Symposium 9.4 – New aspects in AKI prevention and treatment

Symposium Summary

Written by Jasna Trbojevic-Stankovic
All the speakers reviewed and approved the contents

Would you like to know more?

Cost-effective prevention strategies for AKI

Melanie Meersch, Germany

Acute kidney injury (AKI) is among the most common complications for all hospital admissions. Its incidence keeps rising among hospitalized patients, especially those requiring intensive care. Despite major advances in treatment strategies, this syndrome is still associated with significant mortality and dialysis dependence. In light of these facts, it is essential to develop nephroprotective strategies in hospital settings. The latest recommendations from the Acute Disease Quality Initiative Consensus Conference support the use of a combination of damage and functional biomarkers, along with clinical information, to identify patients at high risk for AKI, improve the diagnostic accuracy and therapeutic response.

One possible strategy to prevent AKI is remote ischemic preconditioning (RIPC). RIPC was first applied in cardiac tissue in which brief episodes of myocardial ischemia and reperfusion decreased the size of infarcted tissue. In renal medicine, RIPC attempts to invoke adaptive responses that protect against AKI by triggering brief episodes of ischemia and reperfusion applied in distant tissues or organs before the injury of the kidney. A recent multicentric study on 240 high-risk patients who underwent cardiac surgery concluded that RIPC significantly reduced the rate of AKI and the use of renal replacement therapy. The patients in this study were randomized to receive either remote ischemic preconditioning (3 cycles of 5-minute ischemia and 5-minute reperfusion in one upper arm after induction of anaesthesia) or sham remote ischemic preconditioning (control), both via blood pressure cuff inflation. A more recent study showed that different doses of RIPC significantly increased the production of urinary tissue inhibitor of metalloproteinases 2 (TIMP-2) and insulin-like growth factor-binding protein 7 (IGFBP7), both inducers of G1 cell cycle arrest, thus suggesting that one possible mechanism behind the effect of this intervention is the cell cycle arrest. It is significant to note that the sedative-hypnotic agent propofol seems to interfere with the protective effect of RIPC.

Figure 1. The effects of different doses of RIPC on the risk of AKI development in patients undergoing cardiac surgery (Meersch M et al. Critical Care Medicine 2020)

Another possible option to prevent AKI in high-risk patients is to implement the KDIGO bundles, i.e. a combination of preventive measures including discontinuation of nephrotoxic agents, considering alternatives to radiocontrast agents, maintaining adequate volume status and renal perfusion, applying functional hemodynamic monitoring, tracking serum creatinine and urine output, and avoid hyperglycemia. Despite their feasibility and proven efficacy in preventing AKI, compliance with the KDIGO recommendations in routine clinical practice is low and, according to the recently published results, only 5% of cardiac surgery patients receive the complete bundle. Therefore, more effort is needed to introduce this strategy in routine clinical practice.

“Subclinical” AKI – does it matter?

Jill Vanmassenhove, Belgium

Despite considerable progress over the last decade in the standardization of the AKI definition, the currently available classification criteria still rely on traditional and imperfect parameters such as serum creatinine and urinary output, which may not reliably and timely identify subtle signs of AKI. Namely, the increase in glomerular filtration rate (GFR) during amino acid infusion reveals a “renal reserve,” which can be utilized when the physiological demand for single nephron GFR increases. This suggests that in subclinical renal disease before basal GFR begins to reduce, the renal functional reserve can be recruited in a manner that preserves renal function. Thereupon, once a decline in basal GFR becomes detectable, renal disease is already well progressed. This concept seems to apply in both chronic kidney disease (CKD) and AKI, which led to the introduction of three new entities: subclinical AKI, subclinical acute kidney disease, and subclinical CKD. Subclinical AKI is a condition where there is an increase in biomarkers but without clinical manifestations of AKI.

Figure 2. Entities of AKI syndrome by damage and/or dysfunction

For all these reasons, an extensive search for new biomarkers indicative of early structural renal damage and able to reliably predict the outcome of renal injury has been undertaken. The ideal biomarker should be easily obtained and measurable, preferably from non-invasive sources, organ-specific, able to identify AKI in a stage when functional damage is not yet detectable, and well correlated with the severity of the damage. The test should be easy to perform, with a rapid turnover and high reliability. Several substances have been evaluated for this purpose, including neutrophil gelatinase-associated lipocalin (NGAL) and plasma proenkephalin A 119-159 (penKid), but neither has proven to be causally associated with subclinical AKI. Nevertheless, many more candidates still exist and further studies are needed to evaluate them. For the time being, more effort should be focused on preventing AKI in the clinical setting.

New treatment options for AKI – does anything work?

John A. Kellum, United States of America

AKI management still represents a challenge in clinical practice. The treatment approach depends on clinical context and can vary by resource availability. Existing preventive strategies for AKI include electronic alerts and KDIGO bundle actions, but there are also several emerging novel therapeutics that deserve high attention.

