Objectives: Transplant centers often recommend, but not necessarily require, screening colonoscopies for people over 50 years of age in accordance with the US Preventative Services Task Force guidelines for the general population. We sought to identify risk factors affecting colonoscopy results in renal failure patients undergoing kidney transplant evaluation.

Materials and Methods: We retrospectively examined patients undergoing kidney transplant evaluation from 2009 to 2012 (n = 469 patients). Comparisons were made between colonoscopy reports categorized as normal (no finding or hyperplastic polyp) or abnormal (adenomatous polyp or carcinoma).

Results: Of 469 patients who met the study criteria, 303 (64.6%) had normal colonoscopies and 166 (35.4%) had abnormal colonoscopies. Logistic regression analysis showed that male sex (odds ratio = 2.09; 95% confidence interval, 1.37-3.20; P = .001) and increasing age (odds ratio = 1.04; 95% confidence interval, 1.01-1.08; P = .019) were more likely to correspond to abnormal findings. Those with dialysis vintage (length of time on dialysis) up to 3 years (odds ratio = 2.10; 95% confidence interval, 1.09-4.06; P = .027) and hypertension as the cause of renal failure (odds ratio = 1.79; 95% confidence interval, 1.05-2.87; P = .002) had more abnormal findings. No differences in length of evaluation, rate of being listed for transplant, and rate of transplant were shown.

Conclusions: The overall rate of adenomatous findings on colonoscopy was higher among patients with pretransplant end-stage renal disease than in the general population, as shown in other studies. Age, sex, dialysis vintage up to 3 years, and hypertensive renal failure were associated with adenomatous polyps of the colon in this study population. Because adenomatous polyp rates are high in patients with chronic kidney disease who are undergoing transplant evaluation and colonoscopic findings do not appear to delay transplant evaluations or listing rates, screening colonoscopies should be encouraged.

Key words : Cancer screening, Chronic kidney disease, Colon cancer, Colorectal cancer, End-stage renal disease, Renal transplant

Introduction

Transplant centers frequently recommend, but do not always require, patients to undergo extensive evaluations typically based on national health screening guidelines developed for the general population.¹ However, the utility of such screening programs is not well-defined in the pretransplant renal failure population. Part of the pretransplant evaluation often includes colorectal cancer (CRC) screening for patients who meet screening guidelines. Colorectal cancer is the third most common cancer in the United States and is the third leading cause of cancer deaths in both men and women.² Most CRCs arise from adenomas, which follow a sequence from enlarging polyps, to dysplasia, and then to cancer over an average of 10 years. The adenoma-carcinoma progression model of CRC pathogenesis implies that screening asymp-tomatic adults is crucial for prevention of malignancy, as early removal of adenomatous polyps prevents their degeneration into true malignancy. Colorectal cancer screening programs have been shown to reduce the incidence and mortality of CRC among the general population.³

In the United States, most CRC screening guidelines for pretransplant evaluations follow the general population guidelines recommended by the United States Preventative Services Task Force. The 2016 United States Preventative Services Task Force recommendations suggest that average-risk indi-viduals who are between 50 and 75 years old benefit from CRC screening with modalities such as annual guaiac-based fecal occult blood testing or fecal immunohistochemical testing (FIT), flexible sig-moidoscopy with FIT every 10 years, or colonoscopy every 10 years.3 Currently, there are limited data demonstrating that any of the screening modalities are more effective than the others.^3,4

Screening colonoscopy has been recently endorsed as the criterion standard for CRC screen-ings by organizations such as American College of Gastroenterology and National Comprehensive Cancer Network in 2012.^5,6 It allows direct visu-alization of the entire colon as well as immediate removal of suspicious lesions; however, it is associated with risks such as colonic perforation and major intestinal bleeding, which have estimated rates of occurrence at 4 per 10 000 and 8 per 10 000 screening colonoscopies.³

