V08_No_4_Final_New.pdf Endourology and Stone Disease 277Urology Journal Vol 8 No 4 Autumn 2011 Evaluating Percutaneous Nephrolithotomy- Induced Kidney Damage by Measuring Urinary Farzaneh Sharifiaghdas, Amir Hossein Kashi, Ramin Eshratkhah Purpose: To assess percutaneous nephrolithotomy (PCNL)-induced kidney tubular damage and the associated factors. Materials and Methods: One hundred and eight patients who have undergone PCNL from May 2007 to October 2007 were recruited in this study. Urinary level of 2-microglobulin (U 2MG) was measured on the day before the operation as well as on the 1st and 7th post PCNL days. Percutaneous nephrolithotomy was performed using standard method. Patients’ demographic and peri-operative data were collected to evaluate factors influencing renal injury. Results: Median urinary levels of 2-microglobulin on pre-operative, 1st, and 7th postoperative days were 0.2 mg/dL (range, 0.1 to 82), 0.4 mg/ dL (range, 0.2 to 97), and 0.2 mg/dL (range, 0.2 to 114), respectively. High levels of U 2MG (> 2.3 mg/dL) were observed in 10 (9%), 20 (19%), and 10 (9%) patients pre-operatively and on the 1st and 7th postoperative days, respectively. In multivariable analysis, U 2MG on the 1st postoperative day was associated with pre-operative serum creatinine level (P < .001) and diabetes mellitus (P = .05), while U 2MG on the 7th day after the operation was associated with pre-operative serum creatinine level (P = .01), diabetes mellitus (P = .01), and PCNL time (P = .02). Conclusion: Percutaneous nephrolithotomy does not cause kidney tubular injury beyond one week. In patients with pre-operative high serum creatinine concentration, diabetes mellitus, and/or long operation time, the likelihood of the kidney damage is higher than others. Urol J. 2011;8:277-82. www.uj.unrc.ir Keywords: percutaneous nephrolithotomy, beta 2-microglobulin, acute kidney injury Urology and Nephrology Research Center, Shahid Labbafinejad Medical Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran Corresponding Author: Farzaneh Sharifiaghdas, MD Department of Urology, Shahid Labbafinejad Medical Center, 9th Boustan St., Pasdaran Ave., 16666-94516, Tehran, Iran Tel/Fax: +98 21 2258 8016 E-mail: fsharifiaghdas@yahoo.com Received March 2011 Accepted August 2011 INTRODUCTION Different methods have been used to assess percutaneous nephrolithotomy (PCNL)- induced renal injury, including measurement of serum level of creatinine, creatinine clearance,(1,2) and nuclear scans, such as diethylenetriamine pentaacetic acid (DTPA), dimercaptosuccinic acid (DMSA), and mercaptuacetyltriglycine (MAG-3). (3-7) These markers demonstrate the changes in glomerular function of the kidneys after the PCNL, on which little work has been done, to the best of our knowledge. Previous studies have shown that -2 microglobulin is a more sensitive marker of renal tubular injury in comparison with serum creatinine level. Therefore, its measurement has been advocated Kidney Damage With PCNL—Sharifiaghdas et al 278 Urology Journal Vol 8 No 4 Autumn 2011 as an early marker of tubular injury.(8-12) Furthermore, unlike nuclear scans, concentrations of urinary -2 microglobulin (U 2MG) are not influenced by urinary obstruction.