|Year : 2021 | Volume
| Issue : 1 | Page : 81-88
Immunosuppression after the diagnosis of renal allograft renal cell carcinoma in two transplant recipients: Case reports and review of the literature
Joyita Bharati1, Parikshaa Gupta2, Ujjwal Gorsi3, Ravimohan S Mavuduru4, Vivek Kumar1, Manish Rathi1, Harbir Singh Kohli1, Raja Ramachandran1
1 Department of Nephrology, Post Graduate Institute of Medical Education and Research, Chandigarh, India
2 Department of Cytology and Gynecological Pathology, Post Graduate Institute of Medical Education and Research, Chandigarh, India
3 Department of Radiology, Post Graduate Institute of Medical Education and Research, Chandigarh, India
4 Department of Urology, Post Graduate Institute of Medical Education and Research, Chandigarh, India
|Date of Submission||30-Jun-2020|
|Date of Acceptance||22-Nov-2020|
|Date of Web Publication||31-Mar-2021|
Dr. Raja Ramachandran
Department of Nephrology, Post Graduate Institute of Medical Education and Research, Chandigarh
Source of Support: None, Conflict of Interest: None
Renal cell carcinoma (RCC) is a common solid malignancy among renal transplant recipients. While it commonly involves the native kidneys, renal allograft RCC is increasingly being reported in renal transplant recipients. Most often, renal allograft RCCs are locally confined and nephron-sparing interventions are successful treatments. Immunosuppression is typically reduced in transplant recipients who develop malignancies; however, there is no consensus on the same for transplant recipients with a diagnosis of RCC. We report two cases of renal allograft RCC who were successfully managed with ablative therapy and reduction of immunosuppression. However, both the patients developed irreversible graft dysfunction and are wait-listed in the deceased donor program for the second transplant. We highlight the deficiency of evidence and the need for further studies on the aspect of immunosuppression modification after the diagnosis of RCC in transplant recipients.
Keywords: Ablative therapy, allograft, immunosuppression, renal cell carcinoma, renal transplant
|How to cite this article:|
Bharati J, Gupta P, Gorsi U, Mavuduru RS, Kumar V, Rathi M, Kohli HS, Ramachandran R. Immunosuppression after the diagnosis of renal allograft renal cell carcinoma in two transplant recipients: Case reports and review of the literature. Indian J Transplant 2021;15:81-8
|How to cite this URL:|
Bharati J, Gupta P, Gorsi U, Mavuduru RS, Kumar V, Rathi M, Kohli HS, Ramachandran R. Immunosuppression after the diagnosis of renal allograft renal cell carcinoma in two transplant recipients: Case reports and review of the literature. Indian J Transplant [serial online] 2021 [cited 2021 Jul 30];15:81-8. Available from: https://www.ijtonline.in/text.asp?2021/15/1/81/312757
| Introduction|| |
Kidney cancers, after lymphoproliferative disorders and epithelial neoplasms, are among the most frequent malignancies in renal transplant recipients. While the site of renal cell carcinoma (RCC) postrenal transplant is most commonly the native kidneys, about 10% are in the renal allograft. Most of the renal allograft RCCs are locally confined and amenable for nephron-sparing interventions. There is no consensus on the approach to immunosuppression modification after the diagnosis of RCC in a functioning allograft, which can have a large impact on the course of allograft survival. We report the successful management of two patients with nonmetastatic allograft RCC with ablative therapy and reduction of immunosuppression. However, both the patients developed irreversible allograft dysfunction and are on the waiting list of deceased donor programs for their second transplant. We have also reviewed the literature on immunosuppression modification after the diagnosis of RCC in a renal allograft.
