This case-crossover study demonstrated several critical findings. First, patients with AKI exhibited an increased dialysis risk after sepsis of nearly 15.8- and 6.7-fold when requiring temporary and chronic dialysis within 1 week. The risk remained high for up to 4 weeks after sepsis but gradually decreased as the time interval increased. Second, the risk was consistent after stratification based on gender. Third, in analyses using nonoverlapping time intervals, the risk remained the highest during the time closest to the event.
Sepsis severity increases AKI incidence [14, 15]. In a cohort study in Spain, AKI incidence increased significantly depending on sepsis severity (4.2% for sepsis, 22.7% for severe sepsis, and 52.8% for septic shock) . In another prospective cohort study including 1177 patients from 198 intensive care units in 24 European countries, up to 51% patients with sepsis developed AKI . AKI severity is determined on the basis of changes in serum creatinine levels and urine output . Patients with severe kidney injury may require dialysis to improve survival and outcomes. Although a growth in knowledge has illuminated the association between sepsis and AKI [17, 18], investigations regarding the risk of AKI with dialysis among patients with sepsis are limited.
The incidence of AKI requiring dialysis in patients with severe sepsis has increased in recent years, and this may be attributed to the survival advantage associated with early dialysis initiation in patients with severe AKI, which has been recognized in previous studies . In patients with sepsis-induced AKI, individual differences are variable; therefore, the novelty of our study is the use of a crossover design to minimize within-person confounding biases.
Several pathophysiological mechanisms relatively specific to sepsis-induced AKI have been proposed, including ischemic/hypoxic, nephrotoxic, and inflammatory insults contributing to AKI pathogenesis, and no single pathway can explain all the features of septic AKI [20–22]. Although ischemic injuries are commonly regarded the leading cause of AKI, sepsis-induced AKI may develop in the absence of renal hypoperfusion and clinical signs of hemodynamic instability  and in the presence of normal or increased global renal blood flow .
Chronic medical conditions, such as diabetes mellitus, hyperlipidemia, and hypertension, are common risk factors for both sepsis and renal failure. The CCI is a commonly used clinical scoring system, which assesses prognosis on the basis of the patient’s comorbidities. In a retrospective study, which included 786 critically ill patients who were either admitted with AKI or developed AKI during their hospital stay, a CCI score of > 6 independently predicted poor renal outcomes . Drug toxicity was related to AKI development and dialysis initiation, and NSAIDs were the most commonly used medication, which were frequently associated with AKI. NSAID use is associated with a 3-fold greater risk of acute renal failure in critically ill patients when compared with patients without a history of NSAID use , and this may be particularly dangerous in patients with CKD who have sepsis. In our study, major risk factors associated with dialysis initiation, such as common comorbidities and nephrotoxic agents, were further assessed.
Several studies have demonstrated that preexisting CKD is one of the key modifiers in AKI leading to progression of CKD [27, 28]. In a large community-based cohort of patients with CKD, the risk of end-stage kidney disease (ESKD) was found to vary with preadmission renal function: 42% and 63% patients with baseline estimated glomerular filtration rates of 30–44 and 15–29 mL/min per 1.73 m2, respectively, developed ESKD . Even a single acute insult to already-compromised kidneys may be devastating. Although the mechanism linking CKD progression and AKI is not yet completely understood, recent studies have demonstrated that persistent kidney injury induced by sepsis-associated AKI is coupled with systemic inflammation. Renal repair can lead to malfunctions in inflammation, fibrosis, and vascular rarefaction that lead to continuous cell and tissue disruption [29, 30].
The present study has several strengths. First, this was a national population-based study, which included a sufficiently large sample size, thus increasing the generalizability of the study. Acute temporary or chronic dialysis can be identified correctly by the procedure codes used in the claim database. Second, we used a case-crossover design based on within-individual comparisons, which may implicitly minimize confounding bias through adjusting time-invariant confounding factors. Third, to eliminate the possibility that AKI may be induced by nephrotoxic medications, we also assessed concomitant medications including NSAIDs within 1 year before the first dialysis. Finally, to improve data robustness regarding gradually decreasing dialysis risk after sepsis with increasing time interval, we reassessed data using nonoverlapping time intervals, and the risk remained the highest at the time closest to the event.
This study also has several limitations. First, sepsis diagnosis was identified on the basis of ICD-9-CM codes, and we have no detailed information to define the severity of sepsis. Therefore, we are unable to estimate a severity-related relation between sepsis and the risk of dialysis. Second, the National Health Insurance Research Database (NHIRD) does not provide detailed information on health-related factors, such as body mass index, history of smoking, and dietary habits, all of which may be a confounder. To combat this, we used the case-crossover design to minimize the confounding bias. Third, due to the case-crossover design, all patients who underwent dialysis were 1 year older than those in the control group—age is a major risk factor for CKD and dialysis initiation in these patients. Finally, the NHIRD does not provide detailed information on the severity of sepsis related AKI, and thus, we could not perform a subgroup analysis based on severity. Owing to these limitations, a large prospective study in future may provide helpful information to clinicians.