(13) This study was aimed to assess PCNL-induced renal tubular injury by measuring U 2MG. MATERIALS AND METHODS This study was carried out on 108 patients with nephrolithiasis who underwent PCNL in Labbafinejad Medical Center in Tehran, Iran, from May 2007 to October 2007. The reasons for PCNL were as follows: Obstructive kidney stones > 2 cm, failed extracorporeal shock wave lithotripsy (SWL), kidney stones with distal stenosis, and stones > 1 cm in proximal ureter and failed SWL. Percutaneous nephrolithotomy was done using standard method. Urinary -2 microglobulin was measured pre- operatively and on the 1st and 7th postoperative days by an immunoassaykit (MININEPHTM; The Binding Site Ltd., Birmingham, UK). The U 2MG samples on the 1st and 7th postoperative days were collected from the nephrostomy catheter and the voided urine sample, respectively. The normal reference range of U 2MG according to the manufacturer instructions is 0.3 to 2.3 mg/dL. Therefore, U 2MG values higher than 2.3 mg/dL were considered abnormal. Patients’ demographic, laboratory, and peri-operative data were collected to identify factors correlated with U 2MG changes on postoperative days. Statistical Analysis The gathered data were analyzed using SPSS software (the Statistical Package for the Social Sciences, Version 16.0, SPSS Inc., Chicago, Illinois, USA). Two separate analyses were planned: At first, changes in concentrations of U 2MG on the 1st and 7th postoperative days were compared with pre-operative values. The associations of U 2MG changes with independent categorical and qualitative variables were investigated by Mann-Whitney U test and Spearman correlation coefficient, respectively. The independent variables included age, gender, stone size, hypertension, ischemic heart disease and diabetes mellitus as well as pre-operative hydronephrosis, regional renal cortical atrophy, creatinine level, operation duration, and access numbers. Thereafter, significant variables were entered into two analysis of covariance models with dependent variables defined as U 2MG values on days 1 and 7 after the operation. Pre-operative U 2MG was used as a covariate to remove its effect. The second analysis was restricted to patients with normal pre-operative serum creatinine level (group N). The associations of high postoperative U 2MG with independent variables were assessed by Chi-Square or Fisher’s Exact tests, as appropriate. To obtain odds ratios for significant variables in group N, a logistic regression was used. RESULTS Patients’ characteristics and peri-operative data are summarized in Table 1. Stone location was the renal pelvis in 27 (25.0%), lower calyx in 18 (16.6%), lower calyx and pelvis in 18 (16.6%), multiple calyces in 12 (11.1%), upper calyx in 3 (2.7%), staghorn in 22 (20.3%), middle calyx in 3 (2.7%), diverticulum in 2 (1.8%), and proximal ureter in 3 (2.7%) patients. Mild, moderate, and severe obstructive hydronephrosis due to the kidney stones were present on pre-operative intravenous pyelography in 18 (16.6%), 59 (54.6%), and 13 (12.0%) patients, respectively. High U 2MG on the pre-operative day, 1st, and 7th postoperative days was found in 10 (9%), 20 (19%), and 10 (9%) patients, respectively. The 20 patients with high U 2MG on the 1st postoperative day included 10 patients with high and 10 with normal pre-operative U 2MG. All these patients had normal U 2MG on the 7th postoperative day, except one patient. In bivariable analysis, U 2MG changes on the 1st day after the operation were associated with access numbers and operation time while on the 7th day, they were correlated with hydronephrosis severity, cortical atrophy, and pre-operative serum creatinine level (Table 2). In analysis of covariance, pre-operative serum creatinine level Kidney Damage With PCNL—Sharifiaghdas et al 279Urology Journal Vol 8 No 4 Autumn 2011 and diabetes mellitus were statistically significant predictors of U 2MG on the 1st postoperative day (P < .001 and P = .05, respectively), while pre-operative serum creatinine level (P = .01), presence of diabetes mellitus (P =.01), and operation duration (P = .02) were significant predictors of the U 2MG on the 7th postoperative day (Table 2). Group