Kidney function after nephrectomy for renal cell carcinoma

ADULT UROLOGY

KIDNEY FUNCTION AFTER NEPHRECTOMY FOR RENAL CELL CARCINOMA YOSHINORI SHIRASAKI, TOMOYASU TSUSHIMA, TAKASHI SAIKA, YASUTOMO NASU, HIROMI KUMON

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ABSTRACT Objectives. To evaluate the function of the remaining kidney after nephrectomy for renal cell cancer by technetium-99m-mercaptoacetyltriglycine (99mTc-MAG3) renal scintigraphy. Methods. We evaluated 30 consecutive patients who were undergoing unilateral radical nephrectomy by 99m Tc-MAG3 scintigraphy. All patients underwent three consecutive 99mTc-MAG3 scintigraphy studies. The first study was performed before nephrectomy, the second 1 month after surgery, and the third 1 year after surgery. At these times, the serum creatinine levels were also evaluated. Results. The mean preoperative MAG3 clearance of the remaining kidney of the 30 patients was 155.4 mL/min/1.73 m2. The mean MAG3 clearance of the remaining kidney had increased to 209.2 mL/min/1.73 m2 by 1 month after nephrectomy, and the average percentage increase was 39.5%. After 1 year, it had increased to 211.3 mL/min/1.73 m2, with a 40.5% average percentage increase. The preoperative MAG3 clearance of the remaining kidney was inversely correlated with the percentage of increase in MAG3 clearance of the remaining kidney. Abnormal serum creatinine levels (greater than 1.3 mg/dL) were more common after nephrectomy, occurring in 6 patients at 1 month and in 5 patients at 1 year postoperatively. In all 6 patients with elevated creatinine levels, the preoperative MAG3 clearance of the remaining kidney was less than 150 mL/min/1.73 m2. Conclusions. Adaptive hyperfunction occurs soon after nephrectomy that is not associated with age or sex and continues for at least 1 year. A greater compensatory response is produced in patients with more severe renal deterioration. Using 99mTc-MAG3 scintigraphy, we may be able to predict postoperative renal function. UROLOGY 64: 43–48, 2004. © 2004 Elsevier Inc.

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t has been clearly shown that the removal of a kidney from a patient with 2 normally functioning kidneys results in functional adaptation and compensatory hypertrophy of the remaining kidney. The onset of functional adaptation of the remaining kidney after unilateral nephrectomy is rapid. The effective renal plasma flow (ERPF) increases by about 30% as early as 1 week after surgery and remains at greater than the prenephrectomy level even after 10 years.1 The creatinine clearance increases to 72% to 78% of the preoperative creatinine clearance within several weeks postoperatively, probably within the first week, and stabilizes or increases very slightly for more

From the Department of Urology, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan Reprint requests: Yoshinori Shirasaki, M.D., Department of Urology, Okayama University Graduate School of Medicine and Dentistry, 2-5-1 Shikata, Okayama 700-8558, Japan Submitted: November 25, 2003, accepted (with revisions): February 23, 2004 © 2004 ELSEVIER INC. ALL RIGHTS RESERVED

than 10 years after nephrectomy.2,3 The serum creatinine level usually increases up to 20% above baseline, remaining within the normal range.4 Most of these findings were obtained for donor nephrectomy, and few such studies have been performed in patients undergoing surgery for renal malignancy (ie, renal cell cancer). The most effective treatment for renal cell cancer is radical nephrectomy. If a risk of renal failure after nephrectomy is present, it is important to estimate the split renal function correctly before surgery. The renal uptake of technetium-99m-mercaptoacetyltriglycine (99mTc-MAG3) has been shown to correlate well with the ERPF. The aim of this investigation was to evaluate the function, particularly the compensatory response, of the remaining kidney after nephrectomy by 99mTc-MAG3 renal scintigraphy. Furthermore, we intended to predict the renal function of the remaining kidney after nephrectomy. 0090-4295/04/$30.00 doi:10.1016/j.urology.2004.02.039 43

