Repeat Partial Nephrectomy: Surgical, Functional and Oncological Outcomes

Abstract

Purpose of Review

The greater utilization of partial nephrectomy and ablative procedures has increased the incidence of patients presenting with local renal recurrence. The choice to either perform a partial or radical nephrectomy in these situations can be a challenging decision.

Recent Findings

Repeat and salvage partial nephrectomy, while challenging and potentially associated with increased complications, offers patients the ability to maintain excellent renal functional outcomes and promising oncologic outcomes at intermediate follow up.

Summary

Surgeons should be familiar with the surgical complications and the functional and oncologic outcomes of re-operative nephron-sparing surgery. Recent data and outcome analysis support utilization of these procedures in patients presenting with either local recurrence or de novo lesions in the ipsilateral kidney.

Introduction

Prior to the 1990’s, nephron-sparing surgery (NSS) was reserved for select patients with bilateral disease, multi-focal disease, solitary kidney, hereditary kidney cancer syndromes, or for those with chronic renal insufficiency. However, the past decade has seen the expansion of partial nephrectomy to an elective setting. Based on a panel of experts, the AUA now recommends partial nephrectomy as the gold standard for treatment of small renal masses.¹ After several retrospective series demonstrated equivalence to a radical nephrectomy, elective partial nephrectomy has recently expanded to include patients with larger masses ^2–6 Today, many academic centers believe that the main determinant in deciding to perform NSS is the amount of preservable parenchyma and not tumor size.⁷

While the above paradigms are generally considered options for patients who have not had prior renal surgery, NSS may be even more imperative in someone who has undergone a prior NSS surgery and developed a new or recurrent tumor in the same kidney. While radical nephrectomy may be a reasonable option in select patients, repeat partial nephrectomy may still be the preferred option, as it will maximize preservation of a renal function. While traditionally believed that any subsequent renal tumor formation is a recurrence that portends poor prognosis, in reality most so-called recurrences are due to multifocality and bilateral nature of the disease, which further reinforces the goal to perform NSS if feasible.

Several important clinical scenarios that may necessitate repeat NSS are becoming increasingly common at institutions treating hereditary cancer syndromes and at high volume kidney cancer centers (Figure 1). Managing patients that need repeat or salvage partial nephrectomy, re-operation in a solitary kidney, or post-ablation NSS, can be extremely challenging^8,9 Prior to embarking on these difficult cases, it is important for a clinician to understand the approaches, risks, and benefits.

Figure 1.

Different Clinical Scenarios for Re-Operative Nephron Sparing Surgery

All aspects of re-operative surgery can be difficult. The challenges start from preoperative radiographic evaluation of reoperative field, sometimes due do scarring or multitude of surgical clips (Figures 2 and 3). The decision where to make an incision in a patient with multiple retroperitoneal surgeries must also be carefully planned as each approach present its unique anatomic challenges and structures to be avoided during the dissection (Figure 4). Cases can be physically and mentally exhausting due to the constant challenge of altered landmarks, fused and obliterated tissue planes as well as multiple surgical clips from prior surgical procedures. In order to familiarize clinicians with these cases, we set out to review the surgical, functional, and oncologic outcomes for repeat and salvage partial nephrectomy.

Figure 2.

A Scout film showing multiple clips in a re-operative field

Figure 3.

A CT demonstrating the difficulty in evaluating a post-operative field due to surgical clip artifact

Figure 4.

A prior abdomen in a patient with von Hippel Lindau disease who has had prior midline, thoracoabdominal, and flank approached for multiple kidney, adrenal, pancreas, and lung surgeries.

Definition and Causes of Local Recurrence

Positive margin

The incidence of local recurrence after a partial nephrectomy varies between 0–17% depending on the series.^10–12 While the rate may be low for someone undergoing an elective partial nephrectomy, it is much higher for someone undergoing an imperative partial nephrectomy in a solitary kidney. The definition of local recurrence is also difficult to determine, especially for a patient with multi-focal disease. Whether a recurrence represents a true surgical failure of incompletely resected tumor, new lesion, or residual disease that was present at a time of a prior resection is frequently impossible to determine.

A surgical dichotomy exists with the partial nephrectomy: the goal is to spare normal renal parenchyma while hoping to achieve clear margins to avoid local recurrence. The amount of margin to remove has been subject to debate, especially after excellent survival data has been demonstrated with enucleative surgery in patients with hereditary cancer syndromes.¹³ The classic dogma to remove a 1 cm margin of normal parenchyma was based on the premise that some tumors have an incomplete capsule and can extend several millimeters into the surrounding parenchyma.¹⁴ However, several groups have demonstrated that a minimal rim even up to 1–2 millimeters of normal parenchyma is sufficient to protect against a positive margin and can demonstrate equivalent survival to those with a wider margin.^15,16 One group expanded enucleative surgery for those patients with sporadic renal tumors and demonstrated excellent outcomes with long-term data.^17,18 With surgeons continuing to limit the amount of normal parenchyma removed there may be an increase in positive margins, with the significance of this not clearly understood.

