Longterm Changes in Creatinine Clearance after Laparoscopic Renal Surgery

Longterm Changes in Creatinine Clearance after Laparoscopic Renal Surgery

Longterm Changes in Creatinine Clearance after Laparoscopic Renal Surgery Kelley V Foyil, BS, Caroline D Ames, MD, Genoa G Ferguson, MD, Kyle J Weld, ...

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Longterm Changes in Creatinine Clearance after Laparoscopic Renal Surgery Kelley V Foyil, BS, Caroline D Ames, MD, Genoa G Ferguson, MD, Kyle J Weld, MD, Robert S Figenshau, MD, Ramakrishna Venkatesh, MD, Yan Yan, PhD, Ralph V Clayman, MD, FACS, Jaime Landman, MD Controversy exists about the impact of ischemia on renal function. We evaluated the creatinine clearance of patients having undergone laparoscopic renal extirpative and ablative surgery. STUDY DESIGN: The records of patients undergoing laparoscopic procedures for renal masses from February 2000 to March 2004 were examined. Creatinine clearance (CrCl) for each patient was determined using the Cockcroft-Gault equation and ideal body weight. We compared CrCl changes of patients undergoing laparoscopic partial nephrectomy (without renal ischemia [LPN-none], with warm ischemia [LPN-warm], and with cold ischemia [LPN-cold]) with patients undergoing laparoscopic radical nephrectomy (LRN) and laparoscopic cryoablation. Patients predisposed to medical renal disease were substratified and evaluated. RESULTS: All patients who underwent LRN or LPN-warm sustained a significant drop in CrCl on the first postoperative day, compared with patients who had LPN without ischemia or cryoablation (p ⬍ 0.01). The CrCl decrease correlated directly with warm ischemia time. Six months postoperatively, CrCl changes were no longer significant. Patients with medical renal disease risk factors were more likely to sustain longterm (1 year postoperatively) renal damage if they had renal ischemia, trending toward statistical significance. CONCLUSIONS: Ischemia causes acute renal damage, which is apparently reversible in patients without evidence of medical renal disease. Patients with known medical renal disease have substantial longterm changes in renal function associated with unilateral renal ischemia. Considering the insensitivity of creatinine-based renal function metrics, only eliminating ischemic time will realize the goal of maximal nephron preservation, particularly in patients with preexisting medical renal disease. (J Am Coll Surg 2008;206:511–515. © 2008 by the American College of Surgeons) BACKGROUND:

sult from hilar clamping.3,4 Renal hypothermia has been the standard practice for complex open partial nephrectomy for anticipated ischemic times longer than 30 minutes.5 Isothermic or “warm” ischemia (37°C) adversely affects renal function; the severity of so-called warm ischemia is a function of ischemic time. Wickham and colleagues3 and Ward4 elegantly demonstrated that the temperature range of 5°C to 20°C induces a hypothermic state that substantially decreases renal metabolic activity. Temperatures lower than the protective range are unnecessary and can become damaging to renal tissues. Wickham and colleagues3 concluded through both animal and human studies that an ischemic time of fewer than 10 minutes was necessary to avoid any acute depression of renal function, and an ischemic time fewer than 30 minutes was necessary to avoid any degree of permanent cellular damage. When patients have medical renal disease, the kidney can be less tolerant of ischemia, as these diseased kidneys can be more susceptible to damage from ischemia.6

Nephron-sparing surgery (NSS) has gained acceptance as a means to preserve renal function without compromising oncologic control of renal tumors.1,2 Complex renal tumors often require transient hilar clamping to allow controlled excision of the tumor in a bloodless field, suture repair of the collecting system, and parenchymal reconstruction. Extended renal warm ischemia times are associated with impairment of renal function.3 Adequate renal hypothermia substantially decreases renal metabolic activity and protects the kidney from ischemic inCompeting Interests Declared: None. Received August 2, 2007; Accepted October 31, 2007. From the Department of Biomedical Engineering (Foyil) and Division of Urology (Ames, Ferguson, Weld, Figenshau, Venkatesh, Yan), Washington University School of Medicine, St Louis, MO; University of California, Irvine, Orange, CA (Clayman); and the Department of Urology, Columbia University School of Medicine, New York, NY (Landman). Correspondence address: Jaime Landman, MD, Department of Urology, Columbia University School of Medicine, 161 Fort Washington Ave, Room 1111, New York, NY 10032-3713. email: [email protected]

© 2008 by the American College of Surgeons Published by Elsevier Inc.

