Review Article. Decline in Renal Function after Partial Nephrectomy: Etiology and Prevention

Transcription

1 Review Article Decline in Renal Function after Partial Nephrectomy: Etiology and Prevention Maria C. Mir, Cesar Ercole, Toshio Takagi, Zhiling Zhang, Lily Velet, Erick M. Remer, Sevag Demirjian and Steven C. Campbell* From the Glickman Urological Kidney Institute (MCM, CE, TT, ZZ, LV, EMR, SD, SCC) and Imaging Institute (EMR), Cleveland Clinic, Cleveland, Ohio; Department of Urology, University of Miami, Miami, Florida (MCM); Department of Urology, Tokyo Women s Medical University, Tokyo, Japan (TT); and Department of Urology, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China (ZZ) Purpose: Partial nephrectomy is the reference standard for the management of small renal tumors and is commonly used for localized kidney cancer. A primary goal of partial nephrectomy is to preserve as much renal function as possible. New baseline glomerular filtration rate after partial nephrectomy can have prognostic significance with respect to long-term outcomes. Recent studies provide an increased understanding of the factors that determine functional outcomes after partial nephrectomy as well as preventive measures to minimize functional decline. We review these advances, highlight ongoing controversies and stimulate further research. Materials and Methods: A comprehensive literature review consistent with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) criteria was performed from January 2006 to April 2014 using PubMedÒ, Cochrane and Ovid Medline. Key words included partial nephrectomy, renal function, warm ischemia, hypothermia, nephron mass, parenchymal volume, surgical approaches to partial nephrectomy, preoperative and intraoperative imaging, enucleation, hemostatic agents and energy based resection. Relevant reviews were also examined as well as their cited references. An additional Google Scholar search was conducted to broaden the scope of the review. Only English language articles were included in the analysis. The primary outcomes of interest were the new baseline level of function after early postoperative recovery, percent decline in function, potential etiologies and preventive measures. Results: Decline in function after partial nephrectomy averages approximately 20% in the operated kidney, and can be due to incomplete recovery from the ischemic insult or loss of nephron mass related to parenchymal excision or collateral damage during reconstruction. Compensatory hypertrophy in the contralateral kidney after partial nephrectomy in adults is marginal and decline in global renal function for patients with 2 kidneys averages about 10%, although there is some variance based on tumor size and location. Irreversible ischemic injury can be minimized by pharmacological intervention or surgical approaches such as hypothermia, limited warm ischemia, or zero or segmental ischemia. Excessive loss of nephron mass can be minimized by improved preoperative or intraoperative imaging, use of a bloodless field, enucleation and vascular microdissection. Hemostatic agents or energy based resection that minimizes the need for parenchymal and capsular suturing can also optimize preservation of the vascularized nephron mass. Abbreviations and Acronyms CIT ¼ cold ischemia time CKD ¼ chronic kidney disease CT ¼ computed tomography GFR ¼ glomerular filtration rate PN ¼ partial nephrectomy RCC ¼ renal cell carcinoma VMD ¼ vascular microdissection WIT ¼ warm ischemia time Accepted for publication January 22, * Correspondence: Center for Urologic Oncology, Room Q10-120, 9500 Euclid Ave., Glickman Urological Kidney Institute, Cleveland Clinic, Cleveland, Ohio (telephone: ; FAX: ; campbes3@ccf.org) /15/ /0 THE JOURNAL OF UROLOGY 2015 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION AND RESEARCH,INC. Vol. 193, , June 2015 Printed in U.S.A. j 1889

2 1890 DECLINE IN RENAL FUNCTION AFTER PARTIAL NEPHRECTOMY Conclusions: Our understanding of the decline in renal function after partial nephrectomy has advanced considerably, including better appreciation of its magnitude and impact in various settings, possible etiologies and potential preventive measures. Many controversies persist and this remains an important area of investigation. Key Words: nephrectomy, delayed graft function, ischemia PARTIAL nephrectomy is the reference standard for the management of clinical T1a renal masses and its indications have recently been expanded to include T1b/T2 renal tumors, even in the presence of a normal contralateral kidney. 1 Compelling data on the implications of preexisting CKD have driven much of this change. 1e3 More than 25% of patients with localized renal cancer have preexisting CKD and can benefit from optimized function after PN to minimize the risk of progression to renal failure and increased mortality rates. 