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Relationship Between Renal Parenchymal Volume and Single Kidney Glomerular Filtration Rate Before and After Unilateral Nephrectomy
Oncology Relationship Between Renal Parenchymal Volume and Single Kidney Glomerular Filtration Rate Before and After Unilateral Nephrectomy Yasuhito Funahashi, Ryohei Hattori, Tokunori Yamamoto, Osamu Kamihira, Naoto Sassa, and Momokazu Gotoh OBJECTIVES METHODS
RESULTS
CONCLUSIONS
To measure the renal parenchymal volume (RPV) before and after unilateral nephrectomy and investigate the relationship between the RPV and single kidney glomerular filtration rate (GFR). From November 2003 to August 2009, 183 patients who had undergone unilateral nephrectomy were enrolled in the present study. All patients had undergone preoperative technetium-99m dimercaptosuccinic acid renal scintigraphy. Contrast-enhanced computed tomography was performed before and 6 months after surgery. RPV was calculated as the normally functioning tissue, excluding tumors or nonenhanced areas, using a 3-dimensional image reconstruction program. The mean split GFR of the remaining kidney increased by 21.2%, from 41.6 to 49.5 mL/min/1.73 m2 at 6 months after nephrectomy. The mean RPV of the remaining kidney increased by 9.3%, from 164.2 to 178.8 cm3 after nephrectomy. The preoperative relative RPV of the remaining kidney was 58.8% (range 37.2%-97.9%) and the technetium-99m dimercaptosuccinic acid uptake was 62.2% (range 39.6%-100%), indicating a significant linear correlation (R ⫽ 0.865, P ⬍.001). RPV correlated well with the single kidney GFR and patient age, both preoperatively and postoperatively. The postoperative GFR could be predicted by combining the preoperative factors. Multivariate regression analysis revealed that the RPV was positively associated with the single kidney GFR and negatively associated with patient age. The differential renal function correlated well with the RPV and can be estimated by calculating the RPV. Even without using renal scintigraphy, the postoperative GFR can be predicted using our established formula. UROLOGY 77: 1404 –1408, 2011. © 2011 Elsevier Inc.
I
n recent years, the incidence of renal malignancies has been increasing because of the aging of the population and the widespread use of various imaging modalities, such as ultrasonography, computed tomography (CT), and magnetic resonance imaging. Nephronsparing treatment is possible for small tumors; however, radical nephrectomy is still performed in many cases of renal malignancy. The renal function of the remaining kidney will increase to compensate for the loss of nephrons after unilateral nephrectomy. The glomerular filtration rate (GFR) has been reported to decrease to 60%-80% of the preoperative level within several weeks postoperatively and then stabilizes or increases very slightly for ⬎10 years after nephrectomy.1,2 Advanced age, female gender, hypertension, and proteinuria have
From the Department of Urology, Nagoya University Graduate School of Medicine, Nagoya, Japan; and Department of Urology, Komaki City Hospital, Aichi, Japan Reprint requests: Yasuhito Funahashi, M.D., Ph.D., Department of Urology, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya 466-8550 Japan. E-mail: [email protected] Submitted: March 11, 2010, received (with revisions): March 28, 2010
1404
© 2011 Elsevier Inc. All Rights Reserved
been reported as negative factors affecting functional adaptation.3-5 During the preoperative evaluation, we use CT to characterize the mass, exclude locally advanced or metastatic disease, and investigate the anatomy. In addition, it is necessary to estimate the contribution of each kidney to the total renal function to determine the treatment. The reference standard for evaluating the differential renal function is radioisotope imaging. Although it is a reliable and reproducible method, it cannot be performed in an emergency and is expensive. Therefore, it would be beneficial if the split renal function could be quantified using CT. Reconstruction using CT slice images has been proved to be a reliable, objective, and reproducible method of assessing the renal volume.6,7 Also, the kidney volume has been shown to correlate well, although indirectly, with the number of functioning nephrons in autopsy studies.8 Therefore, assessing the split renal function using CT might be possible. In the present study, we measured the normally functioning renal tissue, excluding tumors and cystic lesions, 0090-4295/11/$36.00 doi:10.1016/j.urology.2010.03.063
using CT images before and after unilateral nephrectomy. We then determined the relationship between the renal parenchymal volume (RPV) and split renal function.
MATERIAL AND METHODS Patient Population Of 230 patients who underwent unilateral nephrectomy at Komaki City Hospital from November 2003 to August 2009, the data from 183 patients were used in the present retrospective study. Excluded from the analysis were 3 patients who had not undergone Technetium-99m dimercaptosuccinic acid (DMSA) renal scintigraphy before surgery, 29 patients who had not undergone CT at our institute, and 15 patients who had not undergone CT 6 months after nephrectomy. Open nephrectomy was performed in 148 patients, and laparoscopy was performed in 35. Of these patients, 139 were men, and 44 were women. Their mean age was 62.6 ⫾ 12.8 years (mean ⫾ standard deviation; range 22-89). Their mean body surface area (BSA), calculated using the Dubois equation, was 1.63 ⫾ 0.18 m2 (range 1.13-2.08). Of the 183 patients, 66 were taking medications for hypertension and 14 for diabetes. All patients underwent unilateral nephrectomy: 102 for renal cell carcinoma, 63 for urothelial carcinoma, 17 for an atrophic kidney, and 1 for liposarcoma.
