Recent Improvements in Survival in Primary Systemic Amyloidosis and the Importance of an Early Mortality Risk Score

Kumar, Shaji; Gertz, Morie A.; Lacy, Martha Q.; Dingli, David; Hayman, Suzanne R.; Buadi, Francis K.; Short-Detweiler, Kristen; Zeldenrust, Steven R.; Leung, Nelson; Greipp, Philip R.; Lust, John A.; Russell, Stephen J.; Kyle, Robert A.; Rajkumar, S. Vincent; Dispenzieri, Angela

doi:10.4065/mcp.2010.0480

Cited by 166 publications

(134 citation statements)

References 36 publications

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“…The factors governing deposition in individual tissues are unknown. Patients with cardiac AL amyloidosis have the worst prognosis, with a median survival of less than a year (2,3).…”

Section: Light Chain (Al)mentioning

confidence: 99%

Cell Damage in Light Chain Amyloidosis

Argany¹,

Lin²,

Misra³

et al. 2016

Journal of Biological Chemistry

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Light chain (AL) amyloidosis is an incurable human disease characterized by the misfolding, aggregation, and systemic deposition of amyloid composed of immunoglobulin light chains (LC). This work describes our studies on potential mechanisms of AL cytotoxicity. We have studied the internalization of AL soluble proteins and amyloid fibrils into human AC16 cardiomyocytes by using real time live cell image analysis. Our results show how external amyloid aggregates rapidly surround the cells and act as a recruitment point for soluble protein, triggering the amyloid fibril elongation. Soluble protein and external aggregates are internalized into AC16 cells via macropinocytosis. AL amyloid fibrils are shown to be highly cytotoxic at low concentrations. Additionally, caspase assays revealed soluble protein induces apoptosis, demonstrating different cytotoxic mechanisms between soluble protein and amyloid aggregates. This study emphasizes the complex immunoglobulin light chain-cell interactions that result in fibril internalization, protein recruitment, and cytotoxicity that may occur in AL amyloidosis. Light chain (AL)2 amyloidosis is a protein misfolding disease characterized by extracellular deposition of immunoglobulin light chains (LC) as amyloid fibrils. LC proteins are comprised of two distinct domains: the variable (V L ) and constant (C L ) domains (also called LC full-length (FL) protein to differentiate with the V L domain). In patients with AL amyloidosis, the LC aggregate and deposit in vital organs, causing organ failure and death (1). The factors governing deposition in individual tissues are unknown. Patients with cardiac AL amyloidosis have the worst prognosis, with a median survival of less than a year (2, 3).The finding that the V L was the primary component of amyloid fibrils influenced previous biophysical studies (4,5). Recent proteomic studies have demonstrated that amyloid deposits are likely heterogeneous in nature and can be formed by FL, V L , C L , or mixtures of all types of LC fragments (6 -8). Thermodynamic studies proposed a stabilizing role for the 3C L domain in the stability and a modulating effect on fibril formation (9). Recently, our laboratory has demonstrated that the C L domain modulates the amyloid formation reaction but has no effect on the stability of the protein (10).Soluble monoclonal LC, isolated from patients with amyloidosis, can impair rat cardiomyocyte function (11) and induce apoptotic events in mouse cardiomyocytes (12, 13). Also, urinederived LC can be internalized into primary rat cardiac fibroblasts (14) and primary human renal mesangial cells (15) through a pinocytic pathway (16) or via receptor, clathrin-mediated mechanisms, respectively (15).Within the amyloid field, it is widely accepted that oligomeric species are potentially more toxic than mature fibrils (17-20). However, toxicity associated with amyloid fibrils may also be pathologically relevant. Engel et al. (21) described a mechanism in which growth of islet amyloid associated polypeptides fibrils is re...

