- Email: [email protected]
Chronic Kidney Disease in Patients With Renal Cell Carcinoma
Chronic Kidney Disease in Patients With Renal Cell Carcinoma Anthony Chang, Antonio Finelli, Jeffrey S. Berns, and Mitchell Rosner Renal cell carcinoma (RCC) is diagnosed in over 65,000 Americans annually, and earlier detection and advances in surgical techniques have resulted in improved oncological outcomes. Given that diabetes and hypertension are independent risk factors for the development of RCC, it is not surprising that diabetic nephropathy or hypertensive nephrosclerosis are commonly encountered in these patients. Data support that at least one third of the 300,000 kidney cancer survivors in the United States have or will develop CKD; however, the effect of CKD in this clinical setting has largely evaded the attention of the medical community. It is likely that CKD which develops from postsurgical therapy for RCC may limit long-term outcomes by increasing the risk for cardiovascular morbidity and mortality. To further improve the clinical outcomes for kidney cancer patients, better recognition and management of CKD, which requires coordination among urologists, pathologists, and nephrologists, will be essential. Q 2014 by the National Kidney Foundation, Inc. All rights reserved. Key Words: Nephrectomy, Non-neoplastic kidney disease, Urology, Nephrology, Pathology
Introduction The substantial burden and harmful effect of CKD in kidney cancer patients has largely evaded the attention of the medical community. Urologists who remove kidney tumors and the pathologists that evaluate these tumor nephrectomy specimens primarily have been focused on the potentially fatal effects of kidney malignancies. Although nephrologists have the expertise to manage CKD, they have not been included in the routine pre- and postoperative care of kidney cancer patients. Many recent developments allow us to re-evaluate the current state of affairs. Nephron-sparing surgery (NSS), which encompasses radiofrequency ablation, cryoablation, and partial nephrectomy (PN), is now a minimally invasive, safe, effective, and routine procedure for kidney tumor resection. Similar oncologic outcomes can be achieved for early-stage renal cell carcinomas (RCCs) that are removed by PN or radical nephrectomy, but PN has demonstrated improved clinical outcomes because of the significant preservation of kidney function1,2 and maintenance of blood pressure,3 especially for small renal masses (SRMs). Therefore, a wide surgical margin is not only unnecessary, but it likely harms the patient because of the loss of kidney function. In addition, several recent studies have demonstrated the prevalence of common non-neoplastic kidney diseases in kidney cancer patients (especially diabetic nephropathy and hypertensive nephrosclerosis), and most diagnoses are not identified in the initial pathologic evaluation of the tumor nephrectomy specimen although they might be present.4-6 This burden of CKD becomes readily apparent after surgical removal of any significant portion of functioning nephron mass and may negatively affect long-term outcomes. This review will focus on the prevalence, harmful effect, and optimal management of CKD in the setting of kidney cancer; recent trends in the surgical removal and active surveillance of kidney masses; and the prevalence of non-neoplastic kidney diseases found during the
pathologic evaluation of tumor nephrectomy specimens. It is hoped that significant gains in the clinical outcomes of kidney cancer patients can be obtained through improved management of CKD. At the core, the optimal management of kidney cancer patients requires increased communication and the coordination of clinical care among urologists, nephrologists, and pathologists.
CKD in Kidney Cancer The harmful effects of CKD are well established and recognized. Huang and colleagues were the first to demonstrate that 26% of kidney cancer patients had CKD on the basis of the Modification of Diet in Renal Disease equation before tumor nephrectomy.7 After surgery, 39% had an estimated glomerular filtration rate (GFR) of less than 60 mL/minute, but 70% of the patients underwent a radical nephrectomy. Hypertension8,9 and diabetes10 are independent risk factors for developing RCC. The risk of kidney cancer in ESRD patients is increased up to 100 times.11 There are limited data that CKD may lead to a similar, albeit smaller, increased risk of kidney cancer.12 According to the U.S. National Cancer Institute, more than 65,000 cancers of the kidney and renal pelvis will be diagnosed in 2013, with 13,680 estimated deaths.13 Over the last 2 decades, there has been a notable migration toward the diagnosis of early-stage kidney cancers in the From Department of Pathology, University of Chicago Medicine, Chicago, IL; Division of Urology, University of Toronto, Toronto, Canada; Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA; and Department of Medicine, University of Virginia, Charlottesville, VA. Financial Disclosure: The authors declare that they have no relevant financial interests. Address correspondence to Anthony Chang, MD, Department of Pathology, University of Chicago Medical Center, 5841 S. Maryland Avenue (MC 6101), Chicago, IL 60637. E-mail: [email protected] Ó 2014 by the National Kidney Foundation, Inc. All rights reserved. 1548-5595/$36.00 http://dx.doi.org/10.1053/j.ackd.2013.09.003