Screening for CRC may be especially important among patients with pretransplant chronic kidney disease. Colorectal cancer has a well-studied progression of arising from adenomatous polyps after 5 to 10 years.^7,8 However, the immunosup-pression therapy required after kidney transplant might increase the risk of progression of adenoma to carcinoma.^9-11 In the kidney transplant population, there have been reports of 1.5- to 2.5-fold increased risk for CRC.¹⁰ Furthermore, the 5-year survival rate of CRC after solid-organ transplant is significantly lower,¹² with 1 study finding the 5-year CRC survival at 74% among transplant recipients compared with 90% for the general population.¹³ On the other hand, requiring patients to undergo CRC screening can delay transplant listing and engraftment, as well as expend transplant center resources to obtain these tests and track down the results. Wait times for kidney transplant have been correlated with worse outcomes among kidney transplant recipients.¹⁴ Therefore, we sought to determine whether the utility of CRC screening by colonoscopy warrants the transplant center resource utilization and the possibility in delay of listing for abnormal colonoscopy results.

Materials and Methods

Patient population
After Internal Review Board approval (No. 09-10-14), we retrospectively collected data on 900 consecutive kidney transplant evaluations from 2009 to 2012 at a single institution. A comprehensive review of medical records on all adults (≥ 18 y old) undergoing kidney transplant evaluation was performed, utilizing the electronic medical records and physical charts. Demographic and clinical information, including age, race, body mass index, smoking history, personal or family history of cancer, type and duration of renal replacement therapy, cause of renal failure, history of transplant, transplant evaluation timeline, pretransplant evaluation-mandated screen-ing colonoscopy, and associated pathology reports, were captured from those sources.

Inclusion criteria consisted of renal failure patients who completed a kidney transplant eval-uation between 2009 and 2012, were ≥ 48 years old by the date they started the transplant evaluation process, had no history of CRC, and had colonoscopies and pathology reports on file that were obtained for the purposes of CRC screening. Colonoscopies obtained for previous CRC history were excluded, as these were deemed to be “for cause” rather than for primary screening. The main outcome variable was findings of the colonoscopy and pathology reports, which were categorized as normal (no finding or hyperplastic polyp) or abnormal (adenomatous polyp or carcinoma) for comparison. Patient comparisons were based on their recorded demographics at the time of transplant evaluation.

Statistical analyses
Descriptive statistics were used to produce frequencies and percentages for categorical variables and mean with standard deviations for continuous variables. Categorical variables were compared using chi-square test, and continuous variables were compared using independent-sample t test. Variables with P ≤ .20 were included in an initial univariate logistic regression. Variables in the univariate logistic model with P ≤ .20 were included in a multivariate logistic regression. Odds ratios (OR) are reported with 95% confidence interval (95% CI) and P values. All statistical analyses were performed using SPSS software version 19.0 (SPSS, Inc., Chicago, IL, USA).

Results

Of 900 patients who were evaluated for kidney transplant listing between 2009 and 2012, 469 patients met the inclusion criteria for the study. Of these, 303 patients (64.6%) had normal colonoscopies, and 166 patients (35.4%) had abnormal colon-oscopies. Table 1 lists the demographic information of the included patients. There were some differences between those patients with normal and those with abnormal colonoscopies (Table 2). Older patients (median age 61.2 vs 59.6 y; P = .015) and male patients (68.7% vs 53.1%; P = .001) were more likely to have an abnormal colonoscopy. Patients who had a prior kidney transplant were more likely to have a normal colonoscopy (6.6% vs 2.4%; P = .049).

Patients with either normal or abnormal screening colonoscopies had similar rates of being listed for transplant (64.7% vs 62.0%; P = .570) and had similar rates of receiving a kidney transplant (15.2% vs 13.3%; P = .571). Furthermore, length of the evaluation period appeared similar in patients with normal versus abnormal screening colon-oscopies (9.12 vs 9.00 mo; P = .881). Patients with end-stage renal disease (ESRD) secondary to hypertension were more likely to have an abnormal colonoscopy. Both patients with abnormal and those with normal screening colonoscopies were placed on renal replacement (hemodialysis or peritoneal dialysis) at similar rates (52.1% vs 51.8%; P = .944). However, patients who had been on dialysis for up to 3 years were more likely to have an abnormal screening colonoscopy (48.1% vs 36.3%; P = .017). Similar conclusions could not be made for patients who were on dialysis for greater than 3 years.