4 Young patients and those with familial RCC also require intensive efforts to preserve renal function after surgery. While the main advantage of PN over radical nephrectomy relates to better function, even PN is associated with some functional decline because it requires the excision of functioning nephrons adjacent to the tumor and reconstruction, which can lead to focal devascularization. In addition, traditional PN has been performed in the setting of hilar occlusion and some nephrons may not recover completely from the ischemic insult. 5 During the last decade our understanding of the magnitude of functional decline after PN and potential etiologies has advanced substantially. We review these data and discuss preventive measures to minimize functional decline after PN. METHODS Our search strategy is highlighted in the abstract and supplementary Appendix ( The focus was 2006 forward correlating with routine use of estimated GFR for reporting. All articles were evaluated for quality and inclusion criteria independently by 2 authors (MCM, SCC) and a third was consulted when necessary (CE). Quality was assessed according to study design, level of evidence and quality of reporting. A synopsis of original data was generated with the priority of informing the practicing urologist of recent advances and their implications, including ongoing controversies. MAGNITUDE OF FUNCTIONAL DECLINE AFTER PN Several recent studies provide data on the magnitude of functional decline after PN in terms of global function or function specifically in the operated kidney. 6e16 Global functional outcomes can be further segregated based on patients with a contralateral kidney, where compensatory hypertrophy can be a factor, versus those with a solitary kidney. These data are summarized in the table, which provides the percentage of GFR saved in each of these circumstances relative to baseline function. These estimates pertain to function observed after early recovery has been achieved, typically after the first few weeks to several months after PN and, thus, represent the patient s new baseline level of function. The table is not intended as a meta-analysis but rather a summary of studies that provide meaningful data on this topic. There is naturally some variance in patient selection and surgical approach. Despite these considerations, the data in the table support certain approximations about the magnitude of decline of function after PN in this era. For patients with bilateral kidneys, most series support the preservation of approximately 88% to 91% of global function after PN. This correlates with an approximate loss of 10% of global function related to the procedure. Most studies of compensatory hypertrophy after PN in adults have demonstrated only limited compensation in the contralateral kidney, representing 2.2% in a recent study 17 and 4% to 6% in most others. 6,13,18 In general, compensatory hypertrophy is blunted in adults compared to children and after PN compared to radical nephrectomy. 17 The signals sensed by the contralateral kidney are weaker after PN in strength (less change in nephron mass) and temporal characteristics (recovery after PN is rapid). Thus, most adult patients experience a minimal increase in contralateral function after PN. Given that the global functional decline after PN averages about 10% in the 2-kidney model, one can estimate that the percentage of functional decline in the operated kidney must average about 20%. This correlates with percentage of function saved in the operated kidney of approximately 80%, with some variance related to tumor size/location demonstrated in various series. Mir et al assessed function specifically in the operated kidney after PN and their findings support these estimates. 6 They included patients with solitary kidneys and patients with 2 kidneys, with the latter group undergoing renal scans to provide split renal function. On average, 80% function was saved in the operated kidney. A multicenter series of 660

3 DECLINE IN RENAL FUNCTION AFTER PARTIAL NEPHRECTOMY 1891 Functional recovery after PN References No. Ischemia Type (No.): Median Minutes Median % Function Saved in Operated Kidney (IQR)* Median % Global Function Saved (IQR)* Bilat kidneys Mir et al 6 92 Hilar occlusion, CIT (35): 28; WIT (57): (75e91) 90 (89e105) Simmons et al Hilar occlusion, CIT (57): 40; WIT (226): Hung et al Discovery era, hilar occlusion, WIT (139): 36 (mean) 80 (74e82) Conventional hilar occlusion, WIT (213): (72e83) Limited ischemia, WIT (104): (80e92) Zero ischemia (78): 0 91 (82e98) Ng et al 9 44 Zero ischemia, no VMD, no occlusion (22): 0 86 Initial cases, VMD þ segmental clamping (22): 0 87 Shao et al Segmental clamping, WIT: (37e82) 83 (75e90) Smith et al Hilar occlusion, WIT (97): (77e99) Unclamped (164): 0 90 (81e100) Desai et al Hilar occlusion (63): WIT Superselective arterial occlusion (58): 0 89 Jeon et al Hilar occlusion, CIT: 28 (mean) 92 (88e95) Golan et al