| Case Reports|| |
A 22-year-old (male) renal transplant recipient presented in 2018 with occasional graft site pain for 2 months. He underwent renal transplantation in 2016 with his 52-year-old father as the donor. After basiliximab induction, maintenance immunosuppression was tacrolimus, mycophenolate mofetil (MMF), and prednisolone therapy. The initial posttransplant course was uneventful; however, his serum creatinine gradually increased to 1.5–2 mg/dl (12 months postsurgery). On examination, there was no allograft tenderness or mass palpated. Urine examination revealed no abnormalities and the serum creatinine was 3 mg/dl. Ultrasonography (USG) and Doppler imaging revealed a heterogeneous mass of 3.0 cm × 2.5 cm × 3.5 cm with increased vascularity in the upper pole of the renal allograft. Contrast-enhanced computed tomography (CECT) confirmed a heterogeneously enhancing round mass of 3.3 cm × 3.2 cm × 3 cm size involving the upper pole along with the pelvicalyceal system of the allograft kidney. There was no similar mass involving any abdominal organ. Fine-needle aspiration cytology (FNAC) revealed clusters of tumor cells admixed with eosinophilic material in a necrotic background suggestive of clear cell carcinoma [Figure 1]a, [Figure 1]b, [Figure 1]c. Fluorodeoxyglucose (FDG)-Positron emission tomography (PET) scan of the whole body did not reveal any metastasis. Radiofrequency ablation under ultrasound guidance was done considering the small size of the tumor (<5 cm), anticipated difficulties with nephron-sparing surgery, and avoidance of dialysis. Tacrolimus and MMF were discontinued after the diagnosis of RCC. However, his urine output declined steadily, and serum creatinine was 7 mg/dl after 3 months. USG of the renal allograft at 3 months showed shrunken kidney (4 cm × 5 cm) without any apparent hypo or hyperechoic lesion. He was started on maintenance hemodialysis and is currently listed in the deceased donor transplant program. At 2 years of follow-up, USG of renal allograft showed no mass or cyst.
|Figure 1: (a-c) Fine needle aspiration smears from the renal mass showing loose clusters of tumor cells with moderate nuclear pleomorphism, large round nuclei, prominent nucleoli, and abundant amount of clear pale cytoplasm. Thin strands of eosinophilic basement membrane-like matrix material can also be noted in the clusters (May Grunwald Giemsa; a: ×10, b: ×20, c: ×40)|
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A 50-year-old (male) renal transplant recipient presented in January 2020 with fever and anorexia for 2 months. He underwent renal transplantation in 2006 with his 55-year-old aunt as the donor. He was on tacrolimus, MMF, and prednisolone therapy without any details on prior induction therapy. The initial posttransplant course was uneventful, and his serum creatinine was 1.5 mg/dl until 2016 when he underwent graft biopsy for increasing serum creatinine to 2.1 mg/dl. The histology revealed posttransplant immunoglobulin A nephropathy, and the serum creatinine slowly increased to 3 mg/dl 3 months before the current presentation. USG revealed a 2.5 cm × 2.5 cm × 3 cm heteroechoic mass along with increased vascularity in the upper pole of the transplanted kidney. CECT of the abdomen showed a similar mass with multiple conglomerated necrotic mesenteric lymph nodes. CE-USG of transplant kidney showed Bosniak type IV cyst suggestive of RCC and FDG-PET scan did not reveal any metastasis. FNAC from the mesenteric node showed necrotic granulomatous inflammation without any atypical cells, and Ziehl–Neelsen stain was strongly positive for acid-fast bacteria suggestive of tuberculous lymphadenopathy. His serum creatinine at presentation was 4 mg/dl with a urine output of 1.5 L/day. With a probable diagnosis of nonmetastatic RCC based on radiological features, cryoablation was performed owing to residual graft function and small size of the tumor. Reduction in immunosuppression (to only steroids) and initiation of antitubercular therapy resulted in fever defervescence. No immediate postprocedure complications were noted; however, after 2 weeks following intervention, he developed increasing serum creatinine and oliguria. On the initiation of maintenance hemodialysis, the patient awaits his second transplant.
