RENAL DATA FROM THE ARAB WORLD
|Year : 2017 | Volume
| Issue : 3 | Page : 579-588
|Postrenal transplant malignancy: Incidence, risk factors, and prognosis
Nabil Abdelfadil Elserwy1, Esam Elden Lotfy2, Mohamad Ashraf Fouda1, Medhat Ibrahim Mahmoud2, Ahmed Farouk Donia2, Mohamed Elsayed Mashaly1, Mohamed Hamed Abbas1, Mohamed Megahed Abuelmagd1, Rasha Kamal Abouelenein1, Mabrouk Ibrahim Ismail2, Mohamed Adel Bakr1
1 Department of Nephrology, The Urology-Nephrology Center, Mansoura, Egypt
2 Department of Nephrology, Zagazig University, Zagazig, Egypt
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|Date of Web Publication||18-May-2017|
| Abstract|| |
The newer and potent immunosuppressive agents have successfully reduced the risk of rejection after kidney transplantation, but the development of cardiovascular diseases, infections, and malignancy is major factors limiting their success. Posttransplantation malignancy is the second most common cause of death in renal transplant recipients after cardiovascular disease; it is expected that mortality due to malignancy may become the most common cause of death within the next two decades. This study is designed to evaluate the incidence, risk factors, and types of malignancies occurring after renal transplantation and their impact on patient and graft survival. A total of 2288 patients underwent living donor renal allotransplantation in the Urology and Nephrology Center, Mansoura University, during the period between 1975 and 2011. Among these patients, 100 patients developed posttransplantation malignancy. Patients were categorized into five major groups according to their type of malignancy; Kaposi’s sarcoma (KS), non-Kaposi’s skin tumors (non-KS), posttransplant lymphoproliferative disorders (PTLD), solid tumors, and genitourinary and reproductive system (GU and RS). Overall, the incidence of cancer in renal transplant recipients was 4%. There were 83 male (83%) and 17 female patients (17%). The most frequent cancer was KS seen in 33 patients (33%). The lowest median time to development of cancer was observed in KS (35 months). The highest median time to development of cancer was observed in PTLD (133 months). The best graft survival was observed in PTLD and the worst in non-KS tumors. The best patient survival was observed in KS and the worst in GU and RS tumors. Azathioprine-based regimen was associated with a higher rate of cancer. The number of patients who died was 65 (65%). Our results indicate that the occurrence of malignancy has an important impact on short- and long-term graft and patient survival.
|How to cite this article:|
Elserwy NA, Lotfy EE, Fouda MA, Mahmoud MI, Donia AF, Mashaly ME, Abbas MH, Abuelmagd MM, Abouelenein RK, Ismail MI, Bakr MA. Postrenal transplant malignancy: Incidence, risk factors, and prognosis. Saudi J Kidney Dis Transpl 2017;28:579-88
|How to cite this URL:|
Elserwy NA, Lotfy EE, Fouda MA, Mahmoud MI, Donia AF, Mashaly ME, Abbas MH, Abuelmagd MM, Abouelenein RK, Ismail MI, Bakr MA. Postrenal transplant malignancy: Incidence, risk factors, and prognosis. Saudi J Kidney Dis Transpl [serial online] 2017 [cited 2019 Jul 23];28:579-88. Available from: http://www.sjkdt.org/text.asp?2017/28/3/579/206456
| Introduction|| |
Kidney transplantation is generally believed to be the best treatment modality for patients with end-stage renal disease since it improves both the quality of life and lifespan of pa- tients. Although the new and potent immuno- suppressive agents have successfully reduced the risk of rejection after kidney transplantation, development of cardiovascular diseases, infections, and malignancy is major limiting factors to their success. The risk of developing malignancy in renal transplant recipients is 3–4 times higher than in the general population, and the risk of certain types of malignancy, such as Kaposi’s sarcoma (KS), is as high as 20–500 folds. In addition, the cancer mortality rate is 2–3 times higher in kidney transplant recipients than in the general population. Furthermore, posttransplant malignancy is the second most common cause of death in renal transplant recipients after cardiovascular disease, and it is expected to become the most common cause within the next two decades. Many risk factors have been identified for the development of malignancies in renal transplant recipients, the most common being immunosuppression. This is validated by the observation that episodes of graft rejection in the 1st year after transplantation increase the likelihood of developing a malignancy, possibly because of the greater level of immunosuppression that is required. Other risk factors include chronic viral infections, genetic factors, advanced age, cigarette smoking, and exposure to ultraviolet radiation, analgesic abuse, geographical factors, and transplantation with cytotoxic agents such as cyclophosphamide.
| Patients and Methods|| |
This retrospective study was carried out on 100 kidney transplant recipients who underwent kidney transplantation at the Urology and Nephrology Center in Mansoura University in the period between March 1976 and December 2011 and developed malignancy post transplant. Some selected patients were compared with 300 matched control kidney transplantations performed during the same period.
