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Upper gastrointestinal bleeding increases risk of dialysis and all-cause mortality in patients with chronic kidney

disease

Journal: BMJ Open

Manuscript ID bmjopen-2015-010439

Article Type: Research

Date Submitted by the Author: 03-Nov-2015

Complete List of Authors: Liang, Chih-Chia; China Medical University Hospital, Division of Nephrology Chou, Che-Yi; China Medical University Hospital, Division of Nephrology Chang, Chiz-Tzung; China Medical University Hosptial, Division of

Nephrology Wang, I-Kuan; China Medical University Hospital, Division of Nephrology Huang, Chiu-Ching; China Medical University Hospital, Department of Internal Medicine

<b>Primary Subject Heading</b>:

Gastroenterology and hepatology

Secondary Subject Heading: Renal medicine

Keywords: chronic kidney disease, Dialysis < NEPHROLOGY, mortality

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Upper gastrointestinal bleeding increases risk of dialysis and

all-cause mortality in patients with chronic kidney disease

Chih-Chia Liang MD1,2,3,4

, Che-Yi Chou PhD1,2,4

, Chiz-Tzung Chang PhD1,2, I-Kuan

Wang MD1,2, Chiu-Ching Huang MD

1,2,3

1Kidney Institute and Division of Nephrology, Department of Internal Medicine, China

Medical University Hospital, Taichung 404, Taiwan

2College of Medicine, China Medical University, Taichung 404, Taiwan

3Graduate Program of Translational Medicine, China Medical University, Taichung

404, Taiwan

4Chih-Chia Liang and Che-Yi Chou equally contribute to this work

Correspondence: Chiu-Ching Huang MD

Address of corresponding author: Kidney Institute and Division of Nephrology,

Department of Internal Medicine, China Medical University Hospital, No. 2, Yu-der

Road, North District, Taichung 40447, Taiwan

Tel: +886-4-22052121-3483, Fax: +886-4-22058883, E-mail: [email protected]

Running title: UGI bleeding and risk of chronic dialysis

Word count: Abstract: 244; Text: 2131

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Abstract

Objective

Lower renal function is associated with higher risk of upper gastrointestinal bleeding

(UGIB) in patients with chronic kidney disease not on dialysis (CKD-ND). It is

unclear if UGIB increases risk for chronic dialysis. The aim of the study was to

investigate risk of chronic dialysis in CKD-ND patients with UGIB using

competing-risks analysis.

Setting

Primary care for CKD patients between 2003 and 2009 were enrolled and

prospectively followed until Sep 2012 in one hospital

Primary and secondary outcome measures

Chronic dialysis (dialysis more than 3 months) started and all-cause mortality. The

risk of chronic dialysis was analyzed using competing-risks regression with

time-varying covariates.

Results

We analyzed 3163 CKD-ND patients with a mean age of 65 ± 14 years in 2.8

(interquartile range, 1.3-4.3) years. Of 3163 patients, 387 (12.4%) patients developed

UGIB, 989 (31.6%) patients started chronic dialysis, and 197 (6.3%) patients died.

UGIB increased all-cause mortality [aHR: 1.21, 95% confidence interval (CI): 1.05-

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1.38, p = 0.01]. UGIB was independently associated with a higher risk of chronic

dialysis (p < 0.01), with sub-distribution hazard ratio (aSHR) of 1.51 [95% CI, 1.24 –

1.83, p < 0.01] with adjustments for risk factors of chronic dialysis including basal

renal function, age, hemoglobin, serum albumin, and diabetes.

Conclusions

In patients with CKD stage 3-5 and not receiving dialysis, UGIB is associated with

increased risk of chronic dialysis and all-cause mortality after adjustments for

confounders.

Keywords

chronic kidney disease, upper gastrointestinal bleeding, chronic dialysis

Strengths and limitations of this study

� Upper gastrointestinal bleeding not only increases all-cause mortality but also

increases the risk of chronic dialysis in patients with chronic kidney disease.

� This association is showed in a cohort of CKD patients with adjustments for

confounders.

� The generalizability of this finding may be limited by one hospital and single

ethnic group.

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Introduction

Upper gastrointestinal bleeding (UGIB) is a common gastrointestinal disorder in

patients with chronic kidney disease and not receiving dialysis (CKD-ND) 1 2. In

CKD-ND patients, the risk of UGIB was negatively associated with their renal

function at baseline 1. UGIB not only increased the risk of hospitalization but also

increased in-hospital mortality in CKD patients with and without dialysis 3. The

increased all-cause mortality associated with UGIB is usually explained by the

worsen comorbid conditions caused by UGIB.

Dialysis may be needed in patients with CKD-ND when UGIB leads to decreased

intravascular volume and the subsequent pre-renal acute kidney injury 4. Furthermore,

UGIB episodes may be the last straw for progression of CKD and may lead to chronic

dialysis if CKD-ND patients do not recover from acute kidney injury. However, the

long-term effect of UGIB on the risk of chronic dialysis in patients with CKD-ND is

not clear. The aim of the study was to investigate the risk of chronic dialysis after

UGIB in patients with CKD-ND. We utilized competing-risks analysis with

adjustments for all known confounders because both UGIB and CKD increase overall

mortality, and the risk of chronic dialysis may be overestimated if patients’ death was

not taken into consideration in the analysis 5 6.

Materials and Methods

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Internal review board approval (DMR 99-IRB-301) was obtained for the review of

medical records, and the need for informed consent was waived. All patients in the

outpatient-based CKD program of China Medical University Hospital from June 2003

to December 2009 were analyzed. The CKD program included patients with CKD

stage 3-5 and not receiving dialysis diagnosed by nephrologists. No exclusion criteria

were applied. All patients were followed to the date of the date of initiation of chronic

dialysis including hemodialysis and peritoneal dialysis, loss to follow-up; death; or

until September 2012. There were two patients received kidney transplant and these

two patients were excluded in the analysis. As we aimed to investigate risk of chronic

dialysis, patients who received dialysis less than 3 months and patients who

discontinued dialysis because of a recovery of renal function were excluded. UGIB

was defined as melena, hematemesis, rectorrhagia, or the presence of red blood in

gastric lavage fluid, together with observation of a bleeding lesion or a lesion likely to

have bled on endoscopy of the upper digestive tract.7 Patients who had UGIB before

the date of enrollment of CKD program was defined as a history of UGIB. CAD was

defined as a positive exercise test, angiographic findings of at least one stenosis of

more than 50%, or positive findings on scintigraphy.8 Diabetes mellitus was defined

as use of insulin, use of a hypoglycemic agent, or a fasting plasma glucose level of

126 mg/dl or more.9 Hypertension was defined as taking antihypertensives without

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regard to the actual measurement of blood pressure, or having a systolic blood

pressure reading greater than 140 mm Hg or a diastolic blood pressure reading greater

than 90 mm Hg.10

A study nurse reviewed all the medical records and consulted a physician over

uncertainties. The study nurse and physician were blinded to the aim of the study, and

other physicians performed the analysis. Each patient’s body mass index (BMI), blood

urea nitrogen (BUN), and creatinine were measured at enrollment. Serum calcium,

phosphorus, and albumin were measured within 3 months. Estimated glomerular

filtration rate (eGFR) was calculated using the Chronic Kidney Disease Epidemiology

Collaboration formula.11 The formula for white or other race was used because the

patients were all Chinese. The time-varying analysis used an average of three eGFR

measurements. Medications associated with a higher risk of UGIB, including

non-steroidal anti-inflammatory drugs (NSAIDs), aspirin, clopidogrel and warfarin,

were recorded based on the review of medical records.

Statistical analysis

Data were reported as mean ± standard deviation, median (interquartile range), or

frequency (percentage). All continuous variables were tested using skewedness and

kurtosis test for their normality. Data were analyzed using Student’s t test for

parametric variables, Kolmogorov-Smirnov test for non-parametric variables, or

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chi-square test for categorical variables. Possible confounders for all-cause mortality

were analyzed using multivariable Cox proportional hazard regression with

time-varying variables (eGFR and UGIB). Possible confounders of chronic dialysis

were analyzed using univariable competing-risks regression followed by multivariable

competing-risks regression with time-varying covariates. The competing-risks

regression was used because the Cox regression may over-estimate the risk of UGIB

when the competing events (mortality) were not analyzed.12 A sub-distribution hazard

ratio (SHR) and 95% confidence interval (CI) of confounders were calculated. In

multivariable analysis, the SHRs were reported as adjusted SHR (aSHR). The primary

outcome was defined as chronic dialysis and the competing event was patient’s death.

All analyses were performed using Stata version 13 SE (StataCorp, TX, USA) and a p

< 0.05 was considered statistically significant.

Results

Patient characteristics

We identified 3163 patients with CKD stage 3–5 and not on dialysis in the CKD

program (Table 1) in a median of 1.9 (interquartile range: 1.2–3.3) years. The mean

age was 65±14 years old and 1714 (54.2%) patients were male gender. Diabetes and

chronic glomerulonephritis were the main primary kidney disease. Of 3163 patients,

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226 (7.2%) patients had a history of UGIB and 380 (12.2%) patients had a history of

cardiovascular disease. The average BMI was 24.2±4.1 kg/m2, hemoglobin 10.6±2.4

g/dl, BUN 48±31 mg/dl, creatinine 3.8±2.9 mg/dl, calcium 9.1±0.7 mg/dl, phosphate

4.6±1.4 mg/dl, and serum albumin 3.4±0.6 mg/dl. In this study population, 61 (2.0%)

patients took NSAIDs, 351 (11.2%) patients took aspirin, 84 (2.9%) patients took

clopidogrel, and 64 (2.1%) patients took warfarin.

Outcomes and characteristics of patients with UGIB

The times of follow-up were similar in patients with and without UGIB (2.9±2.2 vs.