MATERIAL AND METHODS PATIENT POPULATION A total of 33 patients suspected of having renal cell carcinoma were enrolled prospectively in this study. All patients gave informed consent to participate in this study. Three of these patients were excluded: two had widespread disease with lung metastases within 1 year postoperatively, so 99mTcMAG3 renal scintigraphy at 1 year after nephrectomy was not performed, and 1 patient was lost to follow-up. The study population consisted of the remaining 30 patients (19 men and 11 women; average age 63 years, median 64, range 43 to 88). All patients underwent radical nephrectomy, performed by open surgical techniques, of a functioning kidney and had renal cell carcinoma. All patients underwent three consecutive 99m Tc-MAG3 renal scintigraphy studies. The first study was performed before nephrectomy, the second 1 month after surgery, and the third 1 year after surgery. At these times, the patients were also evaluated clinically, and the serum creatinine levels were determined. Pathologic staging was determined by the original pathologic diagnosis, rendered by our pathology department on the basis of the General Rule for Clinical and Pathological Studies on Renal Cell Carcinoma in Japan. Fifteen of the tumors were Stage I, 7 were Stage II, and 8 were Stage III. Fourteen patients (46.7%) had hypertension (defined as systolic pressure greater than 140 mm Hg or diastolic pressure greater than 90 mm Hg or a history of treatment with antihypertensive medication), one (3.3%) had diabetes, and one (3.3%) had hyperuricemia. 99m

TC-MAG3 RENAL SCINTIGRAPHY

Radionuclide scans were performed with 99mTc-MAG3. To ensure adequate hydration, the patients were given 200 mL water to drink 30 minutes before testing. The radiotracer was given intravenously. The studies were performed using a rotating, single-head gamma-camera equipped with an all-purpose, low-energy collimator (GCA 901A/HG, Toshiba, Japan). The data were stored in a computer in a 128 ⫻ 128 matrix image. Data storage was completed for 30 minutes. Regions of interests were assigned for each kidney and a perirenal background region. The renal clearance of MAG3 was calculated based on the absolute renal uptake in each kidney according to an equation reported by Itoh et al.5 This absolute renal clearance was normalized to a body surface area of 1.73 m2, and we used this value as the MAG3 clearance in the study.

STATISTICAL ANALYSIS The Mann-Whitney U test was used to examine the differences between groups in the degree of compensatory hyperfunction, based on the percentage increase in MAG3 clearance of the remaining kidney preoperatively to postoperatively, as well as differences between groups in the preoperative MAG3 clearance of the remaining kidney. The paired t test was used to compare the preoperative and postoperative serum creatinine levels. The values are expressed as the mean ⫾ standard error. Linear regression analysis was used to evaluate the correlation between preoperative MAG3 clearance of the remaining kidney and the degree of compensatory hyperfunction. P values less than 0.05 were considered statistically significant.

RESULTS The serum creatinine data and results of MAG3 renal scintigraphy are summarized in Table I. The mean differential preoperative MAG3 clearance of the remaining kidney of the 30 patients was 155.4 mL/min/1.73 m2. It had increased to 209.2 mL/ 44

