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Malignancy in renal transplant recipients, incidences, and risk factors: More than three decades of experience
FRCP, Ayman Aly Seddik2MBBCH, Hind Alnour1FRCP, Maseer Ahmad1FCPS Nephrology, Sima Najad1MRCP, Osman Elfadil Osman1MD, Hussain Yousif1MD, Shaikha Ali1MD, Mohammad Railey1FRCP, Amna Alhadari1MD
*Corresponding author: Dr. Kashif Gulzar, Department of Nephrology, Dubai Hospital, Dubai Health, Dubai, United Arab Emirates. kashifsmcian@gmail.com
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Received: ,
Accepted: ,
How to cite this article: Gulzar K, Alalawi F, Seddik A, Alnour H, Ahmad M, Najad S, et al. Malignancy in renal transplant recipients, incidences, and risk factors: More than three decades of experience. World Adv Renal Med. 2025;1:16-24. doi: 10.25259/WARM_3_2025
Abstract
Objectives:
This retrospective study was performed to report the incidence of malignancy in renal transplant recipients and also to identify the risk factors causing it.
Material and Methods:
We have studied 506 renal transplant recipients , follow-up patients from 1989 to 2023 at a single center, Dubai Hospital.
Results:
The mean age of renal transplant recipients at the time of transplant in our study population was 55 ± 21 years and 39 ± 14.93 years, respectively, also the predominant gender was male (64.62%, n=327). Diabetic nephropathy (21.93%, n=111), chronic glomerulonephritis (21.14%, n=107), and obstructive uropathy (8.69%, n=44) were the three most common etiologies of chronic kidney disease in transplant recipients. About 94.87% (n=480) of transplant recipients had a living donor; also, 15 (2.96%) patients had a history of multiple renal transplants. Incidence of CMV (cytomegalovirus), HCV (Hepatitis C virus), BK virus (BKV), HBV (Hepatitis B virus) infections was 13.83% (n=70), 12.05% (n=61), 4.94% (n=23), and 2.17% (n=11), respectively. Prednisolone was the most common immunosuppressive used in 98.81% (n=500), followed by cyclosporine (66%, n=334), mycophenolate mofetil (60.67%, n=307), tacrolimus (27.47%, n=139), sirolimus (12.45%, n=63), and everolimus (0.39%, n=2). Triple immunosuppressive was used in 91.30% (n = 462). Biopsy-proven acute rejection (BPAR) is observed in 23.12% (n=117) of transplant recipients. Incidence of malignancy in renal transplant recipients is 8.10% (n=41), 60.9% (n=25) of whom were male. The hematological malignancies were commonest (n=9, 21.9%) in our study population that include post-transplant lymphoproliferative disorder and multiple myeloma in 7 (17.07%) and 2 (4.87%) patients, respectively, followed by skin, urological (14.6%, n=6 each), and colorectal cancer (12.19%, n=5), also other low incidence malignancies involving lung (n=2, 4.87%), breast (n=2, 4.87%), central nervous system (n=2, 4.87%), genital organs (n=2, 4.87%), endocrine(n=2, 4.87%), liver (n=2, 4.87%), prostate (n=1, 2.43%), and oral cavity cancer (n=1, 2.43%). Prednisolone (85.36%, n=35), cyclosporine (60.97%, n=25), and mycophenolate mofetil (56.09%, n=23) were common immunosuppressive used in malignancy affected renal transplant recipients; also, CMV, HCV infection, and BPAR was observed in 17.07% (n=7), 14.63% (n=n=6), and 19.51% (n=8) patients. Seven (17.07%) patients died due to malignancy related complications.
Conclusion:
Overall survival rate of renal transplant recipients without malignancy in our study population is 100%, 95%, and 79% at 1, 5, and 10 years, respectively, and 97%, 92%, and 87% in those with malignancy, respectively. Multivariate analysis reveals that cyclosporine usage poses a greater risk of developing cancer, whereas induction agents and maintenance immunosuppression, including antimetabolites, corticosteroids, and mammalian target of rapamycin inhibitors, were not associated with a high risk of developing post-transplant malignancy.