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United States. According to 1 study, 43% of kidney canlogic outcomes between PN and more radical apcers were Stage 1 in 1993 and currently comprise over proaches.21 However, the adoption of PN had been 14,15 Approximately 20% to 25% of these slower than expected.22,23 Various reasons have been 60% of tumors. 16,17 SRMs are benign (oncocytoma or angiomyolipoma). hypothesized, and there are data to suggest that the For the remaining tumors that consist of RCC, the introduction of laparoscopic radical nephrectomy 5-year survival exceeds 90% to 95% in most studies. impeded the uptake of PN.24 Although the long awaited results of a European Organization for Research and There are currently more than 300,000 kidney cancer surTreatment of Cancer randomized clinical trial showed vivors in the United States. Given the excellent oncologic similar oncologic outcomes, it failed to demonstrate a suroutcomes for most kidney tumor patients, the attention vival advantage for PN over radial nephrectomy.25,26 has now shifted toward the preservation of kidney funcHowever, given some study design limitations,27 tion and should also include the management of CKD. PN remains the first-line treatment for localized RCCs The urological community has spearheaded this effort less than 4 cm.18,19 PN may be performed in the as minimally invasive surgical approaches are more conventional open manner or laparoscopic or robotwidely adopted. The American Urological Association assisted laparoscopic. Despite minor differences in techin 2009 and the European Association of Urology in niques, the goal of PN is to achieve complete tumor 2010 released position statements that PN should be conremoval with a negative margin in an efficient manner sidered for all clinical T1 (less than 7 cm) kidney tusuch that ischemia times are kept to a minimum and conmors.18,19 Although there are data regarding the clinical outcome sequent kidney damage is minimized. of kidney function postsurgery in kidney cancer patients, A less invasive option for T1a RCC and in particular almost all of these studies did not specifically analyze the tumors less than 3 cm is percutaneous probe ablation. pathologic specimens for the This is most commonly in presence or absence of the form of radiofrequency CLINICAL SUMMARY a non-neoplastic kidney disablation or cryotherapy.28 Given that it is performed ease. Therefore, there are CKD involves at least 25% of RCC patients even before percutaneously as an outpaabundant opportunities for nephrectomy. tient procedure, this modalfuture translational and clin Of 300,000 RCC survivors in the United States, at least ity has been a welcome ical research on this topic to 45,000 have an underlying kidney disease (most addition to the ‘‘surgical’’ arbetter define the degree of commonly diabetic nephropathy or hypertensive mamentarium, in particular CKD in patients with RCC. nephrosclerosis). for older patients and pa Improved coordination of care among urologists, tients with significant coLess is Sometimes More pathologists, and nephrologists will result in better morbities. These techniques outcomes for RCC patients. (or at Least Better) are most effective in treating tumors less than 3 cm in size The incidence of SRMs has increased approximately located a distance from ma2% year after year.20 Consequently, the management of jor vessels, which could act as an energy sink and lessen SRMs (,4 cm) has evolved significantly in the recent the effectiveness of therapy.29 Success rates are inferior to PN, but they are considered acceptable at greater than past (Table 1). Although advanced RCC is often lethal, 90% recurrence-free rates; however, these rates vary desurgically treated localized tumors less than 4 cm (T1a) pending on the study population and definition of carry an excellent prognosis with a greater than 90% 10failure.30-32 year recurrence-free survival rate. The era of radical neAlthough many patients presenting with contrast enphrectomy as a ‘‘1-size fits all’’ strategy has been replaced hancing SRMs go directly to some form of treatment, by biopsy to confirm the diagnosis followed by nephronthere is a growing experience and acceptance with percusparing treatment for many and selective surveillance for taneous kidney tumor biopsy and active surveillance for some. Therefore, a discussion of RCC in the context of SRMs. In centers with experience, the diagnostic rates of CKD is pertinent to the management of SRMs and the kidney tumor biopsy are greater than 80% with a very treatment of large advanced tumors in which the effect low complication rate (,5%) and a benign histology on kidney function is clearly greater because of loss of rate of greater than 25%.17 Given that upward of 25% of more kidney mass. solid-enhancing SRMs are benign, some have adopted PN has been a treatment option for years, but it was the practice to biopsy all lesions before treatment. Furmostly applied in instances such as disease in a solitary thermore, repeat biopsy after a nondiagnostic biopsy is kidney, bilateral kidney tumors, or in the setting of successful 80% of the time.33 Lastly, the concordance rates CKD, in which more radical surgery would clearly result between biopsy results and surgical pathology approach in ESRD. The evidence supporting ‘‘elective’’ PN for 100% for SRMs.34 SRMs emerged in the 1990s with equivalent 10-year onco-
CKD in Kidney Cancer Patients
Table 1. Therapeutic Options for Renal Cell Carcinoma Active Surveillance Nephron-sparing surgery Ablative therapy Radiofrequency ablation Percutaneous Laparoscopic Cryoablation Percutaneous Laparoscopic Thermal ablation Partial nephrectomy Laparoscopic Robot-assisted laparoscopic Open Radical nephrectomy Laparoscopic Open
Given the greater than 90% cancer-specific survival for T1a RCC, regardless of the treatment used, it became apparent that many of these tumors were likely to have a favorable natural history. Furthermore, through anecdotal experiences in patients unfit for surgery, we learned that these tumors grew at very slow rates. A large prospective series demonstrated an average growth of 0.13 cm/year, and local progression or metastases were extremely rare.35,36 Active surveillance for T1a RCC is now an acceptable treatment option in older patients and in patients with significant comorbities.
