules (
Figure 4)
and provide a scaffolding for attached arteries/arterioles that
supply the skin as well as the lobules. Functionally, the septa
anchor the skin to the body, and they resist expansion of the
interposed subcutis by adipose tissue. However, with obesity
both septa and arterioles are under a chronic stretch tension
– we found abdominal pannus thicknesses of 6–14
cm – with a taut overlying skin. On incision, skin edges
and septa quickly retract, the lobules bulge above the cut surfaces
and any edema fluid escapes: a fasciotomy effect. Suspensory
ligaments in the female breast serve a function similar to that
of skin septa in skin, and these and mammary arterioles (and
arteries) were calcified in pendulous breasts from morbidly
obese women [
3,
17].
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Fig. 4. Gross specimen. Skin (top) and subcutaneous adipose tissue from lower abdominal wall from an obese female without CKD and prepared after formaldehyde fixation, showing thickened subcutaneous septa partitioning adipose tissue into lobules (associated arterioles are not evident).
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Injured or disturbed soft tissues are potential targets for
pathologic (dystrophic) calcification through the action of
circulating factors, including factors in uraemic serum [
2].
To explain the increased risk for proximally distributed CUA lesions in the obese, we propose that chronic tension on both subcutaneous septa and companion arterioles imposed by excess adipose tissue localizes the calcifying activity of such serum factors. There is a parallel for this proposed biophysical impact: the well-known predominant distribution of coumarin-induced skin necrosis in sites of greatest adiposity, with or without CKD.
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Subcutaneous plaques and nodules in CUA
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These are among the earliest clinical presentations, and skin
necrosis does not always follow [
8]. The pathologic basis for
plaques and nodules has not, to our knowledge, been established.
More study is needed, but focally intensive septal calcification
(
Figure 3) appears to correlate with some plaques – isolated
calcified microinfarcts in lobules with some nodules.
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Limitations of the hypothesis
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The hypothesis is based on cumulative, observational data without
case-control studies. However, it addresses the specific question
of what determines the predominant proximal distribution of
CUA in the obese. It is true that not all patients with proximal
lesions are obese or overweight, including two in our series
with very limited proximal lesions and extensive distal lesions.
This discrepancy is presently unexplained, but a role for local
edema in the subcutaneous evolution of CUA might fruitfully
be explored: like excess adipose tissue, edema fluid can expand
the subcutis to a considerable extent, as witnessed by ‘pitting’
on pressure.
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Conclusion
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Expansion of the subcutaneous compartment by excess adipose
tissue of obesity exerts a chronic stretch tension on the septa
and associated arterioles. Coexisting edema adds to that burden.
This biophysical effect appears to target both structures for
pathological calcification; a hypothesis that explains the increased
risk of obese patients for the proximal locations of CUA.
Conflict of interest statement. None declared.
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References
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Received for publication: 27. 9.05
Accepted in revised form: 11.12.05
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Introduction
The association of proximal...