**4. Discussion**

In this study, based on a large national database of hospitalizations, the day of admission had a significant clinical impact on elderly subjects with AKI. The WE e ffect was independently associated with IHM, along with dialysis treatment and comorbidity burden. The OR for IHM was 1.113, and this finding confirmed previous results from our group, also drawn by analysis of the NHD records, regarding pulmonary embolism (OR 1.15) [20], and acute aortic dissection or rupture (OR 1.34) [21]. The importance of a diverse level of emergency has been underlined by previous studies. Concha et al. studied the 7-day post-admission time patterns of excess mortality following WE admission to investigate whether the phenomenon could be due to poorer quality of care or a case selection. After evaluation of mortality risk for WE and WD, adjusting for age, sex, Charlson Comorbidity Index (CCI), and diagnostic group, they found that WE mortality was diverse for di fferent diagnostic groups, and concluded that the WE e ffect is probably not a uniform phenomenon, but rather a complex cluster of di fferent causal pathways, even associated with quite di fferent risk profiles [22]. Similar results were reported by Roberts et al., who evaluated 30-day mortality for WE admissions in England and Wales. The WE e ffect was more evident for disorders with high mortality during the acute phase, and negligible for less acute ones [23].

Moreover, the presence of comorbidities plays a primary role in determining IHM. In the present study, in fact, the OR of comorbidity score is lower than that of presence of dialysis and age, but the risk of death raised of 4.2% for every 1-point increase. In a previous study conducted by our group, we showed that CCI was significantly higher in subjects admitted during WE, and significantly contributed to clinical outcome, along with gender and age. In logistic regression analysis, in fact, admission on WE, CCI, male sex, and age were significantly associated with IHM [24].

To the best of our knowledge, this is the first study considering the relationship between the WE effect and IHM in elderly patients hospitalized because of AKI. The question of whether the WE e ffect also exists in renal diseases is still matter of debate, because the number of available studies is limited, and results are not univocal. We are aware of only three studies considered the relationship between WE admission and AKI, conducted in the United States (USA), United Kingdom (UK), and Wales, respectively. James et al. analyzed data from the U.S. Nationwide Inpatient Sample and selected more than 200,000 admissions reporting AKI as the primary diagnosis. The prevalence of WE admission was 21% and WE hospitalizations were independently associated with IHM [25]. Kolhe et al. conducted a study on more than 53,000 dialysis-dependent AKI patients. The prevalence of WE admission was 23%, and WE admissions were significantly associated with higher mortality in the unadjusted model, but not in the multivariable analysis [26]. Finally, Holmes et al. did not find any WE e ffect for mortality associated with hospital-acquired AKI [27]. None of these studies, however, included comorbidity analysis.

A higher interest in the WE e ffect has been shown to investigate possible negative outcomes in renal transplantation, but results have not demonstrated any negative outcome thus far. In the U.S., Baid-Agrawal et al. did not confirm the hypothesis that kidney transplants performed during WE could have worse outcomes than those performed during WD. In fact, the day of surgery did not a ffect death, length of hospitalization after transplantation, delayed allograft function, acute rejection within the first year of transplant, and patient and allograft survival at 1 month and at 1 year after transplantation [28]. In Germany, Schütte-Nütgen et al. found no di fferences between subjects transplanted on WD or WE in terms of 3-year patient and graft survival, frequencies of delayed graft function, acute rejections, 1-year estimated glomerular filtration rate, and length of hospital stay [29]. Again, in England, Anderson et al. did not confirm the relationship between WE and mortality, rehospitalization, and kidney allograft failure/rejection [30]. Moreover, a study of the Australia and New Zealand Dialysis and Transplant registry concluded that timing of transplantation did not impact on allograft outcome [31]. Also, our group tested this hypothesis on all cases of the Emilia-Romagna region, but did not find any risk of adverse outcome related to the WE e ffect, observing only that WE admissions were characterized by longer duration of hospitalization [32].

On the other hand, WE admission seems to negatively influence outcomes in dialysis patients, although the available evidence is strictly limited to a couple of studies. In the U.S., Sakhuja et al. reported that WE admissions were more likely to have higher IHM, higher mortality during the first 3 days of admission, longer hospital stays, and less likely to be discharged to home. Moreover, time to death was shorter compared with WD admissions [33]. Finally, data from the Australia and New Zealand Dialysis and Transplant Registry reported higher rates of hospitalization secondary to peritonitis on WE compared to WD [34].

In our present study, dialysis-dependent AKI and the WE e ffect were independently associated with IHM; it could be that the two factors negatively impact patients' survival and complications.
