Angiotensin 2 for AKI After OLT

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

Inclusion criteria

A. End stage liver disease (ESLD) with acceptance of organ allocation offer. B. Stable renal function in the 48 hours prior to transplant (defined as < 30% change in serum creatinine) C. Adult patients > 18 years old

Exclusion criteria

A. Active use of renal replacement therapies B. Recent (within last 3 months) history of CVA or MI C. Patients with hypercoagulable state as evidenced by pre-existing venous thromboembolism or known thrombophilia (Antiphospholipid syndrome, Factor V- Leiden etc.) D. Combined liver transplant and intrathoracic surgery cases (not including chest tube placement) E. Multiple organ transplantation F. Congestive heart failure defined as left ventricular ejection fraction <45% G. Inability to obtain consent from the patient or surrogate H. Known allergy or sensitivity to any study medication I. Hepatocellular Carcinoma