scholarly journals Myeloma cast nephropathy with diffuse amyloid casts without systemic amyloidosis: two cases report

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Zi-hao Yong ◽  
Xiao-juan Yu ◽  
Zi-shan Lin ◽  
Fu-de Zhou ◽  
Xi-nan Cen ◽  
...  
Keyword(s):  
Amyloid Fibrils ◽  
Mononuclear Cells ◽  
Systemic Amyloidosis ◽  
Tubular Epithelial Cells ◽  
Tubular Basement Membrane ◽  
Cast Nephropathy ◽  
Amyloid Deposits ◽  
Myeloma Cast Nephropathy ◽  
History Of ◽  
Serum And Urine

Abstract Background Multiple myeloma (MM) is a plasma-cell derived hematologic malignant disease. The malignant proliferating plasma cells secrete massive monoclonal immunoglobulins which lead to various pathologic types of renal injury. Myeloma cast nephropathy (MCN) is the most common histopathologic lesion with the worst renal prognosis. Rarely, the free light chains in the protein casts can form amyloid fibrils. Here, we reported two rare cases of MCN with diffuse amyloid casts. Case presentation Case 1: A 54-year-old Chinese man presented with a 4-year history of multiple myeloma, proteinuria and hematuria. He had monoclonal IgAλ plus free λ spike in both serum and urine. He had been on chemotherapy for 4 years and maintained normal serum creatinine until 11 months ago. Then, his renal function deteriorated and he went on hemodialysis 4 months before admission. Renal biopsy showed diffuse amyloid casts in the tubular lumens, without any obvious amyloid deposits in other kidney compartments or signs of extra-renal amyloidosis. The amyloid fibrils formed around mononuclear cells which were CD68 negative. According to the morphology and location, these mononuclear cells were considered as tubular epithelial cells. The patient was maintained on chemotherapy and hemodialysis. He died 8 months after renal biopsy. Case 2: A 58-year-old Chinese man presented with a one-and-a-half-year history of proteinuria and slowly rising serum creatinine. He had monoclonal IgDλ spike in both serum and urine. Amyloid casts were observed in the tubular lumens and mononuclear cells could be identified in the center of some casts. There were no amyloid deposits in other kidney compartments and no sign of systemic amyloidosis. The patient also had fine granular deposits along the tubular basement membrane with λ linear staining along tubular basement membrane suggesting light chain deposition disease. He was treated with bortezomib-based chemotherapy followed by lenalidomide-based chemotherapy and achieved very good partial remission (VGPR). After 27 months of follow-up, the patient still showed no signs of systemic amyloidosis. Conclusions These 2 cases of MCN with diffuse amyloid casts have different histopathologic characteristics from the usual myeloma casts and tubular epithelial cells might play important roles in the pathogenesis.

scholarly journals Hereditary transthyretin amyloidosis overview

2020 ◽  
Author(s):  
Fiore Manganelli ◽  
Gian Maria Fabrizi ◽  
Marco Luigetti ◽  
Paola Mandich ◽  
Anna Mazzeo ◽  
...  
Keyword(s):  
Amyloid Fibrils ◽  
Clinical Manifestations ◽  
Missense Mutations ◽  
Presymptomatic Testing ◽  
Transthyretin Amyloidosis ◽  
Amyloid Deposits ◽  
Appropriate Treatment ◽  
History Of ◽  
Partially Unfolded ◽  
Hereditary Transthyretin Amyloidosis

AbstractHereditary amyloidogenic transthyretin (ATTRv) amyloidosis is a rare autosomal dominantly inherited disorder caused by mutations in the transthyretin (TTR) gene. The pathogenetic model of ATTRv amyloidosis indicates that amyloidogenic, usually missense, mutations destabilize the native TTR favouring the dissociation of the tetramer into partially unfolded species that self-assemble into amyloid fibrils. Amyloid deposits and monomer-oligomer toxicity are the basis of multisystemic ATTRv clinical involvement. Peripheral nervous system (autonomic and somatic) and heart are the most affected sites. In the last decades, a better knowledge of pathomechanisms underlying the disease led to develop novel and promising drugs that are rapidly changing the natural history of ATTRv amyloidosis. Thus, clinicians face the challenge of timely diagnosis for addressing patients to appropriate treatment. As well, the progressive nature of ATTRv raises the issue of presymptomatic testing and risk management of carriers. The main aim of this review was to focus on what we know about ATTRv so far, from pathogenesis to clinical manifestations, diagnosis and hence patient’s monitoring and treatment, and from presymptomatic testing to management of carriers.