Imaging Procedures For renal scintigraphy, the patients were injected with 74 MBq DMSA. After 2 hours, posterior images were obtained using a Hitachi/Philips SKYLight gamma camera (Hitachi, Japan) equipped with a low-energy, general-purpose collimator. The regions of interest were drawn on the images for both kidneys showing the calculated percentage of split function. Contrast-enhanced CT scans were obtained with a multislice 16-row unit (Sensation 16 Cardiac, Siemens, Munich, Germany) at a table speed of 20 mm/s and a slice thickness of 5 mm. A 100-mL injection of intravenous iodinated-contrast agent (flow 2 mL/s) was administered. The dose of contrast agent was reduced or stopped, if necessary. The regions of interest were drawn around the kidneys, excluding the peripelvic fat and renal pelvis from the images, by 1 experienced radiologist who was unaware of the patients’ clinical information. The functioning renal tissue was determined as the normally enhanced areas on the CT images, and tumor and cysts were excluded from the regions of interest. The RPV was calculated using Volume software (Siemens), a 3-dimensional image reconstruction program. All patients underwent CT before and 6 months after unilateral nephrectomy. The serum creatinine was simultaneously determined, and the GFR was calculated using the revised equation for the estimated GFR for the Japanese [GFR (mL/min/1.73 m2) ⫽ 194 ⫻ age⫺0.287 ⫻ Cr⫺1.094 (⫻ 0.739 if female)].9 The preoperative single kidney GFR was calculated as the preoperative total GFR multiplied by the uptake ratio of the single kidney on DMSA renal scintigraphy.
Statistical Analysis All values are presented as the mean ⫾ standard deviation. Paired t tests were used to compare the preoperative and postUROLOGY 77 (6), 2011
Figure 1. Comparison of normal/diseased ratio between RPV and DMSA. X axis shows uptake of DMSA by normal kidney; y axis shows relative ratio of nRPV to sum of volumes of both kidneys.
operative values. Correlation differences were calculated using Pearson’s correlation coefficient. Univariate and multiple linear regression analyses were used to identify potential factors significantly associated with the postoperative GFR, preoperative RPV, and postoperative RPV. All tests were 2-sided, and P ⬍.05 was considered statistically significant. Statistical analyses were performed using the Statistical Package for Social Sciences for Windows, version 16.0 (SPSS, Chicago, IL).
RESULTS Changes in Serum Creatinine, GFR, and RPV The preoperative serum creatinine level was 0.87 ⫾ 0.23 mg/dL (range 0.45-1.89), and it had increased to 1.19 ⫾ 0.33 mg/dL (range 0.54-3.29) by 6 months after unilateral nephrectomy. The preoperative GFR was 68.5 ⫾ 17.1 mL/min/1.73 m2, and the split GFR of the remaining kidney increased by 21.2%, from 41.6 ⫾ 11.9 to 49.5 ⫾ 13.3 mL/min/1.73 m2 by 6 months after nephrectomy (P ⬍.001). The preoperative RPV of the normal kidney (nRPV) was 161.9 ⫾ 36.6 cm3, and the RPV of the diseased kidney (dRPV) was 120.3 ⫾ 53.1 cm3. The nRPV increased after nephrectomy by 9.3% to 175.9 ⫾ 40.3 cm3 (P ⬍.001) in 143 of the 183 patients.
Comparison of Normal/Diseased Ratio Between RPV and DMSA The preoperative relative nRPV, expressed as a percentage, was 58.8% ⫾ 13.4% (range 37.2%-97.9%) and the percentage of DMSA uptake of the normal side was 62.2% ⫾ 15.9% (range 39.6%-100%). A statistically significant linear correlation was observed between these 2 parameters (R ⫽ 0.865, P ⬍.001; Fig. 1). 1405
Table 1. Statistical significance of factors related to postoperative glomerular filtration rate at 6 months
Variable Age Sex BSA Preoperative nRPV Preoperative GFR ⫻ relative nRPV Preoperative GFR ⫻ relative dRPV Hypertension Diabetes mellitus
Univariate Analysis  P Value
Multivariate Analysis  P Value
⫺0.429 ⬍.001 ⫺0.197 .001 0.230 .761 0.037 .473 0.005 .945 ⫺0.057 .334 0.402 ⬍.001 0.048 .435 0.698 ⬍.001 0.625 ⬍.001 ⫺0.002
.983
0.113
.031
⫺0.148 ⫺0.027
.046 ⫺0.013 .713 0.015
.810 .774
BSA, body surface area; nRPV, renal parenchymal volume of normal kidney; GFR, glomerular filtration rate; dRPV, renal parenchymal volume of diseased kidney.
Figure 2. Relationship between preoperative RPV and single GFR. X axis shows preoperative RPV of normal kidney; y axis shows preoperative single kidney GFR of normal side.
Table 2. Statistical significance of factors related to preoperative nRPV
Variable
Univariate Analysis  P Value
Age ⫺0.431 Sex ⫺0.209 BSA 0.475 Preoperative single 0.529 kidney GFR Hypertension ⫺0.043 Diabetes mellitus 0.037
Multivariate Analysis  P Value
⬍.001 .005 ⬍.001 ⬍.001
0.021 0.059 0.523 0.574
.736 .314 ⬍.001 ⬍.001
.563 .618
0.077 0.051
.133 .315
Abbreviations as in Table 1.
Figure 3. Relationship between postoperative RPV and GFR. X axis shows postoperative RPV of remaining kidney; y axis shows GFR at 6 months after nephrectomy.
Relationship Between Preoperative nRPV and Single Kidney GFR We investigated the relationship between the preoperative nRPV and single kidney GFR of the normal side (Fig. 2). Pearson’s correlation coefficient analysis revealed a statistically significant correlation (R ⫽ 0.517, P ⬍.001).
