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The correlation between preoperative renal scintigraphy and postoperative renal function in upper urinary tract urothelial carcinoma patients following radical nephroureterectomy
Urological Science xxx (2016) 1e5
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Urological Science journal homepage: www.urol-sci.com
Original article
The correlation between preoperative renal scintigraphy and postoperative renal function in upper urinary tract urothelial carcinoma patients following radical nephroureterectomy Chan-Jung Liu, Wen-Horng Yang, Chien-Hui Ou* Department of Urology, National Cheng-Kung University Hospital, Medical College, National Cheng-Kung University, Tainan, Taiwan
a r t i c l e i n f o
a b s t r a c t
Article history: Received 31 December 2015 Received in revised form 1 November 2016 Accepted 4 November 2016 Available online xxx
Objective: To predict the renal function after nephroureterectomy (NUR) for upper urinary tract urothelial cancer (UTUC) based on preoperative technetium-99m mercaptoacetyltriglycine (99mTc-MAG3) renal scintigraphy. Subjects and methods: We retrospectively reviewed 238 patients who originally underwent nephroureterectomy for UTUC between 2007 and 2010. Of these patients, 129 underwent MAG3 renal scintigraphy before unilateral NUR. Serum creatinine was measured in all of the patients before surgery, and renal function was monitored for one year after surgery. Preoperative and postoperative eGFRs were compared and analyzed based on the preoperative MAG3 renal scintigraphy. Results: A total of 129 patients, including 62 men (48%) and 67 women (52%) with an average age at surgery of 69.0 years (range from 48 to 87) were included in this study. The mean preoperative creatinine level was 1.42 mg/dL, and the baseline eGFR was 54.76 ml/min/1.73 m2. One year after NUR, the mean creatinine level was 1.89 mg/dL, and the eGFR was 44.44 ml/min/1.73 m2, a mean decrease of 18.73%. The preoperative effective renal plasma flow (ERPF) of the operated kidney was 91.65 ml/min/1.73 m2, and that of the remaining kidney 158.30 ml/ min/1.73 m2. The average preoperative ERPF of the resected kidney accounted for 34% of total preoperative ERPF, which was statistically significant in its relation to the decrease in eGFR. The decrease in eGFR ratio was also significantly correlated with the calculated decrease in ERPF ratio (R2 ¼ 0.279, p < 0.001). The predictive equation of renal function one year after NUR was established as following: eGFR decreased ratio ¼ e0.80 predictive ERPF decreased ratio +0.72. Conclusion: We developed an equation to predict postnephroureterectomy 1 year eGFR before surgery based on preoperative MAG3 renal scintigraphy results and preoperative eGFR. The equation could be more accurate in the situation if the diseased kidney is not hydronephrotic. Copyright © 2016, Taiwan Urological Association. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Keywords: Estimated glomerular filtration rate Nephroureterectomy and bladder cuff resection Renal function predictive equation Tc-mercaptoacetyltriglycine (MAG3) renal scintigraphy Upper urinary tract urothelial carcinoma
1. Introduction Upper urinary tract urothelial cancer (UTUC) accounts for < 5% of all urothelial cancers (UC).1 The incidence of UC in the area endemic for “Blackfoot disease” in southern Taiwan has been reported to be significantly higher than anywhere else in the world.2,3 In Taiwan, UC of the renal pelvis accounts for 10.7% of all urothelial cancer, and for ~40% of all renal carcinomas.3 Ipsilateral radical nephroureterectomy (NUR) and bladder cuff resection (BCR) is currently the standard treatment for UTUC. Possible renal function * Corresponding author. Department of Urology, National Cheng-Kung University Hospital, Number 138, Sheng Li Road, Tainan 700, Taiwan. E-mail address: [email protected] (C.-H. Ou).
deterioration after surgery remains an important patient concern, however, studies concerning changes in renal function after radical nephroureterectomy and bladder cuff resection are limited. Deterioration of renal function may influence the use of perioperative chemotherapy. Recently, two studies have demonstrated a decline in renal function following radical NUR,4,5 with a reported decrease in estimated glomerular filtration rate (eGFR) of 21% and 32%, respectively. Preoperative hypertension, older age, and preoperative eGFR < 60 mL/min/1.73 m2 have been reported to be predictive factors for impaired renal function after radical NUR. However, preoperative predictive tools are still under investigation. Dimercaptosuccinic acid renal scintigraphy has been used as a potentially predictive exam used to identify patients with preoperative absolute uptake of < 11% in the remaining kidney who are at risk of
http://dx.doi.org/10.1016/j.urols.2016.11.001 1879-5226/Copyright © 2016, Taiwan Urological Association. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/).
