Introduction
Chronic kidney disease (CKD) is highly prevalent worldwide and is drawing considerable attention from clinical and public health perspectives [1]. Numerous studies have provided evidence that declining kidney function is associated with increased hospitalization, and that CKD is an essential predictor of hospitalization, causing a tremendous health burden to patients [1–4]. Hospitalizations that occur in CKD patients are also more likely to lead to further complications, including greater re-hospitalization rates [5], higher mortality [3,6], worsening kidney function [3], and severely diminishing quality of life [7,8] compared with patients without CKD.
Many of the hospitalizations experienced by CKD patients are due to cardiovascular disease [3,9] or renal-related events [10]. However, little is known about the other reasons for hospitalization or why people with kidney disease have a higher risk of hospitalization. Therefore, it is important to understand cause-specific hospitalizations in CKD patients, not only for significant causes like cardiovascular disease and renal events but also to gain a broader perspective of risks associated with CKD. Analysis of the incidence of cause-specific surgeries according to CKD stage is also crucial because hospitalization due to surgery type is not systematically known, even though many hospitalization events are for planned surgical treatments.
The purpose of this study is to characterize the hospitalization burden in CKD patients with a multicenter observational study: KoreaN cohort study for Outcomes in patients With Chronic Kidney Disease (KNOW-CKD). We examined the incidence rate of cause-specific hospitalization in CKD patients, along with the incidence rate of cause-specific surgeries practiced in CKD patients. We also explored the association between CKD stage and hospitalization risk. This study is expected to clarify and improve treatment for CKD disease by ascertaining various hospitalization-related events that may occur in CKD patients.
Methods
Study design
This is a longitudinal study from a prospective cohort of nondialyzed CKD patients in South Korea, entitled KNOW-CKD, which enrolled adult (20–75 years old) patients with CKD stages G1 to G5 from nine centers between 2011 and 2016 [11]. Exclusion criteria included history of chronic dialysis, severe heart failure, liver cirrhosis, history of malignancy, current pregnancy, organ transplantation, or single kidney due to trauma or nephrectomy. Enrolled patients were prospectively followed up for hospitalization events until March 31, 2020. Of the 2,238 subjects enrolled, subjects during the follow-up period were censored on the date of their death, dialysis, or at the end of follow-up, whichever came first (Fig. 1). Informed consent was obtained from all patients voluntarily at the time of enrollment. The study was approved by the Institutional Review Board of each participating hospital: Seoul National University Hospital (No. H-1704-025-842), Seoul National University Bundang Hospital (No. B-1106/129-008), Severance Hospital (No. 4-2011-0163), Kangbuk Samsung Medical Center (No. 2011-01-076), The Catholic University of Korea, Seoul St. Mary’s Hospital (No. KC11OIMI0441), Gachon University Gil Medical Center (No. GIRBA2553), Eulji Medical Center (No. 201105-01), Chonnam National University Hospital (No. CNUH-2011-092), and Pusan Paik Hospital (No. 11-091). This study follows the guidelines of the Declaration of Helsinki.
Data collection and measurements
Demographic and laboratory data were collected, including CKD and comorbidities. Among demographic data, the Charlson comorbidity index (CCI) was used to quantify different patients’ severity and health status in clinical studies. CCI is calculated by assigning a constant weight of 1 to 6 points to 17 diseases defined through medical record surveys, and then adjusting the sum of those weights [12]. The following laboratory variables were measured using a blood sample with at least 8 hours of fasting at each participating center’s laboratory: estimated glomerular filtration rate (eGFR), hemoglobin, albumin, and high-sensitivity C-reactive protein. The CKD epidemiology collaboration equation based on serum creatinine was used to calculate eGFR [13]. For urine biochemistry, urine protein and creatinine were measured using immunoturbidimetry.
Event adjudication
Hospitalization in the KNOW-CKD patients was defined as admission to the hospital through any route. The date, main reason for hospitalization, surgery history, and department of surgery during the hospitalization were collected. The main reason for hospitalization was determined based on diagnosis and treatment performed, categorized by primary reason for admission first confirmed by investigators in each center, and then cross-adjudicated by two different nephrologists at a central adjudication committee afterward. Surgical treatment related to dialysis access (such as arteriovenous fistula and peritoneal dialysis catheter insertion) was excluded.
