Renal Functional Outcomes After Partial Nephrectomy With Extended Ischemic Intervals are Better Than After Radical Nephrectomy Brian R. Lane,* Amr F. Fergany,* Christopher J. Weight* and Steven C. Campbell‡,† From Michigan State University, Grand Rapids, Michigan (BRL), and Glickman Urological & Kidney Institute, Cleveland Clinic, Cleveland, Ohio (BRL, AFF, CJW, SCC)
Abbreviations and Acronyms CKD ⫽ chronic kidney disease GFR ⫽ glomerular filtration rate PN ⫽ partial nephrectomy RN ⫽ radical nephrectomy sCr ⫽ serum creatinine Submitted for publication January 31, 2010. * Nothing to disclose. † Correspondence and requests for reprints: Glickman Urological & Kidney Institute, Cleveland Clinic, 9500 Euclid Ave., Q10, Cleveland, Ohio 44195 (telephone: 216-444-5595; FAX: 216-6360770; e-mail: [email protected]
). ‡ Financial interest and/or other relationship with Pfizer, Sanofi Aventis and Novartis.
Editor’s Note: This article is the third of 5 published in this issue for which category 1 CME credits can be earned. Instructions for obtaining credits are given with the questions on pages 1580 and 1581. See Editorial on page 1251.
Purpose: Partial nephrectomy is now a standard of care for clinical stage T1 renal cancers amenable to a nephron sparing approach. Based on tumor size and location, some partial nephrectomies can be more challenging and necessitate longer ischemic intervals, and radical nephrectomy is considered an alternative standard of care for these tumors. We evaluate whether partial nephrectomy with extended ischemia provides improved renal functional outcomes compared with radical nephrectomy. Materials and Methods: Renal functional outcomes were analyzed in 2,402 consecutive patients with serum creatinine 1.4 mg/dl or less and 2 functioning kidneys treated for cT1 renal cancer at Cleveland Clinic with partial (1,833, 76%) or radical nephrectomy (569, 24%). Patients treated with partial nephrectomy were grouped according to duration of ischemia using the categories of limited (less than 30 minutes), unknown or extended (greater than 30 minutes). Results: Patients in all 4 groups had similar preoperative creatinine (median 0.9 mg/dl) and estimated glomerular filtration rate (median 82 to 84 ml/minute/1.73 m2). Patients undergoing radical nephrectomy on average were older, and had more comorbidities and larger tumors (p ⬍0.001). Regardless of type of surgery, this cohort as a whole was at low risk (less than 1%) for renal failure (estimated glomerular filtration rate less than 15 ml/minute/1.73 m2). However, patients in the radical nephrectomy cohort were far more likely (p ⬍0.001) to have an estimated glomerular filtration rate less than 45 ml/minute/1.73 m2 (35%) than any of the partial nephrectomy groups (limited 11%, unknown 15%, extended ischemia 19%). Conclusions: Even when performed with extended ischemia, partial nephrectomy is associated with renal functional outcomes superior to those of radical nephrectomy for clinical stage T1 renal cancers. Partial nephrectomy should be considered even for tumors in which anticipated ischemia may exceed 30 minutes. Key Words: kidney neoplasms; nephrectomy; kidney failure, chronic; warm ischemia; glomerular filtration rate
PARTIAL nephrectomy is now established as a reference standard for the treatment of small renal cortical tumors that are amenable to a nephron sparing approach.1 There is a growing body of literature demonstrating equivalent oncologic outcomes and better preservation of renal function compared with radical nephrectomy in selected patients.2– 8 Information from
national databases indicates that more than 80% of renal tumors have been treated with RN nationwide, although more recent evidence suggests an increase in the use of various nephron sparing interventions.9,10 Several recent reports have proposed that the renal functional advantages of PN are associated with a reduction in morbid cardiovascular events
0022-5347/10/1844-1286/0 THE JOURNAL OF UROLOGY® © 2010 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION
Vol. 184, 1286-1290, October 2010 Printed in U.S.A. DOI:10.1016/j.juro.2010.06.011
PARTIAL NEPHRECTOMY WITH EXTENDED ISCHEMIA
and improved overall survival after surgery.5,8,11,12 It has also come to light that preoperative renal dysfunction is more common in patients with kidney cancer than originally thought, and that these patients are at greater risk for the development or progression of CKD.6,13,14 The greatest modifiable risk factors for CKD in patients undergoing nephrectomy are the amount of parenchyma removed and the extent of ischemic injury experienced by the renal remnant in those undergoing PN. Traditionally PN has been performed with a goal to restrict the ischemic interval to less than 30 minutes to limit ischemic injury.15,16 This management schema might lead the urologist to perform RN when extended ischemia would be expected during PN. Therefore, we investigated the renal functional outcomes in 2,402 patients with normal baseline renal function and 2 functioning kidneys who underwent so-called elective PN or RN for clinical stage T1 renal cancer to determine whether RN is comparable to PN with extended ischemia in this regard.
