Does Reduced Renal Function Predispose to Cancer-specific Mortality from Renal Cell Carcinoma? - Beyond the Abstract

The arguments in favor of partial nephrectomy (PN) over radical nephrectomy (RN) for patients with localized renal cell carcinoma (RCC) have been diverse and compelling,1 leading many to advocate for PN whenever feasible, even for potentially aggressive tumors.2 However, some patients with tumors with increased oncologic potential and/or high complexity may not be well-served by PN, and exactly where the appropriate boundaries between PN and RN should reside remains a point of great controversy.3  Many academic urologists are naturally biased in favor of PN because they enjoy the surgical challenges inherent to the procedure, and there are many patients, such as those with preexisting chronic kidney disease (CKD), who clearly benefit from a nephron-sparing approach.4,5  From a practical standpoint, a policy of PN whenever potentially feasible encourages referral to tertiary care centers.


The most recent argument in favor of PN is that reduced renal function and related metabolic alterations may predispose to suboptimal oncologic outcomes.6,7 Along this line of reasoning, reduced renal function, as typically seen after RN, would lead to compromised immune surveillance and increased risk of cancer recurrence.  If true, and there is evidence from other malignancies to support an association between renal functional status and oncologic outcomes,6 then PN would be preferred whenever feasible to improve cancer-specific survival. Recent publications suggest that the risk of cancer-specific mortality (CSM) increases 27% for each 10 unit reduction of estimated glomerular filtration rate (eGFR).7  Is this true and are renal functional differences driving these associations?

Our recent analysis in European Urology also showed a strong correlation between reduced new baseline GFR after renal cancer surgery and CSM when assessed in a univariable framework.8 However, on multivariable analysis incorporating tumor stage, grade, and histology, this association evaporated. In the final analysis, the main predictors of CSM proved to be aggressive tumor characteristics, rather than functional differences.  How can we reconcile this?

In general, larger tumors and those with invasive or infiltrative features have typically replaced more parenchymal volume leading to reduced baseline renal function. Our group is now studying this phenomenon in greater detail and we are finding that parenchymal volume replacement is a major contributor to preexisting CKD in many renal cancer patients.  Our analysis also demonstrates that such tumors are more likely to be selected for RN, leading to further compromise of renal function. Of course, this tumor phenotype is more likely to be associated with tumor recurrence and increased CSM no matter how it is managed (Figure 1). Our data suggest that when all of the potential confounding factors are accounted for, the functional differences fall out – they are not independently associated with CSM or other oncologic outcomes.8

Figure 1.  Reduced renal function correlates with poor oncologic outcomes for localized RCC, although the main driver appears to be an association between reduced renal function and aggressive tumor characteristics. 
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Our center has strongly advocated for PN for over four decades and we remain very committed to the nephron-sparing mission, although we believe that this should be pursued in a sensible, evidence-based approach.  Unfortunately, there has only been one randomized trial of PN versus RN (EORTC 30904) and our field has largely chosen to sweep this study under the rug, as its findings were difficult to understand (it did not show an overall survival advantage to PN even in a population of patients with small renal masses where PN would have the greatest advantage).9,10  EORTC 30904 certainly had flaws but its most fundamental findings were very provocative, and it is relevant to note that it also did not show an oncologic advantage to PN.9  Sadly, it is now a decade since the publication of EORTC 30904, and we are still left with literature that is devoid of level one data about this topic…

The 2021 AUA Guidelines for the Management of Localized Renal Mass now provide updated evidence-based recommendations regarding priority for RN versus PN that are more granular than those provided by other organizations (Key Points).11  Nevertheless, given the limitations of the current literature and the complexities of patient management in this domain, there is still much room for flexibility in decision-making.

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Written by: Steven C. Campbell, MD, PhD, Professor of Surgery, Section of Urologic Oncology, Department of Urology, Glickman Urological and Kidney Institute, Cleveland Clinic

Co-Authors: Diego Aguilar Palacios, Rebecca A. Campbell, Gustavo Roversi, Nityam Rathi, Department of Urology, Cleveland Clinic

References:

  1. Kim SK, Thompson RH, Boorjian SA, et al (2012) Comparative effectiveness for survival and renal function of partial and radical nephrectomy for localized renal tumors: a systematic review and meta-analysis. J Urol, 188:51-57.
  2. Stief CG (2011) If a Partial Nephrectomy Could Be Done Safely for a Renal Tumor, Would Radical Nephrectomy Be Considered Malpractice?  Eur Urol, 60: 465-467.
  3. Crane A, Suk-Ouichai C, Campbell JA, et al (2017) Imprudent Utilization of Partial Nephrectomy. UROLOGY, 117: 22-26.
  4. Lane BR, Campbell SC, Demirjian S, et al (2013) Surgically-induced chronic kidney disease may be associated with lesser risk of progression and mortality than medical chronic kidney disease.  J Urol, 189:1649-55.
  5. Lane BR, Demirjian S, Derweesh IH, et al (2015) Survival and Functional Stability of Chronic Kidney Disease Due to Surgical Removal of Nephrons: Importance of New Baseline GFR. Eur Urol, 68:996-1003.  
  6. Antonelli A, Minervini A, Sandri M, et al (2018) Below Safety Limits, Every Unit of Glomerular Filtration Rate Counts: Assessing the Relationship between Renal Function and Cancer-specific Mortality in Renal Cell Carcinoma. Eur Urol 74:661-7.
  7. Antonelli A, Palumbo C, Sandri M, et al (2020) Renal Function Impairment Below Safety Limits Correlates With Cancer-specific Mortality in Localized Renal Cell Carcinoma: Results From a Single-center Study. Clin Genitourin Cancer 18:e360-e7.
  8. Aguilar Palacios D, Zabor EC, Munoz-Lopez C, et al (2021) Does Reduced Renal Function Predispose to Cancer-Specific Mortality due to Renal Cell Carcinoma?  Eur Urol, doi:10.1016/j.eururo.2021.02.035.
  9. Van Poppel H, Da Pozzo L, Albrect W, et al (2011) 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, 59(4):543-552.
  10. Scosyrev E, Messing EM, Sylvester R, et al (2014) Renal function after nephron-sparing surgery versus radical nephrectomy: results from EORTC randomized trial 30904. Eur Urol, 65(2):372-377.
  11. Campbell SC, Uzzo RG, Allaf ME, et al (2017) Renal Mass and Localized Renal Cancer: AUA Guideline.  Available at: https://www.auanet.org/guidelines/renal-mass-and-localized-renal-cancer-new-(2017).

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