Reasons for hospitalization were categorized into 16 groups, as previously described elsewhere [14]: 1) acute kidney injury (AKI), 2) all-cause infectious disease, 3) neoplasm (including chemotherapy), 4) endocrine-nutrition-metabolic–related causes, 5) diseases of the blood and blood-forming organs, 6) mental illness, 7) diseases of the nervous system and sensory organs, 8) circulatory system diseases, 9) respiratory tract diseases, 10) digestive system diseases, 11) diseases of the genitourinary system, 12) pregnancy complications, 13) diseases of the musculoskeletal system and connective tissue, 14) injuries and poisonings, 15) diseases of the skin and subcutaneous tissues, 16) other symptoms, signs, and ill-defined conditions and factors influencing health status. Detailed information on the above classifications is attached as Supplementary Table 1 (available online).
Control population
All-cause hospitalization in the KNOW-CKD patients was compared with hospitalization data from the general population. Control population data were procured from the National Sample Cohort Database of the National Health Insurance Service, which is generally considered the most nationally representative data for Korea because, as the single Korean insurer, it includes nearly the entire Korean population [15,16]. Major exclusion criteria were: 1) subjects who had been previously admitted with a disease code for pregnancy, cancer, liver cirrhosis, or organ transplantation; or 2) subjects who had already experienced dialysis. The control group did not exclude the nondialysis CKD population. Therefore, it is estimated that about 5% of our control population has CKD [17]. Eventually, 224,756 subjects were sorted from a one million cohort sample from 2002 to 2013 whose hospitalization data were compared with our study patients.
Statistical methods
Baseline characteristics were compared with outcomes using the chi-square test and the analysis of variance test. For non-normally distributed continuous variables, the Kruskal-Wallis test was used. Hospitalization incidence by each category with respect to the CKD stage was compared with the Jonckheere-Terpstra test. Incidence rates are represented as per 1,000 person-years. All-cause hospitalization rates for each stage were then compared in a negative binomial regression model to account for overdispersion. Using variables that showed significant differences between CKD stages and after removing potential mediator variables, models were adjusted for age, sex, diabetes mellitus (DM), and body mass index (BMI). Length of follow-up was also included to account for varying durations of follow-up periods between stages. The incidence rate ratio (IRR) was calculated with a 95% confidence interval. All statistical analyses were performed using IBM SPSS version 26.0 (IBM Corp.) and R version 4.1.1 (R Foundation for Statistical Computing). The p-value significance limit was set at 0.05.
Results
Basic characteristics
Baseline characteristics are reported elsewhere and summarized in Table 1. The median age was 55 years, and 61.1% were male. Among 2,238 study subjects, 360 (16.1%) were in CKD G1, 425 (19.0%) in G2, 835 (37.3%) in G3a–3b, and 618 (27.6%) in G4–5. The most common CKD etiology in the KNOW-CKD population was glomerular disease followed by DM and hypertension.
When subjects were stratified into four groups according to CKD stage, we found differences between groups in mean age, sex proportion, BMI, blood pressure, CKD etiology, comorbidities, and laboratory findings. Higher stages were associated with a higher prevalence of comorbid diseases such as congestive heart failure, peripheral vascular disease, cerebrovascular disease, connective tissue disease, and DM. CCI scores were also higher in the advanced CKD stage.
Hospitalization incidence rate according to chronic kidney disease stage
The incidence rate of all-cause hospitalization and cause-specific hospitalization is shown in Table 2. A total of 184.96 hospitalizations per 1,000 person-years were observed in the cohort, and the hospitalizations were categorized into 16 groups. The most common cause of hospitalization was circulatory system disease, followed by infection, and neoplasm, indicating incidence rates of 29.23, 23.46, and 21.57 per 1,000 person-years, respectively. AKI occurred at an incidence of 10.88 per 1,000 person-years.
All-cause hospitalization incidences increased significantly as the CKD stage increased. As the stage increased, incidence rates of AKI, endocrine-nutrition-metabolic–related disease, blood- or blood-forming organ-related disease, and diseases of the nervous system and sensory organs significantly increased. In contrast, no significant difference was found in hospitalization rates related to infection, neoplasm, digestive system disease, diseases of the musculoskeletal system or connective tissue, injury or poisonings, respiratory tract diseases, and mental illness. Hospitalization incidence rate due to genitourinary system diseases and pregnancy-related complications showed a decreasing pattern.