Non-Neoplastic Kidney Diseases: If You Do Not Look, You Will Not Find It Subspecialization is an integral part of the current delivery of medical care, which often optimizes outcomes, but several weaknesses of this system have contributed to the suboptimal care of kidney cancer patients. Specifically, within the practice of pathology, nephropathology is a very specialized area of expertise. A 2007 survey of pathology residency training programs found that only 36% required any rotation in nephropathology during the entire anatomic pathology training.5 Therefore, most boardcertified surgical pathologists have not been trained and are ill equipped to evaluate the non-neoplastic kidney parenchyma of tumor nephrectomy specimens. Approximately 60% to 88% of such background diagnoses are not identified during the initial nephrectomy evaluation.5,6 A recent European survey of genitourinary pathologists revealed that over 25% do not evaluate the non-neoplastic kidney parenchyma, although a portion of the tissue is properly sampled for every specimen.37 The pathologic evaluation of tumor nephrectomy specimens has traditionally focused entirely on the kidney mass with many parameters that must be analyzed and reported for every carcinoma, including size, Fuhrman grade, margin status, capsule or renal vein invasion,
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and others. Synoptic reports, such as those created by the College of American Pathologists38 and Association of Directors of Anatomic and Surgical Pathology,39 have been important in ensuring that all of the important parameters are systematically evaluated and reported for every specimen. A modification of the College of American Pathologist kidney cancer protocol and checklist in January 2010 established the status of non-neoplastic kidney as a required parameter for reporting, which was an optional parameter before this date.38 Although this requirement is now in place, there are no data regarding compliance with this specific parameter. Given that most kidney masses are Stage 1 tumors, the status of the non-neoplastic kidney is arguably the most important pathologic parameter for these patients and may discover previously unrecognized kidney pathology, such as glomerular disease, interstitial fibrosis, diabetic nephropathy, and others. Pathologists have a unique opportunity and important responsibility to diagnose non-neoplastic kidney diseases, which are commonplace. Data support the fact that investigation of nonneoplastic kidney tissue can lead to important diagnoses. The prevalence of diabetic nephropathy in these specimens ranges from 7% to 9%.5,6 Also, focal segmental glomerulosclerosis (2-9%), hypertensive nephrosclerosis, amyloidosis, thrombotic microangiopathy, collapsing glomerulopathy, immunoglobulin A nephropathy, membranous nephropathy, thin basement membrane disease, acute interstitial nephritis, and rarely pauci-immune crescentic glomerulonephritis are encountered. Similar to cancer management, the early detection of a nonneoplastic kidney disease provides better opportunities for medical intervention. There are currently more than 300,000 kidney cancer survivors in the United States, and an estimated 15% (or 45,000) of these patients have underlying medical kidney diseases, which can only be diagnosed by pathologists. Furthermore, pathologists should regard these diagnoses as critical values, which require direct communication with the treating physician to convey the clinical importance and to ensure that appropriate consultations occur. Simply adding these diagnoses of coincidental non-neoplastic kidney diseases to a surgical pathology report may not trigger the appropriate management.
The Role of the Nephrologist in Patients With RCC Because more patients are surviving with RCC and CKD is common as the population ages, it follows that nephrologists will have an increasing role in the care of these patients. However, the nature of this role is unclear. As described above, CKD has been noted to be a common complication of nephrectomy for RCC. However, the move to nephron-sparing surgery (NSS) will diminish the likelihood of there being a large reduction in GFR after
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kidney cancer surgery and thus will also lessen the burden of subsequent CKD. This may be offset by other factors such as the increasing prevalence of RCC as well as the older age of the population undergoing treatment for RCC. Furthermore, if pathologists consistently review non-neoplastic kidney tissue, previously undiagnosed kidney parenchymal diseases that require nephrological evaluation and possibly therapy may be discovered. Thus, prudent recommendations for nephrological evaluation for the patient with RCC include the following: (1) the finding of any kidney parenchymal pathological process on evaluation of noncancerous kidney tissue (such as previously undiagnosed glomerular or interstitial disease or significant [.25%] fibrosis), and (2) postoperative estimated GFR (once kidney function is stable) less than 60 mL/minute. Furthermore, those patients with preoperative estimated GFRs less than 60 mL/minute would also benefit from nephrology consultation before surgery. Such consultations would focus on routine CKD care as outlined in the recent Kidney Disease Improving Global Outcomes guidelines for the evaluation and management of CKD (http://kdigo.org/ home/ckd-evaluation-management/).
