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CREATININE CLEARANCE AS EFFECTIVE NON-INVASIVE MARKER IN DETERMINING GASTROINTESTINAL LESIONS AND HELICOBACTER PYLORI INFECTION.

Byline: Zubia Jamil, Saima Ambreen and Omar Ahsan

Abstract

Objective: The objective of this study focuses to unfold the importance of creatinine clearance in determining the gastrointestinal mani-festations and Helicobacter Pylori infection.

Study Design: Cross-sectional comparative study.

Place and Duration of Study: Medicine department of Fauji Foundation Hospital Rawalpindi, from Jun 2015 to Dec 2016.

Material and Methods: Creatinine clearance of 73 CKD patients was calculated. UGI endoscopy was performed to detect gastro-intestinal lesions. H.pylori was detected by histopathology of gastric mucosal biopsy. The diagnostic accuracy of CCl in determining the presence of gastrointestinal (GI) lesions was determined by receiver operating characteristic (ROC) curve (AUC). Cut-off value, sensitivity, specificity, positive and negative predictive values, positive and negative likelihood ratios were obtained by Youden index.

Results: Mean CCl was 27.09 +- 12.16 ml/min. Diabetes mellitus was the top most cause of CKD (45.2%). Upper GI endoscopic lesions were present in 68.5% patients (p-value0.05). The AUC for CCl in determining the gastrointestinal lesions was 0.8 (p-valuea$?0.0001), cutoff value was <35ml/min (Sensitivity 81.82%, Specificity 72.4%). The AUC for CCl in determining the presence of H. Pylori infection was 0.7 (p-value=0.0004), cutoff value was 90ml/min; Stage 2: CCl 60-90ml/min; Stage 3: CCl 30-60ml/min; Stage 4: CCl 15-30ml/min; Stage 5: CCl<15ml/min or on hemodialysis).

The upper GI endoscopy was considered as a standard modality for detecting upper GI lesions. All the patients underwent upper GI endoscopy by using Video scope. (Exera 160 series; olympus endoscopy system, Japan) All endoscopies were performed by single trained physician. Multiple biopsies were taken from the antrum of stomach of all patients and sent for histopathological evidence of presence of H.pylori infection.

Table-I: Baseline characteristics of the study group in terms of number of patient and percentage.

Eitiology of CKD###N=Number of patients###Percentage (%)

Diabetes mellitus###33###45.2

Hypertension###10###13.6

Diabetes mellitus and hypertension###23###31.5

Glomerulonephritis###5###6.8

Renal stones###2###2.7

KDOQI Stages of CKD

Stage 3###32###43.8

Stage 4###24###32.9

Stage 5###17###23.3

Clinical Features

Asymptomatic###6###8.2

Heartburn###48###65

Nausea###44###60.3

Vomiting###20###27.4

Anorexia###19###26

Constipation###13###17.8

Diarrhea###6###8.2

Borbrygmi###8###11

Upper GI bleed###4###5.5

Table-II: Comparison of variables between patients with chronic kidney disease and control group.

###CKD patients###Control group###Contingency

Variables###p-value

###Positive###Negative###Positive###Negative###Coefficient

Outcome of upper GI

###44 (60.3%)###29 (39.7%)###25 (34.2%)###48 (65.8%)###0.226###0.002

endoscopy

Presence of H. pylori

###18 (24.7%)###55 (75.3%)###43 (58.9%)###30 (41.1%)###0.103###<0.001

associated gastritis

Detection of H.pylori in biopsy specimen was done by two kinds of staining method. First hematoxylin and eosin staining was used and then giemsa staining was used Seventy three patients who were age and sex matched with study group were taken as control group. Control group was not having any renal disease and all individuals of control group underwent upper GI endoscopy for the presence of GI lesions and H. pylori infection after informed consent. Total sample size was 146.

Statistical Analysis

Quantitative data was statistically analyzed using the terms mean, standard deviation and ranges. Frequencies and percentages were used for qualitative data. A p-value was calculated by using contingency coefficient. The area under the receiver operating characteristic (ROC) curve was used to determine the accuracy of CCI in determining the upper GI lesions and H pylori infection. The cutoff value of CCl and sensitivity, specificity, positive, negative predictive values and positive, negative likelihood ratios of this cutoff value was calculated by Younden index.

