Abstract
Aim: The complement system is activated in acute kidney injury (AKI). Anti-C5 antibody targets the common terminal portion of the complement cascade that generate the terminal complex C5b-9 and has a renal-protective effect in paroxysmal nocturnal hemoglobinuria. However, the anti-C5 antibody’s role in ischemia/reperfusion (I/R)-induced AKI has not been fully investigated. We therefore evaluated its effect on the pathophysiological cascade of I/R-induced AKI.Methods: Sprague–Dawley rats underwent unilateral right kidney nephrectomies with simultaneous clamping of the contralateral hilum for 60 min (ischemia), followed by reperfusion. In addition to a placebo, two treatment groups received either high or low doses of anti-C5 monoclonal antibody. After 48 h, the rats were euthanized, blood was drawn to evaluate systemic inflammation and to estimate glomerular filtration rate (GFR). The remaining kidney was removed for pathological evaluation and intra-renal complement activation.Results: I/R induced significant intra-renal complement activation and systemic inflammation compared with unilateral nephrectomy group. The anti-C5 antibody ameliorated the intra-renal complement activation (intra-renal C3 and C6), reduced systemic inflammation (C-reactive protein, and systemic C3), decreased intra-renal acute tubular necrosis damage and improved GFR (seen by the sensitive marker, serum cystatin C; 1.63 mg/L (I/R + placebo), 1.36 mg/L (I/R + low dose) and 1.21 mg/L (I/R + high dose), p = .08 and .03 compared with I/R + placebo).Conclusion: In I/R-induced AKI, the monoclonal anti-C5 complement factor ameliorates intra renal complement activation, decreases local and systemic inflammation and may improve GFR.
Highlights
Acute kidney injury (AKI) is a common medical complication of up to 25% of intensive care unit admissions, with severe consequences, and mortality increasing up to 60% [1,2,3]
The complement system is involved in several types of AKIs including paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome, dense deposit disease and C3 glomerulopathy [10,11]
Administration of the high anti-C5 dosage to the sham group was found to be safe with no significant changes as compared to the sham þ placebo group with respect to blood count, renal function tests, C-reactive protein (CRP), complement cascade and kidney histological and immunofluorescence findings (Table 1)
Summary
Acute kidney injury (AKI) is a common medical complication of up to 25% of intensive care unit admissions, with severe consequences, and mortality increasing up to 60% [1,2,3]. AKI pathogenesis includes hypoxia that causes ischemia, followed by reperfusion [4,5]. The ischemia-reperfusion (I/R) process triggers intra-renal, and systemic inflammation responses [6]. The complement system has an important role in the pathogenesis of renal failure, and is involved in glomerular, tubulointerstitial and vascular kidney injuries among others [9]. C3 and C6 knockout mice are relatively protected from renal I/R injury. This protection is missing in C4 knockout mice [13] This indicates that the dominant part of the complement system involved in I/R injury is the alternative pathway [13]. The use of monoclonal antibody that prevent cleavage of C5 in an attempt to inhibit the effect of I/R injury in mice models has resulted in reduced inflammation and improved renal function [14]. An attempt to block C3 by the potent murine complement inhibitor CR1 related
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