European Urology

4. Discussion

To our knowledge, this is the largest report evaluating the renal consequences of warm ischemia time in patients undergoing partial nephrectomy in the setting of a solitary kidney. Compared with our previous results [5] x R.H. Thompson, I. Frank, C.M. Lohse, et al. The impact of ischemia time during open nephron sparing surgery on solitary kidneys: a multi-institutional study. J Urol. 2007;177:471-476 Crossref. , we include more than twice as many patients (362 vs 174 treated with warm ischemia), we better assess renal function with estimated GFR according to the MDRD equation (as opposed to serum creatinine alone), and we include patients treated with both open and laparoscopic approaches. Our results demonstrate that longer warm ischemia time during partial nephrectomy is associated with an increased risk of short- and long-term renal consequences, including ARF in the postoperative period and new-onset development of stage IV chronic kidney disease during follow-up. For example, each additional minute of warm ischemia was associated with a 5% and 6% increased odds of developing ARF or a GFR < 15 ml/min per 1.73 m² in the postoperative period, respectively, and was associated with a 6% increased risk of new-onset stage IV chronic kidney disease during follow-up. These observations suggest that every minute counts when the renal hilum is clamped without hypothermic techniques, and efforts to minimize ischemia time should be entertained when planning a surgical approach, especially during imperative situations such as a tumor in a solitary kidney.

In an attempt to identify a potential ischemic time cut point, we evaluated time in 5-min increments to determine the threshold that best distinguishes between ARF, acute GFR < 15, and new-onset stage IV chronic kidney disease individually. Somewhat surprisingly, the cut point that best distinguished between each of these three end points was 25 min. This is in agreement with our previous collaboration, where we found >20 min of warm ischemia to be an important predictor of adverse renal outcomes [5] x R.H. Thompson, I. Frank, C.M. Lohse, et al. The impact of ischemia time during open nephron sparing surgery on solitary kidneys: a multi-institutional study. J Urol. 2007;177:471-476 Crossref. , and a limit of 20 min of warm ischemia was recently supported by an international collaborative review of the literature [6] x F. Becker, H. Van Poppel, O.W. Hakenberg, et al. Assessing the impact of ischaemia time during partial nephrectomy. Eur Urol. 2009;56:625-635 Abstract, Full-text, PDF, Crossref. . With the current results, we submit that although 20 or 25 min of warm ischemia may represent the best cutoff for predicting adverse renal consequences, the observation that warm ischemia as a continuous variable is significantly associated with short- and long-term renal functional decline suggests that each increasing minute of warm ischemia invites additional risk of renal consequences. This also confirms our previous finding that the duration of renal ischemia is the largest modifiable risk factor during partial nephrectomy in the solitary or two-kidney setting [4] x B.R. Lane, D.C. Babineau, E.D. Poggio, et al. Factors predicting renal functional outcome after partial nephrectomy. J Urol. 2008;180:2363-2368 discussion 2368–9 . Thus clamp time should be minimized whenever possible, and if longer ischemic times are anticipated, techniques such as ice slush should be considered. If a laparoscopic approach is employed, an early unclamping technique can be used with shorter warm ischemia times [13] x M.M. Nguyen, I.S. Gill. Halving ischemia time during laparoscopic partial nephrectomy. J Urol. 2008;179:627-632 discussion 632 Crossref. . Furthermore, robotic assistance has recently shown promise for maintaining within 25–30 min [14] x B.M. Benway, S.B. Bhayani, C.G. Rogers, et al. Robot assisted partial nephrectomy versus laparoscopic partial nephrectomy for renal tumors: a multi-institutional analysis of perioperative outcomes. J Urol. 2009;182:866-872 . Collectively, these observations support the use of shorter warm ischemic times, which must be obtained regardless of surgical approach.

