Kidneys from patients with small renal tumours: a novel source of kidneys for transplantation

Authors

  • David L. Nicol,

    1. Renal Transplant Unit and Southern Clinical School, University of Queensland, Princess Alexandra Hospital, Woolloongabba, Brisbane, Australia
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  • John M. Preston,

    1. Renal Transplant Unit and Southern Clinical School, University of Queensland, Princess Alexandra Hospital, Woolloongabba, Brisbane, Australia
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  • Daryl R. Wall,

    1. Renal Transplant Unit and Southern Clinical School, University of Queensland, Princess Alexandra Hospital, Woolloongabba, Brisbane, Australia
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  • Anthony D. Griffin,

    1. Renal Transplant Unit and Southern Clinical School, University of Queensland, Princess Alexandra Hospital, Woolloongabba, Brisbane, Australia
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  • Scott B. Campbell,

    1. Renal Transplant Unit and Southern Clinical School, University of Queensland, Princess Alexandra Hospital, Woolloongabba, Brisbane, Australia
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  • Nicole M. Isbel,

    1. Renal Transplant Unit and Southern Clinical School, University of Queensland, Princess Alexandra Hospital, Woolloongabba, Brisbane, Australia
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  • Carmel M. Hawley,

    1. Renal Transplant Unit and Southern Clinical School, University of Queensland, Princess Alexandra Hospital, Woolloongabba, Brisbane, Australia
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  • David W. Johnson

    1. Renal Transplant Unit and Southern Clinical School, University of Queensland, Princess Alexandra Hospital, Woolloongabba, Brisbane, Australia
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David Nicol, Director of Urology and Renal Transplantation, Princess Alexandra Hospital, Ipswich Road, Woolloongabba, Brisbane, Queensland, 4102, Australia.
e-mail: d.Nicol@uq.edu.au

Abstract

OBJECTIVE

To report the use of a novel donor source as a further option to increase the number of patients who might be able to receive a renal transplant.

PATIENTS AND METHODS

Between May 1996 and July 2007, 43 kidneys were transplanted using kidneys obtained from patients with small (<3 cm diameter) incidentally detected tumours. After bench surgery to excise the tumour, they were all successfully transplanted into patients who were elderly or had significant comorbidities.

RESULTS

Apart from four patients who died from unrelated illnesses, all grafts continued to function with a median and mean follow-up of 25 and 32 months. The follow-up, which included 3-monthly renal ultrasonography and chest X-rays, showed only one case of tumour recurrence, which occurred 9 years after transplantation; the patient remains stable under observation after 18 months.

CONCLUSIONS

From our experience we consider that where nephrectomy is used for small, localized, incidentally detected renal tumours, the kidney should be considered for transplantation into carefully selected patients. Such patients with numerous medical comorbidities might benefit from renal transplantation, but not survive the waiting period if they are dependent on a deceased donor graft. Paradoxically the use of these marginal kidneys has the potential to increase the quality and length of life of these patients, despite the apparent contradiction of an intuitive principle of organ transplantation and immunosuppression.

Abbreviations
(P)RN

(partial) radical nephrectomy

HLA

human leukocyte antigen

US

ultrasonography.

INTRODUCTION

The shortage of donor organs represents the single greatest challenge in renal transplantation. Various strategies have been suggested to address this problem, including the use of marginal kidneys from deceased donors. Kidneys obtained from older donors and non-heart-beating donors are now used, despite concerns about the functional outcome. There has also been an increased reliance on living-donor transplants. Excellent results were reported from genetically unrelated donors with outcomes exceeding those of well-matched deceased-donor kidneys [1]. Consequently there has been a dramatic rise in the use of spouses, partners and friends for living-donor transplantation [2].

Unfortunately, many patients do not have a suitable live donor. The long waiting times to cadaveric-donor transplantation mean that many older patients, and those with comorbid illnesses, will die or become unfit for transplantation before they have an opportunity to be transplanted [3]. Other donor sources therefore need to be considered. Kidneys with otherwise satisfactory function removed for other disease processes represent a potential resource that might warrant consideration in selected patients. In this report we review our experience of renal transplantation using kidneys with small renal tumours, used after ex-vivo excision of the lesion.

