152 Chapter 7 Discussion The main finding of our study is the high overall incidence of AKI in patients with SAB (37%), particularly in patients with complicated disease. This high incidence, combined with the limited reversibility, illustrates the significance of this complication. We found that AKI in SAB develops early in most patients. In a high proportion (39%) of patients developing AKI the creatinine level peaked at the day of first positive blood culture. Furthermore, the median time to peak creatinine was 3 days after first positive blood culture. These findings are similar with those reported by Holmes et al. [3]. The slightly higher incidence of AKI in the study by Holmes may be explained by a different definition of AKI. They included low urine output in their definition, whereas our definition was based on serum creatinine alone. Other research on AKI in SAB is limited to studies that were primarily aimed at comparing treatment outcome of different antibiotic therapies. In these studies, the incidence of nephrotoxicity was highly variable, ranging from 2 to 33% [10–14]. Acute kidney injury was reversible in the majority of patients (59%), but a significant proportion of patients suffered from irreversible renal impairment. In patients with reversible AKI, recovery occurred within 7 days after onset in the majority of patients (82%). Persistent kidney injury beyond this time point is prognostically unfavorable. In patients with persistent AKI at T = 7 days, recovery was observed in only 20%. The high proportion of non-reversible AKI in our study may partially be explained by disease severity. The association between disease severity and both the prevalence and the reversibility of AKI has been demonstrated for sepsis-associated kidney injury in general [15,16]. Several risk factors for the development of AKI were identified in our study. Apart from diagnosis of complicated SAB, the use of diuretics as well as hemodynamic instability at time of admission remained independent risk factors for AKI in multivariable analysis. Together with the time course of renal insufficiency showing early onset and quick recovery, this finding suggests that hemodynamic deterioration early in the disease plays an important role in the development of AKI. However, the results of our study do not yield definite answers regarding pathophysiology. Toxicity of antibiotics, i.e., nafcillin and aminoglycosides, has been suggested in the literature to be important in development of AKI, although this assumption was not confirmed by kidney biopsies [10–14, 17, 18]. In the current study, the vast majority (86%) of patients was treated with flucloxacillin according to the Dutch guideline, limiting the comparison of different antibiotic therapies on AKI development [19, 20]. However, based on the median time to AKI of 3 days, toxicity caused by antibiotic therapy does not seem to have been a major cause of AKI. For example, TIN on antibiotic therapy is unlikely if the onset is < 5 days after start of antibiotic therapy [21]. Secondly, TIN is unlikely to recover within 1 week.
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