Please cite this article in press as: Liu C-J, et al., The correlation between preoperative renal scintigraphy and postoperative renal function in upper urinary tract urothelial carcinoma patients following radical nephroureterectomy, Urological Science (2016), http://dx.doi.org/10.1016/ j.urols.2016.11.001
2
C.-J. Liu et al. / Urological Science xxx (2016) 1e5
postoperative chronic renal failure or insufficiency.6 Technetium (Tc)-99m mercaptoacetyltriglycine (MAG3) renal scintigraphy has also been found to be useful in predicting renal insufficiency after nephrectomy.7 However, both of these previously published series were both limited in their relatively small sample size. Thus, we performed a retrospective review of a large single institutional database to survey the renal function outcomes in patients with UTUCs following unilateral radical NUR. MAG3 renal scintigraphy was used in all of these patients to evaluate the renal function before radical NUR. The aims of this study were to report the change of renal function following radical NUR for UTUC and to develop an equation for predicting the renal function (eGFR) 1 year after NUR based on preoperative 99mTc-MAG3 renal scintigraphy. 2. Materials and methods We retrospectively reviewed the medical records of 238 patients who underwent unilateral NUR and BCR for UTUC between 2007 and 2010 in the National Cheng Kung University Hospital, a tertiary medical center in Southern Taiwan. The patients with end-stagerenal disease, and those who underwent a second operation or received bilateral nephroureterectomy were excluded. In total, 129 patients underwent MAG3 renal scintigraphy before unilateral NUR and BCR. The serum creatinine levels were measured in all patients before surgery, and renal functions were monitored for 1 year after surgery. We used revised equations for estimated GFR from serum creatinine.8 For men, the equation is: eGFR (mL/min/ 1.73 m2) ¼ 194 (Serum creatinine) (age) 0.287,
1.094
(1)
and for women Eq. (1) is multiplied by 0.739. All these patients had received preoperative image evaluation, including computed tomography, magnetic resonance imaging, or renal sonography. According to the latest image, we divided all these patients into hydronephrosis group and nonhydronephrosis group. The diagnosis of hydronephrosis was determined by the radiologists or the urologist. It was defined as urinary obstruction and dilatation of the collecting system in ipsilateral upper urinary tract with urothelial cancer. 2.1. MAG3 renal scintigraphy The renal radionuclide scans were carried out using MAG3.One hundred and eleven milliliters of MBq (3 mCi) MAG3 (INER MERTIARISW kit, INER, Taoyuan, Taiwan) was injected into the vein of the forearm and serial scintiphotos were taken using a gamma camera. Blood samples were taken at 44 minutes postinjection from the contralateral forearm. Effective renal plasma flow (ERPF), normalized to body surface area of 1.73 m2, was determined by the procedure developed by Russell et al.9,10 Split renal function was determined by the 1- to 2-minute postinjection images. 2.2. Statistical analysis We used the paired t test to compare pre- and postoperative eGFR and serum creatinine. The predicted decreased in ERPF ratio was compared with a decrease in eGFR using a paired t test. Values are expressed as the mean and 95% confidence interval (CI). Pearson's correlation analysis was performed to evaluate the correlations between the decreases in preoperative ERPF and eGFR ratios for all patients, hydronephrosis group, and nonhydronephrosis group. All statistical analyses were performed using SPSS version 20 (SPSS Inc., Chicago, IL, USA) for Microsoft Windows. Statistical significance was defined as p < 0.05.
3. Results A total of 129 patients, including 62 men (48%) and 67 women (52%) with an average age of 69.0 years at surgery (range, 48e87 years) in this study. The preoperative characteristics of the 129 patients, all of whom had at least 1 year of postoperative follow-up are listed in Table 1. The mean preoperative creatinine level was 1.42 mg/dL (95% CI 1.31e1.53), and the baseline eGFR was 54.76 mL/ min/1.73 m2 (95% CI 50.68e58.85). Baseline renal function was comparable in hydronephrosis and nonhydronephrosis groups with respect to serum creatinine (1.49 ± 0.70 mg/dL vs. 1.3 ± 0.54 mg/dL, p ¼ 0.11), eGFR (54.02 ± 24.31 mL/min/1.73 m2 vs. 56.10 ± 21.51 mL/min/1.73 m2, p ¼ 0.63), and total ERPF (235.24 ± 150.32 mL/min/1.73 m2 vs. 276.51 ± 157.67 mL/min/ 1.73 m2, p ¼ 0.15). The average preoperative ERPF of the resected kidney in hydronephrosis group was 81.37 mL/ min/1.73 m2 (95% CI 63.37e99.38), which was lower than the nonhydronephrosis group (110.20 mL/ min/1.73 m2, 95% CI 88.35e132.06; p ¼ 0.05). The renal function was comparable in hydronephrosis and nonhydronephrosis groups 1 year after NUR with respect to serum creatinine (1.96 ± 1.320 mg/dL vs. 1.77 ± 1.34 mg/dL, p ¼ 0.48), and eGFR (44.28 ± 21.15 mL/min/1.73 m2 vs. 44.74 ± 19.66 mL/min/ 1.73 m2, p ¼ 0.91). One year after NUR, the mean creatinine level was 1.92 mg/dL (95% CI 1.68e2.16, p < 0.001) and eGFR was 44.44 mL/min/1.73 m2 (95% CI 40.72e48.17, p < 0.001), which represented a decrease of 18.73% with comparison to preoperative data. The preoperative ERPF of the operated kidney was 91.65 mL/ min/1.73 m2, and that of the remaining kidney 158.30 mL/ min/ 1.73 m2 (Table 2). The average preoperative ERPF of the resected kidney accounted for 34% of the total preoperative ERPF. The decrease in eGFR ratio was defined as the change in eGFR (preoperative eGFR subtracted by the postoperative eGFR) divided by preoperative eGFR. The predicted decrease in ERPF ratio was defined as the ERPF of the operated kidney divided by total ERPF. The decrease in eGFR ratio was significantly correlated with the calculated decrease in ERPF ratio (R ¼ 0.279, p < 0.001; Fig. 1). Based on the patients' preoperative imaging results, the patients were divided into two groups: with hydronephrosis (n ¼ 46) or without hydronephrosis (n ¼ 83). In linear regression analysis, the nonhydronephrosis group had a higher correlation between the decreases in ERPF ratio and eGFR ratio (R2 ¼ 0.362, Fig. 2) than the hydronephrosis group (R2 ¼ 0.248, Fig. 3). Based on the Pearson's
Table 1 Baseline characteristics of 129 patients. Patient characteristics (n ¼ 129) Gender Male Female Age at surgery, y Mean (range) Tumor location Left Right Age 70 y Pathological stage pT1 pT2 pT3 pT4 Other pNþ Hydronephrosis Hydronephrosis Nonhydronephrosis
62 (48) 67 (52) 69 (46e87) 60 (47) 69 (53) 66 (51) 50 (39) 22 (17) 46 (36) 9 (7) 2 (1) 10 (8) 46 (36) 83 (64)
Data are presented as n (%).
Please cite this article in press as: Liu C-J, et al., The correlation between preoperative renal scintigraphy and postoperative renal function in upper urinary tract urothelial carcinoma patients following radical nephroureterectomy, Urological Science (2016), http://dx.doi.org/10.1016/ j.urols.2016.11.001
C.-J. Liu et al. / Urological Science xxx (2016) 1e5
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Table 2 Preoperative MAG3 renal scintigraphy data and effect of nephroureterectomy on renal function.