Relationship Between Postoperative RPV and GFR The relationship between the RPV of the remaining kidney and GFR at 6 months after nephrectomy is plotted in Figure 3. A significant correlation was also found between the 2 variables after nephrectomy (R ⫽ 0.434, P ⬍.001). 1406
Formula to Predict Postoperative Renal Function We investigated whether the postoperative renal function could be estimated from preoperative factors without DMSA scanning. We defined “relative nRPV” as nRPV/ (nRPV ⫹ dRPV) and “relative dRPV” as dRPV/(nRPV ⫹ dRPV). Univariate linear regression analysis revealed a statistically significant relationship between the postoperative GFR and patient age. Multivariate regression analysis revealed that the postoperative GFR was positively associated with “preoperative GFR ⫻ relative nRPV” and “preoperative GFR ⫻ relative dRPV” and negatively associated with patient age (Table 1). Thus, the postoperative renal function can be predicted using the following formula: postoperative GFR ⫽ 14.03 ⫻ (preoperative GFR ⫻ relative nRPV)0.595 ⫻ age⫺0.229 (R ⫽ 0.721). In this formula, we omitted the influence of the “preoperative GFR ⫻ relative dRPV,” because its contribution to the formula was limited. Relationship Between RPV and Patient Characteristics The multivariate regression analysis revealed that RPV was significantly associated with the BSA and single kidney GFR both before (Table 2) and after (Table 3) nephrectomy. The following relationships were revealed. The preoperative nRPV equaled 15.17 ⫻ BSA1.080 ⫻ UROLOGY 77 (6), 2011
Table 3. Statistical significance of factors related to postoperative RPV
Variable
Univariate Analysis  P Value
Multivariate Analysis  P Value
Age ⫺0.509 ⬍.001 ⫺0.110 .074 Gender ⫺0.219 .003 0.047 .414 BSA 0.552 ⬍.001 0.588 ⬍.001 Postoperative GFR 0.474 ⬍.001 0.471 ⬍.001 Hypertension ⫺0.109 .140 ⫺0.029 .559 Diabetes mellitus 0.006 .937 0.022 .652 RPV, renal parenchymal volume; other abbreviations as in Table 1.
preoperative single kidney GFR0.492 in the preoperative state (R ⫽ 0.743), and the RPV equaled 20.65 ⫻ BSA1.201 ⫻ GFR0.395 in the postoperative state (R ⫽ 0.755).
COMMENT Our study had 4 major findings. First, the differential renal function ratio correlated well with the RPV ratio. Second, the GFR can be estimated by measuring the RPV. These 2 results have shown that the single kidney GFR can be assessed by measuring the RPV from CT scans. This method can reduce the cost, speed up the process, and decrease the radiation exposure required for preoperative evaluation. Third, the postoperative GFR after unilateral nephrectomy can be predicted from the preoperative RPV, patient age, and serum creatinine level. This is, to our knowledge, the first attempt to predict postoperative renal function without using renal scintigraphy. Finally, RPV was associated with patient age, BSA, and GFR in patients with 1 or both kidneys. In rats, the renal weight begins to increase 7 to 28 days after nephrectomy.10 Histologic analysis has revealed that the primary site of hypertrophy is the cortex, in which proximal tubular cell hypertrophy, collecting tubular cell enlargement, and glomerular mesangium expansion occur within weeks after nephrectomy.11,12 The results from the present study have shown that the RPV of the remaining side increases in a large proportion of patients by 6 months postoperatively. Several attempts have been made to investigate whether split renal function can be calculated by measuring the RPV. Cheung et al13 measured the bipolar length, RPV, and parenchymal and cortical thickness of 65 kidneys in 34 patients with renal artery atherosclerosis using magnetic resonance imaging. They noted that the RPV correlated best with renal function (R ⫽ 0.740). Widjaja et al14 measured the RPV of 138 kidneys in 69 patients with renal artery atherosclerosis using CT images. They showed that the RPV correlates with the single kidney GFR (R ⫽ 0.57) and that the GFR can be predicted using the equation: GFR ⫽ ⫺6.36 ⫹ 0.24 ⫻ RPV. Kato et al7 evaluated the split function in 28 potential renal transplant donors. They reported a good linear correlation between the renal function and volume UROLOGY 77 (6), 2011
ratio (R ⫽ 0.90). Summerlin et al6 also investigated 152 potential renal transplant donors and reported a correlation between the 2 factors (R ⫽ 0.61). The correlation coefficient obtained in the present study concurs with those obtained in previous studies. The recently developed automating software that can measure the renal volume will greatly reduce the time and effort required to determine the split renal function.7 The subjects for these studies were patients with both kidneys. We have demonstrated that the correlation between the RPV and single kidney GFR differed if the patient had 1 or both kidneys. At the same RPV, the GFR was greater in the patients with just 1 kidney. In addition, the RPV increased by an average of 9.3% and the GFR increased by an average of 21.2% after unilateral nephrectomy. These results indicate that a greater effect was loaded on the unit volume in the remaining kidney after the other had been removed. It is still not clear whether compensatory hypertrophy ultimately leads to renal insufficiency. A critical reduction in the renal mass might result in remnant single nephron hyperfiltration with associated proteinuria and accelerated loss of kidney function.15 Compensatory hemodynamic changes in some animal models after a reduction of ⱖ50% in renal mass have been reported to be ultimately deleterious,16,17 and unilateral nephrectomy could negatively affect the remaining kidney.18,19 In contrast, many studies on the functional outcome after renal donation reported no increased risk of renal failure.20,21 We suspect that kidneys that increase less in volume after contralateral nephrectomy might have poorer compensatory potential and a greater risk of renal insufficiency.22 Because iodinated contrast medium is cleared by glomerular filtration, it should be possible to apply the same principle used in radionuclide studies to derive the split renal function. Several investigators have measured the absolute GFR using iodinated contrast clearance, with blood sampling as a surrogate for inulin.23,24 In addition, some attempts have been made to calculate the GFR using the degree of renal enhancement by iodinated contrast medium on CT scans.25-28 The changes with time in renal parenchymal and vascular attenuation after the injection of an intravascular contrast medium can be measured on a regional basis by obtaining sequential CT data from 1 anatomic level and applying a graphic analysis to the baseline subtracted CT numbers. Fowler et al25 measured the enhancing renal volume from CT scans as the RPV multiplied by the increase in the density of the renal parenchyma, using enhancement. They reported a good correlation between the CT- and nuclear medicinederived split renal function (r ⫽ 0.96). The correlations in our study were not as high as those reported by other groups. These methods provide the exact split renal function; however, they require a dedicated scan protocol, excessive additional radiation, or considerable operator input to be useful in routine clinical practice. One study of renal transplant donors re1407
ported no statistically significant difference in the degree of enhancement between the right and left kidneys, indicating that difference in RPV is mainly related to renal function.7 However, if enhancement of the renal parenchyma is weak, as is often the case in patients with impaired renal function or severe hydronephrosis, the renal volume will not reflect renal function. In such cases, recently performed CT scans or nuclear medicine are necessary for accurate evaluation of the split renal function. However, establishing a simple relationship between the RPV and renal function would be useful for easy and rapid calculation of the split renal function. A small, but significant, number of patients could progress to end-stage renal failure after unilateral nephrectomy. In the present study, we followed up patients for 6 months after nephrectomy. To clarify the prognostic factors that determine declining renal function and whether compensatory hypertrophy ultimately leads to renal insufficiency, longer follow-up of patients with different backgrounds is required.