2.8±2.1 years, p = 0.38, Table 2). The rate of chronic dialysis in patients with UGIB

was higher than that of patients without UGIB (61.5% vs. 27.4%, p < 0.01). Patients

with UGIB were associated with a higher overall mortality rate, compared to patients

without UGIB (11.6% vs. 5.6%, p < 0.01). Therefore, a competing-risks analysis was

necessary to determine the risk of chronic dialysis in patients with and without UGIB.

In patients’ characteristics, patients with UGIB (68±12 years) were older than patients

without UGIB (64±14 years, p < 0.01) were. The percentage (55.6%) of diabetes as

the primary kidney disease was higher in patients with UGIB had diabetes (35.3% in

patients without UGIB, p < 0.01). Hypertension was the primary kidney disease in

11.4% of the patients with UGIB and 17.4% of the patients without UGIB (p < 0.01).

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The proportion of patients with cardiovascular disease in patients with UGIB was not

different from that of patients without UGIB. The patients with UGIB had a lower

eGFR (p < 0.01), a lower hemoglobin (p < 0.01), a higher BUN (p < 0.01), a higher

creatinine (p < 0.01), and a lower serum albumin (p < 0.01) than the patients without

UGIB did. There were no differences in serum calcium and phosphate levels in the

patients with and the patients without UGIB. The proportion of patients who took

NSAIDs, aspirin, clopidogrel, and warfarin were not different between the patients

with UGIB and the patients without UGIB.

UGIB increases all-cause mortality

In the Cox regression with adjustments for confounders of all-cause mortality (Table

3), UGIB was independently associated with higher all-cause mortality with an

adjusted hazard ratio (aHR) of 1.21 (95% CI: 1.05-1.38, p = 0.01). Age (p < 0.01),

hemoglobin (p = 0.01), and albumin (p < 0.01) were associated with all-cause

mortality. The aHR were 1.57 (95% CI: 1.37-1.81) for every 10 additional years, 0.90

(95% CI: 0.83-0.97) for every 1 g/dl higher in hemoglobin, and 0.51 (95% CI:

0.40-0.64) for every 1 g/dl higher in serum albumin. Patients’ eGFR, gender, diabetes,

and comorbid cardiovascular disease were not associated with all-cause mortality.

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UGIB increased risk of chronic dialysis

The SHRs of the competing-risks analysis were showed in Table 4 in both univariable

and multivariable analyses. UGIB largely increased risk for chronic dialysis in

univariable analysis with a SHR of 2.51 (95% CI: 2.17-2.90, p < 0.01). Higher eGFR

(SHR: 0.74, 95% CI: 0.71–0.76, p < 0.01), male gender (SHR: 0.78, 95% CI: 0.69–

0.89, p < 0.01), higher hemoglobin (SHR: 0.78, 95% CI: 0.76–0.81, p < 0.01), and

higher serum albumin (SHR: 0.53, 95% CI: 0.48–0.59, p < 0.01) were associated

lower risk for chronic dialysis. In contrast, a history of UGIB (SHR: 1.36, 95% CI:

1.08–1.71, p = 0.01), diabetes as the primary kidney disease (SHR: 1.66, 95% CI:

1.46–1.89, p < 0.01), and higher BUN (SHR: 1.19, 95% CI: 1.17–1.22 for every 10

mg/dl higher, p < 0.01) were associated with higher risk of chronic dialysis. The

cumulative sub-hazard of chronic dialysis in patients with UGIB and patients without

UGIB was shown in Figure 1. Patients with UGIB were associated with a higher

hazard for chronic dialysis than patients without UGIB did (aSHR: 1.51, 95% CI:

1.24-1.83, p < 0.01). The confounders of chronic dialysis included patients’ eGFR

(aSHR: 0.81, 95% CI: 0.77–0.85, p < 0.01) and patients’ age (aSHR: 0.92, 95% CI:

0.86–0.98 for every 10 additional year, p < 0.01). Patients with diabetes as the

primary kidney disease were also associated with higher risk for chronic dialysis

(aSHR: 1.29, 95% CI: 1.10–1.51, p < 0.01). Hemoglobin (aSHR: 0.94, 95% CI: 0.90–

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0.98, p < 0.01) and serum albumin (aSHR: 0.75, 95%CI: 0.66–0.86, p < 0.01) were

associated with lower risk of chronic dialysis.

Discussion

In this cohort study of CKD stage 3-5 ND patients, UGIB was associated with higher

risk of chronic dialysis using competing-risks analysis with adjustments for

confounders. The competing-risks analysis was critical to this study because UGIB

remarkably increased all-cause mortality (Table 3). Patients’ renal function was one of

the most important confounders for chronic dialysis. The risk of chronic dialysis was

reduced by 20% for every five ml/min/1.73m2 higher of eGFR (Table 4) and the

SHRs of eGFR were similar in univariable and multivariable analysis. In summary of

our previous studies 1 13 14

and this study (Figure 2), patients with CKD-ND were

more at risk for developing UGIB and UGIB may further accelerate the progression

of CKD to chronic dialysis. The common aggravating factors of CKD and UGIB are

anemia, diabetes, and hypoalbuminemia. On the other hand, higher GFR and uses of

angiotensionogen converting enzyme inhibitor (ACEi) or angiotensin II receptor

blocker (ARB) may protect from UGIB in this scenario. Some beneficial effects of

ACEi and ARB may come from their association with decreased risk of UGIB

independent of patients’ renal function 14.

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In other confounders of chronic dialysis, diabetes was consistently associated with the

risk of chronic dialysis in both univariable and multivariable analyses. This may not

be surprised because diabetes is a well-known confounder of dialysis. However, male

patients, a history of UGIB, and BUN were not associated with chronic dialysis in

multivariable analysis, which may imply that UGIB was a more robust confounder of

chronic dialysis in this study. Although NSAIDs were well-known risk factors for

UGIB and chronic dialysis 15, we did not find a significant association of NSAIDs and

chronic dialysis. A limited number of patients who took these medications in this

study may explain this result.

Nausea/vomiting were uremic symptoms 16 and were indications of dialysis.

Nausea/vomiting were also common symptoms in patients with UGIB 17. Although

some CKD patients initiated dialysis because of UGIB-related nausea/vomiting rather

than uremic symptoms, the percentages of patients with nausea/vomiting at the

initiation of dialysis were similar in this study (data not shown). In addition, we

excluded these patients who underwent dialysis less than 3 months and discontinued

dialysis because of a recovery of renal function. UGIB-related nausea/vomiting did

not explain the association of UGIB and chronic dialysis in this study.

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The limitations of this study were its observational study design and the inclusion of

all patients in single medical center in Taiwan. This may limit the generalizability of

our finding to other ethnic groups. More studies of various ethnic groups and multiple

institutions are required to confirm our results. In spite of the limitations, this is the

first study indicating the association between UGIB and chronic dialysis independent

of all confounding factors that were considered. This association suggests UGIB not

only leads to acute renal failure due to intravascular volume depletion, but also

long-term consequence of irreversible kidney injury in this population.

Conclusions

Upper gastrointestinal bleeding is associated with higher risk of chronic dialysis in

patients with chronic kidney disease stage 3-5 and not receiving dialysis independent

of confounders of chronic dialysis such as diabetes and hypoalbuminemia. More

studies will be warranted to investigate if the reduction in UGIB risk may slow the

progression of CKD and delay the need of dialysis in patients with CND-ND.

Acknowledgments

This study was supported in part by Taiwan Ministry of Health and Welfare Clinical

Trial and Research Center of Excellence (DOH102-TD- B-111-004) and China

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Medical University Hospital (DMR-101-019). The funders had no role in study design,

data collection and analysis, decision to publish, or preparation of the manuscript.

Contribution of Authors

Study concept, design, and acquisition of data: CC Liang; analysis, interpretation of

data, and drafting of the manuscript: CY Chou; critical revision of the manuscript for

important intellectual content: CT Chang, IK Wang; study supervision: CC Huang

Conflict of interest statement

The results presented in this paper have not been published previously in whole or

part. The authors have no conflicts of interest regarding the design or publication of

this study.

Data sharing statement

None

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PloS one 2014;9(2):e87952.

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Legends

Figure 1. Cumulative sub-hazard for chronic dialysis in patients with and without

upper gastrointestinal bleeding (UGIB) using competing-risks regression with

adjustments for age, gender, diabetes, a history of UGIB, hemoglobin, blood urea

nitrogen (BUN), and albumin. (the primary outcome was chronic dialysis and the

competing events were patients’ death).

Figure 2. Upper gastrointestinal bleeding (UGIB) may accelerate the progression of

chronic kidney disease (CKD) and further increase the risk of chronic dialysis. In this

interactive scheme of UGIB and CKD, aggravating factors include anemia, diabetes,

and hypoalbuminemia, and protective factors contain a higher glomerular filtration

rate (GFR) and uses of angiotensionogen converting enzyme inhibitor (ACEi)/

angiotensin II receptor blocker (ARV).

