J Gastrointest Surg (2012) 16:19401946 DOI 10.

1007/s11605-012-1961-z

ORIGINAL ARTICLE

Acute Appendicitis in Patients with End-Stage Renal Disease

Pei-Wen Chao & Shuo-Ming Ou & Yung-Tai Chen & Yi-Jung Lee & Feng-Ming Wang & Chia-Jen Liu & Wu-Chang Yang & Tzeng-Ji Chen & Tzen-Wen Chen & Szu-Yuan Li

Received: 22 May 2012 / Accepted: 28 June 2012 / Published online: 10 July 2012 # 2012 The Society for Surgery of the Alimentary Tract

Abstract Background Acute appendicitis in patients with end-stage renal disease (ESRD) poses a diagnostic challenge. Delayed surgery can contribute to higher morbidity and mortality rates. However, few studies have evaluated this disease among ESRD patients. Our study focused on the lack of data on the incidence and risk factors of acute
Contributorship: Chao PW and Ou SM designed the study, ran the data, performed the statistical analysis, analyzed the data, and helped write the manuscript. Chen YT contributed to the study design and ran the data. Wang FM, Lee YJ, and Liu CJ advised on data analysis. Chen TJ and Yang WC contributed to the study design. Li SY designed the study, helped write the manuscript, and is the guarantor. P.-W. Chao Department of Anesthesiology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan S.-M. Ou Division of Nephrology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan Y.-T. Chen Department of Medicine, Taipei City Hospital Heping Fuyou Branch, Taipei, Taiwan Y.-T. Chen Division of Nephrology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan Y.-J. Lee Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan Y.-J. Lee Department of Neurology, Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan F.-M. Wang : T.-W. Chen Division of Nephrology, Department of Internal Medicine, Taipei Medical University Hospital, Taipei, Taiwan C.-J. Liu Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan

C.-J. Liu Division of Hematology and Oncology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan

W.-C. Yang Division of Nephrology, Department of Medicine, Taipei Veterans General Hospital and School of Medicine, National Yang-Ming University, Taipei, Taiwan

T.-J. Chen Department of Family Medicine, Taipei Veterans General Hospital and School of Medicine, National Yang-Ming University, Taipei, Taiwan

S.-Y. Li (*) Division of Nephrology, Department of Medicine, Taipei Veterans General Hospital and Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan e-mail: syli@vghtpe.gov.tw

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appendicitis among ESRD patients and compared the outcomes in patients who underwent different dialysis modalities. Methods This national survey was conducted between 1997 and 2005 and included ESRD patients identified from the Taiwan National Health Insurance database. The incidence rate of acute appendicitis in ESRD patients was compared with that in randomly selected age-, sex-, and Charlson comorbidity score-matched non-dialysis controls. A Cox regression hazard model was used to identify risk factors. Results Among 59,781 incident ESRD patients, matched one-to-one with controls, there were 328 events of acute appendicitis. The incidence rate of 16.9 per 10,000 person-years in the ESRD cohort was higher than that in the control cohort (p0 0.003). The independent risk factors were atrial fibrillation (hazard ratio [HR], 2.08), severe liver disease (HR, 1.74), diabetes mellitus (HR, 1.58), and hemodialysis (HR, 1.74). Compared with the control cohort, subsequent perforation and mortality rates of acute appendicitis were also higher in the ESRD cohorts. There was no effect of dialysis modality on the patient outcomes. Conclusions ESRD patients had a higher risk for acute appendicitis and poorer outcomes than non-dialysis populations. A careful examination of ESRD patients presenting with atypical abdominal pain to avoid misdiagnosis is extremely important to prevent delayed surgery. Keywords Acute appendicitis . End-stage renal disease . Epidemiology . Renal replacement therapy . Mortality evaluate the rate of acute appendicitis among ESRD patients. We designed a longitudinal nationwide population-based cohort study to evaluate the relative risks of acute appendicitis in ESRD patients and compared the hazards for different dialysis modalities. The aim of our study was to examine incidence rate, perforation or complication rate, mortality rate, and risk factors of acute appendicitis in ESRD patients. The results also facilitated comparison between prior findings in general populations and ESRD patients.

