**4. Discussion**

To the best of our knowledge, our study is the first to evaluate inpatient prevalence, mortality, and resource utilization of GS in the United States. We demonstrated overall inpatient prevalence of GS among hospitalized patients in the United States of 10.3 cases per 1,000,000 admissions. The in-hospital mortality rate was 8%. The factors associated with increased in-hospital mortality were age older than 70 years, sepsis, the development of respiratory failure, circulatory failure, renal failure, and liver failure, whereas the factors associated with decreased in-hospital mortality were more recent year of hospitalization and the use of therapeutic plasmapheresis.

GS is often described to have an incidence of GS of 0.5 to 1.8 cases per million population per year in European and Asian populations, primarily based on single-center biopsy or serology-based series [1–3,8,9,12]. A recent nationwide study from Ireland identified all GS cases over a decade via reference immunology laboratories and a nationwide pathology database over an 11-year period, which reported a disease rate of 1.64 per million population per year [10]. In this study, we utilized the United States inpatient hospitalization data from the NIS database and demonstrated inpatient prevalence of GS among hospitalized patients in the United States of 10.3 cases per 1,000,000 admissions. Although hospitalization for GS is infrequent, we found that hospitalized patients with GS commonly had high rates of end-organ failure, including renal failure (62%) and respiratory failure (29%). While 19% of hospitalization for GS required invasive mechanical ventilation, 52% required renal replacement therapy. The median hospitalization cost for GS was as high as \$75,831.

Our findings confirmed a bimodal age distribution of GS, with younger patients <39 years having a male predominance, whereas older patients >60 years old were more frequently female [2,12]. We also observed an increase in the inpatient prevalence of GS from 2004 to 2007, which subsequently stabilized (Figure 1). Although the reason remains unclear, we speculated that this is because of the increasing awareness and widespread availability of diagnostic tests around that time [4,13]. Previous studies have suggested that, in addition to genetic factors, environmental factors can also trigger the development of GS, such as cigarette smoking, inhaled hydrocarbons, or potential infectious triggers damaging the alveolar basement membrane and exposing type IV collagen epitopes [3,4,6,14–18]. Future studies are needed to assess if these factors play an important role in the trends of inpatient prevalence of GS in the United States.

Our study demonstrated that 52% of hospitalization for GS required dialysis, which was consistent with previous literature indicating that approximately half of patients with GS require hemodialysis [19]. There are limited data on how frequently artificial ventilation is required. Small series estimated that this occurred in 11% of patients with GS [20–23]. Our study demonstrated that 19% of hospitalizations for GS needed invasive mechanical ventilation, and 5% needed non-invasive ventilation support. GS is life-threatening, with irreversible kidney damage and respiratory failure. Aggressive therapy with modern treatment protocols with antibody removal by plasmapheresis, use of corticosteroids, and immunosuppressive agents, particularly cyclophosphamide, has dramatically improved patient outcomes compared to the past [4,18,24–26]. The 5-year survival rate exceeds 80% and fewer than 30% of patients require long-term dialysis [2]. In our study, we demonstrated that in-hospital mortality rate of GS in the United States between the years 2003 and 2014 was 8%. Although the data on medication were limited in the database, we found that recent year of hospitalization and the use of therapeutic plasmapheresis were associated with decreased in-hospital mortality among patients with GS. While the underlying explanations of decreased in-hospital mortality among patients with GS in the recent years of hospitalization remain unclear and require further investigations, this finding may potentially represent an improvement in patient care of GS in recent years of hospitalization.

There are several limitations of this study. Firstly, although the utilization of the NIS database allowed us to evaluate U.S. inpatient prevalence and burden of patients with GS, possible inaccuracies in ICD-9 CM coding may have confounded the results. Secondly, given the administrative nature of the dataset, the data on medication such as immunosuppression were limited in this study. Consequently, we could not assess the potential e ffects of immunosuppression, such as cyclophosphamide treatment on hospital outcomes of patients with GS. Thirdly, this was an analysis of an inpatient database in the United States. Sixty-five percent of patient populations with GS in NIS database were Caucasian, and this limits generalizability to the patient population in other countries. Fourthly, kidney biopsy, and laboratory data were lacking in the database. Previous studies have suggested that no patient with 100% glomerular crescents and dialysis dependence at presentation recovered kidney function, and so current guidelines do not recommend treatment in these cases [27,28]. Furthermore, studies have also demonstrated that those patients with higher serum creatinine (5.7 mg/dL or higher) and reduced proportion of normal glomeruli on kidney biopsy have poor renal outcomes [2,13]. Therefore, future studies are needed to assess the impacts of kidney biopsy findings on the treatment and outcomes during hospitalizations for GS.