Hilar occlusion, WIT: Solitary kidney Lane et al Hilar occlusion, CIT (360): 45; WIT (300): (54e100) 79 (54e100) Smith et al Hilar occlusion (19), WIT: (60e90) 80 (60e90) Unclamped (28): 0 96 (76e100) 96 (76e100) Takagi et al Hilar occlusion, CIT (30): 35; WIT (29): (70e90) 86 (70e90) Inclusion required provision of data about percent GFR saved within the operated kidney or globally, substantial number of subjects (more than 40), details about management of the renal hilum, and sufficient quality of study design and reporting. * Functional recovery associated with PN after the early postoperative period (first few weeks to several months), which reflects the patient s new baseline level of renal function. IQR provided when available. solitary kidneys also supports this approximation as the average percentage of preservation of function was 79%. 15 Most studies demonstrate that PN is generally associated with a percentage of preservation of renal function in the operated kidney of approximately 76% to 86%, with some variance as illustrated in the table. The current literature suggests that PN preserves approximately 80% of the function in the operated kidney and 90% of global function for patients with 2 kidneys. ETIOLOGY OF FUNCTIONAL DECLINE AFTER PN It is intuitive that decline in function after PN must be primarily due to removal or devascularization of nephrons or incomplete recovery of nephrons from ischemia (fig. 1). 19 The only major exception would be PN that yields a urine leak or ureteral obstruction. However, in such instances any associated decline in function tends to be temporary and retrievable with appropriate urological management. Medical renal disorders that can occur perioperatively, such as antibiotic induced interstitial nephritis, can also impair renal function. However, these are uncommon occurrences and are usually reversible. Many studies have demonstrated the importance of preoperative GFR, commonly referred to as the quality factor, as a determinant of ultimate renal function after PN. 15,19 However, this factor merely sets the baseline of function and, thus, the ceiling for recovery. For example, a patient with a GFR of 40 ml/minute/1.73 m 2 will at best settle out with a GFR approximating 40 ml/minute/1.73 m 2 if minimal nephron mass has been removed and irreversible ischemic injury has been avoided, but the latter factors will remain the main determinants of any decline in function. 20 In reality, the quality factor is typically nonmodifiable. It does not contribute to the decline in function after PN and, thus, will not be a major focus of this review. Optimized PN requires 1) precise excision of the tumor and careful reconstruction to maximize the number of preserved, vascularized nephrons; and 2) complete recovery from any ischemia associated with the procedure. 5,6 In general, almost all other considerations must exert their influence through these primary factors. For instance, tumor size and complexity are highly relevant because they strongly impact the number of nephrons that can be preserved with PN. 21 In addition, they may also influence surgical approach and duration of ischemia. However, ultimately the final pathways of number of vascularized nephrons preserved and their recovery from ischemia will predominate with respect to functional recovery (fig. 1). The relative importance of each of these pathways with respect to the decline of function after PN has been an active area of investigation during the last several years. 19 RELATIVE IMPORTANCE OF ISCHEMIA Traditional PN has been performed with hilar occlusion to provide a bloodless field, which facilitates

4 1892 DECLINE IN RENAL FUNCTION AFTER PARTIAL NEPHRECTOMY Figure 1. Renal function preservation after PN averages about 80% in operated kidney but can be compromised by incomplete recovery from ischemic insult or excessive loss of nephron mass during tumor excision and reconstruction. a safe and efficacious procedure. 5 Recent studies demonstrate that hilar occlusion is often not required, 8,11,12,22 yet most PNs are still performed with hilar clamping. How important is ischemia (fig. 2), which can contribute to the decline of function after PN? Previous studies suggest that ischemia contributes substantially to functional decline after PN, leading to the commonly expressed adage every minute counts. 23 In a study of 360 solitary kidneys managed with PN, each additional minute of warm ischemia correlated with a 6% increased incidence of de novo severe CKD, suggesting a cause/effect relationship. 23 However, this and many such studies were flawed by not including all potentially relevant predictive factors, thus allowing surrogate factors to achieve undeserved significance. Most notably, the quantity of preserved parenchyma was not included in the analysis. Further data demonstrated a strong relationship between ischemic interval and the amount of parenchyma saved by PN, suggesting that ischemia time could act as a surrogate for surgical complexity. 