Keywords
BK virus
Cytomegalovirus
Immunosuppressant
Malignancy
Transplant
INTRODUCTION
Renal transplant is the only way to extend the lives of many patients with end-stage renal failure. This procedure is not without the associated risks involved since the time of inception.[1] Despite the decrease in the incidence of rejection due to effective immunosuppression, infection, cardiovascular disease, and malignancy are the main limiting factors for graft success.[2] Malignancy is the third most common cause of death, and a 2–3-fold increased risk of cancer is reported in transplant recipients as compared to the general population.[3,4 ] The Risk of developing malignancy is not the same for all types of cancers. In contrast, in some solid organ cancers (Breast, prostate, ovary, brain, and cervical), incidences are not increased. In contrast, for others, that is, lung, colon, liver, lymphoma, melanoma, and non-melanoma skin cancers, incidence increased substantially.[5] Risk factors behind post-transplant malignancy can be patient related, graft related, and medication related. Immunosuppressive medications are considered the most important reason.[6] Although it is accepted generally that increased risk of post-transplant malignancy is associated with dose of immunosuppressive medications, this observation is validated by the fact that number of episodes of acute rejection in 1st year post transplant, determine the likelihood of developing malignancy, probably because greater level of immunosuppression that is required,[7] whereas for different immunosuppressive agents, contributive effect is not proved yet, rather for mammalian target of rapamycin (mTOR) is reported to reduce cancer risk compared to other immunosuppressive agents.[8] Increased age, smoking, ultraviolet rays’ exposure, genetic factors, analgesic abuse, chronic viral infections, geographical factors, and transplantation with cytotoxic agents are other known risk factors.
MATERIAL AND METHODS
This retrospective study was carried out in Dubai hospital, Dubai. It includes 506 renal transplant recipients who were followed up in the span of 34 years (1989–2023). The primary immunosuppression consists of the drug combination of cyclosporine, tacrolimus, antimetabolite (mycophenolate mofetil [MMF] ,mycophenolic acid, or azathioprine) and steroids. Trough levels for tacrolimus and cyclosporine were maintained at 4–6 and 50–80 ug/L, respectively, over the long term. The daily dosage of MMF and mycophenolic acid (MPA) was 50–2000 and 360–1440 mg/day, respectively, also the daily dose of azathioprine was 0.5–1.5 mg/kg/day. Steroids were maintained at a dose of 5 mg/day or withdrawn according to immunologic risk. Recipients with suspected malignancy were evaluated with a detailed history focusing on weight loss, fatigue, pain, and mass. Laboratory workup includes alpha fetoprotein for liver cancer, carcinoma embryonic antigen for colon cancer, CA 15–3 for breast cancer, CA 125 for reproductive cancer, prostate-specific antigen for prostate cancer, and histopathology diagnosis using tissue biopsy. Qualitative data were displayed in cross tabulations, and quantitative data were described in terms of arithmetic mean ± standard deviation. Bivariate techniques were used for the initial evaluation of contrasts. Thus, Chi-square and Fisher’s exact tests were used for comparisons of frequencies of qualitative variables; Mann–Whitney test and the unpaired t-test were used for comparisons of means of two quantitative variables. P <0.05 was considered statistically significant. Graft and patient survival rates were assessed using the Kaplan–Meier method. All analyses were carried out using the Statistical Package for the Social Sciences (SPSS) for Windows, version 20.0 (SPSS Inc., Chicago, IL, USA).
