Doxycycline treatment in dialysis related amyloidosis: discrepancy between antalgic effect and inflammation, studied with FDG-positron emission tomography: a case report

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Abstract

Background

No effective treatment is currently available and dialysis related amyloidosis continues to be invalidating in long-term dialysis patients. A recent case series reported reduction of osteoarticular pain on doxycycline treatment, extending the indications of this drug, used in other uncommon forms of amyloidosis, to dialysis patients. Explanations of the antalgic effect were the anti-inflammatory properties and anti-coiling effects of tetracycline.

Case presentation

Our report regards a 54-year-old woman, who was never transplanted and has been on hemodialysis and hemodiafiltration for overall 37 years, due to renal hypoplasia. In spite of high efficiency hemodiafiltration, she complained of increasing, invalidating osteoarticular pain; history and imaging suggested beta-2 microglobulin amyloid. Positron emission tomography (PET scan) identified metabolically active lesions in the involved settings. Low-dose doxycycline (100 mg/day) was started, leading to a considerable decrease in pain (over 6 months, from 7 to 8 to 4–5 on a 0–10 scale). At 6 months, a PET scan showed unmodified or increased uptake in the involved settings.

Conclusions

In summary, the previously described antalgic effect of doxycycline in dialysis related amyloidosis is confirmed in our case, the first studied using PET scan. The pattern at PET can suggests that the antalgic effect is independent from inflammation and points to other factors, such as interaction with fibril geometry or with bone structure.

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Most cited references 32

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Antibodies to human serum amyloid P component eliminate visceral amyloid deposits

Karl Bodin, Stephan Ellmerich, Melvyn C. Kahan … (2010)

Accumulation of amyloid fibrils in the viscera and connective tissues causes systemic amyloidosis, which is responsible for about one per thousand deaths in developed countries1. Localised amyloid can also be very serious, for example cerebral amyloid angiopathy is an important cause of haemorrhagic stroke. The clinical presentations of amyloidosis are extremely diverse and the diagnosis is rarely made before significant organ damage is present1. There is therefore a major unmet medical need for therapy which safely promotes the clearance of established amyloid deposits. Over 20 different amyloid fibril proteins are responsible for different forms of clinically significant amyloidosis and treatments that substantially reduce the abundance of the respective amyloid fibril precursor protein can arrest amyloid accumulation1. Unfortunately control of fibril protein production is not possible in some forms of amyloidosis and in others is often slow and hazardous1. There is no therapy that directly targets amyloid deposits for enhanced clearance. However, all amyloid deposits contain the normal, non-fibrillar, plasma glycoprotein, serum amyloid P component (SAP)2, 3. Here we show that administration of anti-human SAP antibodies to mice with amyloid deposits containing human SAP, triggers a potent, complement dependent, macrophage-derived giant cell reaction which swiftly removes massive visceral amyloid deposits without adverse effects. Anti-SAP antibody treatment is clinically feasible because circulating human SAP can be depleted in patients by the bis-D-proline compound, CPHPC4, thereby enabling injected anti-SAP antibodies to reach residual SAP in the amyloid deposits. The unprecedented capacity of this novel combined therapy to eliminate amyloid deposits should be applicable to all forms of systemic and local amyloidosis.

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Dialysis-related amyloidosis: challenges and solutions

R Scarpioni, Martiniano M Ricardi, V Albertazzi … (2016)

Amyloidosis refers to the extracellular tissue deposition of fibrils composed of low-molecular-weight subunits of a variety of proteins. These deposits may result in a wide range of clinical manifestations depending upon their type, location, and the amount of deposition. Dialysis-related amyloidosis is a serious complication of long-term dialysis therapy and is characterized by the deposition of amyloid fibrils, principally composed of β2 microglobulins (β2M), in the osteoarticular structures and viscera. Most of the β2M is eliminated through glomerular filtration and subsequent reabsorption and catabolism by the proximal tubules. As a consequence, the serum levels of β2M are inversely related to the glomerular filtration rate; therefore, in end-stage renal disease patients, β2M levels increase up to 60-fold. Serum levels of β2M are also elevated in several pathological conditions such as chronic inflammation, liver disease, and above all, in renal dysfunction. Retention of amyloidogenic protein has been attributed to several factors including type of dialysis membrane, prolonged uremic state and/or decreased diuresis, advanced glycation end products, elevated levels of cytokines and dialysate. Dialysis treatment per se has been considered to be an inflammatory stimulus, inducing cytokine production (such as interleukin-1, tumor necrosis factor-α, interleukin-6) and complement activation. The released cytokines are thought to stimulate the synthesis and release of β2M by the macrophages and/or augment the expression of human leukocyte antigens (class I), increasing β2M expression. Residual renal function is probably the best determinant of β2M levels. Therefore, it has to be maintained as long as possible. In this article, we will focus our attention on the etiology of dialysis-related amyloidosis, its prevention, therapy, and future solutions.

