Risk factors influencing the outcome of peptic ulcer bleeding in end stage renal diseases after initial endoscopic haemostasis

Risk factors influencing the outcome of peptic ulcerbleeding in end stage renal diseases after initialendoscopic haemostasis

S.-C. Lin,1 K.-L. Wu,1 K.-W. Chiu,1 C.-T. Lee,2 Y.-C. Chiu,1 Y.-P. Chou,1 M.-L. Hu,1 W.-C. Tai,1

S.-S. Chiou,1 T.-H. Hu,1 C.-S. Changchien,1 S.-K. Chuah1

Introduction

Taiwan is ranked as the top three nations in the

world in terms of the incidence of end-stage renal

disease (ESRD) with the rate of 384 per million pop-

ulations (1). It is definitely not something commend-

able but a threat to the health of the people in the

nation. The prevalence of peptic ulcer (PU) in

patients with ESRD is comparable with those in the

general population (2–5). Nevertheless they are asso-

ciated with more bleeding complications than those

in the general population (6). The major cause of

clinical bleeding among patients with CKD is upper

gastrointestinal bleeding (UGIB) and PU is the most

common cause (7). Patients with CKD are thought

to be associated with higher mortality because of PU

bleeding (8,9). In addition, renal insufficiency is a

predictor of mortality in validated UGIB scoring sys-

tems, such as Rockall score (10). However, improve-

ment in the outcomes of PU bleeding was observed

after the era of interventional endoscopic therapy

and high-dose acid suppression (11).

Reports on outcome studies of PU bleeding in

CKD patients after invasive endoscopic haemostasis

are limited. An interesting study conducted by Che-

ung and colleagues reported that the overall reblee-

ding rates were significantly higher in ESRD patients,

for both high and low-risk ulcers, but had similar in-

hospital mortality compared with those with normal

kidney function (12). However, enquiries regarding

the small sample size and patient selection bias were

made because ESRD patients in the study were

SUMMARY

Background and Aims: Patients suffering from peptic ulcer (PU) bleeding who

have end-stage renal disease (ESRD) may encounter more adverse outcomes. The

primary objective is to investigate the risk factors that influence the outcomes of

ESRD and chronic kidney disease (CKD) patients with PU bleeding after successful

initial endoscopic haemostasis. Methods: A total of 540 patients with PU bleed-

ing after initial endoscopic haemostasis in a tertiary hospital were investigated ret-

rospectively. They were sorted into three groups after randomised age-matched

adjustment: ESRD group (n = 90), CKD group (n = 90) and control group

(n = 360). Main outcome measurements were rebleeding, requirement for blood

transfusion and surgery, length of hospital stay and mortality. Results: The reblee-

ding rates were 43% for the ESRD group vs. 21% for the CKD group vs. 12% for

the control group (overall p = < 0.001). Multivariate analysis showed the predic-

tors of rebleeding were ESRD, time to endoscope, and non-high-dose proton-pump

inhibitors (PPI) users. The risk factors for bleeding-related mortality were presence

of moderate degree of CKD and ESRD group, time to endoscope, and Rockall

score. All-cause mortality was related to presence of moderate degree of CKD and

ESRD group, platelet count, time to endoscope, Rockall score and length of hospi-

tal stay. Conclusions: ESRD patients who suffered from PU bleeding were at risk

of excessive rebleeding and mortality with frequent occurrence of delayed reblee-

ding. This study suggests that early endoscopy for initial haemostasis and high-

dose intravenous PPI are associated with the reduction of rebleeding risk especially

in patients with high Rockall scores.

What’s known• PU bleeding is a major cause of UGI bleeding in

ESRD patients.

What’s new• Age-matched multivariate analysis revealed that

moderate degree of chronic kidney disease,

longer time needed to initiate endoscopic

treatment and non-high-dose PPI users were the

independent risks factor for PU rebleeding in

ESRD patients after initial endoscopic

haemostasis.