Patients with other organ transplants, history of previous malignancy, and those with previous kidney transplantation were excluded from the study.
Cancer patients were distributed into five major groups based on the types of malignancy according to the report of Einollahi et al, 2012.
- Group 1: KS: 33 patients
- Group 2: Genitourinary and reproductive system (GU and RS): 15 patients including bladder cancer in nine patients (all male), breast cancer in 5 (4 male and 1 female), and prostatic cancer in one patient
- Group 3: Posttransplant lymphoprolife- rative disorder (PTLD): 17 patients
- Group 4: Solid tumors: 28 patients with malignancies other than skin, GU, and PTLD
- Group 5: Non-KS tumors (Non-KS): seven patients including squamous cell carcinoma in five and basal cell carcinoma in two patients.
All patients were evaluated before kidney transplantation; thorough history was taken with special stress on the original kidney disease, hypertension, diabetes mellitus, hepatitis С or В viral infection, history of infection, history of malignancy, and duration on hemodialysis. Thorough clinical examination and laboratory investigations including immuno- logical workup were performed.
All patients received the graft from living related donors except in some situations, in which unrelated donors were accepted; this included the presence of hereditary kidney disease, second transplant, and absence of medically suitable related donor.
After kidney transplantation, our recipients were primarily immunosuppressed according to the standard protocols including different immunosuppressive drugs such as steroids, tacrolimus, cyclosporine, mycophenolate mo- fetil, sirolimus, azathioprine.
When malignancy was suspected, a detailed history was taken with special emphasis on weight loss, fatigue, pain, and mass (palpable or visible).
Laboratory workup including tumor markers such as alpha-fetoprotein for liver cancer, CA 15–3 level for breast cancer, CA 125 level for reproductive cancer, carcinoembryonic antigen level for colon cancer, prostate-specific antigen for prostatic cancer, and histopathological diagnosis using tissue biopsy.
| Statistical Analysis|| |
Qualitative data were displayed in cross tabulations, and quantitative data were described in terms of arithmetic mean ± standard deviation. Bivariate techniques were used for 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 /?-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 Kaplan–Meier method. All analyses were carried out using the Statistical Package for the Social Sciences (SPSS) for Windows, version 16.0 (SPSS Inc., Chicago, IL, USA).
| Results|| |
From March 1976 to December 2011, 2288 living donor kidney transplants were performed at the Urology and Nephrology Center in Mansoura University. Of these, 100 patients developed posttransplant malignancy including 83 males and 17 females with a mean age of 35.11 ± 10.04 years. The mean age at diagnosis of the tumor was 43 ± 10 years.
Demographic data of donors and recipients
The mean age of recipients was comparable in both study and control groups (35.1 years for study group versus 34.9 years for the control group), but mean age of donors was lower in the study group (34.1 years) than the control group (37.7 years) with statistical significance (P = 0.0003). There were more male recipients than females (83% and 81.7%, respectively), whereas there were more female donors than males (56% and 58.7%, respectively); there was no statistical significance. Majority of the donors were related [Table 1].
|Table 1: Demographic characteristics and immunological work-up of the study patients.|
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Pretransplant human leukocyte antigen (HLA) Class-I and HLA-DR were tested, and there was no statistically significant difference between the malignant and control groups regarding HLA matching, DR matching, and blood group matching [Table 2].
|Table 2: Pretransplant medical disorder and virology workup in the study patients.|
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Original kidney disease and pretransplant dialysis
No statistically significant difference was obtained between the two groups regarding original kidney disease with most of them having unknown original kidney disease (56% in the study group and 67% in the control group) [Table 2]
Virology workup, schistosomiasis, and dialysis pretransplant
Both groups are comparable to each other regarding the prevalence of hepatitis C virus and hepatitis B virus infection, with no statistical significance; schistosomiasis was more prevalent in both donors and recipients who developed malignancy in relation to the control group (P = 0.0001). Regarding pretrans- plant dialysis, more patients in the study group were treated with hemodialysis (HD) when compared with the control group with statistical significance (P = 0.04); also, the mean duration on dialysis was longer in the study group (P = 0.03) [Table 2].
