Presentation Summary

Written by Jasna Trbojevic-Stankovic
Reviewed by Wim Van Biesen

Is acute kidney injury the direct cause or merely a correlate of poor outcome in critically ill patients?
Critically ill patients who develop acute kidney injury (AKI) exhibit a notably higher mortality rate. Several clinical conditions, such as sepsis, nephrotoxins and hypotension, may cause AKI eventually resulting in fatal outcome. In such cases, it might seem that simply by managing AKI it would be possible to prevent or delay mortality. In practice, however, this is not always the case and AKI may sometimes simply be a confounding factor and not the direct cause of mortality. In such circumstances, even the optimum AKI treatment would not change the final outcome. Finally, there are situations when a combination of these mechanisms is present. Thus, the importance of renal replacement therapy (RRT) for the outcome varies from necessary to fundamental, depending on the interrelationship between AKI and mortality in each particular case.

The extent to which AKI might be related to adverse short-term outcomes of critical illness has been recently investigated using the Bradford Hill criteria for causality. This study concluded that AKI is associated with substantially increased mortality, and that association is graded and persists after accounting for known confounders (1). However, this gradient is not linear. Instead, it is U-shaped, implying that both low and high serum creatinine, and low and high urine output, have an equally important effect on the outcome (2, 3).

Even though it might seem that RRT has a crucial impact on the outcome, several studies found otherwise. In the meta-analysis of the prospective multicenter observational FINNAKI study it was concluded that high propensity to receive RRT does not aleviate mortality risk (4). Conversely, witholding RRT is not necessarily associated with worse outcome, provided that urine output is preserved and creatinine is stable, regardless its level (5). These data support the impression that there is no direct causal relationship between AKI and mortality, unless certain life threatening AKI-related factors, such as hyperkalemia, anuria, extreme acidosis or intoxication, are present. In such cases RRT may have a fundamental impact on the outcome.

When is the right time to start dialysis?
Defining the optimal time to initiate RRT for AKI does not seem to be an easy task. This is especially true for critically ill patients with AKI but no potentially life-threatening complications directly related to renal failure. The ELAIN trial concluded that early compared to delayed initiation of RRT reduces mortality over the first 90 days (6). On the other hand, the AKIKI multicenter randomized trial on patients with severe AKI and requiring mechanical ventilation, catecholamine infusion, or both, and not having a potentially life-threatening complication directly related to renal failure, no significant difference was found with regard to mortality between an early and a delayed strategy for the initiation of RRT (7). Similar results were obtained in patients with AKI and sepsis in the IDEAL-ICU trial and very recently the STARRT-AKI trial (8, 18).

Such conflicting results call for further and more detailed evaulation of the methodology. These studies differ substantialy in design, number of subjects, inclusion criteria, level of kidney injury at the onset of follow-up, and comorbidities (Figure 1). Namely, in the ELAIN trial KDIGO renal failure stage 3 was the indication to start RRT, while in the other two studies the same level of renal failure was merely the baseline. This reflected in the number of days free of RRT and prevalence of patients who avoided RRT, both of which were higher in the AKIKI and IDEAL-ICU studies than in the ELAIN trial (6, 7, 8, 9).

Figure 1. Comparison of the recent randomized controlled trials on the timing of RRT initiation in AKI (6, 7, 8, 9, 10)

To shed more light on this subject, Gaudry et al. preformed a systematic review and individual patient data meta-analysis of randomized trials published from April 1, 2008, to Dec 20, 2019, that compared delayed and early RRT initiation strategies in patients with severe AKI (11). Among the initially identified 1031 studies, nine had available individual patients’ data and were thus included in the analysis. The conclusion was that timing of RRT initiation does not affect survival in critically ill patients with severe AKI in the absence of urgent indications for RRT, implying that commencing RRT solely for the presence of AKI criteria does not improve patient survival. Actually, delaying RRT in patients with stable AKI does not affect survival, but it does lower the treatment costs. However, early RRT is mandatory in patients with AKI-associated life threatening conditions, such as hyperkalemia, fluid overload, extreme acidosis or intoxication, in which cases an early start may improve prognosis.

Which dialysis modality and how much dialysis is necessary?
The currently considered standard intensity of continuous RRT to provide optimum outcomes is 20-25 mL/kg/h (12). Furthermore, intermittent hemodialysis seems to be as effective as continuous RRT in terms of achieving favorable outcome, provided strict guidelines to improve tolerance and metabolic control are used (13). Another treatment option is extended daily hemodialysis or hemodiafiltration with sessions lasting between 6 and 24 hours using a conventional dialysis machine. This technique is equally efficient in fluid removal, achieving renal recovery and survival as continuous RRT in randomized controlled trials, thus presenting an equally valuable option (14).

The amount of fluid removal is another issue to consider when defining optimal dialysis prescription, since early net ultrafiltration rates may be associated with differential outcomes. In critically ill patients there is often sequestration of fluid in third space hindering fluid removal with dialysis. One recent retrospective observational study concluded that ultrafiltration rates over 1.75 mL/kg/h are associated with increased mortality compared to net ultrafiltration rates <1.01 mL/kg/h, thus implying that in this case more is not necessarily better (15). Furthermore, both intermittent and continuous RRT are associated with recurrent myocardial stunning contributing to heart failure and cardiac death, with ultrafiltration and intradialytic hypotension being the principal determinants of this injury (16).

The final issue to consider when prescribing RRT in critically ill patients is when and under what circumstances to ideally liberate a patient from RRT. A recent meta-analysis identified the amount of urine output as the best indicator of renal function recovery, regardless of RRT method used. Achievening diuresis warrants a test stop of the RRT, provided close follow-up of the patient is maintained and, if necessary, dialysis restarted.