Serum creatinine (mg/dL) Estimated GFR (mL/min/1.73 m2) Estimated GFR decreased ratio MAG3 clearance (mL/min/1.73 m2): Remaining kidney Operated kidney Bilateral kidneys Calculated ERPF decreased ratio
Mean preoperation (95% CI, SD)
Mean postoperation (95% CI, SD)
p
1.42 (1.31e1.53, 0.65) 54.76 (50.68e58.85, 23.46) 18.73 (14.49e22.97, 24.3)
1.89 (1.66e2.12, 1.34) 44.44 (40.72e48.17, 21.38)
< 0.0001 < 0.0001
158.30 (141.69e174.93, 95.40) 91.65 (77.66e105.65, 80.33) 249.96 (222.98e276.94, 154.86) 33.94 (31.04e36.84, 16.7)
Data are presented as %, unless otherwise indicated. CI ¼ confidence interval; ERPF ¼ effective renal plasma flow; GFR ¼ glomerular filtration rate; MAG3 ¼ MAG3 ¼ technetium-mercaptoacetyltriglycine; SD ¼ standard deviation.
correlation coefficient, we established the following predictive equation for the nonhydronephrosis group: Decrease in eGFR ratio ¼ 0.80 predicted decrease in ERPF ratio þ 0.72 (p < 0.05, R2 ¼ 0.362).
Postoperative eGFR Preoperative eGFR mL=min=1:73m Preoperative eGFR mL=min=1:73m2
(2)
2
¼ 0:80
MAG3 clearance of resected kidney mL=min=1:73m2 MAG3 clearance of bilateral kidney mL=min=1:73m2
þ 0:72 (3) 4. Discussion To the best of our knowledge, this is the first study to develop an equation to predict renal function deterioration after unilateral nephroureterectomy for patients with UTUCs based on preoperative MAG3 renal scintigraphy and to report change of renal function 1 year after nephroureterectomy. Serum creatinine was found to increase by 0.5 mg/dL, which was 35.2% above baseline, and eGFR was found to decrease by 18.73%, from 54.76 mL/min/1.73 m2 to 44.44 mL/min/1.73 m2.
Fig. 1. The correlated between calculated decrease in MAG3 renal scintigraphy ratio and decreased in eGFR ratio in all patients group. eGFR ¼ estimated glomerular filtration rate; MAG3 ¼ technetium-mercaptoacetyltriglycine.
Fig. 2. The correlated between calculated decrease in MAG3 renal scintigraphy ratio and decreased in eGFR ratio in nonhydronephrosis group. eGFR ¼ estimated glomerular filtration rate; MAG3 ¼ technetium-mercaptoacetyltriglycine.
Many preoperative methods have been used to evaluate renal function. Serum creatinine is the simplest and most readily accessible examination to estimate renal excretion function. However, creatinine level requires correction for age and gender, and therefore, eGFR is the most reliable index of renal function. In recent
Fig. 3. The correlated between calculated decrease in MAG3 renal scintigraphy ratio and decreased in eGFR ratio in hydronephrosis group. eGFR ¼ estimated glomerular filtration rate; MAG3 ¼ technetium-mercaptoacetyltriglycine.
Please cite this article in press as: Liu C-J, et al., The correlation between preoperative renal scintigraphy and postoperative renal function in upper urinary tract urothelial carcinoma patients following radical nephroureterectomy, Urological Science (2016), http://dx.doi.org/10.1016/ j.urols.2016.11.001
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C.-J. Liu et al. / Urological Science xxx (2016) 1e5
years, many studies have been designed to find an optimal diagnostic tool to predict postnephrectomy renal function progression. MAG3 renal scintigraphy and technetium-99m dimercaptosuccinic acid (DMSA) renal scintigraphy are widely used as predictive tools. Mullerad et al6 reported that DMSA renal scintigraphy has been used as a potentially predictive examination used to identify patients with preoperative absolute uptake of < 11% in the remaining kidney who are at risk of postoperative chronic renal failure or insufficiency. Shirasaki et al7 used MAG3 renal scintigraphy in patients with renal malignancy, including renal cell carcinoma and urothelial cancer to evaluate renal function before and after nephrectomy, and it was found to be helpful to predict renal insufficiency after nephrectomy. A preoperative MAG3 clearance in the remaining kidney of < 130 mL/ min/1.73 m2 was found to be significantly correlated with postoperative renal insufficiency. However, these two series consisted of a relatively small number of cases (n ¼ 42 and n ¼ 35, respectively). Kanamaru et al11 reported the clinical usefulness of preoperative MAG3 renal scintigraphy to predict long-term renal function after nephrectomy, and found that total ERPF, ERPF of the unilateral kidney, serum creatinine, and preoperative eGFR were all significantly correlated with postoperative eGFR. In particular, preoperative ERPF of the contralateral kidney had the highest correlation, and the correlation coefficient between preoperative ERPF of the contralateral kidney and postoperative eGFR was significant (r ¼ 0.421, p ¼ 0.003). Our results showed an even stronger correlation (r ¼ 0.646, p < 0.001) based on a greater number of cases (n ¼ 129 vs. n ¼ 47). The role of perioperative chemotherapy with regards to UTUC has still not been well established. Adjuvant chemotherapy can provide a recurrence-free rate of up to 50%, However, it has not been proven to influence survival.12,13 The clinical decision for adjuvant chemotherapy mainly depends on the patient's postoperative renal function. An eGFR of 60 mL/min/1.73 m2 is generally recognized as being acceptable for full-dose cisplatin chemotherapy. In our study, 45 patients were preoperatively eligible for cisplatin chemotherapy but only 23 patients (51.11%) were still eligible at the end of the study period. We assessed the value of preoperative ERPF to predict postoperative chronic renal insufficiency, and the results showed that the decrease in eGFR ratio was significantly correlated with the decrease in preoperative ERPF ratio. This indicates that ERPF can predict postoperative renal function. Notably, ERPF was a more accurate predictive tool in the nonhydronephrosis patient group. This may be due to the retention of MAG3 in the renal calyces or renal pelvis which can deform the Tmax, T1/2, and 20-min/max count ratios,14 and slightly influence the accuracy of the results. Therefore, we calculated the predicative equation (Eq. (2)) for the nonhydronephrosis group. A linear correlation between the decrease in eGFR ratio and predicted decrease in ERPF ratio was also computed for the patients overall. However, the correlation was not solid enough to make a definite conclusion (r < 0.3). Nevertheless, this equation may be able to aid clinicians in predicting postoperative renal function and determine whether perioperative chemotherapy is suitable or not. We also corrected the results for age, gender, and clinical staging, none of which had an impact on the results. Furthermore, Rodriguez et al5 analysed 138 patients with upper urinary tract urothelial carcinoma following nephroureterectomy, and found that preoperative hydronephrosis was an independent risk factor for postoperative chronic kidney insufficiency, suggesting that such patients are not good candidates for perioperative chemotherapy (p ¼ 0.027, odds ratio ¼ 10.34, eGFR 60 mL/min/1.73 m2). Consequently, radical NUR and BCR is considered the best treatment option for patients with UUT-UC, and ERPF can be used to predict postoperative renal function especially for those without preoperative hydronephrosis.