Dose-Dependent Progressive Immunotherapeutic Clearance of Systemic Amyloid Deposits By Repeated Doses of Antibody to Serum Amyloid P Component (SAP)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1836-1836 ◽  
Author(s):  
Mark B Pepys ◽  
Louise M Cookson ◽  
Sharon V Barton ◽  
Alienor C Berges ◽  
Thirusha Lane ◽  
...  
Keyword(s):  
Research Funding ◽  
Amyloid Fibrils ◽  
Systemic Amyloidosis ◽  
Employment Equity ◽  
Serum Amyloid P ◽  
Serum Amyloid P Component ◽  
Amyloid Deposits ◽  
Amyloid Load ◽  
Equity Ownership ◽  
Amyloid P

Abstract In systemic amyloidosis, disease is caused by the extracellular accumulation of amyloid fibrils which do not elicit the normally efficient mechanisms of clearance of interstitial debris, and which progressively disrupt tissue architecture and function. Diagnosis is often late, with advanced organ dysfunction and major morbidity. The condition is usually fatal despite organ support and efforts to reduce production of the fibril precursor protein. In the most common type, AL, caused by monoclonal gammopathy, treatment with cytotoxic chemotherapy can slow or arrest amyloid deposition in some patients, and amyloid deposits may sometimes slowly regress but about 20% of patients still die within 6 months of diagnosis. No specific interventions exist for many of the rarer forms of systemic amyloidosis. Directly targeted measures are required to specifically remove amyloid deposits in order to preserve and possibly restore organ function. We have identified the normal plasma protein, serum amyloid P component (SAP), as a therapeutic target for this purpose. SAP binds to amyloid fibrils of all types and is thus always present in human amyloid deposits. Acute administration of (R)-1-[6-[(R)-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl]pyrrolidine-2-carboxylic acid (CPHPC), swiftly depletes circulating SAP but leaves some SAP in amyloid deposits as an amyloid-specific antigen target. In patients with systemic AL, AA and AApoAI amyloidosis, we have lately reported that, following depletion of circulating SAP by CPHPC, a single dose of humanized monoclonal anti-SAP antibody substantially reduced the amyloid load, especially from the liver (D.B. Richards et al, New England Journal of Medicine, July 15, 2015; DOI: 10.1056/NEJMoa1504942). Here we show that repeated administration of the obligate therapeutic partnership of CPHPC with appropriate doses of anti-SAP antibody, progressively removed amyloid from the liver and other organs, including the kidney. Up to three antibody doses were given at intervals to patients, mostly with AL or AFib amyloidosis, in this second part of a phase I dose-ascending study. Treatments were generally well tolerated. Infusion reactions were largely mitigated by hydrocortisone and antihistamine premedication. Pharmacodynamic responses were associated with an early transient inflammatory cytokine response and increased CRP and SAA production, followed by substantial depletion of plasma C3 and a less marked fall in C4 and CH50. Pharmacodynamic responses were sometimes associated with self-limiting cutaneous rashes, especially in subjects without hepatic amyloidosis. Reduced amyloid load was demonstrated by radiolabelled SAP scintigraphy (liver, spleen, kidneys), extracellular volume measurement by equilibrium MRI (liver, spleen) and liver stiffness determined by transient elastography. Amyloid removal was not associated with detectable additional organ dysfunction. Abnormal liver function tests improved following clearance of hepatic amyloid. Renal parameters were stable but follow up is still too short to ascertain long term renal effects. In the preclinical mouse model, amyloid clearance mediated by anti-SAP antibody requires complement and macrophages and is effected by multinucleated giant cells. Consistent with this mechanism, the extent of amyloid clearance in patients depended on the dose of anti-SAP antibody in relation to the whole body amyloid load. In patients with hepatic and splenic amyloid, the anti-SAP antibody rapidly disappeared from the circulation, consistent with its easy access to these organs via their sinusoidal endothelium. Liver and spleen amyloid were cleared first but, after major reduction of liver and spleen load, renal amyloid was cleared by subsequent antibody doses. These preliminary observations demonstrate that progressive amyloid removal can probably be achieved in all types of systemic amyloidosis by repeated courses of CPHPC and anti-SAP antibody. A phase II study is now planned. This program is funded by GlaxoSmithKline. Figure 1. Figure 1. Disclosures Pepys: Pentraxin Therapeutics Ltd: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; UK NIHR: Research Funding; UK MRC: Research Funding. Cookson:GlaxoSmithKline: Employment, Equity Ownership. Barton:GlaxoSmithKline: Employment, Equity Ownership. Berges:GlaxoSmithKline: Employment, Equity Ownership. Moon:GlaxoSmithKline: Consultancy, Research Funding. Richards:GlaxoSmithKline: Employment, Equity Ownership.

