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Macromolecular crowding and supersaturation protect hemodialysis patients from the onset of dialysis-related amyloidosis

ABSTRACT: Dialysis-related amyloidosis (DRA), a serious complication among long-term hemodialysis patients, is caused by amyloid fibrils of β2-microglobulin (β2m). Although high serum β2m levels and a long dialysis vintage are the primary and secondary risk factors for the onset of DRA, respectively, patients with these do not always develop DRA, indicating that there are additional risk factors. To clarify these unknown factors, we investigate the effects of human sera on β2m amyloid fibril formation, revealing that sera markedly inhibit amyloid fibril formation. Results from over 100 sera indicate that, although the inhibitory effects of sera deteriorate in long-term dialysis patients, they are ameliorated by maintenance dialysis treatments in the short term. Serum albumin prevents amyloid fibril formation based on macromolecular crowding effects, and decreased serum albumin concentration in dialysis patients is a tertiary risk factor for the onset of DRA. We construct a theoretical model assuming cumulative effects of the three risk factors, suggesting the importance of monitoring temporary and accumulated risks to prevent the development of amyloidosis, which occurs based on supersaturation-limited amyloid fibril formation in a crowded milieu. Amyloid fibrils of β2-microglobulin (β2m) can cause dialysis-related amyloidosis. Here, the authors show that a decrease in serum albumin levels in long-term dialysis deteriorates the inhibitory effects of serum milieux on supersaturation-limited amyloid formation of β2m, suggesting that macromolecular crowding protects the onset of amyloidosis.

SUBMITTER: Nakajima K

PROVIDER: S-EPMC9530240 | biostudies-literature | 2022 Jan

REPOSITORIES: biostudies-literature

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Project description:Rationale & objectiveChronic kidney disease (CKD)-associated pruritus, generalized itching related to CKD, affects many aspects of hemodialysis patients' lives. However, information regarding the relationship between pruritus and several key outcomes in hemodialysis patients remains limited.Study designProspective cohort.Setting & participants23,264 hemodialysis patients from 21 countries in the Dialysis Outcomes and Practice Patterns Study (DOPPS) phases 4 to 6 (2009-2018).ExposurePruritus severity, based on self-reported degree to which patients were bothered by itchy skin (5-category ordinal scale from "not at all" to "extremely").OutcomesClinical, dialysis-related, and patient-reported outcomes.Analytical approachCox regression for time-to-event outcomes and modified Poisson regression for binary outcomes, adjusted for potential confounders.ResultsThe proportion of patients at least moderately bothered by pruritus was 37%, and 7% were extremely bothered. Compared with the reference group ("not at all"), the adjusted mortality HR for patients extremely bothered by pruritus was 1.24 (95% CI, 1.08-1.41). Rates of cardiovascular and infection-related deaths and hospitalizations were also higher for patients extremely versus not at all bothered by pruritus (HR range, 1.17-1.44). Patients extremely bothered by pruritus were also more likely to withdraw from dialysis and miss hemodialysis sessions and were less likely to be employed. Strong monotonic associations were observed between pruritus severity and longer recovery time from a hemodialysis session, lower physical and mental quality of life, increased depressive symptoms, and poorer sleep quality.LimitationsResidual confounding, recall bias, nonresponse bias.ConclusionsOur findings demonstrate how diverse and far-reaching poor outcomes are for patients who experience CKD-associated pruritus, specifically those with more severe pruritus. There is need for change in practice patterns internationally to effectively identify and treat patients with pruritus to reduce symptom burden and improve quality of life and possibly even survival.

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Macromolecular crowding and supersaturation protect hemodialysis patients from the onset of dialysis-related amyloidosis

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