Objectives: Malignancy is a common cause of death in renal transplant patients. The aim of this study was to investigate incidence, risk factors, and survival rates associated with posttransplant malignancy in kidney transplant recipients.
Materials and Methods: Between January 2015 and December 2020, 1154 patients underwent kidney transplant at the Affiliated Hospital of Qingdao University. Patients with a history of malignancy or other organ transplant (liver, pancreas, heart, or lungs) were excluded from this study. Patients with incomplete follow-up records were also excluded. Ultimately, our study comprised 811 kidney transplant recipients. The patient characteristics and incidence, type, and risk factors associated with posttransplant malignancy were examined. We also analyzed the overall survival of recipients with posttransplant malignancy.
Results: A total of 811 renal transplant recipients were followed up, with a median follow-up period of 3.0 years. Fourteen kidney recipients developed posttransplant malignancy (1.7%), with a mean time to malignancy diagnosis of 2.7 years. The 3-year and 5-year overall survival rates were 91.7% and 91.7%, respectively, in recipients with malignancy and 99.2% and 98.8%, respectively, in recipients without malignancy. The overall survival rate was significantly higher in recipients without malignancy than in those with malignancy (P = .03). Female sex, older recipient age, and history of prior kidney transplant were significant predictors of malignancy development.
Conclusions: Postoperative malignancy in kidney transplant recipients was associated with lower overall survival rates. Malignancy screening is important for kidney transplant patients, especially for older women and patients with a history of prior kidney transplant.
Key words : Cancer, Kidney transplantation, Posttransplant lymphoproliferative disorders
Kidney transplant can effectively improve quality of life and overall survival of patients with end-stage renal disease.1 With the optimization and systema-tization of immunosuppressive regimens, the survival rate of patients after kidney transplant has been significantly improved. However, recipients often develop serious complications, including cardiovascular disease, infection, and malignancy, which are the leading causes of mortality in kidney transplant patients.2,3 Malignancy is the third leading cause of death (exceeded only by cardiovascular diseases and infections) for kidney transplant recipients. Notably, the incidence of malignancy in patients with renal transplants is at least 2-fold to 4-fold higher than in the general population.3 A study of 12 805 Dutch kidney transplant recipients showed that the survival of recipients with malignancy is significantly lower than that of recipients without malignancy.4 Immunosuppressants and viral infections may be major factors for higher risk of posttransplant malignancy in kidney recipients.5
In addition, the type of malignancy that develops after kidney transplant is variable in different countries, and differences in ethnicity and lifestyle habits are the likely reasons for this geographic variability. Skin malignancy is the most common posttransplant cancer in Western countries.4,6,7 Posttransplant lymphoproliferative disorders (PTLD) and skin cancer are the most common types of malignancy in Japan.8 Urologic neoplasms comprise the most common type of posttransplant malignancy among recipients in Taiwan.9,10 Gastric malignancy and PTLD are the most common types of posttransplant cancer among Korean recipients,11 whereas PTLD is the most common type of posttransplant malignancy in recipients in Hong Kong12 and Singapore.13 Presently, few studies have investigated the development of malignancy among kidney transplant recipients in mainland China.
In this single-center analysis, we have evaluated the incidence, risk factors, and overall survival rates associated with postoperative malignancy among kidney transplant recipients.
Materials and Methods
Between January 2015 and December 2020, 1154 patients underwent kidney transplant at the Affiliated Hospital of Qingdao University. We excluded patients for the following criteria: (1) patients who received dual pancreas-kidney transplant; (2) patients who received another organ transplant (liver, pancreas, heart, or lungs) before kidney transplant, (3) patients whose follow-up records were incomplete and patients with a history of cancer before kidney transplant (because our study focused on de novo malignancies after transplant), and (4) patients with kidney transplant failure (n = 9) from thrombosis. In total, 811 kidney transplant recipients were included in the study. Using the Scientific Research Database of the Affiliated Hospital of Qingdao University, we retrospectively reviewed the medical records of 811 recipients. Among these, 801 patients received transplants from deceased donors, and 10 patients received transplants from living related donors (their father or mother).
Most patients received immunosuppressive drugs as induction therapy with anti-CD25 antibody or antithymocyte globulin. All patients underwent a standard triple immunosuppression therapy (tacrolimus or cyclosporine, mycophenolic acid or mizoribine, and steroids). Methylprednisolone was administered for T-cell-mediated rejection in patients as indicated by renal biopsy, and this treatment was also used in patients who were clinically diagnosed with rejection. Antithymocyte globulin was used after methylprednisolone treatment in patients with steroid resistance. Rituximab, plasma exchange, and intravenous immunoglobulin were used for antibody-mediated rejection. Before 2020, there has been no case of ABO-incompatible kidney transplant in our center. Patients were followed up until diagnosis of malignancy, death, date of last follow-up contact, or November 30, 2021, whichever event was first. This study was evaluated and approved by the ethics committee of the Affiliated Hospital of Qingdao University (No. QYFY-WZLL-26839) and conducted in accordance with the Helsinki Declaration.