Introduction Acute appendicitis is a condition characterized by inflammation of the inner lining of the vermiform appendix that spreads to its other parts.1 Fitz et al.2 presented the first comprehensive description of appendicitis and advocated early surgical removal of the appendix in 1886. Appendicitis thus became one of the common diseases for emergency abdominal surgery, with a lifetime occurrence of approximately 79% and perforation rates of 1935%.35 The annual incidence of appendicitis is about 25 cases per 10,000, with a malefemale ratio of 1.4:1.3 The disease can present with an extremely wide variety of clinical manifestations, and the diagnosis may elude even the most experienced clinicians. Delays in surgery can lead to perforation of the appendix, sepsis, shock, and even death. The prognosis of uncomplicated appendicitis is excellent, but misdiagnosis worsens the situation appreciably, resulting in higher morbidity and mortality.6,7 Diagnosis of appendicitis is a challenge in patients with end-stage renal disease (ESRD) treated with hemodialysis (HD) or peritoneal dialysis (PD) due to minimal abdominal signs, lack of febrile responses, and atypical laboratory results.812 In addition, ESRD patients are usually burdened with more comorbidities, motor and endocrine function disturbances of gastrointestinal tract, and increased inflammation status and uremic toxins.13,14 However, data are still lacking on the incidence, risk factors, perforation, and mortality rates in ESRD patients presenting with acute appendicitis. In addition, no published studies have explored whether different dialysis modalities have a different impact on patient survival. Because the Taiwan National Health Insurance provides comprehensive coverage, it offered us a good opportunity to

Patients and Methods Data Source This study used data from the National Health Insurance Research Database (NHIRD) of Taiwan. The Taiwan National Health Insurance (NHI) program, which the government initiated in 1995, covers 99% of the population of 23 million people 15. In 1999, the Bureau of NHI began to release all claims data in electronic form under the NHIRD project. Various extracted datasets are available to researchers, and hundreds of researchers have used the NHIRD as the basis for their studies. Since the NHI dataset consists of de-identified secondary data for research purposes, the study was exempted from a full review by the Institutional Review Board of our hospital. We excerpted data from a specially ordered dataset that includes all claim information from patients under the registry of catastrophic illness from January 1997 to December 2005. Because patients who have NHI-defined catastrophic illness, including ESRD requiring chronic dialysis, can be exempted from related medical expenses, the government has implemented a strict verification program. Certification of ESRD requiring chronic dialysis involves careful exclusion of the causes of acute renal failure, supported medical records, examination reports, and imaging studies with a comprehensive review by nephrology specialists.

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Study Design and Patient Selection We conducted a retrospective cohort study from January 1, 1997 to December 31, 2005. Age, gender, modality of renal replacement therapy (RRT), and comorbid diseases of patients were retrieved from the database. Each patient was followed from the initiation of RRT to the diagnosis of acute appendicitis, death, withdrawal from the original RRT, or until December 31, 2005. To compare the incidence of appendicitis of our ESRD patients and the general population, a longitudinal health insurance dataset of 1,000,000 beneficiaries (randomly sampled from the original NHIRD) was used as a control group. NHIRD published the Longitudinal Health Insurance Database (LHID) dataset in 2000. The LHID-2000 contains the entire original claim data of 1,000,000 beneficiaries who enrolled in 2000, which were randomly sampled from the 2000 Registry for Beneficiaries (ID) of the NHIRD. Registration data of all beneficiaries of the National Health Insurance program from January 1 to December 31 2000 were drawn for random sampling. Definition of Renal Replacement Therapies, Appendicitis, and Comorbidity Stable HD patients are those with catastrophic illness registration cards for ESRD and insurance claims for HD treatment for more than 3 months. Stable PD patients are those with catastrophic illness registration cards for ESRD and insurance claims for PD for more than 3 months. Kidney transplant recipients are those with catastrophic illness registration cards for kidney transplantation (V42.0) and insurance claims for immunosuppressant agents for more than 3 months. Acute appendicitis is defined by ICD-9 codes 540541. ICD-9 code 540.9 was classified as an uncomplicated case of appendicitis, and codes 540.0 and 540.1 were classified as perforated appendicitis.16 Charlson score and patient comorbidities including diabetes mellitus (DM), dyslipidemia, hypertension, connective tissue disease, heart failure, severe liver disease, dementia, and atrial fibrillation were also analyzed. Charlson score was calculated as defined previously.17 Statistical Analysis Normally distributed continuous data are expressed as means standard deviations. Numeric data with nonnormal distributions are expressed as medians and interquartile ranges. To compare parameters between different dialysis modalities, the 2 test was used for categorical variables; ANOVA and the MannWhitney U test were used for parametric and nonparametric continuous variables, respectively. The incidence of acute appendicitis was calculated by the KaplanMeier method and compared by the log-rank test.