RESULTS
A total of 506 renal transplant recipients were followed up at Dubai Hospital between January 1, 1989, and December 31, 2023. The demographic and clinical characteristics of renal transplant recipients with and without malignancy are listed in Table 1. The mean age of renal transplant recipients in our study population was 55 ± 21 years, while the mean age at the time of transplant was 39 ± 14.93 years, predominant gender was male (64.62%, n = 327). About 52.57% (n = 266) patients were from United Arab Emirates and diabetic nephropathy (21.93%, n = 111) was most common etiology of chronic kidney disease in transplant recipients, followed by chronic glomerulonephritis (21.14%, n = 107), obstructive uropathy (8.69%, n = 44), hypertension (7.70%, n = 39), autosomal dominant polycystic kidney disease (4.34%, n = 22), focal segmental glomerulosclerosis (3.95%, n = 20), and immunoglobulin A nephropathy (3.55%, n = 18). About 94.87% (n = 480) of transplant recipients had living donors, also 15 (2.96%) patients had a history of multiple renal transplants. Incidence of cytomegalovirus, hepatitis C virus, B.K virus, and hepatitis B virus infection were 13.83% (n = 70), 12.05% (n = 61), 4.94% (n = 23), and 2.17% (n = 11), respectively. Prednisolone was the most common immunosuppressive used in 98.81% (n = 500), followed by cyclosporine (66%, n = 334), mycophenolate mofetil (60.67%, n = 307), tacrolimus (27.47%, n = 139), sirolimus (12.45%, n = 63), and everolimus (0.39%, n = 2). Triple immunosuppressive was used in 91.30% (n = 462), also dual and quadruple immunosuppressive agents were used in 4.74% (n = 24) and 3.95% (n = 20), respectively. Biopsy-proven acute rejection (BPAR) is observed in 23.12% (n = 117) of transplant recipients. Incidence of malignancy in renal transplant recipients is 8.10% (n = 41), 60.9% (n = 25) of whom were male. The mean age is 59.07 ± 14.25 years, and age at transplant was 44 ± 24.04 years, most of malignancy patients were above 60 years of age (<40 years 14.8%, 40–60 years 36.8%, and >60 years 47.4%); also, majority of post-transplant malignancy patients had living donor (97.57%, n = 40). Diabetic nephropathy was the most common etiology in renal transplant recipients with or without malignancies (With malignancy vs. without malignancy: 19.51%, n = 8 vs. 22.15%, n = 103). Hematological malignancies were most common (n = 9, 21.9% [Figure 1]) in our study population that include post-transplant lymphoproliferative disorder (PTLD) and multiple myeloma in 7 (17.07%) and 2 (4.87%) patients, respectively, followed by skin and urological (14.6%, n = 6 each) cancers and colorectal cancer (12.19%, n = 5); also, other low incidence malignancies involving lung (n = 2, 4.87%), breast (n = 2, 4.87%), central nervous system (n = 2, 4.87%), genital organs (n = 2, 4.87%), endocrine (n = 2, 4.87%), liver (n = 2, 4.87%), prostate (n = 1, 2.43%), and oral cavity cancer (n = 1, 2.43%). Prednisolone (85.36%, n = 35), cyclosporine (60.97%, n = 25), and mycophenolate mofetil (56.09%, n = 23) were common immunosuppressive used in malignancy affected renal transplant recipients; also, cytomegalovirus, hepatitis C virus infection, and BPAR were observed in 17.07% (n = 7), 14.63% (n = 6), and 19.51% (n = 8) patients. Seven (17.07%) patients died due to malignancy-related complications. Overall survival rate of renal transplant recipients without malignancy in our study population is 100%, 95%, and 79% at 1, 5, and 10 years , respectively; 97%, 92%, and 87% in those with malignancy, respectively. To determine the association between predictors and post-transplant malignancy, Cox proportion hazard regression analysis was performed. Multivariate analysis reveals that cyclosporine usage poses a greater risk of developing cancer, whereas induction agents and maintenance immunosuppression, including antimetabolites, corticosteroids, and mTOR inhibitors, were not associated with a high risk of developing post-transplant malignancy [Table 2 and Figure 2].
