A Rare Case of Donor-Derived Renal Cell Carcinoma in a Kidney Transplant Recipient

Background

Approximately 80% of primary renal malignancies are renal cell carcinoma (RCC), with clear-cell RCC and papillary RCC being the most common subtypes, distinguished by their morphological and cytogenetic features. Patients with end-stage renal disease (ESRD) have a significantly higher risk of RCC, with an incidence of 0.4%, compared to the general population’s 0.005% [1–4]. Dialysis is the primary renal replacement therapy, but renal transplantation may offer better long-term outcomes. However, lifelong immunosuppression to maintain allograft function increases the risk of malignancies, including RCC. The incidence of RCC in kidney transplant recipients (KTR) is 7 times higher than in the general population, and mainly occurs in the native kidneys (90%) rather than the allografts [5]. RCC is rare in KTRs, accounting for only 0.2% of reported cases, and risk factors include older donor age, patient history of smoking, obesity, acquired cystic kidney disease (ACKD), and hypertension. Interestingly, KTRs who received a deceased donor transplant are associated with a higher incidence of allograft RCC [6]. This report presents a case of probable donor-derived RCC of the allograft diagnosed in the early post-transplantation period.

Case Report

A 71-year-old woman with a past medical history significant for hypertension, hyperlipidemia, and ESRD secondary to uncontrolled type 2 diabetes underwent an uneventful deceased donor kidney transplantation (DDKT) following 13 years of hemodialysis therapy. The deceased donor was a 69-year-old man who died following a cerebral vascular accident, making him an extended-criteria donor. The past medical history was significant for essential hypertension and tobacco use. The donor’s terminal creatinine was at a baseline of 1.1 mg/dL. Prior to selection, the donor underwent an abdomen and pelvis CT scan, which yielded no evidence of any suscpicious lesions. Once the kidneys were recovered, they were biopsied and placed on hypothermic pulsatile perfusion pumps. Once selected as a candidate for transplantation, the donor and recipient were cross-matched. HLA screening was conducted utilizing PCR-SSP and PCR-SSO via Luminex. HLA class I and class II demonstrated negative antibody thresholds along with no identifiable panel reactive antibodies. HLA mismatch was found at 2, 2, 2 at A, B, and DR loci, respectively, but was not a contraindication for transplantation.

Due to the recipient being over age 65 and the HLA report demonstrating an imperfect match, the medical decision was made to induce the patient with a hybrid immunosuppressive combination utilizing thymoglobulin and basiliximab in preparation for the procedure, following in-place hospital guidelines. The immune-suppressive regimen following the transplant consisted of 3 mg Envarsus, 360 mg Myfortic BID, and 5 mg prednisone.

The allograft function following placement was stable with a baseline creatinine of 1.4–1.5 mg/dL and had minimal fluctuation over the next year. Ultrasound immediately after transplantation demonstrated appropriate perfusion without identifiable lesions. Following discharge, the patient was scheduled to undergo annual screening ultrasounds. During the year following the precedure, she had multiple office visits for recurring UTIs despite aggressive antibiotic therapy. Due to the extreme circumstances of the COVID-19 pandemic, she was unable to keep her appointment for the initial screening ultrasound. Her sixth office visit for a refractory UTI since undergoing a transplant prompted an investigative ultrasound (US) that showed a worrisome mass on the donor’s kidney. Following the US, she went through an extensive malignancy workup. Abdominal imaging demonstrated a heterogeneous 3.5-cm mass in the upper posterior pole of the transplant (Figures 1–3). The native kidneys demonstrated no evidence of mass or hydronephrosis. Following the MRI, the patient underwent an US-guided biopsy, which yielded a diagnostic pathology of clear-cell RCC, with a Fuhrman nuclear grade 3. A follow-up PET did not show signs of metastasis. With no signs of metastasis on staging and a favorable tumor position, the patient qualified for nephron-sparing surgery or radiofrequency ablation. Although ablation was a promising alternative therapy, due to determinants of health, it was not warranted for our patient’s care. Ultimately, the medical and patient decision to undergo an open partial nephrectomy was established. Postoperative care was complicated by urinary retention and subsequent urine leak secondary to a urinoma. A short-term ureteral stent and Foley catheter were placed, which resolved this issue. Since the nephrectomy, the patient’s baseline serum creatinine has been 1.7–2 mg/dL. The patient was diagnosed with CKD stage IIIA due to focal segmental glomerulosclerosis (FSGS) due to hyperfiltration. Following the diagnosis, she was discharged with a slight adjustment to the immunosuppressive therapy by switching to 2 mg Rapamune instead of Envarsus. Seven months following the procedure, the patient’s allograft was functioning within the newly established baseline, with no signs of recurrence or metastatic disease detected by a screening Doppler US.