1. Girling BJ, Channon SW, Haines RW, Prowle JR. Acute kidney injury and adverse outcomes of critical illness: correlation or causation? Clin Kidney J. 2019;13(2):133-141. doi: 10.1093/ckj/sfz158.

2. Lassnigg A, Schmidlin D, Mouhieddine M, Bachmann LM, Druml W, Bauer P, Hiesmayr M. Minimal changes of serum creatinine predict prognosis in patients after cardiothoracic surgery: a prospective cohort study. J Am Soc Nephrol. 2004;15(6):1597-605. doi: 10.1097/01.asn.0000130340.93930.dd.

3. Pickering JW, Ralib AM, Endre ZH. Combining creatinine and volume kinetics identifies missed cases of acute kidney injury following cardiac arrest. Crit Care. 2013;17(1):R7. doi: 10.1186/cc11931.

4. Poukkanen M, Koskenkari J, Vaara ST, Pettilä V, Karlsson S, Korhonen AM, Laurila JJ, Kaukonen KM, Lund V, Ala-Kokko TI; FINNAKI Study Group. Variation in the use of renal replacement therapy in patients with septic shock: a substudy of the prospective multicenter observational FINNAKI study. Crit Care. 2014 ;18(1):R26. doi: 10.1186/cc13716.

5. Bagshaw SM, Uchino S, Kellum JA, et al; Beginning and Ending Supportive Therapy for the Kidney (B.E.S.T. Kidney) Investigators. Association between renal replacement therapy in critically ill patients with severe acute kidney injury and mortality. J Crit Care. 2013;28(6):1011-8. doi: 10.1016/j.jcrc.2013.08.002.

6. Zarbock A, Kellum JA, Schmidt C, et al. Effect of Early vs Delayed Initiation of Renal Replacement Therapy on Mortality in Critically Ill Patients With Acute Kidney Injury: The ELAIN Randomized Clinical Trial. JAMA. 2016;315(20):2190-9. doi: 10.1001/jama.2016.5828.

7. Gaudry S, Hajage D, Schortgen F, et al; AKIKI Study Group. Initiation Strategies for Renal-Replacement Therapy in the Intensive Care Unit. N Engl J Med. 2016 Jul 14;375(2):122-33. doi: 10.1056/NEJMoa1603017.

8. Barbar SD, Dargent A, Quenot JP. Timing of Renal-Replacement Therapy in Acute Kidney Injury and Sepsis. N Engl J Med. 2019;380(4):399. doi: 10.1056/NEJMc1815142.

9. Barbar SD, Binquet C, Monchi M, Bruyère R, Quenot JP. Impact on mortality of the timing of renal replacement therapy in patients with severe acute kidney injury in septic shock: the IDEAL-ICU study (initiation of dialysis early versus delayed in the intensive care unit): study protocol for a randomized controlled trial. Trials. 2014;15:270. doi: 10.1186/1745-6215-15-270.

10. Van Biesen W. Dialysis in AKI: indications, timing, type and more. Presented at the 57th European Renal Association – European Dialysis Transplantation Association (fully virtual), June 6, 2020. Available at Virtual Meeting.

11. Gaudry S, Hajage D, Benichou N, et al. Delayed versus early initiation of renal replacement therapy for severe acute kidney injury: a systematic review and individual patient data meta-analysis of randomised clinical trials. Lancet. 2020;395(10235):1506-1515. doi: 10.1016/S0140-6736(20)30531-6.

12. Uchino S, Toki N, Takeda K, et al; Japanese Society for Physicians and Trainees in Intensive Care (JSEPTIC) Clinical Trial Group. Validity of low-intensity continuous renal replacement therapy*. Crit Care Med. 2013;41(11):2584-91. doi: 10.1097/CCM.0b013e318298622e.

13. Vinsonneau C, Camus C, Combes A, et al; Hemodiafe Study Group. Continuous venovenous haemodiafiltration versus intermittent haemodialysis for acute renal failure in patients with multiple-organ dysfunction syndrome: a multicentre randomised trial. Lancet. 2006;368(9533):379-85. doi: 10.1016/S0140-6736(06)69111-3.

14. Zhang L, Yang J, Eastwood GM, Zhu G, Tanaka A, Bellomo R. Extended Daily Dialysis Versus Continuous Renal Replacement Therapy for Acute Kidney Injury: A Meta-analysis. Am J Kidney Dis. 2015;66(2):322-30. doi: 10.1053/j.ajkd.2015.02.328.

15. Naorungroj T, Neto AS, Zwakman-Hessels L, et al. Early net ultrafiltration rate and mortality in critically ill patients receiving continuous renal replacement therapy. Nephrol Dial Transplant. 2020 Apr 7:gfaa032. doi: 10.1093/ndt/gfaa032. Epub ahead of print.

16. Slessarev M, Salerno F, Ball IM, McIntyre CW. Continuous renal replacement therapy is associated with acute cardiac stunning in critically ill patients. Hemodial Int. 2019;23(3):325-332. doi: 10.1111/hdi.12760.

17. Al Saadon A, Katulka R, Sebastianski M, et al. Determining the optimal time for liberation from renal replacement therapy in critically ill patients: protocol for a systematic review and meta-analysis (DOnE RRT). BMJ Open. 2018;8(11):e023306. doi: 10.1136/bmjopen-2018-023306.

18. Investigators S-A, Canadian Critical Care Trials G, Australian, New Zealand Intensive Care Society Clinical Trials G, United Kingdom Critical Care Research G, Canadian Nephrology Trials N, et al. Timing of Initiation of Renal-Replacement Therapy in Acute Kidney Injury. N Engl J Med. 2020;383(3):240-51. DOI: 10.1056/NEJMoa2000741

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