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ISSN 1072-7515/08/$34.00 doi:10.1016/j.jamcollsurg.2007.10.014

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IBW equation for women: weight (kg) ⫽ {[height (inches) ⫺ 60] Abbreviations and Acronyms

CrCl ⫽ IBW ⫽ LPN ⫽ LRN ⫽ NSS ⫽ POD ⫽

⫻ 2.3} ⫹ 45.5 IBW equation for men: weight (kg) ⫽ {[height (inches) ⫺ 60]

creatinine clearance ideal body weight laparoscopic partial nephrectomies laparoscopic radical nephrectomies nephron-sparing surgery postoperative day

⫻ 2.3} ⫹ 50

Traditionally, in open operations, hypothermia is obtained by clamping the renal vasculature and packing ice around the kidney. With the expansion of advanced laparoscopic renal procedures, the problem of obtaining renal hypothermia has become increasingly salient. Numerous methods for achieving renal cold ischemia have been used, including arterial perfusion,7,8 retrograde “intrarenal” cooling,9 and external parenchymal hypothermia.10-12 More recently, several authors have suggested that renal function is not impaired during laparoscopic renal operations with warm ischemia even longer than 40 minutes.13,14 As such, we evaluated our patient population that underwent ablative and extirpative renal surgery with and without hilar control.

METHODS This study was performed with the permission of the Washington University Human Studies Committee. We reviewed the records of all patients who underwent laparoscopic renal surgery for small renal masses between February 2000 and March 2004. Patients with solitary kidneys were excluded from study. During the study period, 197 patients underwent treatment for small masses. There were a total of 98 laparoscopic partial nephrectomies (LPN) performed. Thirty-seven (38%) LPN were performed with warm ischemia (LPN-warm), 6 (6%) LPN were performed with cold ischemia (LPN-cold) using intrarenal cooling as described previously,9 and 55 (56%) LPN were performed without ischemia (LPN-none). During this same time period, 50 patients underwent cryoablation of small renal masses, and 49 laparoscopic radical nephrectomies (LRN) were performed. Creatinine clearance (CrCl) was calculated preoperatively, at postoperative day 1 (POD1), 6 months postoperatively, and 12 months postoperatively, using the Cockcroft-Gault equation with ideal body weight (IBW). Cockcroft-Gault equation: CrCl (men) ⫽ (140 ⫺ age) ⫻ IBW (kg) ⁄ 72 ⫻ serum creatinine CrCl (women) ⫽ 0.85 ⫻ (140 ⫺ age) ⫻ IBW (kg) ⁄ 72 ⫻ serum creatinine

In addition, charts were reviewed to identify patients with medical conditions of diabetes mellitus and hypertension, placing their kidneys at risk for medical renal disease. Patients with both insulin-dependent and non⫺insulindependent diabetes were included in this group. Duration and severity of hypertension were not considered. Additionally, patients with postoperative longterm loss of renal function (loss of ⱖ 2 mL/minute CrCl 6 months after operation) were identified. Statistical analysis, using SAS software (SAS Institute), was provided by least squares means procedures with adjustment for multiple comparisons by the Tukey method and Fisher’s exact t-test and Spearman correlation.

RESULTS Table 1 represents the patient populations, including age, number of patients with comorbidities, tumor size, ischemia times, and CrCl at each time point. Mean warm ischemia for the LPN-warm group was 26.9 ⫾ 9.0 minutes (range 13 to 52 minutes) and mean cold ischemia for the LPN-cold group was 38 ⫾ 8.2 minutes (range 32 to 52 minutes; p ⬍ 0.01). The longer ischemic time in the LPNcold group allowed for more complex reconstruction in these patients. Although ischemic time for the LPN-cold group was an average of 11 minutes longer than for the LPN-warm group, there were no significant differences in renal damage between the 2 groups at POD1 (p ⫽ 0.99), 6-month (p ⫽ 1.00), or 12-month (p ⫽ 0.99) time periods. Ischemic time correlated with the change in CrCl on POD1 for patients undergoing LPN-warm (p ⫽ 0.05) but not for patients in the LPN-cold group (p ⫽ 0.82). Mean preoperative CrCl of the LPN-warm group (71.97 ⫾ 26.75) was significantly higher than both the cryoablation group (56.21 ⫾ 27.46) (p ⫽ 0.03) and the radical nephrectomy group (56.11 ⫾ 24.74) (p ⫽ 0.03). No other groups had significant differences in preoperative CrCl. Data are presented as change in CrCl from baseline. On POD1, all groups experienced a substantial decrease in CrCl compared with baseline levels (Fig. 1). The drop in mean CrCl for the LPN-none group (⫺1.61 ⫾ 11.98) was significantly lower than the LPN-warm group (⫺11.58 ⫾ 14.42) (p ⬍ 0.01) and LRN group (⫺13.62 ⫾ 11.56) (p ⬍ 0.01). The difference between the LPN-warm group and cryoablation group (⫺4.19 ⫾ 13.54) trended toward, but did not reach, statistical significance (p ⫽ 0.07). Laparoscopic cryoablation resulted in less of a decline in CrCl