min/1.73 m2 by 1 month after nephrectomy. The average percentage increase in MAG3 clearance of the remaining kidney was 39.5%. After 1 year, the mean MAG3 clearance of the remaining kidney had increased to 211.3 mL/min/1.73 m2, and the average percentage increase was 40.5%. To evaluate the effects of particular variables on the degree of compensatory hyperfunction after nephrectomy, we subdivided the patients by sex and age at nephrectomy (younger than 60 years and older than 60 years) and compared the degree of compensatory hyperfunction by the percentage increase in MAG3 clearance of the remaining kidney preoperatively to postoperatively (Table I). Male patients and younger patients had more compensatory hyperfunction at 1 month (43.6% versus 32.5% and 49.0% versus 33.2%, respectively), but these differences were not statistically significant. At 1 year after nephrectomy, male patients had less compensatory hypertrophy, and the older patients were similar to the younger ones in the degree of compensatory hypertrophy. Additionally, we examined whether hypertension as an underlying disease influenced renal function (Table I). No statistically significant difference was observed in preoperative MAG3 clearance of the remaining kidney between patients with and without hypertension. The patients with hypertension had less compensatory hyperfunction than those without hypertension at 1 month postoperatively (28.4% versus 49.3%), but this difference was not statistically significant. The degree of compensatory hypertrophy in the former group was almost the same as in the latter group at 1 year. To examine whether compensatory hypertrophy occurs preoperatively in patients with renal cell cancer, we compared the preoperative MAG3 clearance of the remaining kidney with tumor size in the excised kidney (more than 7 cm versus less than 7 cm), because it is thought that the preoperative MAG3 clearance of the remaining kidney in patients with a larger tumor will be greater than that in patients with a smaller tumor if a compensatory reaction occurs preoperatively in the other kidney. The mean preoperative MAG3 clearance of the remaining kidney was 158.7 mL/min/1.73 m2 in 20 patients with tumor less than 7 cm and was 148.9 mL/min/1.73 m2 in 10 patients with tumor more than 7 cm. No statistically significant difference was found in the preoperative MAG3 clearance of the remaining kidney between patients with larger and smaller tumors. Moreover, we performed linear regression analysis to evaluate the correlation between the preoperative MAG3 clearance of the remaining kidney and the degree of compensatory hyperfunction. Figure 1 shows scatter plots demonstrating the relationship between the preoperative MAG3 clearUROLOGY 64 (1), 2004

TABLE I. Serum creatinine and MAG3 renal scintigraphy data before and after nephrectomy Variable Overall Serum creatinine (mg/dL) MAG3 clearance (mL/min/1.73 m2) Percentage increase (%) Sex Female MAG3 clearance (mL/min/1.73 m2) Percentage increase (%) Male MAG3 clearance (mL/min/1.73 m2) Percentage increase (%) Age (yr) ⱕ60 MAG3 clearance (mL/min/1.73 m2) Percentage increase (%) ⬎60 MAG3 clearance (mL/min/1.73 m2) Percentage increase (%) Hypertension Yes MAG3 clearance (mL/min/1.73 m2) Percentage increase (%) No MAG3 clearance (mL/min/1.73 m2) Percentage increase (%)

Patients (n)

Postoperative Baseline

1 mo

1 yr

0.82 ⫾ 0.05* 155.4 ⫾ 7.6 —

1.16 ⫾ 0.07* 209.2 ⫾ 10.3 39.5 ⫾ 7.5

1.09 ⫾ 0.06* 211.3 ⫾ 9.9 40.5 ⫾ 6.6

11

166.0 ⫾ 9.3 —

221.2 ⫾ 18.7 32.5 ⫾ 8.1

243.9 ⫾ 17.5 48.6 ⫾ 10.7

19

149.3 ⫾ 10.6 —

202.2 ⫾ 12.3 43.6 ⫾ 10.9

192.4 ⫾ 9.8 35.9 ⫾ 8.3

12

168.1 ⫾ 10.5 —

245.4 ⫾ 14.3 49.0 ⫾ 9.5

232.6 ⫾ 17.8 40.7 ⫾ 10.9

18

147.0 ⫾ 10.2 —

185.0 ⫾ 11.3 33.2 ⫾ 10.8

197.1 ⫾ 10.6 40.4 ⫾ 8.4

14

154.4 ⫾ 12.1 —

195.3 ⫾ 16.2 28.4 ⫾ 6.8

216.8 ⫾ 17.6 42.4 ⫾ 8.2

16

156.3 ⫾ 9.8 —

221.3 ⫾ 12.8 49.3 ⫾ 12.5

206.5 ⫾ 10.8 38.9 ⫾ 10.2

30

KEY: MAG3 ⫽ mercaptoacetyltriglycine. Values expressed as mean ⫾ standard error. No statistically significant difference observed in sex, age, or underlying disease for percentage of increase. * Statistically significant difference (P ⬍0.0001) observed between serum creatinine levels preoperatively and 1 year postoperatively and preoperatively and 1 month postoperatively.