N included 98 patients with normal pre-operative serum creatinine level. All of these patients had normal pre-operative U 2MG. Ten (10%) patients in group N developed high U 2MG on the 1st day while only 1 patient had increased U 2MG levels on the 7th postoperative day. Therefore, we did not perform statistical analysis for factors contributing to increased U 2MG on the 7th postoperative day. The factors contributing to high U 2MG on day 1 after the operation in this subgroup of patients with normal pre-operative U 2MG were analyzed (Table 3). Injury in this subgroup of patients was correlated with operation time and access numbers. On day 1, U 2MG levels significantly increased as operation time exceeded 40 minutes. Stone size was neither associated with pre-operative U 2MG nor operation Characteristic Age (y), mean ± SD 44 ± 15 Gender (Male/Female), N/N 74/34 Stone size (mm), mean ± SD 2.6 ± 0.6 Pre-operative creatinine (mg/dL), median (range) 1.0 (0.1 to 3.6) Pre-operative hemoglobin (g/dL), mean ± SD 14.0 ± 1.3 Pre (range) 0.2 (0.12 to 82) History of stone intervention, N (%) SWL 37 (34) PCNL 4 (4) Open surgery 12 (11) Multiple 12 (11) Hypertension, N (%) 19 (18) Diabetes, N (%) 5 (5) Ischemic heart disease, N (%) 7 (7) Access numbers, N (%) One 91 (84) Two 17 (16) Postoperative creatinine (mg/dL), median (range) 1.1 (0.5 to 4.1) Hemoglobin drop (g/dL), median (range) 0.8 (0 to 6.1) Operation duration (min), median (range) 40 (20 to 120) Hospital stay (d), median (range) 4 (1 to 10) (range) 0.4 (0.2 to 97) (range) 0.2 (0.2 to 114) Table 1. Patients’ characteristics and peri-operative data SWL, extracorporeal shock wave lithotripsy; and PCNL, percutaneous nephrolithotomy. Variables Number /dL day 1 day 7 Pre-operative Creatinine, mg/dL 98 0.20 (0.20 to 0.23) 0.34 (0.20 to 1.07)† 0.20 (0.20 to 0.21)*† > 1.5 10 13.5 (5.4 to 27.7) 12.5 (6.9 to 62.5)† 14.3 (6.7 to 58.5)*† Pre-operative Hydronephrosis Moderate to Severe 72 0.20 (0.20 to 0.29) 0.50 (0.20 to 2.30) 0.20 (0.20 to 0.50)* None to Mild 36 0.21 (0.20 to 0.29) 0.37 (0.20 to 1.09) 0.20 (0.20 to 0.20)* Cortex Thickness Normal 53 0.20 (0.20 to 0.27) 0.23 (0.20 to 1.07) 0.20 (0.20 to 0.20)* Decreased 55 0.20 (0.20 to 0.40) 0.53 (0.20 to 3.40) 0.20 (0.20 to 0.70)* Operation Duration, min 20 to 40 57 0.20 (0.20 to 0.27) 0.20 (0.20 to 0.89)* 0.20 (0.20 to 0.22)† 40 to 120 51 0.20 (0.20 to 0.40) 0.86 (0.20 to 6.00)* 0.20 (0.20 to 0.56)† Access Numbers One 91 0.20 (0.20 to 0.30) 0.34 (0.20 to 1.35)* 0.20 (0.20 to 0.36) Two 17 0.20 (0.20 to 0.23) 0.90 (0.28 to 6.15)* 0.20 (0.20 to 0.49) Diabetes Mellitus Yes 5 0.70 (0.20 to 10.90) 2.20 (1.55 to 12.00)† 0.30 (0.20 to 11.50)† No 103 0.20 (0.20 to 0.28) 0.36 (0.20 to 1.40)† 0.20 (0.20 to 0.36)† Table 2. demographic and operative factors statistically significant in bivariable analysis between two subgroups of the factor under variables column (P < .05) †Statistically significant difference column in the analysis of covariance (P < .05) Kidney Damage With PCNL—Sharifiaghdas et al 280 Urology Journal Vol 8 No 4 Autumn 2011 tubular injury in group N. The odds ratios (95% confidence interval) predicting the possibility of high postoperative U 2MG for pre-operative creatinine, pre-operative U 2MG, operation duration, and access numbers were 0.00 (0 to 0.64), 35.80 (1.11 to 11200), 1.07 (1.01 to 1.12), and 18.50 (2.7 to 120.3), respectively. DISCUSSION Early studies of PCNL that induced injury to the kidneys in animal models reported 1.5± 0.5% anatomic scar with no or minimal long- term functional changes.(2) Later human studies showed that this procedure does not result in impaired renal function.