Introduction
Chronic kidney disease (CKD) is a global public health problem [
1]. Multiple cohort studies have been initiated worldwide to investigate its causes and effects [
2]. The chronic renal insufficiency cohort (CRIC) study [
3,
4] in the United States enrolled 4000 participants with CKD, and the resulting data have been used in many publications. On a strong cooperative relationship with the CRIC organizers, Japanese researchers initiated the chronic kidney disease-Japan cohort (CKD-JAC) study, a multicenter prospective cohort study of Asian patients with stages 3, 4, or 5 CKD living in Japan, aged 20–75 years that monitored patients for 4 years [
5,
6]. Data from these studies are being used to determine disease-risk profiles for CKD patients and establish risk factors predicting CKD progression [
7,
8].
The CRIC, CKD-JAC, and other cohort studies have clearly established CKD as an independent risk factor for end-stage kidney disease (ESKD), cardiovascular disease (CVD), and all-cause death [
4,
7,
9]. Proteinuria, hypertension, diabetes, and dyslipidemia can worsen CKD [
10‐
13], and diabetes is particularly important in countries where it is becoming increasingly common, such as Japan. Diabetic nephropathy is the primary cause of ESKD in Japan, and diabetes accounts for 45% of all ESKD cases. Chronic glomerulonephritis, which accounted for 60% of ESKD cases in Japan approximately 30 years ago, is now the etiology in only 20% of cases [
14].
Hospitalization is another concern for CKD patients. Studies on hospitalizations are limited but report a relatively high incidence of hospitalization for arteriovenous shunting, CVD, and infection [
15]. In another study, all-cause hospitalization increased with CKD stage [
16]. Meanwhile, Japanese medical checkup data have shown that a lower estimated glomerular filtration rate (eGFR) is associated with increased risk of all-cause hospitalization and CVD death [
17].
CKD patients are hospitalized not only for CKD, but for diabetes and related diseases. However, there are no reports on CKD patients’ hospitalization for other diseases or the contribution of CKD to them.
We aimed to determine the frequency and causes of hospitalization of CKD patients, to elucidate the prognosis using hospitalization as an indicator, and find high-risk population among them.
Discussion
In this study, we used data from nearly 4 years of follow-up on 2966 participants to profile risk factors and underlying causes of hospitalization in CKD patients. With 2897 hospitalization events (252.3 events/1000 person-years), we have strong data supporting a few important findings in this vulnerable patients.
These data demonstrate that CKD patients are at high risk of hospitalization for many diseases. All-cause hospitalization was 17.1-fold more common in CKD-JAC patients than in the control cohort. CKD is a risk factor for ESKD and CVD, and the high hospitalization rate for the [
10] kidney diseases (86.1 events/1000 person-years) and [06] heart (24.6 events/1000 person-years) classifications is consistent with previous findings [
7,
8,
15]. However, the magnitude of that effect in this study was greater than expected: a 218.0-fold higher risk for [
10] kidney diseases and 46.3-fold higher risk for [06] heart diseases than in the control cohort. Hospitalizations were also more frequent for diseases of the [04] eye and adnexa (100.5-fold) and [03] endocrine, nutritional, and metabolic diseases (39.9-fold). Both classifications are related to diabetes, which is a major underlying disease in CKD. Even after we removed [04] eye and adnexa [03] endocrine, nutritional, and metabolic, as well as [
10] kidney diseases, in which ESKD plays a major role, CKD-JAC hospitalizations were still substantially more frequent (9.7-fold) than hospitalizations in controls. This indicates that CKD is a risk factor for many diseases, and CKD patients are highly vulnerable to many conditions that may require hospitalization. This analysis provides a unique comprehensive profile of all kinds of hospitalizations.
Our study also provides valuable data on the effects of CKD stage on hospitalization. Hospitalizations for [
10] kidney disease increased dramatically with CKD stage, and hospitalizations for [05] circulatory system and [06] heart diseases were greater at CKD stage 4 than at stage 3a (Fig.
1b). Previous research has clearly shown that CKD stages 3 through 5 are independent predictors of ESKD and CVD [
16,
21‐
24]. Our data confirm these findings, except for decreased hospitalizations at stage 5 for [05] circulatory system and [06] heart diseases. That may be because only the main disease names from hospitalization data including maximum three diagnoses were analyzed. Competing risk analysis will be done in the future.
