Early renal replacement therapy in critical illness did not improve outcomes (AKIKI)

When is the optimal time to initiate renal-replacement therapy in the ICU? Patients with acute renal failure (a.k.a. acute kidney injury or AKI) in the ICU experience worse outcomes than patients who do not. As the kidneys shut down, toxic electrolytes and metabolic waste products build up in the blood. Intuition says -- screams, really -- that correcting the derangements with renal replacement therapy (hemodialysis or CRRT) must be helpful. But it's never been shown to what extent renal failure itself makes critical illness worse, or whether treating it (or when) helps. Some studies have suggested that rapid initiation of RRT in critical illness might help, but others suggested no benefit or even harm from early RRT. Investigators in the AKIKI trial randomized 620 critically ill patients with severe acute kidney injury (e.g., Cr > 4 or severe oliguria) at multiple French centers to undergo either:

• immediate renal-replacement therapy (within ~4 hours), or

• RRT only if severe problems occurred (hyperkalemia, acidosis, pulmonary edema, uremia, or 3 days of oliguria).

This was a gutsy trial design for both investigators and enrollees: besides their severe acute renal failure, all patients were also either receiving vasopressors, mechanical ventilation or both. RRT could be hemodialysis, continuous renal replacement therapy, or any other modality, according to the treatment team. About half the patients got HD as the first treatment, and only 30% received only CRRT (70% got HD at some point).

No Benefits Seen From Early RRT in AKI ... but ...

Early renal-replacement therapy didn't improve outcomes: patients getting early RRT had near-identical 60-day mortality (48.5% vs 49.7%) and slower return of native renal function (as measured by spontaneous diuresis). Twice as many patients in the early-RRT group experienced catheter-related blood stream infections (10% vs. 5%). Lengths of stay in the ICU and hospital were also similar between groups. Almost half the patients in the delayed-RRT group avoided receiving RRT altogether. When they did receive RRT for one of the hypercritical events above, it was almost 5 days after enrollment. So is delaying RRT better? Not so fast: the highest mortality (61%) was in the sickest patients at baseline randomized to the delayed-RRT group. When these patients deteriorated further and needed RRT, things often went very badly. (Yet in a severity-matched comparison, the sickest patients in the early-RRT group had similar 60-day mortality.) While these findings effectively prove that there is no survival advantage to early initiation of hemodialysis in critically ill patients with severe acute kidney injury, they don't definitively settle the question of whether early initiation of continuous renal replacement therapy might somehow help, at least in some patients. The large proportion of patients in AKIKI on vasopressors (most of whom would undergo CRRT in the U.S.) leave this question unanswered. But because CRRT does not seem to be superior to HD for critically ill patients with AKI, it's unlikely that performing CRRT early would improve survival overall, either. A large randomized trial testing early RRT in patients with septic shock and AKI is currently recruiting patients. Others are planned or underway testing early vs. delayed RRT in general critical illness with AKI.

Summing Up

As with other problems in critical illness, problems that seem to require urgent intervention -- in this case, severe AKI with oliguria -- often are better managed conservatively. It's possible that most AKI in critical illness develops, evolves, and resolves according to a program whose complexity we cannot fathom and whose course we cannot substantially modify. If that's so, RRT amounts to busywork to improve lab values, while the patient's essential illness proceeds inevitably toward its destination, as unmoved as a train by erasing its graffiti. It remains a possibility that the "just right" patient population, RRT modality, or timing strategy will be discovered by diligent researchers, providing much needed clarity to intensivists, nephrologists, and patients' loved ones. An editorialist rightly argues for data-driven design of "dynamic risk-stratification tools to identify patients who will not need renal-replacement therapy for management of their acute kidney injury," a proportion approaching 50% in the AKIKI study. After many clinical trials, there is no consensus among nephrologists or their specialty societies as to when to start RRT or which modality to use. Maybe the lifesaving answer is out there, to be discovered in a large multicenter trial. But a posteriori, the more likely reality is that the timing and modality of RRT do not change survival or other outcomes in critically ill patients with severe AKI. (Sleep well, nephrologists.) Read more: Initiation Strategies for Renal-Replacement Therapy in the Intensive Care Unit. N Engl J Med. 2016 Jul 14;375(2):122-33. Clinical trials planned or ongoing on RRT in the ICU Timing of dialysis initiation in acute kidney injury and acute-on-chronic renal failure. Semin Dial 2013;26:675-681 Implementing the Kidney Disease: Improving Global Outcomes/acute kidney injury guidelines in ICU patients. Curr Opin Crit Care. 2013 Dec;19(6):544-53.