CONCLUSIONS The RPV correlated well with the single kidney GFR, and the differential renal function could be evaluated by measuring the RPV. GFR can be estimated by BSA and RPV. The procedures described in the present study were easy to perform and useful for the rapid calculation of split renal function. References 1. Johansson M, Moonen M. Prediction of post-operative glomerular filtration rate after nephrectomy for renal malignancy. Clin Physiol. 2001;21:688-692. 2. Tanaka N, Fujimoto K, Tani M, et al. Prediction of postoperative renal function by preoperative serum creatinine level and threedimensional diagnostic image reconstruction in patients with renal cell carcinoma. Urology. 2004;64:904-908. 3. Sorbellini M, Kattan MW, Snyder ME, et al. Prognostic nomogram for renal insufficiency after radical or partial nephrectomy. J Urol. 2006;176:472-476. 4. Anderson RG, Bueschen AJ, Lloyd LK, et al. Short-term and long-term changes in renal function after donor nephrectomy. J Urol. 1991;145:11-13. 5. Ito K, Nakashima J, Hanawa Y, et al. The prediction of renal function 6 years after unilateral nephrectomy using preoperative risk factors. J Urol. 2004;171:120-125. 6. Summerlin AL, Lockhart ME, Strang AM, et al. Determination of split renal function by 3D reconstruction of CT angiograms: a comparison with gamma camera renography. AJR Am J Roentgenol. 2008;191:1552-1558. 7. Kato F, Kamishima T, Morita K, et al. Rapid estimation of split renal function in kidney donors using software developed for computed tomographic renal volumetry. Eur J Radiol. Epub 2009 Dec 4. 8. Nyengaard JR, Bendtsen TF. Glomerular number and size in relation to age, kidney weight, and body surface in normal man. Anat Rec. 1992;232:194-201.
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9. Matsuo S, Imai E, Horio M, et al. Revised equations for estimated GFR from serum creatinine in Japan. Am J Kidney Dis. 2009;53: 982-992. 10. Sigmon DH, Gonzalez-Feldman E, Cavasin MA, et al. Role of nitric oxide in the renal hemodynamic response to unilateral nephrectomy. J Am Soc Nephrol. 2004;15:1413-1420. 11. Lee GS, Nast CC, Peng SC, et al. Differential response of glomerular epithelial and mesangial cells after subtotal nephrectomy. Kidney Int. 1998;53:1389-1398. 12. Preisig P. What makes cells grow larger and how do they do it? Renal hypertrophy revisited. Exp Nephrol. 1999;7:273-283. 13. Cheung CM, Shurrab AE, Buckley DL, et al. MR-derived renal morphology and renal function in patients with atherosclerotic renovascular disease. Kidney Int. 2006;69:715-722. 14. Widjaja E, Oxtoby JW, Hale TL, et al. Ultrasound measured renal length versus low dose CT volume in predicting single kidney glomerular filtration rate. Br J Radiol. 2004;77:759-764. 15. Ibrahim HN, Foley R, Tan L, et al. Long-term consequences of kidney donation. N Engl J Med. 2009;360:459-469. 16. Robertson JL, Goldschmidt M, Kronfeld DS, et al. Long-term renal responses to high dietary protein in dogs with 75% nephrectomy. Kidney Int. 1986;29:511-519. 17. Bourgoignie JJ, Gavellas G, Hwang KH, et al. Renal function of baboons (Papio hamadryas) with a remnant kidney, and impact of different protein diets. Kidney Int Suppl. 1989;27:S86-S90. 18. Tapson JS. End-stage renal failure after donor nephrectomy. Nephron. 1986;42:262-264. 19. Mullerad M, Kastin A, Issaq E, et al. The value of quantitative 99m technetium dimercaptosuccinic acid renal scintigraphy for predicting postoperative renal insufficiency in patients undergoing nephrectomy. J Urol. 2003;169:24-27. 20. Ladefoged J. Renal failure 22 years after kidney donation. Lancet. 1992;339:124-125. 21. Garg AX, Muirhead N, Knoll G, et al. Proteinuria and reduced kidney function in living kidney donors: a systematic review, metaanalysis, and meta-regression. Kidney Int. 2006;70:1801-1810. 22. Funahashi Y, Hattori R, Yamamoto T, et al. Change in contralateral renal parenchymal volume 1 week after unilateral nephrectomy. Urology. 2009;74:708-712. 23. Gaspari F, Perico N, Remuzzi G. Application of newer clearance techniques for the determination of glomerular filtration rate. Curr Opin Nephrol Hypertens. 1998;7:675-680. 24. Lindblad HG, Berg UB. Comparative evaluation of iohexol and inulin clearance for glomerular filtration rate determinations. Acta Paediatr. 1994;83:418-422. 25. Fowler JC, Beadsmoore C, Gaskarth MT, et al. A simple processing method allowing comparison of renal enhancing volumes derived from standard portal venous phase contrast-enhanced multidetector CT images to derive a CT estimate of differential renal function with equivalent results to nuclear medicine quantification. Br J Radiol. 2006;79:935-942. 26. Bjorkman H, Eklof H, Wadstrom J, et al. Split renal function in patients with suspected renal artery stenosis: a comparison between gamma camera renography and two methods of measurement with computed tomography. Acta Radiol. 2006;47:107-113. 27. El-Ghar ME, Shokeir AA, El-Diasty TA, et al. Contrast enhanced spiral computerized tomography in patients with chronic obstructive uropathy and normal serum creatinine: a single session for anatomical and functional assessment. J Urol. 2004;172:985-988. 28. El-Diasty TA, Shokeir AA, El-Ghar ME, et al. Contrast enhanced spiral computerized tomography in live kidney donors: a single session for anatomical and functional assessment. J Urol. 2004;171: 31-34.