Summary Advances in the care of the patient with RCC mean that fewer patients are receiving radical nephrectomies. However, because of changing demographics (older patients with hypertension and diabetes), more patients with RCC have underlying CKD, which may or may not be recognized before surgical interventions. To improve outcomes for these patients, a tripartite communication scheme that includes the surgeon, pathologist, and nephrologist is ideal. The surgeon is responsible for treatment planning and referral to the nephrologist if the GFR is preoperatively less than 60 mL/minute. The pathologist is responsible for careful review of the neoplastic and non-neoplastic kidney tissue as well as for communication with the surgeon and nephrologist regarding their findings. Finally, the nephrologist is responsible for long-term management of the patient’s CKD following established guidelines. Through this scheme, long-term outcomes can be optimized.
References 1. Lau WK, Blute ML, Weaver AL, Torres VE, Zincke H. Matched comparison of radical nephrectomy vs nephron-sparing surgery in patients with unilateral renal cell carcinoma and a normal contralateral kidney. Mayo Clin Proc. 2000;75(12):1236-1242. 2. Tan HJ, Norton EC, Ye Z, Hafez KS, Gore JL, Miller DC. Long-term survival following partial vs radical nephrectomy among older patients with early-stage kidney cancer. JAMA. 2012;307(15):1629-1635. 3. Lawrentschuk N, Trottier G, Mayo K, Rendon RA. Effects of partial nephrectomy on postoperative blood pressure. Korean J Urol. 2012;53(3):154-158.
4. Bijol V, Mendez GP, Hurwitz S, Rennke HG, Nose V. Evaluation of the nonneoplastic pathology in tumor nephrectomy specimens: predicting the risk of progressive renal failure. Am J Surg Pathol. 2006;30(5):575-584. 5. Henriksen KJ, Meehan SM, Chang A. Non-neoplastic renal diseases are often unrecognized in adult tumor nephrectomy specimens: a review of 246 cases. Am J Surg Pathol. 2007;31(11):1703-1708. 6. Salvatore SP, Cha EK, Rosoff JS, Seshan SV. Nonneoplastic renal cortical scarring at tumor nephrectomy predicts decline in kidney function. Arch Pathol Lab Med. 2013;137(4):531-540. 7. Huang WC, Levey AS, Serio AM, et al. Chronic kidney disease after nephrectomy in patients with renal cortical tumours: a retrospective cohort study. Lancet Oncol. 2006;7(9):735-740. 8. Choi MY, Jee SH, Sull JW, Nam CM. The effect of hypertension on the risk for kidney cancer in Korean men. Kidney Int. 2005;67(2): 647-652. 9. Chow WH, Gridley G, Fraumeni JF Jr, Jarvholm B. Obesity, hypertension, and the risk of kidney cancer in men. N Engl J Med. 2000;343(18):1305-1311. 10. Zucchetto A, Dal Maso L, Tavani A, et al. History of treated hypertension and diabetes mellitus and risk of renal cell cancer. Ann Oncol. 2007;18(3):596-600. 11. Denton MD, Magee CC, Ovuworie C, et al. Prevalence of renal cell carcinoma in patients with ESRD pre-transplantation: a pathologic analysis. Kidney Int. 2002;61(6):2201-2209. 12. Christensson A, Savage C, Sjoberg DD, et al. Association of cancer with moderately impaired renal function at baseline in a large, representative, population-based cohort followed for up to 30 years. Int J Cancer. 2013;133(6):1452-1458. 13. Kidney cancer. U.S. National Cancer Institute; 2013. Available at: http://www.cancer.gov/cancertopics/types/kidney. Accessed August 19, 2013. 14. Kane CJ, Mallin K, Ritchey J, Cooperberg MR, Carroll PR. Renal cell cancer stage migration: analysis of the national cancer data base. Cancer. 2008;113(1):78-83. 15. Pichler M, Hutterer GC, Chromecki TF, et al. Renal cell carcinoma stage migration in a single European centre over 25 years: effects on 5- and 10-year metastasis-free survival. Int Urol Nephrol. 2012;44(4):997-1004. 16. Frank I, Blute ML, Cheville JC, Lohse CM, Weaver AL, Zincke H. Solid renal tumors: an analysis of pathological features related to tumor size. J Urol. 2003;170(6.1):2217-2220. 17. Volpe A, Finelli A, Gill IS, et al. Rationale for percutaneous biopsy and histologic characterisation of renal tumours. Eur Urol. 2012;62(3):491-504. 18. Campbell SC, Novick AC, Belldegrun A, et al. Guideline for management of the clinical t1 renal mass. J Urol. 2009;182(4):1271-1279. 