It is essential to be prepared to deal with a pathology report of a positive surgical margin, especially in patients with multifocal RCC. While there are likely differences in the outcomes of patients with gross positive margins than a microscopic margin, the best scenario is to avoid the positive margin altogether. Nevertheless, it is important to state that a positive surgical margin in certain malignancies such as sarcomas are associated with a high incidence of local recurrence while positive margins in RCC have much lower local recurrence rate. While some data does point to an increase in local recurrence with a positive margin, several retrospective studies have demonstrated that a microscopic margin does not negatively impact overall survival or the development of metastatic disease. ^{19,20,19,21,22} Therefore, in the setting of a positive margin, observation rather than a salvage nephrectomy is strongly recommended, as surgery in the setting of a positive margin frequently demonstrates no evidence of residual disease.^22,23

De Novo Lesions/Multifocality

A more frequent cause of a local recurrence is likely the development of a de novo lesion due to multifocality. Well-characterized syndromes such as von Hippel-Lindau, Hereditary Papillary Renal Carcinoma, and Birt-Hogg-Dube are associated with bilateral multi-focal disease.^24–29 However even patients with apparently sporadic renal tumors frequently demonstrate multifocal disease in the absence of a recognized syndrome or documented germline genetic mutation. While this was once believed to be a rare occurrence, multifocal disease now is estimated to occur in 3–25% of patients.^30–33 While there appears to be differences in the incidence of multifocality between the histologic subtypes, occurring most frequently in papillary RCC, many types of renal cancer may be multifocal.³⁴ It is therefore paramount to appreciate that patients presenting with multifocal RCC will likely develop a de novo lesion in a previously operated renal unit, and will likely have bilateral disease. In the NCI series on repeat partial or salvage nephrectomy, most contralateral renal units have been operated on before.^35,36 Additionally, in cases of aggressive partial nephrectomy performed at NCI for resection of greater than 20 tumors most contralateral kidneys have had prior interventions and as many as one third have been removed before.³⁷ Although completion radical nephrectomy may be considered for these patients, as they are prone to the development of bilateral and multifocal disease, a repeat partial nephrectomy should be considered if feasible.

Advantages with Repeat Partial Nephrectomy

Improved Renal Outcomes and Avoidance of Dialysis

With equivalent oncologic outcome to radical nephrectomy for small renal masses, partial nephrectomy began to be offered in the elective setting in the 1990’s.^11,38 However, there was little data supporting an elective partial nephrectomy in the setting of a normal contralateral kidney. Only several small quality of life studies that evaluated patients who underwent elective NSS demonstrated greater physical function and health outcomes compared to their counterparts undergoing radical nephrectomy.^39,40 Later, it was noted that the prevention of proteinuria could also be avoided with the use of NSS.⁴¹ However, it was not until several major studies characterized the significance of chronic kidney disease and its impact on overall health, that the idea of an elective partial nephrectomy was thrust into mainstream. Go and colleagues demonstrated the morbidity associated with chronic kidney disease.⁴² A graded relationship was found between the degree of chronic kidney disease and the risk of developing cardiovascular complications, hospitalizations and all cause mortality. Matsushita and colleagues reported a meta-analysis of a large population cohort that demonstrated similar findings of a graded association of all-cause and cardiovascular mortality with lower glomerular filtration rate.⁴³ Several other retrospective studies demonstrated that patients undergoing radical nephrectomy were more likely to develop adverse renal outcomes including CKD and the need for dialysis as compared to those receiving NSS.^44,45 In terms of cardiovascular outcomes, one institutional study also demonstrated increased cardiovascular complications associated with nephrectomy-induced chronic kidney disease.⁴⁶ However, a larger SEER-Medicare study did not find any association with cardiovascular events.^45,46

When patients have a normal contralateral kidney, clinicians may have more flexibility in the setting of an ipsilateral tumor recurrence. However, when detecting a recurrent renal mass in a patient with CKD or with a solitary kidney, surgery may be potentially life altering. NSS and the avoidance of dialysis should be considered whenever possible due extremely high cardiovascular morbidity and mortality associated with artificial renal replacement therapy. The overall threat to survival for someone on dialysis is frequently greater than threat due to their renal mass, with a 5-year overall survival on dialysis of 33%.⁴⁷ While some patients who are placed on dialysis after nephrectomy may be transplant candidates, many could die waiting for a graft. Although there are no specific policies regarding listing practices for transplant recipients with history of cancer, many centers follow the recommendations that are set forth by the American Society of Transplantation (AST).⁴⁸ AST recommends that RCC patients with tumors larger than 5 cm should have a two-year wait time, potentially delaying receipt of a kidney graft.^47–49 Compounding this wait time with even longer wait time for cadaveric grafts (6+ years in some areas), it is likely that most patients without a living donor will not receive a kidney transplant.