It has previously been reported that the removal of one kidney in patients with bilateral normally functioning kidneys leads to compensatory hypertrophy of the remaining kidney, and ERPF has been reported to be increased by nearly 30% 1 week after surgery.15 Shirasaki et al16 described the change of renal function after nephrectomy for renal cell carcinoma. They included 30 patients with a mean preoperative MAG3 clearance of the remaining kidney of 155.4 mL/min/1.73 m2, and the mean MAG3 clearance of the remaining kidney was found to have increased by 39.5% and 40.5% after 1 month and 1 year, respectively. A lack of data on postoperative ERPF prevented us from repeating this study design. Moreover, Shirasaki et al16 found that serum creatinine was increased from 0.82 mg/dL to 1.16 mg/dL, which is an average increase of 32.9%, which is comparable to our result. They concluded that a greater compensatory response is produced in patients with more severe preoperative chronic kidney disease. However, in the present study, no similar functional correlation was found in our UUT-UC patients (p ¼ 0.154). The results of our study should be interpreted in light of its limitations. The results of a retrospective design may be influenced by patients being lost to follow-up or errors due to concurrent physiological condition. The lack of postoperative ERPF data is also a limitation. Furthermore, eGFR was estimated by the Modification of Diet in Renal Disease (MDRD) equation in our study. The MDRD equation may overestimate the true GFR because some creatinine is cleared through proximal tubules. Further large-scaled prospective studies are necessary to test this calculated equation. 5. Conclusion In comparison to preoperative baseline eGFR for patients with UTUCs, the mean eGFR 1 year after unilateral nephroureterectomy represented a decrease of 18.73%. We developed an equation for predicting the renal function (eGFR) 1 year after unilateral nephroureterectomy for patients with UTUCs based on preoperative 99mTc-MAG3 renal scintigraphy. Further large-scaled prospective studies are necessary to test this equation and confirm our results. Conflicts of interest The authors have no conflicts of interest to declare. References 1. Jemal A, Siegel R, Xu J. Cancer statistics, 2010 CA Cancer J Clin 2010;60: 277e300. 2. Chou YH, Huang CH. Unusual clinical presentation of upper urothelial carcinoma in Taiwan. Cancer 1999;85:1342e4. 3. Yang MH, Chen KK, Yen CC, Wang WS, Chang YH, Huang WJ, et al. Unusually high incidence of upper urinary tract urothelial carcinoma in Taiwan. Urology 2002;59:681e7. 4. Kaag M, Trost L, Thompson RH, Favaretto R, Elliott V, Shariat SF, et al. Preoperative predictors of renal function decline following radical nephroureterectomy for upper tract urothelial carcinoma. BJU Int 2014;114:674e9. mez JM, Wong A, 5. Rodríguez Faba O, Palou J, Breda A, Maroto P, Fern andez Go et al. Predictive factors for impaired renal function following nephroureterectomy in upper urinary tract urothelial cell carcinoma. Urol Int 2014;92: 169e73. 6. Mullerad M, Kastin A, Issaq E, Moskovitz B, Groshar D, Nativ O, et al. The value of quantitative 99M technetium dimercaptosuccinic acid renal scintigraphy for predicting postoperative renal insufficiency in patients undergoing nephrectomy. J Urol 2003;169:24e7. 7. Shirasaki Y, Saika T, Tsushima T, Nasu Y, Arata R, Kumon H. Predicting postoperative renal insufficiency in patients undergoing nephrectomy for renal malignancy: assessment by renal scintigraphy using 99m technetium-mercaptoacetyltriglycine. J Urol 2005;173:388e90. 8. Matsuo S, Imai E, Horio M, Yasuda Y, Tomita K, Nitta K, et al. Collaborators developing the Japanese equation for estimated GFR. Am J Kidney Dis 2009;53: 982e92. 9. Russell CD, Thorstad BL, Yester MV, Stutzman M, Dubovsky EV. Quantitation of renal function with technetium-99m MAG3. J Nucl Med 1988;29:1931e3.
Please cite this article in press as: Liu C-J, et al., The correlation between preoperative renal scintigraphy and postoperative renal function in upper urinary tract urothelial carcinoma patients following radical nephroureterectomy, Urological Science (2016), http://dx.doi.org/10.1016/ j.urols.2016.11.001
C.-J. Liu et al. / Urological Science xxx (2016) 1e5 10. Russell CD, Taylor A, Eshima D. Estimation of technetium-99m-MAG3 plasma clearance in adults from one or two blood samples. J Nucl Med 1989;30:1955e9. 11. Kanamaru H, Yamamoto M, Nagahama K, Yagihashi Y, Kato K, Oida T, et al. Mercaptoacetyltriglycine-3 renogram is not superior to estimated glomerular filtration rate measurement for the prediction of long-term renal function after nephrectomy. Int J Urol 2011;18:570e4. 12. Hellenthal NJ, Shariat SF, Margulis V, Karakiewicz PI, Roscigno M, Bolenz C, et al. Adjuvant chemotherapy for high risk upper tract urothelial carcinoma: results from the upper tract urothelial carcinoma collaboration. J Urol 2009;182:900e6. 13. Vassilakopoulou M, de la Motte Rouge T, Colin P, et al. Outcomes after adjuvant chemotherapy in the treatment of high-risk urothelial carcinoma of the upper
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urinary tract (UUT-UC): results from a large multicenter collaborative study. Cancer 2011;117:5500e8. 14. Esteves FP, Taylor A, Manatunga A, Folks RD, Krishnan M, Garcia EV. 99mTcMAG3 renography: normal values for MAG3 clearance and curve parameters, excretory parameters, and residual urine volume. AJR Am J Roentgenol 2006;187:W610e7. 15. Anderson RG, Bueschen AJ, Lloyd LK, Dubovsky EV, Burns JR. Short-term and long-term changes in renal function after donor nephrectomy. J Urol 1991;145: 11e3. 16. Shirasaki Y, Tsushima T, Saika T, Kumon H. Kidney function after nephrectomy for renal cell carcinoma. Urology 2004;64:43e7. discussion 48.
