Increased risk of end-stage renal disease among hip fracture
patients
Chun-Hung Tseng
a,e,1, Wei-Shih Huang
a,e,1, Tsai-Chung Li
f,g, Hsuan-Ju Chen
b,d,
Chih-Hsin Muo
b,d, Chia-Hung Kao
c,e,⁎
1. Introduction
End-stage renal disease (ESRD), a condition characterized by faradvanced renal dysfunction, is a major worldwide threat to public
health because it frequently results in disability or death [1–3]. Hence,
the early recognition of risk factors for ESRD for improving prevention is crucial to reduce social and economic burdens related to ESRD. The decline of renal function may progress through several nephropathic
mechanisms including renal microvascular disease associated with infammatory
processes [4–8], albuminuria [4–8] and rapid deterioration
of renal function [4–8]. With further deterioration of renal function by
cardiovascular dysfunctions, ESRD could be triggered by some traditional
cardiovascular disorders, such as hypertension [1–3,9–11], hyperlipidemia
[1,2,9–11], and peripheral arterial disease (PAD) [9,10],
and non-cardiovascular disorders, for example, osteoporosis [12,13]
and asthma [13,14]. Nevertheless, researchers have identifed no risk
factors in certain ESRD patients. Therefore, investigating the possible predictor for ESRD, beyond well-known risk factors such as hypertension
[1–3,9–11], hyperlipidemia [1,2,9–11], PAD [9,10], osteoporosis
[12,13] and asthma [13–15] is required.
In addition to the traditional atherosclerosis-associated factors that can trigger and exacerbate renal dysfunction, the likely role of chronic systemic infammation in triggering a decline in renal function and inducing
subsequent ESRD has been studied [16–18]. Researchers have
associated the possibility of ESRDwith chronic infammations due to infections,
including hepatitis B virus (HBV) [19–21], hepatitis C virus
(HCV) [19–22], and human immunodefciency virus (HIV) [19–21],
and autoimmune disorders, such as rheumatoid arthritis (RA) [23,24] and systemic lupus
erythematosus (SLE) [25,26]. However, the precise
mechanisms of the possible association of infammationwith the development of renal dysfunction to ESRD remain unclear.
Osteoporosis, which is the main risk factor for fractures in older adults, is characterized by a long termchronic infammatory component
[27,28]. Osteoporosis can also be associated with microvascular disease
[29,30] thatmight enhance the deterioration of renal function in chronic
kidney disease (CKD) and, hence, accelerates the formation of ESRD [12,
13]. After fractures, bone healing is a complicated process comprising
hematoma formation, infammation, cell proliferation and differentiation,
ossifcation, and bone remodeling [31]. As a fracture occurs, an
acute infammatory response is generated immediately and is crucial
in bone healing [31–33], and this fracture-related acute infammation
in combination with osteoporosis-associated chronic illness, microvascular disease and chronic infammation might further exaggerate the
deterioration of renal dysfunction. No researchers have identifed the possible association between hip fracture (HFr), a disorder involving a strong infammatory process, and the risk of ESRD formation. The Taiwan National Health Insurance (NHI) program covers most of the population of Taiwan, and the NHI inpatient claim database was used in this study to explore the likely association between HF and ESRD during follow-up periods between 2000 and 2011.
2. Methods andmaterials 2.1. Data source
The data of this studywas retrieved fromthe TaiwanNationalHealth
Insurance ResearchDatabase (NHIRD),which is a claims databasemaintained by the Department of Health and the National Health Research
Institutes (NHRI) of Taiwan. The National Health Insurance (NHI) program, which was implemented in 1995, has covered more than 99% of
the entire population of Taiwan (23 million residents) in 2007 [34,35].
All personal information is encrypted before being released to the public to protect patient privacy.
In this study, we used the hospitalization claims data of all enrollees (23 million residents) in Taiwan, which contained information on sex, birthday, and dates of admission and discharge, diagnoses, discharge status and expenditures by admission. Diseases were coded based on the International Classifcation of Disease Diagnoses, 9th Revision of Clinical Modifcation (ICD-9-CM codes). The study was also approved by the Institutional Review Board of China Medical University and Hospital (CMU-REC-101-012).