• ESRD patients who suffered from peptic ulcer

bleeding were at risk of excessive rebleeding and

mortality with frequent occurrence of delayed

rebleeding even at the earlier stage of the renal

disease. Early endoscope and high-dose

intravenous proton-pump inhibitors are associated

with the reduction of rebleeding risk especially in

the diseased patients with high Rockall score.

1Division of Hepato-

Gastroenterology, Department

of Internal Medicine, Kaohsiung

Chang Gung Memorial Hospital

and Chang Gung University

College of Medicine,

Kaohsiung, Taiwan2Division of Nephrology,

Department of Internal

Medicine, Kaohsiung Chang

Gung Memorial Hospital and

Chang Gung University College

of Medicine, Kaohsiung, Taiwan

Correspondence to:

Seng-Kee Chuah,

Division of

Hepatogastroenterology,

Department of Internal

Medicine, Chang Gang

Memorial Hospital, Kaohsiung

123, Ta-Pei Road, Niaosung,

Hsiang, Kaohsiung Country,

833, Taiwan

Tel.: 886 7 7317123, ext. 8301

Fax: 886 7 7322402

Email: [email protected]

Disclosures

All authors have no disclosure

of any financial involvement in

any organisation with a direct

financial interest in the subject

matter or materials discussed in

the manuscript.

OR IG INAL PAPER

ª 2012 Blackwell Publishing LtdInt J Clin Pract doi: 10.1111/j.1742-1241.2012.02974.x 1

associated with significantly more co-morbidities

which could be misleading in an outcome study.

Therefore, after randomised age-matching patients

with moderate CKD and normal kidney function to

the ESRD patients, we conducted this study to iden-

tify the risk factors that influence the outcomes of

ESRD patients with PU bleeding after initial endo-

scopic haemostasis.

Methods

PatientsFrom January 2008 to December 2010, medical

records of 903 patients with PU bleeding who

received initial successful endoscopic haemostasis

from a university-affiliated tertiary care center were

reviewed. We excluded 77 patients whose bleeding

was not PU-related, 4 patients with unsuccessful

endoscopic haemostasis and 113 patients with

incomplete chart records or insufficient follow-up

period (< 30 days) for reasons other than mortality.

Eventually, a total of 709 patients were entered for

age-matched analysis (Figure 1). Among them,

patients with ESRD were identified and classified as

ESRD group (n = 90). The remaining 239 CKD

patients and 380 normal renal function patients were

randomly age-matched to ESRD patients and subse-

quently sorted to CKD group (n = 90) and control

group (n = 360).

Patient’s baseline characteristics, concomitant co-

morbid diseases (including cardiovascular diseases,

stroke, liver cirrhosis, chronic obstructive pulmonary

disease, diabetes mellitus, and hypertension), present-

ing haemoglobin levels, platelet counts, haemody-

namic status, use of aspirin, non-steroidal anti-

inflammatory drugs (NSAIDs), warfarin ⁄ heparin and

proton-pump inhibitor (PPI) prior to endoscopic

therapy, were recorded using a predetermined

spreadsheet. PU bleeding was defined by endoscop-

ist’s diagnosis combined with no other identifiable

bleeding cause. Endoscopic findings such as ulcer

locations, sizes, difficult treatment sites (lesser curva-

ture of high body; posterior wall of bulb and supe-

rior duodenal angle), Forrest grade, Rockall scores

and treatment methods were also recorded. Patients

who were followed for 30 days after initial endo-

scopic haemostasis were enrolled and analysed. The

end-points were rebleeding within 30 days after ini-

tial endoscopic haemostasis, requirement for surgical

intervention, length of hospital stay and total

amount of blood transfusion required, bleeding–

related mortality and all-cause mortality. This study

was approved in accordance with the principles of

Helsinki, by both the Institutional Review Board and

the Ethics Committee of Chang Gung Memorial

Hospital, Taiwan (IRB 100-2140B).

