EXPERIMENTAL AND CLINICAL TRANSPLANTATION

Objectives: Cervical cytology screening has been successful in reducing deaths from cervical cancer. We sought to determine risk factors for abnormal Pap test results in women undergoing kidney transplant evaluation.

Materials and Methods: We retrospectively examined women undergoing kidney transplant evaluations from 2008 to 2011. Patients were stratified based on normal cytology and atypical/malignant cytology.

Results: Of 404 patients, 293 patients (72.5%) had normal cytologic findings, whereas 111 (27.5%) had abnormal findings. On univariate logistic regression analyses, patients who had chronic kidney disease with an autoimmune cause (odds ratio = 2.71 [95% confidence interval, 1.41-5.19]; P = .003), previous renal transplants (odds ratio = 2.64 [95% confidence interval, 1.20-5.82], P = .016), or age ≤ 50 years (odds ratio = 1.68 [95% confidence interval, 1.08-2.61], P = .022) were more likely to have abnormal findings. Patients with normal and abnormal findings had similar rates of dialysis use. On multivariate logistic regression, patients who had chronic kidney disease with autoimmune causes (odds ratio = 2.48 [95% confidence interval, 1.26-4.88]; P = .008) and who had previous renal transplants (odds ratio = 2.67 [95% confidence interval, 1.20-5.95]; P = .017) were more likely to have abnormal findings.

Conclusions: Previous kidney transplant, autoimmune disease, and age ≤ 50 years were associated with abnormalities on cervical cancer screening in our female group of patients. Patients with these characteristics may benefit more from routine cervical cancer screening than other patients evaluated for kidney transplant.

Key words : Cancer screening, Cervical cancer, Cervical cytology screening, Chronic kidney disease, End-stage renal disease, Kidney transplant evaluation

Transplant centers have historically required prospective organ recipients to undergo evaluations based on national preventative health guidelines for the general population, including cervical cancer screening. An estimated 13 000 new cases of invasive cervical cancer and 4100 cervical cancer deaths occur in the United States each year.¹ These rates have greatly decreased since the introduction of the Papanicolaou (Pap) cytologic test in the 1940s. Multiple studies have shown that cervical screening has had protective benefits in female populations worldwide and is associated with reduced incidence of invasive cervical disease.²

Transplant centers rely on current Pap test guidelines for the general population that are recommended by the American Congress of Obstetricians and Gynecology (ACOG) and the United States Preventative Services Task Force (USPSTF). Women from age 21 to 65 years are recommended to have a Pap test every 3 years. Alternatively, women age 30 to 65 years old may choose to lengthen the screening interval to 5 years by combining cytology with human papillomavirus (HPV) testing. Abnormal findings on the Pap test may be investigated further with cervical biopsy guided by colposcopy.3 The American Society of Transplantation recommends patients to additionally undergo annual cervical cancer screening after kidney transplant procedures.

For the pretransplant chronic kidney disease (CKD) population, the value of cervical cancer screening remains unclear. Proponents of cervical cancer screening would argue that the benefits of the Pap test have been clearly demonstrated for the general population and are therefore transferable to the pretransplant CKD population. However, abnormal Pap test findings may prevent or delay a patient from being listed for transplant. After transplant, required immunosuppressive agents may increase the risk of high-grade cervical dysplasia and progression to carcinoma.⁴ Due to the burden placed on transplant centers to ensure that patients have the necessary preventive health screenings before placement on a wait list, some transplant centers have switched from requiring cervical cancer screening to simply recommending it. Because data on the utility of mandatory cervical cancer screening for female CKD patients undergoing pretransplant evaluations are scarce, the goal of this study was to determine the risk factors in CKD patients that impact Pap test results.

Materials and Methods

Patient population
We retrospectively assembled data on 493 female CKD patients who began pretransplant evaluations at the University Hospitals Cleveland Medical Center from January 2008 to December 2011. We reviewed electronic and physical medical records of all female adults (≥ 18 years old) who were undergoing kidney transplant evaluations. Demographic and clinical data regarding age, race, body mass index (BMI), smoking history, personal or family history of cancer, type and duration of dialysis, cause of CKD, history of transplantation, and Pap test pathology reports during the transplant evaluation were recorded. To remain active on the wait list at our transplant center, a current screening Pap test as recommend by the current ACOG guidelines is required.

Inclusion criteria for this study consisted of female patients with CKD who completed a kidney transplant evaluation between 2008 and 2011, were ≥ 21 years old by the date of initial transplant evaluation, and had the required Pap tests in compliance with the current ACOG cervical cancer screening guidelines. The evaluation period for each patient was defined as starting at the patient’s initial visit and ending when the patient was added to the transplant wait list or denied. Only the Pap tests used to determine patient eligibility during the evaluation period were recorded. The Pap test cytology reports were categorized into normal (no findings) or abnormal for comparison. Abnormal cytology reports included low-grade squamous intraepithelial lesion, high-grade squamous intraepithelial lesion, atypical squamous cells of undetermined significance, atypical squamous cells and “cannot rule out” high-grade squamous intraepithelial lesion, and atypical glandular cells. These cytology results on Pap test were deemed abnormal because they would require further testing.