average of 1.6 years after surgery (range 2 days to 30 years). Estimated GFR was calculated using the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) formulas (www.qxmd.com/renal/Calculate-CKD-EPI-GFR. php).17 Postoperative change in renal function was determined by the percent decrease in GFR between preoperative and highest postoperative GFR measured within 90 days after surgery. At latest followup percent loss from baseline was determined by the percent decrease in GFR between preoperative and latest GFR measurements. The distribution of continuous variables among the 4 groups was compared using t tests for independent samples and Wilcoxon rank sum tests with continuity correction when the data appeared to violate normality assumptions. The distribution of categorical variables in both groups was compared using Pearson chi-square tests with Yates’ continuity correction and Fisher’s exact tests when the proportion of patients in 1 or more categories was less than 5%. KaplanMeier analyses were used to evaluate overall and cardiovascular specific survival, and differences among the cohorts were tested with the log rank test. Statistical significance was assessed based on a 2-sided significance level of 0.05.
MATERIALS AND METHODS
Information regarding all patients with normal renal function (defined as baseline sCr 1.4 mg/dl or less) and 2 functioning kidneys who underwent PN (1,833, 76%) or RN (569, 24%) for clinically localized renal tumor between 1983 and 2009 were recorded in the Cleveland Clinic kidney cancer registry in accordance with institutional review board guidelines. Patients younger than 18 years and those with preoperative renal dysfunction (defined as sCr greater than 1.4 mg/dl), tumor greater than 7 cm, or preoperative radiographic evidence suspicious for lymph node or distant metastases were excluded from study. Preoperative evaluation included medical history, physical examination, routine laboratory studies including sCr and urinalysis, chest x-ray and abdominopelvic computerized tomography or magnetic resonance imaging. Tumor size was reported as the longest single dimension of the lesion as measured by the radiologist. Clinical tumor staging classified tumors 4 cm or less as cT1a and those greater than 4 to 7 cm as cT1b. Pathological staging was performed according to the 2009 International Union Against Cancer and the American Joint Committee on Cancer TNM staging system. The techniques used during PN and RN have been previously described.16 The ischemic interval is routinely measured as the number of minutes between placement of the first vascular clamp and removal of the last clamp. PN cases performed without occlusion of the renal vasculature were included in the limited ischemia group. The percentage of renal parenchyma preserved was generally recorded at case completion. Acute kidney injury was defined as the use of hemodialysis or any GFR measurement less than 15 ml/minute/1.73 m2 within 90 days of surgery. Preoperative and postoperative sCr measurements and clinical information about renal function were recorded for each patient. Postoperative sCr was generally measured daily until the day of discharge home and at 4 to 12 weeks after surgery. Latest GFR estimation was based on the most recent sCr measurements, which were obtained an
Characteristics of the 2,402 patients with 2 functioning kidneys and sCr 1.4 mg/dl or less who underwent PN (1,833) or RN (569) for clinical stage T1 renal tumor are shown in table 1. During the 20 years under study 76% of patients underwent PN for a clinical T1 tumor, including 804 with limited ischemia (30 minutes or less), 546 with ischemia of unknown duration and 483 with extended ischemia (more than 30 minutes). Ischemia time in the limited group ranged from 0 to 30 minutes (median 19) and in the extended group from 31 to 144 minutes (median 36). Many characteristics differentiated the RN group from the 3 PN groups. For example, the RN cohort included patients who were older, had more comorbidities and had larger tumors (p ⬍0.001 for each). In addition, final pathological analysis revealed that tumors treated with RN were more aggressive based on higher grade and stage (p ⬍0.001). Preoperative renal function was similar in all 4 groups with a median sCr of 0.9 mg/dl, and median GFR between 82 and 84 ml/minute/1.73 m2 (table 2). In contrast, renal functional outcomes were significantly different in the postoperative period and at latest followup. Acute kidney injury, which was defined as any GFR less than 15 ml/ minute/1.73 m2 or dialysis within 90 days of surgery, occurred in 14 of 1,833 patients treated with PN (0.8%) vs 8 of 569 treated with RN (1.4%) (Fisher’s exact test p ⫽ 0.2). Median postoperative decrease in renal function was 0% for PN with limited or unknown ischemia, 15% for PN with extended ischemia and 35% for RN (p ⬍0.001). The percentage of patients with the best postoperative GFR less than 45 and less than 15 ml/ minute/1.73 m2 within 90 days of surgery was higher
PARTIAL NEPHRECTOMY WITH EXTENDED ISCHEMIA
Table 1. Clinical information PN Limited Ischemia
PN Unknown Ischemia
PN Extended Ischemia
Median pt age (IQR) % Male (No.)