Discussion

In our case report, we present a unique situation where an allograft malignancy was discovered only 1 year after DDKT, which is earlier than most cases reported in previous studies. According to a retrospective analysis of cohort studies, the average prevalence of such cases is 0.2%. Typically, allograft RCC after transplant is diagnosed 5–15 years following transplantation. Although DNA analysis was not conducted in our case, the early appearance of the malignancy suggests the possibility of it being donor-derived RCC, which is supported by the results of a significant retrospective study that observed that de novo malignancies tend to occur beyond 2 years after transplant, and those found in the earlier stages following transplantation are more likely to be donor-derived [7].

In 2022, an amazing milestone was reached in the transplantation field, with over 25 000 kidney transplants taking place globally, making it the most frequently transplanted organ. While the procedure dramatically improves clinical outcomes for recipients, the need for lifelong anti-rejection medication comes with a great cost of significant immunosuppression. This ultimately leads to an increased risk of malignancies. Cancer, along with cardiovascular disease and infections, remains a significant cause of death in KTRs, making preventive screening necessary. With the rise in kidney transplants taking place, there has been a rise in reported renal malignancies in KTRs [8]. Despite an increase in renal cancer incidence in KTRS, there is no established protocol for preventive screening for this type of malignancy in this population group due to it being deemed a cost-ineffective approach, although various guidelines advise screening for other types of malignancies such as skin, cervical, and colorectal cancers [8]. Although much of the increase in allograft RCC cases can probably be attributed to the number of transplants, other factors have been identified such as an increase in the age of donors, better overall graft, patient survival, and the increasing number of deceased donors, making preventive screening protocols for this malignancy, a must in this population. Nonetheless, the incidence of allograft RCC is low, and without proper screening tools in place, identifying potential kidney dysfunction through patient symptomatology may indicate an early sign of an underlying malignancy. In our case, the patient’s recurrent UTIs prompted a further investigation that led to a cancer diagnosis. Similarly, a comparable case of allograft RCC also involved a cancer diagnosis following refractory UTIs [9,10]. Hence, transplant recipients presenting with constitutional symptoms such as UTIs should be closely monitored for early signs of malignancy, in the absence of screening protocols.

Currently, there is no established standard guideline for managing allograft RCC in KTRs. Management options include radical nephrectomy, nephron-sparing surgery (NSS), radiofrequency ablation (RFA), and active surveillance. According to a systematic review, the recurrence rate of cancer after partial nephrectomy was 3.6% after 3.1 years, which was similar to non-transplanted kidneys [5]. Our patient’s CKD after transplant was due to FSGS, a common initiating etiology that necessitates transplantation [11].

Immunosuppression is critical for graft function, but it inherently increases the risk of developing infections such as UTIs, as well as cancer. One study found that patients on immunosuppressive therapy following renal transplantation had an increase rate in multi-drug resistant bacterial UTIs, which poses a survivability risk for the allograft [12]. Nevertheless, the optimal maintenance immunotherapy to balance anti-cancer and anti-rejection treatment for renal cancer in KTRs remains uncertain. One potential option is mTOR inhibitors, which may be beneficial for these patients. A study found that mTOR inhibition improved survival for de novo malignancies following transplant, but trials assessing mTOR inhibitors for RCC in KTRs are limited [13]. A systematic review showed the use of Sirolimus significantly decreased the risk of developing cancer in KTRs, but increased mortality risk [14]. Another study found that transitioning from calcineurin inhibitors to mTOR inhibitors after RCC diagnosis resulted in a lower rate of recurrence, which was done for our patient’s care [15]. However, mTOR inhibitor use raises concerns about negative effects on graft function. The CONVERT trial randomized 830 renal allograft recipients between calcineurin inhibitors and mTOR inhibitors, and the mTOR group had a lower incidence of all malignancies, with no difference in rejection [16]. Notably, certain post-transplant immunosuppressants such as cyclosporine, mycopheno-late, and prednisolone were associated with a higher rate of allograft RCC development in KTRs [17].

Conclusions

Even though the incidence of allograft malignancies is increasing, there is no standardized approach for screening and diagnosing renal-derived malignancies in kidney transplant recipients. Nevertheless, patients presenting with constitutional symptoms such as recurrent UTIs should be carefully evaluated for potential malignancies. Treatment of allograft RCC requires balancing anti-cancer and anti-rejection immunosuppression, which lacks sufficient evidence to support a standard protocol. Therefore, additional research is needed to identify the optimal therapy regimen.