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Table 1. Clinical characteristics of all patients at enrollment

Characteristics n=3163

Age (year) 65±14

Male gender n (%) 1714(54.2)

Primary kidney disease

Diabetes 1141 (36.5)

Chronic glomerulonephritis 1059 (33.9)

Hypertension 520 (16.6)

History of UGIB 226 (7.2)

Cardiovascular disease 380 (12.2)

eGFR (ml/min/1.73 m2) 19.2 (9.5-34.7)

BMI (kg/m2) 24.2±4.1

Hemoglobin (g/dl) 10.6±2.4

BUN (mg/dl) 48±31

Creatinine (mg/dl) 3.8±2.9

Calcium (mg/dl) 9.1±0.7

Phosphorus (mg/dl) 4.6±1.4

Albumin (g/dl) 3.4±0.6

Medications n(%)

NSAIDs 61 (2.0)

Aspirin 351 (11.2)

Clopidogrel 84 (2.9)

Warfarin 64 (2.1)

UGIB: upper gastrointestinal bleeding, eGFR: estimated glomerular filtration rate

using CKD-EPI formula, BMI: body mass index, BUN: blood urea nitrogen, NSAIDs:

non-steroidal anti-inflammatory drugs,

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Table 2. Clinical characteristics and outcomes according to upper gastrointestinal

bleeding

Characteristics and outcomes UGIB (-)

n=2739

UGIB (+)

n=387 p

Follow-up (year) 2.9 ±2.2 2.8 ±2.1 0.38

Chronic dialysis n(%) 751 (27.4) 238 (61.5) <0.01

Mortality n(%) 152 (5.6) 45 (11.6) <0.01

Age (year) 64 ±14 68 ±12 <0.01

Male n(%) 1476 (53.9) 215 (55.6) 0.54


Diabetes 968 (35.3) 173 (44.7) <0.01

Chronic glomerulonephritis 938 (34.3) 121 (31.3) 0.24

Hypertension 476 (17.4) 44 (11.4) <0.01

History of UGIB 162 (5.9) 64 (16.5) <0.01

Cardiovascular disease 324 (11.8) 56 (14.5) 0.14

eGFR (ml/min/1.73 m2) 27 ±21 21 ±16 <0.01

BMI (kg/m2) 24.2 ±4.1 24.1 ±3.9 0.51

Hemoglobin (g/dl) 10.7 ±2.4 10.1 ±2.3 <0.01

BUN (mg/dl) 48 ±31 54 ±31 <0.01

Creatinine (mg/dl) 3.7 ±2.8 4.3 ±2.9 <0.01

Calcium (mg/dl) 9.1 ±0.7 9.1 ±0.8 0.77

Phosphorus (mg/dl) 4.5 ±1.4 4.6 ±1.2 0.26

Albumin (g/dl) 3.5 ±0.6 3.3 ±0.6 <0.01

Medications n(%)

NSAIDs 50 (1.8) 11 (2.8) 0.18

Aspirin 305 (11.1) 46 (11.9) 0.66

Clopidogrel 73 (2.9) 11 (3.1) 0.80

Warfarin 52 (1.9) 12 (3.1) 0.12


using CKD-EPI formula, BMI: body mass index, BUN: blood urea nitrogen, NSAIDs:

non-steroidal anti-inflammatory drugs

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Table 3. Adjusted hazard ratio of confounders for all-cause mortality

aHR 95% CI P

UGIB 1.21 1.05 1.38 0.01

eGFR (every 5 ml/min/1.73m2 higher) 1.00 0.99 1.02 0.67

Age (every 10 additional years) 1.57 1.37 1.81 <0.01

Male 1.23 0.90 1.70 0.19

Diabetes 1.01 0.74 1.38 0.95

Cardiovascular disease 1.02 0.66 1.55 0.94

Hemoglobin (every 1 g/dl higher) 0.90 0.83 0.97 0.01

Albumin (every 1 g/dl higher) 0.51 0.40 0.64 <0.01


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Table 4. Subdistribution hazard ratio (SHR) of risk factors for chronic dialysis in

univariable and multivariable competing-risks regression with time-varying covariates

Risk factors Univariable Multivariable

SHR 95% CI aSHR 95% CI

UGIB 2.51 (2.17-2.90)* 1.51 (1.24-1.83)*

eGFR (every 5 ml/min/1.73m2 higher) 0.74 (0.71–0.76)* 0.81 (0.77–0.85)*

Age (every 10 additional years) 0.95 (0.91–1.21) 0.92 (0.86–0.98)*

Male 0.78 (0.69–0.89)* 1.09 (0.92–1.28)

History of UGIB 1.36 (1.08–1.71)* 0.93 (0.71–1.22)

Diabetes 1.66 (1.46–1.89)* 1.29 (1.10–1.51)*

Hemoglobin (every 1 g/dl higher) 0.78 (0.76–0.81)* 0.94 (0.90–0.98)*

BUN (every 10 mg/dl higher) 1.19 (1.17–1.22)* 1.02 (0.99–1.06)

Albumin (every 1 g/dl higher) 0.53 (0.48–0.59)* 0.75 (0.66–0.86)*

NSAIDs 0.83 (0.49–1.38) 0.73 (0.38–1.40)

Aspirin 1.03 (0.84–1.26) 1.15 (0.91–1.45)

Clopidogrel 1.33 (0.94-1.88) 1.15 (0.76-1.73)

Warfarin 1.09 (0.69–1.74) 1.13 (0.63–2.04)

SHR: subdistribution hazard ratio, CI: confidence interval, aSHR: adjusted

subdistribution hazard ratio, UGIB: upper gastrointestinal bleeding, eGFR: estimated

glomerular filtration rate, BMI: body mass index, BUN: blood urea nitrogen, NSAIDs:

non-steroidal anti-inflammatory drugs

* p < 0.05

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Figure 1

127x104mm (150 x 150 DPI)

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Figure 2

187x82mm (150 x 150 DPI)

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1

STROBE Statement Checklist of items that should be included in reports of observational studies

Section/Topic Item

No Recommendation

Reported

on Page No

Title and abstract 1 (a) Indicate the study’s design with a commonly used term in the title or the abstract 3

(b) Provide in the abstract an informative and balanced summary of what was done and what was found 3

Introduction

Background/rationale 2 Explain the scientific background and rationale for the investigation being reported 4

Objectives 3 State specific objectives, including any prespecified hypotheses 4

Methods

Study design 4 Present key elements of study design early in the paper 6

Setting 5 Describe the setting, locations, and relevant dates, including periods of recruitment, exposure, follow-up, and data collection

6

Participants 6

(a) Cohort study—Give the eligibility criteria, and the sources and methods of selection of participants. Describe methods of

follow-up

Case-control study—Give the eligibility criteria, and the sources and methods of case ascertainment and control selection. Give the

rationale for the choice of cases and controls

Cross-sectional study—Give the eligibility criteria, and the sources and methods of selection of participants

6

(b) Cohort study—For matched studies, give matching criteria and number of exposed and unexposed

Case-control study—For matched studies, give matching criteria and the number of controls per case 6

Variables 7 Clearly define all outcomes, exposures, predictors, potential confounders, and effect modifiers. Give diagnostic criteria, if

applicable 7

Data sources/measurement 8* For each variable of interest, give sources of data and details of methods of assessment (measurement). Describe comparability of

assessment methods if there is more than one group 7

Bias 9 Describe any efforts to address potential sources of bias 13

Study size 10 Explain how the study size was arrived at NA

Quantitative variables 11 Explain how quantitative variables were handled in the analyses. If applicable, describe which groupings were chosen and why NA

Statistical methods 12

(a) Describe all statistical methods, including those used to control for confounding 8

(b) Describe any methods used to examine subgroups and interactions 8

(c) Explain how missing data were addressed 8

(d) Cohort study—If applicable, explain how loss to follow-up was addressed

Case-control study—If applicable, explain how matching of cases and controls was addressed

Cross-sectional study—If applicable, describe analytical methods taking account of sampling strategy

7

(e) Describe any sensitivity analyses NA

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2

Section/Topic Item

No Recommendation

Reported

on Page No

Results

Participants 13*

(a) Report numbers of individuals at each stage of study—eg numbers potentially eligible, examined for eligibility, confirmed

eligible, included in the study, completing follow-up, and analysed 7

(b) Give reasons for non-participation at each stage 7

(c) Consider use of a flow diagram NA

Descriptive data 14*

(a) Give characteristics of study participants (eg demographic, clinical, social) and information on exposures and potential

confounders 8

(b) Indicate number of participants with missing data for each variable of interest 8

(c) Cohort study—Summarise follow-up time (eg, average and total amount) 8

Outcome data 15*

Cohort study—Report numbers of outcome events or summary measures over time 8

Case-control study—Report numbers in each exposure category, or summary measures of exposure NA

Cross-sectional study—Report numbers of outcome events or summary measures NA

Main results 16

(a) Give unadjusted estimates and, if applicable, confounder-adjusted estimates and their precision (eg, 95% confidence interval).

Make clear which confounders were adjusted for and why they were included 9

(b) Report category boundaries when continuous variables were categorized 9

(c) If relevant, consider translating estimates of relative risk into absolute risk for a meaningful time period 9

Other analyses 17 Report other analyses done—eg analyses of subgroups and interactions, and sensitivity analyses 10

Discussion

Key results 18 Summarise key results with reference to study objectives 10

Limitations 19 Discuss limitations of the study, taking into account sources of potential bias or imprecision. Discuss both direction and magnitude

of any potential bias 13

Interpretation 20 Give a cautious overall interpretation of results considering objectives, limitations, multiplicity of analyses, results from similar

studies, and other relevant evidence 11

Generalisability 21 Discuss the generalisability (external validity) of the study results 12

Other Information

Funding 22 Give the source of funding and the role of the funders for the present study and, if applicable, for the original study on which the

present article is based 16

*Give information separately for cases and controls in case-control studies and, if applicable, for exposed and unexposed groups in cohort and cross-sectional studies.

Note: An Explanation and Elaboration article discusses each checklist item and gives methodological background and published examples of transparent reporting. The STROBE checklist is

best used in conjunction with this article (freely available on the Web sites of PLoS Medicine at http://www.plosmedicine.org/, Annals of Internal Medicine at http://www.annals.org/, and

Epidemiology at http://www.epidem.com/). Information on the STROBE Initiative is available at www.strobe-statement.org.

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Upper gastrointestinal bleeding increases risk of dialysis and all-cause mortality in patients with chronic kidney

disease

Journal: BMJ Open

Manuscript ID bmjopen-2015-010439.R1


Date Submitted by the Author: 28-Jan-2016




Gastroenterology and hepatology


Keywords: chronic kidney disease, Dialysis < NEPHROLOGY, mortality, upper gastrointestinal bleeding


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Upper gastrointestinal bleeding increases risk of dialysis and

all-cause mortality in patients with chronic kidney disease

Chih-Chia Liang MD1,2,3,4, Che-Yi Chou PhD1,2,4, Chiz-Tzung Chang PhD1,2, I-Kuan

Wang MD1,2, Chiu-Ching Huang MD1,2,3





404, Taiwan







Running title: upper gastrointestinal bleeding and risk of chronic dialysis


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Abstract

Objective

Impaired renal function is associated with higher risk of upper gastrointestinal

bleeding (UGIB) in patients with chronic kidney disease and not on dialysis

(CKD-ND). It is unclear if UGIB increases risk for chronic dialysis. The aim of the

study was to investigate risk of chronic dialysis in CKD-ND patients with UGIB.