Economic Benefit

The high expense of end stage renal disease (ESRD) makes the overall economic impact of this disease a major factor in United States health care policy. The number of patients with ESRD continues to climb each year and now the financial burden is estimated to be greater than 35 billion dollars a year.⁵⁰ Repeat NSS may be more costly than an initial partial nephrectomy due to the inherent complications of re-operative surgery and an expected prolonged hospital stay. Nevertheless, a recent cost analysis of the NCI experience with re-operative renal surgery by Agochukwu et al compared these surgeries to the alternative of a completion nephrectomy and progression to dialysis. Costs were modeled using Medicare reimbursement rates based on current procedural terminology (CPT) codes. The authors reported comparable costs after one year.⁵¹ As hemodialysis and its associated complications cost approximately $70,000 per year, after the first year, reoperative NSS to prevent dialysis leads to significant reductions in healthcare costs.⁵⁰

Potential Overall Survival Advantage with Nephron Sparing Surgery

The choice of surgery, either a radical or partial nephrectomy, in most large series has not impacted disease-specific survival. However in light of adverse renal outcomes associated with radical nephrectomy, several recent series evaluate overall survival for those with renal masses treated with both approaches. For those patients with renal masses both institutional and population based data demonstrate an improvement in overall survival for those treated with NSS. ^6,45,52,53 As these studies are not randomized, they may be biased by patient selection. One randomized controlled trial, EORTC 30904 compared the outcomes of patients undergoing elective radical versus partial nephrectomy for low stage disease. While this study did not fully accrue, it randomized 541 patients, and showed no difference in cancer specific and overall survival for patients with renal cancer.⁵⁴

Prevention of Future Imperative NSS due to Metachronous, Contralateral Disease

Performing a completion nephrectomy after prior NSS leaves a patient with a solitary kidney that still is at risk from metachronous, contralateral disease. Those that formed a de novo recurrence in the ipsilateral kidney may have multi-focal disease and therefore it is important to consider the future of the contralateral kidney. It has been shown that among patients with multifocal tumors 90% will have bilateral involvement.⁸ Conversely, in those with bilateral renal involvement, a majority will have multifocal tumors.⁵⁵ Additionally, an older review of the Mayo clinic series demonstrated that for patients who underwent a radical nephrectomy, 1.2% of patients demonstrated metachronous, contralateral recurrence at a mean time of 5 years. In a large population-based study, Rabbani also confirmed a similar 1% risk of metachronous, contralateral tumor recurrence after nephrectomy.⁵⁶ As both these studies included patients from the 1970’s and 1980’s where cross sectional imaging may not have been performed as frequently, both may underestimate the true incidence of contralateral disease.

Preventing an Imperative Partial Nephrectomy on a Solitary Kidney

The elective partial nephrectomy gained popularity as techniques evolved and have demonstrated a low rate of complications. However compared to those patients who require an imperative NSS on a solitary kidney, the rates of complication and morbidity associated with surgery was greatly increased.⁵⁷ While this likely is influenced by patient selection (larger tumors in the imperative arm- 4.0 vs 3.2 cm), having the option of performing a radical nephrectomy can make surgical planning less daunting. Potential saving a renal unit could allow for a more flexible surgical planning in the event that a kidney is not salvageable or a surgeon faces unexpected intraoperative challenges.