The patients were divided into malignancy-positive and malignancy-negative groups. Descriptive data are shown as percentages for categorical variables. Continuous variables are shown as mean values with SD or median values with interquartile range (IQR, 25%-75%). When 2 groups were compared, statistical significance was determined with the t test, the Mann-Whitney test, the Pearson chi-square test, and the Fisher exact test for continuous and categorical variables, as appropriate. Cox proportional hazards regression univariate and multivariate analyses were performed to ascertain risk factors associated with malignancy development after kidney transplant. All statistical analyses were performed with R software (version 4.1.2, http://www.r-project.org/). All tests were 2-sided, and the significance level was defined as P < .05.
A total of 811 renal transplant recipients were followed up. Characteristics of included patients are listed in Table 1. The median follow-up time was 3.0 years (IQR, 1.6-4.3 years). The mean age of all the transplant patients was 41.2 ± 11.1 years, and 70.4% were male. Of the 811 patients, only 10 patients received their transplanted kidney from living related donors. Most recipients (92.5%) received dialysis prior to transplant. Most transplant patients received an immunosuppressive regimen based on tacrolimus combined with mycophenolic acid and methylprednisolone after transplant. The most common primary kidney disease was chronic glomerulonephritis (41.5%). Nineteen patients had undergone a retransplant procedure.
Malignancy types and malignancy incidence rates after kidney transplant
During the follow-up period, 14 patients developed malignancy after renal transplant as shown in
Table 2. The prevalence of malignancy in our patients was 1.7%. The mean time to cancer diagnosis after transplant was 2.7 years (range, 0.6-4.7 years). Three-fifths of the patients with posttransplant malignancy were female. The most prevalent types of malignancy were PTLD (n = 4), thyroid cancer (n = 2), and urologic neoplasms (n = 2). Malignancy was diagnosed in 1 patient (7.1%) within 1 year after kidney transplant, in 5 patients (35.7%) within 2 years, in 9 patients (64.3%) within 3 years, and in 12 patients (85.7%) within 4 years after kidney transplant. In addition, 3 patients (21.4%) with posttransplant malignancy were administered sirolimus after diagnosis.
Patient survival and graft function
The overall survival rate was significantly lower in the malignancy-positive group than in the malignancy-negative group (P = .03, log-rank test; Figure 1). By the end of the follow-up period, 1 patient (7.1%) died of malignancy in the malignancy-positive group, and 7 patients (0.9%) died of severe pneumonia in the malignancy-negative group. The 3-year and 5-year overall rates for patient survival were 91.7% and 91.7%, respectively, in the malignancy-positive group and 99.2% and 98.8%, respectively, in the malignancy-negative group.
By the end of the follow-up period, only 1 patient in the malignancy-negative group underwent allograft resection to treat a transplant kidney infection, and 16 patients in the malignancy-negative group had returned to dialysis to treat graftloss.
Cox regression analyses for malignancy development
To ascertain risk factors of malignancy development, Cox regression analyses were used (Table 3). By multivariate analysis, female sex (hazard ratio, 4.208; 95% CI, 1.253-14.138; P = .020), older age (hazard ratio, 1.057; 95% CI, 1.004-1.112; P = .035), and history of prior kidney transplant (hazard ratio, 8.776; 95% CI, 1.576-48.888; P = .013) were significant predictors of cancer development (Table 3).
Recipients had a higher incidence of malignancy after renal transplant than general population. The crude incidence rate of cancer was 0.28% in the general population in China in 2015.14 The incidence of malignancy after renal transplant was 1.7% in our center, which is lower than the incidence in other countries. For example, in Japan, the incidence of malignancy after renal transplant was 7.3% and 12.2% in 2 studies, respectively.8,15 The proportion of malignancy was 4.2% and 7.1% in 2 studies with kidney transplant recipients in Western countries.4,7 The low incidence of malignancy in our center may be related to the following reasons: (1) different immunosuppressive regimens in different countries and regions and (2) short follow-up time in this study. A 12-year-long Singapore study showed cyclosporine was an independent risk factor to predict malignancy development after renal transplant.13 In our center, cyclosporine was used in only a few patients, and tacrolimus was used in 98.8% of patients. After transplant, trough levels of tacrolimus were maintained in the range of 8 to 12 ng/mL during the early period, in the range of 6 to 10 ng/mL until month 3, in the range of 4 to 8 ng/mL until month 12, and in the range of 4 to 8 ng/mL thereafter. Imamura and colleagues have speculated that low-dose tacrolimus might help reduce the risk of malignancy development.8 In our study, the median follow-up period was 3.0 years and the longest follow-up period was only 9 years. The relatively low incidence of malignancy may also be related to the short follow-up period.