scholarly journals Colocalization of Apolipoprotein AI in Various Kinds of Systemic Amyloidosis

2005 ◽  
Vol 53 (2) ◽  
pp. 237-242 ◽  
Author(s):  
Naohiro Sakata ◽  
Yoshinobu Hoshii ◽  
Tomomi Nakamura ◽  
Makiko Kiyama ◽  
Hirofumi Arai ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Amyloid Fibrils ◽  
Senile Plaques ◽  
Systemic Amyloidosis ◽  
High Density Lipoproteins ◽  
Apolipoprotein Ai ◽  
Aa Amyloidosis ◽  
Amyloid A ◽  
Amyloid Deposits ◽  
A Minor

Apolipoprotein AI (apoAI), a major component of high-density lipoproteins, is one of the major amyloid fibril proteins and a minor constituent of the senile plaques observed in Alzheimer's disease. We examined colocalization of apoAI in various kinds of systemic amyloidosis in this study. Forty-three of 48 formalin-fixed paraffin-embedded heart specimens with various forms of systemic amyloidosis reacted immunohistochemically with anti-human apoAI antibody. ApoAI was also detected in water-extracted amyloid material by immunoblotting. In addition, we observed colocalization of apoAI and murine amyloid A (AA) amyloidosis in human apoAI transgenic mice. This is the first report of colocalization of apoAI with amyloid deposits in various forms of human systemic amyloidosis and murine AA amyloidosis in human apoAI transgenic mice. ApoAI may not always be a major component of amyloid fibrils, even when it is present in systemic amyloid deposits.

Incidence and natural history of primary systemic amyloidosis in Olmsted County, Minnesota, 1950 through 1989 [see comments]

Blood ◽  
1992 ◽  
Vol 79 (7) ◽  
pp. 1817-1822 ◽  
Author(s):  
RA Kyle ◽  
A Linos ◽  
CM Beard ◽  
RP Linke ◽  
MA Gertz ◽  
...  
Keyword(s):  
Light Chain ◽  
Mayo Clinic ◽  
Incidence Rates ◽  
Systemic Amyloidosis ◽  
Amyloid Deposits ◽  
Medical Groups ◽  
History Of ◽  
Adjusted Rate ◽  
Immunohistochemical Studies ◽  
Immunohistochemical Stains

Abstract No reports of the incidence rates for primary systemic amyloidosis (AL) have come to our attention. Records of all residents of Olmstead County, Minnesota, with a diagnosis of amyloidosis were obtained from the Mayo Clinic and its affiliated hospitals, as well as other medical groups that might have seen local patients for the period January 1, 1950 to December 31, 1989. Twenty-one patients fulfilled the criteria for the diagnosis of AL. The median age was 73.5 years, and 62% were men. In all but one patient the diagnosis was made ante mortem. The clinical data of the 21 patients were similar to those referral patients with AL seen at Mayo Clinic. Immunohistochemical stains were positive for monoclonal light chains in the amyloid deposits in 15 of the 21 cases. In six cases, tissue was not available for immunohistochemical studies. Three of the six patients without immunohistochemical stains had a free monoclonal lambda light chain in the urine, and the other three had a monoclonal serum protein. Immunoelectrophoresis/immunofixation detected a monoclonal (M)-protein in the serum of 16 of 17 patients tested. A monoclonal light chain was found in the urine of 10 of 15 patients. The overall sex- and age- adjusted rate per million person-years was 6.1 from 1950 to 1969 and 10.5 from 1970 to 1989. The similarity of these rates suggests no significant increase over time.