| Characteristics | Number of renal transplant recipients (n=506) | With malignancy (41, 8.10%) | Without malignancy (465, 91.90%) |
|---|---|---|---|
| Recipient age (mean±standard deviation) years | 55±21 | 59.07±14.25 | 50.54±15.205 |
| Recipient age at transplantation (mean±standard deviation) years | 39±14.93 | 44±24.04 | 37.8±15.95 |
| Recipient gender (%) | |||
| Male | 327 (64.62) | 25 (60.97) | 302 (64.94) |
| Female | 179 (35.37) | 16 (39.03) | 163 (35.05) |
| Nationalities (%) | |||
| U.A.E | 266 (52.57) | 28 (68.29) | 238 (51.18) |
| India | 56 (11.06) | 2 (4.87) | 54 (11.61) |
| Pakistan | 45 (8.90) | 1 (2.43) | 44 (9.46) |
| Yemen | 20 (3.95) | 2 (4.87) | 18 (3.87) |
| Others | 119 (23.51) | 8 (19.51) | 111 (23.87) |
| Etiology of ESRD | |||
| Diabetic nephropathy | 111 (21.93) | 8 (19.51) | 103 (22.15) |
| Chronic glomerulonephritis | 107 (21.14) | 5 (12.19) | 102 (21.93) |
| Chronic allograft nephropathy/rejected renal transplant | 15 (2.96) | 4 (9.75) | 11 (2.36) |
| Hypertension | 39 (7.70) | 3 (7.31) | 36 (7.74) |
| Obstructive uropathy | 44 (8.69) | 2 (4.87) | 42 (9.03) |
| ADPKD | 22 (4.34) | 2 (4.87) | 20 (4.30) |
| Lupus erythematosus | 14 (2.76) | 1 (2.43) | 13 (2.79) |
| Alport syndrome | 6 (1.18) | 1 (2.43) | 5 (1.07) |
| Cystinosis | 3 (0.59) | 1 (2.43) | 2 (0.43) |
| F.S.G.S | 20 (3.95) | 3 (7.31) | 17 (3.65) |
| M.P.G.N | 13 (2.56) | 1 (2.43) | 12 (2.58) |
| IgA nephropathy | 18 (3.55) | 2 (4.87) | 16 (3.44) |
| Chronic tubulointerstitial Nephritis | 3 (0.59) | 1 (2.43) | 2 (0.43) |
| Unknown/others | 91 (17.98) | 7 (17.07) | 84 (18.06) |
| Donor type | |||
| Live related | 117 (23.12) | 6 (14.63) | 111 (23.87) |
| L ive unrelated | 363 (71.73) | 34 (82.92) | 329 (70.75) |
| Deceased | 26 (5.13) | 1 (2.43) | 25 (5.37) |
| History of multiple transplants | |||
| Yes | 15 (2.96) | 4 (9.7) | 11 (2.36) |
| No | 491 (97.03) | 37 (9.02) | 454 (97.63) |
| CMV | 70 (13.83) | 7 (17.07) | 63 (13.54) |
| BK virus: | 23 (4.94) | 0 (0.00) | 23 (4.94) |
| HCV | 61 (12.05) | 6 (14.63) | 55 (11.82) |
| HBV | 11 (2.17) | 2 (4.87) | 9 (1.93) |
| BPAR | 117 (23.12) | 8 (19.51) | 109 (23.44) |
| Prednisolone | 500 (98.81) | 35 (85.36) | 440 (94.62) |
| Azathioprine | 124 (24.50) | 12 (29.26) | 112 (24.08) |
| Cyclosporin | 334 (66) | 25 (60.97) | 309 (66.45) |
| Tacrolimus | 139 (27.47) | 8 (19.51) | 131 (28.17) |
| MMF | 307 (60.67) | 23 (56.09) | 284 (61.07) |
| Sirolimus | 63 (12.45) | 4 (9.75) | 59 (12.68) |
| Evorlimus | 2 (0.39) | 1 (2.43) | 1 (0.21) |
ADPKD: Autosomal dominant polycystic kidney disease, IgA: Immunoglobulin A, ESRD: End-stage renal disease, F.S.G.S: Focal segmental glomerulosclerosis, M.P.G.N: Membranoproliferative glomerulonephritis, BPAR: Biopsy-proven acute rejection, CMV: Cytomegalovirus: BK virus: B.K. virus, HCV: Hepatitis C virus, HBV: Hepatitis B virus, MMF: Mycophenolate mofetil. Figures in brackets represent number and percentage of patient survival with and without malignancy.
