Rezk, Tamer; (2019) Novel techniques in the diagnosis, monitoring and outcome of renal and cardiac amyloidosis. Doctoral thesis (Ph.D), UCL (University College London).

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Text Novel techniques in the diagnosis, monitoring and outcomes of renal and cardiac amyloidosis PhD thesis Post Viva Corrections.pdf - Accepted Version Download (2MB) | Preview

Abstract

Background: Systemic amyloidosis is a rare, progressive and fatal disorder of protein folding, treatment of which requires definitive amyloid fibril typing. Cardiac and renal involvement are common and are not only leading causes of mortality and morbidity, but also give rise to major challenges, complications and adverse effects of therapies aiming to suppress amyloid fibril precursor protein production. Aims: To refine and improve diagnosis, typing and management of patients with amyloidosis, through: proteomic analysis; development of novel biomarker-based risk stratification in patients with cardiorenal syndrome; evaluation of changes in body composition and cardiac dysfunction during and after systemic chemotherapy; and measures to support amyloidotic organ function. Results and Conclusions: I confirmed and extended previous studies demonstrating that proteomic analysis of amyloidotic tissue is superior overall to IHC for typing amyloid, but identified important limitations relating to certain tissues and amyloid types. I characterised the complex combined cardiac and renal phenotypes that occur in one third of patients with AL amyloidosis, and performed new analyses of biomarkers that are widely used to guide chemotherapy. Very encouragingly I have shown that rapid and deep clonal responses to chemotherapy can result in meaningful improvements in patient and renal survival in individuals with advanced kidney disease, which has previously been considered beyond salvage. Heart and kidney dysfunction both cause ECV overload and sarcopenia, which cannot be quantified clinically but contribute to poor outcomes. I used bioimpedence vector analysis to comprehensively estimate body composition at diagnosis and to aid clinical assessment during treatment. Despite these improvements in clinical monitoring and in chemotherapy generally, sudden cardiac death is common in amyloidosis. Sadly, ICD implantation in 15 patients described in my final chapter failed to translate into clinical benefit. Patients with amyloidosis continue to have unmet needs, many of which stem from heart and kidney involvement, but outcomes are gradually improving.

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