PATIENTS AND METHODS

We reviewed our single-centre experience with the transplantation of kidneys removed from patients with small (<3 cm) incidentally detected renal lesions, with a presumed diagnosis of RCC. Data were retrieved from prospective databases of patients undergoing nephrectomy, as well as all renal transplants at our centre. Information on transplant recipients was cross-referenced with the Australian and New Zealand Dialysis and Transplant Registry, a national centrally maintained data base which captures information from all patients with end-stage renal failure in these two countries, who were receiving dialysis or undergoing renal transplantation. Donors comprised deceased donors who had a small tumour detected at the time of organ retrieval, or patients referred to urologists with a radiologically detected renal lesion with a suspicion of RCC. With the latter the treatment options of observation, partial (PN) and radical nephrectomy (RN) were discussed with the patient, without reference to the possible use of the kidney for transplantation. Patients selecting RN were approached after making their treatment decision to ask if the kidney could be used for transplantation. RN was performed at their local hospital by their referring urologist, with assistance from a transplant urologist. After nephrectomy the kidney was perfused with preservation fluid and cooled in a similar fashion to standard living-donor nephrectomy. The tumour was then excised by the transplant urologist, with a margin of normal renal parenchyma based on macroscopic assessment. The parenchymal defect was then repaired using the standard procedures for PN.

Potential recipients were identified from our transplant waiting list, considering their age and comorbidities. Only elderly patients (>60 years) or those with significant comorbidities (access problems, known cardiovascular disease or multiorgan effects of diabetes) and a significant prospect of death without transplantation, were considered. Patients who were either highly sensitized and at high-risk of rejection, requiring increased immunosuppression, or with high levels of human leukocyte antigen (HLA) matching with the patient undergoing nephrectomy, were excluded. All potential recipients were provided with a rigorous informed consent process highlighting the possibilities of tumour recurrence and death due to metastatic disease, as well as surgical complications related to excision of the tumour (bleeding and urinary leakage).

The recipient surgery was performed by a surgeon who had no involvement with the nephrectomy. In all cases ureteric stents were used, which is the standard protocol with all transplants in our unit. Immunosuppression comprised a combination of cyclosporin, azathioprine and prednisolone.

A prospective follow-up was maintained on all recipients, which was updated at 3-monthly intervals by direct contact with the patient and their treating clinician.

RESULTS

Between May 1996 and July 2004, 43 patients were transplanted from donors who had small renal lesions. These were obtained from three deceased donors and 38 patients undergoing RN for a presumed RCC. With the deceased donors, the lesion was excised from the tumour-bearing kidney and frozen-section analysis used to confirm a clear margin before transplantation. The contralateral kidney was also transplanted into another recipient. In one patient, the tumour was detected at the time of the transplant and considered to be a benign cyst. Subsequent paraffin sections showed a focus of malignancy in the wall. The recipient was advised of the result and elected to undergo transplant nephrectomy. The remaining kidney was transplanted. With the other two donors both kidneys were transplanted after removing the tumour from the affected kidney. In 38 cases the donors were patients who had small (≤3 cm) solid or complex lesions detected as incidental findings when they had imaging for unrelated symptoms. RN was an open procedure in 12 cases and laparoscopic in 26. One case was a living-donor transplant (laparoscopic RN) in which the donor had a 1-cm diameter renal tumour detected during assessment imaging. Histologically, the resected tumours were clear cell carcinoma (25), papillary carcinoma (five), chromophobe carcinoma (one) oncocytoma (four), angiomyolipoma (three) and complex/multiloculated cysts (three). The remaining two kidneys were from deceased donors in which the contralateral kidney contained a clear cell carcinoma.