- Spectrum of malignancy after kidney transplantation.
| Clinical factors | Hazard ratio | P-value | |
|---|---|---|---|
| Unadjusted | Adjusted | ||
| Age at transplantation (years) | 0.06 | ||
| <30 | 1 (ref) | 1 (ref) | |
| 30–39 | 1.35 (0.25–7.36) | 1.41 (0.26–7.76) | |
| 40–49 | 2.04 (0.44–9.46) | 1.93 (0.41–9.02) | |
| 50–59 | 4.47 (1.02–19.62) | 4.35 (0.96–19.66) | |
| >60 | 10.36 (0.92–116.52) | 11.24 (0.92–135.62) | |
| Gender | 0.17 | ||
| Male | 1 (ref) | 1 (ref) | |
| Female | 0.62 (0.30–1.27) | 0.60 (0.29–0.25) | |
| Etiology | 0.86 | ||
| Diabetic nephropathy | 1 (ref) | 1 (ref) | |
| Chronic glomerulonephritis | 0.49 (0.06–3.63) | 0.79 (0.10–6.04) | |
| C.A.N./rejected renal transplant | 1.35 (0.25–7.36) | 1.41 (0.26–7.76) | |
| Hypertension | 0.99 (0.11–8.93) | 1.18 (0.13–0.84) | |
| Obstructive uropathy | 1.35 (0.25–7.36) | 1.41 (0.26–7.76) | |
| ADPKD | 0.97 (0.09–10.68) | 1.43 (0.13–16.10) | |
| Donor Type | 0.92 | ||
| Living | 1 (ref) | 1 (ref) | |
| Deceased | 1.53 (0.63–3.74) | 1.05 (0.40–2.80) | |
| Immunosuppressive drugs at time of malignancy diagnosis | |||
| Cyclosporine | 0.03 | ||
| No | 1 (ref) | 1 (ref) | |
| Yes | 7.33 (2.21–24.35) | 6.63 (1.86–20.83) | |
| Tacrolimus | 0.23 | ||
| No | 1 (ref) | 1 (ref) | |
| Yes | 0.39 (0.09–1.66) | 0.41 (0.09–1.77) | |
| Mycophenolate mofetil | 0.15 | ||
| No | 1 (ref) | 1 (ref) | |
| Yes | 0.84 (0.83–4.05) | 0.79 (0.81–3.98) | |
| Azathioprine | 0.7 | ||
| No | 1 (ref) | 1 (ref) | |
| Yes | 2.52 (1.09–5.80) | 2.25 (0.94–5.40) | |
| Corticosteroid | 0.1 | ||
| No | 1 (ref) | 1 (ref) | |
| Yes | 6.17 (0.84–45.49) | 5.48 (0.74–40.82) | |
| mTOR inhibitors | 0.52 | ||
| No | 1 (ref) | 1 (ref) | |
| Yes | 0.51 (0.07–3.73) | 0.52 (0.07–3.84) | |
| CNI+AZA | 0.13 | ||
| No | 1 (ref) | 1 (ref) | |
| Yes | 2.22 (0.98–4.99) | 1.92 (0.82–4.46) | |
| CNI_MPA | 0.15 | ||
| No | 1 (ref) | 1 (ref) | |
| Yes | 1.70 (0.83–3.46) | 1.70 (0.82–3.51) | |
| Immunosuppression regimen at the time of malignancy diagnosis | 0.05 | ||
| Single | 1 (ref) | 1 (ref) | |
| Double | 1.69 (0.21–13.73) | 1.66 (0.16–17.07) | |
| Triple | 1.40 (0.19–10.44) | 0.15 (0.01–1.71) | |
| >1 BPAR | 0.67 | ||
| No | 1 (ref) | 1 (ref) | |
| Yes | 0.88 (0.42–1.84) | 0.85 (0.40–1.80) | |
| G.F.R | 0.81 | ||
| ≥60 mL/min | 1 (ref) | 1 (ref) | |
| <60 mL/min | 1.08 (0.46–2.53) | 1.11 (0.47–2.61) | |
| Recipient CMV serostatus | 0.05 | ||
| Negative | 1 (ref) | 1 (ref) | |
| Positive | 0.60 (0.21–1.71) | 0.30 (0.09–0.99) | |
ADPKD: Autosomal dominant polycystic kidney disease, mTOR: Mammalian target of rapamycin, BPAR: Biopsy proven acute rejection, G.F.R: Glomerular filtration, CMV: Cytomegalovirus, CAN: Chronic allograft nephropathy, CNI: Calcineurin inhibitors (Cyclosporine & Tacrolimus), AZA: Azathioprine, MPA: Mycophenolic acid. Ref indicates reference point.
- Patient survival with and without malignancy.
DISCUSSION
Malignancy and kidney transplantation are long known and are one of the major causes of morbidity and mortality in renal transplant recipients.[5,9,10] Post-transplant malignancy incidence ranges from 2 to 31%[11] and is third most common cause of death in renal transplant recipient.[12] Malignancies in kidney transplant recipient can develop de novo, as recurrent malignancy in kidney transplant recipient or even transmit from donor.[13] After extensive research, several risk factors have been identified for the development of malignancy in transplant recipients, which include immunosuppression, chronic viral infections, geographical factors, genetic factors, sun exposure, and transplantation with cyclophosphamide.