Jpn J Clin Oncol 2013;43(12)1243– 1248 doi:10.1093/jjco/hyt149 Advance Access Publication 5 November 2013
Incidence and Risk Factors of Chronic Kidney Disease in Korean Patients with T1a Renal Cell Carcinoma Before and After Radical or Partial Nephrectomy Sung Han Kim1, Sang Eun Lee2, Sung Kyu Hong2, Chang Wook Jeong2, Yong Hyun Park1, Yong-June Kim3, Seok Ho Kang4, Sung-Hoo Hong5, Won Suk Choi6 and Seok-Soo Byun2,* Department of Urology, Seoul National University College of Medicine, Seoul, 2Department of Urology, Seoul National University Bundang Hospital, Seongnam, 3Department of Urology, Chungbuk National University College of Medicine, Cheongju, 4Department of Urology, College of Medicine, Korea University, Seoul, 5Department of Urology, College of Medicine, the Catholic University of Korea, Seoul and 6Urologic Clinic, Yongin, Korea *For reprints and all correspondence: Seok Soo Byun, Department of Urology, Seoul National University Bundang Hospital, 82 Gumi-ro 173 Beon-gil, Bundang-gu, Seongnam 463-707, Korea. E-mail: [email protected] Received May 9, 2013; accepted September 5, 2013
Objective: The aim of the study was to investigate the incidence of chronic kidney disease in patients with T1a renal cell carcinoma both before and after partial or radical nephrectomy, and to assess risk factors for chronic kidney disease. Methods: From January 2001 to December 2011, 1928 patients with a single renal mass 4 cm undergoing partial nephrectomy or radical nephrectomy with the existence of a normal contralateral kidney were retrospectively reviewed for the evaluation of preoperative chronic kidney disease, and reviewed only 1676 patients for the postoperative chronic kidney disease. The estimated glomerular filtration rates were used to define chronic kidney disease ,60 ml/ min/1.73 m2 by the Modification of Diet in Renal Disease equation. Demographics and clinicopathological parameters were evaluated to determine the risk factors with the development of chronic kidney disease both before and after surgery. Results: Chronic kidney disease was found preoperatively in 10.0% (n ¼ 192) of patients; 16.1% (n ¼ 269) of patients developed chronic kidney disease postoperatively, including 102 (6.1%) chronic kidney disease patients .65 years of age. Between the non-chronic kidney disease and chronic kidney disease patients, male gender (odds ratio 3.55 vs. 3.78, respectively) and diagnostic age (odds ratio 1.04 vs. 1.05) were significantly distinctive common risk factors for chronic kidney disease both before and after surgery (P , 0.002). In addition, hypertension (odds ratio 0.46), serum albumin (odds ratio 0.23) and calcium (odds ratio 2.06) were significant as preoperative risk factors (P , 0.015), and preoperative serum creatinine (odds ratio 1.90) and surgical type ( partial nephrectomy or radical nephrectomy; odds ratio 11.89) were significant as postoperative risk factors (P , 0.030). Conclusions: Old, male hypertensive patients with a small renal mass would be better candidates for partial nephrectomy to prevent postoperative chronic kidney disease. Key words: carcinoma – renal cell – nephrectomy – renal insufficiency – chronic – incidence – risk factors
# The Author 2013. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected]
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INTRODUCTION
PATIENTS AND METHODS Approval of the study was obtained from the Institutional Review Board (IRB No. B-1202/145-102). A total of 1982 patients with sporadic RCC ,4 cm and non-metastatic RCC (pathologic T1aN0M0, International Union Against Cancer/ American Joint Committee on Cancer, 2009) at the time of surgery were collected from five institutions between January 2001 and December 2011 in the Republic of Korea. After excluding patients with a solitary kidney, metastatic disease, bilateral disease or previous renal surgery, 1928 patients were enrolled in the study. The patients’ clinicopathological information was retrospectively reviewed. All patients had undergone PN or RN with a curative intent and had a follow-up of at least 6 months. Follow-up consisted of a history, physical examination, routine blood work and serum chemistry, chest radiography and abdomen computed tomography (CT) every 6 months for 3 years, and then yearly in most patients. Other radiographic evaluations, including bone scan, MRI or positron emission tomography – CT, were performed when clinically indicated. Patients were divided into CKD and non-CKD groups before ( pre-CKD vs. pre-non-CKD) and after surgery