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Effect of tetracyclines on the dynamics of formation and destructuration of beta2-microglobulin amyloid fibrils.

Sofia Giorgetti, Riccardo Porcari, Massimo Stefani … (2011)

The discovery of methods suitable for the conversion in vitro of native proteins into amyloid fibrils has shed light on the molecular basis of amyloidosis and has provided fundamental tools for drug discovery. We have studied the capacity of a small library of tetracycline analogues to modulate the formation or destructuration of β2-microglobulin fibrils. The inhibition of fibrillogenesis of the wild type protein was first established in the presence of 20% trifluoroethanol and confirmed under a more physiologic environment including heparin and collagen. The latter conditions were also used to study the highly amyloidogenic variant, P32G. The NMR analysis showed that doxycycline inhibits β2-microglobulin self-association and stabilizes the native-like species through fast exchange interactions involving specific regions of the protein. Cell viability assays demonstrated that the drug abolishes the natural cytotoxic activity of soluble β2-microglobulin, further strengthening a possible in vivo therapeutic exploitation of this drug. Doxycycline can disassemble preformed fibrils, but the IC(50) is 5-fold higher than that necessary for the inhibition of fibrillogenesis. Fibril destructuration is a dynamic and time-dependent process characterized by the early formation of cytotoxic protein aggregates that, in a few hours, convert into non-toxic insoluble material. The efficacy of doxycycline as a drug against dialysis-related amyloidosis would benefit from the ability of the drug to accumulate just in the skeletal system where amyloid is formed. In these tissues, the doxycycline concentration reaches values several folds higher than those resulting in inhibition of amyloidogenesis and amyloid destructuration in vitro.

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Author and article information

Contributors

Giorgina Barbara Piccoli: 0033(0)669733371 , gbpiccoli@yahoo.it

Mammar Hachemi: mhachemi@ch-lemans.fr

Ida Molfino: idamolfino@gmail.com

Jean Philippe Coindre : jpcoindre@ch-lemans.fr

Charles Boursot : cboursot@ch-lemans.fr

Journal

Journal ID (nlm-ta): BMC Nephrol

Journal ID (iso-abbrev): BMC Nephrol

Title: BMC Nephrology

Publisher: BioMed Central (London )

ISSN (Electronic): 1471-2369

Publication date (Electronic): 6 September 2017

Publication date PMC-release: 6 September 2017

Publication date Collection: 2017

Volume: 18

Electronic Location Identifier: 285

Affiliations

[1 ]ISNI 0000 0001 2336 6580, GRID grid.7605.4, Dipartimento di Scienze Cliniche e Biologiche, , Università di Torino, ; Turin, Italy

[2 ]ISNI 0000 0004 1771 4456, GRID grid.418061.a, Nuclear Medicine Centre Hospitalier Le Mans, ; 72000 Le Mans, France

[3 ]ISNI 0000 0004 1771 4456, GRID grid.418061.a, Nephrologie, Centre Hospitalier du Mans, ; 198 Avenue Roubillard, 72000 Le Mans, France

Article

Publisher ID: 698

DOI: 10.1186/s12882-017-0698-z

PMC ID: 5586015

PubMed ID: 28874122

SO-VID: 5f962108-d55e-499e-9d2c-dbb2b5e036be

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 9 March 2017

Date accepted : 23 August 2017

Custom metadata

ScienceOpen disciplines: Nephrology

Keywords: dialysis related amyloidosis,hemodialysis,hemodiafiltration,long-term survival,positron emission tomography,doxycycline

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ScienceOpen disciplines: Nephrology

Keywords: dialysis related amyloidosis, hemodialysis, hemodiafiltration, long-term survival, positron emission tomography, doxycycline

Doxycycline treatment in dialysis related amyloidosis: discrepancy between antalgic effect and inflammation, studied with FDG-positron emission tomography: a case report

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Abstract

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Case presentation

Conclusions

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Karger: Nephrology

Most cited references 32

Antibodies to human serum amyloid P component eliminate visceral amyloid deposits

Dialysis-related amyloidosis: challenges and solutions

Effect of tetracyclines on the dynamics of formation and destructuration of beta2-microglobulin amyloid fibrils.

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