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Below safety limits, every unit of glomerular filtration rate counts: assessing the relationship between renal function and cancer-specific mortality in renal cell carcinoma

  • Alessandro Antonelli 3,
  • Andrea Minervini 2,
  • Marco Sandri 3,
  • Roberto Bertini 4,
  • Riccardo Bertolo 4,
  • Marco Carini 2,
  • Maria Furlan 1,
  • Alessandro Larcher 4,
  • Guglielmo Mantica 6,
  • Andrea Mari 2,
  • Francesco Montorsi 4,
  • Carlotta Palumbo 1,
  • Francesco Porpiglia 5,
  • Paola Romagnani 5,
  • Claudio Simeone 1,
  • Carlo Terrone 6,
  • Umberto Capitanio 4
1 Department of Urology, Spedali Civili Hospital, University of Brescia, Brescia, Italy 2 Department of Urology, Careggi Hospital, University of Florence, Florence, Italy 3 Data Methods and Systems Statistical Laboratory, University of Brescia, Brescia, Italy 4 Division of Experimental Oncology, Department of Urology, URI—Urological Research Institute, Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute, Milan, Italy 5 Department of Urology, San Luigi Gonzaga Hospital, School of Medicine, Orbassano, Turin, Italy 6 Department of Urology, IRCCS San Martino Hospital, University of Genoa, Genoa, Italy 7 Department of Biomedical Experimental and Clinical Science “Mario Serio”, University of Florence, Florence, Italy

Publication: European Urology, Volume 74, Issue 5, November 2018, Pages 661-667

DOI: https://doi.org/10.1016/j.eururo.2018.07.029

Background

The hypothesis that renal function could influence oncological outcomes is supported by anecdotal literature.

Objective

To determine whether estimated glomerular filtration rate (eGFR) is related to cancer-specific mortality (CSM) in patients who had undergone surgery for renal cell carcinoma (RCC).

Design, setting, and participants

A retrospective analysis of 3457 patients who underwent radical (39%) or partial nephrectomy (61%) for cT1–2 RCC between 1990 and 2015.

Outcome measurements and statistical analysis

The eGFR was calculated by the Chronic Kidney Disease Epidemiology Collaboration equation. CSM was analyzed in a multivariable competing-risk framework, estimating the subdistribution hazard ratio (SHR) accounting for deaths from other causes. The relationship between eGFR and CSM was investigated from multiple statistical approaches—extended Cox regression with eGFR incorporated as a time-dependent covariate, landmark analysis, and joint modeling. Other predictors were selected by competing-risk random forest method and backward elimination.

Results and limitations

The relationship between eGFR and CSM was graphically described by a linear spline, i.e. a continuous piecewise linear function with two lines joined by a knot. For eGFR treated as a time-dependent covariate, the knot was located at 65 ml/min; at landmark analysis with eGFR at the baseline, 12 mo, and last functional follow-up, the knots were 85, 60, and 65 ml/min, respectively. In multivariable competing-risk analysis, CSM was associated with eGFR only for values of eGFR below these cutoffs, with SHRs for every 10 ml/min of reduction in eGFR of 1.25 (p = 0.003), 1.16 (p = 0.028), 1.44 (p = 0.02), and 1.16 (p = 0.042), corresponding to time-dependent eGFR, and eGFR at baseline, 12 mo, and last functional follow-up, respectively. Joint modeling confirmed these results. A retrospective design with inherent biases in data collection represents a limitation.

Conclusions

In patients undergoing surgery for RCC, renal function should be preserved in order to improve cancer-related survival.

Patient summary

The relationship between renal function and probability of dying due to renal cancer is complex. The present study found a correlation between glomerular filtration rate and cancer specific mortality that could reconsider the oncological role of renal function in patients undergoing surgery for renal cancer.

Commented by Dr. Alessandro Antonelli

Partial nephrectomy (PN) is favored over radical nephrectomy (RN) for T1 renal cell carcinoma (RCC) based on the evidence that preserving renal function (RF) protects from non-cancer related mortality. However, large longitudinal population studies published in the nephrological literature showed that RF is associated also to cancer specific mortality (CSM) for several solid tumors. This finding could play a crucial role in the management of RCC but to date it has been neglected within the urological community. Thus we investigated the relationship between estimated glomerular filtration rate (eGFR) and CSM on a cohort of approximately 3,500 patients – with 7400 eGFR readings – undergone PN or RN for a cT1/2 RCC at 5 academic referral Institutions. The statistical analysis – accounting for tumor-, patient- and surgery-related confounders and for competitive causes of mortality – found that the association between eGFR and CSM described a “piecewise” curve, where below certain values of eGFR there was an inverse linear relationship, while above those values the 2 variables were not related. These thresholds were calculated at 85 ml/min, considering  pre-operative eGFR values,  60/65 for post-operative data only. As a clinical implication from these results, any effort to maintain eGFR above these “safety limits” should be done, offering RN only to the few patients with baseline eGFR largely above 85 ml/min and a predicted post-operative eGFR above 60/65 ml/min. On the other hand the patients with baseline eGFR already below 85 ml/min or those at risk of reaching values below 60/65 ml/mi in case of RN, should receive PN as first option, whenever technically feasible. If confirmed by other studies these results could add a piece of knowledge to the ongoing debate on the selection of the optimal candidate for PN or RN.