Sara Muhammad, Ellen D McPhail, W Oliver Tobin, Surendra Dasari, Jason Theis, Julie A Vrana, Elie Naddaf
{"title":"A second case of liraglutide-type localised amyloidosis.","authors":"Sara Muhammad, Ellen D McPhail, W Oliver Tobin, Surendra Dasari, Jason Theis, Julie A Vrana, Elie Naddaf","doi":"10.1080/13506129.2022.2151889","DOIUrl":"https://doi.org/10.1080/13506129.2022.2151889","url":null,"abstract":"Amyloidosis is characterised by extracellular deposition of proteinaceous fibrils, disrupting tissue structure and function. There are at least 36 different types of amyloid, and correct identification of the specific amyloid precursor protein is of paramount importance, as therapy varies dramatically depending on the amyloid type. The most common amyloid types encountered in peripheral nerves are AL (immunoglobulin light chain) and ATTR (transthyretin) [1]. Iatrogenic amyloidosis is a form of localised amyloidosis, caused by the repetitive injection of protein medications, such as insulin [2]. A 78-year-old male, with a history of well-controlled diabetes mellitus, presented with a 30-year history of bilateral foot soreness and numbness. Six months prior to the presentation, he developed intermittent burning and a hot/cold sensation in his feet which spontaneously improved. He also reported a 15-year history of nonradiating low back pain. He had no weakness, weight loss, orthostatic light-headedness, or bowel or bladder dysfunction. Other family members have reported similar sensory symptoms. Neurological examination was remarkable for decreased pinprick sensation from the mid-shin down to the toes, and mildly decreased hot temperature sensation in the right foot. Reflexes were decreased at the right patella, absent at the left patella and bilateral ankles. Motor and gait examination were normal. Nerve conduction studies/electromyography demonstrated mild bilateral old or chronic L5 radiculopathies with no evidence of ongoing denervation, and no evidence of a large fibre peripheral neuropathy. Thermoregulatory sweat test showed no evidence of a small fibre neuropathy either. However, serologic evaluation, performed to screen for potential peripheral neuropathy causes prior to our evaluation, showed a triclonal gammopathy of uncertain significance (IgG j, IgG k and IgA j). Congo red stain performed on an abdominal fat aspirate was positive for amyloid (Figure 1), raising the possibility of systemic amyloidosis. The patient had TTR sequencing which revealed no mutation. Upon questioning about insulin injections, known to cause focal amyloid deposits, the patient acknowledged using liraglutide 0.6mg subcutaneously once daily. Typing of the amyloid deposit by mass spectrometry-based proteomics (liquid chromatography with tandem mass spectrometry; LC-MS-MS) using previously published methods confirmed the presence of liraglutide-type amyloid deposit (Figure 1) [3]. Immunohistochemical studies were not performed because the specimen was a fat aspirate and hence, paraffin-embedded samples were not available. Liraglutide is an acylated glucagon-like peptide-1 analogue that is administered as a subcutaneous injection for the treatment of type 2 diabetes mellitus. To date, a single case of liraglutide-type amyloidosis has been reported [4]. Liraglutide should be considered as a potential amyloidogenic agent. Our case highlights the importance of","PeriodicalId":50964,"journal":{"name":"Amyloid-Journal of Protein Folding Disorders","volume":null,"pages":null},"PeriodicalIF":5.5,"publicationDate":"2023-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9786739","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
David A Tess, Tristan S Maurer, Zhenhong Li, Christine Bulawa, James Fleming, Amy T Moody