FIGURE 1. Relationship between preoperative MAG3 clearance of remaining kidney and percentage increase in MAG3 clearance of remaining kidney at (a) 1 month and (b) 1 year postoperatively.

ance of the remaining kidney and the percentage increase in MAG3 clearance of the remaining kidney preoperatively to postoperatively. The preoperative MAG3 clearance of the remaining kidney correlated inversely with the percentage increase in MAG3 clearance of the remaining kidney at both UROLOGY 64 (1), 2004

1 month (r ⫽ ⫺0.475, P ⫽ 0.0080) and 1 year (r ⫽ ⫺0.506, P ⫽ 0.0043) after nephrectomy. The serum creatinine levels before surgery were within normal limits in all patients, except for 2 (6.7%), who had creatinine levels of 1.78 and 1.37 mg/dL. The mean preoperative serum creatinine 45

level was 0.82 mg/dL. It had increased to 1.16 mg/dL at 1 month postoperatively (P ⬍0.0001) and 1.09 mg/dL at 1 year postoperatively (P ⬍0.0001). Moreover, statistically significant improvements in the creatinine values were found from 1 month to 1 year postoperatively (1.16 mg/dL versus 1.09 mg/dL; P ⫽ 0.0087). Abnormal serum creatinine levels (greater than 1.3 mg/dL) were more common after nephrectomy, occurring in 6 patients (20%) at 1 month postoperatively and in 5 patients (16.7%) at 1 year postoperatively. In the 6 patients with elevated creatinine levels at 1 month postoperatively, the preoperative MAG3 clearance of the remaining kidney was less than 150 mL/min/1.73 m2. COMMENT The loss of one kidney from either disease or surgical removal results in compensatory changes in the remaining kidney.6 Little is known concerning the factors responsible for the compensatory increases in renal function after unilateral nephrectomy. Increased renal blood flow and glomerular pressure may stimulate growth mechanically. Some studies have suggested that hormonal and neural factors regulate this growth response. Hyperplasia and hypertrophy are characteristic of the compensatory growth response. The functional hypertrophy that follows loss or removal of renal tissue is generally considered beneficial in that it minimizes the decrease in the total glomerular filtration rate that would otherwise occur. Although several studies have examined the effect of renal donation on the contralateral kidney, few studies have investigated the effects of unilateral nephrectomy for renal cell cancer on the remaining kidney. The renal clearance methods associated with renography are considered one of the most accurate methods for individual renal function measurements.7 Although the glomerular filtration rate is familiar to most clinicians as an index of renal function, other parameters can be used to monitor renal function. The ERPF has been estimated by radioisotopic tracers in place of urinary clearance of para-aminohippuric acid. Orthoiodohippuric acid (OIH), which is excreted from the renal tubules, has been the tracer most widely used for this purpose. Recently, the use of another tubule-extracted tracer, MAG3, has been proposed. MAG3 has the advantage that it can be labeled with 99mTc and is more suitable for renal imaging.8 The plasma clearance of MAG3 correlates well with that of iodine-131 (131I)-OIH.5 Therefore, clearance of MAG3 is proportional to the ERPF (OIH clearance) and can be used as an excellent index of renal function. External counting methods using a gamma camera are very simple and enable simul46