Systemic light-chain amyloidosis incidentally diagnosed after subtotal parathyroidectomy and thyroid lobectomy

2021 ◽  
Vol 14 (4) ◽  
pp. e241282
Author(s):  
Karen Tsai ◽  
Alice Chen Yu ◽  
Masha J Livhits ◽  
Dipti Sajed ◽  
Angela M Leung ◽  
...  
Keyword(s):  
Light Chain ◽  
Congo Red ◽  
Systemic Amyloidosis ◽  
Subtotal Parathyroidectomy ◽  
Endocrine Organ ◽  
Amyloid Deposits ◽  
Thyroid Lobectomy ◽  
Pacemaker Placement ◽  
History Of ◽  
Congo Red Staining

A 74-year-old woman with a history of primary hyperparathyroidism, thyroid nodules, atrial fibrillation and pacemaker placement for sick sinus syndrome presented with fatigue, constipation and persistent lower extremity oedema. She underwent subtotal parathyroidectomy and left thyroid lobectomy. Histopathology revealed amyloidosis affecting the thyroidand parathyroids confirmed by Congo Red Staining with Mayo Clinic subtyping of light chain kappa-type amyloidosis. She was found to have combined systolic and diastolic cardiac dysfunction, carpal tunnel neuropathy and pre-diabetes suggestive of systemic amyloidosis with involvement of the heart, nerves and pancreas. Congo red stain was positive for amyloidosis on bone marrow biopsy suggestive of a diagnosis of systemic amyloidosis. She was treated with daratumumab with good clinical response. This case illustrates the necessity of considering systemic amyloidosis in patients with incidentally discovered diffuse amyloid deposits on biopsy of an endocrine organ, as endocrine effects are a rare but likely underdiagnosed consequence of systemic amyloidosis.

scholarly journals Incidence and natural history of primary systemic amyloidosis in Olmsted County, Minnesota, 1950 through 1989 [see comments]

Blood ◽  
1992 ◽  
Vol 79 (7) ◽  
pp. 1817-1822 ◽  
Author(s):  
RA Kyle ◽  
A Linos ◽  
CM Beard ◽  
RP Linke ◽  
MA Gertz ◽  
...  
Keyword(s):  
Light Chain ◽  
Mayo Clinic ◽  
Incidence Rates ◽  
Systemic Amyloidosis ◽  
Amyloid Deposits ◽  
Medical Groups ◽  
History Of ◽  
Adjusted Rate ◽  
Immunohistochemical Studies ◽  
Immunohistochemical Stains

No reports of the incidence rates for primary systemic amyloidosis (AL) have come to our attention. Records of all residents of Olmstead County, Minnesota, with a diagnosis of amyloidosis were obtained from the Mayo Clinic and its affiliated hospitals, as well as other medical groups that might have seen local patients for the period January 1, 1950 to December 31, 1989. Twenty-one patients fulfilled the criteria for the diagnosis of AL. The median age was 73.5 years, and 62% were men. In all but one patient the diagnosis was made ante mortem. The clinical data of the 21 patients were similar to those referral patients with AL seen at Mayo Clinic. Immunohistochemical stains were positive for monoclonal light chains in the amyloid deposits in 15 of the 21 cases. In six cases, tissue was not available for immunohistochemical studies. Three of the six patients without immunohistochemical stains had a free monoclonal lambda light chain in the urine, and the other three had a monoclonal serum protein. Immunoelectrophoresis/immunofixation detected a monoclonal (M)-protein in the serum of 16 of 17 patients tested. A monoclonal light chain was found in the urine of 10 of 15 patients. The overall sex- and age- adjusted rate per million person-years was 6.1 from 1950 to 1969 and 10.5 from 1970 to 1989. The similarity of these rates suggests no significant increase over time.