The use of a clinical decision support system is based on the presumption that early detection of AKI could trigger an early nephrologist consultation which might contribute to improve outcome. Although testing such systems has rendered conflicting results, it does appear that they contribute to a discrete but sustained decrease in in-hospital mortality, dialysis use, and length of stay in AKI patients. Therefore, this intervention might contribute to substantial improvements in outcomes and financial savings globally. The KDOQI bundle is a set of general, stage-based management principles in AKI. Their implementation in practice significantly reduced the frequency and severity of AKI, postoperative creatinine increase, length of intensive care, and hospital stay after both cardiac and noncardiac surgery in high-risk patients. Nevertheless, their success depends on the early identification of patients at risk to develop AKI and for this purpose, several biomarkers have been investigated. According to the latest results, both TIMP-2 and IGFBP7, as well as their product, seem to be superior to other existing markers, providing additional information over clinical variables and adding mechanistic insight into AKI.

Recent publications offer an insight into the novel agents that are expected to transform the therapeutic landscape of AKI. These are most notably related to mitochondrial dysfunction which has recently been recognized to have an enormous role in kidney injury and regeneration. The three most promising interventions to treat AKI at present include targeting genes that encode mitochondrial transcriptional factors, coenzyme NAD+ which holds key roles in the regulation of redox status and energy metabolism, and peroxisome proliferator-activated receptor delta nuclear receptor which controls genes that regulate mitochondrial levels and function thud decreasing inflammation and fibrosis. Another possible approach is to promote renal cell regeneration by expanding the renal progenitor cell population.

The impracticality of conducting large individual clinical trials, especially for existing drugs, have recently shifted attention to adaptive clinical trial design which allows evaluation of multiple treatment options simultaneously and efficiently and looks for interactions between them. The potential candidates for AKI to be investigated by this study design include metformin, glutamine, biotin, theophylline, acetaminophen, corticosteroids, cyclosporin, tocilizumab, fenoldopam, and dexmedetomidine.

Further reading

Ostermann M, Zarbock A, Goldstein S, et al. Recommendations on Acute Kidney Injury Biomarkers From the Acute Disease Quality Initiative Consensus Conference: A Consensus Statement. JAMA Netw Open. 2020;3(10):e2019209. doi: 10.1001/jamanetworkopen.2020.19209.

Zarbock A, Schmidt C, Van Aken H; RenalRIPC Investigators. Effect of remote ischemic preconditioning on kidney injury among high-risk patients undergoing cardiac surgery: a randomized clinical trial. JAMA. 2015;313(21):2133-41. doi: 10.1001/jama.2015.4189.

Meersch M, Küllmar M, Pavenstädt H, et al. Effects of Different Doses of Remote Ischemic Preconditioning on Kidney Damage Among Patients Undergoing Cardiac Surgery: A Single-Center Mechanistic Randomized Controlled Trial. Crit Care Med. 2020;48(8):e690-e697. doi: 10.1097/CCM.0000000000004415.

Zarbock A, Küllmar M, Ostermann M, et al. Prevention of Cardiac Surgery-Associated Acute Kidney Injury by Implementing the KDIGO Guidelines in High-Risk Patients Identified by Biomarkers: The PrevAKI-Multicenter Randomized Controlled Trial. Anesth Analg. 2021. doi: 10.1213/ANE.0000000000005458.

Vanmassenhove J, Van Biesen W, Vanholder R, Lameire N. Subclinical AKI: ready for primetime in clinical practice? J Nephrol. 2019;32(1):9-16. doi: 10.1007/s40620-018-00566-y.

Dépret F, Hollinger A, Cariou A, et al. Incidence and Outcome of Subclinical Acute Kidney Injury Using penKid in Critically Ill Patients. Am J Respir Crit Care Med. 2020;202(6):822-829. doi: 10.1164/rccm.201910-1950OC.

Ronco C, Bellomo R, Kellum JA. Acute kidney injury. Lancet. 2019;394(10212):1949-1964. doi: 10.1016/S0140-6736(19)32563-2.

Al-Jaghbeer M, Dealmeida D, Bilderback A, Ambrosino R, Kellum JA. Clinical Decision Support for In-Hospital AKI. J Am Soc Nephrol. 2018;29(2):654-660. doi: 10.1681/ASN.2017070765.

Bataineh A, Dealmeida D, Bilderback A, et al. Sustained effects of a clinical decision support system for acute kidney injury. Nephrol Dial Transplant. 2020;35(10):1819-1821. doi: 10.1093/ndt/gfaa099.

Kashani K, Al-Khafaji A, Ardiles T, et al. Discovery and validation of cell cycle arrest biomarkers in human acute kidney injury. Crit Care. 2013;17(1):R25. doi: 10.1186/cc12503.

Meersch M, Schmidt C, Hoffmeier A, et al. Prevention of cardiac surgery-associated AKI by implementing the KDIGO guidelines in high risk patients identified by biomarkers: the PrevAKI randomized controlled trial. Intensive Care Med. 2017;43(11):1551-1561. doi: 10.1007/s00134-016-4670-3.

Kellum JA, Fuhrman DY. The handwriting is on the wall: there will soon be a drug for AKI. Nat Rev Nephrol. 2019;15(2):65-66. doi: 10.1038/s41581-018-0095-2

Wen X, Li S, Frank A, et al. Time-dependent effects of histone deacetylase inhibition in sepsis-associated acute kidney injury. Intensive Care Med Exp. 2020;8(1):9. doi: 10.1186/s40635-020-0297-3.