The results of our study elucidate the role of hyperglycemia in ischemia reperfusion injury during renal transplantation and have clinical implications for the perioperative management of glucose levels. Furthermore, our findings provide more information for the use of serum NGAL as a diagnostic tool.
This study is the first to document intra-operative trends in blood glucose levels during renal transplantation for both diabetic and non-diabetic recipients. While diabetic recipients were clearly at greater risk for intra-operative hyperglycemia, 33% of non-diabetic recipients reached a blood glucose exceeding 120
mg/dL. These patterns imply more rigorous glucose monitoring, and treatment may be warranted in all patients undergoing transplant. From a diagnostic perspective, this study is also the first to document a drop in serum NGAL levels as early as one hour after transplant. Serum NGAL levels were markedly elevated and began to fall almost immediately after living donor renal transplantation. This decrease fits with the near instant urine output and rapidly falling creatinine clinically seen in living donor renal transplantation. Furthermore, high initial levels and rapid changes limit the utility of using any single NGAL measurement for the purpose of clinical prediction. Instead, an overall trajectory or relative change should be considered when using serum NGAL in patients with existing renal disease. Additionally, the percentage change in serum NGAL at one hour correlated well with the percentage change in creatinine 2 days after transplantation as well as the recipients' GFR at 90 days. These findings are consistent with those in previous studies and reinforce NGAL's utility as a marker for injury and short-term graft function in renal transplantation [18
Of greater clinical importance, elevated glucose level at the time of reperfusion was inversely proportional to the percentage change in serum NGAL and creatinine. In other words, increasing blood glucose led to greater ischemia reperfusion injury as evidenced by changes in these markers. Even though NGAL levels fell in most patients, these levels fells less rapidly and even increased when the allograft was exposed to higher glucose levels at the time of reperfusion. Similarly, serum creatinine fells less rapidly with increasing blood glucose at the time of reperfusion. This phenomenon may imply that recipients with peri-operative hyperglycemia are at greater risk for DGF. As recipient blood glucose rises, the extent of ischemia reperfusion injury, and therefore the risk of DGF, may also increase. Overall, this pattern of injury is likely due to greater oxidative stress and inflammatory response, which fits with our animal model in which rats with hyperglycemia at the time of injury suffered higher terminal creatinine and greater acute tubular necrosis [11
This relationship between hyperglycemia and ischemia reperfusion injury may explain, in part, the mechanism by which recipient diabetes leads to DGF. Although glucose levels increased both in diabetic and non-diabetic recipients during transplantation, diabetic recipients had much higher levels. Diabetes and blood glucose level at the time of reperfusion were clearly predictors of the percentage change in NGAL according to our univariate analysis. However, when we included both in our multivariate model, diabetes was no longer a statistically significant predictor. This finding supports the theory that hyperglycemia is the mechanism by which diabetes leads to DGF in kidney transplant recipients. Fortunately, this effect can be attenuated with greater attention to peri-operative glucose levels. Although targeting glucose levels <100
mg/dL can be difficult and potentially dangerous, our analysis demonstrates a potential benefit to any reduction in glucose level. Therefore, we believe that glucose levels should be checked in patients at risk for hyperglycemia and treated according to standardized protocols.
Despite the strength of being a prospective study, our analysis has some limitations. Use of the living donor population allowed us to eliminate cold ischemia time and minimize variation in donor characteristics but prevented us from analyzing clinical outcomes such as DGF. Furthermore, the size of our population made it difficult to strictly control for every potential confounding factor, such as exact blood pressure throughout the case. The use of NGAL as a surrogate for ischemia reperfusion injury also raises a number of questions. While numerous studies link NGAL to graft function in renal transplantation, these studies vary in the type of NGAL tested (serum versus urine), the time points collected, and the method of comparison (absolute versus relative change in levels). We think that our use of the relative or percentage change in NGAL levels is critical in serum samples given the fact that patients with end stage renal disease have markedly elevated and variable levels at baseline. However, one clear metric for how to use NGAL and interpret it clinically has yet to be established.
Overall, our study is a starting point to determine if peri-operative hyperglycemia has a clear effect on clinical outcomes in renal transplantation. We still need to determine if the observed effects of elevated glucose can be reversed with better glucose control. Similarly, if elevated glucose does increase ischemia reperfusion injury, it is not known how long the allograft is susceptible to injury or how long tight glucose control would be required to prevent injury. Most importantly, we need to determine if clinically significant endpoints like DGF and overall graft survival are clearly affected by intra-operative glucose levels. We have already begun to study the effect of glycemic control in deceased organ donors in prospective randomized trials and hope to extend this work to renal transplant recipients.