scholarly journals Cryo-EM structure of a transthyretin-derived amyloid fibril from a patient with hereditary ATTR amyloidosis

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Matthias Schmidt ◽  
Sebastian Wiese ◽  
Volkan Adak ◽  
Jonas Engler ◽  
Shubhangi Agarwal ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
Amyloid Fibrils ◽  
Amyloid Fibril ◽  
The Body ◽  
Systemic Amyloidosis ◽  
Attr Amyloidosis ◽  
Cryo Electron Microscopy ◽  
Terminal Fragment ◽  
Amyloid Deposits ◽  
Hereditary Attr Amyloidosis

Abstract ATTR amyloidosis is one of the worldwide most abundant forms of systemic amyloidosis. The disease is caused by the misfolding of transthyretin protein and the formation of amyloid deposits at different sites within the body. Here, we present a 2.97 Å cryo electron microscopy structure of a fibril purified from the tissue of a patient with hereditary Val30Met ATTR amyloidosis. The fibril consists of a single protofilament that is formed from an N-terminal and a C-terminal fragment of transthyretin. Our structure provides insights into the mechanism of misfolding and implies the formation of an early fibril state from unfolded transthyretin molecules, which upon proteolysis converts into mature ATTR amyloid fibrils.

scholarly journals Personalizing Amyloidosis Therapy with Real Time PET Imaging of Fibril-Reactive Monoclonal Antibody Cael-101

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1003-1003 ◽  
Author(s):  
Jing Fu ◽  
Alan Solomon ◽  
Patrick Carberry ◽  
John Castrillon ◽  
Jongho Kim ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Real Time ◽  
Pet Imaging ◽  
Amyloid Fibrils ◽  
Amyloid Fibril ◽  
Systemic Amyloidosis ◽  
Al Amyloidosis ◽  
Amyloid Deposits ◽  
First Time