[13] In the period of 35 years, out of 506 follow-up transplant patients, 41 developed post-transplant malignancies of different organs, constituting an overall incidence of 8.10%, which is higher than most Asian and Mediterranean countries (China 5.1%, Egypt 4%, and Pakistan and India 2.5%).[14-16] The latency period between diagnosis and transplantation is 130.1 months, which is more than reported by Elserwy et al.[14] In our study population, there was a male preponderance (57.9%), which many other researchers also describe.[14,15,17] In our study population, the most common malignancies encountered included PTLD, which occurred in 7 (17.5%) patients, followed by nonmelanotic skin cancers (NMSC), urologic cancers (n=6, 14.6% each), and colorectal cancers (n=5,12.19%). The distribution pattern of post-transplant malignancies in our study population is different from the Western pattern and the pattern reported by other Mediterranean countries. The study at Duke University Medical Center of South Carolina concluded that 82% of malignancies were NMSC in organ transplant recipients. In comparison, PTLD and Kaposi constituted up to 11 and 6% of patients,[18]. In contrast, results from studies of Zagazig University, Egypt[14] and Baskent University, Turkey[19] suggest that Kaposi sarcoma was the most common malignancy in their study population (33% and 32%). The most common malignancy in our study population is post-transplant lymphoma, incidence is 17.5%, which is the same as reported by Elserwy et al.,[14] whereas a high incidence rate up to 60–75% is observed in South Asian studies.[15,16] In this study, PTLD developed on average 93 months after transplantation (36–192 months), whereas Elserwy et al.[14] reported even higher latency period for PTLD in the Egyptian population, which is contrary to the USRDS database, which observed higher rates of lymphoma in the first 12 months of transplantation.[20] The mean age for our transplant population is 38.7 ± 15.56 years, while USRDS suggests younger (<25 years) and older (>60 years) patients suffer high rates of post-transplant lymphoma.[20] Epstein-Barr virus (EBV) has conclusively been implicated in the pathogenesis of PTLD following kidney transplantation. Most of the PTLD cases (>50%) are EBV related and 20-fold increased risk of PTLD is associated with EBV mismatch between donor and recipient (EBV-negative recipient is grafted with EBV positive graft). In addition, primary EBV infection is a major risk factor for the early onset of EBV-positive PTLD in renal transplant recipients.[21,22] We were unable to analyze the association between EBV and PTLD in our study population, unfortunately, as the EBV virology data of our recipients were mostly unavailable. NMSCs are the second most common post-transplant malignancy in our study population; 14.6% (6 patients) of patients were suffering from it. Squamous cell carcinoma and basal cell carcinoma were found in three and two patients, respectively, and one patient had both. Incidence of NMSC is highest reported in western studies (82%), and up to 22% in Turkish renal transplant recipients.[19] A copious amount of sunshine exposure, lifelong immune suppression, and mutation of p53 and proto-oncogenes are potential factors causing skin cancers; despite this fact, only 7% of patients had NMSCs in an Egyptian study.[14] Genitourinary malignancies are not common in renal transplant recipients. University of Minnesota demonstrate 30 years that cumulative incidence of prostate, kidney, and urinary bladder cancer is 11%, 4%, and 1.5% in renal transplant recipient,[23] Furthermore, ten cases of genitourinary malignancies (nine urinary bladder and one prostate) were reported by Elserwy et al.