Keywords

Hereditary cancer syndromes; Renal cell carcinoma; Cancer therapy; Disease management; Urologic oncology

Introduction

Multifocal kidney cancer presents unique challenges for treating physicians. After the initial radiologic, genetic and interventional evaluation to determine the etiology of the tumors, the appropriate extirpative strategy must be identified. Historically, total nephrectomy and hemodialysis with possible renal transplant later was the primary therapeutic strategy for these patients. Later, as partial nephrectomy techniques were developed, nephron sparing surgical (NSS) approaches became the standard of care for patients presenting with multifocal and hereditary renal cell carcinoma (RCC) conditions. Retaining functional native renal parenchyma in the face of multifocal RCC is not without risk however. Surgery to remove multiple renal tumors simultaneously requires alteration of standard surgical techniques and consequently produce different perioperative outcomes [1] and increased risk of complications [2,3]. Due to these differences in technique and outcomes, the term multiplex partial nephrectomy (MxPNx) has been coined to denote these differences [1,4]. Furthermore, after initial multitumor partial nephrectomy, recurrent ipsilateral renal tumors may arise necessitating repeat and salvage renal surgery (RRS and SRS). These repeat partial nephrectomies, while highly successful in preserving native renal function, are highly morbid with complications rates exceeding 50% [5-8]. In addition, these procedures may be required at a median of every 6 years [9].

Alternative Strategies

The alternative to multiple complex and morbid renal surgeries for multifocal RCC—renal transplant—have improved immensely over the past few decades, with 5-year patient survival rates as high as 91% [10]. On the other hand, dialysis patients have a life expectancy that is 9.8 years shorter than transplant recipients [11]. Additionally, allograft survival is also improving. McCullough et al. determined that graft survival from 2000-2005 was significantly higher than from 1994-1999, with 81% of living donor grafts surviving 5 years, and 58% of living donor grafts surviving 10 years.10 Chang et al. reported the allograft half-life to be as high as 16 in some patient subgroups [12]. The improvement in graft survival is largely due to an increased understanding of immunosuppression [13]. While these statistics are promising, it is important to note that these were studies of patients predominantly with medical end-stage renal disease (ESRD) with concomitant comorbidities such as diabetes mellitus, hypertension and hyperlipidemia. Chronic kidney disease (CKD) and ESRD due to surgery, as seen in some patients with hereditary or multifocal kidney cancer, has a different natural history [14] than ESRD due to medical renal disease [15]. Patients with hereditary and multifocal RCC tend to be younger and healthier [16] than the average patient on dialysis with ESRD due to medical renal disease and the relative lack of those comorbidities almost certainly affects the applicability of these data to this patient population.

As transplant outcomes continue to improve, and hospital systems and insurers increasingly focus on complications and spiraling costs of care, [17] the continued economic feasibility of current surgery-based approaches for multifocal RCC must be reconsidered. Agochukwu et al. using Medicare reimbursement rates, estimated the accumulated cost of uncomplicated completion nephrectomy, fistula placement, and dialysis to be just under $200,000 at 5 years post nephrectomy [18]. In this analysis the cost of dialysis was intentionally underestimated for the model between $40,000 and $50,000 per year. On the other hand, Nassir et al., using US Medicare claims, determined the mean cost of renal transplant to be just over $65,000 [19]. Agochukwu et al. also compared the cost of SRS in a solitary kidney to the cost of nephrectomy and dialysis. This modeling indicated that a financial benefit of repeat partial nephrectomy was reached at 0.68 years when compared to the hypothetical cohort of patients undergoing uncomplicated total nephrectomy, fistula placement, and dialysis. Even when the cost of salvage partial nephrectomy was over-estimated—to account for the high complication rate—the financial benefit was reached within one year [18]. Comparing these two studies suggests RRS and renal transplant are economically favorable to total nephrectomy and dialysis, but the greatest obstacle to renal transplant becoming a reasonable treatment option in multifocal RCC continues to be organ availability.

Donor kidney shortage has been a problem for decades. However, thanks in part to the kidney exchange program and extended donor criteria, the median wait time for any donor was 4.5 years in 2009. Despite the success of these kidney exchange programs, this still represents a 50% increase in wait time from the 3 year wait in 2003 [20,21]. The increased demand is due to an increasing number of patients on the waitlist and an unchanged donation rate. The number of patients on the waiting list doubled from 2003 to 2013, with diabetes being the most common and fastest increasing cause of ESRD. Additionally, more and more kidneys are being rejected due to donor diabetes [10,20] Consequently, despite marked improvements in immunosuppression tolerability, graft survival, and related transplant outcomes, RRS continues to be the gold standard treatment of choice for multifocal and hereditary RCC despite the well-documented high rate of periand post-operative complications.

Conclusion and Outcomes

As complications and hospital re-admissions continue to gain prominence at an administrative level, the improving outcomes and longevity of transplant allografts along with decreasing costs of peri- and post-transplant care and dialysis make this approach an increasingly attractive treatment option for patients with multifocal and hereditary RCC. However, widespread adoption of this transplant strategy is not reasonable due to extremely limited organ availability. Currently, the standard of care for multifocal RCC is initial, repeat and salvage multiplex partial nephrectomy but this strategy is increasingly unappealing due to high complication rates and prolonged hospital admissions. With the skyrocketing incidence of obesity and diabetes nationally, the current shortage of available transplantable kidneys shows no signs of improving; and, thus, prevents bilateral nephrectomy and transplant from being a feasible option for patients with bilateral multifocal and hereditary kidney cancer. Consequently, at present, MxPNx, repeat and salvage partial nephrectomy continue to have a primary role in the treatment of hereditary and multifocal RCC.