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Table 1. Patient Characteristics Risk factors* n %

Group

n

Age (y) (range)

LPN-none LPN-warm LPN-cold LRN Cryo

55 37 6 50 49

61.4 (21⫺89) 54.9 (30⫺82) 59.2 (44⫺74) 60.7 (39⫺86) 67.8 (28⫺90)

31 24 2 40 36

56 65 33 80 73

Tumor size (cm) (range)

2.4 (0.7⫺9.0) 3.1 (1.4⫺7.0) 2.9 (2.0⫺3.6) 5.9 (1.7⫺15.9) 2.5 (1.3⫺6.0)

Mean ischemic time (min) (range)

CrCl (mL/min): change from baseline POD1 6 months 12 months

CrCl (mL/min) Preop

⫺1.61 ⫺11.58 ⫺14.39 ⫺13.62 ⫺4.19

63.20 71.97 63.34 56.11 56.21

27 (13⫺52) 38 (32⫺52)

⫺2.24 ⫺1.65 ⫺2.61 ⫺13.37 ⫺4.54

3.74 4.12 7.81 ⫺13.24 ⫺1.95

*Patients with risk factors for medical renal disease of diabetes mellitus and hypertension. CrCl, creatinine clearance; Cryo, cryoablation; LPN, laparoscopic partial nephrectomy; LRN, laparoscopic radical nephrectomy; POD1, postoperative day 1; Preop, preoperative.

compared with LRN (p ⬍ 0.01). The LRN group had a greater decrease in CrCl compared with the LPN-none and cryoablation cohorts. At the 6-month time point, there were no significant differences among the LPN or cryoablation groups from preoperative CrCl levels. At 6 months, the CrCl was minimally depressed from baseline for the LPN-none (⫺2.24 ⫾ 15.15) and LPN-warm groups (⫺1.65 ⫾ 20.96), which trended toward significance compared with the LRN group, whose CrCl remained depressed (⫺13.37 ⫾ 20.79) (p ⫽ 0.06 and p ⫽ 0.07, respectively). At the 12-month time point, the LRN cohort had a greater decrease in CrCl (⫺13.24 ⫾ 10.21) compared with

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Figure 1. Mean change in creatinine clearance after renal surgery. LPN, laparoscopic partial nephrectomy.

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LPN-warm (4.12 ⫾ 16.98, p ⬍ 0.01), LPN-cold (7.81 ⫾ 26.59, p ⫽ 0.03), LPN-none (3.74 ⫾ 16.09, p ⬍ 0.01), and cryoablation (⫺1.95 ⫾ 9.71, p ⫽ 0.01) compared with preoperative levels. One year after the operation, all groups (unstratified by risk factors) undergoing NSS had CrCl return to baseline. Fewer patients in the LPN-none group (7%) sustained longterm renal damage as compared with the LPN-warm (13%) and LRN (14%) groups (Fig. 2). A larger portion of patients with risk factors sustained longterm renal damage in LPN-warm (17% versus 7%) and LRN (14% versus 0%) groups compared with patients without risk factors. Patients with risk factors were more likely to experience renal damage compared with patients without risk factors for all surgical methods (p ⬍ 0.0001) except cold ischemia (p ⬍ 0.10).

Figure 2. Relative percent of patients in each group with suspected medical renal disease. Red bar, percent of patients without risk factors; blue bar, percent of patients with risk factors. LPN, laparoscopic partial nephrectomy.

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DISCUSSION Recent studies have evaluated renal function using serum creatinine levels and radionuclide renal scans.13,15 In patients with two normally functioning kidneys undergoing unilateral renal surgery, assessment of overall renal function by application of serum creatinine levels is of limited value, as creatinine levels often remain unchanged because of compensation by the normal contralateral kidney. As such, serum creatinine is too crude a metric to reliably measure a patient’s postoperative renal function. Serum creatinine does not account for muscle/body mass and can be affected by variations in catabolic rate and diet. Our study used creatinine clearance to more accurately reflect changes in renal function. Robert and colleagues showed that using the Cockcroft-Gault equation with IBW to determine CrCl is a more sensitive marker for evaluating renal function than other predictive methods, such as CockcroftGault with actual body weight.16 Several authors have suggested that ischemic times longer than 30 minutes do not result in longterm ischemia. Kane and colleagues retrospectively compared 15 patients undergoing LPN with warm ischemia with 12 patients who underwent LPN without vascular occlusion.13 With an ischemia time of 43 minutes, the authors demonstrated no difference in serum creatinine or renal scans between the 2 cohorts. Although this small series had a mean followup of only 6 months, with a wide range of 26 to 321 days, it certainly brings to light the issue that warm ischemia, even longer than 40 minutes, might be better tolerated by the kidney than can be assumed by acute decreases in renal function. Bhayani and colleagues17evaluated 118 patients who underwent LPN for renal mass and stratified changes in renal function 6 months postoperatively based on the time of warm ischemia (none, fewer than 30 minutes, and longer than 30 minutes). The authors reported no difference among these cohorts. The authors used uncorrected serum creatinine as their end point and inclusion criteria involved patients with normal contralateral kidneys and solitary lesions. Patients had a relatively low incidence of diabetes mellitus (8% to 12%) and only a moderate incidence of hypertension (31% to 34%) compared with our patient population. Although this article begins to illustrate the resilience of the kidney, it lacks substantial representation of patients with comorbidities, a population more likely to undergo NSS. Recently, Desai and colleagues15 evaluated renal function in a group of patients undergoing LPN with warm ischemia and using uncorrected serum creatinine and renal scintigraphy in a small cohort of these patients. Despite application of uncorrected serum creatinine as a metric, and the presence of a normal contralateral kidney,

