Hemodialysis exacerbates proteolytic imbalance and pro-fibrotic platelet dysfunction

Abstract

Multi-organ fibrosis among end stage renal disease (ESRD) patients cannot be explained by uremia alone. Despite mitigation of thrombosis during hemodialysis (HD), subsequent platelet dysfunction and tissue dysregulation are less understood. We comprehensively profiled plasma and platelets from ESRD patients before and after HD to examine HD-modulation of platelets beyond thrombotic activation. Basal plasma levels of proteolytic regulators and fibrotic factors were elevated in ESRD patients compared to healthy controls, with isoform-specific changes during HD. Platelet lysate (PL) RNA transcripts for growth and coagulative factors were elevated post-HD, with upregulation correlated to HD vintage. Platelet secretome correlations to plasma factors reveal acutely induced pro-fibrotic platelet phenotypes in ESRD patients during HD characterized by preferentially enhanced proteolytic enzyme translation and secretion, platelet contribution to inflammatory response, and increasing platelet dysfunction with blood flow rate (BFR) and Vintage. Compensatory mechanisms of increased platelet growth factor synthesis with acute plasma matrix metalloproteinase (MMP) and tissue inhibitor of MMPs (TIMP) increases show short-term mode-switching between dialysis sessions leading to long-term pro-fibrotic bias. Chronic pro-fibrotic adaptation of platelet synthesis were observed through changes in differential secretory kinetics of heterogenous granule subtypes. We conclude that chronic and acute platelet responses to HD contribute to a pro-fibrotic milieu in ESRD.

Cyclical depressurization degranulates platelets in an agonist-free mechanism of platelet activation

“…Taken together, these data suggest that depressurization circumvents receptor signal transduction to induce exocytosis and further that this mechanism desensitizes platelets to chemical stimuli. In hemodialysis, this may contribute to bleeding disorders [ 2 ] while still exacerbating the circulation of platelet factors [ 6 ].…”

“…Early studies reported platelet morphological expansion [ 22 ], aggregation [ 23 ], and free ion flux [ 24 ] in both hyper- and hypotonic solutions with implications on blood storage. Considering the drastic shifts in osmolarity experienced in the renal medulla and procoagulant platelet phenotypes observed in representative hyperosmotic solutions [ 21 ], agonist-free platelet degranulation may contribute to worsening CKD in dialysis patients exhibiting pro-fibrotic platelet disposition [ 6 ].…”

“…However, these mechanisms activate platelets by receptor adhesion, whether by defective GPIb and GPIIb/IIIa [ 4 ], hydrophobic capture [ 2 ], or rolling immobilization to RGDS sites on unfurled vWF [ 5 ]. Recent hemodialysis findings link chronically pro-fibrotic circulations to increasingly differential platelet granule secretory kinetics [ 6 ], amplifying the need to interrogate the drivers and mechanisms of platelet degranulation.…”

“…Common expression trends reveal a novel and universal basis for pressure-driven degranulation distinct from shear-based activation, while contrasting population baselines substantiate response variability owing to uremic dysfunction. Depending on the proteomic and transcriptomic contents of circulating platelets, this could exacerbate platelet contributions to fibrotic pathologies and cardiovascular dysregulation in vulnerable patient demographics [ 6 ].…”

Crosstalk between bone and muscle in chronic kidney disease

“…Moreover, FGF2 was found to reduce glucocorticoid-mediated bone resorption via inhibition of sclerostin signalling, reinforcing its anabolic effects on bone metabolism ( 107 ). Circulating FGF2 levels have been reported to be lower in patients with more advanced CKD ( 108 , 109 ), though its role in the development of sarcopenia in CKD is yet to be determined.…”