Treatment options for patients with localized kidney tumors

RN was developed as the standard treatment of kidney tumors in the latter half of the twentieth century. In 1969, Robson reported the outcomes of 88 patients who underwent RN (described as the perifascial resection of the kidney along with the perirenal fat, ipsilateral adrenal gland, and regional lymph nodes). He found a survival rate of 65% for patients with tumors confined within the Gerota fascia. This technique represented a significant survival benefit over other treatments and became the standard approach to renal tumors for the next 20 years. Laparoscopic RN (LRN) was introduced in 1991 and has since been readily adopted as a less invasive approach. Transperitoneal, retroperitoneal, robot-assisted, and hand-assisted LRN techniques are all proven techniques that are selected primarily based on surgeon experience and preference. In appropriately selected patients, LRN has comparable oncologic efficacy and improved morbidity and recovery compared with open RN (ORN). In the 1980s and 1990s, open partial nephrectomy (OPN) began emerging in academic centers as an option for patients with an absolute need to preserve renal parenchyma. Patients with bilateral renal tumors, tumors in a solitary functioning kidney, and/or chronic renal failure were considered candidates. The goal for such patients was avoidance of dialysis, even if oncologic efficacy was somewhat compromised. The concept of elective partial nephrectomy (PN) met resistance in the surgical community based on an increased potential for local recurrence. In addition, the deleterious cardiovascular effects of CKD in patients not yet requiring dialysis were still unknown at this time. As the concept of the risks associated with CKD expanded throughout the surgical community and the oncologic efficacy of PN became established, the role of elective PN for small renal masses (SRMs) of sizes less than 4 cm began to expand. Building off of techniques used for LRN and OPN, Gill and others pioneered the development of laparoscopic PN (LPN) as a minimally invasive, nephron-sparing approach for the management of SRMs. The addition of robotics as a tool for LPN is expanding the application of this surgery in appropriately selected patients. Thermal ablation (TA) technologies, such as cryoablation (CA) and radiofrequency ablation (RFA), are alternative minimally invasive, nephron-sparing treatments of SRMs. Surveillance of renal tumors is also an option, particularly for patients with SRMs and major comorbidities in whom avoidance of the risks of intervention may be preferable to the small risk of cancer progression. With so many options for kidney tumors, particularly for SRMs, patients and clinicians must be well informed to make decisions that are associated with the most favorable outcomes. The importance of avoiding CKD through the appropriate use of nephron-sparing approaches is gaining ground in the urologic surgical community and is reflected in the recent release of clinical guidelines for the management of SRMs by the American Urologic Association (AUA) and European Association of Urology.

AUA guidelines

The natural history of renal tumors that are smaller than 7 cm is variable; only 20% to 30% demonstrate aggressive features, and up to 20% are benign. However, the most recently published summary of current practice pattern in the United States shows that 65% of kidney cancers are treated with RN and 35% with PN. These data, coupled with the growing emphasis on the importance of preserving renal function, prompted the AUA to release clinical guidelines to address the management of clinical stage 1 renal masses. Recommendations for 4 index patients were discussed, including patients with tumors that are less than 4 cm or 4 to 7 cm in size and those who are healthy or with major comorbidities and increased surgical risk. RN and PN were both recommended as standard for 3 index patients. For index patient 4 (medical comorbidities, increased surgical risk, and a tumor of 4–7 cm), RN was thought to be “standard” with “complete surgical excision by PN… a recommended modality when there is a need to preserve renal function, although it can be associated with increased urologic morbidity.” TA and active surveillance (AS) were discussed as options for healthy patients and were recommended particularly in patients with increased surgical risk. Throughout these guidelines, a discussion of the risks and benefits of each approach was emphasized, given the complexity of the landscape for treatment of SRMs and the significant impact of treatment approach on various outcomes.

AUA guidelines

The natural history of renal tumors that are smaller than 7 cm is variable; only 20% to 30% demonstrate aggressive features, and up to 20% are benign. However, the most recently published summary of current practice pattern in the United States shows that 65% of kidney cancers are treated with RN and 35% with PN. These data, coupled with the growing emphasis on the importance of preserving renal function, prompted the AUA to release clinical guidelines to address the management of clinical stage 1 renal masses. Recommendations for 4 index patients were discussed, including patients with tumors that are less than 4 cm or 4 to 7 cm in size and those who are healthy or with major comorbidities and increased surgical risk. RN and PN were both recommended as standard for 3 index patients. For index patient 4 (medical comorbidities, increased surgical risk, and a tumor of 4–7 cm), RN was thought to be “standard” with “complete surgical excision by PN… a recommended modality when there is a need to preserve renal function, although it can be associated with increased urologic morbidity.” TA and active surveillance (AS) were discussed as options for healthy patients and were recommended particularly in patients with increased surgical risk. Throughout these guidelines, a discussion of the risks and benefits of each approach was emphasized, given the complexity of the landscape for treatment of SRMs and the significant impact of treatment approach on various outcomes.