UROLOGY 77 (6), 2011
RESULTS
CONCLUSIONS
To measure the renal parenchymal volume (RPV) before and after unilateral nephrectomy and investigate the relationship between the RPV and single kidney glomerular filtration rate (GFR). From November 2003 to August 2009, 183 patients who had undergone unilateral nephrectomy were enrolled in the present study. All patients had undergone preoperative technetium-99m dimercaptosuccinic acid renal scintigraphy. Contrast-enhanced computed tomography was performed before and 6 months after surgery. RPV was calculated as the normally functioning tissue, excluding tumors or nonenhanced areas, using a 3-dimensional image reconstruction program. The mean split GFR of the remaining kidney increased by 21.2%, from 41.6 to 49.5 mL/min/1.73 m2 at 6 months after nephrectomy. The mean RPV of the remaining kidney increased by 9.3%, from 164.2 to 178.8 cm3 after nephrectomy. The preoperative relative RPV of the remaining kidney was 58.8% (range 37.2%-97.9%) and the technetium-99m dimercaptosuccinic acid uptake was 62.2% (range 39.6%-100%), indicating a significant linear correlation (R ⫽ 0.865, P ⬍.001). RPV correlated well with the single kidney GFR and patient age, both preoperatively and postoperatively. The postoperative GFR could be predicted by combining the preoperative factors. Multivariate regression analysis revealed that the RPV was positively associated with the single kidney GFR and negatively associated with patient age. The differential renal function correlated well with the RPV and can be estimated by calculating the RPV. Even without using renal scintigraphy, the postoperative GFR can be predicted using our established formula. UROLOGY 77: 1404 –1408, 2011. © 2011 Elsevier Inc.
I
n recent years, the incidence of renal malignancies has been increasing because of the aging of the population and the widespread use of various imaging modalities, such as ultrasonography, computed tomography (CT), and magnetic resonance imaging. Nephronsparing treatment is possible for small tumors; however, radical nephrectomy is still performed in many cases of renal malignancy. The renal function of the remaining kidney will increase to compensate for the loss of nephrons after unilateral nephrectomy. The glomerular filtration rate (GFR) has been reported to decrease to 60%-80% of the preoperative level within several weeks postoperatively and then stabilizes or increases very slightly for ⬎10 years after nephrectomy.1,2 Advanced age, female gender, hypertension, and proteinuria have
From the Department of Urology, Nagoya University Graduate School of Medicine, Nagoya, Japan; and Department of Urology, Komaki City Hospital, Aichi, Japan Reprint requests: Yasuhito Funahashi, M.D., Ph.D., Department of Urology, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya 466-8550 Japan. E-mail: [email protected] Submitted: March 11, 2010, received (with revisions): March 28, 2010
1404
© 2011 Elsevier Inc. All Rights Reserved
been reported as negative factors affecting functional adaptation.3-5 During the preoperative evaluation, we use CT to characterize the mass, exclude locally advanced or metastatic disease, and investigate the anatomy. In addition, it is necessary to estimate the contribution of each kidney to the total renal function to determine the treatment. The reference standard for evaluating the differential renal function is radioisotope imaging. Although it is a reliable and reproducible method, it cannot be performed in an emergency and is expensive. Therefore, it would be beneficial if the split renal function could be quantified using CT. Reconstruction using CT slice images has been proved to be a reliable, objective, and reproducible method of assessing the renal volume.6,7 Also, the kidney volume has been shown to correlate well, although indirectly, with the number of functioning nephrons in autopsy studies.8 Therefore, assessing the split renal function using CT might be possible. In the present study, we measured the normally functioning renal tissue, excluding tumors and cystic lesions, 0090-4295/11/$36.00 doi:10.1016/j.urology.2010.03.063
using CT images before and after unilateral nephrectomy. We then determined the relationship between the renal parenchymal volume (RPV) and split renal function.
MATERIAL AND METHODS Patient Population Of 230 patients who underwent unilateral nephrectomy at Komaki City Hospital from November 2003 to August 2009, the data from 183 patients were used in the present retrospective study. Excluded from the analysis were 3 patients who had not undergone Technetium-99m dimercaptosuccinic acid (DMSA) renal scintigraphy before surgery, 29 patients who had not undergone CT at our institute, and 15 patients who had not undergone CT 6 months after nephrectomy. Open nephrectomy was performed in 148 patients, and laparoscopy was performed in 35. Of these patients, 139 were men, and 44 were women. Their mean age was 62.6 ⫾ 12.8 years (mean ⫾ standard deviation; range 22-89). Their mean body surface area (BSA), calculated using the Dubois equation, was 1.63 ⫾ 0.18 m2 (range 1.13-2.08). Of the 183 patients, 66 were taking medications for hypertension and 14 for diabetes. All patients underwent unilateral nephrectomy: 102 for renal cell carcinoma, 63 for urothelial carcinoma, 17 for an atrophic kidney, and 1 for liposarcoma.
Imaging Procedures For renal scintigraphy, the patients were injected with 74 MBq DMSA. After 2 hours, posterior images were obtained using a Hitachi/Philips SKYLight gamma camera (Hitachi, Japan) equipped with a low-energy, general-purpose collimator. The regions of interest were drawn on the images for both kidneys showing the calculated percentage of split function. Contrast-enhanced CT scans were obtained with a multislice 16-row unit (Sensation 16 Cardiac, Siemens, Munich, Germany) at a table speed of 20 mm/s and a slice thickness of 5 mm. A 100-mL injection of intravenous iodinated-contrast agent (flow 2 mL/s) was administered. The dose of contrast agent was reduced or stopped, if necessary. The regions of interest were drawn around the kidneys, excluding the peripelvic fat and renal pelvis from the images, by 1 experienced radiologist who was unaware of the patients’ clinical information. The functioning renal tissue was determined as the normally enhanced areas on the CT images, and tumor and cysts were excluded from the regions of interest. The RPV was calculated using Volume software (Siemens), a 3-dimensional image reconstruction program. All patients underwent CT before and 6 months after unilateral nephrectomy. The serum creatinine was simultaneously determined, and the GFR was calculated using the revised equation for the estimated GFR for the Japanese [GFR (mL/min/1.73 m2) ⫽ 194 ⫻ age⫺0.287 ⫻ Cr⫺1.094 (⫻ 0.739 if female)].9 The preoperative single kidney GFR was calculated as the preoperative total GFR multiplied by the uptake ratio of the single kidney on DMSA renal scintigraphy.