19. Ljungberg B, Cowan NC, Hanbury DC, et al. EAU guidelines on renal cell carcinoma: the 2010 update. Eur Urol. 2010;58(3): 398-406. 20. Patard JJ. Incidental renal tumours. Curr Opin Urol. 2009;19(5): 454-458. 21. Fergany AF, Hafez KS, Novick AC. Long-term results of nephron sparing surgery for localized renal cell carcinoma: 10-year followup. J Urol. 2000;163(2):442-445. 22. Miller DC, Hollingsworth JM, Hafez KS, Daignault S, Hollenbeck BK. Partial nephrectomy for small renal masses: an emerging quality of care concern? J Urol. 2006;175(3.1):853-857. 23. Abouassaly R, Finelli A, Tomlinson GA, Urbach DR, Alibhai SM. How often are patients with diabetes or hypertension being treated with partial nephrectomy for renal cell carcinoma? A populationbased analysis. BJU Int. 2011;108(11):1806-1812. 24. Abouassaly R, Alibhai SM, Tomlinson G, Timilshina N, Finelli A. Unintended consequences of laparoscopic surgery on partial nephrectomy for kidney cancer. J Urol. 2010;183(2):467-472. 25. Scosyrev E, Messing EM, Sylvester R, Campbell S, Van Poppel H. Renal function after nephron-sparing surgery versus radical
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26.
27.
28.
29.
30.
31.
nephrectomy: results from EORTC randomized trial 30904. Eur Urol., http://dx.doi.org/10.1016/j.eururo.2013.06.044. Van Poppel H, Da Pozzo L, Albrecht W, et al. A prospective, randomised EORTC intergroup phase 3 study comparing the oncologic outcome of elective nephron-sparing surgery and radical nephrectomy for low-stage renal cell carcinoma. Eur Urol. 2011;59(4): 543-552. Terrone C, Volpe A. Can emerging level 1 evidence ‘‘Discourage’’ Elective nephron-sparing surgery for small renal tumors? Eur Urol. 2011;59(4):553-555. Atwell TD, Schmit GD, Boorjian SA, et al. Percutaneous ablation of renal masses measuring 3.0 cm and smaller: Comparative local control and complications after radiofrequency ablation and cryoablation. AJR Am J Roentgenol. 2013;200(2):461-466. Gervais DA, McGovern FJ, Arellano RS, McDougal WS, Mueller PR. Radiofrequency ablation of renal cell carcinoma: part 1, indications, results, and role in patient management over a 6-year period and ablation of 100 tumors. AJR Am J Roentgenol. 2005;185(1):64-71. Psutka SP, Feldman AS, McDougal WS, McGovern FJ, Mueller P, Gervais DA. Long-term oncologic outcomes after radiofrequency ablation for T1 renal cell carcinoma. Eur Urol. 2013;63(3):486-492. Tan YK, Best SL, Olweny E, Park S, Trimmer C, Cadeddu JA. Radiofrequency ablation of incidental benign small renal mass: outcomes and follow-up protocol. Urology. 2012;79(4):827-830.
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32. Zagoria RJ, Pettus JA, Rogers M, Werle DM, Childs D, Leyendecker JR. Long-term outcomes after percutaneous radiofrequency ablation for renal cell carcinoma. Urology. 2011;77(6):1393-1397. 33. Leveridge MJ, Finelli A, Kachura JR, et al. Outcomes of small renal mass needle core biopsy, nondiagnostic percutaneous biopsy, and the role of repeat biopsy. Eur Urol. 2011;60(3):578-584. 34. Volpe A, Mattar K, Finelli A, et al. Contemporary results of percutaneous biopsy of 100 small renal masses: a single center experience. J Urol. 2008;180(6):2333-2337. 35. Jewett MA, Mattar K, Basiuk J, et al. Active surveillance of small renal masses: progression patterns of early stage kidney cancer. Eur Urol. 2011;60(1):39-44. 36. Smaldone MC, Kutikov A, Egleston BL, et al. Small renal masses progressing to metastases under active surveillance: a systematic review and pooled analysis. Cancer. 2012;118(4):997-1006. 37. Algaba F, Delahunt B, Berney DM, et al. Handling and reporting of nephrectomy specimens for adult renal tumours: a survey by the European Network of Uropathology. J Clin Pathol. 2012;65(2):106113. 38. Srigley JR, Amin MB, Delahunt B, et al. Protocol for the examination of specimens from patients with invasive carcinoma of renal tubular origin. Arch Pathol Lab Med. 2010;134(4):e25-e30. 39. Higgins JP, McKenney JK, Brooks JD, Argani P, Epstein JI. Recommendations for the reporting of surgically resected specimens of renal cell carcinoma: the Association of Directors of Anatomic and Surgical Pathology. Hum Pathol. 2009;40(4):456-463.