(1-3,5-7,14) However, there is the possibility of renal tubular injury after PCNL, but few studies have addressed this issue. Understanding the presence and importance of the kidney tubular injury during PCNL can provide further injury through medications or interventions like early re-PCNL. Many studies have shown that U 2MG increases in renal tubular injury as an early marker;(8,12) therefore, it has been suggested as a screening tool for diagnosis of such injuries.(10) Urinary -2 microglobulin has also been used to measure the kidney tubular injury after SWL.(15-17) An important point in using U 2MG as a renal injury assessment tool is its simple, non-invasive measurement, and the convenient serial tracking of its levels.(18) Several human studies reported elevation of U 2MG in some conditions, such as obstructive pediatric and fetal uropathies, pediatric reflux disease,(19) heavy metal poisoning,(20,21) kidney trauma,(22) and spinal cord injuries.(23) One human study after PCNL reported increased levels of U 2MG that returned to normal level before one month.(24) The results of this study suggest that pre- operative serum creatinine level plays a valuable predictive role in estimating PCNL-induced renal injury as pre-operative serum creatinine levels were correlated with postoperative changes of U 2MG on days 1 and 7. Urinary levels of -2 microglobulin remained elevated and usually increased relative to their pre-operative values on the 7th day after the operation. High pre-operative serum creatinine level indicates prior kidney injury due to a chronic inflammatory process initiated by a renal stone.(25) These patients experienced further tubular injury during PCNL and its magnitude judged by U 2MG was higher than patients with normal pre-operative serum creatinine level. Characteristic 1 st N = 88 1st day High N = 10 P Gender, N (%) NSMale 60 (88) 8 (12) Female 28 (93) 2 (7) Stone size, cm, N (%) NS27 (90) 3 (10) > 2 61 (90) 7 (10) Pre-operative hydronephrosis, N (%) NSNone to Mild 33 (92) 3 (8) Moderate to Severe 55 (89) 7 (11) Pre-operative kidney cortex, N (%) NSThin 41 (89) 5 (11) Normal 47 (90) 5 (10) Operation duration, min, N (%) < .001 20 to 50 66 (99) 1 (1) 51 to 80 20 (74) 7 (26) 81 to 120 2 (50) 2 (50) Access numbers, N (%) < .0011 78 (96) 3 (4) 2 10 (59) 7 (41) Table 3. st postoperative day NS indicates non-significant. Kidney Damage With PCNL—Sharifiaghdas et al 281Urology Journal Vol 8 No 4 Autumn 2011 In addition to pre-operative serum creatinine level, operation time was also associated with U 2MG changes on day 7. Operation time may result in more renal injury by factors, such as more prolonged litholapaxy, or indirectly through more complicated operations that prolong both operation duration and renal injuries. In bivariable analysis, access numbers (one or two) were related to U 2MG changes on the 1st day, but not the 7th day. The same relationship was observed in group N. This finding has been previously reported by Eshghi and colleagues.(4) In their study on the kidney effects of PCNL measured by nuclear scans several weeks after the operation, no difference was noticed in cases of more than one nephrostomy tract creation compared with one tract creation. Increased access numbers can result in transient kidney injury that may be recovered soon. Stone size was not a statistically significant predictor of postoperative U 2MG. We think that part of this observation is related to the narrow window of variability in the size of renal stones in this study, 95% of stones were 2 to 3.5 cm. Therefore, other factors, including stone composition, location, and caliceal anatomy could play more substantial roles in operation duration and tubular induced injury than stone size. 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