Multivariate Cox proportional hazard regression was performed using backward elimination to analyze independent risk factors for acute appendicitis. Risk factors with p values less than 0.1 in univariate Cox analysis were entered into the multivariate analysis. All probabilities were two-tailed. A p value less than 0.05 was considered significant.

Results Characteristics of the Study Population Figure 1 shows a flowchart for patient selection. A total of 74,921 incident ESRD patients were identified in our 9-year study cohort. After excluding patients who were under 20 years of age or older than 100 years of age (n0790), those who were kidney transplant recipients (n03,367), those who were on dialysis for less than 90 days (n010,642), and those who had history of appendicitis before receiving RRT (n0 341), we enrolled 59,781 patients for analysis. Study subjects were predominantly female (52.5%), and the mean age was 60.8 years (standard deviation013.7). Our ESRD cohort included 54,588 HD patients (91.3%) and 5,193 PD patients (8.7%). Hypertension (87.9%), dyslipidemia (31.4%), and DM (31.2%) were the most common comorbidities. After matching based on age, sex, Charlson score, and all listed comorbidities, 59,781 ESRD patients were successfully matched one-to-one with 59,781 control subjects. Demographic characteristics and comorbidities of the ESRD and matched cohorts are shown in Table 1. Comparison of the Incidence Rates of Acute Appendicitis Between the ESRD and Matched Cohort A total of 328 cases acute appendicitis occurred in ESRD patients (314 HD and 14 PD patients) during the follow-up

Fig. 1 Patient selection flow chart

J Gastrointest Surg (2012) 16:19401946 Table 1 Baseline patient characteristics ESRD group N=59,781 Demographic data Age (years)SD Male gender Charlson score Score 1 Score 2 Score 3 Score 4-6 Score7 Comorbid disease Diabetes mellitus Dyslipidemia Hypertension Connective tissue disease Heart failure Severe liver disease Atrial fibrillation Control group N=59,781 P value

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60.813.7 47.5% (28,409) 57.4% (34,311) 20.5% (12,278) 11.9% (7,102) 9.9% (5,891) 0.3% (199) 31.2% (18,656) 31.4% (18,772) 87.9% (52,545) 2.5% (1,465) 14.3% (8,546) 3.4% (2,033) 1.7% (1,013)

60.813.8 47.5% (28,409) 57.4% (34,311) 20.5% (12,278) 11.9% (7,102) 9.9% (5,891) 0.3% (199) 31.2% (18,656) 31.4% (18,772) 87.2% (52,112) 5.0% (2,969) 7.9% (4,730) 1.1% (628) 2.2 (1,291)

0.833 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000 0.047 <0.001 <0.001 <0.001 <0.001 Fig. 2 KaplanMeier plots of the cumulative incidence of acute appendicitis among ESRD and control cohort

Data are % (no.) of patients, unless otherwise indicated ESRD end-stage renal disease, SD standard deviation

period of 193,692 person-years. The incidence of acute appendicitis in the ESRD cohort was higher than that in the matched cohort (16.9 vs. 13.1 per 10,000 person-years, p00.003, Table 2, Fig. 2). Among the male and female patients, the incidences were 17.5 and 16.5 per 10,000 person-years, respectively. In terms of different dialysis modalities, the incidence of acute appendicitis in HD patients was significantly higher than that in PD patients (17.7 vs. 8.6 per 10,000 person-years, p00.007, Fig. 3). Independent Predictors of Acute Appendicitis in the ESRD Cohort The univariate Cox regression analysis identified the risk factors for acute appendicitis were ESRD, Charlson score, DM, severe liver disease, atrial fibrillation, and HD