Statistical Analysis All values are presented as the mean ⫾ standard deviation. Paired t tests were used to compare the preoperative and postUROLOGY 77 (6), 2011
Figure 1. Comparison of normal/diseased ratio between RPV and DMSA. X axis shows uptake of DMSA by normal kidney; y axis shows relative ratio of nRPV to sum of volumes of both kidneys.
operative values. Correlation differences were calculated using Pearson’s correlation coefficient. Univariate and multiple linear regression analyses were used to identify potential factors significantly associated with the postoperative GFR, preoperative RPV, and postoperative RPV. All tests were 2-sided, and P ⬍.05 was considered statistically significant. Statistical analyses were performed using the Statistical Package for Social Sciences for Windows, version 16.0 (SPSS, Chicago, IL).
RESULTS Changes in Serum Creatinine, GFR, and RPV The preoperative serum creatinine level was 0.87 ⫾ 0.23 mg/dL (range 0.45-1.89), and it had increased to 1.19 ⫾ 0.33 mg/dL (range 0.54-3.29) by 6 months after unilateral nephrectomy. The preoperative GFR was 68.5 ⫾ 17.1 mL/min/1.73 m2, and the split GFR of the remaining kidney increased by 21.2%, from 41.6 ⫾ 11.9 to 49.5 ⫾ 13.3 mL/min/1.73 m2 by 6 months after nephrectomy (P ⬍.001). The preoperative RPV of the normal kidney (nRPV) was 161.9 ⫾ 36.6 cm3, and the RPV of the diseased kidney (dRPV) was 120.3 ⫾ 53.1 cm3. The nRPV increased after nephrectomy by 9.3% to 175.9 ⫾ 40.3 cm3 (P ⬍.001) in 143 of the 183 patients.
Comparison of Normal/Diseased Ratio Between RPV and DMSA The preoperative relative nRPV, expressed as a percentage, was 58.8% ⫾ 13.4% (range 37.2%-97.9%) and the percentage of DMSA uptake of the normal side was 62.2% ⫾ 15.9% (range 39.6%-100%). A statistically significant linear correlation was observed between these 2 parameters (R ⫽ 0.865, P ⬍.001; Fig. 1). 1405
Table 1. Statistical significance of factors related to postoperative glomerular filtration rate at 6 months
Variable Age Sex BSA Preoperative nRPV Preoperative GFR ⫻ relative nRPV Preoperative GFR ⫻ relative dRPV Hypertension Diabetes mellitus
Univariate Analysis  P Value
Multivariate Analysis  P Value
⫺0.429 ⬍.001 ⫺0.197 .001 0.230 .761 0.037 .473 0.005 .945 ⫺0.057 .334 0.402 ⬍.001 0.048 .435 0.698 ⬍.001 0.625 ⬍.001 ⫺0.002
.983
0.113
.031
⫺0.148 ⫺0.027
.046 ⫺0.013 .713 0.015
.810 .774
BSA, body surface area; nRPV, renal parenchymal volume of normal kidney; GFR, glomerular filtration rate; dRPV, renal parenchymal volume of diseased kidney.
Figure 2. Relationship between preoperative RPV and single GFR. X axis shows preoperative RPV of normal kidney; y axis shows preoperative single kidney GFR of normal side.
Table 2. Statistical significance of factors related to preoperative nRPV
Variable
Univariate Analysis  P Value
Age ⫺0.431 Sex ⫺0.209 BSA 0.475 Preoperative single 0.529 kidney GFR Hypertension ⫺0.043 Diabetes mellitus 0.037
Multivariate Analysis  P Value
⬍.001 .005 ⬍.001 ⬍.001
0.021 0.059 0.523 0.574
.736 .314 ⬍.001 ⬍.001
.563 .618
0.077 0.051
.133 .315
Abbreviations as in Table 1.
Figure 3. Relationship between postoperative RPV and GFR. X axis shows postoperative RPV of remaining kidney; y axis shows GFR at 6 months after nephrectomy.
Relationship Between Preoperative nRPV and Single Kidney GFR We investigated the relationship between the preoperative nRPV and single kidney GFR of the normal side (Fig. 2). Pearson’s correlation coefficient analysis revealed a statistically significant correlation (R ⫽ 0.517, P ⬍.001).
Relationship Between Postoperative RPV and GFR The relationship between the RPV of the remaining kidney and GFR at 6 months after nephrectomy is plotted in Figure 3. A significant correlation was also found between the 2 variables after nephrectomy (R ⫽ 0.434, P ⬍.001). 1406
Formula to Predict Postoperative Renal Function We investigated whether the postoperative renal function could be estimated from preoperative factors without DMSA scanning. We defined “relative nRPV” as nRPV/ (nRPV ⫹ dRPV) and “relative dRPV” as dRPV/(nRPV ⫹ dRPV). Univariate linear regression analysis revealed a statistically significant relationship between the postoperative GFR and patient age. Multivariate regression analysis revealed that the postoperative GFR was positively associated with “preoperative GFR ⫻ relative nRPV” and “preoperative GFR ⫻ relative dRPV” and negatively associated with patient age (Table 1). Thus, the postoperative renal function can be predicted using the following formula: postoperative GFR ⫽ 14.03 ⫻ (preoperative GFR ⫻ relative nRPV)0.595 ⫻ age⫺0.229 (R ⫽ 0.721). In this formula, we omitted the influence of the “preoperative GFR ⫻ relative dRPV,” because its contribution to the formula was limited. Relationship Between RPV and Patient Characteristics The multivariate regression analysis revealed that RPV was significantly associated with the BSA and single kidney GFR both before (Table 2) and after (Table 3) nephrectomy. The following relationships were revealed. The preoperative nRPV equaled 15.17 ⫻ BSA1.080 ⫻ UROLOGY 77 (6), 2011
Table 3. Statistical significance of factors related to postoperative RPV
Variable
Univariate Analysis  P Value
Multivariate Analysis  P Value
Age ⫺0.509 ⬍.001 ⫺0.110 .074 Gender ⫺0.219 .003 0.047 .414 BSA 0.552 ⬍.001 0.588 ⬍.001 Postoperative GFR 0.474 ⬍.001 0.471 ⬍.001 Hypertension ⫺0.109 .140 ⫺0.029 .559 Diabetes mellitus 0.006 .937 0.022 .652 RPV, renal parenchymal volume; other abbreviations as in Table 1.
