Long-term all-cause mortality rate is higher in patients with non-recovered AKI
We studied the effect of acute kidney injury and urea-to-creatinine ratio on long-term mortality in 665 patients presented with an infection to the ED and who were alive at the moment of hospital discharge (Fig. 1). The median SIRS score was 2 (2–3, 95% CI) and 476 (72%) patients had sepsis, based on the Sepsis-2 criteria. In total 14 (2%) had septic shock, while 21 patients (3%) were admitted to the intensive care unit (ICU). During the median follow-up duration of 686 days (664–713, 95% CI) after presentation to the ED, in total 123 (18%) patients died (Table 1). More than half of the patients had a heart frequency of more than 90 beats per minute (54%) and one third had a respiratory frequency of more than 20 per minute (34%), while other SIRS criteria were met less frequently (Table 1). The most common infection focus was in the respiratory tract (31%), followed by urogenital (19%) and abdominal infections (17%) (Table 1). Although patients might have more than one diagnosis upon presentation to the ED, none of the patients had a gastro-intestinal bleeding, which are known to increase the urea-to-creatinine-ratio as well. AKI was present in 130 patients (19%), which was recovered at hospital discharge in the vast majority (n = 93, 72%) (Table 1). In order to assess the association between transient versus recovered AKI and long-term all-cause mortality, we generated Kaplan–Meier survival curves of the patients stratified to type of AKI (Fig. 2). In contrast to transient AKI that was not associated with long-term mortality, non-recovered AKI was strongly associated with long-term all-cause mortality, as 13 of 37 (35%) patients with non-recovered AKI died during follow-up compared to 12 of 94 (13%) of patients who had recovered from AKI (p < 0.05, Fig. 2). Thus, in contrast to transient AKI, non-recovered AKI, which occurred in 6% of the patients presenting with an infection to the ED, was associated with increased long-term all-cause mortality.
An increased urea-to-creatinine ratio is not a predictor of transient AKI
To determine whether an increased urea-to-creatinine ratio upon admission to the ED is associated with recovery of AKI during hospitalization, patients were divided in tertiles according to their urea-to-creatinine ratio (< 61 n = 221, 61–84 n = 223 and > 84 n = 221; Table 1). Patients with a higher urea-to-creatinine ratio were on average older, used more often ACE-inhibitors (ACEi), angiotensin receptor blockers (ARB), potassium-sparing diuretics and loop diuretics (Table 1). Co-morbidity and infection focus or severity (i.e. incidence of sepsis, septic shock, SIRS-score, and ICU admittance) was not different between the tertiles (Table 1). Patients with a high urea-to-creatinine-ratio presented with a significant rise in serum urea as compared to pre-existent values, while the serum creatinine levels were not significantly changed upon presentation to the ED as compared to baseline values (Table 2). Patients with the highest urea-to-creatinine-ratio had higher serum urea levels as compared to the other groups at baseline, hospital admission and discharge. Importantly, the incidence of transient AKI, non-recovered AKI and both types of AKI combined was not different between the different groups stratified according to the urea-to-creatinine levels (Table 1). Multivariate binary logistic regression analysis demonstrated that the urea-to-creatinine-ratio was not associated with recovery of renal function in the subgroup of patients who were admitted with AKI (n = 130, Table 3). In contrast, a higher SIRS score was associated with transient AKI (OR 1.55 [1.08–2.24, 95% CI], p = 0.02), while use of potassium-sparing diuretics (OR 0.27 [0.08–0.95, 95% CI], p = 0.04) or thiazide diuretics (OR 0.24 [0.08–0.75, 95% CI], p = 0.02) were associated with failure to recover from AKI (non-recovered AKI) (Table 3). In order to dissect which items of the SIRS score were associated with recovery from AKI, we entered the different SIRS criteria separately in the regression model. Of these, only heart rate > 90/min was associated with recovery of renal function (OR 3.06 [1.02–9.13, 95% CI], p = 0.04; constant OR 1.21, p = 0.59; model characteristics: χ2 4.2, df 1, p < 0.05). Hence, an increased urea-to-creatinine ratio was not predictive of the course of AKI.
Patients with an increased urea-to-creatinine ratio are at increased risk for long-term all-cause mortality
To study whether an increased urea-to-creatinine ratio identifies patients at risk for long-term all-cause mortality, we stratified patients in tertiles according to the urea-to-creatinine ratio to generate Kaplan–Meier survival curves and perform a multivariate Cox regression survival analysis. The all-cause mortality rate was 32% among patients with the highest urea-to-creatinine ratio as compared to 12% among patients with the lowest urea-to-creatinine ratio during long-term follow-up of 605 (536–672) days and 729 (687–760) days, respectively (Table 1). An increased urea-to-creatinine ratio was associated with long-term all-cause mortality both among patients with and without AKI (p < 0.01, Fig. 3a,b). Also after adjusting the urea-to-creatinine ratio for non-recovered AKI, transient AKI, age, sex, co-morbidity (i.e. diabetes mellitus, cardiovascular disease, chronic kidney disease, malignancy), SIRS score, septic shock and the relative change in creatinine and urea as compared to baseline, the urea-to-creatinine ratio remained strongly and independently associated with long-term all-cause mortality (HR 2.00 [1.37–2.91, 95% CI], p < 0.01, Table 4). Other risk factors predictive of long-term all-cause mortality were age (HR 1.32 [1.18–1.47, 95% CI] per 10 years, p < 0.01), malignancy (HR 2.31 [1.61–3.32, 95% CI], p < 0.01) and non-recovered AKI (HR 1.86 [1.03–3.33, 95% CI], p = 0.04), while female sex (HR 0.49 [0.33–0.45, 95% CI], p < 0.01) was associated with a lower risk of mortality. Thus, an increased urea-to-creatinine ratio is even stronger associated with long-term mortality than non-recovered AKI. Moreover, different from non-recovered AKI, the urea-to-creatinine ratio can already be determined upon presentation to the ED.