Posttransplant lymphoproliferative disorders comprised the most common type of malignancy in our center, followed by thyroid cancer and urologic neoplasms. Similarly, PTLD comprised the most common type of malignancy in Japan, Hong Kong, and Singapore.8,12,13 A study of 8164 kidney transplant recipients in Australia and New Zealand showed that non-Hodgkin lymphoma occurred with bimodal distribution after transplant. Increased risk of early non-Hodgkin lymphoma (<2 years after the first transplant) was observed in patients whose serology at transplant tested negative for Epstein-Barr virus (EBV) and in patients who received treatment with T-cell-depleting antibodies. Late non-Hodgkin lymphoma (≥2 years) was associated with older recipient age, longer posttransplant periods before onset, and use of calcineurin inhibitors.16
There are 2 important pathogenic mechanisms for postoperative development of lymphoma in kidney transplant recipients. One mechanism is primary EBV infection in strong immunosuppressed state. In the context of immunosuppression, transplant recipients who experience EBV infection may fail to mount an adequate EBV-specific immune response as a result of their lack of essential EBV-specific CD8+ T cells and insufficient production of anti-EBV nuclear antigen antibodies.17 In addition, this inadequate immune response could be exacerbated in recipients treated with T-cell-depleting antibodies.18 Another mechanism is lymphoproliferative dysregulation in a prolonged immunosuppressive state. In our study, 2 transplant recipients with EBV infection were diagnosed with PTLD. One of these patients was diagnosed at 7 months after transplant, and the other patient was diagnosed at 32 months (≥2 years) after transplant. The association between EBV and PTLD was not analyzed in this study because of the scarce number of cases and the lack of available EBV virology data for our participants. A study of pediatric kidney transplant in Japan noted that regular monitoring of EBV levels may have contributed to a lower incidence of PTLD in their study.19
Compared with the malignancy-negative group, there were more deaths in the malignancy-positive group (0.9% and 7.1%, respectively). This is consistent with the results of other studies.8,12,13 Similarly, the overall survival rates were lower in the malignancy-positive group compared with the malignancy-negative group. By the end of the follow-up period, only 1 patient in the malignancy-negative group underwent allograft resection to treat a transplant kidney infection. Therefore, graft survival rates were not analyzed. Some studies from Japan have shown lower graft survival rates in malignancy-positive recipients compared with malignancy-negative recipients.8,15
By multivariate analysis, our results show that female sex, older age, and history of prior kidney transplant were associated with higher risk of malignancy. Two studies have shown a higher risk of malignancy for male transplant recipients compared with female recipients,20,21 which contradicts our results. Other studies have shown a higher risk of malignancy in older transplant recipients compared with their younger counterparts.8,15,20 We observed that cyclosporine was not associated with a higher risk of malignancy development. A previously published study reported that recipients treated with tacrolimus had a lower incidence of malignancy compared with recipients treated with cyclosporine.22 Low-dose tacrolimus for induction and maintenance of immunosuppression may reduce the risk of malignancy development. The study by Bustami and colleagues22 differs from our study in that most patients in our study received an induction regimen, whereas the patients in the study by Bustami and colleagues did not receive an induction regimen. In addition, cyclosporine was used in only a few patients (n = 59) in our center.
The present study has several advantages. This is the first study on new malignancy in patients after kidney transplant in mainland China. The data that we have reported here have captured the most common risk factors related to malignancy, such as smoking habit, history of transfusion, recipient body mass index, and history of rejection. Compared with some previously published studies in which the immunosuppression regimens were modified during the course of treatment, the induction and maintenance of immunosuppression in our study were not modified significantly.
Our study has some limitations. First, the length of the follow-up period was brief, which may be the reason for the low incidence of posttransplant malignancies. Second, this was a retrospective single-center study with a relatively small group of enrolled participants.
The incidence of malignancy in our recipients is low compared with published data. Our present study found more deaths and lower overall survival rates in recipients with malignancy versus recipients without malignancy. Female sex, older recipient age, and history of prior kidney transplant were significant predictors of malignancy development.
Volume : 20
Issue : 6
Pages : 558 - 563
DOI : 10.6002/ect.2022.0087
From the Department of Pharmacy, the Affiliated Hospital of Qingdao University, Shandong Qingdao, China
Acknowledgements: The authors have not received any funding or grants in support of the presented research or for the preparation of this work and have no declarations of potential conflicts of interest.
Corresponding author: Jing Fanbo, Doctor of Pharmacy, Department of Pharmacy, the Affiliated Hospital of Qingdao University, Haier Road 59, Laoshan District, Qingdao City, Shandong Province, China
Phone: +86 0532 8291 5827
Table 1. Characteristics of Kidney Transplant Recipients Included in the Study
Table 2. Malignancy Types Diagnosed in 14 Patients
Figure 1. Kaplan-Meier Analysis of Patient Overall Survival Between Patients With and Without Malignancy
Table 3. Cox Proportional Hazards Regression Analyses of Risk Factors for Malignancy Development