SPSS-20 was used for analysis. A p-value less than or equal to 0.05 was considered as a significant value.

RESULTS

The average age of 73 patients was 48.84 +- 14.29 years (mean +- SD) ranging from 15-85 years. Among them, 49 (67.1%) were males and 24 (32.9%) were females. The main cause of CKD was diabetes mellitus. The CCl was 27.09 +- 12.16 ml/min (mean +- SD) ranging from 6.60-47.00 ml/min. Among 73 patients 91.8% patients were having GI symptoms. The baseline characteristics of the study group is shown in table-I.

In 73 patients, upper GI endoscopy was performed which showed normal study in 23 (31.5%) patients. The most common endoscopic finding was erythematous gastritis found in 19 (26%) patients. Other endoscopic abnormalities found were erythematous duodenitis 9 (12.3%), pangastritis 7 (9.6%), erosive gastritis 6 (8.2%), erythematous esophagitis 4 (5.5%), hiatal hernia 2 (2.7%), peptic ulcers 1 (1.4%), GAVE disease 1 (1.4%) and gastric polyp in 1(1.4%) patients. Among the causes of bleeding, 3 patients were bleeding from erosions and one was found to have watermelon stomach (GAVE disease). Three patients out of 6 asymptomatic patients were having gastrointestinal lesions on endoscopy. Two patients were having erythematous gastritis and one was having hiatal hernia.

Age and sex matched control group also underwent upper GI endoscopy and it was found that GI lesions were found in only 34.2% patients (p=0.002). Histopathology of gastric specimens of 73 patients with CKD showed H pylori was present in 18 (24.7%) patients. Nonspecific antral gastritis was found in 44 (60%) patients and 11 (15.1%) were having normal gastric mucosa. In the control group, H pylori associated antral gastritis was present in 58.9% patients. Although the higher frequency of individuals were infected with H. Pylori infection in the control group than the disease group, but statistically this difference was significant (p<0.001). Comparison between patients with CKD and control group in terms of contingency coefficient and p-value is shown in table-II.

The area under the ROC curve for CCl in determining the presence of GI lesion was 0.8 (AUC=0.78, 95% Confidence interval=0.67 to 0.87, Standard Error=0.05, p-valuea$?0.0001). The cutoff value calculated by Younden Index was found <35 ml/min (fig-1). The area under the ROC curve for CCl in determining the presence of H. Pylori infection in patients with CKD was 0.7 (AUC=0.71, 95% Confidence interval=0.59 to 0.81, Standard Error=0.06, p-value <0.001). The cutoff value of creatinine clearance calculated by Younden Index was found <27 ml/min (fig-2).

The cutoff value of CCl with its sensitivity, specificity, positive and negative likelihood ratios, positive and negative predictive values in determining the presence of upper GI lesions and H. pylori infection in patients with CKD is shown in table-III.

Table-III: The accuracy of creatinine clearance in determining the presence of upper gastrointestinal lesions and H-pylori infection in patients with CKD. Its cutoff value, sensitivity, specificity, positive and negative likelihood ratios, positive and negative predictive values.

###Cutoff###95%###95%###95%###95%

Parameter###AUC###Sensitivity###Specificity###+LR###-LR###+PV###-PV

###point###CI###CI###CI###CI

CCl for

###67.3-###52.8-###1.6-###0.1-

upper GI###0.78###35###81.82%###72.4%###2.97###0.25###24.8###97.3

###91.8###87.3###5.4###0.5

lesions

CCl for H

###58.6-###44.1-###1.4-###0.1-

pylori###0.71###27###83.33%###58.18%###1.99###0.29###18.1###96.9

###96.4###71.3###2.9###0.8

infection

DISCUSSION

Patients with CKD suffer from many GI diseases which complicate the natural course of disease1. We primarily focused on the importance of CCl in determining the GI lesions and H.pylori infection in CKD patients in this study. We found diabetes mellitus as the foremost cause of CKD. Many meta-analyses have favored the similar results showing diabetes mellitus is the chief cause of CKD21-23. We found that GI symptoms are common among these patients. GI symptoms were present in 92% (67) of our study group. This shows a majority of uremic patients are symptomatic. Many studies have also shown that GI symptoms are common in uremic patients. Sales Junior et al6 showed that about 70% of patients present with GI symptoms. The upper GI symptoms which we found in our study are similar to those found in other studies13,16. The upper GI endoscopy was carried out in all patients with chronic kidney disease in our study.