Summary of studies describing immunosuppression after the diagnosis of renal cell carcinoma in renal allograft
We conducted an extensive literature search on postrenal transplant RCC managed with nephron-sparing intervention and modification of immunosuppressive therapy. We used the following search terms in English manuscripts: RCC and renal transplant, RCC in the renal allograft, kidney cancer, and renal allograft and renal mass in transplanted kidney in MEDLINE database using PubMed interface. After careful reading, pertinent references from the articles were selected for further search. Of 49 articles with desired characteristics, 27 were excluded on the following grounds: 9 articles as they included cases of RCC in renal allograft which were treated with graft nephrectomy and cessation of immunosuppression and 18 articles as they did not mention if modification of immunosuppression was done or not after the diagnosis of RCC. We included 23 articles: 3 single-center prospective observational studies,,, (1) multi-center retrospective study, (2) single-center retrospective studies,, (4) case series,,,, and 13 case reports,,,,,,,,,,,, which had information on modification (yes/no) of immunosuppression therapy and allograft outcomes after the intervention of RCC in the renal allograft. All, except four,,, articles, were published after the year 2000. The details, as shown in [Table 1] and [Table 2], were noted from each article. A total of 110 patients from 23 articles were analyzed. The mean time to the diagnosis of RCC posttransplant ranged from 5.7 to 15.6 years, and the mean age of the transplanted kidney at the time of diagnosis ranged between 37 and 55 years [Table 1]. Among the studies in [Table 1], papillary type of RCC was the most common histology in five studies,,,,, clear cell type histology was the most common in three studies,,, and other types of histology constituted a minority. Donor age was available in 12 studies and ranged from 24 to 78 years. Out of the total 110 patients included in [Table 1] and [Table 2], 78 (70.9%) patients did not have any change in immunosuppression after the diagnosis of RCC. However, immunosuppression details before the diagnosis of RCC were available in 100 of these 110 patients. Of these 100 patients, 76% patients were on cyclosporine A (CsA)-based therapy, 18% were on tacrolimus-based therapy, 35% received azathioprine, and 36% received MMF. Among 32 (29.1%) patients with a change in immunosuppression after diagnosis of RCC, 18 and 1 were switched to mTOR inhibitors from calcineurin inhibitors (CNIs) and MMF, respectively, 3 were switched from CsA to low dose tacrolimus (trough level <5 ng/ml) regimen, azathioprine was discontinued in 6, and the details of others are shown in [Table 1] and [Table 2]. Major (56.3%) immunosuppression change in patients involved switching CNI to mTOR inhibitors, and the mean prediagnosis serum creatinine ranged from 113.2 to 152.7 micromol/L in these patients. Among 78 patients with no change in immunosuppression, graft survival was stable in all except one patient who returned to dialysis for an unrelated cause; one patient had local tumor recurrence; and another one patient had residual tumor after nephron-sparing intervention. Among 32 patients with immunosuppression modification, 29 (90.6%) had stable graft function and 2 had recurrence at 3 months and 5 years following National Service Scheme (NSS), respectively. All the three patients who experienced deteriorating graft functions after the intervention (i.e., NSS and immunosuppression change) had poor graft function pre intervention., Information on other side effects of mTOR inhibitors was not available. The mean follow-up duration ranged from 17.4 to 43 months among the studies included in [Table 1].
|Table 1: Cases series and observational studies which described immunosuppressive therapy modifications in patients with renal allograft renal cell carcinoma|
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|Table 2: Cases reports which described immunosuppressive therapy modifications in patients with renal allograft renal cell carcinoma|
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| Discussion|| |
We report renal allograft RCC in two transplant recipients, diagnosed 2- and 14-year posttransplant, respectively, who were treated with ablative therapy and reduction of immunosuppression. Both the patients had underlying chronic allograft injury at the time of diagnosis. While none of them had residual tumor or recurrence of cancer, they returned to maintenance dialysis during follow-up. A review of the literature highlights the uncertainty about the management of immunosuppression in renal transplant recipients who develop curable RCC. The balance between anticancer and antirejection treatment should be maintained as far as possible in such cases as treatment of cancer may come with the cost of pushing patients back to dialysis. Of note, patient survival on dialysis was found to be lower than survival with several solid-organ cancers.