Setting

All CKD-ND stages 3-5 patients of a CKD program in one hospital between 2003 and

2009 were enrolled and prospectively followed until Sep 2012



risk of chronic dialysis was analyzed using Cox proportional hazard regression with

adjustments for age, gender, and renal function, followed by competing-risks analysis.

Results

We analyzed 3126 CKD-ND patients with a mean age of 65 ± 14 years in 2.8 years.

Of 3126 patients, 387 (12.4%) patients developed UGIB, 989 (31.6%) patients started

chronic dialysis, and 197 (6.3%) patients died. UGIB increased all-cause mortality

[adjusted Hazard Ratio (aHR): 1.47, 95% confidence interval (CI): 1.04- 2.07, p <

0.01] and the risk of chronic dialysis (aHR; 1.30, 95% CI; 1.12-1.51, p < 0.01). The

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sub-distribution hazard ratio (SHR) of UGIB for chronic dialysis (competing event:

all-cause mortality) was 1.37 (95% CI, 1.15-1.64, p < 0.01) in competing-risks

analysis with adjustments for age, renal function, gender, diabetes, hemoglobin,

albumin, and urine protein/creatinine ratio.

Conclusions

UGIB is associated with increased risk of chronic dialysis and all-cause mortality in

patients with CKD-ND stages 3-5. This association is independent age, gender, basal

renal function, hemoglobin, albumin, and urine protein levels.

Keywords

chronic kidney disease, chronic dialysis, mortality, gastrointestinal bleeding,




� This association is showed in a cohort of CKD patients with adjustments for

confounders.

� The generalizability of this finding may be limited by one hospital and single

ethnic group.

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Introduction


patients with chronic kidney disease and not receiving dialysis (CKD-ND) [1,2]. In

CKD-ND patients, the risk of UGIB is negatively associated with their renal function

at baseline [1]. UGIB not only increases the risk of hospitalization but also increases

in-hospital mortality in CKD-ND patients and CKD 5 patients on dialysis [3]. The


worsen comorbid conditions caused by the UGIB[3-5].


intravascular volume and the subsequent pre-renal acute kidney injury [6].

Furthermore, UGIB episodes may be the last straw for progression of CKD and may

lead to chronic dialysis if CKD-ND patients do not recover from acute kidney injury.

However, the long-term effect of UGIB on the risk of chronic dialysis in patients with

CKD-ND is not clear. The aim of the study was to investigate the risk of chronic

dialysis after UGIB in patients with CKD-ND.


Patient enrollment


medical records, and the need for informed consent was waived. All patients in the

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outpatient-based CKD program of China Medical University Hospital (CMUH) from

June 2003 to December 2009 were included. The CKD program included patients

with CKD-ND stages 3-5 diagnosed by nephrologists and no exclusion criteria were

applied. The CKD program supported by National Health Insurance Taiwan include

clinical endocrinologists, nephrologists, CKD nurses, dietitians, and social workers.

The purpose of the CKD program is to monitor the progression of CKD patients;

laboratory measurements and CKD education are performed at least four times a year.

All patients were followed to the date of the date of initiation of chronic dialysis

including hemodialysis and peritoneal dialysis, loss to follow-up; death; or until

September 2012. There were two patients received kidney transplant and these two

patients were excluded in the analysis because the timing of kidney transplantation

was not related to uremic symptoms. As we aimed to investigate risk of chronic

dialysis, patients who received dialysis less than 3 months and patients who

discontinued dialysis because of a recovery of renal function were excluded.

Definition of predictors

UGIB was defined as melena, hematemesis, or the presence of red blood in gastric

lavage fluid, together with observation of a bleeding lesion or a lesion likely to have

bled on endoscopy of the upper digestive tract[1]. Coronary artery disease (CAD) was


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more than 50%, or positive findings on scintigraphy.[7] Diabetes mellitus was defined

as use of insulin, use of oral anti-diabetic medication, or a fasting plasma glucose

level of 126 mg/dl or more.[8] Hypertension was defined as taking antihypertensives

without regard to the actual measurement of blood pressure, or having a systolic blood


than 90 mm Hg.[9] Patients’ primary kidney disease including diabetes, chronic

glomerular nephritis (CGN), and hypertension was diagnosed by the primary care

physician and was recorded at enrollment.

Measurements of parameters

Each patient’s body mass index (BMI), blood urea nitrogen (BUN), and creatinine

were measured at enrollment. Serum calcium, phosphorus, albumin, urine

albumin/creatinine ratio (ACR), and urine protein/creatinine ratio (PCR) were

measured in 3 months after enrollment. Estimated glomerular filtration rate (eGFR)

was calculated using the MDRD Collaboration formula.[10] The formula for white or

other race was used because the patients were all Chinese. The time-varying analysis

used an average of three eGFR measurements. Medications associated with a higher

risk of UGIB, including steroids, non-steroidal anti-inflammatory drugs (NSAIDs),

aspirin, clopidogrel and warfarin, were recorded based on the review of medical

records.

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Outcomes measurements

The CKD nurses recorded the outcomes (dialysis for more than 3 months or mortality)

and date of the outcomes in the computerized case-management system. The CKD

nurses also checked patients’ status in the computerized medical record system in

CMUH and contacted the patients who did not returned to the outpatient every 6

months. The percentage of patients who were lost to follow-up was 6% in the CKD

program. The outcomes were validated by a study nurse through a review of medical

records and the study nurse was blinded to the aim of the study, and other physicians

performed the analysis.



frequency (percentage) as appropriate. All continuous variables were tested using

skewedness and kurtosis test for their normality. Data were analyzed using Student’s t

test for parametric variables, Kolmogorov-Smirnov test for non-parametric variables,

or chi-square test for categorical variables. Factors with a p-value < 0.05 in

univariable Cox proportional hazard regression and risk factors of chronic dialysis in

the literature were considered as possible confounders. Possible confounders for

all-cause mortality and chronic dialysis were analyzed using multivariable Cox

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proportional hazard regression. An adjusted hazard ratio (aHR) and 95% confidence

interval (CI) of aHR in multivariable Cox regression with adjustments for age, gender,

and eGFR was calculated. We utilized competing-risks analysis [11] with adjustments

for confounders identified in Cox regression because the risk of chronic dialysis may

be overestimated if patients’ death was not taken into consideration [12,13]. An

adjusted sub-distribution HR (aSHR) and 95% CI of aSHR was calculated in

competing-risks analysis with adjustments for age, gender, eGFR, and confounders

for chronic dialysis. The primary outcome was defined as chronic dialysis and the

competing event was patient’s death in the competing-risks analysis. All analyses

were performed using Stata version 13 SE (StataCorp, TX, USA) and a p-value < 0.05

was considered statistically significant.

Results


We identified 3126 patients with CKD-ND stages 3–5 including 1691 males and 1435

female, aged 65±14 years (Table 1). Diabetes and chronic glomerulonephritis (CGN)

were the major forms of primary kidney disease. The basal eGFR of the patients was

21 (11-37) ml/min/1.73m2 and the urine PCR was 1.4 (0.5-3.6) g/g at enrollment.

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Outcomes and characteristics of patients with UGIB

The times of follow-up were similar in the patients with UGIB and the patients

without (p = 0.38). The proportion of the patients with UGIB who start chronic

dialysis was higher than that of the patients without UGIB (61.5% vs. 27.4%, p < 0.01,

chi-square test). Patients with UGIB were associated with a higher all-cause mortality

than patients without UGIB (11.6% vs. 5.6%, p < 0.01). Patients with UGIB were

older than patients without UGIB (p < 0.01) were. The proportion of diabetes as the

primary kidney disease and the proportion of hypertension as the primary kidney

disease were higher in patients with UGIB. The proportion of patients with CAD was

not different among the patients with UGIB and the patients without UGIB. The

patients with UGIB had a lower eGFR, a lower hemoglobin, a higher BUN, a higher

creatinine, and a lower serum albumin than the patients without UGIB did. There

were no differences in serum calcium and phosphate levels in the patients with UGIB

and the patients without. The proportion of patients who took steroid, patients who

took NSAIDs, patients who took aspirin, patients who took clopidogrel, and patients

who took warfarin were not different among the patients with UGIB and those

without.


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UGIB was independently associated with higher all-cause mortality (Table 2) with an

aHR of 1.47 (95% CI: 1.04-2.07, p < 0.01). Serum albumin was independently

associated with all-cause mortality (p < 0.01) and the aHR was 0.52 (95% CI:

0.42-0.66) per 1 g/dl. Diabetes, CAD, hemoglobin, and PCR was not associated with

all-cause mortality. Use of steroid, NSAIDs, clopidogrel, and warfarin was not

associated all-cause mortality.

UGIB increased risk of chronic dialysis

UGIB was associated with an increased risk for chronic dialysis with an aHR of 1.30

(95% CI: 1.12-1.51, p < 0.01) in multivariable Cox regression with adjustments for

age, gender and eGFR. Diabetes was independently associated with increased risk of

chronic dialysis with an HR of 1.50 (95% CI: 1.31-1.72). Hemoglobin and serum

albumin were associated with lower risk of chronic dialysis. PCR was associated with

increased risk of chronic dialysis with an HR of 1.03 (95% CI: 1.02-1.05) per 1g/g.

Steroids, NSAIDs, clopidogrel, and warfarin were not associated with the risk of

chronic dialysis. The aSHR of UGIB for chronic dialysis was 1.37 (95% CI: 1.15-1.64,

p < 0.01) in competing-risks analysis with adjustments for age, gender, eGFR,

diabetes, hemoglobin, albumin, and PCR. The cumulative incidence of chronic

dialysis in patients with UGIB and those without is showed in Figure 1.