Introduction The substantial burden and harmful effect of CKD in kidney cancer patients has largely evaded the attention of the medical community. Urologists who remove kidney tumors and the pathologists that evaluate these tumor nephrectomy specimens primarily have been focused on the potentially fatal effects of kidney malignancies. Although nephrologists have the expertise to manage CKD, they have not been included in the routine pre- and postoperative care of kidney cancer patients. Many recent developments allow us to re-evaluate the current state of affairs. Nephron-sparing surgery (NSS), which encompasses radiofrequency ablation, cryoablation, and partial nephrectomy (PN), is now a minimally invasive, safe, effective, and routine procedure for kidney tumor resection. Similar oncologic outcomes can be achieved for early-stage renal cell carcinomas (RCCs) that are removed by PN or radical nephrectomy, but PN has demonstrated improved clinical outcomes because of the significant preservation of kidney function1,2 and maintenance of blood pressure,3 especially for small renal masses (SRMs). Therefore, a wide surgical margin is not only unnecessary, but it likely harms the patient because of the loss of kidney function. In addition, several recent studies have demonstrated the prevalence of common non-neoplastic kidney diseases in kidney cancer patients (especially diabetic nephropathy and hypertensive nephrosclerosis), and most diagnoses are not identified in the initial pathologic evaluation of the tumor nephrectomy specimen although they might be present.4-6 This burden of CKD becomes readily apparent after surgical removal of any significant portion of functioning nephron mass and may negatively affect long-term outcomes. This review will focus on the prevalence, harmful effect, and optimal management of CKD in the setting of kidney cancer; recent trends in the surgical removal and active surveillance of kidney masses; and the prevalence of non-neoplastic kidney diseases found during the
pathologic evaluation of tumor nephrectomy specimens. It is hoped that significant gains in the clinical outcomes of kidney cancer patients can be obtained through improved management of CKD. At the core, the optimal management of kidney cancer patients requires increased communication and the coordination of clinical care among urologists, nephrologists, and pathologists.
CKD in Kidney Cancer The harmful effects of CKD are well established and recognized. Huang and colleagues were the first to demonstrate that 26% of kidney cancer patients had CKD on the basis of the Modification of Diet in Renal Disease equation before tumor nephrectomy.7 After surgery, 39% had an estimated glomerular filtration rate (GFR) of less than 60 mL/minute, but 70% of the patients underwent a radical nephrectomy. Hypertension8,9 and diabetes10 are independent risk factors for developing RCC. The risk of kidney cancer in ESRD patients is increased up to 100 times.11 There are limited data that CKD may lead to a similar, albeit smaller, increased risk of kidney cancer.12 According to the U.S. National Cancer Institute, more than 65,000 cancers of the kidney and renal pelvis will be diagnosed in 2013, with 13,680 estimated deaths.13 Over the last 2 decades, there has been a notable migration toward the diagnosis of early-stage kidney cancers in the From Department of Pathology, University of Chicago Medicine, Chicago, IL; Division of Urology, University of Toronto, Toronto, Canada; Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA; and Department of Medicine, University of Virginia, Charlottesville, VA. Financial Disclosure: The authors declare that they have no relevant financial interests. Address correspondence to Anthony Chang, MD, Department of Pathology, University of Chicago Medical Center, 5841 S. Maryland Avenue (MC 6101), Chicago, IL 60637. E-mail: [email protected] Ó 2014 by the National Kidney Foundation, Inc. All rights reserved. 1548-5595/$36.00 http://dx.doi.org/10.1053/j.ackd.2013.09.003
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United States. According to 1 study, 43% of kidney canlogic outcomes between PN and more radical apcers were Stage 1 in 1993 and currently comprise over proaches.21 However, the adoption of PN had been 14,15 Approximately 20% to 25% of these slower than expected.22,23 Various reasons have been 60% of tumors. 16,17 SRMs are benign (oncocytoma or angiomyolipoma). hypothesized, and there are data to suggest that the For the remaining tumors that consist of RCC, the introduction of laparoscopic radical nephrectomy 5-year survival exceeds 90% to 95% in most studies. impeded the uptake of PN.24 Although the long awaited results of a European Organization for Research and There are currently more than 300,000 kidney cancer surTreatment of Cancer randomized clinical trial showed vivors in the United States. Given the excellent oncologic similar oncologic outcomes, it failed to demonstrate a suroutcomes for most kidney tumor patients, the attention vival advantage for PN over radial nephrectomy.25,26 has now shifted toward the preservation of kidney funcHowever, given some study design limitations,27 tion and