taneous evaluation of renal function. The properties of 99mTc-MAG3 may be preferable for the gamma camera method of evaluating renal function because of high protein binding, which allows less background activity owing to the smaller distribution volume than 131I-OIH and 99mTc-diethylenetriamine pentaacetic acid.9 Therefore, a renal study with 99mTc-MAG3 is considered the first choice for use in routine practice. However, no studies have discussed the quantification of renal function with 99mTc-MAG3 for renal cell cancer. In this study, after nephrectomy for renal cell cancer, patients exhibited a compensatory response in the remaining kidney. The function of the remaining kidney increased by 39.5% ⫾ 7.5% at 1 month and by 40.5% ⫾ 6.6% at 1 year after surgery compared with the preoperative baseline. Pabico et al.10 found a 55% increase in ERPF calculated with p-aminohippurate clearance within 10 to 14 days after donor nephrectomy. Anderson et al.1 measured renal function using 131I-labeled o-iodohippurate scans and found an increase in ERPF of 32.5% by 1 week and 30.1% within 1 year greater than baseline preoperative values after renal donation. Ben-Haim et al.11 reported that the relative function of the remaining kidney increased from 56.8% to 79.1% of global renal function before surgery as determined by quantitative 99m Tc-dimercaptosuccinic acid (DMSA) singlephoton emission computed tomography in patients undergoing radical nephrectomy for renal malignancy. Our results agree for the most part with their observations. Anderson et al.1 found that the degree of compensatory hypertrophy was significantly greater in male patients (46.9% after 1 week) than in female patients (26.7%) and was most pronounced in patients younger than 30 years old. However, we did not find statistically significant differences in this variable by sex and age, although trends toward them were observed. This may have been because our patients were older, and compensatory hypertrophy may occur regardless of sex. A tendency for patients with hypertension to have less compensatory hyperfunction than those without hypertension was found at 1 month after surgery, when we examined hypertension as a factor possibly affecting renal function. It may be difficult for patients with hypertension to produce compensatory reaction greatly immediately after nephrectomy. However, their remaining kidney appears to lead to the same degree of compensatory hypertrophy as in patients without hypertension within an adequate postoperative period. Notably, the preoperative MAG3 clearance of the remaining kidney was inversely correlated with the percentage increase in MAG3 clearance of the remaining kidney, indicating that greater compensatory response is produced in patients with more UROLOGY 64 (1), 2004

severe preoperative renal deterioration. Thus, no remarkable change in clinical condition may occur after nephrectomy for patients with moderate deterioration in renal function. Whether compensatory hypertrophy occurs preoperatively in patients with renal cell cancer is an interesting question. Prassopoulos et al.12 stated that the compensatory reaction of the remaining kidney might occur preoperatively in patients with renal cell cancer, because the unaffected kidney had been 36% larger than the corresponding normal kidney in binephric individuals 1 month before nephrectomy. To answer this question, we compared preoperative MAG3 clearance of the remaining kidney with tumor size in the excised kidney (more than 7 cm versus less than 7 cm). No statistically significant difference was found in preoperative MAG3 clearance of the remaining kidney between patients with larger and those with smaller tumors. Thus, the likelihood is low that the compensatory reaction of the remaining kidney occurs preoperatively in patients with renal cell cancer. Najarian et al.4 monitored 57 patients for 20 years or more (mean 23.7) after donation. The serum creatinine levels increased in these patients by 10% (from 1.0 to 1.1 mg/dL), although this increase was not statistically significant. Ben-Haim et al.11 stated that the serum creatinine levels significantly increased in patients undergoing nephrectomy for renal malignancy by 55% (from 1.04 to 1.55 mg/dL). In our study, this increase reached to 32.9% greater than baseline (from 0.82 to 1.09 mg/ dL), 1 year postoperatively, similar to the finding by Ben-Haim et al.11 This result seemed to be because our patients were older. The MAG3 clearance of the remaining kidney increased at each point after surgery, and the serum creatinine increased initially and then later decreased. The serum creatinine increased initially because the total MAG3 clearance (reflecting ERPF) decreased immediately after nephrectomy. A persistently increased ERPF of the remaining kidney, which was accompanied by hyperfiltration and anatomic hypertrophy, resulted in a decreased serum creatinine later. It is obviously important to estimate correctly the contralateral renal function in cases of renal cell cancer, necessitating consideration of different surgical treatment (eg, partial nephrectomy) when contralateral renal function is markedly reduced. This study also assessed the possibility of predicting the postoperative renal function on the basis of preoperative MAG3 clearance of the contralateral kidney. In all 6 patients with an elevated creatinine level 1 month postoperatively that reached the abnormal range (greater than 1.3 mg/dL), preoperative MAG3 clearance of the remaining kidney was UROLOGY 64 (1), 2004