{"title":"Relationship of binding-site occupancy, transthyretin stabilisation and disease modification in patients with tafamidis-treated transthyretin amyloid cardiomyopathy.","authors":"David A Tess, Tristan S Maurer, Zhenhong Li, Christine Bulawa, James Fleming, Amy T Moody","doi":"10.1080/13506129.2022.2145876","DOIUrl":"https://doi.org/10.1080/13506129.2022.2145876","url":null,"abstract":"<p><strong>Background: </strong>Tafamidis inhibits progression of transthyretin (TTR) amyloid cardiomyopathy (ATTR-CM) by binding TTR tetramer and inhibiting dissociation to monomers capable of denaturation and deposition in cardiac tissue. While the phase 3 ATTR-ACT trial demonstrated the efficacy of tafamidis, the degree to which the approved dose captures the full potential of the mechanism has yet to be assessed.</p><p><strong>Methods: </strong>We developed a model of dynamic TTR concentrations in plasma to relate TTR occupancy by tafamidis to TTR stabilisation. We then developed population pharmacokinetic-pharmacodynamic models to characterise the relationship between stabilisation and measures of disease progression.</p><p><strong>Results: </strong>Modelling individual patient data of tafamidis exposure and increased plasma TTR confirmed that single-site binding provides complete tetramer stabilisation <i>in vivo</i>. The approved dose was estimated to reduce unbound TTR tetramer by 92%, and was associated with 53%, 56% and 49% decreases in the rate of change in NT-proBNP, KCCQ-OS, and six-minute walk test disease progression measures, respectively. Simulating complete TTR stabilisation predicted slightly greater reductions of 58%, 61% and 54%, respectively.</p><p><strong>Conclusions: </strong>These findings support the value of TTR stabilisation as a clinically beneficial treatment option in ATTR-CM and the ability of tafamidis to realise nearly the full therapeutic benefit of this mechanism.</p><p><strong>Clinicaltrials.gov identifier: </strong>NCT01994889.</p>","PeriodicalId":50964,"journal":{"name":"Amyloid-Journal of Protein Folding Disorders","volume":null,"pages":null},"PeriodicalIF":5.5,"publicationDate":"2023-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10161693","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Felix J Tsai, Luke T Nelson, Gabriel M Kline, Marcus Jäger, John L Berk, Yoshiki Sekijima, Evan T Powers, Jeffery W Kelly
{"title":"Characterising diflunisal as a transthyretin kinetic stabilizer at relevant concentrations in human plasma using subunit exchange.","authors":"Felix J Tsai, Luke T Nelson, Gabriel M Kline, Marcus Jäger, John L Berk, Yoshiki Sekijima, Evan T Powers, Jeffery W Kelly","doi":"10.1080/13506129.2022.2148094","DOIUrl":"10.1080/13506129.2022.2148094","url":null,"abstract":"<p><p>Transthyretin (TTR) dissociation is the rate limiting step for both aggregation and subunit exchange. Kinetic stabilisers, small molecules that bind to the native tetrameric structure of TTR, slow TTR dissociation and inhibit aggregation. One such stabiliser is the non-steroidal anti-inflammatory drug (NSAID), diflunisal, which has been repurposed to treat TTR polyneuropathy. Previously, we compared the efficacy of diflunisal, tafamidis, tolcapone, and AG10 as kinetic stabilisers for transthyretin. However, we could not meaningfully compare diflunisal because we were unsure of its plasma concentration after long-term oral dosing. Herein, we report the diflunisal plasma concentrations measured by extraction, reversed phase HPLC separation, and fluorescence detection after long-term 250 mg BID oral dosing in two groups: a placebo-controlled diflunisal clinical trial group and an open-label Japanese polyneuropathy treatment cohort. The measured mean diflunisal plasma concentration from both groups was 282.2 <math><mi>μ</mi></math>M <math><mo>±</mo><mi> </mi></math>143.7 <math><mi>μ</mi></math>M (mean <math><mo>±</mo></math> standard deviation). Thus, quantification of TTR kinetic stabilisation using subunit exchange was carried out at 100, 200, 300, and 400 <math><mtext>μM diflunisal</mtext></math> concentrations, all observed in patients after 250 mg BID oral dosing. A 250 <math><mi>μ</mi></math>M diflunisal plasma concentration reduced the wild-type TTR dissociation rate in plasma by 95%, which is sufficient to stop transthyretin aggregation, consistent with the clinical efficacy of diflunisal for ameliorating transthyretin polyneuropathy.</p>","PeriodicalId":50964,"journal":{"name":"Amyloid-Journal of Protein Folding Disorders","volume":null,"pages":null},"PeriodicalIF":5.5,"publicationDate":"2023-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10225472/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10144286","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Angela Dispenzieri, Jeffrey Zonder, James Hoffman, Sandra W Wong, Michaela Liedtke, Rafat Abonour, Anita D'Souza, Charlene Lee, Sarah Cote, Ravi Potluri, Eric Ammann, NamPhuong Tran, Annette Lam, Sandhya Nair
