Serum Amyloid A Protein–Associated Kidney Disease: Presentation, Diagnosis, and Management

Thorne, Jordan; Clark, David; Geldenhuys, Laurette; More, Keigan M.; Vinson, Amanda J.; Tennankore, Karthik

doi:10.1016/j.xkme.2022.100504

Cited by 8 publications

(6 citation statements)

References 61 publications

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“…Increased amyloid A in patients 1, 2 and 3 indicated a chronic inflammation that could be secondary to autoimmune or chronic infection 29 (Table 2). Glomerulonephritis in patient 6 and inflammatory bowel disease in patient 7, both have immune‐related or autoimmune backgrounds 30,31 .…”

Section: Resultsmentioning

confidence: 99%

IFIH1 loss of function predisposes to inflammatory and SARS‐CoV‐2‐related infectious diseases

Najm,

Yavuz,

Jain

et al. 2024

Scand J Immunol

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The IFIH1 gene, encoding melanoma differentiation‐associated protein 5 (MDA5), is an indispensable innate immune regulator involved in the early detection of viral infections. Previous studies described MDA5 dysregulation in weakened immunological responses, and increased susceptibility to microbial infections and autoimmune disorders. Monoallelic gain‐of‐function of the IFIH1 gene has been associated with multisystem disorders, namely Aicardi–Goutieres and Singleton–Merten syndromes, while biallelic loss causes immunodeficiency. In this study, nine patients suffering from recurrent infections, inflammatory diseases, severe COVID‐19 or multisystem inflammatory syndrome in children (MIS‐C) were identified with putative loss‐of‐function IFIH1 variants by whole‐exome sequencing. All patients revealed signs of lymphopaenia and an increase in inflammatory markers, including CRP, amyloid A, ferritin and IL‐6. One patient with a pathogenic homozygous variant c.2807+1G>A was the most severe case showing immunodeficiency and glomerulonephritis. The c.1641+1G>C variant was identified in the heterozygous state in patients suffering from periodic fever, COVID‐19 or MIS‐C, while the c.2016delA variant was identified in two patients with inflammatory bowel disease or MIS‐C. There was a significant association between IFIH1 monoallelic loss of function and susceptibility to infections in males. Expression analysis showed that PBMCs of one patient with a c.2016delA variant had a significant decrease in ISG15, IFNA and IFNG transcript levels, compared to normal PBMCs, upon stimulation with Poly(I:C), suggesting that MDA5 receptor truncation disrupts the immune response. Our findings accentuate the implication of rare monogenic IFIH1 loss‐of‐function variants in altering the immune response, and severely predisposing patients to inflammatory and infectious diseases, including SARS‐CoV‐2‐related disorders.

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Section: Resultsmentioning

confidence: 99%

IFIH1 loss of function predisposes to inflammatory and SARS‐CoV‐2‐related infectious diseases

Najm,

Yavuz,

Jain

et al. 2024

Scand J Immunol

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show abstract

“…Increased Amyloid A in patients 1, 2, and 3 indicated a chronic inflammation that could be secondary to autoimmune or chronic infection 29 ( Table 2 ). Glomerulonephritis in patient 6 and Inflammatory Bowel Disease in patient 7, both have immune-related or autoimmune backgrounds 30,31 .…”

Section: Resultsmentioning

confidence: 99%

“…Increased Amyloid A in patients 1, 2, and 3 indicated a chronic inflammation that could be secondary to autoimmune or chronic infection 29 (Table 2). Glomerulonephritis in patient 6…”

Section: Clinical and Laboratory Characteristics Of Patients With Ifi...mentioning

confidence: 99%

IFIH1loss-of-function predisposes to inflammatory and SARS-CoV-2-related infectious diseases

Najm,

Yavuz,

Jain

et al. 2023

Preprint

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The IFIH1 gene, encoding melanoma differentiation-associated protein 5 (MDA5), is an indispensable innate immune regulator involved in the early detection of viral infections. Previous studies described MDA5 dysregulation linking it to weakened immunological responses, and increased susceptibility to microbial infections and autoimmune disorders. Monoallelic gain-of-function of the IFIH1 gene has been associated with multisystem disorders, namely Aicardi-Goutieres and Singleton-Merten syndromes, while biallelic loss of this gene causes immunodeficiency. In this study, nine patients suffering from different cases of recurrent infections, inflammatory diseases, severe COVID-19, or multisystem inflammatory syndrome in children (MIS-C) were identified with putative loss-of-function IFIH1 variants by whole exome sequencing. All patients revealed signs of lymphopenia and an increase in inflammatory markers, including CRP, amyloid A, ferritin, and IL-6. One patient with a pathogenic homozygous variant c.2807+1G>A was the most severe case showing immunodeficiency and glomerulonephritis. The c.1641+1G>C variant was identified in the heterozygous state in patients suffering from periodic fever, COVID-19, or MIS-C, while the c.2016delA variant was identified in two patients with inflammatory bowel disease or MIS-C. Expression analysis showed that PBMCs of one patient with a c.2016delA variant had a significant decrease in ISG15, IFNA and IFNG transcript levels, compared to normal PBMCs, upon stimulation with poly(I:C), suggesting that MDA5 receptor truncation disrupts the immune response. Our findings accentuate the implication of rare monogenic IFIH1 loss-of-function variants in altering the immune response, and severely predisposing patients to inflammatory and infectious diseases, including SARS-CoV-2 related disorders.

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“…Therapeutisch steht bei der AA-Amyloidose die möglichst effektive Behandlung der Grunderkrankung mit der Normalisierung des C-reaktiven Proteins und SAA an vorderster Stelle [41].…”

Section: Vorläuferproteinunclassified

Renale Amyloidosen

Gaedeke

2024

Nephrologie aktuell

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ZUSAMMENFASSUNGDie Amyloidosen sind eine Gruppe von seltenen Erkrankungen, die sich durch die Bildung und Ablagerung von aberrant gefalteten Proteinen definieren. Grundsätzlich können sowohl Mutationen als auch die Überproduktion von Proteinen den komplexen Prozess der Amyloidogenese starten. Krankheitswert bekommen diese Ablagerungen teilweise durch direkte zytotoxische Effekte, größtenteils jedoch durch eine mechanische Störung der Organarchitektur (z. B. Ablagerung in der glomerulären Basalmembran). Die Diagnose wird oft erst in späteren Stadien über einen manifesten Organschaden (z. B. Proteinurie) gestellt. Die Klinik wird wesentlich von der Art des Vorläuferproteins beziehungsweise der daraus folgenden Organlokalisation bestimmt. Das Überleben hängt bei vielen Amyloidoseerkrankungen vom Grad der kardialen Beteiligung ab. Etablierte Therapiestrategien zielen vor allem auf die Produktionshemmung der Vorläuferproteine ab; experimentelle Ansätze verfolgen das Ziel, bereits abgelagertes Amyloid aufzulösen.

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Serum Amyloid A Protein–Associated Kidney Disease: Presentation, Diagnosis, and Management

Cited by 8 publications

References 61 publications

IFIH1 loss of function predisposes to inflammatory and SARS‐CoV‐2‐related infectious diseases

IFIH1 loss of function predisposes to inflammatory and SARS‐CoV‐2‐related infectious diseases

IFIH1loss-of-function predisposes to inflammatory and SARS-CoV-2-related infectious diseases

Renale Amyloidosen

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