Please cite this article in press as: Liu C-J, et al., The correlation between preoperative renal scintigraphy and postoperative renal function in upper urinary tract urothelial carcinoma patients following radical nephroureterectomy, Urological Science (2016), http://dx.doi.org/10.1016/ j.urols.2016.11.001
Contents lists available at ScienceDirect
Urological Science journal homepage: www.urol-sci.com
Original article
The correlation between preoperative renal scintigraphy and postoperative renal function in upper urinary tract urothelial carcinoma patients following radical nephroureterectomy Chan-Jung Liu, Wen-Horng Yang, Chien-Hui Ou* Department of Urology, National Cheng-Kung University Hospital, Medical College, National Cheng-Kung University, Tainan, Taiwan
a r t i c l e i n f o
a b s t r a c t
Article history: Received 31 December 2015 Received in revised form 1 November 2016 Accepted 4 November 2016 Available online xxx
Objective: To predict the renal function after nephroureterectomy (NUR) for upper urinary tract urothelial cancer (UTUC) based on preoperative technetium-99m mercaptoacetyltriglycine (99mTc-MAG3) renal scintigraphy. Subjects and methods: We retrospectively reviewed 238 patients who originally underwent nephroureterectomy for UTUC between 2007 and 2010. Of these patients, 129 underwent MAG3 renal scintigraphy before unilateral NUR. Serum creatinine was measured in all of the patients before surgery, and renal function was monitored for one year after surgery. Preoperative and postoperative eGFRs were compared and analyzed based on the preoperative MAG3 renal scintigraphy. Results: A total of 129 patients, including 62 men (48%) and 67 women (52%) with an average age at surgery of 69.0 years (range from 48 to 87) were included in this study. The mean preoperative creatinine level was 1.42 mg/dL, and the baseline eGFR was 54.76 ml/min/1.73 m2. One year after NUR, the mean creatinine level was 1.89 mg/dL, and the eGFR was 44.44 ml/min/1.73 m2, a mean decrease of 18.73%. The preoperative effective renal plasma flow (ERPF) of the operated kidney was 91.65 ml/min/1.73 m2, and that of the remaining kidney 158.30 ml/ min/1.73 m2. The average preoperative ERPF of the resected kidney accounted for 34% of total preoperative ERPF, which was statistically significant in its relation to the decrease in eGFR. The decrease in eGFR ratio was also significantly correlated with the calculated decrease in ERPF ratio (R2 ¼ 0.279, p < 0.001). The predictive equation of renal function one year after NUR was established as following: eGFR decreased ratio ¼ e0.80 predictive ERPF decreased ratio +0.72. Conclusion: We developed an equation to predict postnephroureterectomy 1 year eGFR before surgery based on preoperative MAG3 renal scintigraphy results and preoperative eGFR. The equation could be more accurate in the situation if the diseased kidney is not hydronephrotic. Copyright © 2016, Taiwan Urological Association. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Keywords: Estimated glomerular filtration rate Nephroureterectomy and bladder cuff resection Renal function predictive equation Tc-mercaptoacetyltriglycine (MAG3) renal scintigraphy Upper urinary tract urothelial carcinoma
1. Introduction Upper urinary tract urothelial cancer (UTUC) accounts for < 5% of all urothelial cancers (UC).1 The incidence of UC in the area endemic for “Blackfoot disease” in southern Taiwan has been reported to be significantly higher than anywhere else in the world.2,3 In Taiwan, UC of the renal pelvis accounts for 10.7% of all urothelial cancer, and for ~40% of all renal carcinomas.3 Ipsilateral radical nephroureterectomy (NUR) and bladder cuff resection (BCR) is currently the standard treatment for UTUC. Possible renal function * Corresponding author. Department of Urology, National Cheng-Kung University Hospital, Number 138, Sheng Li Road, Tainan 700, Taiwan. E-mail address: [email protected] (C.-H. Ou).
deterioration after surgery remains an important patient concern, however, studies concerning changes in renal function after radical nephroureterectomy and bladder cuff resection are limited. Deterioration of renal function may influence the use of perioperative chemotherapy. Recently, two studies have demonstrated a decline in renal function following radical NUR,4,5 with a reported decrease in estimated glomerular filtration rate (eGFR) of 21% and 32%, respectively. Preoperative hypertension, older age, and preoperative eGFR < 60 mL/min/1.73 m2 have been reported to be predictive factors for impaired renal function after radical NUR. However, preoperative predictive tools are still under investigation. Dimercaptosuccinic acid renal scintigraphy has been used as a potentially predictive exam used to identify patients with preoperative absolute uptake of < 11% in the remaining kidney who are at risk of
http://dx.doi.org/10.1016/j.urols.2016.11.001 1879-5226/Copyright © 2016, Taiwan Urological Association. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/).