{"title":"Real-world treatment patterns, costs, and outcomes in patients with AL amyloidosis: analysis of the Optum EHR and commercial claims databases.","authors":"Angela Dispenzieri, Jeffrey Zonder, James Hoffman, Sandra W Wong, Michaela Liedtke, Rafat Abonour, Anita D'Souza, Charlene Lee, Sarah Cote, Ravi Potluri, Eric Ammann, NamPhuong Tran, Annette Lam, Sandhya Nair","doi":"10.1080/13506129.2022.2137400","DOIUrl":"https://doi.org/10.1080/13506129.2022.2137400","url":null,"abstract":"<p><strong>Background: </strong>This study characterised real-world treatment patterns, clinical outcomes, and cost-of-illness in patients with light-chain (AL) amyloidosis.</p><p><strong>Methods: </strong>Data were extracted from the US-based Optum® EHR and Clinformatics® Data Mart (claims) databases (2008-2019) for patients newly diagnosed with AL amyloidosis and who initiated anti-plasma cell therapies. Healthcare resource utilisation (HCRU) and related costs were compared across lines of therapy (LOT). Incidences of cardiac and renal failure were evaluated using the Kaplan-Meier method.</p><p><strong>Results: </strong>About 1347 patients (EHR, <i>n</i> = 776; claims, <i>n</i> = 571) were included. Median age was 68 years; 56.8% were male. At initial diagnosis, 33.1% and 15.1% of patients had cardiac and renal failure, respectively. Most patients received bortezomib-containing treatment in LOT1 (69%); bortezomib-cyclophosphamide-dexamethasone was most common (26%). HCRU was similar across LOTs. Mean per-patient-per-month and per-patient-per-LOT costs were $19,343 and $105,944 for LOT1, $19,183 and $95,793 for LOT2, and $16,611 and $128,446 for LOT3, respectively. Costs were primarily driven by anti-plasma cell therapies, outpatient visits, and hospitalisations. The 5-year cardiac and renal failure rates following initial diagnosis were 64.5% and 39.0%, respectively.</p><p><strong>Conclusion: </strong>AL amyloidosis is associated with substantial costs and suboptimal outcomes, highlighting the need for new therapeutic approaches to prevent organ deterioration, and reduce disease burden.</p>","PeriodicalId":50964,"journal":{"name":"Amyloid-Journal of Protein Folding Disorders","volume":null,"pages":null},"PeriodicalIF":5.5,"publicationDate":"2023-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9785346","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Isabel Conceição, Isabel de Castro, Andrés Diaz, José Castro
{"title":"Quantitative sensory testing: a good tool to identify subclinical neuropathy in ATTRV30M amyloidosis patients?","authors":"Isabel Conceição, Isabel de Castro, Andrés Diaz, José Castro","doi":"10.1080/13506129.2022.2155132","DOIUrl":"https://doi.org/10.1080/13506129.2022.2155132","url":null,"abstract":"<p><strong>Background: </strong>Quantitative sensory testing (QST) has been one of the neurophysiological tools used for follow-up and disease progression assessment in ATTRv amyloidosis. We aimed to detect the utility of QST in identifying subclinical neuropathic involvement in ATTRV30M amyloidosis carriers.</p><p><strong>Methods: </strong>A cohort of ATTRV30M amyloidosis carriers were assessed with vibratory (VDT) and cooling (CDT) detection thresholds and heat pain responses. Subjects were divided into asymptomatic carriers (Group 1), paucisymptomatic carriers (Group 2) and stage 1 ATTRv-PN patients (Group 3). Nonparametric statistics were used for group comparisons.</p><p><strong>Results: </strong>A total of 207 ATTRV30M amyloidosis carriers (83 males) were included. Of these, 113 subjects were asymptomatic and 94 symptomatic carriers. In asymptomatic carriers, CDT and Heat Pain (HP 5.0 and HP 0.5) were significantly lower when compared to both group of symptomatic carriers (<i>p</i> ≤ 0.005). In Group 3, VDT, CDT and HP 5.0 were significantly higher, when compared to Group 2 (<i>p</i> < 0.05).</p><p><strong>Conclusions: </strong>QST, in particular CDT, HP 5 and HP 0.5 modalities, seems a good tool to identify subclinical neuropathy in ATTRv amyloidosis carriers, with CDT showing a higher sensitivity to detect and early neuropathic involvement.</p>","PeriodicalId":50964,"journal":{"name":"Amyloid-Journal of Protein Folding Disorders","volume":null,"pages":null},"PeriodicalIF":5.5,"publicationDate":"2023-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9787207","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Tatiana Prokaeva, Elena S Klimtchuk, Polina Feschenko, Brian Spencer, Haili Cui, Eric J Burks, Roshanak Aslebagh, Khaja Muneeruddin, Scott A Shaffer, Elizabeth Varghese, John L Berk, Lawreen H Connors