preoperative single kidney GFR0.492 in the preoperative state (R ⫽ 0.743), and the RPV equaled 20.65 ⫻ BSA1.201 ⫻ GFR0.395 in the postoperative state (R ⫽ 0.755).
COMMENT Our study had 4 major findings. First, the differential renal function ratio correlated well with the RPV ratio. Second, the GFR can be estimated by measuring the RPV. These 2 results have shown that the single kidney GFR can be assessed by measuring the RPV from CT scans. This method can reduce the cost, speed up the process, and decrease the radiation exposure required for preoperative evaluation. Third, the postoperative GFR after unilateral nephrectomy can be predicted from the preoperative RPV, patient age, and serum creatinine level. This is, to our knowledge, the first attempt to predict postoperative renal function without using renal scintigraphy. Finally, RPV was associated with patient age, BSA, and GFR in patients with 1 or both kidneys. In rats, the renal weight begins to increase 7 to 28 days after nephrectomy.10 Histologic analysis has revealed that the primary site of hypertrophy is the cortex, in which proximal tubular cell hypertrophy, collecting tubular cell enlargement, and glomerular mesangium expansion occur within weeks after nephrectomy.11,12 The results from the present study have shown that the RPV of the remaining side increases in a large proportion of patients by 6 months postoperatively. Several attempts have been made to investigate whether split renal function can be calculated by measuring the RPV. Cheung et al13 measured the bipolar length, RPV, and parenchymal and cortical thickness of 65 kidneys in 34 patients with renal artery atherosclerosis using magnetic resonance imaging. They noted that the RPV correlated best with renal function (R ⫽ 0.740). Widjaja et al14 measured the RPV of 138 kidneys in 69 patients with renal artery atherosclerosis using CT images. They showed that the RPV correlates with the single kidney GFR (R ⫽ 0.57) and that the GFR can be predicted using the equation: GFR ⫽ ⫺6.36 ⫹ 0.24 ⫻ RPV. Kato et al7 evaluated the split function in 28 potential renal transplant donors. They reported a good linear correlation between the renal function and volume UROLOGY 77 (6), 2011
ratio (R ⫽ 0.90). Summerlin et al6 also investigated 152 potential renal transplant donors and reported a correlation between the 2 factors (R ⫽ 0.61). The correlation coefficient obtained in the present study concurs with those obtained in previous studies. The recently developed automating software that can measure the renal volume will greatly reduce the time and effort required to determine the split renal function.7 The subjects for these studies were patients with both kidneys. We have demonstrated that the correlation between the RPV and single kidney GFR differed if the patient had 1 or both kidneys. At the same RPV, the GFR was greater in the patients with just 1 kidney. In addition, the RPV increased by an average of 9.3% and the GFR increased by an average of 21.2% after unilateral nephrectomy. These results indicate that a greater effect was loaded on the unit volume in the remaining kidney after the other had been removed. It is still not clear whether compensatory hypertrophy ultimately leads to renal insufficiency. A critical reduction in the renal mass might result in remnant single nephron hyperfiltration with associated proteinuria and accelerated loss of kidney function.15 Compensatory hemodynamic changes in some animal models after a reduction of ⱖ50% in renal mass have been reported to be ultimately deleterious,16,17 and unilateral nephrectomy could negatively affect the remaining kidney.18,19 In contrast, many studies on the functional outcome after renal donation reported no increased risk of renal failure.20,21 We suspect that kidneys that increase less in volume after contralateral nephrectomy might have poorer compensatory potential and a greater risk of renal insufficiency.22 Because iodinated contrast medium is cleared by glomerular filtration, it should be possible to apply the same principle used in radionuclide studies to derive the split renal function. Several investigators have measured the absolute GFR using iodinated contrast clearance, with blood sampling as a surrogate for inulin.23,24 In addition, some attempts have been made to calculate the GFR using the degree of renal enhancement by iodinated contrast medium on CT scans.25-28 The changes with time in renal parenchymal and vascular attenuation after the injection of an intravascular contrast medium can be measured on a regional basis by obtaining sequential CT data from 1 anatomic level and applying a graphic analysis to the baseline subtracted CT numbers. Fowler et al25 measured the enhancing renal volume from CT scans as the RPV multiplied by the increase in the density of the renal parenchyma, using enhancement. They reported a good correlation between the CT- and nuclear medicinederived split renal function (r ⫽ 0.96). The correlations in our study were not as high as those reported by other groups. These methods provide the exact split renal function; however, they require a dedicated scan protocol, excessive additional radiation, or considerable operator input to be useful in routine clinical practice. One study of renal transplant donors re1407
ported no statistically significant difference in the degree of enhancement between the right and left kidneys, indicating that difference in RPV is mainly related to renal function.7 However, if enhancement of the renal parenchyma is weak, as is often the case in patients with impaired renal function or severe hydronephrosis, the renal volume will not reflect renal function. In such cases, recently performed CT scans or nuclear medicine are necessary for accurate evaluation of the split renal function. However, establishing a simple relationship between the RPV and renal function would be useful for easy and rapid calculation of the split renal function. A small, but significant, number of patients could progress to end-stage renal failure after unilateral nephrectomy. In the present study, we followed up patients for 6 months after nephrectomy. To clarify the prognostic factors that determine declining renal function and whether compensatory hypertrophy ultimately leads to renal insufficiency, longer follow-up of patients with different backgrounds is required.