Not surprisingly, univariate logistic regression analysis (Table 3) showed that male sex (OR = 1.99; 95% CI, 1.33-2.97; P = .001) and age as a continuous variable (OR = 1.04; 95% CI, 1.00-1.07; P = .015) were significant risk factors for abnormal colonoscopy findings. Similar results were observed in patients who were on dialysis for up to 3 years (OR = 1.65; 95% CI, 1.12-2.43; P = .012) or who had hypertension as the cause of ESRD (OR = 1.61; 95% CI, 1.03-2.51; P= .038). Dialysis vintage > 3 years was not a significant risk factor (OR = 0.74; 95% CI, 0.41-1.32; P = .304). In a multivariate logistic regression analysis (Table 4), independent predictors of abnormal colonoscopy findings included age as a continuous variable (OR = 1.04; 95% CI, 1.01-1.08; P = .019), male sex (OR = 2.09; 95% CI, 1.37-3.20; P = .001), increased body mass index (OR = 1.04; 95% CI, 1.00-1.08; P = .047), hypertension as cause of ESRD (OR = 1.79; 95% CI, 1.05-2.87; P = .026), and dialysis vintage up to 3 years (OR = 2.10; 95% CI, 1.09-4.06; P = .027).

Of the 166 abnormal colonoscopies, 357 adeno-matous polyps were found in a variety of locations (Table 5). Only 1 colonoscopy detected adenocar-cinoma in our study, whereas 38 of 469 total screening colonoscopies (8.1%) detected the presence of at least 1 high-risk polyp, which is defined as a polyp with villous features, high-grade dysplasia, or a tubular adenoma ≥ 10 mm in diameter.15 Patients with ad-vanced polyps continued their evaluations, and pa-tients with adenocarcinoma had their evaluations closed and were referred for treatment. Of note, 41 of 166 abnormal colonoscopies (24.7%) demonstrated both distal and proximal colon polyps, whereas 75 (34.2%) showed only proximal lesions, suggesting a role for full colonoscopy, as opposed to sigmoidoscopy.

Discussion

In 2016, the United States Preventative Services Task Force updated their CRC screening recom-mendations to state that CRC screening should be offered at age 50 and continued until age 75 years old using various screening methods such as guaiac-based fecal occult blood testing, FIT, flexible sigmoidoscopy, computed tomography colono-graphy, and colonoscopy.3 The task force did not report a preference for any particular screening modality; rather, it recommended that the preferred screening modality would be one that actually occurs, as one-third of eligible patients have never been screened for CRC.3,16 However, the effects of colonoscopy on CRC mortality have yet to be evaluated by a randomized controlled trial, although many are ongoing (the US CONFIRM Trials and the Northern European Initiative on Colorectal Cancer). Other studies have suggested that screening and removal of polyps decrease the incidence of CRC by 30%.¹⁷ Conflicting studies have suggested that colonoscopy may miss up to 26% adenomas ≤ 5 mm in diameter, with a further ~10% of neoplastic polyps being incompletely removed.^18,19 Furthermore, colonoscopy screening has been shown to reduce distal CRC mortality by 47% to 67%, although it may not affect proximal CRC mortality.20 Although studies have shown screening colonoscopies to be beneficial in the general population, there are currently sparse data on colonoscopic utility specific to pretransplant chronic kidney disease patients.

The cost-effectiveness of a screening colonoscopy is dependent on the incidence of CRC in the screened population, the expected survival of the patients, and the sensitivity and specificity of the test. High-risk adenomas have been used as surrogate findings for CRC in terms of determining colonoscopy effectiveness.¹⁵ However, the incidence of adenomas is controversial. Imperiale and associates²¹ found that 17.7% of 1994 asymptomatic patients screened had at least a single adenoma, whereas Bretthauer and associates22 reported adenoma detection rates of 30.7%, 10.4%, and 0.5% for overall adenomas, advanced adenomas, and CRC, respectively, in 94 959 asymptomatic patients. In our study, the prevalence of overall adenoma, advancedadenoma, and CRC among the pretransplant ESRD patients was 35.4%, 8.1%, and 0.2%, respectively. The rate of adenoma detection via colonoscopy among pretransplant ESRD patients in our study (35.4%) is higher than most reported adenoma detection rates for the general population, although there are other recent reports^23-26 of higher rates of adenomatous polyps in chronic kidney disease and ESRD patients that vary from 24% to 54%. Furthermore, the risk of CRC appears higher in solid-organ transplant patients than in the general population.²⁷ Given the high prevalence of adenomatous polyps in pretransplant ESRD patients and the increased risk for CRC after transplant, broader use of screening colonoscopy during kidney transplant evaluation appears appropriate. In addition, colonoscopy findings (abnormal vs normal) do not appear to delay the evaluation process or affect patient eligibility to be listed for transplant based on the similar duration of evaluation and listing rates for both groups found in our study.

