Acute kidney injury (AKI) is a severe yet common complication among critically ill patients in the intensive care unit (ICU). The incidence of AKI is now considered to be higher than previously believed, with over 50% of patients in the ICU developing AKI at some point during their critical illness and up to 38% requiring Renal Replacement Therapy (RRT) 1. Mortality among ICU patients with AKI and multi-organ failure can be higher than 50% and even 80% in those needing RRT 2,3. However, there is considerable heterogeneity between different reports due to differences in examined patient populations (e.g., medical and surgical ICUs), applied definitions of AKI, and various treatment modalities.
RRT as support for insufficient kidney function during an acute injury condition has become a routine procedure in managing critically ill patients, resulting in the widespread adoption of various techniques, such as intermittent hemodialysis (IHD) and continuous RRT (CRRT).
The decision to stop RRT is a critical step that necessitates careful consideration of various clinical parameters. Currently, the liberation process is informed by changes in traditional kidney function markers, such as serum creatinine and urine output, in conjunction with the patient's clinical status.
The current routine practice fails to determine the optimal time for RRT liberation:
Clinicians initiate RRT when confronted with life-threatening complications of acute uremia. However, the situation is often less obvious when it comes to discontinuation. Unintentional interruption of therapy might occur when clotting in the extracorporeal circuit. Besides, diagnostic or interventional measures such as MRI scans or surgery often require immediate pausing of dialysis therapy to facilitate patient logistics 4. But – in the absence of the aforementioned factors - when can an informed decision be made to stop dialysis?
The 2012 Clinical Practice Guidelines for Acute Kidney Injury of the Kidney Disease Improving Global Outcomes (KDIGO) organization recommends that "RRT should be discontinued when it is no longer required because intrinsic kidney function has recovered to the point that it is adequate to meet patients need." However, these guidelines are based on expert opinions and lack precise criteria for when and how clinicians should consider stopping a current therapy 4.
With currently no established guidelines for discontinuation of RRT in patients with AKI, the practices of RRT discontinuation remain dependent on the healthcare facility policy and vary from early ("fast track" approach) to late ("wait and see" approach) stopping of RRT, accompanied by an unacceptably high rate of unsuccessful attempts 6.
Daily assessment is warranted to evaluate whether the patient meets the clinical criteria to move forward with the liberation process, including 5:
- Resolution of the precipitating cause of AKI requiring dialysis.
- Improvement in multi-organ failure.
- Hemodynamic stability.
- The need for volume removal does not exceed daily urine output.
- Absence of electrolyte imbalance refractory to medical management.
- Assumed intrinsic kidney function capable of maintaining acid-base and metabolic homeostasis.
One survey of nephrologists treating patients requiring dialysis due to AKI found that the most common criteria to stop RRT were resolution of oliguria (51%), resolution of volume overload (29%), improvement in serum creatinine (27%), as well as resolution of hyperkalemia (21%) 7.
Increasing urine output and decreasing serum creatinine concentrations may also indicate the beginning of renal recovery. However, as previously discussed, serum creatinine has limitations, including technical removal by dialysis, leading to low plasma levels, complicating the decision-making process. Like serum creatinine, urine output is influenced by factors unrelated to kidney function, leading to false-positive interpretations and potentially premature weaning decisions 8.
Despite the current reliance on these traditional markers, accurately determining the optimal time for RRT liberation remains challenging, and there is a need for a more precise biomarker to support this decision-making process.
PenKid serves as a valuable potential tool to guide clinicians in RRT liberation.
Proenkephalin A 119–159 (penKid) is a stable surrogate marker for endogenous enkephalins, and it is considered a functional kidney marker closely related to the iohexol-determined GFR, the gold standard of kidney function determination.
In the realm of AKI, there is a recognized need for relevant biomarkers that can accurately assess kidney function, especially in the context of RRT. The data we generated with penKid during our real-world evaluation at University Hospital Heidelberg allowed us to observe that penKid seems not to be affected by the RRT procedure, as standard markers are. In this case, penKid may help to identify patients at high risk for liberation failure or patients with unnecessary prolongation of RRT, potentially supporting successful RRT liberation decisions in the future.
Recently published data supported these real-world findings. The post-hoc analysis of the multicentric RICH and ELAIN trials demonstrates that penKid may be a competent biomarker to monitor the recovery of kidney function during continuous RRT (CRRT) and predict successful liberation from CRRT 9,10.
As ongoing research and clinical validation continue, the further incorporation of penKid and other innovative biomarkers into routine clinical practice may pave the way for more personalized and successful approaches to stop RRT in critically ill patients with AKI.
If you want to learn more about the integration process of penKid the clinical routine and its performance, read our latest interview with Professor Gernot Marx, Head of the Department of Operative Intensive Care Medicine and Intermediate Care at the University Hospital RWTH Aachen:
(1) Kaufman J, Dhakal M, Patel B, Hamburger R. Community-acquired acute renal failure. Am J Kidney Dis. 1991;17:191–8.
(2) Mehta R et al. Spectrum of acute renal failure in the intensive care unit: the PICARD experience. Kidney Int. 2004;66:1613–21.
(3) Uchino S, Kellum JA, Bellomo R, Doig GS, Morimatsu H, Morgera S, et al. Acute renal failure in critically ill patients: a multinational, multicenter study. JAMA. 2005;294:813–8.
(4) Acute Kidney injury Work Group. KDIGO clinical practice guideline for acute kidney injury. Kidney Int. 2012;2(Suppl):1–138.
(5) Schiffl, H. Anticipation of recovery of native renal function and liberation from renal replacement therapy in critically ill patients with severe acute kidney injury. Ren Replace Ther 8, 7 (2022). https://doi.org/10.1186/s41100-022-00395-7
(6) Mallappallil M. et al. Parameters Used to Discontinue Dialysis in Acute Kidney Injury Recovery: A Survey of United States Nephrologists. Nephron 1 May 2015; 130 (1): 41–47. https://doi.org/10.1159/000381924
(7) Liu C. et al. Continuous Renal Replacement Therapy Liberation and Outcomes of Critically Ill Patients With Acute Kidney Injury. Mayo Clin Proc. 2021;96(11):2757-2767. doi:10.1016/j.mayocp.2021.05.031
(8) Post, A., Schutten, J.C., Kremer, D. et al. Creatine homeostasis and protein energy wasting in hemodialysis patients. J Transl Med 19, 115 (2021). https://doi.org/10.1186/s12967-021-02780-y
(9) von Groote T. et al. Proenkephalin A 119–159 predicts early and successful liberation from renal replacement therapy in critically ill patients with acute kidney injury: a post hoc analysis of the ELAIN trial. Crit Care 26, 333 (2022). doi.org/10.1186/s13054-022-04217-4
(10) von Groote T. et al. Evaluation of Proenkephalin A 119-159 for liberation from renal replacement therapy: an external, multicenter pilot study in critically ill patients with acute kidney injury. Crit Care. 2023 Jul 10;27(1):276. doi: 10.1186/s13054-023-04556-w.
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