Renal replacement therapy neutralizes elevated MIF levels in septic shock

Abstract

BackgroundMacrophage migration inhibitory factor (MIF) is known to amplify the immune response in septic animal models. Few clinical data support this pro-inflammatory role in septic patients. Renal replacement therapy (RRT) as adjuvants in the complex therapy of sepsis has been proposed as a possible approach to eliminate elevated circulating cytokines. Since recent data suggest that MIF can be effectively removed from the circulating blood pool in patients with chronic kidney disease, we here aimed to investigate whether RRT in septic shock can lower plasma levels of this pro-inflammatory cytokine in septic shock patients.MethodsAn observational single-center study on an internist intensive care unit (ICU) was conducted. MIF plasma levels and mortality of n = 25 patients with septic shock were assessed with a previously validated method for reliable MIF values. The effect of continuous renal replacement therapy (CRRT) on daily MIF levels and mortality was assessed by comparing patients with and without need for CRRT due to acute kidney injury (AKI).ResultsMIF plasma levels in patients undergoing CRRT due to septic AKI were steadily decreased compared to those from patients without CRRT hinting at a MIF removal by hemodialysis. MIF release during ICU stay as assessed by MIFAUC was lower in patients undergoing CRRT, and Kaplan-Meier analysis revealed a distinctly lower mortality in patients undergoing CRRT. Analysis of daily MIF levels showed that patients who did not survive septic shock exhibited steadily higher MIF plasma levels and higher MIFAUC compared to those surviving sepsis. Low MIF levels were closely associated with improved survival.ConclusionsThis is the first study investigating the effect of efficient MIF removal from the plasma pool of patients with septic shock. Reduction of high circulating MIF by CRRT therapy was accompanied by improved survival. Thus, targeted removal of MIF from the circulating blood pool might be a promising approach to reduce mortality in severe sepsis.Electronic supplementary materialThe online version of this article (doi:10.1186/s40560-016-0163-2) contains supplementary material, which is available to authorized users.

Blood purification treatment initiated at the time of sepsis diagnosis effectively attenuates serum HMGB1 upregulation and improves patient prognosis

“…As techniques improve, blood purification methods, including continuous renal replacement therapy (CRRT) and hemoperfusion (HP), are becoming more commonly used as treatment methods for sepsis ( 8 , 9 ). Previous reports have suggested that the attenuation of several pro-inflammatory cytokines, such as interleukins and tumor necrosis factors, may be the primary underlying mechanism of blood purification as an effective treatment for sepsis ( 10 , 11 ). However, other studies have reported no association between the attenuation of cytokines and the use of blood purification techniques during sepsis ( 12 , 13 ).…”

How Does Continuous Renal Replacement Therapy Affect Septic Acute Kidney Injury?

“…The cutoff value of standard CRRT is 30–40 kDa [21], and the molecular weight of common cytokines such as interleukin (IL) 1 beta is 17 kDa, IL-1RA is 15–20 kDa, IL-2 is 15 kDa, IL-6 is 26 kDa, IL-8 is 8 kDa, macrophage migration inhibitory factor (MIF) is 12.5 kDa, IL-10 is 35–40 kDa and tumor necrosis factor (TNF) α is 51kDa. So among the most included cytokines, only IL-10 and TNF-α are outside the cutoff value of standard CRRT; all other cytokines can be slowly removed in standard CRRT [21, 23-25]. However, certain clinical research declared that the concentration of plasma cytokines makes no difference during CRRT, though some cytokines can be detected in the filtrate fluid [24].…”

“…It has been proved that decreased MIF concentration in cancer can induce macrophage polarization from proinflammatory macrophages (predominantly CD11b + /Ly6C high cells) to pro-wound healing macrophages (CD11b + /Ly6C intermediate cells) [33]. The MIF level decreases obviously during CRRT or hemodialysis and can improve the prognosis [23, 34]; however, how it works is still unknown and the MIF plasma pool is reconstituted early after the termination of hemodialysis from unknown sources. Probably the same thing happens during CRRT of septic AKI patients.…”

Timing of renal replacement therapy in acute kidney injury—an issue of importance?

“…This is important, as acute kidney injury is a systemic disease affecting inflammation and function of different organs (16). Against this background it can be speculated that early treatment attenuates pro-inflammatory effects and a further decline in other organs function (17). Patients assigned to the early group in the AKIKI trial are almost identical with, but at least very similar to the patients assigned to the late group in the ELAIN trial.…”