All recipients but three were aged >60 years. The recipients had either five or six HLA mismatches with donors. Transfusion during surgery due to haemorrhage from the site of tumour excision was required in one patient, which was secured after 1500 mL of blood loss. Transfusion was required after surgery in a further five patients. Three patients had technical complications and two of these required reoperation. One was related to a perinephric haematoma, although a specific bleeding site was not identified, and the other had a calyceal fistula related to the site of tumour resection. The transplant was re-explored and the leakage controlled by placing a nephrostomy tube into the renal pelvis through the defect, and inserting a ureteric stent. This was left in place for 3 weeks and the stent was removed 2 weeks later; no further problems were encountered. One patient represented 4 weeks after transplantation with macroscopic haematuria. Doppler US showed an arteriovenous fistula at the site of tumour resection; this was confirmed on angiography and closed with selective embolization.

One morbidly obese patient subsequently required laparotomy 3 weeks after transplantation for intra-abdominal sepsis related to a bowel perforation. Seven patients had a rejection episode, treated with pulse steroids, and one required OKT3 for steroid-resistant rejection. The mean and median follow-up was 32 and 25 months, respectively. Graft survival is shown in Fig. 1. One patient returned to dialysis at 30 months, after developing recurrent focal sclerosing glomerulonephritis. All other grafts maintained function, with serum creatinine levels of 0.09–0.31 mmol/L. Four patients died with functioning grafts; all deaths were from unrelated causes, i.e. carcinoma of the pancreas (6 months) and breast (27 months), systemic sepsis (5 months) and myocardial infarction (2 months).

Figure 1.

A Kaplan-Meier curve showing graft survival.

Follow-up with 3-monthly US of the allograft, and chest X-rays, in addition to standard medical review and investigations, showed only one possible tumour recurrence. This occurred 9 years after transplantation, when a small lesion was detected in the graft but remote from the initial tumour-resection site. The patient, a 71-year-old man, has refused both nephrectomy or treatment with radiofrequency ablation of the tumour. The lesion has been monitored for 18 months and increased from 1.0 cm to 1.2 cm on serial US.

DISCUSSION

To date we have successfully used 43 kidneys for transplantation from donors with small renal tumours. These kidneys are clearly outside the standard criteria for donor organs and would otherwise have been discarded. We think that this experience should be considered in the efforts to expand the availability of kidneys for transplantation.

The widespread availability and use of abdominal US and CT has significantly altered the presentation of RCC. Over the past few decades there has been a dramatic increase in the incidence of RCC in Western nations [4,5]; most RCC are now detected as incidental findings when imaging is used for unrelated symptoms [6]. Consequently, they are frequently small and localized. Many of these tumours will not prove to be clinically significant in the course of the patients’ lives. The increased incidence of RCC probably reflects the increased diagnosis. Autopsy studies over several decades have shown that small renal tumours are present histologically in 1–2% of people dying from unrelated diseases [7,8]. Longitudinal studies show that many small tumours have a very slow growth pattern, with a low risk of metastatic spread in tumours of <3 cm in diameter [9,10]. Unfortunately, there is currently no mechanism to establish the likely disease course of a small, incidentally detected tumour in an individual, and hence excision is usually used as definitive management [6].

Whilst small renal tumours are easily detected using several abdominal imaging techniques, the pathology of the lesion is often difficult to predict. Only angiomyolipomas can be distinguished from other solid or complex renal lesions using imaging studies, if they contain a significant component of adipose tissue [6]. Those with minimal fat content might be indeterminate on imaging studies, and treated as suspicious for RCC, as occurred in three cases in our series. Of the remaining lesions of <3 cm in diameter, ≈75% will comprise clear cell carcinoma and 10% papillary carcinoma [11]. Oncocytomas, a tumour with minimal or no metastatic potential, are present in 10% of cases. A range of other malignancies or complicated benign lesions, usually cysts, comprise the rest. With RCC the prognosis is closely linked to tumour stage and size. Recurrence or metastases occur or are present in 1–4% of pT1 tumours [12,13].

