Curr Urol Rep (2016) 17: 3 DOI 10.1007/s11934-015-0557-z

KIDNEY DISEASES (G CIANCIO, SECTION EDITOR)

Use of Kidneys with Small Renal Tumors for Transplantation Alejandro Lugo-Baruqui 1 & Giselle Guerra 2 & Adriana Arocha 1 & George W. Burke 1 & Gaetano Ciancio 1

Published online: 22 December 2015 # Springer Science+Business Media New York 2015

Abstract Population of patients with end-stage renal disease increases every day. There is a vast difference in the number of patients on the waiting list for a kidney transplant, and the number of donors and the gap increases every year. The use of more marginal organs can increase the donor pool. These organs include the kidneys with small renal cell carcinomas (RCTC). There has been a number of reports in the literature about the use of these grafts for renal transplant after tumor excision and reconstruction. These grafts have been reported to be used with good renal function outcomes without an increased risk for malignancy recurrences. We present the collection of evidence for the use of kidneys with RCC for transplantation, technique used for surgical resection, and

reconstruction as well as insights on the recommendations for the use of these grafts. Keywords End-stage renal disease . Kidney transplant . Deceased donors . Living donors . Kidney tumor . Renal cell carcinoma

Abbreviations (ESRD) End-stage renal disease (RCC) Renal cell carcinoma (m-TOR) Mammalian target of rapamycin

Introduction This article is part of the Topical Collection on Kidney Diseases * Gaetano Ciancio [email protected] Alejandro Lugo-Baruqui [email protected] Giselle Guerra [email protected] Adriana Arocha [email protected] George W. Burke [email protected]

1

Department of Surgery, Division of Transplantation, Miami Transplant Institute, Jackson Memorial Hospital, University of Miami Miller School of Medicine, Highland Professional Building 1801 N.W. 9th Avenue, Miami, FL 33136, USA

2

Department of Medicine, Division of Nephrology, Miami Transplant Institute, Jackson Memorial Hospital, University of Miami Miller School of Medicine, Miami, FL, USA

Population of patients with end-stage renal disease (ESRD) increases every year. In 2012, approximately 114,813 patients initiated dialysis therapy for ESRD. [1] In the same year, 28, 867 patients were added to the transplant waiting list. Kidney transplant represents the gold standard of care for ESRD patients. The excess risk of death for dialysis patients increases 45 % per additional year on the waiting compared to patients who received kidney transplant [2]. Transplantation represents a benefit in life expectancy of 3–15 years, compared to remaining on dialysis [3], depending on age and comorbidities of the recipient. The expense of management of patients with ESRD represents a heavy burden towards any health system worldwide. The United States Renal Data System (USRDS) 2009 Annual Data Report mentions that hemodialysis treatment costs an average of $82,000 (UDS) per patient per year, representing a total of $42 billion annually in USA alone. This contrasts with the initial cost of kidney transplant surgery with an average of $29,000 and with estimated cost of $25,000 USD per year per patient after surgery [4].

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According to the Organ Procurement and Transplantation Network (OPTN) as of August 2015, there are 100,938 patients on the waiting list for a kidney transplant and 1972 patients waiting for a kidney/pancreas transplant. Only in 2014, a total of 37,780 new patients were enrolled in this list, with only 29,532 kidney transplants done in the same period of time [5]. The gap between patients in need for kidney transplant and organs available continues to increase since donor rate has remained relatively unchanged for the last 10 years; thus, the problem of organ shortage has prevented universality of this therapy. Increasing Donor Pool Strategies have been implemented to promote the use of organs that would increase the donor pool [1]. Specific areas for potential growth are living donor and paired donation programs as well as the possible use of marginal donors such as expanded criteria donors (ECD or KDPI >85 as identified by the new kidney allocation system) and donors after cardiac death (DCD) for specific recipients. With the use of marginal-donor kidneys, Ojo et al. demonstrated an increase of life expectancy of 5 years compared to maintenance dialysis [6•]. When considering expanding the use of marginal grafts, transplant centers should consider a balance between risk and benefit as in the case with donors diagnosed with malignancies at procurement time. Desai et al. found that the benefit for recipients to receive an organ from a donor categorized as unacceptable or high risk is greater than the risk of malignancy transmission [7]. Improvements in donor selection have rendered donor tumor transmission infrequent. Kauffman estimated the risk of malignancy transmission of only 0.012 % for patients with grafts coming from deceased donors with history of malignancies [1]. However, donors with a history of malignant melanomas, lung cancers, sarcomas, and grade IV central nervous system (CNS) neoplasms are considered unacceptable for donation and have worst overall survival, with less than 50 % of recipients surviving after 24 months from transplantation [8••]. Renal Mass and Renal Cell Carcinoma The widespread use of abdominal imaging for living and deceased donors has increased the diagnosis of incidental renal masses (IRM). IRM are defined as asymptomatic tumors discovered by any imaging study required after a patient complains with a symptom not related with a renal tumor [9]. Most of these masses are non-enhancing simple cysts that are benign and require no treatment. However, the minority are contrast-enhancing solid lesions that may suggest malignancy. Renal cell carcinoma (RCC) is the most frequent malignant kidney tumor. RCC is diagnosed 50 to 69 % of the times as small incidental renal tumor [10].

