Post-transplantation Recurrence of Fibrinogen A-α Amyloidosis.
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ABSTRACT:
SUBMITTER: Feitosa VA
PROVIDER: S-EPMC7783572 | biostudies-literature | 2021 Jan
REPOSITORIES: biostudies-literature
Publications
Post-transplantation Recurrence of Fibrinogen A-α Amyloidosis.
Feitosa Valkercyo A VA Ferreira Fernanda T FT Neves Precil D M M PDMM Watanabe Andreia A Watanabe Elieser H EH Proença Henrique M S HMS Azevedo Vega F S VFS Pestana José Osmar M JOM Onuchic Luiz F LF
Kidney international reports 20201030 1
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Project description:Introduction: Systemic amyloidosis is a diverse group of diseases that, although rare, pose a serious health issue and can lead to organ failure and death. Amyloid typing is essential in determining the causative protein and initiating proper treatment. Mass spectrometry-based proteomics is currently the most sensitive and accurate means of typing amyloid. Areas covered: Amyloidosis can be systemic or localized, acquired or hereditary, and can affect any organ or tissue. Diagnosis requires biopsy, histological analysis, and typing of the causative protein to determine treatment. The kidneys are the most commonly affected organ in systemic disease. Fibrinogen alpha chain amyloidosis (AFib) is the most prevalent form of hereditary renal amyloidosis. Select mutations in the fibrinogen Aα (FGA) gene lead to AFib. Expert commentary: Mass spectrometry is currently the most specific and sensitive method for amyloid typing. Identification of the mutated fibrinogen alpha chain can be difficult in the case of 'private' frameshift mutations, which dramatically change the sequences of the expressed fibrinogen alpha chain. A combination of expert pathologist review, mass spectrometry, and gene sequencing can allow for confident diagnosis and determination of the fibrinogen alpha chain mutated sequence.
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Project description:ObjectivesFibrinogen A alpha-chain amyloidosis (AFib amyloidosis) is the most common form of hereditary renal amyloidosis in the United Kingdom and Europe, but has rarely been reported in Asia. In this study, we reported two AFib amyloidosis patients in China, reviewing the literature and summarizing main characteristics of AFib amyloidosis in Asia.MethodsTwo unrelated Chinese patients were diagnosed with AFib amyloidosis by clinical presentation, renal biopsy, mass spectrometry and DNA sequencing in Peking University First Hospital of China from 2014 to 2016.ResultsBoth of the patients presented with proteinuria, edema and hypertension. Renal biopsies of two patients showed extensive amyloid deposits (Congo red positive) in glomeruli, and focal tubulointerstitial amyloid deposits was also found in patient 1. Besides, hepatic involvement of amyloidosis has been detected by liver biopsy in patient 1. By electron microscopy, randomly arranged fibrils in a diameter of 8-12 nm was identified in mesangial matrix and subendothelial area of glomeruli. Immunohistochemistry demonstrated amyloid deposits were strongly positive for fibrinogen Aα in glomeruli and positive for LECT2 in the interstitium of renal medulla and the liver in Patient 1. Unevenly positive staining for both fibrinogen Aα and ApoA-I were found in Patient 2. Fibrinogen Aα was the most abundant amyloidogenic protein in both patients identified by laser microdissection and mass spectrometry-based proteomic analysis. Genetic analysis revealed the fibrinogen A a-chain gene (FGA) mutation in both patients, including a new deletion mutation [c.1639delA (p.Arg547Glyfs*21; NM_000508)] in Patient 2. Genetic analysis of the LECT2 gene in patient 1 revealed a codon change from ATC to GTC at position 172 [c.172A>G (p.Ile58Val; NM_002302)], which is a common polymorphism (SNP rs31517) in all ALECT2 amyloidosis patients.ConclusionsWe reported two AFib amyloidosis patients in China, one of them coexisted with ALECT2 amyloidosis simultaneously.
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Project description:Mutations in the fibrinogen A alpha-chain gene are the most common cause of hereditary renal amyloidosis in the United Kingdom. Previous reports of fibrinogen A alpha-chain amyloidosis have been in isolated kindreds, usually in the context of a novel amyloidogenic mutation. Here, we describe 71 patients with fibrinogen amyloidosis, who were prospectively studied at the UK National Amyloidosis Centre. Median age at presentation was 58 yr, and renal involvement led to diagnosis in all cases. Even after a median follow-up of 4 yr, clinically significant extra-renal disease was rare. Renal histology was characteristic: striking glomerular enlargement with almost complete obliteration of the normal architecture by amyloid deposition and little or no vascular or interstitial amyloid. We discovered four amyloidogenic mutations in fibrinogen (P552H, E540V, T538K, and T525fs). A family history of renal disease was frequently absent. Median time from presentation to ESRD was 4.6 yr, and the estimated median patient survival from presentation was 15.2 yr. Among 44 patients who reached ESRD, median survival was 9.3 yr. Twelve renal transplants survived for a median of 6.0 (0-12.2) yr. Seven grafts had failed after median follow up from transplantation of 5.8 yr, including three from recurrent amyloid after 5.8, 6.0, and 7.4 yr; three grafts failed immediately for surgical reasons and one failed from transplant glomerulopathy after 5.8 yr with no histological evidence of amyloid. At censor, the longest surviving graft was 12.2 yr. In summary, fibrinogen amyloidosis is predominantly a renal disease characterized by variable penetrance, distinctive histological appearance, proteinuria, and progressive renal impairment. Survival is markedly better than observed with systemic AL amyloidosis, and outcomes with renal replacement therapy are comparable to those for age-matched individuals with nondiabetic renal disease.