Note that the main cause of hospitalization varies depending on the cause of CKD (Supplementary Table 2, available online). The most common cause of hospitalization in diabetic kidney disease and hypertensive nephropathy was circulatory system disease, whereas infection was the most common cause of hospitalization in patients with polycystic kidney disease.
Surgical incidence rate according to chronic kidney disease stage
This study also analyzed surgery during admission (Table 3). Among surgical departments, the highest incidence was found among ophthalmologic surgery followed by musculoskeletal surgery, and intraabdominal surgery. The ophthalmologic surgery incidence rate increased while intraabdominal surgery was associated with a decreasing trend with increasing the CKD stage. Operation incidence based on the etiology of CKD is presented as Supplementary Table 3 (available online).
Hospitalization incidence rate ratio according to chronic kidney disease stage
The IRR for all-cause hospitalization is shown in Table 4, with G1 as the reference. The IRR of G3 and G4–5 was statistically higher than G1 in a crude model. The increasing trend of all-cause hospitalization was also statistically significant after adjustments for age, sex, and follow-up duration. We further analyzed IRR based on age and presence of DM (Table 5). The hospitalization rate was significantly elevated at advanced CKD stages regardless of age and DM. The elderly subgroup (aged >65 years, n = 418, 18.7% of the total cohort population) showed a marginally significant increase of IRR for advanced CKD stages (IRR of 1.85, 2.21, and 3.38 for G2, G3a–3b and G4, respectively) possibly due to insufficient statistical power.
Hospitalization incidence rate ratio compared with the general population
Table 6 shows the IRR for all-cause hospitalization between the control group and the study population. A total of 11,780,421 person-years were observed, and there were 38.95 hospitalization events/1,000 person-years. The KNOW-CKD subjects had a 6.19-fold higher all-cause hospitalization event rate after adjusting for multiple variables. Hospitalization rates were also consistently elevated with higher CKD stages after adjusting for covariates, except between G3 and G4–5.
Discussion
Hospitalization is a major health burden for patients with CKD. Previous studies observing hospitalization in CKD patients confirmed that the hospitalization rate in CKD patients was higher than among the general population, but few studies have evaluated the causative diseases that lead to hospitalization [3,4,18]. We analyzed the medical and surgical reasons for hospitalization in the KNOW-CKD patient cohort. According to this study, circulatory system disease, infection, and neoplastic disease were the three most common reasons for hospitalization in CKD patients. As the CKD stage increased, patients became more vulnerable to comorbid diseases such as AKI, endocrine-nutrition-metabolic–related disease, blood and blood-forming organ-related disease, and diseases of the nervous system and sensory organs. The most common reason for surgery among CKD patients was ophthalmologic treatment, followed by musculoskeletal and intraabdominal surgery.
Disease categories with high incidence rates in this study were observed consistently with previous studies [4,18], but unlike previous reports, admission for AKI was lower in this study. This difference might be due to different classification categories and methods between the previous studies and ours. We analyzed only the primary and main causes of hospitalization. For instance, heart failure with cardiorenal syndrome may be classified as circulatory system disease. Therefore, it is likely that AKI episodes, which are concomitant to, but not the main cause of, hospitalization might be omitted in our analysis. This might underestimate the total AKI episodes in CKD subjects. Nevertheless, our findings are in line with other hospitalization studies, which all found that hospitalizations due to AKI as the primary cause were not uncommon and AKI incidence increased with higher CKD stages.
The hospitalization incidence for endocrine disease, nervous system and sensory organ diseases, and blood-related diseases increased with higher CKD stage. Considering that complications such as anemia and electrolyte imbalance occur as the CKD stage increases, this observation is reasonable. Also, the increasing hospitalization trend for endocrine-nutrition-metabolic–related causes may underscore the importance of nutritional assessment and medical nutrition therapy (MNT), which all seem beneficial but have uncertain effects on mortality reduction among kidney disease patients [19,20]. The effect of MNT on the reduction of hospitalization rates requires further study. Hospitalizations for nervous system and sensory organ diseases might be related to ophthalmic diseases, which will be discussed in future work. The hospitalization rate for genitourinary system diseases seems high at early CKD stages. It is well known that polycystic kidney disease carries multiple renal manifestations such as flank pain, rupture, and stone formation [21]. Early stage of CKD excessively included patients with polycystic kidney disease, which might have contributed to a substantially high incidence rate of hospitalization related to the genitourinary system.