should also include the management of CKD. PN remains the first-line treatment for localized RCCs The urological community has spearheaded this effort less than 4 cm.18,19 PN may be performed in the as minimally invasive surgical approaches are more conventional open manner or laparoscopic or robotwidely adopted. The American Urological Association assisted laparoscopic. Despite minor differences in techin 2009 and the European Association of Urology in niques, the goal of PN is to achieve complete tumor 2010 released position statements that PN should be conremoval with a negative margin in an efficient manner sidered for all clinical T1 (less than 7 cm) kidney tusuch that ischemia times are kept to a minimum and conmors.18,19 Although there are data regarding the clinical outcome sequent kidney damage is minimized. of kidney function postsurgery in kidney cancer patients, A less invasive option for T1a RCC and in particular almost all of these studies did not specifically analyze the tumors less than 3 cm is percutaneous probe ablation. pathologic specimens for the This is most commonly in presence or absence of the form of radiofrequency CLINICAL SUMMARY a non-neoplastic kidney disablation or cryotherapy.28 Given that it is performed ease. Therefore, there are CKD involves at least 25% of RCC patients even before percutaneously as an outpaabundant opportunities for nephrectomy. tient procedure, this modalfuture translational and clin Of 300,000 RCC survivors in the United States, at least ity has been a welcome ical research on this topic to 45,000 have an underlying kidney disease (most addition to the ‘‘surgical’’ arbetter define the degree of commonly diabetic nephropathy or hypertensive mamentarium, in particular CKD in patients with RCC. nephrosclerosis). for older patients and pa Improved coordination of care among urologists, tients with significant coLess is Sometimes More pathologists, and nephrologists will result in better morbities. These techniques outcomes for RCC patients. (or at Least Better) are most effective in treating tumors less than 3 cm in size The incidence of SRMs has increased approximately located a distance from ma2% year after year.20 Consequently, the management of jor vessels, which could act as an energy sink and lessen SRMs (,4 cm) has evolved significantly in the recent the effectiveness of therapy.29 Success rates are inferior to PN, but they are considered acceptable at greater than past (Table 1). Although advanced RCC is often lethal, 90% recurrence-free rates; however, these rates vary desurgically treated localized tumors less than 4 cm (T1a) pending on the study population and definition of carry an excellent prognosis with a greater than 90% 10failure.30-32 year recurrence-free survival rate. The era of radical neAlthough many patients presenting with contrast enphrectomy as a ‘‘1-size fits all’’ strategy has been replaced hancing SRMs go directly to some form of treatment, by biopsy to confirm the diagnosis followed by nephronthere is a growing experience and acceptance with percusparing treatment for many and selective surveillance for taneous kidney tumor biopsy and active surveillance for some. Therefore, a discussion of RCC in the context of SRMs. In centers with experience, the diagnostic rates of CKD is pertinent to the management of SRMs and the kidney tumor biopsy are greater than 80% with a very treatment of large advanced tumors in which the effect low complication rate (,5%) and a benign histology on kidney function is clearly greater because of loss of rate of greater than 25%.17 Given that upward of 25% of more kidney mass. solid-enhancing SRMs are benign, some have adopted PN has been a treatment option for years, but it was the practice to biopsy all lesions before treatment. Furmostly applied in instances such as disease in a solitary thermore, repeat biopsy after a nondiagnostic biopsy is kidney, bilateral kidney tumors, or in the setting of successful 80% of the time.33 Lastly, the concordance rates CKD, in which more radical surgery would clearly result between biopsy results and surgical pathology approach in ESRD. The evidence supporting ‘‘elective’’ PN for 100% for SRMs.34 SRMs emerged in the 1990s with equivalent 10-year onco-
CKD in Kidney Cancer Patients
Table 1. Therapeutic Options for Renal Cell Carcinoma Active Surveillance Nephron-sparing surgery Ablative therapy Radiofrequency ablation Percutaneous Laparoscopic Cryoablation Percutaneous Laparoscopic Thermal ablation Partial nephrectomy Laparoscopic Robot-assisted laparoscopic Open Radical nephrectomy Laparoscopic Open
Given the greater than 90% cancer-specific survival for T1a RCC, regardless of the treatment used, it became apparent that many of these tumors were likely to have a favorable natural history. Furthermore, through anecdotal experiences in patients unfit for surgery, we learned that these tumors grew at very slow rates. A large prospective series demonstrated an average growth of 0.13 cm/year, and local progression or metastases were extremely rare.35,36 Active surveillance for T1a RCC is now an acceptable treatment option in older patients and in patients with significant comorbities.