J Am Coll Surg

the authors remarkably demonstrated that patients 70 years of age and older, or with preexisting renal insufficiency, had a higher postoperative serum creatinine after LPN with ischemic times longer than the 30-minute threshold. Mean followup time for this study was only 4.8 months and did not address the longterm effects of warm ischemia on renal function. Serum creatinine and other calculations short of a 24-hour creatinine clearance fail to identify renal damage in patients who are young or have healthy contralateral kidneys. In older patients or patients with other medical complications, renal damage is identified even with insensitive evaluation parameters, such as in previous studies.15 Creatinine clearance is a more sensitive evaluation parameter and the renal damage is more clearly identified in all patients. As our study was retrospective, the CockcroftGault equation was used in lieu of a true 24-hour creatinine clearance. Although this is a more accurate assessment of renal function than serum creatinine, and an improvement on previous studies, it is still only an estimate of creatinine clearance based on a single serum creatinine value. Clearly, future prospective studies need to be done using a 24-hour creatinine clearance, in addition to comparison with mathematical estimates of creatinine clearance to elucidate the issue. In our study, the degree of acute damage correlated directly with time of warm ischemia. Patients as a whole were able to compensate for the acute damage, and by 6 months, CrCl approached baseline for all groups undergoing NSS, regardless of the length of warm ischemia up to our maximum time of 52 minutes. Of note, this report demonstrates patients with hypertension and diabetes can be at increased risk for longterm renal damage. If possible, these patients should avoid the threat posed by warm ischemia. Patients with a suboptimal contralateral kidney or other medical problems are more likely to be considered for NSS compared with young patients with healthy contralateral kidneys. Patients chosen for NSS are often at inherently greater risk of longterm renal damage, as shown by the similar incidence of longterm renal damage in the LPNwarm group compared with the LRN group. One would expect a greater incidence of renal damage in the LRN group, as the entire kidney is removed, but there is a similar incidence, suggesting that patients undergoing NSS likely were patients at physician-perceived higher risk for renal damage. The amount of decrease in the LRN group was immediate and remained unchanged during the 1-year followup, as would be expected, but the LPN groups all showed improvement during 1-year followup. Future studies with even longer followup are needed to elucidate if renal function eventually improves in the LRN group and if it continues to improve in the LPN.

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Patients with a history of hypertension, diabetes mellitus, or both, have a high likelihood of experiencing postoperative renal damage, regardless of the procedure chosen, with the exception of cold ischemia. Although it would appear that use of cold ischemia could reduce risk of renal damage in patients with a history of hypertension and diabetes mellitus, the small number of patients undergoing operations with cold ischemia renders our data only suggestive of the protective nature of cold ischemia. As cold ischemia methods are developed and implemented, the extent of this protective nature will be elucidated. In conclusion, although patients without medical renal disease have acute renal damage after ischemia, this resolves within 6 months and shows continued improvement even to 1 year postoperatively. Patients with hypertension, diabetes, or both, had a higher incidence of longterm renal damage, but even here recovery continued and was ongoing, even at 1-year followup. The importance of longterm followup on patients undergoing NSS appears to be of primary importance for determining the amount of warm ischemia that must occur before “permanent” renal damage ensues. Our data support the work of others in finding a warm ischemia time of up to 45 minutes to be “safe” in this regard.

3. 4. 5. 6. 7. 8.

9. 10. 11. 12.

Author Contributions Study conception and design: Ames, Clayman, Landman Acquisition of data: Foyil, Ames, Ferguson, Weld, Figenshau, Venkatesh, Landman Analysis and interpretation of data: Foyil, Ames, Ferguson, Yan Drafting of manuscript: Foyil, Ferguson Critical revision: Clayman, Landman

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