It was found that 68% of patients were having endoscopic abnormalities (p=0.002). Tamadon et al24 also showed that 72% of patients were having abnormal gastric mucosa during endoscopic examination. Among endoscopic abnormalities the most common abnormality was erythematous gastritis. Gastric erosions and inflammation affecting esophagus, gastric and duodenal mucosa are common, as found in our study and studies conducted by Ala-Kaila et al17 and Ahmed et al18. Four patients in our study presented with GI bleeding. But none of them was suffering from massive GI bleeding, which can lead to shock or death. Three out of four patients had gastric erosions as cause of GI bleeding. Many studies have shown that gastric erosions are the common cause of GI bleeding in these patients16. Peptic ulcers, angiodysplasias and Dieulafoy's lesions also result in gastrointestinal bleeding4,25.

Endoscopic lesions were present in 50% asymptomatic patients. Bunchorntavakul et al26 conducted their study on asymptomatic patients with CKD and found that nearly 45% asymptomatic patients were having GI lesions. It shows that GI lesions are common in these patients regardless of the presence or absence of GI symptoms. H.pylori infection was found in 24.7% patients (p<0.05). Our study showed that CKD patients have lower frequency of H. pylori infection as compared to the control group (24.7% vs 58.9%). Many studies have also suggested the low prevalence of H. pylori infection in these patients12. Bunchorntavakul et al26 found that H. pylori infection was found in 27.1% of uremic patients.

Alterations in gastric pH due to hyper-gastrenemia, achlorhydria, inflammatory cyto-kines, inhibition of H. pylori growth due to high urea and nitrogen levels, repeated use of anti-biotics in these patients are all known to be causing low prevalence of H. pylori in CKD patients12,27. H. pylori infection was determined by histopathological examination of gastric mucosa and double staining method. The other methods like H pylori antigens from patient's stools, anti H pylori antibodies and urea breath tests are also available for detection of H.pylori infection. These tests have debatable sensitivity and specificity24,28,29. Therefore, Calvet et al and Lopez et al28,29 carried out multiple tests for detection of H.pylori infection in their study group. The results suggestive of low prevalence of H.pylori infection should be further elaborated by using different diagnostic tests on this disease group.

The relationship between rising urea levels in the body and gastrointestinal manifestations are well established and well understood. Limiting studies are available showing any association of creatinine clearance to presence of GI diseases. Seyyedmajidi et al30 showed the effect of CCl on eradication of H. pylori infection. But still, this study does not show any direct relationship between GI lesions and CCl. In our study, we proposed that CCl calculated at the bedside of patients by Cockcroft-Gault GFR formula, is a useful non-invasive marker in patients with CKD in determining the presence of GI lesions (AUC=0.8, p-value a$?0.001) and the presence of H pylori infection in these patients. (AUC=0.71, p-value<0.001).

The cutoff value of <35 ml/min showed sensitivity of 81.82% and specificity 72.4% in determining GI lesions and the cutoff value of 1 and negative likelihood ratios are <1 indicating that CCl at these cutoff value can be used as a predictive marker.

CONCLUSION

CCl was identified as bedside and a useful noninvasive marker in patients with chronic kidney disease for determining the presence of GI lesions. (AUC=0.8, p-value<0.001). CCl can be used to identify the high risk patients who are more likely to develop GI lesions and subsequent complications. Patients with complications can undergo upper GI endoscopy for further advanced management. H pylori eradication therapy should be offered to those patients in whom tests with better sensitivity and specificity have proven its presence.

CONFLICT OF INTEREST

This study has no conflict of interest to declare by any author.

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Publication:Pakistan Armed Forces Medical Journal
Date:Oct 31, 2018
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