⬍0.001 (t test)* Not significant (Pearson chi-square with Yates’ continuity correction)†
% Race (No.): White
Not significant (Pearson chi-square with Yates’ continuity correction)†
Black Other % Charlson comorbidity index 2 or greater (No.)
4 7 13
(34) (62) (62)
8 8 20
(52) (52) (85)
6 4 15
(32) (22) (54)
7 3 24
(39) (18) (117)
Median cm clinical tumor size (IQR) % T1b or greater tumor (greater than 4 cm)
2.8 (2.0–3.7) 19 (154)
3.0 (2.2–4.2) 26 (143)
2.9 (2.2–3.6) 15 (72)
% Central tumor (abuts collecting system) (No.)
% Interpolar tumor (No.)
Median % parenchyma preserved (IQR)
% Ca (No.)
% Grade 3 or 4 Ca (No.)
% Pathological tumor stage (No.): pT1a
pT1b pT2 or greater
4.7 (3.6–5.9) 64 (362)
⬍0.001 (Pearson chi-square with Yates’ continuity correction) ⬍0.001 (t test)* ⬍0.001 (Pearson chi-square with Yates’ continuity correction) Not significant (Pearson chi-square with Yates’ continuity correction)† Not significant (Pearson chi-square with Yates’ continuity correction)† ⬍0.001 (Wilcoxon rank sum test with continuity correction)* ⬍0.001 (Pearson chi-square with Yates’ continuity correction)* ⬍0.001 (Pearson chi-square with Yates’ continuity correction)* ⬍0.001 (Pearson chi-square with Yates’ continuity correction)*
* RN was significantly different from all PN groups, while limited, unknown and extended cohorts were not statistically different from each other. † No statistical differences among any of the groups.
after RN than after PN with any duration of ischemia (p ⬍0.001). For example, GFR less than 45 ml/minute/ 1.73 m2 occurred in 6.1%, 6.6% and 14% of patients undergoing PN with ischemia of limited, unknown or extended duration, compared with 35% for RN.
At last followup, although further decline in renal function was seen in the PN groups, the percentage of renal functional loss was still lower than with RN (p ⬍0.001). The proportion of patients with GFR less than 45 ml/minute/1.73 m2 at last followup and,
Table 2. Renal functional outcomes PN Limited Ischemia
PN Unknown Ischemia
PN Extended Ischemia
Median mg/dl preop sCr (IQR) Median ml/min/1.73 m2 preop GFR (IQR) Median ml/min/1.73 m2 nadir GFR (IQR)† % Postop acute kidney injury (No.) Median ml/min/1.73 m2 postop GFR (IQR)§ % Decrease from preop to postop GFR (IQR) % Postop GFR less than 45 ml/min/1.73 m2 (No.)
