nephrology

1. AN UPDATE ON CANCER AFTER
KIDNEY TRANSPLANTATION
NEPHROLDIAL TRANSPLANT
SCIENTHIA SANJEEVANI
MODERATOR –DR GAGANDEEP CHHABRA
JOURNAL CLUB
22/11/18

2. INTRODUCTION
• CKD and cancer have bidirectional relationship- cancer can cause CKD and CKD itself a risk
factor for cancer.
• Kidney transplant recipients (KTRs) - 2- to 3-fold increased cancer risk when compared with the
general population.
• Causes -
Related to CKD including cancers of the kidney, urinary tract and thyroid
Related to oncogenic viruses that include non-Hodgkin lymphoma, cervical cancer,
nonmelanoma skin cancer and Kaposi’s sarcoma.

3. CKD AND CANCER
Predisposing factors
• chronic infections
• increased susceptibility to oncogenic viruses
(e.g., HPV, hep B and C)
• altered immune system
• acquired cystic disease in ESRD patients is a well
known Risk for RCC
SPECIFIC RISK FACTORS FOR cancer of the
kidney/renal pelvis and bladder
• acquired renal cystic disease in dialysis patient
• Balkan nephropathy
• aristolochic acid exposure,
• analgesic abuse, cyclosphosphamide

4. CANCER SCREENING IN ESRD
• Over one-third of patients with limited life expectancies still receive such testing with little
likelihood of benefit
• early detection through screening will lead to the need for additional procedures and tests with
the potential for harm.

5. Incidence of cancer in ESRD

6. SCREENING IN ESRD-not easy!!

7. Use individual approach
• Clinical judgment is critical
Who are going to benefit ??
• patients with acceptable life expectancy benefit from age-appropriate cancer screening.
• strong family history of cancer or specific risks
• candidates for transplantation

8. Cancer surveillance as pre-transplant work-
up
• No clinical practice guidelines have specific recommendations for surveillance of pretransplant
cancers
• In general, applying the cancer surveillance program used in the regional general population
for the evaluation of potential KTRs is a reasonable approach

9. Ratio observed/expected malignancies in graft recipients
Christian Morath et al. JASN 2004;15:1582-1588
©2004 by American Society of Nephrology

10. Relative risk of cancer
Lip cancer >10 fold
Kaposi sarcoma >50 fold
Anogenital area >4 fold
Colorectal cancer, lung cancer 40-50 %
NHL >8 fold

11. DE NOVO CANCER IN KIDNEY
TRANSPLANT RECIPIENTS
• KTRs are approximately two to three times more likely to develop cancers than the age- and
gender-matched general population
Risk factors of cancer after kidney transplant
• Related to ESRD (RCC and urinary tract infection)
• Immunosuppression
• Viral infections

12. Immunosuppresive drug
• Most important modifiable factor
• antilymphocyte globulin, particularly OKT3 (muromonab-CD3) lymphoma
• Cyclosporine can promote carcinogenesis
• Tacrolimus  stimulate TGFβ expression and exert neoplastic effects
-Collaborative Transplant Study (CTS) database, deceased KTRs had a 2-fold higher risk
of developing lymphoma with tacrolimus than with cycloporine.
• In MMF group there was even a trend toward a lower risk of malignancy in both registries
[OPTN/UNOS and CTS and a significant increase in time to cancers in the CTS database
-can be due to lower rates of acute rejection in mycophenolate-containing regimens.