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RCC is the ninth most common cancer worldwide with the highest incidence in developed countries [11•]. RCC represents 90–95 % of kidney neoplasms. It is growing rapidly in the prevalence of population with 3.9 % of new cancers reported with a median age of 64 years. The American Cancer Society estimates that 63,920 patients will be diagnosed with RCC in 2014 and 13,960 would die because of it [12]. It is estimated that approximately 25–30 % of patients will present with metastatic disease at the moment of diagnosis [13]. The two main histologic types are clear cell RCC and papillary RCC [14]. The most common staging system used is the tumor, node, metastasis (TNM) system by the American Joint Committee on Cancer (AJCC) [15] (Table 1). There are a myriad of treatment modalities for RCC, according to the stage it is diagnosed. For small localized tumors, local control with surgical resection is the mainstay therapy [16•]. For a T1a renal mass, the 2014 NCCN guideline recommends local control with partial nephrectomy [17]. Targeted therapy for metastatic renal cell carcinoma has revolutionized treatment of the disease by targeting new signaling pathways and prolonging survival [18]. Some of the target-directed therapies include use of IL-2, vascular-endothelial growth factor (VEGF) inhibition with sorafenib, sunitinib, or pazopanib, and mammalian target of rapamycin (mTOR) inhibitors such as tersirolimus and everolimus. Prognosis of the tumor is correlated with the stage. Late recurrences of RCC after surgical treatment have been reported [19]. Follow-up recommendations have been published to direct surveillance test and detect early recurrence and metastases. National Comprehensive Cancer Network (NCCN) guidelines recommend abdominal imaging (CT, MRI) to be done within 3–12 months after partial or radical nephrectomy for tumors on stages pT1a and pT1b. Subsequent abdominal imaging may be performed annually thereafter (CT, MRI, US) for 3 years. Patients with biopsy-proven RCC are recommended to asses chest metastases on an annual basis (radiography or CT) [20]. Even with the implementation of DCD, ECD kidneys to increase the donor pool, there has only been a slight increase in kidney transplants. Marginal grafts have been used more frequently in other centers. Organs that were previously not considered for donation are being transplanted with good success. Among these marginal organs, the use of kidneys with incidental masses has been reported increasingly over the past years. From anecdotal reports to series and cases with longer follow-up, use of kidneys with small tumors have good reports within certain characteristics. Use of Kidneys with RCC for Transplantation Several reports of the use of kidneys with RCC have been published in the transplant literature (Table 1). One of the earliest reports of kidneys used for transplants from grafts with

43

42

5

3

11

4

Nicol, 2007 [22••]

Mannami, 2008 [26••]

Sener, 2009 [25••]

Valente, 2012

Musquera, 2013 [23••]

LugoBaruqui, 2015 [27••]

pRCC = 1

cRCC = 3

Chromophobe = 1

4 DD

4 LD

ccRCC = 7

RCC = 3 (pRCC = 1, ccRCC = 1 cRCC = 1) N/A

8 RCC (unspecfied)

RCC = 25, pRCC =5, chromophobe = 1

N/A

4 LD

3 DD

5 LD

38 LD

38 LD

3 DD

3DD

11 LD

14

14.8 (range3 to 43)

8.3

15.6

24, (12 to 35)

<30 (unspecified)

(range 5 to 40)

20

Mean size (mm)

II-1

I=3

I = 11

II-1

I=2

II = 2, III = 1

II = 4

I=4

I = 15, II = 11, III = 4 *

II = 8

I=6

Fuhram (I-IV)

57.1

53.3

44.6

54

50.8

>60 (unspecified)

40.8

CT, CXR as indicated

Yearly US,

Annual CXR for 5 years, CT at 2 and 4 years (donor and recipient)