Financial Funding

This research was supported by the Intramural Research Program of the National Institutes of Health (NIH), National Cancer Institute, Center for Cancer Research, and the Center for Interventional Oncology. NIH and Philips Healthcare have a cooperative research and development agreement. NIH and Philips share intellectual property in the field.

This research was also made possible through the National Institutes of Health Medical Research Scholars Program, a public-private partnership supported jointly by the NIH and generous contributions to the Foundation for the NIH from Pfizer Inc., The Doris Duke Charitable Foundation, The Alexandria Real Estate Equities, Inc. and Mr. and Mrs. Joel S. Marcus, and the Howard Hughes Medical Institute, as well as other private donors. For a complete list, please visit the Foundation website at: http: //fnih.org/work/education-training-0/ medical-research-scholars-program

References

1. Hankins RA, Walton-Diaz A, Truong H, Shih J, Bratslavsky G, et al. (2016) Renal functional outcomes after robotic multiplex partial nephrectomy:  The National Cancer Institute experience with robotic partial nephrectomy for 3 or more tumors in a single kidney. Int Urol Nephrol 48: 1817-1821.
2. Maurice MJ, Ramirez D, Nelson RJ, Caputo PA, Kara O, et al. (2016) Multiple tumor excisions in ipsilateral kidney increase complications after partial nephrectomy. J Endourol 30: 1200-1206.
3. Fadahunsi AT, Sanford T, Linehan WM, Pinto PA, Bratslavsky G, et al. (2011) Feasibility and outcomes of partial nephrectomy for resection of at least 20 tumors in a single renal unit. J Urol 185: 49-53.
4. Metwalli AR, Linehan WM (2014) Nephron-sparing surgery for multifocal and hereditary renal tumors. Curr Opin Urol 24: 466-473.
5. Bratslavsky G, Liu JJ, Johnson AD, Sudarshan S, Choyke PL, et al. (2008) Salvage partial nephrectomy for hereditary renal cancer:  feasibility and outcomes. J Urol 179: 67-70.
6. Johnson A, Sudarshan S, Liu J, Pinto PA, Bratslavsky G, et al. (2008) Feasibility and outcomes of repeat partial nephrectomy. J Urol 180: 89-93.
7. Liu NW, Khurana K, Sudarshan S, Pinto PA, Marston WL, et al. (2010) Repeat partial nephrectomy on the solitary kidney:  Surgical, functional and oncological outcomes. J Urol 183: 1719-1724.
8. Watson MJ, Sidana A, Diaz AW, Siddiqui MM, Hankins RA, et al. (2016) Repeat robotic partial nephrectomy:  Characteristics, Complications, and Renal Functional Outcomes. J Endourol 30: 1219-1226.
9. Singer EA, Vourganti S, Lin KY, Gopal NG, Pinto PA, et al. (2012) Outcomes of patients with surgically treated bilateral renal masses and a minimum of 10 years of followup. J Urol 188: 2084-2088.
10. McCullough KP, Keith DS, Meyer KH, Stock PG, Brayman KL, et al. (2009) Kidney and pancreas transplantation in the United States, 1998-2007:  access for patients with diabetes and end-stage renal disease. Am J Transplant 9: 894-906.
11. Gill JS, Tonelli M, Johnson N, Kiberd B, Landsberg D, et al. (2005) The impact of waiting time and comorbid conditions on the survival benefit of kidney transplantation. Kidney Int 68: 2345-2351.
12. Chang P, Gill J, Dong J, Rose C, Yan H, et al. (2012) Living donor age and kidney allograft half-life:  implications for living donor paired exchange programs. Clin J Am Soc Nephrol 7: 835-841.
13. Halloran PF (2004) Immunosuppressive drugs for kidney transplantation. N Engl J Med 351: 2715-29.
14. Mason R, Kapoor A, Liu Z, Saarela O, Tanguay S, et al. (2016) The natural history of renal function after surgical management of renal cell carcinoma:  Results from the Canadian Kidney Cancer Information System. Urologic Oncology:  Seminars and Original Investigations 34: 486.e1-486.e7.
15. Menon V, Wang X, Sarnak MJ, Hunsicker LH, Madero M, et al. (2008) Long-term outcomes in non-diabetic chronic kidney disease. Kidney Int 73: 1310-1315.
16. Shuch B, Vourganti S, Ricketts CJ, Middleton L, Peterson J, et al. (2014) Defining early-onset kidney cancer:  implications for germline and somatic mutation testing and clinical management. J Clin Oncol 32: 431-437.
17. Healy MA, Mullard AJ, Campbell DA, Dimick JB (2016) Hospital and payer costs associated with surgical complications. JAMA Surg 151: 823-830.
18. Agochukwu NQ, Metwalli AR, Kutikov A, Pinto PA, Linehan WM, et al. (2012) Economic burden of repeat renal surgery on solitary kidney-Do the ends justify the means? A cost analysis. J Urol 188: 1695-1700.
19. Nassir BA, Dean CE, Li S,  Nicholas S, Craig SA, et al. (2015) Variation in cost and quality in kidney transplantation. Transplantation 99: 2150-2157.
20. Matas AJ, Smith JM, Skeans MA, Thompson B, Gustafson SK, et al. (2015) OPTN/SRTR 2013 Annual Data Report:  Kidney. Am J Transplant 15 Suppl 2: 1-34.
21. Roth AE, Sonmez T, Unver MU, Delmonico FL, Saidman SL, et al. (2006) Utilizing list exchange and nondirected donation through 'chain' paired kidney donations. Am J Transplant 6: 2694-2705.