{"title":"An additive destabilising effect of compound T60I and V122I substitutions in ATTRv amyloidosis.","authors":"Tatiana Prokaeva, Elena S Klimtchuk, Polina Feschenko, Brian Spencer, Haili Cui, Eric J Burks, Roshanak Aslebagh, Khaja Muneeruddin, Scott A Shaffer, Elizabeth Varghese, John L Berk, Lawreen H Connors","doi":"10.1080/13506129.2022.2135988","DOIUrl":"https://doi.org/10.1080/13506129.2022.2135988","url":null,"abstract":"<p><strong>Background: </strong>The amyloidogenic transthyretin (TTR) variant, V122I, occurs in 4% of the African American population and frequently presents as a restricted cardiomyopathy. While heterozygosity for TTR V122I predominates, several compound heterozygous cases have been previously described. Herein, we detail features of ATTRv amyloidosis associated with novel compound heterozygous TTR mutation, T60I/V122I and provide evidence supporting the amyloidogenecity of T60I.</p><p><strong>Methods: </strong>A 63-year-old African American female presented with atrial fibrillation, congestive heart failure, autonomic and peripheral neuropathy. <i>In vitro</i> studies of TTR T60I and V122I were undertaken to compare the biophysical properties of the proteins.</p><p><strong>Results: </strong>Congophilic deposits in a rectal biopsy were immunohistochemically positive for TTR. Serum screening by isoelectric focussing revealed two TTR variants in the absence of wild-type protein. DNA sequencing identified compound heterozygous <i>TTR</i> gene mutations, c.239C > T and c.424G > A. Adipose amyloid deposits were composed of both T60I and V122I. While kinetic stabilities of T60I and V122I variants were similar, distinct thermodynamic stabilities and amyloid growth kinetics were observed.</p><p><strong>Conclusions: </strong>This report provides clinical and experimental results supporting the amyloidogenic nature of a novel TTR T60I variant. <i>In vitro</i> data indicate that the destabilising effect of individual T60I and V122I variants appears to be additive rather than synergistic.</p>","PeriodicalId":50964,"journal":{"name":"Amyloid-Journal of Protein Folding Disorders","volume":null,"pages":null},"PeriodicalIF":5.5,"publicationDate":"2023-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10161660","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Meng Jiang, Mengdie Wang, Zhengyu Tao, Yezi Chai, Qiming Liu, Qifan Lu, Qizhen Wu, Xiaoying Ying, Yanan Huang, Ying Nie, Yuqi Tang, Xin Zhang, Yu Liu, Jun Pu
{"title":"Biochemical and biophysical properties of an unreported T96R mutation causing transthyretin cardiac amyloidosis.","authors":"Meng Jiang, Mengdie Wang, Zhengyu Tao, Yezi Chai, Qiming Liu, Qifan Lu, Qizhen Wu, Xiaoying Ying, Yanan Huang, Ying Nie, Yuqi Tang, Xin Zhang, Yu Liu, Jun Pu","doi":"10.1080/13506129.2022.2142109","DOIUrl":"https://doi.org/10.1080/13506129.2022.2142109","url":null,"abstract":"<p><strong>Objectives: </strong>We presented an unreported T96R mutation induced transthyretin cardiac amyloidosis (ATTR). The biochemical and biophysical properties were explored to support its pathogenicity.</p><p><strong>Background: </strong>Understanding the biochemical and biophysical nature of genetically mutated transthyretin (TTR) proteins is key to provide precise medical cares for ATTR patients.</p><p><strong>Results: </strong>Genetic testing showed heterozygosity for the T96R pathogenic variant c.347C > G (ATTR <i>p.T116R</i>) after myocardial biopsy confirmed amyloid deposition. Biochemical characterizations revealed slight perturbation of its thermodynamic stability (C<sub>m</sub>=3.7 M for T96R, 3.4 M for WT and 2.3 M for L55P (commonly studied TTR mutant)) and kinetic stability (t<sub>1/2</sub>=39.8 h for T96R, 42 h for WT and 4.4 h in L55P). Crosslinking experiment demonstrated heterozygous subunit exchange between wild-type and TTR T96R protein destabilized the tetramer. Inhibitory effect of tafamidis and diflunisal on TTR T96R fibril formation was slightly less effective compared to WT and L55P.