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Discussion

In this cohort study of patients with CKD-ND stages 3-5, UGIB was associated with

higher risk of chronic dialysis using Cox proportional hazard regression adjustments

for age, sex, eGFR. The association of UGIB and increased risk of chronic dialysis was

further validated using competing-risks analysis with adjustments for age, gender,

eGFR, diabetes, hemoglobin, albumin, PCR and all-cause mortality was considered as

a competing endpoint. The competing-risks analysis was critical to this study because

UGIB was associated with increased all-cause mortality. UGIB can be a complication

of uremia because of the uremic coagulopathy. In this study, UGIB patients started

chronic dialysis after a median of 1.2 (interquartile range: 0.7-1.3) years. Uremic

coagulopathy associated UGIB may not be one of the uremic symptoms that required

dialysis in these patients. In summary of our previous studies [1,14,15] and this study

(Figure 2), patients with CKD-ND were more at risk for developing UGIB and UGIB

may further accelerate the progression of CKD to chronic dialysis. The common

aggravating factors of CKD and UGIB are anemia, diabetes, and hypoalbuminemia.

On the other hand, higher GFR and uses of angiotensionogen converting enzyme

inhibitor (ACEi) or angiotensin II receptor blocker (ARB) may protect from UGIB in

this scenario. Some beneficial effects of ACEi and ARB may come from their

association with decreased risk of UGIB [15].

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Most of CKD patients died from CAD during the course of CKD progression and

only some of the CKD patients started chronic dialysis [16-18]. In our study, the

proportion of patients who started chronic dialysis was higher than that of patients

who died. This was not only observed in our previous studies [1,19] but also in other

cohort of CKD patients in Taiwan [20]. The high prevalence of chronic dialysis in

Taiwan may be explained by an ethnic difference [21] or the effectiveness of

multidisciplinary care for CKD in Taiwan [20].

Diabetes was associated with the risk of chronic dialysis because diabetes is a

well-known confounder of dialysis. NSAIDs were also well-known risk factors for

UGIB and chronic dialysis [22], but we did not find a significant association of

NSAIDs and chronic dialysis. Aspirin, clopidogrel, warfarin were not associated with

the risk of chronic dialysis in patients with CAD either. Steroids treatment was

relatively common in patients with CKD [23] and 3% of patients took steroids in this

study. Steroids treatment was not associated with the risk of chronic dialysis in this

study. A limited number of patients who took these medications in this study may

explain this result. In addition, nausea/vomiting can be uremic symptoms [24] and are

indications of dialysis. Nausea/vomiting are common in patients with UGIB [25].

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Although some CKD patients initiated dialysis because of UGIB-related

nausea/vomiting rather than uremic symptoms, the percentages of patients with

nausea/vomiting at the initiation of dialysis were similar among patients with UGIB

and those without. In addition, we excluded patients who underwent dialysis less than

3 months and discontinued dialysis because of a recovery of renal function.

UGIB-related nausea/vomiting did not explain the association of UGIB and chronic

dialysis in this study.


all patients in single hospital in Taiwan. This may limit the generalizability of our

finding to other ethnic groups. More studies of various ethnic groups and multiple

institutions are required to confirm our results. Patients of a CKD program were

analyzed in this study and therefore patient selection bias cannot be avoided. We also

recorded proton-pump inhibitor treatment for UGIB but did not find any beneficial

effect of proton-pump inhibitor in decreasing risk of chronic dialysis and all-cause

mortality. In spite of the limitations, this the first study that showed an association of

UGIB and chronic dialysis, independent of all confounders of chronic dialysis. This

suggests that UGIB not only leads to acute kidney injury but also results in long-term

consequence of irreversible kidney injury in this population.

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Conclusions

Upper gastrointestinal bleeding is associated with increased risk of chronic dialysis in

patients with chronic kidney disease stages 3-5 and not receiving dialysis. This

association is independent of age, gender, basal renal function, diabetes, hemoglobin,

albumin, and urine protein levels. More studies will be warranted to investigate if

prevention of UGIB may slow the progression of CKD and delay the need of dialysis

in patients with CND-ND.

Acknowledgments

This study was supported in part by Taiwan Ministry of Health and Welfare Clinical

Trial and Research Center of Excellence (MOHW104-TDU-B-212-113002) and

China Medical University Hospital (DMR-101-019 & DMR-102-015). The funders

had no role in study design, data collection and analysis, decision to publish, or

preparation of the manuscript.





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this study.


No additional data available.

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References


CKD. Clin J Am Soc Nephrol 2014;9(8):1354-9.


gastrointestinal bleeding in dialysis patients. J Am Soc Nephrol

2012;23(3):495-506.




4. Åhsberg K, Höglund P, Staël von Holstein C. Mortality from peptic ulcer bleeding:

the impact of comorbidity and the use of drugs that promote bleeding. Alimentary

pharmacology & therapeutics 2010;32(6):801-10.

5. Leontiadis GI, Molloy-Bland M, Moayyedi P, et al. Effect of comorbidity on

mortality in patients with peptic ulcer bleeding: systematic review and meta-analysis.

Am J Gastroenterol 2013;108(3):331-45; quiz 46.








mellitus and impaired glucose tolerance. Arch Intern Med 2005;165(8):863-7.


hypertension: population study. BMJ 2000;320(7233):479-82.

10. Levey AS, Bosch JP, Lewis JB, et al. A more accurate method to estimate

glomerular filtration rate from serum creatinine: a new prediction equation.

Modification of Diet in Renal Disease Study Group. Annals of internal medicine

1999;130(6):461-70.










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Association 2014;29(11):2127-35.



PloS one 2014;9(2):e87952.




16. Winkelmayer WC, Levin R, Avorn J. Chronic kidney disease as a risk factor for

bleeding complications after coronary artery bypass surgery. Am J Kidney Dis

2003;41(1):84-9.

17. Go AS, Chertow GM, Fan D, et al. Chronic kidney disease and the risks of death,

cardiovascular events, and hospitalization. N Engl J Med 2004;351(13):1296-305.

18. Tangri N, Stevens LA, Griffith J, et al. A predictive model for progression of

chronic kidney disease to kidney failure. JAMA 2011;305(15):1553-9.

19. Chen IR, Wang SM, Liang CC, et al. Association of walking with survival and RRT

among patients with CKD stages 3-5. Clin J Am Soc Nephrol 2014;9(7):1183-9.

20. Wang SM, Hsiao LC, Ting IW, et al. Multidisciplinary care in patients with chronic

kidney disease: A systematic review and meta-analysis. European journal of internal

medicine 2015;26(8):640-5.

21. Xu R, Zhang L, Zhang P, et al. Comparison of the prevalence of chronic kidney

disease among different ethnicities: Beijing CKD survey and American NHANES.

Nephrology, dialysis, transplantation : official publication of the European Dialysis

and Transplant Association - European Renal Association 2009;24(4):1220-6.



2011;9(5):423-30.

23. Levin A, Bakris GL, Molitch M, et al. Prevalence of abnormal serum vitamin D,

PTH, calcium, and phosphorus in patients with chronic kidney disease: results of the

study to evaluate early kidney disease. Kidney Int 2007;71(1):31-8.



disease managed without dialysis. J Palliat Med 2007;10(6):1266-76.


overview of randomised controlled trials. Br J Clin Pharmacol 1993;35(3):219-26.

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Legends

Figure 1. Cumulative incidence of chronic dialysis in patients with and without upper

gastrointestinal bleeding (UGIB) using competing-risks regression with adjustments

for age, gender, renal function, diabetes, hemoglobin, albumin, and urine

protein/creatinine ratio. The primary event was chronic dialysis and the competing

event was all-cause mortality.






angiotensin II receptor blocker (ARB).

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Table 1. Clinical characteristics and outcomes according to upper gastrointestinal bleeding

Basal characteristics Total

n=3126

UGIB (-)

n=2739

UGIB (+)

n=387 p

Follow-up (year) 2.8 1.0-4.3 2.8 0.8-4.3 2.4 0.9-4.1 0.38

Chronic dialysis n(%) 989 31.6 751 27.4 238 61.5 <0.01

Mortality n(%) 197 6.3 152 5.6 45 11.6 <0.01

Age (year) 65 ±14 64 ±14 68 ±12 <0.01

Male n(%) 1691 54.1 1476 53.9 215 55.6 0.54


Diabetes 1141 36.5 968 35.3 173 44.7

<0.01 CGN 1059 33.9 938 34.3 121 31.3

Hypertension 520 16.6 476 17.4 44 11.4

CAD 380 12.2 324 11.8 56 14.5 0.14

eGFR (ml/min/1.73 m2) 21 11-37 21 11-38 16 9-28 <0.01

BMI (kg/m2) 24.2 ±4.1 24.2 ±4.1 24.1 ±3.9 0.51

Hemoglobin (g/dl) 10.6 ±2.4 10.7 ±2.4 10.1 ±2.3 <0.01

BUN (mg/dl) 48 ±31 48 ±31 54 ±31 <0.01

Creatinine (mg/dl) 3.8 ±2.9 3.7 ±2.8 4.3 ±2.9 <0.01

Calcium (mg/dl) 9.1 ±0.7 9.1 ±0.7 9.1 ±0.8 0.77

Phosphorus (mg/dl) 4.6 ±1.4 4.5 ±1.4 4.6 ±1.2 0.26

Albumin (g/dl) 3.4 ±0.6 3.5 ±0.6 3.3 ±0.6 <0.01

ACR (g/g) 0.6 0.1-2.2 0.5 0.1-2.0 1.6 0.2-3.5 0.08

PCR (g/g) 1.4 0.5-3.6 1.3 0.5-3.4 2.2 0.9-4.5 <0.01

Medications n(%)

