Soluble Thrombomodulin Protects Ischemic Kidneys

Sharfuddin, Asif; Sandoval, Ruben M.; Berg, David T.; McDougal, Grant E.; Campos, Sílvia B.; Phillips, Carrie L.; Jones, Bryan E.; Gupta, Akanksha; Grinnell, Brian W.; Molitoris, Bruce A.

doi:10.1681/asn.2008060593

Cited by 118 publications

(109 citation statements)

References 49 publications

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“…However, a soluble thrombomodulin form (sTM) circulates in plasma and possesses similar functional activities as membrane-bound thrombomodulin. Treatment with sTM attenuated ischemia-reperfusion renal injury in the rat (41). One could speculate that, because of dysfunctional sTM, in THBD-mutated recipients, the grafts were not sufficiently protected against complement activation and prothrombotic stimuli triggered by ischemia-reperfusion injury.…”

Section: Discussionmentioning

confidence: 99%

Relative Role of Genetic Complement Abnormalities in Sporadic and Familial aHUS and Their Impact on Clinical Phenotype

Noris¹,

Caprioli²,

Bresin³

et al. 2010

Clinical Journal of the American Society of Nephrology

913

1,194

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Background and objectives: Hemolytic uremic syndrome (HUS) is characterized by microangiopathic hemolytic anemia, thrombocytopenia, and renal impairment. Most childhood cases are caused by Shiga toxin-producing bacteria. The other form, atypical HUS (aHUS), accounts for 10% of cases and has a poor prognosis. Genetic complement abnormalities have been found in aHUS.Design, setting, participants, and measurements: We screened 273 consecutive patients with aHUS for complement abnormalities and studied their role in predicting clinical phenotype and response to treatment. We compared mutation frequencies and localization and clinical outcome in familial (82) and sporadic (191) cases.Results: In >70% of sporadic and familial cases, gene mutations, disease-associated factor H (CFH) polymorphisms, or anti-CFH autoantibodies were found. Either mutations or CFH polymorphisms were also found in the majority of patients with secondary aHUS, suggesting a genetic predisposition. Familial cases showed a higher prevalence of mutations in SCR20 of CFH and more severe disease than sporadic cases. Patients with CFH or THBD (thrombomodulin) mutations had the earliest onset and highest mortality. Membrane-cofactor protein (MCP) mutations were associated with the best prognosis. Plasma therapy induced remission in 55 to 80% of episodes in patients with CFH, C3, or THBD mutations or autoantibodies, whereas patients with CFI (factor I) mutations were poor responders. aHUS recurred frequently after kidney transplantation except for patients with MCP mutations.Conclusions: Results underline the need of genetic screening for all susceptibility factors as part of clinical management of aHUS and for identification of patients who could safely benefit from kidney transplant.

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Section: Discussionmentioning

confidence: 99%

Relative Role of Genetic Complement Abnormalities in Sporadic and Familial aHUS and Their Impact on Clinical Phenotype

Noris¹,

Caprioli²,

Bresin³

et al. 2010

Clinical Journal of the American Society of Nephrology

913

1,194

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“…55 Another emerging possibility to act therapeutically on endothelial vascular integrity involves Toll-like receptor 4-dependent activation of endothelial cells 56 and modulation thrombomodulindriven pathways. 57 From the long-term perspective, postinsult recovery of the peritubular capillary network may prevent chronic tubulointestinal hypoxia and fibrosis. 58 Therefore, the therapeutic potential of strategies targeting vascular repair and regeneration, such as angiogenic factors, and stem or progenitor cell populations is worthy of further preclinical testing.…”

Section: Targets To Protect the Nephrovascular Unitsmentioning

confidence: 99%

Renal Hemodynamics in AKI

Matějovič

İnce

Chawla

et al. 2016

Journal of the American Society of Nephrology

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Novel therapeutic interventions are required to prevent or treat AKI. To expedite progress in this regard, a consensus conference held by the Acute Dialysis Quality Initiative was convened in April of 2014 to develop recommendations for research priorities and future directions. Here, we highlight the concepts related to renal hemodynamics in AKI that are likely to reveal new treatment targets on investigation. Overall, we must better understand the interactions between systemic, total renal, and glomerular hemodynamics, including the role of tubuloglomerular feedback. Furthermore, the net consequences of therapeutic maneuvers aimed at restoring glomerular filtration need to be examined in relation to the nature, magnitude, and duration of the insult. Additionally, microvascular blood flow heterogeneity in AKI is now recognized as a common occurrence; timely interventions to preserve the renal microcirculatory flow may interrupt the downward spiral of injury toward progressive kidney failure and should, therefore, be investigated. Finally, development of techniques that permit an integrative physiologic approach, including direct visualization of renal microvasculature and measurement of oxygen kinetics and mitochondrial function in intact tissue in all nephron segments, may provide new insights into how the kidney responds to various injurious stimuli and allow evaluation of new therapeutic strategies.

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“…23 Nonetheless, these and other cytokine-blocking experiments have not been conclusive and have also failed in clinical trials. 24 Recent preclinical studies suggest an anti-inflammatory role for soluble thrombomodulin in AKI, 25 and release of stem cell factor by MMP-9 has an antiapoptotic effect through activation of cKit. 26 Toll-like receptors (TLRs) are a class of proteins that play an important role in alerting the innate immune system.…”

mentioning

confidence: 99%