Disadvantages and Complications with Re-operative Renal Surgery

Operative Time, Blood Loss, and Prolonged Hospital Stay

A re-operative partial nephrectomy is a challenging surgery due to intense perinephric fibrosis obscuring the normal tissues planes. These surgeries are often prolonged with a mean surgical time approaching 7–8 hours even in experienced hands.^51,58 Due to resection of large number of tumors (more than 70 in some cases) and to minimize the amount of ischemia to the renal remnant, these surgeries are frequently performed without renal hilar clamping, resulting in substantial intra-operative blood loss. Several series report the transfusion rates and blood loss associated with these surgeries to be over five times higher than those patients undergoing a routine partial nephrectomy.^36,57,58 Due to the extended operative times and the need for multiple transfusions, patients frequently need to be monitored in the intensive care unit, and their hospital stay is likely to be prolonged.⁵¹

Complications More Commonly Seen with Re-Operative Renal Surgery

Open surgical techniques for partial nephrectomy have evolved over the past two decades.^12,59 While complications were initially higher for laparoscopic NSS, with evolution of the procedure the complications have decreased in parallel to shortened ischemic and operative times.^1,60 For re-operative and salvage NSS, the adjacent fibrosis from the prior surgery can increase the incidence of injury to adjacent structures such as the bowel, spleen, liver, or diaphragm. Interestingly, one of the initial series from Magera and colleagues from the Mayo Clinic did not demonstrate any increased morbidity with repeat open NSS.⁶¹ In this series, the 18 patients who underwent repeat NSS had peri-operative outcomes and complications compared to their initial partial nephrectomy. The overall rate of complications was similar to that observed with the initial operation leading the authors to conclude the procedure is safe in select patients.

More recent series from the NCI have seen more of the anticipated complications with re-operative surgery. Dissecting the surrounding organs off the kidney led to higher rates of complications not frequently reported in classic series.¹² Complications such as pleural injuries (17.6%) and pancreatic leakage (4%) appear to be more common with re-operative NSS. ^36,58 One major complication seen in almost 25% of patients in one series has been major renovascular injuries, and it was occasionally the cause of the loss of the renal unit.⁵⁸ Finally the incidence of urine leak (20%) appeared to be about three times higher than most series. Clearly patient selection, number of tumors removed, and the timing of re-intervention may influence the rates and types of complications.

Post-Ablative Partial Nephrectomy

The AUA Renal Mass Panel recently established new guidelines for the patient with the small renal mass.¹ For older patients or those with significant comorbidities, the use of ablative intervention is considered acceptable. Concerns over difficulty with the definition of ablative success and the potential for local recurrence limit the applicability of this modality to younger, healthier patients. Recent reports demonstrate the difficulties associated with salvage procedures in the case of tumor recurrence. Nguyen reviewed the Cleveland Clinic experience with attempted partial nephrectomy after either RFA or cryotherapy. In this small series, only 2 of 10 patients were able to have a successful NSS due to the large amount of peri-nephric fibrosis and the remaining patients either had a radical nephrectomy or had the procedure aborted.⁶² The NCI series reported a more successful outcome of 16 surgeries after RFA.⁶³ Most of these cases had severe fibrosis, but NSS was completed in all cases despite a prolonged surgical time and the frequent need for transfusions. In this series, as expected, there was a moderate increase in the rate of complications such as a prolonged urine leak and the need for re-operation.

Laparoscopic Renal Intervention After Prior Ipsilateral, Retroperitoneal Surgery

Laparoscopic and robotic partial nephrectomy has gained momentum in the past half-decade due to several studies demonstrating similar oncologic efficacy and improved convalescence.¹ Over time surgeons have pushed laparoscopic surgery towards more and more complex surgeries. After a prior open, ipsilateral, retroperitoneal surgery, a laparoscopic NSS approach may be feasible in experienced hands for select patients. Turna reported the experience with laparoscopic NSS in patients who had undergone ipsilateral procedures, although half of them had undergone only prior percutaneous nephrolithotomy and nephrostomy tube placement. ⁶⁴ In that series, all cases were successfully completed with no need for open conversion.⁶⁴ Boris and colleagues reviewed the NCI experience with laparoscopic surgery after prior ipsilateral kidney or adrenal surgeries.⁶⁴ In this patient cohort, 28% of patients required an open conversion; however, among those cases completed laparoscopically there was no increase in blood loss or operative time compared to patients having no history of a prior surgery. Although this series has encouraging outcomes the importance of patient selection cannot be overemphasized.

Functional Outcomes

While the series looking at re-operative partial nephrectomy are small and have been performed in a select group of patients, several important findings have been noted. Of most importance, is that in all series, it appears that more than 80% of the initial renal function was preserved in cases of successful re-operative renal surgery (Table 1).^9,65 In the Mayo and the initial NCI experience, vast majority of patients undergoing a repeat partial nephrectomy had a successful attempt at NSS.^36,61 The functional outcomes of repeat partial nephrectomy reported by Johnson et al demonstrate only minimal decline in both serum creatinine and creatinine clearance after surgery. For those patients with two kidneys, nuclear renography also demonstrated a minimal decline in split renal function.³⁶ In a later series from the NCI including only patients with solitary kidneys who underwent a re-operative NSS for a median of four tumors, 22 of 25 patients (88%) were able to keep their kidney in place.⁵⁸ Short-term functional measurements at one and three months did demonstrate some decline in glomerular filtration rate, however at one year, renal function returned to pre-operative levels. Unlike in repeat renal interventions, during salvage partial nephrectomy, defined by Bratslavsky et al as the third or fourth attempt at NSS, the incidence of renal loss is much higher. In this series of 13 attempted salvage partial nephrectomies, 3 renal units (23%) were lost and major complications occurred in 6 (46%) cases.³⁵

Table 1.