Several studies have shown that colonoscopy is less protective from CRC in the right colon than in the left colon.^28,29 This detection failure may be due to poor bowel preparation or the presence of sessile or serrated adenomas that are difficult to visualize or remove completely.^30-32 Among the screening colonoscopies that were conducted in the pret-ransplant ESRD patients in our study, 34.2% contained polyps only in the proximal colon, which would be undetectable by sigmoidoscopy, as similarly presented in a previous study.²⁵ Another study in patients from 40 to 80 years old with average risk of CRC demonstrated that sigmoidoscopy would fail to detect 21% to 43% of all polyps.³³ The high prevalence of right-sided colon polyps among pretransplant ESRD patients in this study suggests that colonoscopy should remain the preferred CRC screening tool over sigmoidoscopy. In fact, transplant recipients may be at greater risk for proximal CRCs than for distal or rectal cancers compared with the general population.²⁷

In the multivariate logistic regression model, age, male sex, hypertension-induced kidney disease, and a history of dialysis for up to 3 years were associated with a screening colonoscopy resulting in the detection of adenomatous polyps. Age and male sex are known risk factors for adenomatous polyps in the general population.34,35 Therefore, it is not surprising that pretransplant screening colonoscopies of older or male patients with ESRD are more likely to result in finding adenomatous polyps.

We showed that patients who had chronic kidney disease secondary to hypertension or who were on dialysis for up to 3 years before evaluation had a higher risk for abnormal colonoscopy. Hypertension and dialysis are associated with chronic inflam-matory states, which can lead to increased risk of intestinal hyperplasia and malignancies.36-39 Chronic inflammation and systemic vascular inflammation have been implicated as mechanisms for hypertension.^40-44 Patients on hemodialysis or peritoneal dialysis have elevated levels of C-reactive protein and other markers of inflammation, a finding attributed to clots in access grafts, persistent infections, and imperfect clearing of inflammatory cytokines.^45-52 Previous studies have not found that dialysis vintage has a significant effect.23,25 In our study, dialysis vintage up to 3 years was associated with increased risk of finding adenomatous

polyps on screening colonoscopy, although patients on dialysis for greater than 3 years do not share the same risks (OR = 0.74; 95% CI, 0.41-1.32; P = .304). However, the sample size was small for this group (n = 61).

This study has limitations. This is a retrospective study, having all of the typical limitations of a retrospective study design. A significant proportion of the initial study population was excluded for missing colonoscopy reports (97 of 900). It is certainly possible that some of these patients had significant colonoscopic findings but simply did not follow-up or formally communicate the results with the transplant center before closing the evaluation. Patients who underwent screening colonoscopy resulting in cancerous findings as part of their general health maintenance may not have been referred for transplant evaluation, whereas a similar patient without such findings may have been promptly referred. Similarly, not all patients in the cohort will receive transplants, and such patients may have underlying differences from those that do. Additionally, some patients may have had colon-oscopies before the index colonoscopy that was in the transplant record, and those earlier colonoscopies may have removed polyps, lowering the number of abnormal colonoscopies in this study.

In summary, for patients undergoing kidney transplant evaluation, hypertensive renal failure and dialysis vintage up to 3 years may be risk factors for adenomatous polyp findings on colonoscopies. Interestingly, both of these factors can cause chronic inflammation, which has been implicated in car-cinogenesis. The adenoma detection rate of 35.4% found in our study appears to be higher than the adenoma detection rate in the general population. There seemed to be no significant delay in the evaluation process, listing rate, or transplant rate based on colonoscopy findings. Therefore, it is reasonable to either strongly encourage or require screening colonoscopy for ESRD patients undergoing transplant evaluation.

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