Acute kidney injury in non-severe pneumonia is associated with an increased immune response and lower survival

Abstract

While sepsis is a leading cause of acute kidney injury in critically ill patients, the relationship between immune response and acute kidney injury in less severely ill patients with infection is not known. Here we studied the epidemiology, 1-year mortality, and immune response associated with acute kidney injury in 1836 hospitalized patients with community-acquired severe and non-severe pneumonia. Acute kidney injury developed in 631 patients of whom 329 had severe and 302 had non-severe sepsis. Depending on the subgroup classification, 16-25% of the patients with non-severe pneumonia also developed acute kidney injury. In general, patients with acute kidney injury were older, had more comorbidity, and had higher biomarker concentrations (interleukin-6, tumor necrosis factor, D-dimer) even among patients without severe sepsis. The risk of death associated with acute kidney injury varied when assessed by Gray's survival model and after adjusting for differences in age, gender, ethnicity, and comorbidity. This risk was significantly higher immediately after hospitalization but gradually fell over time in the overall cohort and in those with non-severe pneumonia. A significantly higher risk of death (hazard ratio 1.29) was also present in those never admitted to an intensive care unit. Hence acute kidney injury is common even among patients with non-severe pneumonia and is associated with higher immune response and an increased risk of death.

Figure 1. Subject disposition for the Genetic and Inflammatory Markers of Sepsis study cohort

AKI, acute kidney injury

Figure 2. One-year mortality in patients with and without AKI in the overall cohort and within non-severe CAP subgroups

(a) The Kaplan–Meier failure plots by maximum RIFLE stage for probability of death in the entire CAP cohort, which at 1 year was higher in patients with AKI than in patients without AKI (log rank P<0.001). (b) Failure plots for probability of death at 1 year within the four non-severe CAP subgroups. Non-severe CAP patients with AKI in each of the four subgroups had higher probability of death associated with AKI at 1 year compared to those without AKI (log rank P<0.01 for all subgroups). AKI, acute kidney injury; CAP, community-acquired pneumonia; RIFLE, Risk, Injury, and Failure criteria.

Figure 3. Varying risk of death associated with AKI over one year after CAP hospitalization

Varying hazard ratios with 95% confidence intervals (CIs) for risk of death associated with AKI over 365 days among the overall cohort (a), and within the CURB-65 group 1 subgroup (b). Hazard ratios were estimated from Gray's model using nine time nodes and eight intervals and adjusted for age, gender, race, and Charlson Comorbidity Index. In the overall cohort, the 95% CIs are above 1 for 100 days in patients with AKI, suggesting significant increased risk of death associated with AKI. Thereafter the risk declines showing no association between AKI and risk of death (a). In the CURB-65 group 1 subgroup, the association between AKI and risk of death persists up to 50 days following hospitalization for pneumonia (b). AKI, acute kidney injury; CURB, confusion, uremia, respiratory rate, low blood pressure, age 65 years or older.

Figure 4. Circulating inflammatory, coagulation, and fibrinolysis marker concentrations in 1380, 712, and 710 patients with and without acute kidney injury, stratified by severe sepsis during first week of CAP

(a) Inflammatory biomarkers (interleukin (IL)-6, -10 and tumor necrosis factor (TNF)). (b) Coagulation biomarkers (thrombin-antithrombin complexes, factor IX, and antithrombin (AT)), (c) Biomarkers of fibrinolysis (D-dimer and plasminogen activator inhibitor-1 (PAI-1)). Geometric mean plasma concentrations of IL-6, 10, TNF, TAT, D-dimer, and PAI-1 were significantly increased in patients with AKI who developed severe sepsis (solid line with diamonds) when compared to patients without AKI (dashed line with triangles), during the first week of pneumonia (P<0.001). In contrast, plasma antithrombin concentrations were lower in patients with AKI (P<0.001). Of patients without severe sepsis, plasma concentrations of IL-6, TNF, and D-dimer were significantly higher in patients with AKI (solid line with squares) compared to those without AKI (dashed line with crosses) (P<0.001). AKI, acute kidney injury; CAP, community-acquired pneumonia.