Renal Functional Outcomes of Re-Operative Renal Surgery

Series	Indication	# patients/# kidneys	Solitary Kidney	Peri-Operative Mortality	Renal Units Lost	Chronic Hemodialysis	Preop Creatinine*	Post-Op Creatinine*	% Δ Creatinine Clearance
Magera61	Repeat NSS	18/18	12 (67%)	0%	0%	0%	1.4 (0.9–3.6)	1.4 (0.9–4.4)	NA
Johnson36	Repeat NSS	47/51	17 (33%)	1 (1.9%)	3 (5.8%)	3 (5.8%)	1.16 (0.8–1.80)	1.35 (0.8–2.9)	−11%
Liu58	Solitary Kidney Repeat NSS	25/25	25 (100%)	1 (4%)	3 (12%)	3 (12%)	1.5 (1.0–2.0)	1.55 (1.55–2.80)	−15%
Bratslavsky35	Salvage NSS	11/13	4 (31%)	0%	3 (23%)	2 (15%)	1.2 (0.5–2.2)	1.4 (0.9–3.3)	−17%
Kowalczyk63	Post-Ablative NSS	13/16	NA	0%	0%	0%	1.0 (0.6–1.2)	(0.8–1.3)	−11%

^*Of Successfully Completed NSS

NA- Not available

For post-ablation NSS, the series reported by Nguyen et al showed that only 2 out of 10 patients were able have NSS after prior ablation, while others had their kidneys lost or had the surgery aborted.⁶² However, as mentioned above, the NCI experience with post-RFA NSS was successful in all 16 surgeries performed on 13 patients. A variety of factors could be responsible for these findings including differences in patient selection, the degree of difficulty after cryotherapy compared to ablation, the timing of surgery after ablation, and experience with reoperative surgery.

Oncologic Outcomes

At this time, the evaluation of oncologic outcome for repeat NSS is only available at intermediate follow up. Importantly, evaluation of oncologic outcomes are challenging in these patients. Because of the propensity to form new tumors, the evaluation of recurrence- or cancer-free survival is not possible, leaving either cancer-specific or metastasis-free survival as valid measures of the oncologic outcomes. Despite this, after repeat NSS (especially after NSS performed for multiple lesions) it can be difficult to or impossible to determine which lesion or surgery was the cause of disseminated disease. For example, Magera et al reported the 5-year overall and cancer-specific survival after repeat NSS to be 71% and 83%, respectively.⁶¹ In their study 91% of the lesions being T1a at time of repeat NSS, but the 5-year cancer-specific survival was only 71%. While a small series, the survival was far worse than reported by Frank and colleagues (97%) in a later series from the same institution.⁶⁶

The time to reoperation is quite variable between individuals. In a mostly hereditary RCC population, the NCI has reported that approximately 20–40% of patients who undergo repeat NSS will subsequently have local recurrence in that kidney and require re-operation within the first four years.^36,58 Nevertheless, recent NCI analysis of patients treated surgically for more than 10 years demonstrate an average of approximately 6 years between re-interventions (range 0.7–21 years).⁶⁷ Of greatest importance, however, is the fact that greater than of all published series from the NCI, metastasis-free and cancer specific survival are greater than 90%.^35,36,58,63 Similarly, for patients with solitary kidneys undergoing repeat NSS, Liu reported excellent results with a 95% metastasis-free survival at approximately five years of follow-up.⁵⁸ While the long-term data are awaited, the intermediate oncologic outcomes strongly supports the use of reoperative renal surgery.

Conclusions

With increased utilization of partial nephrectomy and ablation among urologists, as well as increase in number of partial nephrectomy performed for multifocal RCC, there will be an increased need for the management of patients with ipsilateral tumor recurrence. Performing a re-operative partial nephrectomy rather than a radical nephrectomy may have many potential health benefits to the patient as well as economic advantages to the health care system. While these cases may be technically challenging and labor intensive, urologists should familiarize themselves with the benefits and potential complications of repeat NSS to prepare for anticipated challenges and better patient counseling when faced with these difficult management situations.