2.2. Study patients
We conducted a population-based retrospective cohort study
with HFr (ICD-9-CM code 820.xx) as recorded in the inpatients registry fle during 2000–2006, and the date of the frst diagnosis of HFr was used as the index date. Patients with a previous diagnosis of ESRD (ICD-9-CM code 585.xx from the catastrophic illness registry) (n = 1571) or renal disease (ICD-9-CM code 580.xx–589.xx)
(n= 9807) before the index date, and those with incomplete information (n = 49) were excluded from this study. For each patients with
HFr, one controls were frequency-matched on sex, age (per 5 year), and index year were identifed. Overall, 83,550 patients were included as the HFr cohort and 83,550 patients as the non-HFr cohort.
The socio-demographic factors included gender and age (65–74, 75– 84 and ≥85 years). We considered hypertension (ICD-9-CM code 401.xx–405.xx), hyperlipidemia CM code 272.xx), PAD (ICD-9-CM code 440.2x, 440.3x, 444.2x, and 444.81), osteoporosis (ICD-9-(ICD-9-CM code 733.xx), and asthma (ICD-9-CM code 493.xx and 494.xx), which were identifed as pre-existing comorbidities before the index date. General health status was assessed by the Charlson comorbidity index (CCI),which is the sumof theweighted score of 17 comorbid conditions and is widely used to control confounding in epidemiological studies. All individuals were followed from the index date to the date of ESRD diagnosis, withdrawal from the insurance program, die, or the end of the year 2011. In Taiwan's insurance system, patients with ESRD identifed from the Catastrophic Illness Patients Database (CIPD) were those who require long term renal replacement therapy, such as dialysis or kidney transplant.
2.3. Statistical analysis
We compared the distributions of socio-demographic status and pre-existing comorbidities between the cohort with and without HFr by using chi-square test for categorical variables and two-sample t test for continuous variables. We estimated the cumulative risk of ESRD for both cohorts by using the Kaplan–Meier method, and the signifcance of the cumulative risk curves was assessed by the log-rank test.
The multivariate Cox proportional hazards regression was used to assess the risk of developing ESRD associated with HFr after adjusting for age, gender, hypertension, hyperlipidemia, peripheral arterial disease, osteoporosis, asthma, and CCI score. Hazard ratios (HR) and 95% confdence interval (CI)were calculated using this model. To assess the severity of HFr, we used a severity index of HFr, which divided the
total length of hospital stays for HFr during the follow-up period by the length of the entire follow-up period. By using the tertile method, HFr severitywas classifed as mild (the frstHFr severity tertile),moderate (the second HFr severity tertile), or severe (the third HFr severity
tertile) [35]. All statistical analysis was performed using the SAS 9.3
statistical package (SAS Institute Inc., NC, USA) and R software (R Foundation for Statistical Computing, Vienna, Austria) was used to plot
Kaplan–Meier curves. A two-sided probability value of 0.05was considered signifcant.
3. Results
A total of 83,550 patients with HFr and 83,550 individuals without HFrwere enrolled in our study. Themean ages of cohortswith andwithout HFr were 79.19 (standard deviation, SD = 7.09) years and 78.41
(SD = 7.21) years, respectively (Table 1). Females accounted for
61.29% of the patients for both cohorts. Compared to control cohort, the prevalence of hypertension (45.58% vs. 22.68%), hyperlipidemia
(5.64% vs. 3.81%), PAD (0.66% vs. 0.38%), osteoporosis (22.34% vs. 8.32%), and asthma (8.35% vs. 4.37%) was higher in patients with HFr (p-value b0.001 for all). PatientswithHFrwere signifcantlymore likely to have higher CCI score.
The Kaplan–Meier curves showed that patients with HFr had a higher incidence rate of ESRD events than those without HFr (p-value
b0.001; Fig. 1). During the follow-up period, 83,550 HFr patients had
developed ESRD(n= 1216), die (n= 24,842),withdrawal fromthe insurance program (n = 20,729), and complete follow-up (n= 23763).