0.9 (0.8–1.1) 82 (69–96) 65 (51–80) 0.5 (4) 81 (64–96) 0 (⫺7.6–15) 6.1 (49)
0.9 (0.8–1.1) 84 (69–97) 63 (47–80) 1.5 (8) 82 (64–96) 0 (⫺7.3–15) 6.6 (36)
0.9 (0.8–1.1) 84 (70–98) 58 (45–73) 0.5 (2) 70 (54–87) 15 (0–29) 14 (67)
0.9 (0.8–1.1) 83 (66–94) 50 (39–60) 1.4 (8) 52 (41–63) 35 (25–44) 35 (201)
% Postop GFR less than 15 ml/min/1.73 m2 (No.) Median ml/min/1.73 m2 latest GFR (IQR) % Decrease from preop to latest GFR (IQR) % Latest GFR less than 45 ml/min/1.73 m2 (No.)
0.0 72 12 11
(0) (56–87) (0–25) (84)
0.4 74 12 15
(2) (56–88) (0–26) (79)
0.2 (1) 68 (51–83) 19 (4.7–34) 19 (84)
1.2 (7) 52 (41–63) 35 (25–44) 35 (201)
% Latest GFR less than 15 ml/min/1.73 m2 (No.)
Not significant (t test)* Not significant (t test)* ⬍0.001 (t test)† 0.14 (Fisher’s exact test) ⬍0.001 (t test)‡ ⬍0.001 (t test)‡ ⬍0.001 (Pearson chi-square with Yates’ continuity correction)§ 0.005 (Fisher’s exact test) ⬍0.001 (t test)‡ ⬍0.001 (t test)‡ ⬍0.001 (Pearson chi-square with Yates’ continuity correction) 0.04 (Fisher’s exact test)
* No paired differences ⬍0.05. † Nadir GFR–lowest postoperative GFR. ‡ RN significantly different from all PN groups (⬍0.001), extended PN significantly different from limited and unknown PN (⬍0.05), limited and unknown PN not significantly different (⬎0.05). § Postop GFR–highest postoperative GFR after nadir GFR and within 90 days of surgery.
PARTIAL NEPHRECTOMY WITH EXTENDED ISCHEMIA
tumor resection to be performed in a nearly bloodless field. Several techniques have been described for tumor resection with limited ischemic duration or without ischemia.18,19 Nevertheless, for more complex situations regional ischemia is required and may exceed the 30-minute limit that has commonly been considered the safe duration for warm ischemia.15,16 Several recent reports, particularly with laparoscopic PN, have indicated that ischemic intervals longer than 30 minutes may be tolerated, especially in patients with normal baseline renal function.20,21 In this report we demonstrate that although outcomes in patients with extended ischemia may be poorer than in those with more limited duration ischemia, they are clearly better than with RN. These data add more evidence in support of elective PN whenever feasible. Although the risk of renal failure was low (less than 1%) in this group of patients with a functioning contralateral kidney, recent data indicate that incremental levels of renal dysfunction have been associated with significantly increased cardiovascular risks.14,22 In a population based study examining more than 1 million adults in the ambulatory setting, a GFR less than 45 ml/minute/1.73 m2 was associated with a significantly increased risk of mortality and morbid cardiovascular events compared with patients with a lesser degree of renal dysfunction, even after accounting for hypertension, diabetes mellitus and a variety of potential confounding factors.22 Go et al demonstrated that patients with a GFR between 30 and 44 ml/minute/1.73 m2 had a nearly 5-fold increased risk of all cause mortality, and those with a GFR less than 30 ml/minute/1.73 m2 had a greater than 10-fold increased risk.22 With respect to the risk of morbid cardiovascular events, age standardized rates were more than 10, more than 20 and more than 30-fold higher for GFR between 30 and 44, 15 and 29, and less than 15 ml/ minute/1.73 m2, respectively. Thus, we examined the likelihood of at least moderate CKD, defined as GFR less than 45 ml/minute/1.73 m2 within 90 days of surgery or at latest followup. While 35% of pa-
therefore, at greater risk for a cardiovascular event, remained lower with PN with limited, unknown or extended ischemia (11%, 15%, 19%) than with RN (35%). In a multivariable analysis accounting for age, comorbidity, preoperative GFR and clinical size RN remained a significant predictor of postoperative GFR less than 45 ml/minute/1.73 m2 (p ⬍0.001). Renal failure (estimated GFR less than 15 ml/minute/1.73 m2) occurred in only 22 of 2,402 patients (less than 1.0%) at last followup, including 0.3%, 0.9%, 1.1% and 1.8% of these groups, respectively. Median followup for the study population was 4.5 years (IQR 2.8 to 6.7). Kaplan-Meier estimates of 5-year overall survival in patients undergoing PN with