Research Article: The role of complement activation in rhabdomyolysis-induced acute kidney injury

Date Published: February 21, 2018

Publisher: Public Library of Science

Author(s): XuDong Huang, Wei Zhao, LiXia Zhang, XinJun Yang, LiHui Wang, YunShuang Chen, JingHua Wang, Chao Zhang, GuangLi Wu, Daniela Ponce.


Rhabdomyolysis (RM) may cause kidney damage and results primarily in acute kidney injury (AKI). Complement is implicated in the pathogenesis of renal diseases and ischemia-reperfusion injury (IRI), but the role of complement, especially its activation pathway(s) and its effect in RM-induced AKI, is not clear. This study established a rat model of AKI induced by RM via intramuscular treatment with glycerol. Cobra venom factor (CVF) was administered via tail vein injection to deplete complement 12 h prior to intramuscular injection of glycerol. We found that the complement components, including complement 3 (C3), C1q, MBL-A, factor B(fB), C5a, C5b-9, and CD59, were significantly increased in rat kidneys after intramuscular glycerol administration. However, the levels of serum BUN and Cr, renal tubular injury scores, and the number of TUNEL-positive cells decreased significantly in the CVF+AKI group. These results suggest that complement plays an important role in RM-induced AKI and that complement depletion may improve renal function and decrease renal tissue damage by reducing the inflammatory response and apoptosis.

Partial Text

Rhabdomyolysis (RM) is characterized by the breakdown of skeletal muscle and the release of intracellular muscle contents into the circulatory system. These cell contents include muscle enzymes, such as creatine phosphokinase (CK), lactate dehydrogenase (LDH), and glutamic oxalacetic transaminase (GOT), the heme pigment myoglobin, electrolytes, such as potassium and phosphate, and purines [1,2]. The spectrum of the syndrome ranges from an asymptomatic elevation of serum muscle enzymes to life-threatening extreme enzyme elevations, electrolyte imbalances, and acute kidney injury (AKI) [3]. AKI is the primary and most severe complication of RM, and approximately half of RM patients present with AKI. Rhabdomyolysis accounts for an estimated 8% to 15% of AKI cases, and it is associated with a mortality rate of 5–8% [4,5]. The mortality rate is highly dependent upon the rapidity of access to medical support, with more prompt treatment corresponding to a lower mortality rate. The mortality rate of rhabdomyolysis induced by earthquakes and other natural disasters is significantly higher than that of rhabdomyolysis that occurs in the hospital due to an inability to be treated quickly.

Intramuscular injection of glycerol efficiently reproduces the clinical syndrome of RM-induced AKI in humans. Our previous research revealed that serum myoglobin was obviously increased during the very early stages of renal injury [9], and the results of the present study revealed associated renal dysfunction. BUN and Cr levels increased steadily and significantly, and renal histology revealed damaged tissue. The normal structure at the junction of the cortex and medulla disappeared at 72 h. RM-induced AKI is a complex process, and the exact pathological mechanism is not clear. Research has demonstrated that complement plays a pathological role in a variety of renal diseases [21–24]. For example, uncontrolled AP activation within the kidney is the primary cause of scleroderma renal crisis (SRC) [25]. The complement system is also the primary cause of atypical hemolytic uremic syndrome (aHUS), with uncontrolled activation within the microvasculature [26]. Complement is activated via the AP during the early phase of reperfusion in renal IRI. These results suggest that the kidney may be intrinsically susceptible to complement-mediated injury.




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