**3. Prescribing RRT**

Even though RRT is widely used, and most ICUs have elaborated standardized protocols to simplify IHD/CRRT prescription, many factors need to be considered before, during, and when stopping this therapy: patient's characteristics, local resources, physician's preferences as well as scientific evidence.

## **3.1 Initiating**

## *3.1.1 Indications*

Indications for initiating RRT in acute care are frequently classified as *absolute* vs. *relative* or as *emergent* vs. *semi-urgent*. Although the terms "absolute" or "emergent" might seem dichotomic as if a clear cut-off was defined, they are subject to interpretation in clinical practice [9]. It is generally accepted to begin RRT in a timely manner once any of these conditions occur if concordant with the goals of care (see **Table 2**).

On the other hand, whether to initiate and when to do so while not meeting any of these indications has received a lot of interest in the last few years in the attempt to prevent morbidity and mortality. Indeed, initial observational studies had supported the rationale that a proactive/early RRT will help to quickly normalize renal homeostasis while minimizing inflammation and uremic toxicity. On the other hand, this approach could lead to initiate RRT in patients who will never develop clear indications as some will spontaneously recover in addition to exposing them to unnecessary

1. Refractory to medical treatment:


3. Dialyzable toxin exposure

## **Table 2.**

*Absolute indications of initiating RRT.*

RRT complications. This has led to the constantly evolving *early* vs. *late* paradigm which has been investigated in five recent landmark randomized controlled trials (RCTs) (see **Table 3**). A careful reminder of the definitions used to classify severity of acute kidney injury (AKI) is mandatory before reviewing these trials (see **Table 4**).

In 2016, the results of the first large RCT trying to answer this complex question were published. The Early Versus Late Initiation of Replacement Therapy In Critically Ill Patients with AKI (**ELAIN**) trial was a single-center based in Germany with mostly surgical patients [12]. The RRT modality was CVVHDF at a dosing of 30 ml/kg/h and using regional citrate as anticoagulation. All participants in the early group (< 8 h of stage 2) vs. 91% in the delayed group (< 12 h of stage 3 or K<sup>+</sup> > 6 mmol/L, urea >100 mg/dL, Mg2+ > 4 mmol/L, UO < 200 ml/12 h or refractory edema) received RRT. An important characteristic is a relatively small difference in the time to begin RRT from initial randomization across groups (21 hours (IQR 18–24)) and in the overall use of RRT (9%) between both arms. A significant statistical mortality benefit was obtained favoring the early arm (HR 0.66 (0.37–0.97), p = 0.03). A few months later, the Artificial Kidney Initiation in Kidney Injury (**AKIKI**) trial was published; a multicenter and much larger study from 31 French ICUs totalizing 620 patients [13]. The modality was at the discretion of physicians (30% received CRRT as sole therapy) and 80% had sepsis-related conditions (sepsis, severe sepsis, or septic shock). Almost all participants in the early group (< 6 h of stage 3) compared to 51% in the delayed group (K<sup>+</sup> > 6.0 mmol/L, urea>112 mg/dL, pH < 7.15, pulmonary edema or oliguria/ anuria >72 h) received RRT. The difference in the time to begin RRT between the two arms was 55 hours. No difference was seen in mortality (60 days), but more catheterrelated bloodstream infections were reported in the early group (p = 0.03). In 2018, the Initiation of Dialysis Early Versus Delayed in the Intensive Care Unit (**IDEAL-ICU**) trial, which took place in 29 ICUs in France was published [14]. This trial included 488 patients within the first 48 hours of their septic shock. The modality was also at the discretion of physicians. Almost all participants in the early group (< 12 h of Failure stage) compared to 62% in the delayed group (K<sup>+</sup> > 6.5 mmol/L, pH < 7.15, pulmonary edema or persistent AKI 48 h after inclusion) received RRT. No difference was seen in mortality (90 days). It is important to notice that this trial was stopped early for futility (initially designed for 864 patients).