Most patients with acceptable comorbidities presenting with small localized tumours are advised to have the lesion removed surgically, by either RN or PN. The former has been standard management for renal tumours for many years [11]. PN was originally reserved for patients with a solitary or functionally compromised contralateral kidney. It has been increasingly used for patients with a small incidentally detected tumour with a normal contralateral kidney. Excellent results have been reported from many institutions, with cancer-specific survival comparable to that after RN. PN is associated with a higher risk of complications, including bleeding, urine leakage and wound-related problems [14]. Multifocal disease is evident histologically in up to 25% of kidneys removed for pT1 tumours [15]. This raises the potential concern of local recurrence; clinically local recurrence rates are much lower and reported as 0–4% of patients undergoing elective PN [16,17].

Despite the excellent reported with PN, many patients and their treating urologists will continue to opt for RN in the context of a normal contralateral kidney. It is likely that this will continue, with the disseminated availability of laparoscopic RN. Whilst laparoscopic PN has been reported, it represents a greater technical challenge than RN for small tumours [18]. Thus, whilst many or even most patients with small renal tumours might select PN, significantly many will prefer RN, based on these considerations. This is supported by population studies indicating that RN is the commonest procedure for T1 tumours. Current data from the USA, where most RCCs are detected as T1 tumours, suggest that PN is used in only 12.3–15.5% of patients with renal tumours [19,20].

The present results suggest that RN specimens containing small (<3 cm) tumours might represent a means of enhancing the length and quality of life of marginal transplant recipients who would otherwise have a significant risk of not receiving a renal allograft, due to deterioration of their health whilst waiting on dialysis. Dialysis carries a significant risk of death, particularly in the older patient. A substantial survival advantage is associated with transplantation compared to dialysis in patients with comorbidities or who are aged >60 years [3,21]. Patients in this age group awaiting transplantation have an annual mortality risk of 25% despite aggressive screening to exclude patients at high risk of cardiovascular complications [3]. Due to the increasing number of patients accepted onto dialysis programmes, but static number of organs from deceased donors, longer waiting times for renal transplantation are inevitable. In Australia, the average waiting time for deceased-donor transplantation is now 3–4 years, depending on blood group and tissue typing [2]. Consequently, many older patients or those with significant comorbidities that are accelerated by the effects of end-stage renal disease will die without ever receiving a transplant which would have improved their quality of life and longevity [3].

In several countries cultural and legislative boundaries limit the option of deceased-donor transplantation for patients with end-stage renal failure. In Japan the waiting times for a cadaveric transplant is ≈15 years [22]; consequently many patients will die without ever having the opportunity of a transplant. Japan also has a very high incidence of small RCC, possibly related to more widespread use of US assessment [23]. Presumably many patients have RN, removing a kidney which could serve as a valuable resource for patients with no option of a live-donor transplant.

Although the use of kidneys after removal of a tumour conferred significant benefits for patients in the present study, these need to be balanced against the potential risks. In only one of the present patients was there a tumour recurrence in the transplant. This appears to be related to multifocal disease, as it was remote from the initial tumour site, and consistent with the anticipated incidence after PN [16,17]. The growth pattern has subsequently also shown the slow rate reported with small renal tumours [9,10]. Obviously, with time the tumour in this patient might continue to grow and even undergo metastatic spread.

Transmission of RCC from the donor has been well reported in the past [24]. This would appear to be related to the inadvertent use of a kidney containing an unrecognized tumour that subsequently progressed. On occasions, RCC of donor origin might arise many years after transplantation, suggesting that the tumour might not have been present at the time of retrieval [25,26]. In cases with localized RCC diagnosed in an allograft, patients have been successfully managed with excision of the tumour alone [25,27]. Percutaneous minimally invasive techniques using radiofrequency ablation are now also used as an alternative to surgical excision of small renal tumours, and has also been described in the context of a tumour within a renal allograft [28]. When metastatic disease has been detected, treatment comprises the withdrawal of immunosuppression and removal of the allograft. With this approach, complete regression of the tumour occurs in half the cases [24]. We have avoided well-matched recipients for these grafts, as this could make ‘rejection’ of potential metastatic disease more difficult to achieve. Where other metastatic malignancies, such as melanoma, have been inadvertently transmitted with the donor organ, withdrawal of immunosuppression can result in complete regression of the tumour [29,30]. In selected cases successful re-transplantation can subsequently be used after a period of dialysis [29,30].