We were able to investigate potential risk of underlying diseases on hospitalization. All-cause hospitalization was approximately 1.8 times higher in diabetic patients (345.7 events/1000 person-years in the DM + group vs. 196.8 in the DM − group). Among those with diabetes, hospitalizations were even more frequent in the subgroup of patients diagnosed with diabetic nephropathy (381.2 events/1000 person-years). Results were similar even after excluding disease classifications closely related to diabetes. Clearly, diabetes affects hospitalization for many diseases, both related and unrelated to diabetes. In the group previously diagnosed with glomerulonephritis, the number of hospitalization events was low for most diseases except those in [
10] kidney. These findings demonstrate that the disease underlying CKD has important prognostic value and the subpopulation of patients with diabetic nephropathy is at particularly high risk.
Survival analysis also illustrated the major impact of diabetes on CKD. The time to first hospitalization was shorter in patients with a higher CKD stage and in those with diabetes. If we evaluate all-cause hospitalizations, the time to first hospitalization was shorter in patients with CKD stage 3b and diabetes than those with CKD stage 4 without diabetes. For CVD-related issues, diabetes had an unexpectedly strong effect on the survival time. The time to CVD-related hospitalization was shorter in diabetic patients than in patients who were diabetes-free, across all CKD stages.
This study had some limitations. First, at CKD stage 5, we expected an increase in hospitalizations related to renal diseases. These patients may have been hospitalized for other diseases, but the diagnoses could be obscured by the primary disease name. To address this, we plan a future investigation of competing risks. Second, there is a problem to be considered whether CKD-JAC data had an appropriate representativeness of CKD patients in Japan. Our data were from large leading hospitals that have nephrologists in residence, but the control data were obtained from a survey of hospitals of all sizes, not necessarily with nephrologists in residence. The results of this comparison may reflect not only differences in the incidence of hospitalization between CKD patients and the general population but also differences between large nephrology hospitals and the general population. At large hospitals, patients have the advantage of receiving treatment optimized to their disease state. Therefore, the incidence of hospitalization may be lower than that in ordinary hospitals. Third, proper evaluation of CKD during maintenance period must be based on the comparison between CKD-JAC group and general population which meets inclusion and exclusion criteria of CKD-JAC. However, it was impossible to do that, so we used patient survey data as the substitute. Even though the patient survey population was matched to the CKD-JAC population using sex, age, and person-years of observation as adjustment factors, these data contain both patients who get hospitalized at a certain day and those who have been hospitalized on the same day. That means we may overestimate the incidence of hospitalization in general population. In addition, more and more patients over 75 years old have started dialysis in recent years [
25]. These aged people have higher risk for hospitalization than younger generation under 75 years old, not only for ESKD but also various aging conditions. To evaluate the risk of CKD more precisely, these elderly patients should have included to our study. Further study is expected for evaluating CKD on elderly people.
These might result in underestimation of the overall extent of hospitalization of CKD patients. However, we believe that the magnitude of differences described in this paper is sufficient to justify the generalizability of our results.
As for hospitalization durations, they are likely to be affected by the medical assurance system in Japan, so other suitable studies to evaluate them will be needed.
In addition to validating the previously observed increased risk for CVD and ESKD, this study clearly shows the extreme vulnerability of CKD patients to many other diseases. These data are highly valuable for predicting prognoses in CKD patients, in addition, for identifying high-risk population among CKD patients.
Acknowledgements
This study was conducted by the principal investigators at the following medical centers: Japan Community Health Care Organization Sendai Hospital (Miyagi), JA Toride Medical Center (Ibaraki), Jichi Medical University (Tochigi), Tokyo Women’s Medical University Hospital (Tokyo), St. Luke’s International Hospital (Tokyo), Showa University Hospital (Tokyo), Showa University Yokohama Northern Hospital (Kanagawa), Showa University Fujigaoka Hospital (Kanagawa), Gifu Prefectural General Medical Center (Gifu), Kasugai Municipal Hospital (Aichi), Tosei General Hospital (Aichi), Osaka University Hospital (Osaka), Osaka General Medical Center (Osaka), Osaka City General Hospital (Osaka), Kurashiki Central Hospital (Okayama), Fukuoka Red Cross Hospital (Fukuoka), and Iizuka Hospital (Fukuoka).
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