Partial nephrectomy (PN) is a critical clinical tool in the kidney surgeon’s armamentarium. Although “off clamp” partial nephrectomy is performed at times, clamping of the renal artery not only prevents significant blood loss, but also affords clear visualization of the tumor resection bed (see figure). Yet, during arterial clamping, the kidney is in an ischemic state and may be harmed.

Figure 1. Warm ischemia is achieved during a retroperitoneoscopic robotic partial nephrectomy for a posterior 3.5 cm left upper pole renal mass with R.E.N.A.L. Nephrometry Score=1+2+3+p+1=7p (A). Renal artery is isolated (B), and 2 sequential laparoscopic bulldog clamps are placed on artery to eliminate renal arterial inflow (C), allowing a bloodless field for tumor resection (D).

The magnitude and clinical significance of various ischemia types and lengths have been a point of intense discussion both in the peer-reviewed literature and at academic meetings.¹ The tenet “Every Minute Counts” was canonized into urological dogma and supported by some early reports.² With this principle in mind, innovative surgical strategies such as unclamped tumor enucleation, super-selective arterial clamping and others were developed with the goal to drive down ischemia time in an effort to optimize functional outcomes.³ However, surgical complexity of these approaches was often high, resulted in extended operative times and required expertise that may not have been generalizable to the urological community at large. As a result, the clinical traction garnered by these techniques is currently unclear.

In recent years, the relentless pursuit of shortening ischemia time has come under question. The realization that “Every Minute” may actually “Not Matter Much” stems from better understanding of 3 factors: 1) functional residual parenchymal volume, not ischemia, appears to drive long-term renal function outcomes after PN; 2) the human kidney is extremely resilient to warm ischemia; and 3) in the presence of a normal contralateral kidney harms of even radical nephrectomy (RN) are difficult to prove.

Functional Residual Parenchymal Volume, Not Ischemia, Is the Main Predictor of Long-Term Renal Function

While warm ischemia time (WIT) received significant attention in the early development of partial nephrectomy, several studies have indicated parenchymal preservation is the main driver for long-term postoperative functional outcomes. In a seminal report, Simmons et al demonstrated that both percent of the functional renal volume preserved and ischemia time predicted early postPN estimated glomerular filtration rate (eGFR), while volume preservation alone affected long-term renal function with ischemia falling out as a significant factor in a multivariable model.⁴ Ginzburg et al confirmed that although WIT was associated with decline in eGFR after partial nephrectomy in their univariable models, only preoperative eGFR and functional parenchymal volume were determinants of eGFR at 6 months.⁵ Consistent with the findings by Simmons et al, WIT was not significantly associated with postoperative eGFR after appropriate adjustment.

Human Kidney Tolerates Ischemia Extremely Well

Early animal studies and limited clinical reports were contradictory but suggested ischemia time of >30 minutes was detrimental to both short-term and long-term kidney function recovery. Yet a prospectively designed study by Parekh et al challenges this assertion. In their study, the effect of ischemia was studied in real-time using tissue biopsies taken before, during and after renal clamping in 40 patients underlying partial nephrectomy with a healthy contralateral kidney (ischemia duration >30 minutes in 82.5% of patients).⁶ Their findings crystallized for many in the kidney cancer community the fact that the human kidney is highly resilient to WIT. Patients experienced only mild transient elevations in creatinine, renal functional studies did not correlate with ischemia time and histologic structural changes after prolonged ischemia were significantly less severe than previously shown in animal models with prompt recovery after reinstitution of arterial flow.

This prospectively designed, real-time analysis study represents arguably the highest quality tissue-based evidence to date with findings suggesting that ischemia time up to 60 minutes should result in prompt recovery and lack of long-term renal deficits. The main limitations of this work are heterogeneous use of cold and warm ischemia, lack of followup beyond the hospital stay and absence of data detailing parenchymal volume preservation.⁷

When Harms of Radical Nephrectomy Are Difficult to Prove, Can Ischemia during Partial Nephrectomy Matter?

An argument is often made that the effect of renal ischemia is underappreciated due to the presence of a healthy, contralateral kidney. While this is true in principle, the contextual background for the ischemia debate must be placed in perspective of the PN vs RN debate. The well-known randomized controlled trial pitting PN vs RN, EORTC 30904, although underpowered, demonstrated a survival benefit for patients undergoing radical nephrectomy.⁸ Even when results were controlled for oncologic effect, there was no significant survival benefit for patients undergoing PN.

Furthermore, patients with chronic kidney disease (CKD) resulting from surgery (CKD-S) appear to be largely indistinguishable from patients without CKD and thus face a much more favorable destiny than those with CKD stemming from intrinsic renal disease (CKD-Medical).⁹ Therefore, the role of PN vs RN in patients for whom additional risks of complex surgery may not be justified or for whom oncologic compromise may result from renal preservation is currently being debated.¹⁰ In the context of this larger debate, arguments regarding whether several additional minutes of ischemia during PN are clinically relevant become rather moot.

In conclusion, the guiding principles of partial nephrectomy should be oncologic integrity, renal preservation, and surgical safety. The data of yesteryear has now been clarified by work that shows ischemia to have limited impact on long term functional outcomes. As such, without an entirely cavalier disregard for ischemia time, the urological community should no longer fixate on “counting the minutes.”