</p><p><strong>Conclusions: </strong>A novel T96R mutation was identified for TTR protein. Biochemical and biophysical analyses revealed slightly destabilized kinetic stability. T96R mutation destabilized heterozygous protein but not proteolytic degradation, explaining its pathogenicity. Inhibitory effect of small molecule drugs on T96R mutation was different, suggesting personalized treatment may be required.</p>","PeriodicalId":50964,"journal":{"name":"Amyloid-Journal of Protein Folding Disorders","volume":null,"pages":null},"PeriodicalIF":5.5,"publicationDate":"2023-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9786688","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Eric E Abrahamson, Robert F Padera, Julie Davies, Gill Farrar, Victor L Villemagne, Sharmila Dorbala, Milos D Ikonomovic
{"title":"The flutemetamol analogue cyano-flutemetamol detects myocardial AL and ATTR amyloid deposits: a post-mortem histofluorescence analysis.","authors":"Eric E Abrahamson, Robert F Padera, Julie Davies, Gill Farrar, Victor L Villemagne, Sharmila Dorbala, Milos D Ikonomovic","doi":"10.1080/13506129.2022.2141623","DOIUrl":"10.1080/13506129.2022.2141623","url":null,"abstract":"<p><strong>Background: </strong>[<sup>18</sup>F]flutemetamol is a PET radioligand used to image brain amyloid, but its detection of myocardial amyloid is not well-characterized. This histological study characterized binding of fluorescently labeled flutemetamol (cyano-flutemetamol) to amyloid deposits in myocardium.</p><p><strong>Methods: </strong>Myocardial tissue was obtained post-mortem from 29 subjects with cardiac amyloidosis including transthyretin wild-type (ATTRwt), hereditary/variant transthyretin (ATTRv) and immunoglobulin light-chain (AL) types, and from 10 cardiac amyloid-free controls. Most subjects had antemortem electrocardiography, echocardiography, SPECT and cardiac MRI. Cyano-flutemetamol labeling patterns and integrated density values were evaluated relative to fluorescent derivatives of Congo red (X-34) and Pittsburgh compound-B (cyano-PiB).</p><p><strong>Results: </strong>Cyano-flutemetamol labeling was not detectable in control subjects. In subjects with cardiac amyloidosis, cyano-flutemetamol labeling matched X-34- and cyano-PiB-labeled, and transthyretin- or lambda light chain-immunoreactive, amyloid deposits and was prevented by formic acid pre-treatment of myocardial sections. Cyano-flutemetamol mean fluorescence intensity, when adjusted for X-34 signal, was higher in the ATTRwt than the AL group. Cyano-flutemetamol integrated density correlated strongly with echocardiography measures of ventricular septal thickness and posterior wall thickness, and with heart mass.</p><p><strong>Conclusion: </strong>The high selectivity of cyano-flutemetamol binding to myocardial amyloid supports the diagnostic utility of [<sup>18</sup>F]flutemetamol PET imaging in patients with ATTR and AL types of cardiac amyloidosis.</p>","PeriodicalId":50964,"journal":{"name":"Amyloid-Journal of Protein Folding Disorders","volume":null,"pages":null},"PeriodicalIF":5.5,"publicationDate":"2023-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10199962/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9788814","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Julien Dang, Lauriane Segaux, Anissa Moktefi, Thomas Stehlé, Mounira Kharoubi, Khalil El Karoui, Philippe Rémy, Philippe Grimbert, Violaine Plante-Bordeneuve, Soulef Guendouz, Arnault Galat, Sophie Mallet, Silvia Oghina, Gagan Deep Singh Chadha, Amira Zaroui, Pascale Fanen, Florence Canoui-Poitrine, Thibaud Damy, Vincent Audard