13. • mTOR inhibitors may confer a lower risk of cancer
-Rapamune Maintenance Regimen Study, patients who received sirolimus-based, CNI-free
therapy after cyclosporine withdrawal at Month 3 had a reduced incidence of both skin and
nonskin malignancies at 5 years after kidney transplantation compared with those who received
sirolimus therapy combined with cyclosporine
-A systematic review and meta-analysis of 21 randomized trials demonstrated that sirolimus was
associated with a 40% decrease in the overall risk of and a 56% decrease in the risk of
nonmelanoma skin cancer when compared with controls. This result was most pronounced in
patients who converted from an established immunosuppressive regimen to sirolimus with an
overall decrease in malignancy risk
- Transplant registry study showed that the overall cancer incidence was lower during sirolimus
use the incidence of prostate cancer was higher in the sirolimus group, which could be
by the screening effect or detection bias. The incidence of non prostate cancers was similar or
lower with sirolimus use

14. • Belatacept is associated with an elevated risk of posttransplant lymphoproliferative disease
(PTLD),especially within the central nervous system

15. Viral infection and cancers

16. BKV virus
• urothelial carcinogenesis
• BKV nephropathy had almost a 3-fold increased incidence of bladder cancers when compared
patients without BK nephropathy

17. RCC IN KTP
• most common urologic malignancy following kidney transplantation
• Disproportionately greater incidence of RCC compared to the general population, and the
elevation is substantially higher for papillary than for clear cell tumors.
• Approximately 0.5% and 1.0% of kidney recipients are diagnosed with RCC within 5 and 10 years
after transplant, respectively
• biphasic onset of RCC following transplant: a high risk immediately after transplant, a fall in risk
until roughly 2.5 years after transplant, and then a subsequent gradual increase with time

18. Risk factors for RCC post KTP
• highest in individuals who had prolonged dialysis prior to transplantation
• increased risk related to induction therapy with polyclonal antibodies (for ccRCC) and IL2
antagonists (for papillary RCC)
• early RCC tumors likely arise in the native kidney as a result of malignant transformation of renal
cysts that had developed before transplantation as a part of ACKD

19. Prognosis
• overall risk of cancer death is 2.3 times greater after kidney transplantation in a Chinese registry
study.
• The risk is particularly high in certain types of cancers such as non- Hodgkin lymphoma, kidney
and bladder cancers.
• A recent large cohort study showed that a history of previous malignancy does not have an
additive effect on cancer-specific and all-cause mortality in KTRs who develop cancer

20. Management of posttransplant cancers
• mainstay of treatment for posttransplant cancers, especially those related to immunosuppressed
status such as PTLD and KS, is the judicious reduction of immunosuppression.
• Should be balanced against the risk of allograft rejection or deterioration in kidney function
• In a study of 15 KTRs diagnosed with KS, the lesions in all patients had disappeared 3months
after sirolimus was substituted for cyclosporine
• In another cohort study of 20 KTRs who developed posttransplant cancers, CNIs, azathioprine or
MMF were discontinued abruptly while sirolimus was introduced. After a mean followup of
14months, two patients with large B-cell lymphoma and four with KS had full regression of
tumors. On the other hand, those patients with advanced or disseminated cancers showed
tumor progression. All patients, except one with impaired kidney function at the start ofmTOR
inhibitor treatment, had allograftfunction preserved

21. Novel targeted therapy in kidney
transplant
• Check point inhibitors which enhance antitumor T-cell immunity leading to significant clinical
benefits in tumor regression and prolonged stabilization of various types of cancer
antiprogram death 1 (PD-1)
 anticytotoxic T-lymphocyte-associated protein 4 (CTLA-4)
• B cells may also be activated as a direct effect on memory B cells expressing PD-1 if there was a
reduction in immunosuppression or prior sensitization of the transplanted organ
• increases the activation of T cells, not only against cancer cells, but also against other cells such as
kidney allograft donor antigens
• these antibodies were associated with cell- and antibody-mediated rejection in KTRs
• postulated that a regimen of preemptive glucocorticoid and
• mTOR inhibitor may be able to prevent the adverse immune response of immune checkpoint inhibitor
in the KTR

22. Cancer surveillance

23. Conclusion
• a personalized approach based on the individual cancer risk, life expectancy and concurrent
comorbidities have to be adopted.
• Factors such as competing risks of cardiovascular deaths, life expectancies and differences in
diagnostic performance should be considered