The need to carefully inspect kidneys at the time of surgery was highlighted previously [26,31]. With deceased donors a small proportion will be found to contain a small renal tumour, with the general recommendation being that the organs are discarded [26,31]. We would support the need for careful intraoperative and bench assessment of donor organs and other viscera. If small localized primary renal tumours are detected, we would contend that rather than being discarded, as previously suggested, the kidneys should be considered for older marginal transplant recipients, if the lesion can be excised and leaving an adequate volume of normal parenchyma.

Underpinning the strategy that we have used has been a vigorous informed consent process. In most cases the nephrectomy has been elective, allowing time to identify potential recipients and the opportunity for discussions with one or more of these. Information discussed with potential recipients has included the risk of recurrent malignancy, with stated estimates of tumour recurrence of ≈5%, and that with this, metastases could occur and prove fatal despite withdrawal of immunosuppression. Patients were also made aware of technical considerations, including reduced renal mass, increased risk of haemorrhage and haematoma formation, and the possibility of urinoma/urinary fistula. With meticulous closure of the collecting system we have only encountered one case related to calyceal fistula, that resolved after re-exploration. Arteriovenous fistula formation is a potentially serious complication, although to date we have only had one case, within weeks of transplantation. Regular routine US monitoring of the graft to identify this during this period, in addition to the standard follow-up protocol we use, warrants consideration.

As our experience has increased we have begun to discuss the possible availability of such marginal kidneys with some patients at the time they are placed on the transplant waiting list. These are patients who, by virtue of their age or comorbidities, are felt to have a significant risk of becoming unfit for transplantation before the usual 3–4-year waiting time for a deceased-donor kidney [2]. This allows them to be well informed ahead of time and improves their capacity to make the difficult decision related to consent.

Whilst clearly the preferred option for all patients contemplating renal transplantation is a healthy kidney from either a living or cadaveric donor, many will die while waiting for this opportunity. This is particularly the case for older or medically compromised patients who have a significant risk of death associated with dialysis. Our experience suggests that kidneys from patients with small renal tumours who have elected to undergo RN might provide a valuable resource for many patients with end-stage renal failure that, to date, has been largely overlooked. The utility of these organs should not influence the decision of the patient with a renal tumour about their surgery. This decision must remain an issue entirely between the patient and their treating clinician. Rather, transplant units need to establish liaisons with their urological colleagues in a way that does not influence patient care if this novel donor source is to be considered.

ACKNOWLEDGEMENTS

We acknowledge Beth Morrison for her assistance with the manuscript, David Sillar, John Pisko, Hee Soo Teng, Wes Hii, Peter Heathcote, Glen Wood, Peter MacTaggart, Graham Holmes, Scott McClintock, Alistair Campbell, Geoff Buckham, Greg Malone, John Yaxley, Tim Nathan, Sanjeev Bandi and Geof Hirst as well as their patients for their willingness and co-operation with this work.

CONFLICT OF INTEREST

None declared.

REFERENCES

EDITORIAL COMMENT

This paper reviews the effect on recipients of using kidneys where the donor has had a small renal mass. Although the paper describes transplanting 43 patients, this includes using the uninvolved kidney from cadaveric donors where the tumour involved the opposite kidney (two), and 10 kidneys that had a benign lesion (oncocytoma, angiomyolipoma or complex cyst). The core of the report (31 kidneys) describes using kidneys with a malignant renal tumour, excised on the bench, and then transplanted into a recipient. The concern with this practice is that it might predispose to tumour recurrence or metastasis in an immunosuppressed host. Furthermore, the technical complications associated with PN are experienced by the recipients. The results of the study show low rates of recurrence (only one case) and no patient who developed metastasis within a median follow-up of 25 months. Three patients had technical problems related to tumour removal that required a secondary intervention. The patients selected to receive these kidneys were older and had comorbidities, with a poor outlook for survival on dialysis. They were given information about the renal tumour in the donor. From the perspective of a patient receiving these kidneys, the results look reasonable.