Annual US + CXR, CT as necessary 6 months US

N/A

US and CXR every 3 months

N/A

Mean Monitoring recipient age (years)

recurrence, managed with observation alone

None

None

1

None

36 months

32.3 months

None

None

43.3 months None

15 months

52.2

32 months

nths

69 mo

Mean Recurrences follow up

MPA + prednisone + sirolimus

CNI based

Tac + MMF + steroids (RSW)

NA

CyA + AZA + prednisone

NA

1 Incisional hernia

1 PUJ syndrome

1 Postoperative bleeding

None

None

None

1 Bowel perforation

1 Calyceal fistula

1 Hematoma

1 arteriovenous fistula with hematuria

1 bleeding of repair site

None

Complications

Thymoglobulin + Tac + MMF + prednisone None (RSW) basiliximab + steroids

Thymoglobulin

N/A

N/A

N/A

N/A

N/A

Induction ISP Maintenance ISP

ISP immunosuppression, LD living donor, DD deceased donor, RCC renal cell carcinoma, ccRCC clear cell renal cell carcinoma, pRCC papillary renal cell carcinoma, cRCC cystic Renal cell carcinoma, CT computed tomography, CXR Chest X-ray, US ultrasound, CyA cysclosporin, AZA azathioprine, Tac Tacrolimus, RSW Rapid steroid withdrawal, CNI calcineurin inhibitors, MMF mycophenolate mofetil, MPA mycophenolic acid, PUJ pyeloureteral junction

14

Recipients Donor Malignant type histology

TMN Classification for Renal Cell Carcinoma

Buell, 2005 [21••]

Table 1

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small RCC comes from the Penn International Transplant Tumor Registry database [21••]. This paper opened the discussion for using small, incidental RCC with low histological grade managed with free-margin excision for transplantation. After a mean follow-up period of 69 months, the longest reported, no recurrences were noted. Nicol used kidneys from urologic patients diagnosed with RCC for transplant. After these patients elected radical nephrectomy (RN) for treatment, the resected organ was repaired with partial nephrectomy and were used for transplant without evidence of recurrence [22••]. They performed 38 kidney transplants from patients with diagnosed RCC which were eligible for radical nephrectomy and were consented for kidney donation of the affected organ. These organs had been previously allocated to highrisk patients with ESRD who were of older age (60 years or older) and with significant morbidities or high risk of prospect death in 5 years. All recipients were informed of the high risk nature of the graft due to risk of recurrence. No delays on oncologic treatment for donors were noted because of allocation time. After histologic exam, 31 patients had malignant tumors with a mean diameter of 2.2 cm. They reported two cases of urologic complications (one arterio-venous fistula and one urinary leak from a calyceal fistula) with a mean follow-up of 32 months. One recurrence was reported in a 71-year-old patient who refused surgical treatment and remained on observation. Musquera el al. reported their own experience including analysis of the contralateral kidneys from donors with renal masses for transplant [23••]. Additionally, they mentioned sirolimus as part of maintenance immunosuppression although, it is not explicitly mentioned if this was with the intention of using it due to the antiproliferative properties of the drug. The same group was followed by Brook and found a superior 4-year survival in recipients from excised renal tumor grafts as compared to patients on the waiting list [24••]. Under similar conditions, Mannami et al. used repaired kidneys from donors with a variety of urologic neoplasias, including eight cases with RCC. All patients with RCC (pT1a) underwent radical nephrectomies with back table resection of the tumor and reconstruction. After a considerable follow-up period of 52 months, no recurrences were reported. As living donor programs are expanding the age for donors, it is not unusual that patients being evaluated are diagnosed with incidental renal tumors during protocol imaging studies. Sener reported five cases of living donors with suspicious images for renal malignancy that were used for transplant, with only three cases being RCC. After ex vivo resection of the tumors with free margins, these organs were transplanted. After a median follow-up of 15 months, no local recurrence or metastasis was reported [25••, 26••]. Our group has reported the experience with four kidney transplant recipients from living donors with incidental RCC at time of transplant [27••]. Again, donors and recipients were informed extensively of the situation and decided to continue transplant