limited, unknown or extended ischemia, or RN, were 95.7% (93.9%, 97.5%), 93.9% (91.7%, 96.1%), 94.0% (91.6%, 96.4%) and 84.3% (80.6%, 88.0%), respectively. For the 4 cohorts Kaplan-Meier estimates of 5-year cardiac specific survival were 99.8% (99.5%, 100%), 99.1% (98.2%, 99.9%), 100% (99%, 100%) and 96.4% (94.4%, 98.4%). Kaplan-Meier estimates of 5-year cancer specific survival were 98.7% (97.3%, 99.9%), 99.0% (98.0%, 100%), 99.1% (98.3%, 99.9%) and 93.8% (94.4%, 98.4%) in the 4 groups. Overall survival, cardiac specific survival and cancer specific survival were significantly reduced with RN compared with the PN cohorts on univariate analysis (p ⬍0.001), with no statistical difference among the PN cohorts (see figure). However, differences in baseline parameters such as age and comorbidity may have contributed to these particular results.
DISCUSSION Elective PN was first pursued based on the excellent functional results obtained in patients in whom renal failure would have developed had PN not been performed. Several reports have demonstrated improved renal functional outcomes with PN vs RN. Based on these data nephron sparing surgery has become a reference standard for patients with clinical stage I renal cell carcinoma, normal renal function and a functioning contralateral kidney.1 PN is generally performed with regional ischemia to allow
Unknown Extended Limited Radical
0.8 0.7 Surviving
0.7 0.6 0.5 0.4 0.3
0.6 0.5 0.4 0.3
Unknown Extended Limited Radical
Unknown Extended Limited Radical
0.9 0.8 0.7 Surviving
0.6 0.5 0.4 0.3 0.2 0.1 0.0
Kaplan-Meier analyses demonstrate overall (A), cardiac specific (B) and cancer specific (C) survival after surgery for clinical T1 renal tumor.
PARTIAL NEPHRECTOMY WITH EXTENDED ISCHEMIA
tients undergoing RN had at least this level of renal dysfunction, only 14% of those undergoing PN with extended ischemia had a GFR less than 45 ml/ minute/1.73 m2 within 90 days of surgery and 19% had this GFR at latest followup. There are several limitations to the current study. Most importantly it is a retrospective analysis of data collected in an institutional database and there is a reasonably large amount of missing data, for example regarding the duration of ischemia. However, interestingly the cohort with an unknown ischemic interval appears to fall between the limited and extended cohorts in most categories, further substantiating the major finding of this study because some of these patients undoubtedly experienced limited ischemia and others extended ischemia. We did not stratify patients according to the use of warm or cold ischemia to streamline our analysis and because widespread clinical practice has been to use regional hypothermia when the ischemic interval is anticipated to exceed 30 minutes. Finally the RN and PN cohorts include somewhat distinct groups of patients, with those undergoing RN having more advanced age, more comorbidities and more aggressive cancers on average. It is not our primary objective in this study to determine the best
approach in such patients, but solely to evaluate whether postoperative renal function is compromised in those treated with RN vs PN. Importantly between 1983 and 2009 the majority (at least 76%) of patients were treated with a nephron sparing approach at our institution because those with preoperative renal dysfunction and those treated with thermal ablation or active surveillance were not included in this analysis. Other centers have also reported increased use of nephron sparing in recent years, supporting the statement that radical nephrectomy can be avoided in the majority of these patients with increasing surgeon experience and expertise.23
CONCLUSIONS Patients with clinically localized renal cell carcinoma experience excellent cancer specific outcomes when treated surgically with PN or RN. The majority of patients can be treated with PN and the renal functional outcomes in these patients are superior to those obtained with RN. Our results indicate that even for more complicated tumors, for which regional ischemia may be expected to exceed 30 minutes, PN should be considered based on the long-term benefit of renal functional preservation.
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