(Table 3). The multivariate Cox proportional hazards analysis indicated that the following variables were statistically significant: atrial fibrillation (HR 2.08, 95% confidence interval [CI] 1.034.19; p00.042), HD (HR 1.74, 95% CI 1.052.87; p00.016), severe liver disease (HR 1.74, 95% CI 1.052.87; p00.032), and DM (HR 1.58, 95% CI 1.26 1.97; p<0.001). Analysis of Perforation Rates and Outcome of Acute Appendicitis in the ESRD Cohort Our study showed that the ESRD cohort (106 of 328; 32.3%) suffered from higher rates of perforated appendicitis, as compared with 50 of 347 matched controls (14.4%) (p<0.001). Among 328 ESRD patients, 13 (4.0%) died of acute appendicitis. Of note, none of the matched cohort died of acute appendicitis in our study. The rates of perforated appendicitis (101/314 [32.2%] vs. 5/14 [35.7%], p00.781) and mortality (13/314 [4.1%] vs. 0/14 [0%], p00.437) were comparable between the HD and PD groups.

Table 2 Incidence and crude and adjusted HRs of acute appendicitis in the ESRD and matched cohort No. of patients All patients 119,562 ESRD cohort 59,781 Control cohort 59,781 Crude HR (95% CI) P value Adjusteda HR No. of No. of patients Incidence rate (95% CI) person-years with AP (per 10 4 person-years) 458,210 193,692 264,518 674 327 347 P value

16.9 13.1

1.27 (1.091.48) As reference

0.002

1.26 (1.081.47) 0.003 As reference

HR hazard ratio, ESRD end-stage renal disease, AP acute appendicitis

a

Adjusted for age, sex, Charlson score, and all comorbidities listed in Table 1

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Fig. 3 After adjusting for atrial fibrillation, diabetes mellitus, and severe liver disease, the cumulative risk of acute appendicitis among ESRD patients requiring different dialysis modalities

Discussion This is the first study to confirm that ESRD patients have a higher risk for the development of acute appendicitis and, subsequently, higher perforation and mortality rates than non-dialysis patients. Among them, HD patients have a 1.93-fold higher risk for the development of acute appendicitis than PD patients. There was no significant difference in perforation and mortality rates of acute appendicitis between the HD and PD patients.
Table 3 Multivariate Cox regression for acute appendicitis in the ESRD cohort

Our population-based study demonstrated that the rate of incidence of acute appendicitis in ESRD patients (16.9 per 10,000 person-years) was higher than in the matched cohort (13.1 per 10,000 person-years). The incidence rate in the matched cohort was slightly lower than the incidence found by Addiss et al.3 This may be because patients who were under 20 years of age were excluded from our analysis, while previous epidemiologic studies have reported that appendicitis is most common between the ages of 10 and 20 years. Furthermore, the incidence rate in male ESRD patients (17.5 per 10,000 person-years) was higher than that in female ESRD patients (16.5 per 10,000 person-years). This result is in agreement with that by Addiss et al.3 who reported male preponderance of acute appendicitis in the general population. Previous studies have shown that ESRD patients not only have frequent gastrointestinal symptoms but also have higher incidences of peptic ulcers, gastroparesis, acute pancreatitis, and mesenteric ischemia.1821 However, data on acute appendicitis has been lacking. Appendiceal obstruction has been proposed as the primary cause of appendicitis. Common causes of obstruction include fecaliths (hard fecal masses), calculi, lymphoid hyperplasia, infectious processes, and benign or malignant tumors.2224 Chronic constipation is the common problem in ESRD patients, and fecalith formation may increase with time.25 Several factors are believed to cause constipation in these patients, including poor nutritional status, underlying gastrointestinal motility disorders, sedentary lifestyle, fluid restriction, limited dietary fiber intake to avoid hyperkalemia, and various medications, such as calcium and iron supplements, phosphate binders, and resins.26 Yasuda et al.26 reported that HD patients had 3.14 times higher relative risk of constipation than PD patients. The higher incidence rate of acute

Univariate HR P value Value 0.599 0.493 0.014 <0.001 0.459 0.854 0.329 0.072 0.016 0.558 0.026 0.008 95% Lower 0.85 0.99 1.03 1.31 0.86 0.76 0.72 0.97 1.12 0.38 1.10 1.21 CI Upper 1.32 1.01 1.24 2.04 1.41 1.39 2.70 1.81 3.07 1.69 4.49 3.53