DefinitionsCKD group referred to non-dialysis dependent

patients with an estimated glomerular filtration rate

< 60 ml ⁄ min for ‡ 3 months calculated using the 4-

variable Modification of Diet in Renal Disease Study

equation (13). ESRD group referred to patients who

were on maintenance haemodialysis or peritoneal

dialysis for more than 6 months (12). Patients on

maintenance haemodialysis received three sessions

per week, and 4 hours for each session. All haemodi-

alyzers contained semisynthetic materials, and hae-

modialysis therapy was performed with a

bicarbonate-based dialysate. It is the policy of our

hospital to use non-heparin haemodialysis protocol

in patients suffering from active gastrointestinal

bleeding (including those who have received endo-

scopic haemostasis). Subjects with normal baseline

kidney function (estimated GFR > 60 ml ⁄ min) were

considered as the control group. The non-high-dose

PPI treatment referred to those patients who received

80 mg PPI bolus and followed by intravenous 80 mg

per day, until alimentation was possible, then 40 mg

per day orally. High-dose PPI treatment patients

received 80 mg PPI intravenous bolus injection, then

8 mg per hour continuous infusion for 3 days, fol-

lowed by intravenous 80 mg PPI per day (11). High-

risk ulcers are defined as Forrest grade higher or

equal to 2b (12).

Rebleeding was defined as new onset of haemate-

mesis, coffee-ground vomitus, or haematochezia,

with an increasing pulse rate more than 110 beats ⁄ -min and decreasing blood pressure below 90 mmHg

Figure 1 Schematic flowchart of the study design and the patient numbers during

follow up

2 Peptic ulcer bleeding in end-stage renal disease

ª 2012 Blackwell Publishing LtdInt J Clin Pract

after a 24 h period of stable vital signs and haemato-

crit following endoscopic treatment (14,15). Delay

rebleeding referred to those patients who rebled only

after 7 days of enrollment. Total amount of blood

transfusion required was defined as units given to

the patients between the time PU bleeding occurred

and the day of discharge. Bleeding-related mortality

was defined as in-hospital death resulted solely from

peptic ulcer bleeding.

Statistical analysisComparisons of continuous variables were conducted

by using one-way analysis of variance (ANOVA) with

multiple comparisons being corrected by using Bon-

ferroni’s method. Categorical variables were com-

pared using the Pearson’s v2 test. A two-tailed

significance value of .05 was used. Logistic regression

analysis was used for analysis of rebleeding and mor-

tality rates including the following covariates: group,

age, shock, use of aspirin, NSAIDs, clopidogrel, war-

farin ⁄ heparin, co-morbidity, multiple ulcers, difficult

site, combination therapy modality vs. monotherapy,

high risk ulcer stigmata (>Forrest 2b), time to endo-

scopic treatment, Rockall score, high-dose and non-

high dose PPI users. The cumulative probability of

no rebleeding was calculated with the Kaplan–Meier

method, and probabilities were compared using the

log-rank test. All statistical analyses were performed

using PASW statistics software, version 18 (IBM Co.,

Somers, NY).

Results

The clinical characteristics of these 540 age-matched

patients are summarised in Table 1. Almost all of the

ESRD patients received regular haemodialysis (97%).

There were more females in the ESRD group when

compared with CKD and control group (46% vs.

28% and 29%, respectively, p = 0.009). The ESRD

group were more likely to be taking oral PPI prior

to the bleeding episode than the control group (24%

vs. 14%, p = .018). The mean haemoglobin level in

both ESRD and CKD groups were lower than control

group (7.8 ± 2.1 g ⁄ dl and 8.0 ± 2.3 g ⁄ dl, respec-

tively, vs. 10.4 ± 2.7 g ⁄ dl, p = < 0.001). The mean

platelet counts were lower in the ESRD group than

the control group (158 ± 84 vs. 205 ± 103 · 109 ⁄ l,p = < 0.001), but were not significantly lower com-

pared with CKD group (158 ± 84 vs.