Steroids 106 3.4 97 3.5 9 2.3 0.21

NSAIDs 61 2.0 50 1.8 11 2.8 0.18

Aspirin 351 11.2 305 11.1 46 11.9 0.66

Clopidogrel 94 3.0 83 3.0 11 2.8 0.84

Warfarin 64 2.1 52 1.9 12 3.1 0.12


using MDRD formula, BMI: body mass index, BUN: blood urea nitrogen, ACR: urine

albumin/creatinine ratio, PCR: urine protein/creatinine ratio, NSAIDs: non-steroidal

anti-inflammatory drugs

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Table 2. Adjusted hazard ratio (aHR) of confounders for all-cause mortality and chronic dialysis with adjustments for age, sex and estimated glomerular filtration rate (eGFR)

Confounders All-cause mortality Chronic dialysis

aHR 95% CI aHR 95% CI

UGIB 1.47 1.04 2.07 1.30 1.12 1.51

Diabetes 1.10 0.82 1.48 1.50 1.31 1.72

CAD 1.13 0.74 1.72 0.92 0.75 1.14

Hemoglobin (per 1 g/dl) 0.94 0.87 1.01 0.91 0.88 0.94

Albumin (per 1 g/dl) 0.52 0.42 0.66 0.74 0.66 0.83

PCR (per 1 g/g) 0.98 0.93 1.03 1.03 1.02 1.05

Steroids 1.13 0.46 2.78 1.87 1.33 2.63

NSAIDs 1.26 0.58 2.76 0.63 0.37 1.09

Aspirin 0.81 0.51 1.29 1.18 0.96 1.45

Clopidogrel 0.92 0.42 2.01 1.13 0.79 1.61

Warfarin 1.09 0.47 2.55 1.36 0.87 2.13

UGIB: upper gastrointestinal bleeding, CAD: coronary artery disease, PCR: urine protein/creatinine ratio, NSAIDs: non-steroidal anti-inflammatory drugs

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Figure 1

73x54mm (300 x 300 DPI)

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Figure 2

187x82mm (150 x 150 DPI)

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1


Section/Topic Item

No Recommendation

Reported

on Page No



Introduction



Methods



6

Participants 6


follow-up




6




applicable 7













7


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2

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Reported

on Page No

Results

Participants 13*







confounders 8



Outcome data 15*




Main results 16






Discussion







Other Information







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Upper gastrointestinal bleeding as a risk factor for dialysis and all-cause mortality: a cohort study of chronic kidney

disease patients in Taiwan

Journal: BMJ Open



Date Submitted by the Author: 28-Mar-2016




Renal medicine


Keywords: Chronic renal failure < NEPHROLOGY, Gastroduodenal disease < GASTROENTEROLOGY, Dialysis < NEPHROLOGY


BMJ Open on 29 M


http://bmjopen.bm

j.com/

BM


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Upper gastrointestinal bleeding as a risk factor for dialysis and

all-cause mortality: a cohort study of chronic kidney disease patients

in Taiwan







404, Taiwan









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Abstract

Objective



(CKD-ND). It is unclear if UGIB increases risk of chronic dialysis. The aim of the


Setting


2009 were enrolled and prospectively followed until Sep 2012.





Results




[adjusted Hazard Ratio (aHR): 1.51, 95% confidence interval (CI): 1.07- 2.13] and the

risk of chronic dialysis (aHR; 1.29, 95% CI; 1.11 - 1.50). The sub-distribution hazard

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ratio (SHR) of UGIB for chronic dialysis (competing event: all-cause mortality) was

1.37 (95% CI, 1.15-1.64) in competing-risks analysis with adjustments for age, renal

function, gender, diabetes, hemoglobin, albumin, and urine protein/creatinine ratio.

Conclusions


patients with CKD-ND stages 3-5. This association is independent of age, gender,

basal renal function, hemoglobin, albumin, and urine protein levels.

Keywords





� This association is shown in a cohort of CKD patients with adjustments for

confounders.

� The generalizability of this finding may be limited by one hospital and a single

ethnic group.

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Introduction




at baseline 1. UGIB not only increases the risk of hospitalization but also increases

in-hospital mortality in CKD-ND patients and CKD 5 patients on dialysis 3. The


worsen comorbid conditions caused by the UGIB3-5.







UGIB in patients with CKD-ND.


Patient enrollment

All patients in the outpatient-based CKD program of China Medical University

Hospital (CMUH) from June 2003 to December 2009 were included. The CKD

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program included patients with CKD-ND stages 3-5 diagnosed by nephrologists and

no exclusion criteria were applied. The CKD program supported by National Health

Insurance Taiwan includes clinical endocrinologists, nephrologists, CKD nurses,

dietitians, and social workers. The purpose of the CKD program is to monitor the

progression of CKD patients. Laboratory measurements and CKD education are

performed at least four times a year. All patients were followed to the date of initiation

of chronic dialysis including hemodialysis and peritoneal dialysis, loss to follow-up,

death, or until September 2012. There were two patients who received kidney

transplant and these two patients were excluded in the analysis because the timing of

kidney transplantation was not related to uremic symptoms. As we aimed to

investigate risk of chronic dialysis, patients who received dialysis less than 3 months

and patients who discontinued dialysis because of a recovery of renal function were

excluded.

Definition and measurements



bled on endoscopy of the upper digestive tract1. Coronary artery disease (CAD) was



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level of 126 mg/dl or more.8 Hypertension was defined as taking antihypertensives



than 90 mm Hg.9 Patients’ primary kidney disease including diabetes, chronic

glomerular nephritis (CGN), and hypertension was diagnosed by the primary care

physician and was recorded at enrollment.





was calculated using the MDRD Collaboration formula.10 The formula for white or





records.



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CMUH and contacted patients who did not return to the outpatient every 6 months.

The percentage of patients who were lost to follow-up was 6% in the CKD program.

The outcomes were validated by a study nurse through a review of medical records

and the study nurse was blinded to the aim of the study, and other physicians












intervals (CI) of aHR in multivariable Cox regression with adjustments for age,

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gender, and eGFR were calculated. We utilized competing-risks analysis 11 with

adjustments for confounders identified in Cox regression because the risk of chronic

dialysis may be overestimated if patients’ death was not taken into consideration 12 13.

An adjusted sub-distribution HR (aSHR) and 95% CI of aSHR were calculated in






Ethical considerations


medical records, and the need for informed consent was waived.

Results



female, aged 65±14 years (Table 1). Diabetes and chronic glomerulonephritis (CGN)

were the major forms of primary kidney disease. The basal eGFR of the patients was

21 (11-37) ml/min/1.73m2 and the urine PCR was 1.4 (0.5 - 3.6) g/g at enrollment.

Patients with UGIB were older and more often had diabetes, a lower eGFR, a lower

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hemoglobin, a higher BUN, a higher creatinine, and a lower serum albumin. They,

however, had similar use of steroid, NSAIDs, aspirin, clopidogrel, and warfarin.

There were no differences in serum calcium and phosphate levels in the patients with

UGIB and the patients without.

Mortality and risk of chronic dialysis in patients with upper gastrointestinal

bleeding

The times of follow-up were similar in the patients with UGIB and the patients

without (p = 0.38, Table 2). The proportion of the patients with UGIB who start

chronic dialysis was higher than that of the patients without UGIB (61.5% vs. 27.4%,

p < 0.01). Patients with UGIB were associated with a higher all-cause mortality than

patients without UGIB (11.6% vs. 5.6%, p < 0.01).



aHR of 1.51 (95% CI: 1.07 - 2.13, p = 0.02). Patients’ age, eGFR, and serum albumin

were independently associated with all-cause mortality. The aHR was 1.05 for every

one additional year (95% CI: 1.04 – 1.07, p < 0.01), 0.99 for every ml/min/1.73m2 of

eGFR (95% CI: 0.0.98-1.00, p < 0.01), and 0.52 per g/dl of serum albumin (95% CI:

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0.42 – 0.65, p < 0.01). Diabetes, CAD, hemoglobin, and PCR were not associated

with all-cause mortality. Use of steroid, NSAIDs, clopidogrel, and warfarin were not

associated all-cause mortality, either.

UGIB increases risk of chronic dialysis

UGIB was associated with an increased risk of chronic dialysis with an aHR of 1.29

(95% CI: 1.11-1.50, p < 0.01). Diabetes was independently associated with increased

risk of chronic dialysis with an HR of 1.49 (95% CI: 1.30 - 1.72, p < 0.01).

Hemoglobin and serum albumin were associated with lower risk of chronic dialysis.

PCR was associated with increased risk of chronic dialysis with an HR of 1.29 (95%

CI: 1.11-1.50) per 1g/g. Steroids, NSAIDs, clopidogrel, and warfarin were not

associated with the risk of chronic dialysis. The aSHR of UGIB for chronic dialysis

was 1.37 (95% CI: 1.15-1.64, p < 0.01) in competing-risks analysis with adjustments

for age, gender, eGFR, diabetes, hemoglobin, albumin, and PCR. The cumulative

incidence of chronic dialysis in patients with UGIB and those without is shown in

Figure 1.

Discussion

In this cohort of patients with CKD-ND stages 3-5, UGIB was associated with higher

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risk of chronic dialysis. The association of UGIB and risk of chronic dialysis were

further validated using competing-risks analysis. The competing-risks analysis was

critical to this study because UGIB was associated with increased all-cause mortality.

UGIB can be a complication of uremia because of the uremic coagulopathy. In this

study, UGIB patients started chronic dialysis after a median of 1.2 (interquartile range:

0.7-1.3) years. Uremic coagulopathy associated UGIB therefore may not be one of the

uremic symptoms that required dialysis in these patients. In summary of our previous

studies 1 14 15 and this study (Figure 2), patients with CKD-ND were more at risk for

developing UGIB and UGIB may further accelerate the progression of CKD to

chronic dialysis. The common aggravating factors of CKD and UGIB are anemia16,

diabetes, and hypoalbuminemia1. In addition, higher GFR and uses of

angiotensinogen converting enzyme inhibitor (ACEi) or angiotensin II receptor

blocker (ARB) may protect UGIB in this scenario 15. Some beneficial effects of ACEi

and ARB may come from their association with decreased risk of UGIB 15.


only some of the CKD patients started chronic dialysis 17-19. In our study, the


who died. This was not only observed in our previous studies 1 20 but also in other

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cohort of CKD patients in Taiwan 21. The high prevalence of chronic dialysis in

Taiwan may be explained by an ethnic difference 22 or the effectiveness of

multidisciplinary care for CKD in Taiwan 21.