Multivariate HR P value Value 95% Lower CI Upper

Male gender Age (per 1 year) Charlson score Diabetes mellitus Dyslipidemia Hypertension Connective tissue disease Heart failure Severe liver disease ESRD end-stage renal disease, HR hazard ratio, CI confidence interval, HD hemodialysis, PD peritoneal dialysis Dementia Atrial fibrillation HD (PD as reference)

1.06 1.00 1.13 1.64 1.10 1.03 1.39 1.33 1.86 0.80 2.23 2.07

1.58

<0.001

1.26

1.97

1.74 2.08 1.74

0.032 0.042 0.016

1.05 1.03 1.05

2.87 4.19 2.87

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appendicitis in ESRD patients in our study, especially those on HD, may be partially due to chronic constipation with fecalith formation. In our study, we identified DM and severe liver disease as risk factors for acute appendicitis in ESRD patients. Diabetic nephropathy is the leading cause of ESRD worldwide,27 and Yang et al.28 reported that, since 2001, DM also became the leading cause of ESRD (35.3%) in Taiwan. Diabetic autonomic neuropathy is a stealthy complication of diabetes that results in chronic dyspepsia, disturbed GI motility, or chronic constipation.29 Chronic liver disease and cirrhosis is the fifth leading cause of death in Taiwan, a hepatitis B and C endemic area.30,31 Cirrhotic patients sometimes have disturbed GI motility which correlates well with the severity of liver damage.3235 Disordered motility of the small bowel and colon is usually associated with the development of bezoars and bacterial overgrowth.36,37 Increasing bowel fluid secretion, impaired bowel motility, and bacteria overgrowth may increase intra-luminal pressure of the appendix and induce acute appendicitis. Obstruction by a fecalith is frequently implicated but not always required for the development of appendicitis.38 Bowel ischemia-induced appendicitis has been found in an experimental model by Nunes et al.39 Li et al.40 found that the risk of mesenteric ischemia for ESRD patients was 44.1 times higher than that of the general population. Atrial fibrillation, as an independent risk factor for mesenteric ischemia in ESRD patients, is related to adverse consequences of reduction in cardiac output and atrial or atrial appendage thrombus formation.41,42 The global mortality rate of acute appendicitis is 0.38%, and it is often due to complications of the disease itself rather than surgical intervention. In patients older than 70 years, the rate rises mainly due to diagnostic and therapeutic delay. In addition to the elderly patients, we also found that the rate of mortality due to appendicitis in our ESRD cohort (4.0%) was much higher than that found in previous studies in general populations.43 Furthermore, our study also showed that ESRD patients had significantly higher risk for perforated appendicitis than non-dialysis populations. Perforated appendicitis is associated with increased morbidity and mortality compared with nonperforating appendicitis. The poorer outcomes of acute appendicitis in ESRD patients may be explained by delay in diagnosis, burden of comorbidities, and hemodynamic instability. Previous studies have also suggested that fecalith formations are associated with an increased risk of bowel perforation in ESRD patients.44,45 Potential limitations of this study should be noted. First, as an innate limitation to the NHIRD database, several individual data, including smoking status, body mass index, and hemodynamic stability during HD sessions, were not available in the dataset. Second, the cause of acute appendicitis, such as

obstructive or non-obstructive etiology, was not taken into consideration for the analyses. Third, because the results of imaging studies such as ultrasonography or computed tomography were not available in the dataset, we could not assess correlations between clinical manifestations and imaging features. In conclusion, this cohort study identified an incidence rate of acute appendicitis of 16.9 per 10,000 person-years in ESRD patients. ESRD itself was an independent risk factor for acute appendicitis. ESRD patients had higher perforation and mortality rates than that in non-dialysis patients. Therefore, more liberal use of additional diagnostic tools and early surgical consultation should be recommended for ESRD patients with suspected acute appendicitis.
Acknowledgments This study was based in part on data from the National Health Insurance Research Database provided by the Bureau of National Health Insurance, Department of Health, and managed by the National Health Research Institutes. The conclusions presented in this study are those of the authors and do not necessarily reflect the views of the Bureau of National Health Insurance, the Department of Health, or the National Health Research Institute. Funding Research was funded by Taipei Veterans General Hospital research grant (V100B-030).

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