181 ± 82 · 109 ⁄ l, p = 0.303). Approximately 2 ⁄ 3 of

patients in the ESRD group suffered from PU bleed-

ing during hospitalisation, which was more frequent

compared with CKD (32%) and control group

(32%). Patients in ESRD group and CKD groups

had higher mean Rockall scores than subjects in the

control group (7.6 ± 1.3 vs. 6.2 ± 1.5, vs. 5.5 ± 1.6,

p = < 0.001).

Treatment of peptic ulcer bleedingAll patients received successful initial endoscopic

haemostasis and were prescribed with intravenous

PPI therapy for PU bleeding. The percentage of

patients receiving high-dose PPI among the 3 groups

was similar (ESRD 33%, n = 30; CKD 28%, n = 25;

control 27%, n = 98, p = .512). However, use of

high-dose PPI is associated with significantly lower

rebleeding rates (38.6% vs. 61.4% respectively,

p = .011) but not with bleeding-related mortality

(p = .652) and all-cause mortality (p = .155).

Table 1 Clinical characteristics of the patients

Characteristics ESRD

(n = 90)

CKD

(n = 90)

Control

(n = 360)

p value

Age (years) 63 ± 14 64 ± 12 62 ± 13 .729

Male (%) 49 (54) 65 (72) 254 (71) .009

Smoke (%) 21 (23) 28 (31) 114 (32) .299

Haemoglobin (g ⁄ dl) 7.8 ± 2.1 8.0 ± 2.3 10.4 ± 2.7 < 0.001

Platelets (x 109 ⁄ l) 158 ± 84 181 ± 82 205 ± 103 < 0.001

INR 1.22 ± 0.63 1.33 ± 0.74 1.20 ± 0.51 .240

Creatinine (mg ⁄ dl) 8.11 ± 2.96 2.93 ± 1.99 0.94 ± 0.51 < 0.001

Aspirin (%) 15 (17) 15 (17) 42 (12) .273

NSAID (%) 10 (11 ) 5 (6) 39 (9) .394

Warfarin ⁄ Heparin (%) 5 (6) 2 (2) 18 (5) .480

PPI (%) 22 (24) 18 (20) 51 (14) .045

Haemodialysis (%) 87 (97) n ⁄ a n ⁄ aShock (%)* 45 (50) 45 (50) 181 (50) .998

Co-morbidity� 1.9 ± 1.5 1.9 ± 1.4 1.4 ± 1.2 .135

DM (%) 43 (48) 44 (49) 83 (23) < 0.001

Hypertension (%) 60 (67) 52 (58) 155 (43) < 0.001

Cardiovascular (%) 22 (24) 17 (19) 45 (13) .013

COPD (%) 4 (4) 5 (6) 26 (7) .586

Cirrhosis (%) 16 (18) 20 (22) 69 (19) .733

CVA (%) 14 (16) 14 (16) 56 (16) 1.000

Malignancy (%) 16 (18) 23 (26) 71 (20) .376

Inpatient bleed 57 (63) 29 (32) 116 (32) < 0.001

Rockall score 7.6 ± 1.3 6.2 ± 1.5 5.5 ± 1.6 < 0.001

Time to scope (hour) 17.5 ± 19.5 19.1 ± 20.5 14.2 ± 18.5 .055

Size of ulcer (cm) 1.0 ± 0.7 1.1 ± 0.6 1.1 ± 0.8 .460

Difficult site (%) 13 (14) 14 (16) 50 (14) .920

Low-risk stigmata (%) 2 (2) 6 (7) 12 (3) .234

High-risk stigmata (%)� 88 (98) 84 (93) 348 (97) .234

*Shock = systolic blood pressure < 90 mmHg or heart rate > 100 beats per minute. �Co-

morbidity = mean of the sum of co-mordities. �High-risk ulcer stigmata = Forrest grade

higher or equal to 2b (i.e. active bleeding, visible vessel, or adherent clot). CKD, chronic kid-

ney disease; COPD, chronic obstructive pulmonary disease; CVA, cerebrovascular accident;

DM, diabetes mellitus type 2; ESRD, end-stage renal disease; INR, international normalised

ratio; n ⁄ a, not available; NSAID, nonsteriodal anti-inflammatory drug; PPI, proton-pump

inhibitor.