Statistical analyses
Patients with Pap test reports on file but no abnormal Pap test results during the evaluation period were categorized as “normal,” and patients with at least one abnormal Pap test result during evaluation were categorized as “abnormal.” Data on patient characteristics (age, BMI, race, smoking history, history of prior transplant), cause of CKD (diabetes mellitus only, hypertension only, autoimmune disease, polycystic kidney disease), and dialysis history (no dialysis, any dialysis, and time on dialysis) were used as comparison variables. Patients were dichotomized into those ≤ 50 years old and those >50 years old. Time on dialysis and BMI were included as continuous variables. Descriptive statistics were used to produce frequencies and percentages for categorical variables; mean with standard deviations or median with respective 25th to 75th percentiles were used to describe continuous variables.

Patients in the normal and abnormal categories were compared across each of these variables. Categorical variables were compared with the use of chi-square tests, and continuous variables were compared with the use of independent sample t tests. Univariate logistic regression analysis was performed on each of these comparisons. From the initial univariate logistic regression, variables found to have P values of ≤ .10 were included in a multivariate logistic analysis. Odds ratios (OR) are reported with 95% confidence interval (95% CI) and P values. All statistical analyses were performed using SPSS version 19 (SPSS, Inc., Chicago, IL, USA). The study protocol was approved by the Institutional Review Board at the University Hospitals Cleveland Medical Center (No. 09-10-14).

Of 493 female CKD patients who underwent pretransplant evaluation at University Hospitals Cleveland Medical Center between January 2008 and December 2011, 404 met the inclusion criteria for this study. Of these patients, 293 (72.5%) had normal Pap tests, whereas 111 (27.5%) had at least one abnormal Pap test. Table 1 shows the demographic data for all included patients. A total of 684 Pap tests were performed on the 404 women included in this study, which led to the diagnosis of 25 cases of low-grade squamous intraepithelial lesions, 11 cases of high-grade squamous intraepithelial lesion, 70 cases of atypical squamous cells of undetermined significance, 5 cases of atypical squamous cells and “cannot rule out” high-grade squamous intraepithelial lesion, and 1 case of atypical glandular cells. The Pap tests led to 36 recorded colposcopies overall.

Table 2 shows the comparisons between patients with normal and abnormal Pap test findings. Significant differences between the 2 groups included advanced age and prior transplant history (P ≤ .05). Younger patients (median age 47.8 vs 53.4 years; P = .021) and those with a history of previous transplants (11.7% vs 4.8%; P = .013) were more likely to have an abnormal Pap test during their pretransplant evaluation. Although smoking is a known risk factor for cervical cancer, there was surprisingly no difference in Pap test results between patients with no history of smoking versus those with a history of smoking (43.3% vs 45.0%; P = .693). Causes of CKD also differed between patients with normal and abnormal Pap tests. Patients who had CKD with an autoimmune cause were more likely to have an abnormal Pap test (18.0% vs 7.5%; P = .002). Patients with both normal and abnormal Pap test findings used renal replacement therapy at similar rates and for similar durations.

Univariate logistic regression analysis (Table 3) demonstrated that those patients who had undergone previous renal transplants (OR = 2.64 [95% CI, 1.20-5.82]; P = .016) and with autoimmune disease as the primary cause of CKD (OR = 2.71 [95% CI, 1.41-5.19]; P = .003) were more likely to have abnormal Pap test findings. These findings were supported by multivariate logistic regression analysis (Table 4), which also showed that prior transplant (OR = 2.67 [95% CI, 1.20-5.95]; P = 0.017) and autoimmune disease as the primary cause of CKD (OR = 2.48 [95% CI, 1.26-4.88]; P = .008) were risk factors for abnormal Pap test findings. Chronic kidney disease secondary to diabetes, hypertension, and polycystic kidney disease did not appear to affect Pap test results on univariate analysis. Smoking history also did not appear to affect the results of pretransplant evaluation Pap tests (OR = 1.02 [95% CI, 0.65-1.61]; P = .919). Although univariate analysis showed that patients who were ≤ 50 years old were more likely to have an abnormal Pap test (OR = 1.68 [95% CI, 1.08-2.61]; P = .022), this younger age group was not a significant factor on multivariate analysis (OR = 1.41 [95% CI, 0.89-2.24]; P = .144).