Kidney transplant is associated with the highest risk for kidney cancer amongst all solid-organ transplant recipients. Among various risk factors, old age and possible effect of immunosuppression are common to both RCC in allograft and RCC in native kidneys of renal transplant recipients. Besides the older age of the transplanted kidney (54 years), there were no other obvious risk factors for RCC in case 1. Time to diagnosis after transplant was shorter in case 1 compared to others [Table 1] which could be due to donor-derived RCC origin. Although the donor did not develop RCC (of the contralateral kidney) on follow-up, the possibility of donor-derived RCC cannot be excluded short of DNA analysis of the tumor cells for origin, which was not done in our case. The role of standard maintenance immunosuppression as a risk factor for posttransplant RCC is inconsistent in different studies;,, however, immunosuppression still remains a tentative risk for any cancer in all transplant recipients. Further, the rapid rise in the use of immune checkpoint inhibitors for metastatic native kidney RCC is an indirect evidence of the immune system's role in preventing and treating RCC. Nevertheless, most of the reports describe renal allograft RCC to be locally confined, which are treated with nephron-sparing intervention successfully., We hypothesize that a superfluous reduction in immunosuppressive therapy in patients with renal allograft RCC for fear of tumour recurrence may jeopardize the allograft survival. Prospective clinical studies looking at long-term outcomes might improve our understanding of the management of immunosuppression in patients with renal allograft RCC.
We found that papillary and clear cell carcinoma was the most common RCC among the patients in the reviewed articles and most (71%) were continued on the same immunosuppression after the diagnosis of RCC. Continuation of the same immunosuppression (CNI in 94%) after RCC diagnosis seems to be safe in terms of long-term graft and tumor outcomes. Switch from CNI to mTOR inhibitors was the next common approach in the reviewed articles. It was associated with stable graft survival in those with good graft function at baseline. Among renal transplant recipients with de novo cancer (the majority having kidney cancers) after transplant in Hong Kong, conversion to mTOR inhibitors along with CNI minimization showed a trend toward a lesser recurrence of cancers than nonconversion group (5.4% versus 11.9%, respectively); however, cancer-free survival was similar in both the groups. The worry with mTOR inhibitors is the commonly associated side effects leading to discontinuation. Everolimus, typically at higher doses (5–10 mg daily) than that used as antirejection therapy (0.75–1.5 mg twice a day), is an approved agent to treat metastatic RCC, which would worsen the side effects. Moreover, graft survival is poor with the use of mTOR inhibitors as maintenance immunosuppressive therapy in patients with compromised allograft function. Immunosuppression was reduced in both our patients after the diagnosis of RCC; however, both developed irreversible graft function despite successful tumor management. Both our patients had suboptimal graft function before RCC diagnosis, and therefore, mTOR inhibitors were not used. We assume that allograft rejection could have contributed to allograft dysfunction in them as there were no other apparent factors for the same and we could not perform allograft biopsy.
The major concerns for transplanting a patient with previous RCC are (1) cancer recurrence after transplant (presumably due to immunosuppression) and (2) cancer-specific mortality after transplant, which is higher than the general population and also in patients with previous cancers as compared to those without., Tumor-free waiting time (0–5 years) for transplant in patients with RCC is largely based on data from the Cincinnati transplant registry. Recent studies have reported no association between longer waiting time and risk of RCC recurrence., It is increasingly believed that tumor-free waiting time for transplanting a patient with RCC should be based on a careful consideration of individual characteristics such as histology, stage, and size., Although most studies have addressed waiting time concern in patients with previous native kidney RCC, extrapolation of the same to renal allograft RCC seems the best choice. Our patients are listed in a deceased-donor program due to nonavailability of live donors with a plan to screen them for tumor recurrence immediately before transplantation.
| Conclusion|| |
We found that immunosuppression modification after the diagnosis of allograft RCC in renal transplant recipients lacks consensus and that discontinuation of immunosuppression may hasten allograft loss despite successful tumor management.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
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Conflicts of interest
There are no conflicts of interest.
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