Curr Urol Rep (2016) 17: 3

process. No surgical complications were noted and after a follow-up of 36 months, neither donors nor recipients had any evidence of recurrence. To date, there is no clear consensus on the largest acceptable tumor size or grade (max reported was t1a) that is permissible for resection and transplantation afterwards of kidney. Risk for organ transmission of malignancies is extremely low, considered of two cases per 10,000 organs transplanted [28]. A systematic review by Xiao et al. about risk of malignancy transmission in kidney transplant recipients reported that the most common transmitted cancers were renal cancer followed by melanoma, lymphoma, and lung cancer [8••]. The histologic type of the renal cancers was not specified by the authors. They calculated that those recipients transplanted with incidental renal cancers had the most favorable prognosis with 70 % survival at 5 years. More evidence is needed for use of contralateral kidneys of donors with unilateral renal tumors [29]. It is estimated that metachronus risk for contralateral RCC is of 0.4 % in 10 years and of 0.8 % in 20 years [30, 31]. Monitoring of these patients and treatment options varied depending on the author. This reflects the lack of consensus on how to approach these patients. Some treatment options mentioned consist on graft nephrectomy, reduce immunosuppression, or monitoring alone. There is no clear consensus on the immunosuppression protocols used for these patients. Most authors seem to incline for CNI-based immunosuppression. The use of m-TOR inhibitors renders an interesting alternative due to the known antiproliferative property of these drugs. Another point of discussion is the monitoring of both donor and recipient after the operations. There is no clear consensus as of type and timing of imaging to be used as well as the protocol for monitoring donors after the resulting oncologic resection. Duration of follow-up seems to be determined by every institution protocol. Back Table Preparation of the Kidney Graft After the nephrectomy was completed, the organs can be flushed with cold preservation solution and put in cold ice smudge basin. Graft must be carefully inspected in case there are multiple tumors not previously detected in imaging studies. After proper identification, tumors can be resected with partial nephrectomy, always procuring adequate resection with approximately 5-mm margin from macroscopic edge of the tumor (Figure 1). Special care must be taken in the depth of the resection in order to prevent unnecessary injury to the renal pelvis. After full resection, the renal graft is repaired in two layers. The first layer with running PDS 4–0 suture to repair collecting system injuries and second layer with hemostatic horizontal mattress with PDS 3–0 suture with the additional use of oxidized regenerated cellulose pledgets (Surgicel, Ethicon INC Somerville, NJ). Finally, fibrin sealant (Evicel,

Curr Urol Rep (2016) 17: 3

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Fig. 1 Backtable preparation of kidney graft. Backtable preparation of kidney graft with identification of the tumor (a) partial nephrectomy with appropriate surgical margins (b) final repair of the graft before transplantation (c)

OMRIX Biopharmaceuticals Ltd, Israel) is applied on the surface of the repair site to add hemostatic strength to the repair. This process usually adds 15 min in average to the cold ischemia time of the graft. All the samples are sent for frozensection pathological exam. After confirmation of margin-free resection of the tumor, the transplantation process in the recipient proceeded at the discretion of the surgeon. Methods for Monitoring The most recent AUA guidelines report their recommendations for monitoring renal cell tumors after surgical resection. It is recommended to obtain baseline abdominal scanning (CT or MRI) rather than only US for nephron-sparing surgery whereas US alone may be adequate for patients that underwent radical nephrectomy. Long-term follow-up consists of abdominal imaging (CT, US or MRI) yearly for 3 years in patients with low risk (pT1, N0) [32]. Nevertheless, the guidelines do underline the importance of adjusting monitoring according to the risk factors of every patient (Clinical T1b, positive margins, higher tumor grade, or aberrant histology). The duration of follow-up is not clearly established with longterm recurrences being reported in the past. Recurrence rate for pT1 tumors is considered to be low, around 1–4 % [33]. In reports mentioned, follow-up was adjusted to institution protocols. We recommend adjusting to recommendations in guidelines for both donor and recipient as part of the monitoring and surveillance protocols for RCC recurrence in contralateral donor kidney and recipient-transplanted kidney. According to the NCCN 2014 guidelines, recurrences to the abdomen and chest would have been detected up to 3 years after surgery after partial nephrectomy. In a retrospective study by Stewart et al. of the 3651 patients who underwent partial or radical nephrectomy for low risk tumors, 29.8 % developed recurrence after a median of 1.9 years. Among these patients, 40.2 % developed recurrences in the abdomen and 40.6 % were on the chest. [34••] More interestingly, when evaluating the ability of the current guidelines to detect total recurrences after surgery, there were missed recurrences detected. Standard surveillance to 2014 NCCN recommended protocol would have only captured 68.2 % of all recurrences; whereas, AUA guidelines detected 66.9 % of them.