UGIB and chronic dialysis 23, but we did not find any significant association of


the risk of chronic dialysis in patients with CAD, either. Steroids treatment was

relatively common in patients with CKD 24 but only 3% of patients took steroids in

this study. Steroids treatment was not associated with the risk of chronic dialysis in

this study. A limited number of patients who took these medications in this study may

explain this result. In addition, nausea and vomiting can be uremic symptoms 25 and

are indications of dialysis. Nausea and vomiting are common in patients with UGIB 26.

Although some CKD patients initiated dialysis because of UGIB-related nausea and

vomiting rather than uremic symptoms, the percentages of patients with nausea and

vomiting at the initiation of dialysis were similar among patients with UGIB and

those without. In addition, we excluded patients who underwent dialysis less than 3

months and discontinued dialysis because of a recovery of renal function.

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mortality. In spite of the limitations, this is the first study that shows an association of




Conclusions





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Acknowledgments

This study was supported in part by This study is supported in part by Taiwan

Ministry of Health and Welfare Clinical Trial and Research Center of Excellence

(MOHW105-TDU-B-212-133019) and China Medical University Hospital

(DMR-101-019 & DMR-102-015). The funders had no role in study design, data

collection and analysis, decision to publish, or preparation of the manuscript.








this study.


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None

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References





2012;23(3):495-506.























1999;130(6):461-70.










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Association 2014;29(11):2127-35.



PloS one 2014;9(2):e87952.




16. Hsu TW, Liu JS, Hung SC, et al. Renoprotective effect of

renin-angiotensin-aldosterone system blockade in patients with predialysis

advanced chronic kidney disease, hypertension, and anemia. JAMA Intern Med

2014;174(3):347-54.



2003;41(1):84-9.









medicine 2015;26(8):640-5.







2011;9(5):423-30.









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Legends












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n=3126

UGIB (-)

n=2739

UGIB (+)

n=387 p

Follow-up (year) 2.8 1.0-4.3 2.8 0.8-4.3 2.4 0.9-4.1 0.38


Mortality n(%) 197 6.3 152 5.6 45 11.6 <0.01

Age (year) 65 ±14 64 ±14 68 ±12 <0.01

Male n(%) 1691 54.1 1476 53.9 215 55.6 0.54


Diabetes 1141 36.5 968 35.3 173 44.7

<0.01 CGN 1059 33.9 938 34.3 121 31.3

Hypertension 520 16.6 476 17.4 44 11.4

CAD 380 12.2 324 11.8 56 14.5 0.14

eGFR (ml/min/1.73 m2) 21 11-37 21 11-38 16 9-28 <0.01

BMI (kg/m2) 24.2 ±4.1 24.2 ±4.1 24.1 ±3.9 0.51

Hemoglobin (g/dl) 10.6 ±2.4 10.7 ±2.4 10.1 ±2.3 <0.01

BUN (mg/dl) 48 ±31 48 ±31 54 ±31 <0.01

Creatinine (mg/dl) 3.8 ±2.9 3.7 ±2.8 4.3 ±2.9 <0.01

Calcium (mg/dl) 9.1 ±0.7 9.1 ±0.7 9.1 ±0.8 0.77

Phosphorus (mg/dl) 4.6 ±1.4 4.5 ±1.4 4.6 ±1.2 0.26

Albumin (g/dl) 3.4 ±0.6 3.5 ±0.6 3.3 ±0.6 <0.01

ACR (g/g) 0.6 0.1-2.2 0.5 0.1-2.0 1.6 0.2-3.5 0.08

PCR (g/g) 1.4 0.5-3.6 1.3 0.5-3.4 2.2 0.9-4.5 <0.01

Medications n(%)

Steroids 106 3.4 97 3.5 9 2.3 0.21

NSAIDs 61 2.0 50 1.8 11 2.8 0.18

Aspirin 351 11.2 305 11.1 46 11.9 0.66

Clopidogrel 94 3.0 83 3.0 11 2.8 0.84

Warfarin 64 2.1 52 1.9 12 3.1 0.12


using MDRD formula, BMI: body mass index, BUN: blood urea nitrogen, ACR: urine



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Table 2. Outcomes of patients with and without upper gastrointestinal bleeding

Outcomes Total

n=3126

UGIB (-)

n=2739

UGIB (+)

n=387 p

Follow-up (year) 2.8 1.0-4.3 2.8 0.8-4.3 2.4 0.9-4.1 0.38


Mortality n(%) 197 6.3 152 5.6 45 11.6 <0.01

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Table 3. Adjusted hazard ratio (aHR) of confounders for all-cause mortality and chronic dialysis



UGIB 1.51 1.07 2.13 1.29 1.11 1.50

Age (per year) 1.05 1.04 1.07 0.99 0.99 0.99

Diabetes - - - 1.49 1.30 1.70

eGFR (per ml/min/1.73m2) 0.99 0.98 1.00 0.94 0.93 0.94

Hemoglobin (per g/dl) - - - 0.74 0.66 0.82

Albumin (per g/dl) 0.52 0.42 0.65 1.03 1.02 1.05

PCR (per g/g) - - - 1.29 1.11 1.50

UGIB: upper gastrointestinal bleeding, eGFR: estimated glomerular filtration rate using MDRD formula, PCR: urine protein/creatinine ratio

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Figure 1

196x145mm (300 x 300 DPI)

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Figure 2

250x109mm (300 x 300 DPI)

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Participants 13*







confounders 8



Outcome data 15*




Main results 16






Discussion







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Upper gastrointestinal bleeding as a risk factor for dialysis and all-cause mortality: a cohort study of chronic kidney

disease patients in Taiwan

Journal: BMJ Open



Date Submitted by the Author: 13-Apr-2016




Renal medicine


Keywords: Chronic renal failure < NEPHROLOGY, Gastroduodenal disease < GASTROENTEROLOGY, Dialysis < NEPHROLOGY


BMJ Open on 29 M


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Upper gastrointestinal bleeding as a risk factor for dialysis and

all-cause mortality: a cohort study of chronic kidney disease patients

in Taiwan







404, Taiwan









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Abstract

Objective



(CKD-ND). It is unclear if UGIB increases risk of chronic dialysis. The aim of the


Setting


2009 were enrolled and prospectively followed until Sep 2012.





Results




[adjusted Hazard Ratio (aHR): 1.51, 95% confidence interval (CI): 1.07- 2.13] and the

risk of chronic dialysis (aHR; 1.29, 95% CI; 1.11 - 1.50). The sub-distribution hazard

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ratio (SHR) of UGIB for chronic dialysis (competing event: all-cause mortality) was

1.37 (95% CI, 1.15-1.64) in competing-risks analysis with adjustments for age, renal

function, gender, diabetes, hemoglobin, albumin, and urine protein/creatinine ratio.

Conclusions


patients with CKD-ND stages 3-5. This association is independent of age, gender,

basal renal function, hemoglobin, albumin, and urine protein levels.

Keywords





� This association is shown in a cohort of CKD patients with adjustments for

confounders.

� The generalizability of this finding may be limited by one hospital and a single

ethnic group.

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Introduction




1. UGIB not only increases the risk of hospitalization but also increases in-hospital

mortality in CKD-ND patients and CKD 5 patients on dialysis 3. The increased

all-cause mortality associated with UGIB is usually explained by the worsened

comorbid conditions caused by the UGIB3-5.







UGIB in patients with CKD-ND.


Patient enrollment

All patients in the outpatient-based CKD program of China Medical University

Hospital (CMUH) from June 2003 to December 2009 were included. The CKD

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program included patients with CKD-ND stages 3-5 diagnosed by nephrologists and

no exclusion criteria were applied. The CKD program supported by National Health

Insurance Taiwan includes clinical endocrinologists, nephrologists, CKD nurses,

dietitians, and social workers. The purpose of the CKD program is to monitor the

progression of CKD patients. Laboratory measurements and CKD education are

performed at least four times a year. The UGIB was identified from review of medical

records and the date of UGIB was recorded. All patients were followed to the date of

initiation of chronic dialysis including hemodialysis and peritoneal dialysis, loss to

follow-up, death, or until September 2012. There were two patients who received a

kidney transplant and these two patients were excluded in the analysis because the

timing of kidney transplantation was not related to uremic symptoms. As we aimed to

investigate risk of chronic dialysis, patients who received dialysis less than 3 months

and patients who discontinued dialysis because of a recovery of renal function were

excluded.

Definition and measurements



bled on endoscopy of the upper digestive tract 1. Coronary artery disease (CAD) was


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level of 126 mg/dl or more.8 Hypertension was defined as taking antihypertensives



than 90 mm Hg.9 Patients’ primary kidney disease including diabetes nephropathy,

chronic glomerulonephritis (CGN), and hypertensive nephropathy was diagnosed by

the primary care physician and was recorded at enrollment.





was calculated using the MDRD Collaboration formula.10 The formula for white or





records.


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CMUH and contacted patients who did not return to the outpatient every 6 months.

The percentage of patients who were lost to follow-up was 6% in the CKD program.

The outcomes were validated by a study nurse through a review of medical records

and the study nurse was blinded to the aim of the study, and other physicians












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intervals (CI) of aHR in multivariable Cox regression with adjustments for age,

gender, and eGFR were calculated. We utilized competing-risks analysis 11 with

adjustments for confounders identified in Cox regression because the risk of chronic

dialysis may be overestimated if patients’ death was not taken into consideration 12 13.

An adjusted sub-distribution HR (aSHR) and 95% CI of aSHR were calculated in






Ethical considerations


medical records, and the need for informed consent was waived.