Peptic ulcer bleeding in end-stage renal disease 3


Outcomes

RebleedingAfter initial successful endoscopic treatment, a total

of 101 patients (19%) suffered from recurrent bleed-

ing in the current study. The overall rebleeding rates

were 43% (n = 39) for the ESRD group, 21%

(n = 19), for the CKD group, and 12% (n = 43) for

the control group (overall p = < 0.001). Further-

more, more dialysis-dependent ESRD patients rebled

than CKD group (p = .001). Likewise, more patients

in the CKD group encountered recurrent bleeding

compared with the control group (p = .024). Ninety-

seven percent (n = 98) of the rebleeding ulcers

belonged to high-risk ulcers and only 3% were low-

risk ulcers. Among patients with high-risk ulcer stig-

mata, the rebleeding rates were 44% (n = 39) for

ESRD, 21% (n = 18) for CKD and 12% (n = 41) for

control group respectively (overall p < 0.001). Three

of the twenty patients with low risk ulcers rebled.

One was from the CKD group and two were from

the control group. Overall, the cumulative probabil-

ity of rebleeding was significantly greater in the

ESRD group than the CKD group (p = .001) and

control group (p < .001). In addition, the cumulative

probability for rebleeding was also significantly

greater in the CKD group when compared with con-

trol group (p = .028) (Figure 2).

The average time interval from initial haemostasis

to rebleeding was significantly different among the

ESRD, CKD and control groups (5.4 ± 5.6 days vs.

6.0 ± 6.7 days vs.2.9 ± 2.3 days, p = .048). In the

ESRD group, 43.6% (n = 17) of the rebleeding

occurred within 3 days, 35.9% (n = 14) between 4

and 7 days later, and 20.5% (n = 8) between 8 and

30 days. In the CKD group, 42.1% (n = 8) of the

rebleeding occurred within 3 days, 31.6% (n = 6)

between 4 and 7 days later, and 26.3% (n = 5)

between 8 and 30 days. In the control group, 69.8%

(n = 30) of the rebleeding occurred within 3 days of

the first bleed, 27.9% (n = 12) between 4 and 7 days,

and 2.3% (n = 1) between 8 and 30 days. The

delayed rebleeding rates were higher in ESRD and

CKD group compared with the control group (20.5

vs. 2.3%, p = .009 and 26.3 vs. 2.3%, p = .003,

respectively). No difference was observed between

the ESRD and CKD groups in terms of delayed reb-

leeding (p = .619).

On multivariate regression analysis, significant pre-

dictors for rebleeding were ESRD, time to endo-

scopic treatment and non-high-dose PPI users

(Table 2). Patients with ESRD had a higher reblee-

ding rates than CKD group (OR: 2.9, 95% CI, 1.5–

5.5, p = .002) and control group (OR: 5.6, 95% CI,

3.3–9.5, p < 0.001) (Table 3). CKD group rebled

more frequently than control group on univariate

analysis (OR 2.0; 95% CI, 1.1–3.6; p = .026), but it

was not a significant predictor on multivariate

regression analysis (p = .303).

Need for blood transfusions.The total blood transfusion (units of packed RBCs)

requirements were significantly greater in the ESRD

group (9.3 ± 14.7 units) than the control group

(4.8 ± 7.2 units; p < .001) but no difference was

observed between the CKD group and ESRD group

(p = .438) (Figure 3).

Length of hospital stayThe length of hospital stay was significantly longer for

the ESRD group when compared with the CKD group

and with the control group (33.3 ± 56.5 days vs.16.6 ±

21.1 days vs.12.5 ± 15.7 days, p < 0.001) (Figure 3).