In thinking about this practice we need to ask how the treatment options are discussed with the patients who have a kidney tumour and who are thus prospective donors. These patients are primarily ‘kidney tumour patients’ first and part of the expanded criteria for living donors only secondarily. To become a donor we must satisfy ourselves that patients were given contemporary information on treatment options and access to the best treatment for their primary problem, the tumour. If the ‘best’ therapy remains RN and the patient otherwise meets the criteria as a donor, then proceeding as outlined in the article is reasonable. This is the process described by the authors, who should be commended on their efforts here.

Several new observations should temper the future use of this approach. The study included the period from May 1996 to July 2007, during which considerations for treating RCC were different. For unilateral renal masses of <3 cm and a normal radiographic contralateral kidney, recent reports put the chance of the lesion being benign at 20–30%[1,2]. An accurate diagnosis of malignancy should be assured. RN might represent over-treatment; for 10 cases in the present study a benign pathology was reported. It is now widely acknowledged that equivalent oncological results can be obtained with PN and RN for unilateral T1a lesions of <3 cm. The complications between the techniques differ.

Unlike 10 years ago, there is now persuasive information that patients with RCC are at risk of chronic kidney disease. In a study of 2000 patients from Sloan-Kettering Memorial Cancer Center in New York, RN emerged as an independent predictor of a low GFR (<60 mL/min/1.73m2 or <45 mL/min/1.73 m2) [3]. Chronic kidney disease carries a significant risk of cardiovascular disease and hospitalization [4]. As such, this issue now provides a compelling medical rationale for nephron-sparing surgery. In a competing-risk assessment the magnitude of the problems associated with chronic kidney disease might be a more serious overall health issue than the potential for cancer recurrence in this population, although this remains to be proven.

The low rates of PN for T1 disease in a recent survey of practice trends in the USA [5] should not be used as justification for what represents the best treatment options. That study was a survey of practice patterns during a given period and might not represent optimum treatment. Certainly other considerations, including tumour location, risk tolerance for complications, patient travel, and surgeon comfort with open or laparoscopic PN, need to be addressed. Patient access to centres capable of delivering the ‘best’ therapies should be part of the consent process. In the current environment, lack of surgeon comfort with nephron-sparing surgical techniques does not justify using RN by default. This report has the potential to validate practices involving commercial gain by selling kidneys. One person’s misfortune might be another’s opportunity. The are chances for the abuse of vulnerable populations.

In summary, it appears the transplantation of kidneys with small T1 renal cancers excised ex-vivo has a reasonable oncological and safety profile for recipients. That does not mean it should be done indiscriminately; ‘best practice’ management of the donor must take priority. The use of these kidneys in the setting of cadaveric-donor transplantation is reasonable provided there is appropriate recipient selection and a robust informed consent process. Living patients who have a small unilateral renal mass and a normal contralateral kidney need to be advised about treatment options using the most contemporary information. They must understand the renal functional consequences of this decision. The opportunity for ‘best therapy’ must be afforded to patients, including referral, if needed, to a practitioner who can best accomplish the task. Above all, these patients need to be considered as ‘renal tumour patients’ first and that any consideration for using the kidney for transplantation must be secondary. Failure to proceed in what is perceived as an ethically justifiable manner might disrupt public trust in the transplantation system, with far reaching adverse affects.

David A. Goldfarb,
Section of Renal Transplantation,

and Steven C. Campbell,
Section of Urological Oncology, Glickman Urological and Kidney Institute Cleveland Clinic, Cleveland, OH, USA

REFERENCES

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