Hypothermia and the Kidney

Pathophysiology of Ischemia/Reperfusion Injury and Hypothermic Protection

The most frequent cause of AKI in hospitalized patients is transient or prolonged renal hypoperfusion; in 55% of cases AKI may be considered a consequence of a significant decrease in mean arterial blood pressure (prerenal AKI). Prerenal AKI is generally reversible as long as the cause has been eliminated and the tissue has not been damaged at the cellular level. During blood flow interruption, the reduction in medullary blood flow and the resultant decrease of glucose and oxygen delivery to the tubular structures cause an imbalance between delivery and demand. Cells are forced to maintain adenosine 5′-triphosphate (ATP) production by anaerobic glycolysis using glycogen stores and the remaining glucose in the surrounding tissue fluid. This leads to local tissue acidosis. The ATP depletion is followed by the increase of cytoplasmic calcium load, which activates proteases, phospholipases, and caspases and the cellular accumulation of hypoxanthine and reactive oxygen species (ROS).

Hypoxia, glucose depletion, acidosis, and ROS production can contribute to cell death: apoptosis and active necrosis as well. An early structural manifestation of ischemia is the loss of cell polarity with decreased reabsorption of sodium and water from the tubular lumen. Because of diminished sodium reabsorption, the macula densa releases signals that induce constriction of the vasa afferentia (tubuloglomerular feedback). The terminology acute tubular necrosis is misleading because the dominant pattern of tubular cell damage is apoptosis and not necrosis. During the reperfusion phase in presence of an acidotic pH, the cell killing is abrogated. Acidosis (pH < or = 7.0) provides significant protection against cell death during ischemia. On the contrary, the rise of intracellular pH during reperfusion causes cell death. This phenomenon is defined as “pH paradox,”  and it is mediated by changes of intracellular pH in terms of rapidly increase more after reperfusion are responsible of acceleration of cell killing. Reperfusion induces Ca ²⁺ delivery by depleted cells, producing Ca ²⁺ overload and postischemic injury through multiple pathways (e.g., mitochondrial dysfunction, increased ROS formation, and phospholipase activation). The length of reperfusion is important for prevention or mitigation of ischemic AKI, and then for therapeutic implications. The delay of restoration of a normal renal function may be caused by an intense interstitial inflammation and microvasculopathy.

Tubular epithelial and vascular endothelial cells release a diverse range of proinflammatory cytokines, inducing and perpetuating inflammation. Postischemic renal inflammation may contribute to microvasculopathy characterized by endothelial cell swelling that can lead to prolonged ischemia and then a slower reperfusion, even if the primary cause has been eliminated; this is defined as no reflow-phenomenon. Postischemic microvasculopathy has been associated with the risk of developing chronic renal failure in the long term, and it is therefore a meaningful therapeutic target.

Advances in renal hypothermia to prevent ischemic damage were not introduced until the 1950s and 1960s. Experimental examinations performed in dogs, analyzing the effects of hypothermic renal ischemia, showed a reduction of perfusion probably because of cold-induced vasoconstriction with intact tubular function because of the protective mechanism of hypothermia. In 1964, Shirmer and Walton investigated kidney ischemia in a dog model, and showed the renal effects of hypothermia conducted with local cooling: renal function was depressed only temporarily, and irreversible damage was limited ( Table 227.1 ).

A recent animal model of ischemia/reperfusion in the kidney was performed to evaluate the role of different temperature applications (normothermia [±37°C], mild hypothermia [26°C], moderate hypothermia [15°C], and deep hypothermia [4°C]) on the production of oxidative-stress markers. The results showed an increased catalase expression during deep hypothermia, suggesting the association of this level of temperature with higher antioxidative effects with a decreased free radical production. However, tissue protection was not observed. Experimental studies also have investigated the effect of body temperature on renal susceptibility to ischemic injury showing that an elevated body temperature dramatically accentuates hypoxic injury, having a profound impact on renal ATP losses during hemorrhagic shock. In addition, hyperthermia is correlated significantly to ischemic renal injury, whereas hypothermia confers protection. Minimal temperature changes during renal ischemia alter functional and morphologic outcome. These findings in literature showed that in animals hypothermia is able to reduce the risk of renal failure after renal IRI.