Please cite this article in press as: Liu C-J, et al., The correlation between preoperative renal scintigraphy and postoperative renal function in upper urinary tract urothelial carcinoma patients following radical nephroureterectomy, Urological Science (2016), http://dx.doi.org/10.1016/ j.urols.2016.11.001
2
C.-J. Liu et al. / Urological Science xxx (2016) 1e5
postoperative chronic renal failure or insufficiency.6 Technetium (Tc)-99m mercaptoacetyltriglycine (MAG3) renal scintigraphy has also been found to be useful in predicting renal insufficiency after nephrectomy.7 However, both of these previously published series were both limited in their relatively small sample size. Thus, we performed a retrospective review of a large single institutional database to survey the renal function outcomes in patients with UTUCs following unilateral radical NUR. MAG3 renal scintigraphy was used in all of these patients to evaluate the renal function before radical NUR. The aims of this study were to report the change of renal function following radical NUR for UTUC and to develop an equation for predicting the renal function (eGFR) 1 year after NUR based on preoperative 99mTc-MAG3 renal scintigraphy. 2. Materials and methods We retrospectively reviewed the medical records of 238 patients who underwent unilateral NUR and BCR for UTUC between 2007 and 2010 in the National Cheng Kung University Hospital, a tertiary medical center in Southern Taiwan. The patients with end-stagerenal disease, and those who underwent a second operation or received bilateral nephroureterectomy were excluded. In total, 129 patients underwent MAG3 renal scintigraphy before unilateral NUR and BCR. The serum creatinine levels were measured in all patients before surgery, and renal functions were monitored for 1 year after surgery. We used revised equations for estimated GFR from serum creatinine.8 For men, the equation is: eGFR (mL/min/ 1.73 m2) ¼ 194 (Serum creatinine) (age) 0.287,
1.094
(1)
and for women Eq. (1) is multiplied by 0.739. All these patients had received preoperative image evaluation, including computed tomography, magnetic resonance imaging, or renal sonography. According to the latest image, we divided all these patients into hydronephrosis group and nonhydronephrosis group. The diagnosis of hydronephrosis was determined by the radiologists or the urologist. It was defined as urinary obstruction and dilatation of the collecting system in ipsilateral upper urinary tract with urothelial cancer. 2.1. MAG3 renal scintigraphy The renal radionuclide scans were carried out using MAG3.One hundred and eleven milliliters of MBq (3 mCi) MAG3 (INER MERTIARISW kit, INER, Taoyuan, Taiwan) was injected into the vein of the forearm and serial scintiphotos were taken using a gamma camera. Blood samples were taken at 44 minutes postinjection from the contralateral forearm. Effective renal plasma flow (ERPF), normalized to body surface area of 1.73 m2, was determined by the procedure developed by Russell et al.9,10 Split renal function was determined by the 1- to 2-minute postinjection images. 2.2. Statistical analysis We used the paired t test to compare pre- and postoperative eGFR and serum creatinine. The predicted decreased in ERPF ratio was compared with a decrease in eGFR using a paired t test. Values are expressed as the mean and 95% confidence interval (CI). Pearson's correlation analysis was performed to evaluate the correlations between the decreases in preoperative ERPF and eGFR ratios for all patients, hydronephrosis group, and nonhydronephrosis group. All statistical analyses were performed using SPSS version 20 (SPSS Inc., Chicago, IL, USA) for Microsoft Windows. Statistical significance was defined as p < 0.05.
3. Results A total of 129 patients, including 62 men (48%) and 67 women (52%) with an average age of 69.0 years at surgery (range, 48e87 years) in this study. The preoperative characteristics of the 129 patients, all of whom had at least 1 year of postoperative follow-up are listed in Table 1. The mean preoperative creatinine level was 1.42 mg/dL (95% CI 1.31e1.53), and the baseline eGFR was 54.76 mL/ min/1.73 m2 (95% CI 50.68e58.85). Baseline renal function was comparable in hydronephrosis and nonhydronephrosis groups with respect to serum creatinine (1.49 ± 0.70 mg/dL vs. 1.3 ± 0.54 mg/dL, p ¼ 0.11), eGFR (54.02 ± 24.31 mL/min/1.73 m2 vs. 56.10 ± 21.51 mL/min/1.73 m2, p ¼ 0.63), and total ERPF (235.24 ± 150.32 mL/min/1.73 m2 vs. 276.51 ± 157.67 mL/min/ 1.73 m2, p ¼ 0.15). The average preoperative ERPF of the resected kidney in hydronephrosis group was 81.37 mL/ min/1.73 m2 (95% CI 63.37e99.38), which was lower than the nonhydronephrosis group (110.20 mL/ min/1.73 m2, 95% CI 88.35e132.06; p ¼ 0.05). The renal function was comparable in hydronephrosis and nonhydronephrosis groups 1 year after NUR with respect to serum creatinine (1.96 ± 1.320 mg/dL vs. 1.77 ± 1.34 mg/dL, p ¼ 0.48), and eGFR (44.28 ± 21.15 mL/min/1.73 m2 vs. 44.74 ± 19.66 mL/min/ 1.73 m2, p ¼ 0.91). One year after NUR, the mean creatinine level was 1.92 mg/dL (95% CI 1.68e2.16, p < 0.001) and eGFR was 44.44 mL/min/1.73 m2 (95% CI 40.72e48.17, p < 0.001), which represented a decrease of 18.73% with comparison to preoperative data. The preoperative ERPF of the operated kidney was 91.65 mL/ min/1.73 m2, and that of the remaining kidney 158.30 mL/ min/ 1.73 m2 (Table 2). The average preoperative ERPF of the resected kidney accounted for 34% of the total preoperative ERPF. The decrease in eGFR ratio was defined as the change in eGFR (preoperative eGFR subtracted by the postoperative eGFR) divided by preoperative eGFR. The predicted decrease in ERPF ratio was defined as the ERPF of the operated kidney divided by total ERPF. The decrease in eGFR ratio was significantly correlated with the calculated decrease in ERPF ratio (R ¼ 0.279, p < 0.001; Fig. 1). Based on the patients' preoperative imaging results, the patients were divided into two groups: with hydronephrosis (n ¼ 46) or without hydronephrosis (n ¼ 83). In linear regression analysis, the nonhydronephrosis group had a higher correlation between the decreases in ERPF ratio and eGFR ratio (R2 ¼ 0.362, Fig. 2) than the hydronephrosis group (R2 ¼ 0.248, Fig. 3). Based on the Pearson's
Table 1 Baseline characteristics of 129 patients. Patient characteristics (n ¼ 129) Gender Male Female Age at surgery, y Mean (range) Tumor location Left Right Age 70 y Pathological stage pT1 pT2 pT3 pT4 Other pNþ Hydronephrosis Hydronephrosis Nonhydronephrosis
62 (48) 67 (52) 69 (46e87) 60 (47) 69 (53) 66 (51) 50 (39) 22 (17) 46 (36) 9 (7) 2 (1) 10 (8) 46 (36) 83 (64)
Data are presented as n (%).
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C.-J. Liu et al. / Urological Science xxx (2016) 1e5
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Table 2 Preoperative MAG3 renal scintigraphy data and effect of nephroureterectomy on renal function.