{"title":"Natural course and determinants of short-term kidney function decline in hereditary transthyretin amyloidosis: a French observational study.","authors":"Julien Dang, Lauriane Segaux, Anissa Moktefi, Thomas Stehlé, Mounira Kharoubi, Khalil El Karoui, Philippe Rémy, Philippe Grimbert, Violaine Plante-Bordeneuve, Soulef Guendouz, Arnault Galat, Sophie Mallet, Silvia Oghina, Gagan Deep Singh Chadha, Amira Zaroui, Pascale Fanen, Florence Canoui-Poitrine, Thibaud Damy, Vincent Audard","doi":"10.1080/13506129.2022.2098011","DOIUrl":"https://doi.org/10.1080/13506129.2022.2098011","url":null,"abstract":"<p><p>Data regarding renal involvement in patients with hereditary transthyretin (ATTRv) amyloidosis are scarce and the natural course of chronic kidney disease (CKD) in this population remains unclear. This observational study, including adult patients diagnosed with ATTRv amyloidosis at the French Reference Centre for Cardiac Amyloidosis, investigated renal function outcome and its determinants. Multivariable logistic regression models identified factors associated with CKD at baseline. Determinants of the change in estimated glomerular filtration rate (eGFR) over 24 months of follow-up were assessed with a multivariable linear mixed-effects model. In total, 232 patients (78 women [34%], mean age: 64 years) with ATTRv amyloidosis were classified on the basis of their <i>TTR</i> variants: ATTRV122I (37%), ATTRV30M (29%), and other variants (34%). Median baseline eGFR was 78 ml/min/1.73 m<sup>2</sup>. Seventy-two patients (31%) had an eGFR below 60 ml/min/1.73m<sup>2</sup> and 27/137 patients (20%) had significant proteinuria (urine protein/creatinine ratio ≥30 mg/mmol). Renal biopsy, performed in four cases, found typical Congo red-positive and TTR-labelled amyloid deposits in all cases. Older age (OR 1.07, <i>p</i> < .001) and a prior history of hypertension (OR 2.09, <i>p</i> = .04) were associated with a higher prevalence of CKD at baseline, whereas higher left ventricular global longitudinal strain (LVGLS) (OR 0.83, <i>p</i> < .001) was associated with a lower prevalence. The estimated change in eGFR was -7.12 [-9.61, -4.63] and -8.21 [-10.81, -5.60] ml/min/1.73 m<sup>2</sup> after 12 and 24 months of follow-up, respectively. eGFR decline was independently associated with older age ((67-74], coefficient= -14.35 mL/min/1.73 m<sup>2</sup>, <i>p</i> < .01, >74, coefficient = -22.93 mL/min/1.73 m<sup>2</sup>, <i>p</i> < .001, versus <56), ATTRV122I (coefficient = -17.17 mL/min/1.73m<sup>2</sup>, <i>p</i> < .01, versus ATTRV30M) and LVGLS (coefficient = 1.22, <i>p</i> < .01). These data suggest that CKD is a common finding in patients with ATTRv amyloidosis, and that eGFR decline is rapid during the first year of evaluation. Older age, lower LVGLS and ATTRV122I were associated with a worse renal outcome. Further studies are now needed to evaluate effects of new targeted therapies on long term renal function.</p>","PeriodicalId":50964,"journal":{"name":"Amyloid-Journal of Protein Folding Disorders","volume":null,"pages":null},"PeriodicalIF":5.5,"publicationDate":"2023-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10826023","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Reduction of cardiac AL amyloid deposition after complete response visualised by PiB-PET imaging.","authors":"Kazuhiro Oguchi, Nagaaki Katoh, Yusuke Mochizuki, Yusuke Takahashi, Akihiro Ueno, Ken Takasone, Yoshiki Sekijima","doi":"10.1080/13506129.2022.2120388","DOIUrl":"https://doi.org/10.1080/13506129.2022.2120388","url":null,"abstract":"C-Labeled Pittsburgh compound B (PiB) positron emission tomography (PET) was initially developed to evaluate Alzheimer’s disease. There has been recent progress in research on cardiac amyloidosis using PiB [1] and other amyloid PET diagnostic agents [2]. Previous studies reported that amyloid tracer uptake differed according to amyloidosis subtype [2,3], and in immunoglobulin light chain (AL) amyloidosis, the degree of cardiac PiB uptake was correlated with both the histological amyloid burden in the myocardium and unfavourable disease prognosis [4]. Although a small number of AL amyloidosis patients who underwent repeated amyloid PET before and after treatment have been reported, significant reduction of cardiac tracer uptake has not yet been demonstrated [5].","PeriodicalId":50964,"journal":{"name":"Amyloid-Journal of Protein Folding Disorders","volume":null,"pages":null},"PeriodicalIF":5.5,"publicationDate":"2023-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10829287","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}