Invited Commentary
Nephrology
May 27, 2025
Corticosteroids—A Not-So-Novel Treatment for Sepsis-Associated AKI
Sarah F. Sanghavi
JAMA Netw Open. 2025;8(5):e2512286. doi:10.1001/jamanetworkopen.2025.12286
Sepsis is a multisystem disorder in which infection triggers a dysregulated host response consisting of concurrent hyperinflammation and immune suppression. Acute kidney injury (AKI) is a frequent manifestation of sepsis-induced circulatory failure and is associated with increased morbidity and mortality. Accordingly, multiple clinical trials over the last 4 decades have investigated anti-inflammatory medications in septic shock with the aim to temper its accompanying organ dysfunction.
In this study, Donaldson et al1 describe their post hoc analysis evaluating new kidney replacement therapy (KRT) in the Adjunctive Corticosteroid Treatment in Critically Ill Patients with Septic Shock (ADRENAL) trial,2 a randomized, double-blinded, placebo-controlled trial of hydrocortisone in septic shock. The ADRENAL trial enrolled 3800 participants with septic shock receiving mechanical ventilation who required vasopressors for at least 4 hours. The ADRENAL trial2 found that the administration of 200 mg of intravenous hydrocortisone daily for a median duration of 5.5 days resulted in faster resolution of shock but no difference in mortality, days requiring mechanical ventilation, or the rate of KRT. This post hoc analysis reevaluates these data after excluding 639 participants who had withdrawn or received KRT prior to enrollment and adjusting for variables associated with KRT.1
Of the 3161 participants, 701 (22%) developed a new KRT requirement. Donaldson et al1 found that bacteremia and vasopressor dose were associated with the requirement for KRT. Participants randomized to hydrocortisone had an incidence of KRT of 21%, compared with 24% in the placebo group (odds ratio, 0.84; 95% CI, 0.70-0.99; P = .04), and this result held in the adjusted model. However, in the analysis excluding patients who commenced KRT within 2 days of randomization, this result was no longer statistically significant. There were no differences by group in the number of days alive and free from KRT or in the rate of liberation from KRT.
The use of the patient-centered outcome of KRT rather than AKI is a strength of this study. AKI includes a broad range of clinical phenotypes, and a transient increase in creatinine of 0.3 mg/dL (to convert to micromoles per liter, multiply by 88.4) meets criteria for AKI but is not associated with the morbidity and mortality of KRT. In addition, Donaldson et al1 explored norepinephrine equivalent dose (NEE) at enrollment as a metric for vasopressor response. Although previous observational and interventional studies of AKI in sepsis have regarded mean arterial pressure (MAP) as a modifiable variable, it may also be a biomarker for more severe microcirculatory dysfunction. In this study, MAP was not associated with KRT, but higher vasopressor requirement and MAP:NEE ratio were associated with KRT, supporting a microcirculatory view of sepsis-associated AKI.1 A significant limitation of this study is that the variables included in the adjusted model were not chosen prospectively and were not strongly associated with the outcome.3 Furthermore, the median exposure time to hydrocortisone prior to KRT initiation was 1 day. Although the benefit associated with hydrocortisone was similar when limited to participants with greater than 2 days of exposure, it did not reach statistical significance.
Notably, previous trials of hydrocortisone in septic shock have not shown a decrease in KRT incidence. The VANISH trial4 used a 2 × 2 factorial design to assess the effects of vasopressin and hydrocortisone specifically on kidney outcomes. This design was chosen based on results from the VASST trial, which showed a beneficial interaction between vasopressin and corticosteroids. However, hydrocortisone was used as second-line treatment for hypotension once a pressor threshold was met. Therefore, many patients did not receive hydrocortisone and the power to assess this finding was limited.
Mechanistically, corticosteroids may reduce circulatory dysfunction on the causal pathway of septic shock to multiorgan dysfunction. Sepsis-induced inflammation damages the vascular endothelial glycocalyx, increasing capillary permeability and vasodilation.5 These changes manifest as hypotension, and cumulative exposure to hypotension is a well-known risk factor for AKI.6 In the absence of hypotension, sepsis-induced redistribution of blood flow in the renal microcirculation may cause medullary hypoxia and kidney injury.7 In the ADRENAL trial, participants in the hydrocortisone group had a higher MAP of 5 mm Hg and earlier resolution of shock. It is possible that this salutary effect on global renal blood flow prevented progression of AKI or resulted in less administration of intravenous fluids, which has been associated with higher rates of KRT.8 Alternatively, hydrocortisone may decrease inflammation at the microcirculatory level and promote favorable redistribution of intrarenal blood flow and oxygen utilization.
In clinical practice, the approach to adjunctive corticosteroid use in septic shock is often individualized. The pressor-sparing effect of corticosteroids may mitigate the adverse effects of vasopressors, such as digital ischemia and supraventricular tachycardia. However, vasopressors do not have known deleterious effects on the kidneys.9 The risks of exacerbating sepsis-induced hyperglycemia, myopathy, and delirium may outweigh the benefits of corticosteroids in older patients or those with poor functional status. Additionally, indwelling devices and sepsis-induced lymphopenia pose a risk for secondary infections. In the ADRENAL trial, only data on fungemia and bacteremia were collected; therefore, the risk of secondary infections may be underestimated.
As many nephrologists who evaluate patients who are critically ill can tell you, our recommendations often center on avoidance: fluid overload, nephrotoxic medications, hypotension. The promise of treatment for sepsis-associated AKI is exciting, and corticosteroids deserve further investigation to elucidate the magnitude of their benefit on patient-centered outcomes. This will not only allow for individualized clinical decision-making but may pave the way for the investigation of immune-modulating therapy with fewer adverse effects.