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Project description:Systemic hereditary amyloidoses are autosomal dominant diseases associated with mutations in genes encoding ten different proteins. The clinical phenotype has implications on therapeutic approach, but it is commonly variable and largely dependent on the type of mutation. Except for rare cases involving gelsolin or transthyretin, patients are heterozygous for the amyloidogenic variants. Here we describe the first patient identified worldwide as homozygous for a nephropathic amyloidosis, involving the fibrinogen variant associated with the fibrinogen alpha-chain E526V (p.Glu545Val) mutation. In 1989, a 44-year-old woman presented with hypertension, hepatosplenomegaly, nephrotic syndrome, and renal failure. She started hemodialysis in 1990 and 6 years later underwent isolated kidney transplantation from a deceased donor. Graft function and clinical status were unremarkable for 16 years, despite progressively increased left ventricular mass on echocardiography. In 2012, 4 months before death, she deteriorated rapidly with severe heart failure, precipitated by Clostridium difficile colitis and urosepsis. Affected family members developed nephropathy, on average, nearly three decades later, which may be explained by the gene dosage effects on the phenotype of E526V (p.Glu545Val) fibrinogen A alpha-chain amyloidosis.
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Project description:The annual incidence of hepatocellular carcinoma (HCC) continues to rise. Over the last two decades, liver transplantation (LT) has become the preferable treatment of HCC, when feasible and strict selection criteria are met. With the rise in HCC-related LT, compounded by downstaging techniques and expansion of transplant selection criteria, a parallel increase in number of post-transplantation HCC recurrence is expected. Additionally, in the context of an immunosuppressed transplant host, recurrences may behave aggressively and more challenging to manage, resulting in poor prognosis. Despite this, no consensus or best practice guidelines for post-transplantation cancer surveillance and recurrence management for HCC currently exist. Studies with adequate population sizes and high-level evidence are lacking, and the role of systemic and locoregional therapies for graft and extrahepatic recurrences remains under debate. This review seeks to summarize the existing literature on post-transplant HCC surveillance and recurrence management. It highlights the value of early tumour detection, re-evaluating the immunosuppression regimen, and staging to differentiate disseminated recurrence from intrahepatic or extrahepatic oligo-recurrence. This ultimately guides decision-making and maximizes treatment effect. Treatment recommendations specific to recurrence type are provided based on currently available locoregional and systemic therapies.
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Project description:IntroductionHereditary fibrinogen Aα-chain (AFib) amyloidosis is a relatively uncommon renal disease associated with a small number of pathogenic fibrinogen Aα (FibA) variants; wild-type FibA normally does not result in amyloid deposition. Proteomics is now routinely used to identify the amyloid type in clinical samples, and we report here our algorithm for identification of FibA in amyloid.MethodsProteomics data from 1001 Congo red-positive patient samples were examined using the Mascot search engine to interrogate the Swiss-Prot database and generate protein identity scores. An algorithm was applied to identify FibA as the amyloid protein based on Mascot scores. FibA variants were identified by appending the known amyloidogenic variant sequences to the Swiss-Prot database.ResultsAFib amyloid was identified by proteomics in 64 renal samples based on the Mascot scores relative to other amyloid proteins, the presence of a pathogenic variant, and coverage of the p.449-621 sequence. Contamination by blood could be excluded from a comparison of the FibA score with that of the fibrinogen β and γ chains. The proteomics results were consistent with the clinical diagnosis. Four additional renal samples did not fulfill all the criteria using the algorithm but were adjudged as AFib amyloid based on a full assessment of the clinical and biochemical results.ConclusionAFib amyloid can be identified reliably in glomerular amyloid by proteomics using a score-based algorithm. Proteomics data should be used as a guide to AFib diagnosis, with the results considered together with all available clinical and laboratory information.