The aim of this study was to evaluate the risk factors for abnormal cervical findings in women undergoing kidney transplant evaluation. This study found that women with age ≤ 50 years had higher risk of abnormal Pap test findings during evaluation on univariate logistic regression. We also found that patients who had a prior kidney transplant or had autoimmune disease as the cause of their CKD were more likely to have abnormal Pap test findings on both univariate and multivariate analysis. Although history of smoking is a known risk factor for cervical neoplasia, this study did not find a significant correlation with abnormal Pap test results. This finding may be due to incomplete data because our database recorded whether patients had any smoking history but did not record how many pack-years they smoked.

Although CKD patients experience higher cancer incidence and mortality, some studies have suggested that cancer screening in CKD patients should be given lower priority than in the general population because of their lower life expectancy, giving them a lower potential benefit from screening.^5,6 A recent study demonstrated significantly lower rates of cervical cancer screening in women with advanced CKD.⁷ However, younger CKD patients may benefit more from cervical screening since the peak age of cervical cancer incidence in the United States is 48 years old. Younger patients in general have improved cancer 5-year survival rates and are at a greater risk for virus-related malignancies, including HPV, after kidney transplant.8,9 Our study found that CKD patients undergoing pretransplant kidney evaluation who were ≤ 50 years old had a higher risk of abnormal Pap test findings, supporting the idea that younger CKD patients should continue to be screened for cervical cancer.

Our study, which identified that prior kidney transplants and autoimmune causes of CKD were associated with abnormal Pap tests, could be explained by these patients’ history of immunosup-pression from their previous transplants or as treatment for their autoimmune disease. Immuno-suppression is a known risk factor for numerous cancers and especially cervical cancer through impairing the immune system’s ability to clear the oncogenic HPV.¹⁰ Renal transplant recipients have been found to have a high incidence of HPV infection, with many patients carrying high-risk genotypes.^11,12 The previous immunosuppressed state may allow for reactivation of latent HPV infection and subsequent progression to cervical dysplasia or invasive cancer.^13-15 A recent study demonstrated increased prevalence in high-risk HPV in females after renal transplant despite no changes in their sexual behavior, which may indicate activation of latent HPV infections.¹⁶

Chronic inflammation in general is associated with malignancy, and cervical cancer has recently been linked to many systemic inflammatory diseases.^17-20 The chronic inflammatory states associated with patients with autoimmune diseases could explain why patients with autoimmune disease as cause for CKD had higher risk of abnormal Pap test results. Most of these patients had systemic lupus erythematosus, which is a systemic inflammatory disease that is associated with increased incidence of malignancies like hematologic, lung, and thyroid cancers.^21,22 Systemic lupus erythematosus has also been found to be associated with higher prevalence of HPV infection in cross-sectional studies.^23-25 Meta-analyses have also shown increased incidence of cervical dysplasia in these patients, although there is disagreement over whether there is actually increased incidence of invasive disease.^26,27 In addition to autoimmune disease causing a chronic inflammatory state, most of these patients have an extensive immunosuppression drug history that predates the kidney transplant evaluation.

This study has limitations. This is a retrospective study of a population limited to CKD patients undergoing pretransplant evaluation at a single institution; therefore, our results may not be generalizable to CKD patients as a whole. Patients who are not referred for pretransplant evaluation are more likely to be older, have more comorbidities, or have fewer health care resources. Patients who had previously undergone cervical cancer screening as part of general health maintenance and had significant abnormal findings may not have been referred for evaluation as aggressively. A significant number of patients were also excluded from the study due to missing cytology reports (82 of 493), and many of these patients had history of hysterectomy; thus, there may not be randomness to these missing data. Patients may have had a number of cervical cancer screening events before the evaluation that were not available for analyses. Because these studies were not always available, reporting bias may be present. Some of these patients may have actually had abnormal Pap tests but did not report these results for transplant evaluation. Furthermore, because many of these studies were done externally, reporting of HPV findings varied, limiting the meaningful analysis of the role of HPV subtypes. Our study found that patients with potential exposure to immunosup-pressive therapy (those with prior transplant or autoimmune disease) had a greater risk of abnormal Pap test results, but we did not have sufficient data to explore whether patients were indeed exposed before their transplant evaluation.

In summary, our study demonstrated that CKD secondary to autoimmune disease and prior renal transplant were associated with abnormal Pap test findings. Age ≤ 50 years old was also associated with a higher risk of abnormal Pap test results. Women with these characteristics may benefit from more routine cervical cancer screenings before transplant due to the increased rates of abnormal Pap test findings compared with other transplant candidates and the general population. Although some transplant centers require primary care screening tests such as Pap tests in all patients who undergo transplant evaluations, other centers simply recommend patients to follow recom-mended primary care screening with their primary care physicians. Transplant centers that fall into this latter category may consider requiring, rather than recommending, that certain populations undergo cervical cancer screening during transplant evaluations.

Volume: 17 Issue: 1 February 2019

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