Therapeutic approaches to minimise acute renal failure in an animal model of myoglobinuria

AuszugIn 1941, during the London bombardment, the British physician Eric Bywaters (1910- 2003) studied victims of the bombing. They had suffered from crushed limbs and – even if initially appeared in a good condition - developed kidney failure after release of the crushing pressure. This sequence became known as the “crush syndrome”. Bywaters observed dark brown casts in the urine and casts in the renal tubules containing brown pigment. Ironically, Bywaters himself was rejected from military service because of a kidney problem. A few years later, in 1944, he showed that leakage of muscle contents, as a consequence of ischemia and reperfusion of the affected body parts, into the circulation caused renal failure as demonstrated by experiments he performed by injecting myoglobin (or myohaemoglobin as it was called at that time) into rabbits. This condition, termed rhabdomyolysis (RM), can have various causes such as trauma, exertion, muscle hypoxia, genetic defects, infections, changes in body temperature, metabolic and electrolyte disorders, drugs and toxins or may be idiopathic. Depending on the cause, there is a moderate to high risk for patients to develop acute renal failure (ARF) with fatal outcome. Almost 70 years after Bywaters observations, little is known about the precise molecular events leading to this pathology and further investigation on the mechanism of renal damage and therapeutic approaches to combat this are warranted. Over a long period, renal vasoconstriction, direct heme protein-induced cytotoxicity and intraluminal cast formation have been proposed as the main pathophysiological factors involved in RM-induced renal failure and this has lead to a number of proposed treatments, which were more or less unsuccessful. Recent studies have highlighted the importance of oxidative injury to the kidney in the development of RM-induced renal failure. This work aims to elucidate the role of myoglobin-mediated oxidative stress and how renal tissue may be protected against it. We used both an in vitro cell model and an in vivo rat model to simulate the conditions as they appear under myoglobinuric conditions. We tested selected iron chelators and antioxidants in regards of inhibiting oxidative stress and correlated this with protection from renal dysfunction. The data obtained in these studies may help to gain a deeper understanding of the molecular processes that are initiated by myoglobin and may contribute to develop new strategies to combat ARF after RM.