Results



female, aged 65±14 years (Table 1). Diabetes nephropathy and chronic

glomerulonephritis (CGN) were the major forms of primary kidney disease. The basal

eGFR of the patients was 21 (11-37) ml/min/1.73m2 and the urine PCR was 1.4 (0.5 -

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3.6) g/g at enrollment. Patients with UGIB were older and more often had diabetes, a

lower eGFR, a lower hemoglobin, a higher BUN, a higher creatinine, and a lower

serum albumin. They, however, had similar use of steroid, NSAIDs, aspirin,

clopidogrel, and warfarin. There were no differences in serum calcium and phosphate

levels in the patients with UGIB and the patients without. The times of follow-up

were similar in the patients with UGIB and the patients without (p = 0.38, Table 2).

The proportion of the patients with UGIB who started chronic dialysis was higher

than that of the patients without UGIB (61.5% vs. 27.4%, p < 0.01). Patients with

UGIB were associated with a higher all-cause mortality than patients without UGIB

(11.6% vs. 5.6%, p < 0.01).

Upper gastrointestinal bleeding and risk of mortality


aHR of 1.51 (95% CI: 1.07 - 2.13, p = 0.02). Patients’ age, eGFR, and serum albumin

were independently associated with all-cause mortality. The aHR was 1.05 for every

one additional year (95% CI: 1.04 – 1.07, p < 0.01), 0.99 for every ml/min/1.73m2 of

eGFR (95% CI: 0.0.98-1.00, p < 0.01), and 0.52 per g/dl of serum albumin (95% CI:

0.42 – 0.65, p < 0.01). Diabetes, CAD, hemoglobin, and PCR were not associated

with all-cause mortality. Use of steroid, NSAIDs, clopidogrel, and warfarin were not

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associated all-cause mortality, either.

Upper gastrointestinal bleeding and risk of chronic dialysis

UGIB was associated with an increased risk of chronic dialysis with an aHR of 1.29

(95% CI: 1.11-1.50, p < 0.01). Diabetes was independently associated with increased

risk of chronic dialysis with an HR of 1.49 (95% CI: 1.30 - 1.72, p < 0.01).

Hemoglobin and serum albumin were associated with lower risk of chronic dialysis.

PCR was associated with increased risk of chronic dialysis with an HR of 1.29 (95%

CI: 1.11-1.50) per 1g/g. Steroids, NSAIDs, clopidogrel, and warfarin were not

associated with the risk of chronic dialysis. The aSHR of UGIB for chronic dialysis

was 1.37 (95% CI: 1.15-1.64, p < 0.01) in competing-risks analysis with adjustments

for age, gender, eGFR, diabetes, hemoglobin, albumin, and PCR. The cumulative

incidence of chronic dialysis in patients with UGIB and those without is shown in

Figure 1.

Discussion

In this cohort of patients with CKD-ND stages 3-5, UGIB was associated with higher

risk of chronic dialysis. The association of UGIB and risk of chronic dialysis were

further validated using competing-risks analysis. The competing-risks analysis was

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critical to this study because UGIB was associated with increased all-cause mortality.

UGIB can be a complication of uremia because of the uremic coagulopathy. In this

study, UGIB patients started chronic dialysis after a median of 1.2 (interquartile range:

0.7-1.3) years. Uremic coagulopathy associated UGIB therefore may not be one of the

uremic symptoms that required dialysis in these patients. In summary of our previous

studies 1 14 15 and this study (Figure 2), patients with CKD-ND were more at risk for

developing UGIB and UGIB may further accelerate the progression of CKD to

chronic dialysis. The common aggravating factors of CKD and UGIB are anemia16,

diabetes, and hypoalbuminemia1. In addition, higher GFR and uses of

angiotensinogen converting enzyme inhibitor (ACEi) or angiotensin II receptor

blocker (ARB) may protect UGIB in this scenario 15. Some beneficial effects of ACEi

and ARB may come from their association with decreased risk of UGIB 15.


only some of the CKD patients started chronic dialysis 17-19. In our study, the


who died. This was not only observed in our previous studies 1 20 but also in other

cohort of CKD patients in Taiwan 21. The high prevalence of chronic dialysis in

Taiwan may be explained by an ethnic difference 22 or the effectiveness of

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multidisciplinary care for CKD in Taiwan 21.



UGIB and chronic dialysis 23, but we did not find any significant association of


the risk of chronic dialysis in patients with CAD, either. Steroids treatment was

relatively common in patients with CKD 24 but only 3% of patients took steroids in

this study. Steroids treatment was not associated with the risk of chronic dialysis in

this study. A limited number of patients who took these medications in this study may

explain this result. In addition, nausea and vomiting can be uremic symptoms 25 and

are indications of dialysis. Nausea and vomiting are common in patients with UGIB 26.

Although some CKD patients initiated dialysis because of UGIB-related nausea and

vomiting rather than uremic symptoms, the percentages of patients with nausea and

vomiting at the initiation of dialysis were similar among patients with UGIB and

those without. In addition, we excluded patients who underwent dialysis less than 3

months and discontinued dialysis because of a recovery of renal function.



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mortality. In spite of the limitations, this is the first study that shows an association of




Conclusions







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Acknowledgments

This study was supported in part by This study is supported in part by Taiwan

Ministry of Health and Welfare Clinical Trial and Research Center of Excellence

(MOHW105-TDU-B-212-133019) and China Medical University Hospital

(DMR-101-019 & DMR-102-015). The funders had no role in study design, data

collection and analysis, decision to publish, or preparation of the manuscript.








this study.


None

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References





2012;23(3):495-506.























1999;130(6):461-70.










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Association 2014;29(11):2127-35.



PloS one 2014;9(2):e87952.




16. Hsu TW, Liu JS, Hung SC, et al. Renoprotective effect of

renin-angiotensin-aldosterone system blockade in patients with predialysis

advanced chronic kidney disease, hypertension, and anemia. JAMA Intern Med

2014;174(3):347-54.



2003;41(1):84-9.









medicine 2015;26(8):640-5.







2011;9(5):423-30.









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Legends












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n=3126

UGIB (-)

n=2739

UGIB (+)

n=387 p

Follow-up (year) 2.8 1.0-4.3 2.8 0.8-4.3 2.4 0.9-4.1 0.38

Age (year) 65 ±14 64 ±14 68 ±12 <0.01

Male n(%) 1691 54.1 1476 53.9 215 55.6 0.54


Diabetes nephropathy 1141 36.5 968 35.3 173 44.7

<0.01 CGN 1059 33.9 938 34.3 121 31.3

Hypertensive nephropathy 520 16.6 476 17.4 44 11.4

CAD 380 12.2 324 11.8 56 14.5 0.14

eGFR (ml/min/1.73 m2) 21 11-37 21 11-38 16 9-28 <0.01

BMI (kg/m2) 24.2 ±4.1 24.2 ±4.1 24.1 ±3.9 0.51

Hemoglobin (g/dl) 10.6 ±2.4 10.7 ±2.4 10.1 ±2.3 <0.01

BUN (mg/dl) 48 ±31 48 ±31 54 ±31 <0.01

Creatinine (mg/dl) 3.8 ±2.9 3.7 ±2.8 4.3 ±2.9 <0.01

Calcium (mg/dl) 9.1 ±0.7 9.1 ±0.7 9.1 ±0.8 0.77

Phosphorus (mg/dl) 4.6 ±1.4 4.5 ±1.4 4.6 ±1.2 0.26

Albumin (g/dl) 3.4 ±0.6 3.5 ±0.6 3.3 ±0.6 <0.01

ACR (g/g) 0.6 0.1-2.2 0.5 0.1-2.0 1.6 0.2-3.5 0.08

PCR (g/g) 1.4 0.5-3.6 1.3 0.5-3.4 2.2 0.9-4.5 <0.01

Medications n(%)

Steroids 106 3.4 97 3.5 9 2.3 0.21

NSAIDs 61 2.0 50 1.8 11 2.8 0.18

Aspirin 351 11.2 305 11.1 46 11.9 0.66

Clopidogrel 94 3.0 83 3.0 11 2.8 0.84

Warfarin 64 2.1 52 1.9 12 3.1 0.12

UGIB: upper gastrointestinal bleeding, CGN: chronic glomerulonephritis, eGFR:

estimated glomerular filtration rate using MDRD formula, CAD: coronary artery

disease, BMI: body mass index, BUN: blood urea nitrogen, ACR: urine



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Table 2. Outcomes of patients with and without upper gastrointestinal bleeding

Outcomes Total

n=3126

UGIB (-)

n=2739

UGIB (+)

n=387 p

Follow-up (year) 2.8 1.0-4.3 2.8 0.8-4.3 2.4 0.9-4.1 0.38


Mortality n(%) 197 6.3 152 5.6 45 11.6 <0.01

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Table 3. Risk of all-cause mortality and chronic dialysis in patients with chronic kidney disease and upper gastrointestinal bleeding



UGIB* 1.51 1.07 2.13 1.29 1.11 1.50

Age (per year) 1.05 1.04 1.07 0.99 0.99 0.99

Diabetes - - - 1.49 1.30 1.70

eGFR (per ml/min/1.73m2) 0.99 0.98 1.00 0.94 0.93 0.94

Hemoglobin (per g/dl) - - - 0.74 0.66 0.82

Albumin (per g/dl) 0.52 0.42 0.65 1.03 1.02 1.05

PCR (per g/g) - - - 1.29 1.11 1.50

UGIB: upper gastrointestinal bleeding, eGFR: estimated glomerular filtration rate using MDRD formula, PCR: urine protein/creatinine ratio *Patients without UGIB as reference

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Figure 1

196x145mm (300 x 300 DPI)

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Figure 2

250x109mm (300 x 300 DPI)

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Introduction



Methods



6

Participants 6


follow-up




6




applicable 7













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Reported

on Page No

Results

Participants 13*







confounders 8



Outcome data 15*




Main results 16






Discussion







Other Information







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