less than 150 mL/min/1.73 m2. The likelihood of their resulting in renal deterioration after nephrectomy may be great, even if the creatinine values are normal preoperatively, when patients have less than 150 mL/min/1.73 m2 MAG3 clearance in the nonoperated kidney. CONCLUSIONS Adaptive hyperfunction after nephrectomy for renal cell cancer occurs soon after surgery unconcerning with age, sex, or underlying diseases and continues for at least 1 year. A greater compensatory response is produced in patients with more severe preoperative renal deterioration. By using MAG3 renal scintigraphy, we may be able to predict renal function of the remaining kidney after nephrectomy. However, additional investigation is needed to identify preoperatively those patients who will exhibit deterioration of renal function after nephrectomy. REFERENCES 1. Anderson RG, Bueschen AJ, Lloyd LK, et al: Short-term and long-term changes in renal function after donor nephrectomy. J Urol 145: 11–13, 1991. 2. Vincenti F, Amend WJC Jr, Kaysen G, et al: Long term renal function in kidney donors: sustained compensated hyperfiltration with no adverse effects. Transplantation 36: 626 – 629, 1983. 3. Talseth T, Fauchald P, Skrede S, et al: Long-term blood pressure and renal function in kidney donors. Kidney Int 29: 1072–1076, 1986. 4. Najarian JS, Chavers BM, Mchugh LE, et al: 20 years or more of follow-up of living kidney donors. Lancet 340: 807– 810, 1992. 5. Itoh K, Tsukamoto E, Kakizaki H, et al: Comparative study of renal scintigraphy with 99Tcm-mercaptoacetyltriglycine and 123I-orthoiodohippurate. Nucl Med Commun 14: 644 –652, 1993. 6. Wesson LG: Compensatory growth and other growth responses of the kidney. Nephron 51: 149 –184, 1989. 7. Prigent A, Cosgriff P, Gates GF, et al: Consensus report on quality control of quantitative measurements of renal function obtained from the renogram: International Consensus Committee from the Scientific Committee of Radionuclides in Nephrourology. Semin Nucl Med 29: 146 –158, 1999. 8. Blaufox MD, Aurell M, Bubeck B, et al: Report of the radionuclides in nephrourology committee on renal clearance. J Nucl Med 37: 1883–1890, 1996. 9. Itoh K, Nonomura K, Yamashita T, et al: Quantification of renal function with a count-based gamma camera method using technetium-99m-MAG3 in children. J Nucl Med 37: 71–75, 1996. 10. Pabico RC, McKenna BA, and Freeman RB: Renal function before and after unilateral nephrectomy in renal donors. Kidney Int 8: 166 –175, 1975. 11. Ben-Haim S, Sopov V, Stein A, et al: Kidney function after radical nephrectomy: assessment by quantitative SPECT of 99mTc-DMSA uptake by the kidneys. J Nucl Med 41: 1025– 1029, 2000. 12. Prassopoulos P, Cavouras D, and Gourtsoyiannis N: Pre- and post-nephrectomy kidney enlargement in patients with contralateral renal cancer. Eur Urol 24: 58 –61, 1993. 47