Research indicates that acute kidney injury is the most frequent complication in patients with septic shock and is an independent risk factor for death. Although renal-replacement therapy (RTT) is the standard of care for severe acute kidney injury (AKI), the ideal time for initiation remains debatable.

“Sepsis is the leading etiology of acute kidney injury in intensive care patients and is associated with high mortality (55% in case of septic shock and severe AKI),” says Saber Davide Barbar, MD, PhD. “When AKI is associated with complications like severe hyperkalemia, severe metabolic acidosis, and fluid overload with pulmonary edema in anuric patients, intensivists and nephrologists tend to agree on immediate renal replacement therapy (dialysis). But when those complications are absent, there are no recommendations or guidelines for timing of RRT in patients at the most severe stage of AKI.”

 

Reducing Mortality With RRT

For a study published in The New England Journal of Medicine, Dr. Barbar and colleagues sought to determine if they could reduce mortality in this patient population with early initiation of RRT. The researchers selected patients at the most severe stage of AKI (failure of RIFLE classification) and septic shock. The failure stage of the RIFLE classification system is characterized by a serum creatinine level three times the baseline level (or ≥4 mg/dL with rapid increase of ≥0.5 mg/dL), urine output less than 0.3 ml/kg of body weight per hour for 24 hours or longer, or anuria for at least 12 hours. The primary outcome of the study was 90-day mortality.

Patients were randomized into two groups. In the “early group,” RRT was initiated immediately after enrollment. In the “delayed group,” RRT was initiated 48 hours after enrollment, but patients who developed criteria for emergency RRT during the 48 hours were immediately dialyzed before 48 hours, and patients with spontaneous improvement in renal function were not dialyzed.

No significant between-group differences existed in characteristics at baseline. Among patients for whom follow-up data at 90 days were available, mortality rates were 58% in the early-strategy group and 54% in the delayed-strategy. In the delayed-strategy group, 38% did not receive renal-replacement therapy. Criteria for emergency renal-replacement therapy were met in 17% of patients in the delayed-strategy group.

“Early initiation of RRT in patients with severe AKI (but without emergency criteria for RRT) did not reduce mortality,” says Dr. Barbar. “The more surprising finding is that delaying the initiation of RRT for 48 hours can avoid dialysis in approximately 40% of cases.”

Dr. Barbar explains other takeaways from the study. “We didn’t observe any difference between the two groups in the fluid balance,” he says. “The possible explanation is that in our population of septic shock patients, the hemodynamic instability did not allow fluid depletion with RRT during the first 48 hours.” Delayed initiation of RRT also did not modify dependence to dialysis at day 90. Dr. Barbar adds that no differences in mortality rates were observed at any time point until day 180 (Table).

 

Future Research

Dr. Barbar notes the need for future studies focused on the early detection of patients with AKI who will need RRT. “Two important studies are ongoing,” he says. “The first is the STARRT-AKI trial, a Canadian with an objective to verify whether an even earlier initiation of RRT can reduce mortality. The second, the AKIKI2 trial, is a French study with an objective to determine if we can further delay the initiation of RRT without risk for patients and, doing so, further reduce the need for dialysis.”

References

Barbar S, Clere-Jehl R, Bourredjem A, et al. Timing of Renal-Replacement Therapy in Patients with Acute Kidney Injury and Sepsis. N Engl J Med. 2018;379:1431-1442. Available at
www.nejm.org/doi/full/10.1056/NEJMoa1803213.