The applicability of outcomes of donor nephrectomy

Until recently, urologists used the satisfactory renal functional outcomes in kidney donors to counsel patients that removal of one kidney would not lead to long-term problems. Ibrahim and colleagues published the long-term consequences of kidney donation in a cohort of 3698 healthy donors, finding no significant differences in the development of end-stage renal disease or overall survival compared with matched controls. Although these data might encourage patients and clinicians to suspect that RN for cancer may not carry significant risks attributable to the loss of renal function, caution should be exercised because patients with renal cancer are different from healthy screened donors. The mean age of the donor population is 41 years, whereas the mean age is greater than 60 years for patients who present with a renal mass. Smoking, obesity, and hypertension are established risk factors for the development of renal cell carcinoma and are more prevalent in patients with a renal mass. Bijol and colleagues reviewed a series of nephrectomy specimens for patients undergoing RN. Apart from the tumor within the normal part of the kidney, 62% of the specimens showed microscopic signs of renal disease. Huang and associates reported on 662 patients with SRM, a normal contralateral kidney, and normal sCr levels. Even in these patients, 26% had preexisting CKD, as evidenced by a GFR less than 60 using the MDRD (modification of diet in renal disease) formula. Although long-term sufficient renal function is routine in screened kidney donors, CKD develops in between 50% and 65% of patients after RN. Indeed, radical surgery can often substitute one disease for another.

Radical nephrectomy

RN remains the treatment of choice for large (>7 cm) and locally advanced renal tumors, which are the most lethal of genitourinary malignancies. TA and surveillance are inadequate for prevention of cancer progression in these situations. For such tumors, preservation of sufficient functioning renal parenchyma can often not be possible with PN. The problem with RN is that it is often overused and invariably increases the risk for the development of CKD when compared with these other approaches. LRN can be swiftly performed and can provide the patient with minimal morbidity and a fast recovery, but the long-term effects of this approach can be significant. For clinical stage T1 tumors, PN is associated with a higher rate of urologic complications in the short term but improved early and late renal functional outcomes when compared with RN. Huang and colleagues found that 65% of patients undergoing RN developed stage 3 or higher CKD (estimated GFR <60 mL/min/1.73 m ² ) within 3 years of RN. In addition, patients undergoing RN were 3.8 times more likely to develop stage 3 CKD than those undergoing PN. Although most of these patients will never require dialysis, CKD has a dose-related relationship with cardiovascular events and is a powerful contributor to patient mortality. The negative impact of RN-induced CKD has been confirmed in several subsequent studies.

Although these data should push surgeons to consider PN for SRMs, RN remains the gold standard approach for larger renal masses. The benefits of renal preservation must be weighed against sound oncologic principles. Indeed, the oncologic importance of a complete wide excision for larger tumors is highlighted by the fact that up to 25% have involvement of the perinephric fat. Before performing RN, the surgeon should evaluate each patient’s risk for developing CKD after surgery. A GFR estimation equation, such as the MDRD study equation or the newer CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) study equations, should be used before surgery. Assuming 2 radiographically and functionally similar kidneys, an approximately 35% decline in GFR can be expected with unilateral RN ( Table 1 ). More accurate prediction tools, or nomograms, have also been developed and can be useful for patient counseling. Patients should be counseled regarding the risks of CKD, along with its associated cardiovascular and other complications. Patients found to be at significant risk of becoming dialysis dependent should see a nephrologist for preoperative counseling. In select cases, a dialysis catheter can be placed at the time of surgery or in the immediate postoperative period.

Whether completed in an open or a laparoscopic manner, basic surgical principles should be followed to maintain and protect the unaffected kidney during RN. Patients at risk for cardiopulmonary complications should be screened by a cardiologist before surgery. To reduce the risk of infection and sepsis, preoperative urinalysis and culture results should be obtained and appropriate prophylactic (or therapeutic) antibiotic used. Appropriate patient positioning and the avoidance of prolonged surgery can minimize the risks of rhabdomyolysis and its deleterious effect on kidney function. Adequate exposure and an understanding of the patient’s renal vascular anatomy are paramount to minimize blood loss and risk of intraoperative hypotension. Some investigators have used preoperative embolization to try to minimize intraoperative hemorrhage, but Subramanian and colleagues have recently shown that this maneuver may have the opposite effect. Laparoscopic techniques themselves, by establishment of pneumoperitoneum and reduction of venous bleeding, may lessen the impact of surgery on early renal function as well. Therefore, when a nephron-sparing approach is not feasible, RN is the treatment of choice. The decreased renal function attributable to nephron loss is generally offset by the significant oncologic benefit of the surgery.