The CRIC (Chronic Renal Insufficiency Cohort) study confirmed a distinct and continuous increase in cardiovascular disease incidence along with the eGFR decrease, as well as an association between low eGFR and risk of all-cause death and hospitalization [3]. Additionally, a study from Japan revealed a high incidence of hospitalizations in CKD patients for the following conditions, in the following order: eye and adnexa, heart disease, and heart failure [4]. Although hospitalization in this CKD cohort tended to increase at advanced CKD stages, the overall hospitalization rates were lower than in other cohort studies [3,4]. As previously described [11], the KNOW-CKD subjects are relatively younger which included only 18.7% of patients with age over 65 years. This might explain the difference from other studies due to insufficient statistical power for the elderly subgroup.
The finding that CKD patients underwent higher rates of orthopedic, general, and ophthalmic surgery is consistent with the fact that CKD patients have a high risk of osteoporosis and eye problems [22,23]. Unlike a previous study in which surgical incidence increased rapidly according to the stage [24], the incidence of overall surgical practice did not increase significantly according to the CKD stage in this study.
Similar to other findings, eye surgery was more common in patients with CKD, especially in diabetic kidney disease patients. The incidence of ophthalmic surgery should be carefully interpreted since the incidence of cataract surgery is unusually high in Korea [25]. Apart from cataracts, CKD patients, especially those with diabetic kidney disease share common risk factors as well as pathophysiology with several ophthalmic diseases such as retinopathy [23,26–28]. Early identification and intervention for ophthalmic problems in CKD patients especially with DM may be important for reducing hospitalization. The incidence of general surgery seems to have decreased as the CKD stage increased, but this phenomenon was not seen in the subgroup; rather incidence of intraabdominal surgery increased in polycystic kidney disease. Intraabdominal surgery is commonly known to be increased based on previous studies, and follow-up studies with a population more reflecting real-world might be needed [23,29,30].
The KNOW-CKD population had a 6.19-fold higher hospitalization rate compared with the general population, which is consistent with other studies although the rate ratio of each study was different [4,14]. Simple comparison between countries for hospitalization rates might be impractical because healthcare systems vary between countries. A key finding from our study is that hospitalization rates were higher even at low CKD stages, 3.84- to 5.92-fold more common in G1/G2 stages, compared with the general population after adjustment. It warrants careful interpretation because glomerular disease and polycystic kidney disease are overrepresented in our cohort. These patients were more vulnerable to infection and genitourinary system disease, which were the major causes of hospitalization in G1 CKD patients. This may indicate the importance of individualized monitoring and intervention based on the etiology of CKD, apart from stages.
Our study had several limitations. First, subjects were followed up for hospitalization events until the development of end-stage renal disease. Therefore, the follow-up duration was shorter for subjects at higher CKD stages median of 2.52 years in G4–5 compared with 4.97 years overall. This might partly explain the decreasing rate ratio for G3 and G4–5 in comparison with the general population. Second, this study had limitations in considering every confounder that may affect the prognosis for CKD patients. Third, admission rates for specific diseases cannot be assessed, and we just estimated etiology based on disease category. Since the study purpose of KNOW-CKD Phase I included the comparison of CKD outcomes among the four main causes of CKD, the study oversampled glomerular disease and polycystic kidney disease patients. Therefore, the cohort population might not exactly mirror the actual Korean CKD patients in the real world. Nevertheless, we had robust findings that highlighted the outcomes of hospitalization for various causes, including differences between causes of CKD. Phase II KNOW-CKD study has recently finished recruitment, which further reflects the real-world Korean population [31], and this follow-up study will provide more concrete perspectives to help specify the patterns of hospitalization in actual CKD patients.
In conclusion, the hospitalization rate in this study was much higher than the general population, even in lower stages. Various causes such as infection, neoplasm, and sensory-nervous system diseases have contributed to the hospitalization event, which showed a difference between the causes of CKD. We hope this study serves as a reference for an individualized approach for active follow-up and care for specific comorbidities of CKD patients regarding causative diseases.
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