19,24 More challenging PN will typically take longer to complete and will be associated with greater loss of parenchymal mass. 15,24 Studies that comprehensively included all relevant predictive factors, including the percentage of parenchymal mass saved, have shown that ischemia time loses statistical significance, presuming that limited warm ischemia or hypothermia have been used. 6,15,24e28 In fact, most recent studies have shown that functional recovery after PN is proportionate to parenchymal mass saved, which suggests that most nephrons make a near complete recovery from the ischemic insult after traditional clamped PN. For instance, in studies by Song et al parenchymal mass preservation strongly correlated with functional recovery (p <0.003) in contrast to ischemia time (p¼0.64). 26,27 The table also provides data on the type and duration of ischemia, and suggests that recovery of function after PN is not substantially different when comparing series with cold ischemia, limited warm ischemia or zero ischemia. However, it is

5 DECLINE IN RENAL FUNCTION AFTER PARTIAL NEPHRECTOMY 1893 Figure 2. Decline in renal function after PN primarily due to poor recovery from ischemic insult. Schematic illustrates case in which parenchymal mass preservation is optimized but some nephrons do not recover from ischemia. On average optimal PN would save about 80% of nephron mass (160 cc/200 cc) in this setting and would ideally experience complete recovery from any ischemic insult. It would yield GFR of about 40 ml/minute/1.73 m 2 with loss of function proportionate to loss of nephron mass. In this example final GFR is 30 ml/minute/1.73 m 2 rather than expected 40 ml/minute/1.73 m 2, consistent with suboptimal recovery from ischemia (75%). Loss of GFR specifically due to incomplete recovery from ischemia is 10 ml/minute/1.73 m 2. Potential measures to prevent poor recovery from ischemia are detailed. difficult to draw definitive conclusions when comparing series from different centers that may be using different surgical approaches and operating on divergent patient populations. A recent study by Mir et al yielded more granular information because it provided data on nephron mass and function derived specifically from the operated kidney and normalized for loss of parenchymal mass. 20 Vascularized nephron mass was measured from CT before and 4 to 12 months after clamped PN in 155 patients, and split renal function was obtained from nuclear renal scans for patients with 2 kidneys. Recovery from ischemia was defined as the percent GFR saved in the operated kidney divided by the percent parenchymal mass saved. This would be 100% if all nephrons made a complete recovery from ischemia. In this series overall median recovery from ischemia was 95% and 100% for hypothermic cases vs 92% when warm ischemia was used (p <0.05). WIT was less than 25 minutes in most patients, so conclusions should not be extended beyond these limits. It is notable that poorly functioning kidneys recovered as well as robustly functioning kidneys in this series, proportionate to the nephron mass preserved. 20 Additional studies are needed in this domain to more rigorously evaluate the effect of preexisting CKD and morbidities on the recovery of function after PN. What about extended warm ischemia, which has been much less intensively studied? Available data suggest that prolonged ischemia begins to have deleterious effects, although not as profound as previously believed. Experimental studies on histological changes and biochemical markers of ischemic damage have shown only marginal changes associated with WIT out to 45 or more minutes, although

6 1894 DECLINE IN RENAL FUNCTION AFTER PARTIAL NEPHRECTOMY it is not clear that optimal markers were used in these analyses and further studies will be required. 29 In the report by Thompson et al, warm ischemia greater than 25 minutes was associated with a 2.3-fold increased risk of de novo stage IV CKD after PN (p¼0.049) on multivariable analysis, 24 and other studies have also suggested a potential threshold close to this time frame. However, the literature is not clear with respect to an absolute limit at which ischemic damage becomes irreversible, and this may vary based on individual patient characteristics. 30 The analysis of outcomes after minimally invasive PN by Hung et al provides useful data on this topic. 