[14] While in our study, a total of six patients had these malignancies, which constitute 20% of our study population. The predominant cancer was renal (Native = 2, Graft = 2), followed by urinary bladder (n = 2). Solid organ tumors (other than PTLD, skin, and genitourinary cancers) are usually aggressive and associated with high mortality in renal transplant recipients.[24,25] Colorectal cancer is the second most common cancer in the U.A.E. Its overall incidence is 14.1%, and 21% in males only.[26] It’s the third most common cancer in our study population (n = 5, 12.5%). In the U.A.E., the screening strategy for colorectal cancer begins at the age of 50 years with tools such as fecal occult blood and colonoscopy. Immunosuppressive as a cause of cancer is a topic of debate for a long time among transplant physicians. Multivariate analysis of our study data revealed that cyclosporin use was an independent risk factor in predicting an increased risk of cancer after renal transplant (P = 0.02). Theoretically, cyclosporine upregulates tumor growth factor-beta and vascular endothelial growth factor, which interfere with DNA damage repair and promote carcinogenesis [27,28], but literature reports show conflicting results. Shuttleworth et al. reported 22 and 9% incidence of cutaneous dysplasia associated with cyclosporine and azathioprine, respectively; also, Caillard et al. reported a relative risk of 2.7 of developing graft lymphoma in renal transplant recipients with cyclosporin use.[29,30] However, the Collaborative Transplant Study analysis by Opelz et al.[31] shows that cyclosporin does not increase the added risk for the development of non-Hodgkin lymphoma (NHL) compared to azathioprine/steroid treatment. In 2015, Traynor et al. studied the clinical effect of cytochrome P450 in renal transplant recipients and observed that the CYP3A4*22 allele was significantly associated with the development of malignancy after renal transplantation.[32] Induction agents are the cornerstone for the prevention of rejection after transplantation. The relationship between cancer development and induction agents is well studied. Opelz and Cherikh observed a high incidence of NHL in renal transplant recipients, who receive anti-lymphocyte antibodies for induction or treatment of rejection;[31,33] also, Caillard et al. reported a 1.4-fold higher risk of developing PTLD with polyclonal induction agents.[30] Nonetheless, we did not observe increased risk of malignancy with lymphocyte-depleting agents; this is consistent with Webster et al.’s meta-analysis, which showed that the risk of malignancy at 1 year was statistically insignificant among monoclonal and polyclonal induction agents, though the authors appreciate that the period was not adequate to detect new malignancies.[34] For maintenance immunosuppressive, we observe lower incidence of malignancy with tacrolimus as compared to cyclosporine but this difference was not statistically significant as sample size was small; also, there was statistically insignificant difference in patients on azathioprine and those on mycophenolate, this is similar to the finding of Bustami et al. who also reported low incidence of malignancy with tacrolimus compared to cyclosporine in those renal transplant recipients who did not receive induction therapy.[35] Gallagher et al. studied three different immunosuppressive regimens on 489 renal transplant recipients, and no association was found between the type of regimen and the development of skin and non-skin cancer.[36] In our study, there is no statistically significant difference in the incidence of post-transplant malignancy between a combination of calcineurin inhibitor and azathioprine versus calcineurin inhibitor and mycophenolate. Other than immunosuppressive medications, older age is also recognized risk factor for de novo cancer development in renal transplant recipients.