Serum creatinine (mg/dL) Estimated GFR (mL/min/1.73 m2) Estimated GFR decreased ratio MAG3 clearance (mL/min/1.73 m2): Remaining kidney Operated kidney Bilateral kidneys Calculated ERPF decreased ratio
Mean preoperation (95% CI, SD)
Mean postoperation (95% CI, SD)
p
1.42 (1.31e1.53, 0.65) 54.76 (50.68e58.85, 23.46) 18.73 (14.49e22.97, 24.3)
1.89 (1.66e2.12, 1.34) 44.44 (40.72e48.17, 21.38)
< 0.0001 < 0.0001
158.30 (141.69e174.93, 95.40) 91.65 (77.66e105.65, 80.33) 249.96 (222.98e276.94, 154.86) 33.94 (31.04e36.84, 16.7)
Data are presented as %, unless otherwise indicated. CI ¼ confidence interval; ERPF ¼ effective renal plasma flow; GFR ¼ glomerular filtration rate; MAG3 ¼ MAG3 ¼ technetium-mercaptoacetyltriglycine; SD ¼ standard deviation.
correlation coefficient, we established the following predictive equation for the nonhydronephrosis group: Decrease in eGFR ratio ¼ 0.80 predicted decrease in ERPF ratio þ 0.72 (p < 0.05, R2 ¼ 0.362).
Postoperative eGFR Preoperative eGFR mL=min=1:73m Preoperative eGFR mL=min=1:73m2
(2)
2
¼ 0:80
MAG3 clearance of resected kidney mL=min=1:73m2 MAG3 clearance of bilateral kidney mL=min=1:73m2
þ 0:72 (3) 4. Discussion To the best of our knowledge, this is the first study to develop an equation to predict renal function deterioration after unilateral nephroureterectomy for patients with UTUCs based on preoperative MAG3 renal scintigraphy and to report change of renal function 1 year after nephroureterectomy. Serum creatinine was found to increase by 0.5 mg/dL, which was 35.2% above baseline, and eGFR was found to decrease by 18.73%, from 54.76 mL/min/1.73 m2 to 44.44 mL/min/1.73 m2.
Fig. 1. The correlated between calculated decrease in MAG3 renal scintigraphy ratio and decreased in eGFR ratio in all patients group. eGFR ¼ estimated glomerular filtration rate; MAG3 ¼ technetium-mercaptoacetyltriglycine.
Fig. 2. The correlated between calculated decrease in MAG3 renal scintigraphy ratio and decreased in eGFR ratio in nonhydronephrosis group. eGFR ¼ estimated glomerular filtration rate; MAG3 ¼ technetium-mercaptoacetyltriglycine.
Many preoperative methods have been used to evaluate renal function. Serum creatinine is the simplest and most readily accessible examination to estimate renal excretion function. However, creatinine level requires correction for age and gender, and therefore, eGFR is the most reliable index of renal function. In recent
Fig. 3. The correlated between calculated decrease in MAG3 renal scintigraphy ratio and decreased in eGFR ratio in hydronephrosis group. eGFR ¼ estimated glomerular filtration rate; MAG3 ¼ technetium-mercaptoacetyltriglycine.
Please cite this article in press as: Liu C-J, et al., The correlation between preoperative renal scintigraphy and postoperative renal function in upper urinary tract urothelial carcinoma patients following radical nephroureterectomy, Urological Science (2016), http://dx.doi.org/10.1016/ j.urols.2016.11.001
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C.-J. Liu et al. / Urological Science xxx (2016) 1e5
years, many studies have been designed to find an optimal diagnostic tool to predict postnephrectomy renal function progression. MAG3 renal scintigraphy and technetium-99m dimercaptosuccinic acid (DMSA) renal scintigraphy are widely used as predictive tools. Mullerad et al6 reported that DMSA renal scintigraphy has been used as a potentially predictive examination used to identify patients with preoperative absolute uptake of < 11% in the remaining kidney who are at risk of postoperative chronic renal failure or insufficiency. Shirasaki et al7 used MAG3 renal scintigraphy in patients with renal malignancy, including renal cell carcinoma and urothelial cancer to evaluate renal function before and after nephrectomy, and it was found to be helpful to predict renal insufficiency after nephrectomy. A preoperative MAG3 clearance in the remaining kidney of < 130 mL/ min/1.73 m2 was found to be significantly correlated with postoperative renal insufficiency. However, these two series consisted of a relatively small number of cases (n ¼ 42 and n ¼ 35, respectively). Kanamaru et al11 reported the clinical usefulness of preoperative MAG3 renal scintigraphy to predict long-term renal function after nephrectomy, and found that total ERPF, ERPF of the unilateral kidney, serum creatinine, and preoperative eGFR were all significantly correlated with postoperative eGFR. In particular, preoperative ERPF of the contralateral kidney had the highest correlation, and the correlation coefficient between preoperative ERPF of the contralateral kidney and postoperative eGFR was significant (r ¼ 0.421, p ¼ 0.003). Our results showed an even stronger correlation (r ¼ 0.646, p < 0.001) based on a greater number of cases (n ¼ 129 vs. n ¼ 47). The role of perioperative chemotherapy with regards to UTUC has still not been well established. Adjuvant chemotherapy can provide a recurrence-free rate of up to 50%, However, it has not been proven to influence survival.12,13 The clinical decision for adjuvant chemotherapy mainly depends on the patient's postoperative renal function. An eGFR of 60 mL/min/1.73 m2 is generally recognized as being acceptable for full-dose cisplatin chemotherapy. In our study, 45 patients were preoperatively eligible for cisplatin chemotherapy but only 23 patients (51.11%) were still eligible at the end of the study period. We assessed the value of preoperative ERPF to predict postoperative chronic renal insufficiency, and the results showed that the decrease in eGFR ratio was significantly correlated with the decrease in preoperative ERPF ratio. This indicates that ERPF can predict postoperative renal function. Notably, ERPF was a more accurate predictive tool in the nonhydronephrosis patient group. This may be due to the retention of MAG3 in the renal calyces or renal pelvis which can deform the Tmax, T1/2, and 20-min/max count ratios,14 and slightly influence the accuracy of the results. Therefore, we calculated the predicative equation (Eq. (2)) for the nonhydronephrosis group. A linear correlation between the decrease in eGFR ratio and predicted decrease in ERPF ratio was also computed for the patients overall. However, the correlation was not solid enough to make a definite conclusion (r < 0.3). Nevertheless, this equation may be able to aid clinicians in predicting postoperative renal function and determine whether perioperative chemotherapy is suitable or not. We also corrected the results for age, gender, and clinical staging, none of which had an impact on the results. Furthermore, Rodriguez et al5 analysed 138 patients with upper urinary tract urothelial carcinoma following nephroureterectomy, and found that preoperative hydronephrosis was an independent risk factor for postoperative chronic kidney insufficiency, suggesting that such patients are not good candidates for perioperative chemotherapy (p ¼ 0.027, odds ratio ¼ 10.34, eGFR 60 mL/min/1.73 m2). Consequently, radical NUR and BCR is considered the best treatment option for patients with UUT-UC, and ERPF can be used to predict postoperative renal function especially for those without preoperative hydronephrosis.