Patients with HFr had a higher incidence of ESRD than those without HFr (3.10 vs 1.78 per 1000 person-years), with an adjusted hazard ratio (aHR) of 1.42 (95% CI:1.29–1.55) after adjustment for age, gender, hypertension, hyperlipidemia, PAD, osteoporosis, asthma, and CCI score (Table 2). Furthermore, based onmodel adjusted for competing risk, the HR of the HFr group to the non-HFr group was 1.51 (95% CI:1.38–1.66) for ESRD (data not show).
Stratifed by gender, the incidence rates of ESRD in females and maleswith HFrwere 3.39 and 2.54 per 1000 person-years, respectively; higher than those in the comparison cohort (1.91 and 1.57 per 1000 person-years, respectively). In addition, female showed 1.45-fold (95% CI:1.30–1.62) and male showed 1.36-fold (95% CI:1.15–1.60) higher risk of developing ESRD than the comparison cohort. Among age groups,
the adjusted HR of ESRD was greatest in patients with HFr aged 65–74 years old (aHR = 1.56, 95% CI:1.35–1.81). In individuals with hypertension, hyperlipidemia or asthma, patients with HFr were more likely to have ESRD than those without HFr (aHR = 1.44, 95%
CI:1.26–1.65; 1.50, 1.07–2.09; and 3.28, 1.87–5.76, respectively). In addition, in individuals without hypertension, hyperlipidemia, PAD, osteoporosis, or asthma patients with HFr were more likely to have ESRD
than those without HFr (aHR = 1.37, 95% CI:1.20–1.56; 1.41,
1.28–1.55; 1.41, 1.28–1.54; 1.45, 1.32–1.60; and 1.38, 1.25–1.51, respectively). We observed that patients with HFr with a CCI score of 1–2 had
the greatest magnitude of ESRD risk compared with those without HFr
(aHR= 1.41, 95% CI:1.22–1.64) (Table 2).
The interaction and joint effect of HFr and comorbidity including hyperlipidemia, hyperlipidemia, PAD, osteoporosis, or asthma on risk of
ESRD were shown in Table 3.We observed a signifcant interaction between
HFr and osteoporosis and HFr and asthma (both p b 0.05). A
greater magnitude of HRs of ESRD for patients with HFr and hypertension, hyperlipidemia, PAD or osteoporosis was also observed compared
with patients without HFr and without counterpart comorbidity (aHR = 2.92, 95 % CI:2.60–3.27; 2.34, 1.92–2.86; 5.24, 3.44–7.97; and 1.40, 1.22–1.61, respectively).
Length of hospital stay due to HFr was used as proxy variable for severity of HFr, which was classifed into mild, moderate, and severe categories according to tertiles, and the comparison cohort was used as the reference cohort.We observed a dose–response relationship between
severity of HFr and the risk of ESRD (Table 4). Comparedwith the
comparison cohort, the aHRs of ESRD increased as severity of HFr increased, from 0.69 (95% CI:0.61–0.78) for the mild group to 2.59 (95%
CI:2.28–2.95) for the moderate group, and to 6.71 (95% CI:5.90–7.63) for the severe group (p for trend b0.001). The higher risks were observed for developing ESRD in the follow-up periods of within 5 year and 5–9 year (aHR = 1.44, 95% CI:1.28–1.62 and 1.43,
1.22–1.67, respectively) (Table 5).
4. Discussion
Studies have reported that patients with HBV [19–21], HCV[19–22],
and HIV [19–21] infections and autoimmune disorders, such as RA [23,
24] and SLE [25,26], are at a high risk of developing ESRD. In this
periods between 2000 and 2011, revealing that the HFr patients were 1.42 times more possible to develop subsequent ESRD than the control cohort. A dose–response relationship between the severity of HFr and the risk of development of ESRD was also discovered.
More than one half of the HFr patients examined in this study were women. This is consistent with previous investigations, indicating that
aged women are at a high risk of HFr [36,37]. These discoveries ensure
the validity of the HFr diagnosis delineated in the Taiwan NHI database. An HFr diagnosiswas associatedwith increased ESRD risk (aHR= 1.42,
95% CI:1.29–1.55), as shown in Table 2. The table also shows that although
women comprised themajority in the HFr group, HFr increased the risk of ESRD for both sexes, with a higher risk in women than in men.
