The Daily Dose • Sunday, May 16, 2021

Studying AKI: An Important yet Challenging Complication to Tackle

Allison M. Janda, MD

Acute kidney injury (AKI) is one of the most common causes of organ failure following surgery and is associated with substantially worse outcomes, including longer hospital stays, increased short- and long-term mortality and increased hospital costs even with subtle increase in creatinine. The presenters of the Early-Stage Anesthesiology Scholars sponsored panel, “AKI from Bench to Bedside: Hopeless or Hopeful Progress?” on May 15 at the IARS 2021 Annual Meeting, examined the difficulties in treating and preventing AKI in the perioperative and critical care setting. Three experts in this study area, Jaime Privratsky, MD, PhD, Loren Smith, MD, PhD, and Marcos Lopez, MD, MS, shared their findings and examined the unanswered questions around AKI.

“Novel mitochondrial protectants for postsurgical and critical illness AKI”

The first panelist Jamie Privratsky, MD, PhD, an Assistant Professor and intensive care physician scientist at Duke University Medical Center, spoke about novel mitochondrial protectants for postsurgical and critical illness AKI. Dr. Privratsky explained that the primary focus of his research was on a potential immune system modulation therapy for treatment of AKI, but one of the compounds he and his team were studying, Annexin A1sp (ANXA1sp), was found to be associated with decreased incidence of postsurgical AKI through a mitochondrial protective mechanism. ANXA1sp was found to mediate mitochondrial protection by augmenting oxidative damage and stress, which in turn causes less mitochondrial fission and fragmentation, and allows for more efficient mitophagy to remove damaged mitochondria by upregulating SIRT3 in the mitochondria kidney tubules.

His work showed that ANXA1sp ameliorates ischemic AKI, limits kidney cell death following ischemia and promotes mitochondrial integrity through this mechanism. Other preclinical and clinical studies have shown favorable results for potential mitochondrial protection therapies and improvement of AKI incidence after surgery including remote ischemic preconditioning and mitochondrial transplantation after a stressor, he also explained. Mitochondrial protective agents have promise in ameliorating postsurgical AKI supported by his work and the work of other clinical and preclinical studies.

“Bridging the Gap between the Bench and the Bedside: Developing Lipoprotein-based Therapeutics to Prevent AKI”

Loren Smith, MD, PhD, an Assistant Professor at Vanderbilt Medical Center and second panelist, provided some context regarding AKI, stating that AKI is extremely common with an incidence between 15-30% after cardiac surgery, 15-40% after vascular surgery with over 6 million cases of AKI in the world annually. She also described the potential questions about AKI that preclinical research and observational research can generate new treatments for AKI or methods of preventing AKI. Her research leverages both preclinical and clinical work to focus on the relationship between high-density lipoproteins (HLD) and AKI. As mechanisms of AKI include inflammation, oxidative stress endothelial dysfunction, ischemia and nephrotoxins, and HDL has shown to counter these known mechanisms of AKI, it followed that HDL should be investigated as a way to potentially mitigate AKI.

Additionally, previous studies have shown that patients with lower HDL levels had increased rates of AKI in sepsis compared to those with normal or high HDL levels. In her work in the cardiac surgery population, Dr. Smith and her team demonstrated an association between preoperative HDL concentrations and a decreased risk of AKI after cardiac surgery and demonstrated that statin exposure strengthens the association between a high preoperative HDL concentration and a decreased risk of AKI after cardiac surgery. The relationship with statins alone and AKI is not direct, likely due to non-HDL-mediated harmful renal effects. Dr. Smith also found that as the concentration of small HDL particles preoperatively increased, the incidence of postoperative AKI and oxidative stress decreased, and in cardiac surgery those with higher levels of HDL preoperatively had improved renal function 12-16 months postoperatively than those with lower HDL levels. Preclinical studies in rats have also shown a favorable relationship between HDL and prevention of AKI. The findings of these preclinical research studies and observational clinical research studies can inform clinical trials to test possible novel treatments for AKI.

“Recent clinical trials and acute kidney injury: what we have learned and where we are headed”

Marcos Lopez, MD, MS, Assistant Professor of Anesthesiology, Division of Anesthesiology Critical Care Medicine at Vanderbilt University Medical Center, and the final panelist, discussed the current and future state of clinical trials pertaining to reducing perioperative AKI. Dr. Lopez’s group conducted a systematic review on perioperative AKI clinical trials and found 104 high-impact clinical trials studying perioperative AKI spanning multiple categories of interventions. During this talk, Dr. Lopez focused on those trials that included interventions in the categories of anesthetic technique, ischemia, remote ischemic preconditioning and fluids. Studies on the impact of anesthetic technique include a study published in Kidney International in 2016, “Perioperative dexmedetomidine reduces the incidence and severity of acute kidney injury following valvular heart surgery” from Cho et al., which found a favorable reduction in postoperative AKI severity with administration of dexmedetomidine.

Studies targeting ischemia include those which focused on assessing the impact of levosimendan for hemodynamic support on postoperative outcomes, but did not detect a difference between groups in 30-day mortality, composite complications, or renal endpoints. In the INPRESS study, intraoperative norepinephrine was examined to control arterial pressure in major abdominal surgery compared to ephedrine-based hemodynamic support and found a favorable association in preventing a composite complication outcome. They did not find a significant difference between groups for their renal endpoint. The REVAKI-2 trial investigators studied the impact of sildenafil and AKI after cardiac surgery and did not find a significant effect on creatinine, but did show an increase in other organ dysfunction. Nitric oxide has been shown to decrease AKI and major adverse kidney events after cardiac surgery in a single large RCT, but due to high cost of provision of nitric oxide therapy, more studies are needed. Remote ischemic preconditioning has been studied in multiple clinical trials. Dr. Lopez summarized these studies explaining that some studies showed a benefit of remote ischemic preconditioning on postoperative AKI, but some studies did not find a difference in composite outcomes or renal outcomes. However, these studies differed in the anesthetic technique.

In the fluids category, the RELIEF trial examined restrictive versus liberal fluid therapies and found no difference in their primary outcome of death or disability-free survival at one year, but did find an increase in AKI in the restrictive fluid group. The SMART trial showed that balanced crystalloid treatment as opposed to saline was associated with decreased major adverse kidney events in the critical care population. The FLASH study found that hydroxyethyl starch was detrimental to kidney function postoperatively and this corroborated previous studies that hydroxyethyl starch may be harmful to patients.

Regarding upcoming trials, one exciting study, “Effect of Nitric Oxide in Cardiac Surgery Patients With Endothelial Dysfunction,” is examining the effect of nitric oxide in cardiac surgery patients with endothelial dysfunction. Additionally, NEPHROCAR, a single-center study in France is studying whether a hemodynamic intervention applied to those with elevated early biomarkers of AKI to examine whether early markers of AKI provide a period of intervention providers can utilize to decrease AKI. Another, “Phase 3 for Prevention of Major Adverse Kidney Events (MAKE) in Subjects at High Risk for AKI Following Cardiac Surgery,” is studying the impact of teprasiran, which inhibits apoptosis, on AKI and is awaiting complete results. Finally, an exciting study ongoing at Vanderbilt University, “Risk of Oxygen During Cardiac Surgery Trial (ROCS),” is assessing the risk of hyperoxia during cardiac surgery in a randomized clinical trial and has completed enrollment with results to be released in the near future. To conclude, Dr. Lopez called for more observational outcomes studies to examine patient-centered outcomes and for additional large, pragmatic trials to obtain more high-quality evidence to inform our care of patients and mitigate and treat AKI.