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“…The factors governing deposition in individual tissues are unknown. Patients with cardiac AL amyloidosis have the worst prognosis, with a median survival of less than a year (2,3).…”

Section: Light Chain (Al)mentioning

confidence: 99%

Cell Damage in Light Chain Amyloidosis

Argany¹,

Lin²,

Misra³

et al. 2016

Journal of Biological Chemistry

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“…This is especially true for AL amyloidosis, the most rapidly evolving of the systemic forms, which often targets the heart, with more pronounced signs of myocardial sufferance than observed in other types. In AL, in fact, the development of effective therapeutic regimens has markedly improved survival during the last decade [17,18], but the 25%-30% early death rate (within the first year) has not changed, with patients dying within a few weeks of cardiac failure due to late diagnosis [7].…”

Section: Introductionmentioning

confidence: 99%

Biochemical markers in early diagnosis and management of systemic amyloidoses

Lavatelli

Albertini

Fonzo

et al. 2014

Clinical Chemistry and Laboratory Medicine (CCLM)

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Systemic amyloid diseases are characterized by widespread protein deposition as amyloid fibrils. Precise diagnostic framing is the prerequisite for a correct management of patients. This complex process is achieved through a series of steps, which include detection of the tissue amyloid deposits, identification of the amyloid type, demonstration of the amyloidogenic precursor, and evaluation of organ dysfunction/damage. Laboratory medicine plays a central role in the diagnosis and management of systemic amyloidoses, through the quantification of the amyloidogenic precursor and evaluation of end-organ damage using biomarkers.

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“…A long-term survival of patients with primary amyloidosis was described by Kyle et al, who observed 10 years or more survival in 4.7% of 810 patients with AL [10]. Kumar et al, when examined the trends in overall survival in patients with primary amyloidosis, during the period 1977-2006 found significant improvement in survival time [11]. There is no doubt, that one of factors improving survival in amyloidosis is better and earlier treatment.…”

Section: Discussionmentioning

confidence: 99%

Long-time survival of a female with primary amyloidosis treated by peritoneal dialysis

Grzebalska¹,

Sak²,

Prystupa³

et al. 2017

J Pre Clin Clin Res.

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Grzebalska A M, Sak J, Prystupa A, Książek A. Long-time survival of a female with primary amyloidosis treated by peritoneal dialysis. J PreClin Clin Res. 2017; 11(1): 22-24. doi: 10.26444/jpccr/75444 Abstract Introduction. Amyloidosis, both primary and secondary, is a systemic disease characterized by extracellular deposition of fibrillar protein in vital organs, leading to their injury and even insufficiency. It results in a poor diagnosis, especially for patients with primary amyloidosis. Kidney involvement is typical and usually manifests by proteinuria, mainly nephrotic range, leading to end-stage renal disease (ESRD). Patients with ESRD need renal replacement therapy (RRT). Some data claim that better results and longer patient , survival are observed in peritoneal dialysed rather than in haemodialysed patients. Case report. The case is described of 19-year-old Caucasian woman with primary amyloidosis. Inherited primary amyloidosis with abnormal apolipoprotein A-I was established. The patient was successfully treated with peritoneal dialysis for 87 months. After this period, she was transferred for haemodialysis. Such a long survival time on peritoneal dialysis (PD) in a patient with primary amyloidosis has not been found. It is believed that the lowering of immunoglobulin levels in blood and normalization of total protein in serum effectively removed, through dialysate, the pathological polyclonal proteins. This effect probably also sustained cardio-circulatory sufficiency of the patient and significantly prolonged her survival. Conclusion. Peritoneal dialysis is an effective and recommended method of treatment in patients suffering from primary amyloidosis. Peritoneal dialysis should be the first choice therapy in ESRD patient; contrary to haemodialysis, peritoneal dialysis removes pathological proteins and allows the avoidance of intra-dialytic hypotension.

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Recent Improvements in Survival in Primary Systemic Amyloidosis and the Importance of an Early Mortality Risk Score

Abstract: Objective: To examine whether the outcome of patients with primary systemic amyloidosis (AL) has improved over time and to identify predictors of early mortality in patients with AL.

Cited by 166 publications

References 36 publications

Cell Damage in Light Chain Amyloidosis

Cell Damage in Light Chain Amyloidosis

Biochemical markers in early diagnosis and management of systemic amyloidoses

Long-time survival of a female with primary amyloidosis treated by peritoneal dialysis

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