Figure 2 Kaplan–Meier estimate of cumulative probability of no rebleeding among

the three groups. The cumulative probability of rebleeding was significantly greater in

the ESRD group when compared with the CKD group (p = .001) and control group

(p < .001). Furthermore, cumulative probability for rebleeding is also significantly

greater in the CKD group compared with control group (p = .028)

Table 2 Predictors of peptic ulcer rebleeding on

multivariate analysis

Predictors Comparison OR 95% CI p value

ESRD Control 5.6 3.3–9.5 < .001

ESRD CKD 2.9 1.5–5.5 .001

Time to scope per 1 hour

increase

1.02 1.002–1.032 .028

Non-high-dose

PPI

High-dose PPI 2.25 1.054–4.797 .036

CI, confidence interval; CKD, chronic kidney disease; ESRD,

end-stage renal disease; OR, odds ratio; PPI, proton pump

inhibitor. Time to scope = time taken to initiate endoscopic

therapy in hours.



Surgical interventionThe requirement for surgical intervention in the

ESRD group was slightly higher (4.4%, n = 4) than

the CKD group (2.2%, n = 2) and the control group

(2.5%, n = 9) but was not statistically different when

compared with each other (Figure 3).

Bleeding-related mortalityThe mortality rates related to PU bleeding for the

ESRD and CKD group were both higher than the

control group (6.8% vs. 0.9%, p = .001 and 5.1% vs.

0.9%, p = .009). The cumulative probability of

bleeding related mortality was also significantly

greater in the ESRD and CKD group than control

group (p = .028 and p = .024, respectively) (Fig-

ure 4). On multivariate regression analysis, predictors

for bleeding-related mortality were presence of CKD,

including patients from both CKD and ESRD

groups, as defined in current study (OR, 12.63, 95%

CI, 1.080–147.693), Rockall scores (OR, 2.42, 95%

CI, 1.206–4.868), and time to endoscopic treatment

(OR, 1.04, 95% CI, 1.012–1.073) (Table 3).

All-cause mortalityThe all-cause mortality rates for the ESRD and CKD

group were both higher than the control group

(23.3% vs. 6.9%, p < .001 and 16.7% vs. 6.9%,

p = .004). A trend of significant difference was

observed from the cumulative probability of all-cause

mortality in the ESRD and CKD group when com-

pared with control group (p = .071 and p = .080,

respectively) (Figure 5). Multivariate analysis showed

that all-cause mortality was related to presence of

CKD, including both CKD and ESRD groups (OR,

1.99, 95% CI,1.006–3.945), platelet count (OR, 1.01,

Table 3 Predictors of bleeding related mortality and all-cause mortality on multivariate analysis

Predictors Comparison OR 95% CI p value

Bleeding relate mortality

Chronic kidney disease (ESRD + CKD) Normal 12.63 1.080–147.693 .043

Time to scope Per 1 h increase 1.04 1.012–1.073 .006

Rockall score Per score increase 2.42 1.206–4.868 .013

All-cause mortality

Chronic kidney disease (ESRD + CKD) Normal 1.99 1.006–3.945 .048

Platelet Per 1 · 109 ⁄ l decrease 1.01 1.003–1.012 .001

Time to scope Per 1 h increase 1.02 1.006–1.034 .005

Rockall score Per score increase 1.44 1.132–1.834 .003

Length of hospital stay Per 1 day increase 1.04 1.004–1.070 .026

CI, confidence interval; CKD, chronic kidney disease; ESRD, end-stage renal disease; OR, odds ratio. Time to scope = time taken to initiate endoscopic therapy in

hours.