In an attempt to definitively clarify the question of *Timing*, the Standard versus Accelerated Initiation of RRT in AKI (**STARRT-AKI**) trial was later published in 2020. It included 3019 patients from 168 ICUs in 15 countries [15]. Patients mostly received CRRT (70%) and had both medical (65%) and surgical (35%) conditions. Almost all participants in the early group (*accelerated strategy*) (<12 h of stage ≥2) compared to 62% in the delayed group (*standard strategy*) (K<sup>+</sup> > 6 mmol/L, pH < 7.2, HCO3 < 12, pulmonary edema or persistent AKI 72 h after inclusion) received RRT. Once again, no difference was seen in mortality (90 days), including in the subgroup


*\*Urea conversion to SI units: 100 mg/dL = 35.7 mmol/L, 112 mg/dL = 40 mmol/L, 140 mg/dL = 50 mmol/L. E: Early-group, D: Delayed-group, UO: urine output, CRBI: Catheter-related bloodstream infection, MV: mechanical ventilation.*

### **Table 3.**

*Landmark RCTs on timing of RRT initiation.*


*Creatinine conversion to SI units: 0.3 mg/dL = 26.8 μmol/L; 4.0 mg/dL = 353.6 μmol/L).*

## **Table 4.**

*KDIGO and RIFLE classifications of AKI.*

analysis (including medical vs. surgical). Notably, a difference was obtained in RRT dependence at 90 days which was higher in the accelerated group (RR = 1.74 [95% CI 1.24–2.43]). Significantly more adverse events (23% vs. 16.5% p < 0.001) occurred when exposed to the accelerated strategy, mainly driven by hypotension (p < 0.001), and mild hypophosphatemia (p < 0.001), with the trend toward more bloodstream infections (p = 0.07). Compared to previous studies, distinctive pragmatic characteristics should be noted. First, if the clinician did not have absolute equipoise regarding initiation of RRT (e.g., expected impending renal recovery), the patient was not included. Also, the delayed strategy did not mandate RRT initiation once the criteria were fulfilled but was based on clinical judgment. Results from this study have substantially affected how and when RRT is now initiated in ICUs worldwide.

STARRT-AKI has confirmed evidence against the preemptive use of RRT prior to developing standard RRT initiation criteria. However, a question remained unanswered: how far can we delay RRT initiation without negative outcomes? The Artificial Kidney Initiation in Kidney Injury-2 (**AKIKI-2**) trial, published in 2021, was developed to answer that question, assessing the potential benefits of a more-delayed strategy in terms of RRT-free days. That trial took place in 39 ICUs in France and included 278 patients. To be eligible for randomization, three criteria had to be achieved: (1) mechanical ventilation or vasopressor + (2) AKI stage 3 + (3) Oligoanuria >72 h or urea 112 to 140 mg/dL<sup>1</sup> . Almost all participants in the "early group" (similar to the *delayed group* from STARRT-AKI) (<12 h of fulfilling inclusion criteria) compared to 79% in the delayed group (*more-delayed strategy*) (K<sup>+</sup> > 6 mmol/ L, pH < 7.15, urea>140 mg/dL<sup>2</sup> , pulmonary edema) received RRT. Median time between randomization and initiation of RRT was 3 hours versus 33 hours. Noteworthy, the difference in RRT use of 19% between the two groups is about half of what

<sup>1</sup> Urea criteria led to inclusion of 61% in the *delayed* and 55% in the *more-delayed* strategy.

<sup>2</sup> Urea criteria led to initiation of RRT in 59%.

## *Renal Replacement Therapies in the Intensive Care Unit DOI: http://dx.doi.org/10.5772/intechopen.105033*

has been obtained in the three previous studies. No difference was reported in RRTfree days on day 28 even though no time criteria were applied in the delayed group, contrasting to previous studies. The primary outcome of 60-day mortality was not significantly higher in the more-delayed group compared to delayed (55% vs. 44%, p = 0.07). Though, in the preplanned multivariate analysis, the more-delayed strategy was associated with increased 60-day mortality (HR 1.65 p = 0.018). Overall, the more-delayed strategy did not demonstrate decreased use of RRT, but worrisome findings suggesting potential harms.