Age is a critical risk factor for ESRD. [2,3,11] The evaluated agespecifc
aHRs between the HFr group and control cohort were slightly higher in the relatively younger age groups, with the highest aHR of
1.56 associated with patients 65–74 years old and the lowest (0.88) associated
with the group of patients ≥85 years old (Table 2). Comorbidities
and higher CCI scores were more common in the relatively older people than among the relatively younger people (data not shown). However, in the patients with HFr, a higher hazard of ESRD was exhibited by relatively younger people compared with that of the relatively older people. In this study, the risk of ESRD gradually increased as HFr
severity increased (Table 4). These results indicated that HFr might possibly
be combined with the development of ESRD. 4.1. Comorbidities for end-stage renal disease
Numerous investigations have revealed an association between ESRD
risk and old age [2,3,11], men [2,11,38,39], and comorbidities including
hypertension [1–3,9–11], hyperlipidemia [1,2,9–11], PAD[9,10], osteoporosis
[12,13] and asthma [13–15]. The risk of ESRD in the HFr and control
cohorts with or without comorbidities differed (Table 2). The combination
of distinct comorbidities in both the HFr and control groups caused
the risk of ESRD to increase to various levels (Table 3). These results suggested
that HFr is possibly an independent ESRD predictor that exhibits
greater weight in relatively younger patients (Tables 2 and 3).
4.2. Strengths and limitations
We conducted a retrospective cohort study by using a large study cohort with few losses to follow-up. The large sample size enabled the
analyses of stratifed data to examine the dissimilarities among groups
based on variables such as sex, age, comorbidities, and severity of HFr. The dose–response relationship related to HFr severity extended the
validity of this research. Insurance claims for inpatient reimbursements are strictly calculated and monitored by the NHI to avoid healthcare fraud. The NHI investigation system reinforces the diagnosis declared in insurance claims.
Nevertheless, this study still has several limitations. First, in the
claims data, information on certain vascular risk factors was unavailable, such as physical activity, alcohol consumption, cigarette smoking, body weight, and other factors associated with living habits. However,
because a relatively low smoking rate (less than 4.5%) is associated with women in Taiwan [40] and
the ESRD risk increased for both sexes,
the correlation between HFr and ESRDwas unlikely altered by the factor of cigarette smoking. Second, the results of laboratory studies, such as estimated glomerular fltration rate (eGFR), albuminuria, serum creatinine, staging of CKD, etc.,were not available in the inpatient databank of Taiwan National Health Insurance. Therefore, the correlation between HFr patients with different renal dysfunction (i.e., in different stages of CKD) and the risk of ESRD could not be evaluated in the present study. Nevertheless, with a modifed stratifcation of HFr severity used in this study, a dose–effect phenomenon was still disclosed between the HFr
severity and the relative risk of ESRD (Table 4). In this study, we evaluated
the possible risk of ESRD in patients with HFr. However, a higher prevalence of comorbidities was observed in the HFr cohort compared with that in the control group; after adjustment for the relevant comorbidities, the risk of ESRDwas still relatively higher in theHFr cohort than
in the control group. Therefore, it is likely that HFrmight be relatedwith the development of ESRD, particularly in relatively young people, in whom less ESRD related comorbidities were noted. Rigorous efforts should be made to improve ESRD prevention for relatively younger HFr patients.
5. Conclusion
The results of this investigation revealed that the risk of ESRD is associated with HFr. The results indicated that the risk of ESRD increased
as age decreased, since younger HFr patients had relatively less traditional comorbidities for ESRD. Hence, in combination with renal dysfunction due to underlying chronic illness, microvascular disease and
chronic infammation associated with osteoporosis, HFr became to stand out as an important ESRD predictor. The results also showed
that the risk of ESRD increased as HFr severity increased. Therefore, relatively younger HFr patients and relatively severe HFr cases deserved
more attention for their relatively higher risk for ESRD. Further study is required to substantiate our discoveries. The fndings of this study
can be used to improve ESRD prevention measures forHFr patients, particularly for those who are relatively younger.
