Renal Replacement Therapy in Acute Kidney Injury: It Is All About Timing!

Intensive care physicians often face the conundrum of deciding when to consider renal replacement therapy (RRT) in acute kidney injury (AKI). RRT may be commenced for the early correction of metabolic complications and prevention of volume overload. However, an early strategy may entail unnecessary therapy for some patients who might recover renal function otherwise. Even more concerning is the perpetuation of damage that may occur due to the hemodynamic instability that often accompanies RRT. The proximal tubules located at the corticomedullary junction are particularly vulnerable to ischemic insult. The partial pressure of oxygen at this region is less than 40 mm Hg, which increases the susceptibility of the tubular cells to RRT-induced damage (1) (Fig 1). Hence it is critically important to decide on the requirement for RRT and to initiate therapy at the optimal time.

Fig 1. The corticomedullary junction (marked in red) has a low partial pressure of oxygen (less than 40 mm Hg). The relatively low partial pressure of oxygen makes the proximal tubular cells vulnerable to ischemic insult that may occur during renal replacement therapy

Many of the older studies that support early RRT have been observational in nature (2); besides, the overall management of critically ill patients has changed considerably over the years. Hence, it is appropriate to reconsider the impact of the timing of RRT, particularly with new information available from the more recent randomized controlled studies.

The ELAIN study involved 231 postoperative patients (47% cardiac surgical) with AKI from a single center in Germany (3). The early group was randomized to receive RRT within 8 h of the diagnosis of AKI, KDIGO stage 2; the late group was randomized to undergo RRT within 12 hours of reaching KDIGO stage 3. Besides, at least one of the following conditions had to be present, including severe sepsis, catecholamine use, refractory fluid overload, and new-onset or worsening of non-renal organ dysfunction. All 112 patients randomized to the early group received RRT, compared to 108/119 patients in the late group. The 90-d mortality, the primary outcome, was significantly lower in the early group. Approximately 75% of all patients had evidence of fluid overload according to the pre-defined criteria. This raises the question of whether RRT may have been delayed among patients who had evidence of fluid overload but were randomized to the late group, leading to worse outcomes in this group of patients. Besides, the fragility index for the primary outcome was only 3 patients (the results would have been non-significant if 3 extra patients had suffered 90-day mortality in the early group). Besides, it is hard to explain a mortality benefit at 90 d, with no difference in the 28 and 60 d mortality.

Patients in KDIGO stage 3 were randomized to receive early or late RRT in the AKIKI study (4). In the early group, RRT was initiated immediately after randomization. In the late group, RRT was performed if any of the following criteria were present: K⁺> 6.0 mmol/l (> 5.5 mmol/l after corrective measures), BUN > 112 mg/dl, pH < 7.15, and acute pulmonary edema due to fluid overload. In the early group, 305/311 (98.1%) received RRT, while only 157/308 (51%) patients in the late group underwent RRT. There was no significant difference in mortality between groups on day 60, which was the primary outcome of the study. Thus, in the AKIKI study, nearly half of all patients who were randomized to the late group did not require RRT but did not suffer adverse outcomes.

The IDEAL-ICU investigators, in a multicentric French study, randomized patients in early-stage septic shock who were in the failure stage (stage F) of the RIFLE classification (5). The early group received RRT within 12 h of documentation of stage F; the late group underwent RRT after 48 h if renal recovery had not occurred in the meantime. The primary outcome was 90-d mortality. The study was stopped for futility after a second interim analysis. No difference was observed in the 90-d mortality between the early and late groups (58% vs. 54%, p = 0.38). In the late group, 38% of patients did not receive RRT.

The AKIKI and the IDEAL-ICU studies suggest that in the absence of life-threatening complications, a delayed strategy may be appropriate in most patients with AKI. Such a strategy may facilitate avoidance of RRT, with its associated complications. In fact, these studies reinforce the view that initiation of RRT should not be based on the AKI stage; it may be more appropriate to be guided by the presence of complications, including fluid overload and metabolic abnormalities. Furthermore, a strategy of watchful waiting may enhance the possibility of renal recovery. In contrast, RRT-related hemodynamic instability may lead to worsening or perpetuation of renal damage and adversely impact recovery.

It is also important to assess the trajectory of the underlying disease process and the presence of failure of other organs while considering RRT. If the patient is clinically improving with the resolution of other organ failures, perhaps a waiting strategy would be more appropriate. However, if the metabolic demands continue to remain high with a continued requirement for fluid resuscitation, it may be necessary to consider early RRT. In such situations, the metabolic and fluid demands far exceed the capacity of the kidney necessitating prompt supportive therapy. The “frusemide test” was used to identify patients who are likely to require renal replacement therapy in a previous study (6). It involves the administration intravenous frusemide, 1.0 mg/kg to frusemide-naïve patients and 1.5 mg/kg to those already on frusemide. A urine output of less than 200 ml in the ensuing 2 h was highly predictive of patients who required RRT.

The bottom line

• Previous observational studies of AKI seemed to suggest that an early-RRT strategy may lead to more favorable clinical outcomes.
• Recent randomized controlled trials reinforce the view that a delayed strategy may be appropriate in the absence of life-threatening complications of AKI.
• Apart from the complications directly related to therapy, hemodynamic perturbations during RRT may adversely impact recovery of renal function.
• The decision to perform RRT will also depend on the trajectory of the underlying illness and metabolic demand.
• Fastidious conformance to physiological or biochemical parameters is unlikely to be helpful with the timing of initiation of RRT.
• A holistic, individualized strategy based on clinical, physiological, and biochemical parameters is more likely to be beneficial compared to a “one-size-fits-all” approach.

 

References

1. Gaudry S, Quenot J-P, Hertig A, Barbar SD, Hajage D, Ricard J-D, et al. Timing of Renal Replacement Therapy for Severe Acute Kidney Injury in Critically Ill Patients. Am J Respir Crit Care Med [Internet]. 2019 Feb 20 [cited 2019 Mar 21]; Available from: https://www.atsjournals.org/doi/10.1164/rccm.201810-1906CP
2. Bagshaw SM, Uchino S, Bellomo R, Morimatsu H, Morgera S, Schetz M, et al. Timing of renal replacement therapy and clinical outcomes in critically ill patients with severe acute kidney injury. J Crit Care. 2009 Mar;24(1):129–40.
3. Zarbock A, Kellum JA, Schmidt C, Van Aken H, Wempe C, Pavenstädt H, 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 May 24;315(20):2190.
4. Gaudry S, Hajage D, Schortgen F, Martin-Lefevre L, Pons B, Boulet E, et al. Initiation Strategies for Renal-Replacement Therapy in the Intensive Care Unit. N Engl J Med. 2016 Jul 14;375(2):122–33.
5. Barbar SD, Clere-Jehl R, Bourredjem A, Hernu R, Montini F, Bruyère R, et al. Timing of Renal-Replacement Therapy in Patients with Acute Kidney Injury and Sepsis. N Engl J Med. 2018 Oct 11;379(15):1431–42.
6. Lumlertgul N, Peerapornratana S, Trakarnvanich T, Pongsittisak W, Surasit K, Chuasuwan A, et al. Early versus standard initiation of renal replacement therapy in furosemide stress test non-responsive acute kidney injury patients (the FST trial). Crit Care Lond Engl. 2018 Apr 19;22(1):101.