Use of M-TOR Inhibitors It is well established that transplanted patients have an increased risk for development of malignancies including nonmelanoma skin cancers, lymphoproliferative disorders, Kaposi sarcoma, and kidney malignancies among others [35]. Risk factors for developing de novo or recurrent malignancies include intensity and type of immunosuppression used. Mammalian target of rapamycin (mTOR) inhibitors consist of a family of immunomodulators with well-described antitumor effects. As immunosuppressant, mTOR inhibits IL-2 production and T-cell activation. The anti-oncogenic effect of this drug consists in blockade of signaling pathways associated with cell-proliferation including the PI3K pathway and STAT3 while inhibiting VEGF. Sirolimus has been approved by the FDA as immunosuppressive drug for renal transplant. Due to the dual effect as immunosuppressive and antitumoral drug, Sirolimus has been studied in this setting to compare it against CNI-based protocols in the setting of de novo malignancies after transplant [36•]. In a prospective trial, the CONVERT study group reported a lower rate of malignancy after 2 years in renal graft recipients post-conversion to sirolimus immunosuppression compared to patients who remained on CNI protocol. [37•] This result is consistent with the outcomes reported in previous reports. Early conversion to CNI-free immunosuppression based on sirolimus was also associated with improved renal function in low-risk renal graft recipients. A main side effect of this drug includes hypercholesterolemia, dyslipidemia, and increased rate of discontinuation of therapy [38]. Although there is no evidence to support the use of mTOR inhibitors as part of the immunosuppressive protocol for patients with renal grafts with RCC resections, the antitumoral properties mentioned render this class of drugs very tentative for their inclusion under this indication. More research is needed to conclude the efficacy of mTOR inhibitors in this very selected group of recipients. Ethical Considerations With the increased number of patients going every day into kidney transplant waiting list, new alternatives must be explored to increase the donor pool and maximize this limited

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resource. More often, the kidneys from donors with small RCC excised with partial nephrectomy are being used with good long-term results, in terms of renal function and oncologic outcome. Nevertheless, this should not be considered standard practice as of this day. Ethical considerations are important. As discussed by Fechner, patients with asymptomatic small-renal masses diagnosed during routine imaging studies should not be counseled to have their kidneys removed for donation [39••]. These patients would be treated as oncologic patients, not as donors. Every chance to offer nephronsparing surgery should be considered. Removal of kidneys with small tumors could unintentionally create negative impact on living donor protocols and potential incentives for commercial transplantation. In case of a living donor with incidental finding on renal mass under evaluation, the decision should be addressed carefully considering the donor motivation to donate, the medical history, residual renal function, and scenario where this patient could be managed as oncologic patient instead of donor. If the primary motivation of the person after full psychosocial evaluation is to donate, then the transplant center can proceed with informed consent of both the donor and intended recipient. Monitoring of both patients will need to occur. The third scenario where an incidental mass is found on a deceased donor needs to place in consideration possible metastasis to other organs allocated for donation and to inform next of kin about the findings in case there is a familial predisposition for this malignancy. The risk for receiving this kin of graft should be disclosed and fully understood by the recipient. The use of these organs should probably be allocated to more marginal recipients since long-term follow-up after 10 years is very limited and recurrences probably under reported. Careful monitoring of the donor should also be persuaded to early diagnose any contralateral malignancy.

Conclusion There is an urgent necessity to increase the numbers of organs in the donor pool. Efforts have been made to use onceconsidered marginal grafts such as DCD organs with good outcomes. The use of kidneys with small renal cell carcinomas has been used by different groups in the past. This review offers the evidence for allocating kidney transplants in living and deceased donors with small RCC that were repaired with partial nephrectomy and then used for transplant. The evidence points towards a safe use of kidneys with small renal cell carcinomas (T1a) with very low recurrence rate and good outcomes. There is still lack of evidence towards the longterm follow-up of these patients (donor and recipients) but seems that they should be monitored as oncologic patients. Regular imaging by protocol is recommended for donor and recipients using the most recent guideline recommendations.

Curr Urol Rep (2016) 17: 3

Also, there is no clear evidence as of which immunosuppressive protocol should be used for this group of patients, although mTor inhibitors use is reasonable due to their antitumoral properties. Use of kidneys with small RCC can be considered for transplant after partial nephrectomy and reconstruction. This offers good renal function outcome and low recurrence rate even after immunosuppression. Compliance with Ethical Standards Conflict of Interest Alejandro Lugo-Baruqui, Giselle Guerra, Adriana Arocha, and George W. Burke each declare no potential conflicts of interest. Gaetano Ciancio is a Section Editor for Current Urology Reports. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.

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