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Project description:BackgroundOrthotropic liver transplantation (OLT) offers a therapeutic choice for hepatocellular carcinoma (HCC) patients. The poor outcome of liver transplantation is HCV recurrence. Several genome-wide associated studies (GWAS) have reported many genetic variants to be associated with HCV recurrence. Seven gene polymorphisms formed a cirrhosis risk score (CRS) signature that could be used to distinguish chronic HCV patients at high risk from those at low risk for cirrhosis in non-transplant patients. This study aims to examine the association of CRS score and other clinical parameters with the probability for HCC emergence and/or the rate of HCV recurrence following liver transplantation.ResultsSeven gene polymorphisms, forming the CRS, were genotyped by real-time PCR using allelic discrimination protocol in 199 end-stage liver disease patients (79 child A, 43 child B, and 77child C), comprising 106 patients who encountered liver transplantation. Recipient CRS scores were correlated with HCV recurrence (HCV-Rec) at the end of the third year after OLT. Around 81% (39) recipients with low steatosis (LS; < 3.5%) donor percentage revealed no HCV recurrence (non-Rec) (p<0.001). CRS score could distinguish between child A, child B, and child C only at the low-risk group. Among the HCV Rec group 27% (8/30), 40% (12/30), and 33% (10/30) fell into the high, moderate, and low CRS risk groups, respectively. Stepwise logistic regression evinced two features more likely to be seen in HCV-Rec patients: abnormal ALT [OR, 1.1; 95% CI, 1.02-1.2] and donor steatosis >3.5% [OR, 46.07; 95% CI, 1.5-1407.8].ConclusionsAccordingly, the CRS score seems to be less useful to predict HCV recurrence after OLT. ALT and donor steatosis (exceed 3.5%) can significantly promote the HCV recurrence post-OLT. Moreover, the combination of MMF and CNI positively heightens HCV recurrence.
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Project description:BackgroundWe aimed to investigate whether D-dimer and fibrinogen levels could predict prognosis of patients with hepatocellular carcinoma (HCC) following liver transplantation.MethodsFrom January 2015 to January 2020, we conducted a study on patients with hepatitis B-related liver cancer. Two hundred seventy (270) liver transplant recipients were recruited. Considering D-dimer and plasma fibrinogen levels, a model was established to predict liver cancer recurrence following liver transplantation. Subsequent verification was performed on a validation cohort of 295 recipients from two other hospitals.ResultsElevated D-dimer and plasma fibrinogen levels demonstrated independent correlation between overall survival and tumour-free survival among patients with HCC who underwent liver transplantation. Those who had preoperative fibrinogen ≥2.27 g/L had significantly reduced overall survival and tumour-free survival than those who had preoperative fibrinogen <2.27 g/L, in the discovery cohort. Recipients with increased risk had preoperative plasma D-dimer ≥2400 µg/L. The model was: Y= logit (P) =0.91* fibrinogen concentration +0.967* D-dimer +0.585* alpha-fetoprotein +1.623* Milan criteria +0.68* microvascular invasion -3.159. At a cut-off score of -1.524, the validation cohort had area under curve values of 0.764 and 0.828 respectively; analysis of this data optimised predictive performance for overall and tumour-free survival.ConclusionsFor patients who have undergone liver transplantation for HCC, preoperative D-dimer and fibrinogen levels independently predicted key outcomes such as overall survival and tumour-free survival.
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Project description:BackgroundGenetic defects in podocyte proteins account for up to 30% of steroid-resistant nephrotic syndrome (SRNS) in the paediatric population. Most children with genetic SRNS are resistant to immunosuppression and at high risk of progression to stage 5 chronic kidney disease. Kidney transplantation is often the treatment of choice. The possibility of post-transplantation disease recurrence in genetic SRNS remains controversial, and poses fundamental questions about disease biology.MethodsWe critically evaluated the published cases of post-transplantation recurrence in genetic patients, particularly testing 'mutations' against the most recent population variant databases, in order to clarify the diagnoses, and compare the clinical courses and responses to therapy.ResultsBiallelic pathogenic variants in NPHS1 leading to a complete absence of nephrin were the most commonly reported and best understood instance of nephrotic syndrome occurring post-transplantation. This is an immune-mediated process driven by antibody production against the novel nephrin protein in the allograft. We also identified a number of plausible reported cases of post-transplantation recurrence involving pathogenic variants in NPHS2 (8 patients, biallelic), one in WT1 (monoallelic) and one in NUP93 (biallelic). However, the mechanism for recurrence in these cases remains unclear. Other instances of recurrence in genetic disease were difficult to interpret due to differing clinical criteria, inclusion of patients without true pathogenic variants or the influence of other factors on renal outcome.ConclusionsOverall, post-transplantation recurrence remains very rare in patients with genetic SRNS. It appears to occur later after transplantation than in other patients and usually responds well to plasmapheresis with a good renal outcome.
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