Non-Neoplastic Kidney Diseases: If You Do Not Look, You Will Not Find It Subspecialization is an integral part of the current delivery of medical care, which often optimizes outcomes, but several weaknesses of this system have contributed to the suboptimal care of kidney cancer patients. Specifically, within the practice of pathology, nephropathology is a very specialized area of expertise. A 2007 survey of pathology residency training programs found that only 36% required any rotation in nephropathology during the entire anatomic pathology training.5 Therefore, most boardcertified surgical pathologists have not been trained and are ill equipped to evaluate the non-neoplastic kidney parenchyma of tumor nephrectomy specimens. Approximately 60% to 88% of such background diagnoses are not identified during the initial nephrectomy evaluation.5,6 A recent European survey of genitourinary pathologists revealed that over 25% do not evaluate the non-neoplastic kidney parenchyma, although a portion of the tissue is properly sampled for every specimen.37 The pathologic evaluation of tumor nephrectomy specimens has traditionally focused entirely on the kidney mass with many parameters that must be analyzed and reported for every carcinoma, including size, Fuhrman grade, margin status, capsule or renal vein invasion,
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and others. Synoptic reports, such as those created by the College of American Pathologists38 and Association of Directors of Anatomic and Surgical Pathology,39 have been important in ensuring that all of the important parameters are systematically evaluated and reported for every specimen. A modification of the College of American Pathologist kidney cancer protocol and checklist in January 2010 established the status of non-neoplastic kidney as a required parameter for reporting, which was an optional parameter before this date.38 Although this requirement is now in place, there are no data regarding compliance with this specific parameter. Given that most kidney masses are Stage 1 tumors, the status of the non-neoplastic kidney is arguably the most important pathologic parameter for these patients and may discover previously unrecognized kidney pathology, such as glomerular disease, interstitial fibrosis, diabetic nephropathy, and others. Pathologists have a unique opportunity and important responsibility to diagnose non-neoplastic kidney diseases, which are commonplace. Data support the fact that investigation of nonneoplastic kidney tissue can lead to important diagnoses. The prevalence of diabetic nephropathy in these specimens ranges from 7% to 9%.5,6 Also, focal segmental glomerulosclerosis (2-9%), hypertensive nephrosclerosis, amyloidosis, thrombotic microangiopathy, collapsing glomerulopathy, immunoglobulin A nephropathy, membranous nephropathy, thin basement membrane disease, acute interstitial nephritis, and rarely pauci-immune crescentic glomerulonephritis are encountered. Similar to cancer management, the early detection of a nonneoplastic kidney disease provides better opportunities for medical intervention. There are currently more than 300,000 kidney cancer survivors in the United States, and an estimated 15% (or 45,000) of these patients have underlying medical kidney diseases, which can only be diagnosed by pathologists. Furthermore, pathologists should regard these diagnoses as critical values, which require direct communication with the treating physician to convey the clinical importance and to ensure that appropriate consultations occur. Simply adding these diagnoses of coincidental non-neoplastic kidney diseases to a surgical pathology report may not trigger the appropriate management.
The Role of the Nephrologist in Patients With RCC Because more patients are surviving with RCC and CKD is common as the population ages, it follows that nephrologists will have an increasing role in the care of these patients. However, the nature of this role is unclear. As described above, CKD has been noted to be a common complication of nephrectomy for RCC. However, the move to nephron-sparing surgery (NSS) will diminish the likelihood of there being a large reduction in GFR after
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kidney cancer surgery and thus will also lessen the burden of subsequent CKD. This may be offset by other factors such as the increasing prevalence of RCC as well as the older age of the population undergoing treatment for RCC. Furthermore, if pathologists consistently review non-neoplastic kidney tissue, previously undiagnosed kidney parenchymal diseases that require nephrological evaluation and possibly therapy may be discovered. Thus, prudent recommendations for nephrological evaluation for the patient with RCC include the following: (1) the finding of any kidney parenchymal pathological process on evaluation of noncancerous kidney tissue (such as previously undiagnosed glomerular or interstitial disease or significant [.25%] fibrosis), and (2) postoperative estimated GFR (once kidney function is stable) less than 60 mL/minute. Furthermore, those patients with preoperative estimated GFRs less than 60 mL/minute would also benefit from nephrology consultation before surgery. Such consultations would focus on routine CKD care as outlined in the recent Kidney Disease Improving Global Outcomes guidelines for the evaluation and management of CKD (http://kdigo.org/ home/ckd-evaluation-management/).
Summary Advances in the care of the patient with RCC mean that fewer patients are receiving radical nephrectomies. However, because of changing demographics (older patients with hypertension and diabetes), more patients with RCC have underlying CKD, which may or may not be recognized before surgical interventions. To improve outcomes for these patients, a tripartite communication scheme that includes the surgeon, pathologist, and nephrologist is ideal. The surgeon is responsible for treatment planning and referral to the nephrologist if the GFR is preoperatively less than 60 mL/minute. The pathologist is responsible for careful review of the neoplastic and non-neoplastic kidney tissue as well as for communication with the surgeon and nephrologist regarding their findings. Finally, the nephrologist is responsible for long-term management of the patient’s CKD following established guidelines. Through this scheme, long-term outcomes can be optimized.
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