Median time for diagnosis of malignancy
The lowest median time to development of cancer was observed in KS (35 months) and the highest median time was observed in PTLD (133 months; [Table 3]).
|Table 3: Median time for diagnosis of malignancy and follow-up after transplantation.|
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Graft and patient survival
The best graft survival was observed in PTLD and the worst in non-KS tumors (P <0.001) [Figure 1].
The best overall patient survival rate after treatment of malignancy was observed in patients with KS [21.4 years; 95% confidence interval (CI): 16.9–25.39] and the worst overall survival rate was seen in patients with GU and RS tumors, which was 12.3 years (95% CI: 8.83–15.76) ([Figure 2] and [Table 4]).
|Table 4: Comparison among malignant groups regarding mean survival time in our study group.|
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Risk factors for development of malignancy in kidney transplants assessed by univariate analysis
On univariate analysis, the significant risk factors for posttransplant malignancy included consanguinity (P = 0.004), pretransplant HD (P = 0.004), and primary immunosuppression (P = 0.001). The significant variables obtained from univariate analysis were subjected to multivariate analysis, and it showed two independent risk factors for the development of malignancy, namely, pretransplant HD and consanguinity [Table 5] and [Table 6].
|Table 5: Risk factors for development of malignancy in kidney transplants assessed by univariate analysis.|
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| Discussion|| |
With the advances made in the management of infections and cardiovascular complications after renal transplantation, malignancy may soon become an increasingly common cause of mortality in these patients. The incidence of posttransplant cancer ranges from 2% to 31%. Analyses of multiple databases have shown that malignancies are approximately two to four folds more common in heart transplant recipients compared with renal transplant recipients; this is thought to reflect the greater degree of immunosuppression required by heart transplant recipients. Several factors have been linked to the increased incidence of malignancy among transplant recipients including sun exposure, extent and duration of immuno- suppression, concomitant viral infection, genetic factors, conventional risk factors, and, pretrans- plantation dialysis. In rare cases, malignancy has been transferred from the organ donor.
The overall incidence of malignancy in our kidney transplant population was 4% with a latency period between diagnosis and transplantation of 94 months. The overall incidence is lower than what has been reported by other researchers,, but similar to some other reports, which reported an accumulated data on 7192 organ transplant recipients of different ethnic groups and geographic distribution, giving an average cancer incidence of 6%.
The lower incidence in our patients could be explained by the fact that our patients had a lower mean age at transplantation of 35 ± 10 years, whereas in the series reported by Penn, the mean age was 41.9 ± 10 years. Furthermore, our patients received living donor grafts with lower maintenance immunosuppression than in cadaveric donor transplants.,
Our data showed that the overall mean time between transplantation and development of malignancy was 35 ± 8 months in KS (the earliest malignancy to develop in our patient), 112 months for solid tumors, 84 months for non-Kaposi, 133 months for PTLD, and 121 months for GU tumors; this is in agreement with other researches.,,
The distribution of different cancer types among our Egyptian kidney transplant recipients was different from that of the nontrans- plant population as KS represented nearly one- third of malignancies that developed in our posttransplant population. This is similar to the Mediterranean, African, Jewish, Turkey, and Arabic populations as KS occurs 500 times more frequently in transplant recipients than normal individuals, which may be due to geographic distribution of human herpes virus 8. This is different from other reports.,, As reported in Western countries, KS constitutes about 0.5%, and therefore, it seems that living in hot climate as well as geographic location may be prognostic factors in posttransplant malignancy. Furthermore, HLA antigens may have a role; in Saudi Arabia, an increased incidence of HLA-A2 has been reported in patients who developed KS as reported by Qunibiet.
In our study, 28 patients (28%) were diagnosed to have solid tumors, the most common type being hepatocellular carcinoma seen in 10 patients. Despite complete withdrawal of immu- nosuppression, all patients died from severe septicemia and consumption coagulopathy.