8 The authors experience over 4 eras was analyzed with median warm ischemic times of 36, 31, 14 and zero minutes, respectively. Percentage of total parenchymal mass preserved was similar across the eras, ranging from 88% to 90%, essentially taking this factor out of consideration. As illustrated in the table median global percent functional recovery in these eras was 80%, 79%, 89% and 91%, respectively. Given the presence of a contralateral kidney in most patients, this correlates with an approximate percent functional recovery in the operated kidney of 60% in the 2 early eras with extended WIT vs approximately 80% in the limited warm and zero ischemia eras. 8 Taken together, these data suggest that loss of function due to ischemia is marginal when hypothermia or limited warm ischemia is used, but extended warm ischemia can be deleterious. The clinical relevance of these findings in different clinical settings will require further investigation. PREVENTION OF IRREVERSIBLE ISCHEMIC INJURY Pharmacological Intervention Many pharmacological manipulations have been investigated in an effort to prevent irreversible ischemic renal injury during PN. Mannitol induces an osmotic diuresis and serves as a free radical scavenger, and appears to protect against irreversible ischemic renal injury in animals. However, recent clinical studies have failed to confirm a benefit after open or minimally invasive PN, and the value of this commonly applied maneuver has now been questioned. 31,32 Dopamine, which increases sodium excretion and urine output, was previously routinely administered before PN in high risk situations to avoid acute kidney injury. 33 However, when dopamine was subjected to a randomized trial in patients undergoing PN for a solitary kidney, no renoprotective effect was observed. Fenoldopam is a short-acting dopamine-1 receptor agonist that has also been tested in the setting of PN for a solitary kidney. In this study 90 patients were randomized to a 24-hour perioperative infusion of fenoldopam vs placebo. 34 However, no renoprotective effect was observed. A mixture of renoprotective growth factors, porphyrins and mitochondria protecting amino acids has shown protective effects against ischemia induced renal injury in rodents but clinical studies are lacking. 35 Another study using antioxidants including allopurinol, vitamins E and C, and N-acetylcysteine showed promise as a renoprotective regimen after aortic aneurysm repair, but a role in patients undergoing PN has not be adequately investigated. 36 In summary, a variety of pharmacological manipulations have been investigated in an effort to abrogate the negative effects of ischemia, although most translational studies to date have been negative. Surgical Considerations A variety of intraoperative maneuvers can be considered to reduce the risk of ischemic injury during PN including the use of hypothermia, early unclamping and zero ischemia. Of these options, experience is most substantial with hypothermia. Novick reviewed the rationale and efficacy of hypothermia for PN as far back as 1983, and based on his cumulative experience he strongly advocated for hypothermia whenever ischemia time was anticipated to be greater than 30 minutes. 37 Uzzo and Novick reported strong functional recovery after PN with CIT up to 3 hours. 5 The experience with renal transplantation, where extended hypothermia intervals of several hours are often encountered with near complete functional recovery, also supports these perspectives. 37 Recent clinical studies also suggest a strong protective effect of hypothermia during PN. In the study by Mir et al the median value for recovery from ischemia (percent function saved normalized by parenchymal mass saved) was 100% in 64 kidneys managed with cold ischemia, and only 1 of these patients had recovery from ischemia of less than 80%, corresponding with substantial loss of function due to ischemia. 20 Other studies also support a more consistent functional recovery from ischemia when hypothermia has been applied, and most centers still prefer a hypothermic approach in patients with preexisting CKD or a solitary kidney. 5,24 A variety of approaches can now be applied to achieve hypothermia in addition to traditional surface cooling, and can facilitate the use of hypothermia during minimally invasive PN. These approaches include retrograde perfusion of ice saline via the ureter or antegrade through the renal artery. 38,39 A limited number of centers are now also performing surface cooling during robotic PN with success, essentially replicating traditional open PN. 40

7 DECLINE IN RENAL FUNCTION AFTER PARTIAL NEPHRECTOMY 1895 Early unclamping or other maneuvers to limit warm ischemia are also important advances to prevent ischemic injury. As previously reviewed, recovery from ischemia tends to be high as long as warm ischemia has been kept below about 25 to 30 minutes, although the absolute threshold at which irreversible ischemic injury begins to occur remains poorly defined. 24,30 In the approach popularized by Gill the arterial clamp is removed after the initial parenchymal sutures have been placed, and this substantially reduced median warm ischemic times from 31 minutes to 14 minutes. 41,42 Global renal function preservation thereby improved from 80% to 89%, reaching statistical significance. 