Historically, 30 min was considered the maximum safe duration of warm ischemia during partial nephrectomy. Within the past 5 yr, this notion has been challenged. Observations in the porcine model have suggested that renal pedicle clamping for 90 min is safe 7 x B.A. Laven, M.A. Orvieto, M.S. Chuang, et al. Renal tolerance to prolonged warm ischemia time in a laparoscopic versus open surgery porcine model. J Urol. 2004;172:2471-2474 Crossref. , and 8 x D.D. Baldwin, L.J. Maynes, K.A. Berger, et al. Laparoscopic warm renal ischemia in the solitary porcine kidney model. Urology. 2004;64:592-597 Crossref. . Additionally, retrospective clinical observations have suggested that warm ischemia for 40–55 min is safe and effective 9 x G. Godoy, V. Ramanathan, J.A. Kanofsky, et al. Effect of warm ischemia time during laparoscopic partial nephrectomy on early postoperative glomerular filtration rate. J Urol. 2009;181:2438-2443 discussion 2443–5 , and 10 x S.B. Bhayani, K.H. Rha, P.A. Pinto, et al. Laparoscopic partial nephrectomy: effect of warm ischemia on serum creatinine. J Urol. 2004;172:1264-1266 Crossref. . However, these studies included patients with normal contralateral kidneys, potentially masking the effects of ischemia on a solitary renal unit because serum creatinine and estimated GFR were used to assess renal function. It has previously been reported that a study involving the effect of warm ischemia in solitary kidneys is needed. The current results, which stem from an updated collaboration between the Mayo Clinic and the Cleveland Clinic, strongly support that longer warm ischemic times are associated with adverse renal consequences, even after multivariable analysis adjusting for preoperative GFR, tumor size, and type of partial nephrectomy. To our knowledge, this is the first report to evaluate warm ischemia time as a continuous variable with short- and long-term renal disease in patients with a solitary kidney. Although external validation on patients with a solitary kidney is needed, our results support the notion that every minute counts when the renal hilum is clamped under warm ischemia conditions. However, the results of this work do not have any implications for patients treated with cold ischemia. These patients were omitted during the planning phases of this work for the sole purpose that only the most challenging tumors at the Mayo Clinic and Cleveland Clinic were treated with hypothermic techniques during the study time frame. In fact, one could argue that because approximately 25% of patients in this study with a preoperative estimated ischemia time <30 min actually endured >30 min of warm ischemia, perhaps cold ischemia should be used more often in patients with a solitary kidney.

This study is not without limitations. The data were collected in a retrospective fashion and are subject to the many inherent biases associated with this approach. In our multivariable analyses, we adjusted for tumor size, preoperative GFR, and surgical approach; however, we were unable to factor in recently reported scores that predict for surgical complexity 15 x A. Kutikov, R.G. Uzzo. The R.E.N.A.L. nephrometry score: a comprehensive standardized system for quantitating renal tumor size, location and depth. J Urol. 2009;182:844-853 Crossref. , and 16 x V Ficarra, G. Novara, S. Secco, et al. Preoperative Aspects and Dimensions Used for an Anatomical (PADUA) classification of renal tumours in patients who are candidates for nephron-sparing surgery. Eur Urol. 2009;56:786-793 Abstract, Full-text, PDF, Crossref. . Additionally, all patients had a solitary kidney with imperative indications for partial nephrectomy. Previous observations have suggested that a solitary kidney is more resistant to ischemic damage compared with paired kidneys 17 x A. Askari, A.C. Novick, B.H. Stewart, R.A. Straffon. Surgical treatment of renovascular disease in the solitary kidney: results in 43 cases. J Urol. 1982;127:20-22 , 18 x P. Jablonski, B. Howden, D. Rae, et al. The influence of the contralateral kidney upon recovery from unilateral warm renal ischemia. Pathology. 1985;17:623-627 Crossref. , and 19 x S.E. Okiye, H. Zincke. Renal allograft salvage after prolonged early posttransplant renal artery occlusion. J Urol. 1983;129:1216-1217 . Therefore, our results may overestimate the maximal renal tolerance to ischemia in patients with a normal contralateral kidney. Furthermore, only patients treated with warm ischemia were included in this study. Because the more challenging cases were treated with hypothermic techniques, our results may not apply to all patients with a renal mass. Nevertheless, our results support the recommendation that warm ischemia should be limited to 20–25 min during partial nephrectomy.