Figure 3 Differences in requirements for surgery

(p = .568), blood transfusion (p < .001 between ESRD and

normal) and lengths of stay (p < .001 between ESRD and

normal) among the three groups

Figure 4 Kaplan–Meier estimate of cumulative probability of no bleeding-related

mortality among the 3 groups. The cumulative probability of bleeding-related

mortality was significantly greater in the ESRD and CKD group when compared with

the control group (p = .028 and p = .024, respectively)



95% CI, 1.003–1.012), time to endoscope (OR, 1.02,

95% CI, 1.006–1.034), Rockall score (OR, 1.44, 95%

CI, 1.132–1.834) and length of hospital stay (OR,

1.04, 95% CI, 1.004–1.070) (Table 3).

Discussion

After randomised age-matched adjustment, current

study observed that more patients from the ESRD

and CKD group rebled than the control group after

initial endoscopic haemostasis as expected. However,

more delayed rebleeding was also observed in both

of the diseased groups. The predictors of rebleeding

were ESRD, time to endoscope, and non-high-dose

PPI users. The risk factors for bleeding related mor-

tality were presence of CKD, time to endoscope, and

higher Rockall scores. All-cause mortality was related

to presence of CKD, platelet count, time to endo-

scope, Rockall score and length of hospital stay.

In general, the risk of PU bleeding in dialysis

dependent patients is higher than those in the gen-

eral population (6). The mechanism for the excessive

bleeding in patients with ESRD is still unclear but

may be multifactorial (16). Platelet dysfunction in

the form of impaired platelet adhesiveness and

altered platelet-vessel-wall interaction is believed to

have played an important role (17–22). Cheung et al.

found that rebleeding rates were significantly higher

in the ESRD group for patients with both high and

low-risk ulcer stigmata on endoscopy implying that

all dialysis-dependent patients with PU bleeding need

to be managed as high-risk patients. However, exclu-

sion of patients with acute kidney injury (AKI)

requiring dialysis from the control group might arti-

ficially eliminate severe bleeders. Similarly, inclusion

of patients with significantly more existing co-mor-

bidities in the ESRD group than patients in the con-

trol group might contribute to the high rebleeding

rate in the ESRD group. Therefore, current study

randomly aged-matched patients with moderate

CKD and normal kidney function to ESRD patients

as defined earlier, so that patients with AKI were not

excluded from the normal group (n = 16, according

to the AKIN criteria), consequently making the dif-

ference in co-morbidities statistically insignificant

among the groups (p = .135) after the adjustment

process. All of our enrolled patients suffering from

PU bleeding attained initial successful endoscopic

therapy. It is rational that ESRD patients had a sig-

nificantly high rebleeding rate after initial endoscopic

haemostasis for ulcers with high-risk stigmata (44%)

but the difference was not significant with low-risk

ulcers among the three groups in current study

(p = .822). A trend of increase in rebleeding rate was

observed as the renal function deteriorated in current

study which was not observed in Cheung’s study.

(ESRD vs. CKD, p = .001; CKD vs. control,

p = .024).

Frequent occurrence of the delayed rebleeding in

ESRD and CKD patients was observed. Usually, the

fading time of non-bleeding visible vessel is

approximately 3–6 days and it is rational that recur-

rent bleeding occurs within 3 days (23,24). Cheng

and colleagues reported that co-morbidities influence

the rates of recurrent bleeding (25). Recurrent bleed-

ing may be prolonged in those with co-morbidities

(26). The pathogenic cause remains unclear for this

delay in PU bleeding. Some investigators speculate

that it may be a result of poor nutritional status,

ischaemic change of the GI tract and platelet

dysfunction (17,18,27). Therefore, more careful and

prolonged monitoring for patients in this diseased

entity is important in clinical practice. In addition,

the presence of CKD, regardless of dialysis

requirement, as an independent predictor of both

bleeding-related mortality and all-cause mortality in

current study may imply renal function impairment

could be associated with the risk of mortality in

bleeding PU patients even at the earlier stage of the

renal disease.