Solid tumors were the second most common tumors in this study, which is different from other workers who found that solid tumors, especially gastric cancer, were the most common postrenal transplant malignancies; this was perhaps due to regular endoscopic screening, Helicobacter pylori infections, and genetic predisposition.,,, Our results were also different from Yunus et al who reported that solid tumor was uncommon in Pakistan and that PTLD was most common malignancy.
Solid organ cancers are associated with a far worse prognosis in renal transplant recipients due to aggressive course (23 patients died); this is in agreement with other workers,,, and in contradiction with others who showed that NHL had the highest incidence and highest mortality because NHL shows predominant extranodal distribution and had a more aggressive course.,,
In our study, the incidence of non-Kaposi skin cancer (non-Kaposi SC) was only 7%, which was unexpectedly low despite the fact that our patients are exposed to copious sunshine. The high incidence of KS and rarity of other skin cancers in our transplant population could be postulated to racial and genetic background. In contradiction with our results, ,,, others have reported that non-Kaposi SC was the most common cancer encountered in posttransplant recipients (36.9%), which may be due to lifelong immunosuppression which is an important factor in the pathogenesis of non-Kaposi SC. Furthermore, mutations of p53 and proto- oncogenes occur with the use of immuno- suppression which, in turn, leads to the development of non-Kaposi SC.
In evaluation of the possible risk factors, the independent risk factors of malignancy in our study were pretransplant HD. Although dialysis patients do not generally receive immuno- suppressive medications, there may be onco- genic viral infections due to repeated blood handling. In addition, there is reduced immune surveillance against a variety of nonviral tumor antigens since uremia is associated with many abnormalities in the immune system. Furthermore, uremia is an important promoting factor for urinary tract cancers due to the development of acquired renal cystic disease.
Consanguinity also was an independent risk factor; this may be due to a greater degree of immunosuppression required which may suppress the ability to discover and destroy malignant cells induced by various carcinogens, and also chronic antigenic stimulation by the foreign antigen of the transplanted organs may overcome the partially depressed immune system and lead to malignancy.
| Conclusions|| |
We conclude that occurrence of malignancy has an important impact on short- and long- term graft and patient survival. Hence, meticulous monitoring of the patients and their immunosuppression protocols is crucial for patient and graft safety.
| Acknowledgment|| |
Authors want to thank all the authors for their valuable effort in this manuscript.
Conflict of interest: None declared.
| References|| |
Navarro MD, López-Andréu M, Rodriguez- Benot A, Aguera ML, Del Castillo D, Aljama P. Cancer incidence and survival in kidney transplant patients. Transplant Proc 2008;40: 2936-40.
Marcén R. Immunosuppressive drugs in kidney transplantation: Impact on patient survival, and incidence of cardiovascular disease, malignancy and infection. Drugs 2009;69:2227-43.
Guba M, von Breitenbuch P, Steinbauer M, et al. Rapamycin inhibits primary and metastatic tumor growth by antiangiogenesis: Involvement of vascular endothelial growth factor. Nat Med 2002;8:128-35.
Rees L. Long-term outcome after renal transplantation in childhood. Pediatr Nephrol 2009; 24:475-84.
Wimmer CD, Rentsch M, Crispin A, et al. The janus face of immunosuppression - De novo malignancy after renal transplantation: The experience of the Transplantation Center Munich. Kidney Int 2007;71:1271-8.
Caforio AL, Fortina AB, Piaserico S, et al. Skin cancer in heart transplant recipients: Risk factor analysis and relevance of immuno- suppressive therapy. Circulation 2000;102 19 Suppl 3:III222-7.
Morath C, Mueller M, Goldschmidt H, Schwenger V, Opelz G, Zeier M. Malignancy in renal transplantation. J Am Soc Nephrol 2004;15:1582-8.
Einollahi B, Rostami Z, Nourbala MH, et al. Incidence of malignancy after living kidney transplantation: A multicenter study from Iran. J Cancer 2012;3:246-56.
Vasudev B, Hariharan S. Cancer after renal transplantation. Curr Opin Nephrol Hypertens 2007;16:523-8.
Végso G, Tóth M, Hídvégi M, et al. Malignancies after renal transplantation during 33 years at a single center. Pathol Oncol Res 2007;13:63-9.
Penn I. Malignant melanoma in organ allograft recipients. Transplantation 1996;61:274-8.