8 Mir et al reported 81% of patients in the limited warm ischemia cohort had recovery from ischemia greater than 80%. 20 Several other studies also support strong recovery of function in patients treated with limited warm ischemia. 7,26,28 The ultimate way to avoid irreversible ischemic injury is to avoid ischemia itself, which has led to a variety of approaches including zero ischemia PN and segmental clamping. 8,10,22 In essence the goal is to leave all or most of the kidney perfused, while still accomplishing precise and safe PN. A variety of maneuvers have been described to facilitate the VMD required to isolate the branch vessels leading into the tumor, including detailed 3-dimensional CT reconstructions to more accurately delineate the arterial anatomy, intraoperative color Doppler ultrasonography, and at some centers the use of near infrared fluorescence imaging to further refine the anatomical visualization. Many centers have reported their results with these approaches, although in some functional outcomes are not reported, and in others functional recovery has not been normalized for parenchymal volume loss, 10,12 thus rendering the data difficult to interpret. In the trifecta analysis by Hung et al 104 patients treated with early unclamping (median WIT 14 minutes) could be compared to 78 treated with zero ischemia. 8 Parenchymal volume loss was similar in the 2 groups. Recovery of global renal function was 89% in the limited warm ischemia group vs 91% in the zero ischemia group, and recovery from ischemia, as previously defined, was 99% vs 103%, respectively. Thus, the functional outcomes were similar and loss of function due to ischemia was essentially undetectable in both groups. A potential concern with the zero ischemic approach relates to blood loss and most studies document increased transfusion requirements with this procedure. In the study by Gill et al 11 patients (19%) received perioperative blood transfusion, 22 and gross hematuria requiring embolization, transfusion or prolonged bedrest was also reported in 18 patients (14%) in the series from Shao et al. 10 Some series suggest the potential for improved functional recovery with elimination of ischemia in subsets of patients, which leaves open the possibility of improved outcomes with further study. In a recent analysis by Desai et al, global functional preservation averaged 83% in 63 patients with limited warm ischemia vs 89% in 58 patients with superselective arterial occlusion. 12 However, it is not clear why outcomes for the comparison group of patients with limited warm ischemia were suboptimal compared to most other studies in the literature (see table). In the study by Smith et al a subgroup of 47 patients with a solitary kidney had better results with an unclamped approach than with hilar occlusion. 11 The merits of zero or segmental ischemia will require further investigation but remain at the forefront due to innovative appeal. LOSS OR DEVASCULARIZATION OF PARENCHYMAL MASS The other major etiology of decline of function after PN pertains to loss of vascularized parenchymal mass (fig. 3). Tumor excision is typically designed to include a small rim of normal parenchyma to avoid positive margins. In addition, the placement of sutures to occlude transected vessels within the parenchymal bed and reapproximate the capsule also leads to the devascularization of adjacent tissue. In complex PN, parenchyma radial to the tumor may also become devascularized. Thus, in the paradigm of traditional PN there will always be some loss of function related to these processes. 5 A variety of studies have shown that this is the major contributor to the decline of function associated after PN, and efforts to address this should be prioritized. 19 However, some have questioned whether the amount of vascularized parenchyma preserved by PN is modifiable, because it is strongly influenced by tumor characteristics. While central location and large tumor size strongly correlate with increased parenchymal loss, in a recent study Takagi et al demonstrate that precision of excision and reconstruction is modifiable, and can be optimized when necessary. 16 In this series surgical precision was defined as the amount of parenchyma actually saved normalized by that predicted for an ideal PN, presuming loss of a 5 mm rim of normal parenchyma associated with excision and reconstruction, along with radial tissue that would be devascularized. On multivariable analysis the only factor that correlated with surgical precision was the presence of a solitary kidney, while surgical approach and other factors failed to correlate. 16 Overall, median precision of surgery in this series was 93%, demonstrating that a precise PN was accomplished