Delay in time to endoscope was also an important

risk factor of rebleeding, bleeding-related mortality

and all-cause mortality. This is consistent with the

current updated consensus suggesting for early endo-

scopic management of PU bleeding within 24 h of

presentation (11). Rockall scores were higher for the

groups with renal impairment and was a significant

predictor of mortality. The bottom line is that

patients with higher scores should always be treated

more intensively not to mention those with concom-

itant co-morbidities like CKD and ESRD.

Figure 5 Kaplan–Meier estimate of cumulative probability of no all-cause mortality

among the three groups. A trend of significant difference was observed from the

cumulative probability of all-cause mortality in the ESRD and CKD group when

compared with control group (p = .071 and p = .080, respectively)



Current study also observed that non-high-dose

PPI user was one of the predictors for PU rebleeding

in ESRD. PPIs are mainly metabolised by the path-

way of cytochrome P450 system (CYP) (28). There

are more Caucasians than Asians who belong to

homozygous extensive metabolizer (EM) in the dis-

tribution of genetic polymorphisms of CYP which

may influence the outcome of the effect of PPI

(29,30). Therefore, the effect to maintain intragastric

pH > 6.0 in the EM patients with intravenous pan-

toprazole is inferior to the non-EM patients owing

to the lower plasma concentration (31). Despite con-

troversies on the optimal dosing of PPI in preventing

PU rebleeding, high dose intravenous PPI should be

prescribed for PU bleeding in ESRD (32–34).

This study encounters several limitations. First,

this is a retrospective chart review study. Second, a

significantly higher proportion of ESRD patients

were hospitalised before PU bleeding as compared

with the CKD and control group. We performed

multivariate regression analysis to determine whether

inpatient bleeding was an independent predictor of

adverse outcomes as opposed to severity of the kid-

ney disease but failed to detect any effect. Third,

longer hospital stay in the ESRD group (33 days) as

compared with CKD group (17 days) and control

group (13 days) were probably relevant to the higher

proportion of inpatient bleeding in the ESRD group

enrolled in current study. Fourth, the requirements

for blood transfusion were initially higher for the

patients in the ESRD and CKD groups may be due

partly to the chronic anaemia caused by the kidney

disease itself. Finally, whilst the overall levels of com-

orbidity are apparently the same for the groups in

comparison, diabetes, hypertension and cardiovascu-

lar disease are more common in the renal failure

groups and the presence of these diseases might

adversely affected the outcomes of peptic ulcer bleed-

ing. Given that diabetes and hypertension are the

two most common causes of chronic kidney disease

(making up 33% and 21% of adult CKD, respec-

tively) (13), it could be expected that these diseases

were more common in renal failure groups owing to

disease entity. From the multivariate regression anal-

yses performed, we were unable to demonstrate that

the presence of diabetes, hypertension and cardiovas-

cular diseases were independent predictors of reblee-

ding, bleeding-related mortality and all-cause

mortality.

In conclusion, ESRD patients who suffered from

PUD bleeding were at risk of excessive rebleeding

and mortality with frequent occurrence of delayed

rebleeding. Renal function impairment could be

associated with the risk of rebleeding and mortality

in bleeding PU patients even at the earlier stage of

the renal disease. Despite the debates on the issue of

optimal PPI dosing for patients with bleeding ulcers

among general population, current study suggests

that an early endoscopy for initial haemostasis and

high-dose intravenous PPI are associated with the

reduction of rebleeding risk among ESRD patients

who suffered from PU bleeding especially those with

high Rockall scores.

Acknowledgements

None

Authors’ contributions

S-CL wrote and drafted the article. S-KC is responsible

for the conception and design of the study, critical

revision of the article for important intellectual con-

tent and final approval of the article. K-LW, K-WC,

Y-CC, C-TL, DM-LH, W-CT and T-HH are involved

in the analysis and interpretation of the data.

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Paper received November 2011, accepted May 2012



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Risk factors influencing the outcome of peptic ulcer bleeding in end stage renal diseases after initial endoscopic haemostasis