CONCLUSIONS The RPV correlated well with the single kidney GFR, and the differential renal function could be evaluated by measuring the RPV. GFR can be estimated by BSA and RPV. The procedures described in the present study were easy to perform and useful for the rapid calculation of split renal function. References 1. Johansson M, Moonen M. Prediction of post-operative glomerular filtration rate after nephrectomy for renal malignancy. Clin Physiol. 2001;21:688-692. 2. Tanaka N, Fujimoto K, Tani M, et al. Prediction of postoperative renal function by preoperative serum creatinine level and threedimensional diagnostic image reconstruction in patients with renal cell carcinoma. Urology. 2004;64:904-908. 3. Sorbellini M, Kattan MW, Snyder ME, et al. Prognostic nomogram for renal insufficiency after radical or partial nephrectomy. J Urol. 2006;176:472-476. 4. Anderson RG, Bueschen AJ, Lloyd LK, et al. Short-term and long-term changes in renal function after donor nephrectomy. J Urol. 1991;145:11-13. 5. Ito K, Nakashima J, Hanawa Y, et al. The prediction of renal function 6 years after unilateral nephrectomy using preoperative risk factors. J Urol. 2004;171:120-125. 6. Summerlin AL, Lockhart ME, Strang AM, et al. Determination of split renal function by 3D reconstruction of CT angiograms: a comparison with gamma camera renography. AJR Am J Roentgenol. 2008;191:1552-1558. 7. Kato F, Kamishima T, Morita K, et al. Rapid estimation of split renal function in kidney donors using software developed for computed tomographic renal volumetry. Eur J Radiol. Epub 2009 Dec 4. 8. Nyengaard JR, Bendtsen TF. Glomerular number and size in relation to age, kidney weight, and body surface in normal man. Anat Rec. 1992;232:194-201.
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9. Matsuo S, Imai E, Horio M, et al. Revised equations for estimated GFR from serum creatinine in Japan. Am J Kidney Dis. 2009;53: 982-992. 10. Sigmon DH, Gonzalez-Feldman E, Cavasin MA, et al. Role of nitric oxide in the renal hemodynamic response to unilateral nephrectomy. J Am Soc Nephrol. 2004;15:1413-1420. 11. Lee GS, Nast CC, Peng SC, et al. Differential response of glomerular epithelial and mesangial cells after subtotal nephrectomy. Kidney Int. 1998;53:1389-1398. 12. Preisig P. What makes cells grow larger and how do they do it? Renal hypertrophy revisited. Exp Nephrol. 1999;7:273-283. 13. Cheung CM, Shurrab AE, Buckley DL, et al. MR-derived renal morphology and renal function in patients with atherosclerotic renovascular disease. Kidney Int. 2006;69:715-722. 14. Widjaja E, Oxtoby JW, Hale TL, et al. Ultrasound measured renal length versus low dose CT volume in predicting single kidney glomerular filtration rate. Br J Radiol. 2004;77:759-764. 15. Ibrahim HN, Foley R, Tan L, et al. Long-term consequences of kidney donation. N Engl J Med. 2009;360:459-469. 16. Robertson JL, Goldschmidt M, Kronfeld DS, et al. Long-term renal responses to high dietary protein in dogs with 75% nephrectomy. Kidney Int. 1986;29:511-519. 17. Bourgoignie JJ, Gavellas G, Hwang KH, et al. Renal function of baboons (Papio hamadryas) with a remnant kidney, and impact of different protein diets. Kidney Int Suppl. 1989;27:S86-S90. 18. Tapson JS. End-stage renal failure after donor nephrectomy. Nephron. 1986;42:262-264. 19. Mullerad M, Kastin A, Issaq E, et al. The value of quantitative 99m technetium dimercaptosuccinic acid renal scintigraphy for predicting postoperative renal insufficiency in patients undergoing nephrectomy. J Urol. 2003;169:24-27. 20. Ladefoged J. Renal failure 22 years after kidney donation. Lancet. 1992;339:124-125. 21. Garg AX, Muirhead N, Knoll G, et al. Proteinuria and reduced kidney function in living kidney donors: a systematic review, metaanalysis, and meta-regression. Kidney Int. 2006;70:1801-1810. 22. Funahashi Y, Hattori R, Yamamoto T, et al. Change in contralateral renal parenchymal volume 1 week after unilateral nephrectomy. Urology. 2009;74:708-712. 23. Gaspari F, Perico N, Remuzzi G. Application of newer clearance techniques for the determination of glomerular filtration rate. Curr Opin Nephrol Hypertens. 1998;7:675-680. 24. Lindblad HG, Berg UB. Comparative evaluation of iohexol and inulin clearance for glomerular filtration rate determinations. Acta Paediatr. 1994;83:418-422. 25. Fowler JC, Beadsmoore C, Gaskarth MT, et al. A simple processing method allowing comparison of renal enhancing volumes derived from standard portal venous phase contrast-enhanced multidetector CT images to derive a CT estimate of differential renal function with equivalent results to nuclear medicine quantification. Br J Radiol. 2006;79:935-942. 26. Bjorkman H, Eklof H, Wadstrom J, et al. Split renal function in patients with suspected renal artery stenosis: a comparison between gamma camera renography and two methods of measurement with computed tomography. Acta Radiol. 2006;47:107-113. 27. El-Ghar ME, Shokeir AA, El-Diasty TA, et al. Contrast enhanced spiral computerized tomography in patients with chronic obstructive uropathy and normal serum creatinine: a single session for anatomical and functional assessment. J Urol. 2004;172:985-988. 28. El-Diasty TA, Shokeir AA, El-Ghar ME, et al. Contrast enhanced spiral computerized tomography in live kidney donors: a single session for anatomical and functional assessment. J Urol. 2004;171: 31-34.
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