Bordea C, Wojnarowska F, Millard PR, Doll H, Welsh K, Morris PJ. Skin cancers in renal- transplant recipients occur more frequently than previously recognized in a temperate climate. Transplantation 2004;77:574-9.
Penn I. Cancers following cyclosporine therapy. Transplantation 1987;43:32-5.
Yang TC, Shu KH, Cheng CH, Wu MJ, Lian JD. Malignancy following renal transplantation. Zhonghua Yi Xue Za Zhi (Taipei) 1998; 61:281-8.
Vogt P, Frei U, Repp H, Bunzendahl H, Oldhafer K, Pichlmayr R. Malignant tumours in renal transplant recipients receiving cyclos- porin: Survey of 598 first-kidney transplantations. Nephrol Dial Transplant 1990;5:282-8.
Hiesse C, Kriaa F, Rieu P, et al. Incidence and type of malignancies occurring after renal transplantation in conventionally and cyclosporine- treated recipients: Analysis of a 20-year period in 1600 patients. Transplant Proc 1995;27:972-4.
Dantal J, Hourmant M, Cantarovich D, et al. Effect of long-term immunosuppression in kidney-graft recipients on cancer incidence: Randomised comparison of two cyclosporin regimens. Lancet 1998;351:623-8.
Qunibi W, Akhtar M, Sheth K, et al. Kaposi’s sarcoma: The most common tumor after renal transplantation in Saudi Arabia. Am J Med 1988;84:225-32.
Kasiske BL, Snyder JJ, Gilbertson DT, Wang C. Cancer after kidney transplantation in the United States. Am J Transplant 2004;4:905-13.
Einollahi B, Lessan-Pezeshki M, Nourbala MH, et al. Kaposi’s sarcoma following living donor kidney transplantation: Review of 7,939 recipients. Int Urol Nephrol 2009;41:679-85.
Hoshida Y, Tsukuma H, Yasunaga Y, et al. Cancer risk after renal transplantation in Japan. Int J Cancer 1997;71:517-20.
Ju MK, Joo DJ, Kim SJ, et al. Chronologically different incidences of post-transplant malignancies in renal transplant recipients: Single center experience. Transpl Int 2009;22:644-53.
Hwang JK, Moon IS, Kim JI. Malignancies after kidney transplantation: A 40-year singlecenter experience in Korea. Transpl Int 2011; 24:716-21.
Lee IS, Kim TH, Kim YH, Yook JH, Kim BS, Han DJ. Clinical significance of gastric cancer surveillance in renal transplant recipients. World J Surg 2012;36:1806-10.
Yunus M, Aziz T, Mubarak M. Post-transplant malignancies in renal transplant patients. Asian Pac J Cancer Prev 2012;13:575-8.
Winkelhorst JT, Brokelman WJ, Tiggeler RG, Wobbes T. Incidence and clinical course of de- novo malignancies in renal allograft recipients. Eur J Surg Oncol 2001;27:409-13.
Dantal J, Pohanka E. Malignancies in renal transplantation: An unmet medical need. Nephrol Dial Transplant 2007;22 Suppl 1:i4-10.
Kazi J, Mubarak M, Hashmi A, et al. Incidence and pattern of post-transplant malignancies in living related donor programme: An experience with 1000 renal transplant patients. J Nephrol Urol Transplant 2001;2:133-6.
Cheung CY, Lam MF, Chu KH, et al. Malignancies after kidney transplantation: Hong Kong renal registry. Am J Transplant 2012;12:3039-46.
Euvrard S, Kanitakis J, Claudy A. Skin cancers after organ transplantation. N Engl J Med 2003;348:1681-91.
Adami J, Gäbel H, Lindelöf B, et al. Cancer risk following organ transplantation: A nationwide cohort study in Sweden. Br J Cancer 2003;89:1221-7.
Stallone G, Schena A, Infante B, et al. Sirolimus for Kaposi’s sarcoma in renal-transplant recipients. N Engl J Med 2005;352:1317-23.
Kato S, Chmielewski M, Honda H, et al. Aspects of immune dysfunction in end-stage renal disease. Clin J Am Soc Nephrol 2008;3 (5) :1526-33.
Escudier B, Porta C, Schmidinger M, et al. Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow- up. Ann Oncol 2014;25 Suppl 3:iii49-56.
Nabil Abdelfadil Elserwy
Department of Nephrology, The Urology-Nephrology Center, Mansoura
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]
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