It has previously been reported that the removal of one kidney in patients with bilateral normally functioning kidneys leads to compensatory hypertrophy of the remaining kidney, and ERPF has been reported to be increased by nearly 30% 1 week after surgery.15 Shirasaki et al16 described the change of renal function after nephrectomy for renal cell carcinoma. They included 30 patients with a mean preoperative MAG3 clearance of the remaining kidney of 155.4 mL/min/1.73 m2, and the mean MAG3 clearance of the remaining kidney was found to have increased by 39.5% and 40.5% after 1 month and 1 year, respectively. A lack of data on postoperative ERPF prevented us from repeating this study design. Moreover, Shirasaki et al16 found that serum creatinine was increased from 0.82 mg/dL to 1.16 mg/dL, which is an average increase of 32.9%, which is comparable to our result. They concluded that a greater compensatory response is produced in patients with more severe preoperative chronic kidney disease. However, in the present study, no similar functional correlation was found in our UUT-UC patients (p ¼ 0.154). The results of our study should be interpreted in light of its limitations. The results of a retrospective design may be influenced by patients being lost to follow-up or errors due to concurrent physiological condition. The lack of postoperative ERPF data is also a limitation. Furthermore, eGFR was estimated by the Modification of Diet in Renal Disease (MDRD) equation in our study. The MDRD equation may overestimate the true GFR because some creatinine is cleared through proximal tubules. Further large-scaled prospective studies are necessary to test this calculated equation. 5. Conclusion In comparison to preoperative baseline eGFR for patients with UTUCs, the mean eGFR 1 year after unilateral nephroureterectomy represented a decrease of 18.73%. We developed an equation for predicting the renal function (eGFR) 1 year after unilateral nephroureterectomy for patients with UTUCs based on preoperative 99mTc-MAG3 renal scintigraphy. Further large-scaled prospective studies are necessary to test this equation and confirm our results. Conflicts of interest The authors have no conflicts of interest to declare. References 1. Jemal A, Siegel R, Xu J. Cancer statistics, 2010 CA Cancer J Clin 2010;60: 277e300. 2. Chou YH, Huang CH. Unusual clinical presentation of upper urothelial carcinoma in Taiwan. Cancer 1999;85:1342e4. 3. Yang MH, Chen KK, Yen CC, Wang WS, Chang YH, Huang WJ, et al. Unusually high incidence of upper urinary tract urothelial carcinoma in Taiwan. Urology 2002;59:681e7. 4. Kaag M, Trost L, Thompson RH, Favaretto R, Elliott V, Shariat SF, et al. Preoperative predictors of renal function decline following radical nephroureterectomy for upper tract urothelial carcinoma. BJU Int 2014;114:674e9. mez JM, Wong A, 5. Rodríguez Faba O, Palou J, Breda A, Maroto P, Fern andez Go et al. Predictive factors for impaired renal function following nephroureterectomy in upper urinary tract urothelial cell carcinoma. Urol Int 2014;92: 169e73. 6. Mullerad M, Kastin A, Issaq E, Moskovitz B, Groshar D, Nativ O, et al. The value of quantitative 99M technetium dimercaptosuccinic acid renal scintigraphy for predicting postoperative renal insufficiency in patients undergoing nephrectomy. J Urol 2003;169:24e7. 7. Shirasaki Y, Saika T, Tsushima T, Nasu Y, Arata R, Kumon H. Predicting postoperative renal insufficiency in patients undergoing nephrectomy for renal malignancy: assessment by renal scintigraphy using 99m technetium-mercaptoacetyltriglycine. J Urol 2005;173:388e90. 8. Matsuo S, Imai E, Horio M, Yasuda Y, Tomita K, Nitta K, et al. Collaborators developing the Japanese equation for estimated GFR. Am J Kidney Dis 2009;53: 982e92. 9. Russell CD, Thorstad BL, Yester MV, Stutzman M, Dubovsky EV. Quantitation of renal function with technetium-99m MAG3. J Nucl Med 1988;29:1931e3.
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C.-J. Liu et al. / Urological Science xxx (2016) 1e5 10. Russell CD, Taylor A, Eshima D. Estimation of technetium-99m-MAG3 plasma clearance in adults from one or two blood samples. J Nucl Med 1989;30:1955e9. 11. Kanamaru H, Yamamoto M, Nagahama K, Yagihashi Y, Kato K, Oida T, et al. Mercaptoacetyltriglycine-3 renogram is not superior to estimated glomerular filtration rate measurement for the prediction of long-term renal function after nephrectomy. Int J Urol 2011;18:570e4. 12. Hellenthal NJ, Shariat SF, Margulis V, Karakiewicz PI, Roscigno M, Bolenz C, et al. Adjuvant chemotherapy for high risk upper tract urothelial carcinoma: results from the upper tract urothelial carcinoma collaboration. J Urol 2009;182:900e6. 13. Vassilakopoulou M, de la Motte Rouge T, Colin P, et al. Outcomes after adjuvant chemotherapy in the treatment of high-risk urothelial carcinoma of the upper
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Please cite this article in press as: Liu C-J, et al., The correlation between preoperative renal scintigraphy and postoperative renal function in upper urinary tract urothelial carcinoma patients following radical nephroureterectomy, Urological Science (2016), http://dx.doi.org/10.1016/ j.urols.2016.11.001