Angiotensin 2 for AKI After OLT

Kidney injury is a common complication following liver transplantation and is associated with a higher complication rate and increased risk of death. While there are many factors that likely contribute to kidney injury in the perioperative period, a relative low serum level of angiotensin 2 (Ang 2) (a protein hormone that causes blood vessels to narrow) found in patients with liver cirrhosis (late stage of liver damage) may increase their risk of developing acute kidney injury (sudden episode of kidney failure or damage). We propose to investigate how early administration of Ang 2, a new vasopressor drug approved by the FDA in December 2017 for patients with low blood pressure, during the intra-operative period of liver transplant surgery affects the rate of kidney injury after transplantation. Patients who are deemed appropriate candidates for the study will be randomized 1:1 to the treatment and control groups. The intervention period of the study will occur in the operating room during transplant surgery and will be performed by their anesthesiologists. In the Treatment group, patients will receive Ang 2 infusions in addition to other standard vasopressors while patients in the control group will receive standard vasopressors alone. The infusion of Ang 2 in the treatment group will continue through the duration of the surgery and will be stopped prior to leaving the operating room. Both the treatment group and the control group will then be followed for 14 days to evaluate rates of kidney injury and to look for any complications. The follow up period will be extended to 28 days to look at in-hospital mortality rates in both groups. The daily follow up analysis will occur while the enrolled patients are inpatient following their transplantation surgery and will be done by looking at lab values and other data that is routinely gathered by their managing teams. This study will serve as a pilot study to evaluate feasibility of our protocol and to collect some preliminary data on the use of Ang 2 in this patient population. As such we plan to enroll approximately 30 patients who have accepted an offer to receive a donor liver. We hope to reach our goal enrollment within 5 months of starting the study.

Acute kidney injury is a common perioperative complication following liver transplantation with an incidence of approximately 55%. Due to the complex physiologic derangements present in cirrhotic patients, multiple etiologies and processes may contribute, including chronic and acute hepatorenal syndrome, ATN, renal toxic medication administration, microvascular circulatory dysfunction from vasopressors, and hypoperfusion from the vasodilatory and hypovolemic forms of shock that are common during liver transplantation. While some of the risk factors for these causes of AKI can be mitigated, our current area of investigation revolves around the modulation of the renin-angiotensin system in the prevention of perioperative AKI. In cirrhosis, poor renal blood flow causes an increase in circulating levels plasma renin. However, recent studies suggest low levels of angiotensinogen and angiotensin 2, which are associated with AKI in cirrhotic patients5 and may contribute to the risk of perioperative AKI in liver transplant patients.

Angiotensin 2 was approved for clinical use as a vasopressor in 2017. The efficacy of angiotensin 2 at increasing systemic blood pressure in patients with vasodilatory shock was demonstrated by the ATHOS 3 trial. This study found that the addition of angiotensin 2 increased MAP by close to 10mmHg compared to placebo (12.5 vs 2.9 mmHg p< 0.001) and allowed for a decrease in other vasopressor utilization. Post-hoc analysis of the ATHOS-3 trial by Tumlin et al demonstrated that patients in vasodilatory shock with AKI had higher rates of recovery from AKI and fewer days requiring dialysis than those who did not receive angiotensin 2.

As vasodilatory shock is common among patients undergoing LT, this finding is relevant to our patient population. We hypothesize that angiotensin 2 will reduce AKI in patients undergoing LT, where vasodilatory shock is also very common.

Hypothesis: We propose that a relative deficiency of angiotensin 2 predisposes cirrhotic patients to develop acute kidney injury following liver transplantation. We hypothesize that initiating angiotensin 2 infusion as a short duration infusion during the intra-operative period of liver transplant surgery will decrease the incidence of postoperative acute kidney injury.

Aim1: Evaluate the efficacy of Angiotensin 2 to reduce incidence of acute kidney injury (AKI) following liver transplantation. Rates of recovery from AKI in patients with septic shock have been established in post-hoc analysis of the ATHOS-3 study. With high rates of AKI following transplant surgery as well as a patient population with predisposition for AKI in part due to a relative angiotensin 2 deficiency, we hope to demonstrate that the addition of angiotensin 2 to standard vasopressor regimens during transplant surgery decreases the incidence of postoperative AKI.

Aim 2: Evaluate the safety of angiotensin 2 in cirrhotic patients. While cirrhotic patients were included in the two largest studies of synthetic angiotensin 2 (ATHOS-1 and ATHOS-3), those with MELD > 40 were excluded, and no specific subgroup analysis was done. While several case reports of safe administration of angiotensin 2 in patients with cirrhosis have been published, we hope to further investigate its safety during liver transplant surgery. We hypothesize that angiotensin 2 can safely be administered in cirrhotic patients