Partial nephrectomy

When compared with RN, PN always provides better renal functional outcomes in similar patients (see Table 1 ). Although it would be expected that this benefit would disappear for tumors large enough and/or extending deep enough into the renal hilum, such outcomes have not yet been reported. In fact, several series report on successful use of PN for tumors larger than 7 cm or with renal vein thrombus. This collective experience has led some investigators to conclude that preservable parenchyma, and not tumor size, should be the main determinant of the feasibility of PN.

Initial investigations into the factors predicting renal function after PN revealed that lower preoperative GFR, solitary kidney, lesser parenchymal preservation, longer warm ischemic interval, larger tumor size, and older age are independent predictors of reduced postoperative GFR. Subsequent data specifically regarding patients undergoing PN in a solitary kidney suggested an increase of 5% to 6% in the risk of acute kidney injury or CKD with each additional minute of warm ischemia. Several other studies also suggested a strong correlation between ischemia time and loss of renal function, leading to the concept that every minute counts. The authors’ subsequent work has demonstrated that although the type and duration of renal ischemia may be the strongest modifiable risk factors for decreased renal function after PN, factors that are for the most part nonmodifiable, the preoperative GFR and the amount of spared parenchyma, that is, quality and quantity of the spared parenchyma, play a predominant role. Improved understanding of this complex topic has recently been provided by a 4-center study of open PN under either warm (n = 360) or cold (n = 300) ischemia in patients with solitary kidneys. Despite 23 minutes longer ischemia during PN with cold ischemia (median, 45 minutes) than PN with warm ischemia (median, 22 min), similar decreases in postoperative GFR (21% vs 22%) and ultimate GFR (10% vs 9%) were observed, confirming a protective effect of hypothermia. Reasons for longer ischemia with the hypothermic cases were multifactorial, including the wait for 10 to 15 minutes that had been routinely practiced, selection biases, the cumbersome nature of ice-slush usage, and/or relief of the sense of urgency because of hypothermia. Importantly, factors that strongly correlated with longer ischemic time included not only hypothermia but also the amount of spared parenchyma ( P <.0001). Simpler cases, in which the amount of spared parenchyma was greatest, were performed with the shortest ischemic times. Ischemia time seems to serve as a correlate of complexity in this (and other) series of patients. Final multivariate analysis of this dataset suggested that preoperative GFR and percentage of parenchyma preserved stood out as strongly predictive of early and ultimate renal function (each P <.0001). Ischemia time was not associated with renal function in this particular study ( P = .5). Sixty-eight percent of patients in this series underwent PN under hypothermic conditions or with 20 minutes or less of warm ischemia and only 12% of warm ischemic intervals exceeded 30 minutes, consistent with the high standards for conventional PN at these centers of excellence. This study suggests that if the ischemic interval is kept short or if hypothermia is applied, ultimate loss of function due to ischemic injury pales in comparison to the quantity and quality of kidney preserved. These data are confirmed by analysis of outcomes in the 2-kidney model, in which nonischemic PN, PN under cold ischemia, and PN under warm ischemia up to 20 minutes were associated with similar renal functional outcomes. A reanalysis of the populations of patients from the Cleveland Clinic and Mayo Clinic study on PN in a solitary kidney under warm ischemia (and with a wider range of intervals) indicated that warm ischemia time retained some predictive value. Although the quantity and quality of preserved parenchyma stood out as the predominant predictors of ultimate renal function after PN, the subgroup of patients with warm ischemic interval greater than 25 minutes was at about a 2-fold increased risk for de novo severe CKD.

The use of a minimally invasive approach to PN, including LPN and robot-assisted LPN, does not seem to have an impact on renal function when compared with OPN. Although initial series of LPN reported longer warm ischemia times than used with OPN and infrequently used hypothermia, more recent reports indicate that LPN can be performed with short ischemic intervals, selective clamping of tertiary or quaternary renal arterial branches, or off clamp. In addition, more recent reports now indicate that robot-assisted LPN can be performed with a lesser impact on renal function than traditional LPN, in part because of these same technical variations.

To optimize PN, the authors believe that careful presurgical planning and precision during intrarenal dissection may maximize the amount of preserved parenchyma, while still achieving negative margins, and careful reconstruction can minimize ischemic areas adjacent to the renorrhaphy. One potential way to reduce the amount of healthy parenchyma resected or devascularized is using neoadjuvant systemic therapy to decrease tumor volume. Initial investigations have suggested that various agents, such as sunitinib, sorafenib, temsirolimus, and others, can produce partial reductions in tumor volume and that PN is feasible after these treatments. However, the oncologic efficacy and overall impact of such treatments remain to be determined and should be done in the context of clinical trials. According to the authors, more precise determination of renal damage on the ipsilateral kidney enables more precise evaluation of the causes of such damage. Further advances in radiographic evaluation of renal damage using functional studies, such as technetium renal scintigraphy and functional magnetic resonance imaging or molecular markers, such as KIM-1 and N-GAL, may allow for investigations into early interventions to improve long-term renal functional outcomes. Clearly, this is a fruitful field for subsequent clinical and translational research.