[3,37] However, in our study population, we did not find a significant association between older age, male gender, and diabetes mellitus. We did not find a significant association between CMV seropositivity and malignancy in renal transplant recipients. Nonetheless, Courivaud et al. reported a 30% incidence of post-transplant malignancy in CMV seropositive renal transplant recipients.[38] Studies to date on malignancy-related mortality in renal transplant recipients are quite limited. In our study, 7 (17.07%) patients out of 41 died due to malignancy related complications in the last 35 years. Farrugia et al. listed malignancy third most common cause of death in renal transplant recipient, which reported 367 deaths in 19,103 patients, crude mortality rate is 361 malignancy-related deaths/100,000 patients per year;[39] also, Au et al. reported 923 cancer related deaths in 16,820 transplant recipient, standardized mortality rates (SMRs) reaching up to 2.6.[40] Our study has certain limitations. First, the collected data are retrospective, though trained investigators entered them to ensure accuracy and completeness. Furthermore, common risk factors related to post-transplant malignancy were lacking, such as family history of malignancy, smoking, alcohol consumption, and analgesic abuse. Finally, changes in immunosuppression may affect our ability to correlate the impact of immunosuppression on post-transplant malignancy.
CONCLUSION
In this study, we observe that kidney transplantation is associated with a high frequency of malignancy and a high mortality rate as compared to the general population. Newer immunosuppressive agents and antibody induction agents do not increase the risk of malignancy. However, we found that cyclosporine use is a significant predictor for the development of post-transplant malignancy . Large prospective studies across the nation are needed in the future for a better understanding of malignancy-related incidence and mortality in renal transplant recipients. Also, this study may serve as a baseline for future comparison in the hope of providing insight into those areas where focused support and intervention are needed. Finally, with the help of this study, we implicate the need for a robust screening program for developing strategies for cancer surveillance in renal transplant recipients.
Data availability:
The data that underlie the findings of this article are available from the corresponding author (Kashif Gulzar) on reasonable request.
Acknowledgment:
The authors sincerely appreciate the time and effort of all who contributed.
Author contributions:
KG and FA are involved in the conception and design of the study. FA, AAS, HA, MA, SN, OEO, HY, and SA contributed to data collection. KG performed data analysis and manuscript writing. MR and AA provided supervision and intellectual input.
Ethical approval:
The research/study approved by the Institutional Review Board at Dubai Scientific Research Ethics Committee extension, number DSREC-12/2019_01, dated 5th February 2020.
Declaration of patient consent:
Patient’s consent was not required as patients identity is not disclosed or compromised.
Conflicts of interest:
There are no conflicts of interest.
Use of artificial intelligence (AI)-assisted technology for manuscript preparation:
The authors confirm that there was no use of artificial intelligence (AI)-assisted technology for assisting in the writing or editing of the manuscript and no images were manipulated using AI.
Financial support and sponsorship: Nil.
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