8 1896 DECLINE IN RENAL FUNCTION AFTER PARTIAL NEPHRECTOMY Figure 3. Decline in renal function after PN primarily due to excessive parenchymal excision or collateral damage during reconstruction leading to substantial loss of vascularized parenchymal mass. Schematic illustrates case in which only 60% of parenchymal mass has been saved (120 cc/200 cc) rather than typical 80%. Final GFR is 30 ml/minute/1.73 m 2 rather than expected 40 ml/minute/1.73 m 2. Recovery from ischemic insult has been complete, ie loss of function is proportionate to loss of nephron mass. Potential measures to prevent excessive loss of nephron mass during excision and reconstruction are detailed. NIR, near infrared. in most instances. Median surgical precision was 95% in patients with a solitary kidney vs 89% in all other cases (p¼0.02). The recognized need to preserve as much parenchyma as possible in the absence of a contralateral kidney was perceived to be the main driver. Thus, the amount of vascularized nephron mass preserved by PN appears to be a primary determinant of functional recovery, and while strongly influenced by tumor size and location, recent studies suggest it is potentially modifiable. PREVENTION OF EXCESSIVE LOSS OF NEPHRON MASS Imaging Sophisticated perioperative imaging has improved our ability to visualize the tumor and its relationship to the vasculature, which is fundamentally important in this era. Three-dimensional reconstruction of the anatomy by CT or magnetic resonance imaging facilitates precise tumor excision and careful reconstruction while still achieving negative margins. Most importantly, branch arteries adjacent to the tumor can be visualized and preserved. CT angiography is also now commonly used for zero or segmental ischemic approaches to PN to facilitate the VMD. 10,22,43 Surgical navigation which allows for projection of the anatomical details onto the kidney as the dissection proceeds is also being explored. More routinely used is intraoperative ultrasonography, which is particularly helpful for intrinsic tumors. 44 Near infrared fluorescence imaging has also been investigated to improve surgical precision, although an advantage with respect to new baseline renal function has not yet been demonstrated. 45 While expert opinion strongly recognizes the importance of detailed perioperative imaging,

9 DECLINE IN RENAL FUNCTION AFTER PARTIAL NEPHRECTOMY 1897 studies that quantify the specific contributions of each of these modalities to enhanced precision of excision and reconstruction are lacking. Surgical Considerations Various maneuvers can be considered to optimize the preservation of parenchymal mass with PN, either by minimizing the amount of parenchyma excised or preventing collateral damage during reconstruction. Many believe that a bloodless field allows for precise dissection by providing better visualization, but others argue that a careful, prospective microdissection can bring one directly adjacent to the tumor and achieve the same objective. 5,22 Consensus holds that negative margins, even if only 1 to 2 mm in diameter, should be prioritized to optimize oncologic outcomes. Enucleation is a well described strategy to minimize the amount of normal parenchyma excised with the tumor, taking advantage of the natural fibrotic capsule that surrounds many localized renal tumors. Previous reports summarize the rationale, results and potential limitations of the enucleative approach. 46,47 Enucleation is certainly preferred in patients with familial RCC but is now also being applied more frequently for sporadic cases. A recent study demonstrated substantially improved parenchymal mass preservation with enucleation compared to traditional PN, with mean values of 98% and 89%, respectively. 46 Other studies suggest that enucleation may obviate the need for formal capsular closure because adjacent arteries/veins can often be dissected free and left undisturbed. 47 At present, concerns about margin status and oncologic outcomes with enucleation persist, and further investigation to define appropriate selection criteria is greatly needed. The other major opportunity to improve parenchyma mass preservation relates to minimizing collateral damage during reconstruction of the kidney. As previously mentioned, some resections may not require capsular closure and this should be considered in appropriately selected patients. Beyond this, suture ligation of transected vessels within the parenchymal margins should be performed precisely, avoiding deep ligation whenever feasible. A variety of modalities such as lasers and the harmonic scalpel have been investigated for thermal based dissection during PN, and may obviate the need for capsular closure, particularly when hemostatic agents are used as an adjunct. 48,49 CONCLUSIONS Preservation of renal function after PN is critically important in many patients with localized RCC, such as those with preexisting CKD. Decline in function after PN averages approximately 20% in the operated kidney and 10% globally for patients with 2 kidneys. 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