As far as we know, this is by far the first article concerning the detection rate and risk factors of EC in ESRD patients. Our patients came from different places of China, which means that they have good representativeness. The major finding of our study is that the detection rate of EC in those ESRD patients reached as high as 19.2%, as compared to 0.5% in the control subjects with normal renal function. After adjusting confounding factors, the detection rate of EC in ESRD group was still higher than that in control. Furthermore, both univariate and multivariate analysis showed that past use of rhubarb-containing TCM medicine was the only risk factor for detection of EC in ESRD patients. AlAmeel T et al  published their screening colonoscopic results in 169 renal transplant candidates, but no MC was reported. Zheng Y et al  also reported no MC in 469 screening colonoscopies during kidney transplant evaluation. The difference between their results and ours maybe come from the different population, different treatment background and different focus of attention.
Different detection rates of EC in general population have been reported by different studies in the literature. In autopsy studies, the prevalence of EC is relatively high. In one study, MC was found in 119 of 200 consecutive autopsies, with a prevalence of 59.5% . In another international multicentre study , MC was found in 34% of all autopsies. However, in endoscopic studies, the figure was much lower. Wittoesch JH et al  reported that 750 cases of MC was found in 91,472 colonoscopies from 1950 to 1954 at the Mayo Clinic, with a prevalence of 0.82%. In another series of patients, he found 137 cases of MC in 12,131 routine proctoscopic examinations from March 1 to September 30, 1955, giving a prevalence of 1.13% . Wang S et al  conducted a multicenter study in China, and detected 6,090 cases of MC in 342,922 colonoscopies between January 2006 and October 2016, obtaining a detection rate of 1.78%. Our study is an endoscopic study, so in control subjects with kidney function normal, we observed a detection rate in a similar level, which was 0.5%. Our detection rate is lower than that reported by Wang S et al , possibly because our patients are much younger (mean 44.6 vs. 60 years old). Data showed that elder age was related to higher detection rate of EC. In age ≤44 years group of Wang S et al study , the detection rate of MC was 0.85, which was much similar to our results.
On the other hand, in ESRD group, we found 19 cases of MC in 99 ESRD patients, with a detection rate of 19.2%, which was astonishingly higher than that of control group. After adjusting age, BMI, serum albumin, hemoglobin, charlson comorbidity index, the detection rate in ESRD group was still higher than control, which means that other factors related to ESRD were the cause. In the second part of the study, we examined the risk factors of MC in ESRD patients using univariate and multivariate analyses, and found that only past use of rhubarb-containing TCM medicine was associated with the detection of MC. Rhubarb has long been found as a risk factor of MC. The study results of Badiali D et al  showed that MC was significantly associated with consumption of anthracene drugs. They found that the prevalence of MC in patients taking anthracene drugs was significantly higher (52.0%) than that without taking anthracene drugs (8.0%) . Wittoesch JH et al  reported that in 750 MC patients, 718 were habitual users of laxatives, while in another series of 137 MC patients, laxatives were used regularly by 132 patients, in which 113 patients used cathartics containing emodin. In an animal study, Chen JY et al  fed extract of crude rhubarb to guinea pigs for 60 days, and found that rhubarb successfully induced MC with a dosage dependent manner. In another animal study, Cheng Y et al  fed rhubarb extract to Sprague-Dawley rats for 90 days, and saw MC formation in the rats' colon. They also found that rhein was the metabolite of rhubarb responsible for its toxicity . Our study showed that in 19 ESRD and with MC patients, 15 (78.9%) used rhubarb-containing TCM herbs in the past, while in 80 ESRD and without MC patients, 37 (46.3%) used such herbs, which means a significant difference. Our results indicate that in ESRD patients, consumption of rhubarb-containing TCM medicine carries the risk of MC development, just as in general population with normal renal function.
The relationship between EC and colorectal neoplasm has long been a concern. Liu ZH et al  reported that MC is associated with a higher incidence of colonic non-adenoma polyps, low-grade adenomas, and distal ileal ulcers, which means that MC may not be a harmless pigmentation, but an indication of chronic colonic and intestinal injury. Blackett JW et al  reported that the presence of MC was associated with increased adenoma detection. Siegers CP  found in a prospective study of 1095 patients that the incidence of EC was 6.9% for patients with normal endoscopy, 9.8% for patients with adenomas and 18.6% for patients with colorectal carcinomas. A relative risk of 3.04 (1.18, 4.90; 95% confidence interval) was calculated for colorectal cancer as a result of MC from these data . Morgenstern L et al  reported that 17% of MC was accompanied by invasive adenocarcinoma. The data of Biernacka-Wawrzonek D et al  showed that colon cancer was found in 11.9% of MC patients. Given that ESRD patients undergoing kidney transplantation already have a significantly higher risk of colorectal cancer , the high prevalence of EC in ESRD patients may further raise this risk.
There exist a number of limitations in this study. Firstly, this is a retrospective study, so selection bias can't be avoided. Secondly, this is a single center study, the sample size is relatively small, and only Chinese population is included. Thirdly, because the data is derived from medical record review, sometimes there is the problem of incoherence, inconsistent in the information provided. For example, bowel habit such as constipation or diarrhea was not described in detail but marked as normal in most of the patients, possibly because it's not directly related to the condition for hospitalization, thus can't be analyzed as an risk factor. Therefore, future prospective, multicenter, multi-national, well-designed studies with large sample size are warranted to assess the detection rate and risk factors of MC in ESRD patients.
In conclusion, there is a significantly higher detection rate of EC in this cohort of ESRD patients than control subjects without renal failure. The detection of EC in ESRD patients is independently related to the past use of rhubarb-containing TCM herbs. We feel that use rhubarb-containing TCM herbs to treat renal failure is the main reason for the occurrence of EC, and therefore recommend take cautions when prescribing those kind of therapies in renal failure patients. Caution of the development of EC should also be placed in the package inserts of rhubarb-containing TCM medicine. Considering that EC is a sign of colonic and intestinal mucosa injury, and the possible association of MC with development of colorectal cancer, the clinical significance of the high detection rate of EC in ESRD patients, and its influence on the long-term prognosis of kidney transplantation, demands further study in the future.