Abstract Background AL amyloidosis is the most common type of systemic amyloidosis in western countries and has a poor prognosis, with a median survival of 12 to 18 months. Despite the improved prognosis gained by eliminating the offending plasma cell clone, mortality remains high due to multi-organ dysfunction caused by persistent, insoluble amyloid fibril deposits. The amyloid fibril-reactive murine monoclonal antibody 11-1F4 was designed to target amyloid deposits by directly binding to a conformational epitope present on human light-chain amyloid fibrils. The murine form of this antibody has demonstrated potential to bind amyloid in mice and humans (Blood. 2010 116: 2241) and to clear insoluble fibrils in mice with induced human AL amyloidomas, demonstrating the feasibility of using immunotherapy to elicit rapid destruction of amyloid fibrils. Of great translational importance, a chimeric form of 11-1F4 was produced (CAEL-101) and recently demonstrated therapeutic potential in an open-label, dose-escalation phase 1a/b study where 67% of patients with cardiac or renal amyloidosis demonstrated organ response. There was a statistically significant change in Global Longitudinal Strain with 9/10 patients showing improvement (p=0.004). Since we have shown that CAEL-101 successfully improved organ function, the overall goal of this work is for the first time to explore the diagnostic potential of CAEL-101 radiolabeled with a positron emitting radioisotope for systemic amyloidosis as well as to explore its use as a companion biomarker to stratify patients for CAEL-101 immunotherapy. Methods We obtained human amyloid extracts from the heart (κ1), liver (κ1), spleen (λ1) and kidney (λ6). Lyophilized human amyloid extracts were suspended in 25ml of sterile PBS and homogenized for 3 minutes and centrifuged at 12,000g for 30 minutes. 100mg of the resulting pellet was resuspended in sterile saline. Balb/c mice were then injected subcutaneously with amyloid extract. For imaging experiments, cGMP grade CAEL-101 was radiolabeled with 124I, a positron emitting radioisotope used for PET imaging, with the standard iodegen reaction. Approximately 5 days after human amyloid extract was implanted to form subcutaneous amyloidomas, animals were injected with 200μCi of [124I]CAEL-101 and imaged 1 and 4 days post injection using an Inveon microPET scanner. SUVmax for amyloidomas and contralateral background were obtained by drawing regions of interest in the PMOD software package and calculating tumor-to-background (T:B) ratios at 1 and 4 days post tracer infusion. Results We found that [124I]CAEL-101 successfully imaged 100% of mice bearing human amyloid extracts (κ1, λ1 and λ6 subtypes derived from heart, liver, spleen, and kidney). Human amyloidomas were visualized at both at 1 and 4 days post tracer infusion, with significantly increasing T:B radio by day 4, as expected when imaging large molecular weight antibodies. T:B ratios ranged from 2.1 to 4.2 at 4 days. Mice implanted with κ subtypes demonstrated significantly better in vivo T:B ratios (4.1 +/- 0.20), compared to λ subtypes (2.8 +/- 0.46), although all amyloidomas exhibited T:B uptake > 2.1, which would be clinically significant. Conclusions We have demonstrated for the first time the potential of using radiolabeled CAEL-101 as a companion diagnostic to image real-time targeting of human amyloidosis in vivo. This is highly translatable due to the fact that CAEL-101 has shown great promise in early stage clinical trials to clear insoluble amyloid plaques. Importantly, we successfully used PET imaging to visualize cardiac derived amyloid fibrils from AL amyloidosis patients. Therefore, we anticipate that dedicated gated cardiac PET/CT imaging of radiolabeled CAEL-101 will be successful at visualizing cardiac amyloid deposits in patients, especially with the rich blood flow in cardiac tissue and newer generation highly sensitive, high resolution digital PET scanners, in contrast to the non-cardiac optimized whole body scans used in prior studies with antibody-based PET. Given that we were able to image 100% of implanted human amyloidomas derived from heart, spleen, liver and kidney consisting of both κ and λ subtypes, we envision using CAEL-101 PET imaging to (1) diagnose systemic amyloidosis, (2) stratify patients for CAEL-101 immunotherapy, and (3) quantify peripheral organ amyloid fibril deposition pre and post anti-amyloid therapy. Figure Figure. Disclosures Solomon: Caelum Biosciences: Consultancy, Equity Ownership. Lentzsch:Bayer: Consultancy; BMS: Consultancy; Janssen: Consultancy; Caelum Biosciences: Consultancy, Other: Dr. Lentzsch recused herself as an investigator from the Phase 1a/b trial testing CAEL-101 in 11/2017., Patents & Royalties: Shareholder for Caelum Biosiences. Mintz:Caelum Biosciences: Research Funding.

Efficacy of intrauterine administration of autologous peripheral blood mononuclear cells prior to embryo transfer in patients with recurrent implantation failures in assisted reproductive technology programmes

GYNECOLOGY ◽  
2018 ◽  
Vol 20 (2) ◽  
pp. 28-33
Author(s):  
T S Amyan ◽  
S G Perminova ◽  
L V Krechetova ◽  
V V Vtorushina
Keyword(s):  
Embryo Transfer ◽  
Peripheral Blood Mononuclear Cells ◽  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Peripheral Blood Mononuclear ◽  
Study Objective ◽  
Study Results ◽  
Blood Mononuclear Cells ◽  
History Of ◽  
Group 2

Study objective. To evaluate the efficacy of intrauterine administration of autologous peripheral blood mononuclear cells (PBMC) prior to embryo transfer in patients with recurrent implantation failures in IVF program. Materials and methods. The study enrolled 129 patients with recurrent implantation failures in an IVF programme. Group 1 - 42 patients who had intrauterine administration of autologous PBMC activated with hCG (Pregnyl 500 IU). Group 2 - 42 patients who had intrauterine administration of autologous PBMC without hCG activation. Group 3 (placebo) - 45 patients who had intrauterine administration of saline. Study results. In the hCG-activated PBMC group, the rates of positive blood hCG tests, implantation, and clinical pregnancy were significantly higher than the respective rates in the non-activated PBMC group and in the placebo group, both in a stimulated cycle and in an FET cycle (р≤0.05). Conclusion. Intrauterine administration of autologous PBMC prior to embryo transfer in an IVF/ICSI programme increases the efficacy of IVF program in patients with a history of recurrent implantation failures.

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