How does rhabdomyolysis cause Acute Kidney Injury?
Rhabdomyolysis causes Acute Kidney Injury through a combination of kidney vasoconstriction, direct oxidant injury, and tubular obstruction.
Muscle damage causes interstitial edema at the site of injury. The fluid shift from the intravascular space leads to activation of the renin-angiotensin-aldosterone system (RAAS) and sympathetic nervous system.
Vasoconstrictor mediators including endothelin-1, thromboxane-A2, tumor necrosis factor-α, and F2-isoprostanes are also upregulated.
The binding of nitric oxide to myoglobin may further contribute to vasoconstriction.
The net result is early and prolonged kidney vasoconstriction, which may manifest as oliguria with a low urine sodium concentration prior to progression to acute tubular injury.
Free iron released from myoglobin may lead to the formation of oxygen-free radicals as ferrous iron is converted to ferric iron (Fenton reaction).
Myoglobin itself has been found to be directly toxic to tubular cells by causing lipid peroxidation of tubular cellular membranes.
Under normal conditions, small amounts of myoglobin are filtered, then endocytosed and metabolized by proximal tubular cells.
When myoglobin levels in the tubules exceed the absorptive capacity of the proximal tubular cells, myoglobin may complex with Tamm-Horsfall protein (THP) in the distal nephron to form casts leading to intra-tubular obstruction. An acidic environment (urine pH < 6.5) favors the formation of these complexes.