RESULTS Among the 1928 patients with a single small renal mass 4 cm, pre-CKD was found in 10.0% of patients, whereas
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Improvements in imaging modalities have made the detection of small, localized, renal masses considerably easier. There is, therefore, a corresponding rise in treatment, with radical nephrectomy (RN), partial nephrectomy (PN), thermal ablation or active surveillance among the treatments recommended by the American Urological Association (1). Recent studies have suggested that PN showed an equivalent oncological outcome for renal masses ,4 cm in size, and better postoperative preservation of overall renal function than RN to reduce the prevalence of chronic kidney disease (CKD) (2). Patients with CKD [defined as an estimated glomerular filtration rate (eGFR) , 60 ml/min/1.73 m2] often develop and progress to kidney failure, complications from decreased renal function, cardiovascular disease or death (3,4). As more incidental, small renal masses are increasingly detected, and the negative relationship between long-term CKD and morbidity/mortality is uncovered, the preservation of kidney function and its related aggravating factors will continue to be emphasized, because conservative serum creatinine levels do not exactly reflect renal function and its degree of impairment (5,6). According to Coresh’s study, 25% of patients with normal serum creatinine levels in the study had CKD (7). Therefore, it is important to determine the parameters of renal function and aggravating factors of CKD after renal treatment. In this multicenter, retrospective study, we estimated the incidence of baseline CKD and postoperative development of CKD in patients with a single, small renal mass 4 cm of renal cell carcinoma (RCC), and assessed the parameters of renal function before and after either PN or RN.
(post-CKD vs. post-non-CKD), according to their renal function calculated by the Modification of Diet in Renal Disease (MDRD) equation (8). Pre-CKD and pre-non-CKD are groups of RCC patients who have detected indolent CKD and who have not detected CKD before nephrectomy, respectively. And post-CKD and post-non-CKD are groups of RCC patients who developed or who did not develop CKD after nephrectomy, respectively. The preoperative and postoperative CKD and non-CKD groups ([ pre-CKD vs. pre-non-CKD] and [ post-CKD vs. post-non-CKD]) were analyzed with the following demographic and perioperative parameters: age, sex, body mass index (BMI), diabetes, hypertension, blood tests [hemoglobin, platelet, creatinine, albumin, calcium, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), MDRD eGFR, Eastern Cooperative Oncology Group performance status (ECOG) group, tumor characteristics (size, laterality and location), surgical type (PN or RN), surgical method (laparoscopy or open), operative time, estimated blood loss (EBL), transfusion, pathologic data (included Fuhrman grade and surgical margin status), intra- and postoperative complications, recurrence and survival. The choice of a surgical approach was based on the referrals and the surgeon’s preference. To evaluate renal function and CKD, serum creatinine levels were measured preoperatively and at the 6-month follow-up postoperatively in all patients using the Jaffe´ method. The four-variable MDRD formula (eGFR ¼ 186.3 Pcr21.154 age20.203 0.742; if female) using serum creatinine levels and demographic variables was used to estimate the glomerular filtration rate (GFR). The outcome measure used in this study was the development of new onset CKD with an estimated GFR of ,60 ml/min/1.73 m2 after surgery, with an interval of at least 6 months after the operation. All patients with pre-CKD (n ¼ 192) and those with a deficiency of postoperative serum creatinine level (n ¼ 60) were excluded from the study when evaluating the incidence rate of developing post-CKD and post-CKD risk factors (RFs), yielding a total of 1676 patients. Comparisons of the qualitative and quantitative variables of the CKD and non-CKD groups before and after PN or RN were performed using a x 2 test or independent t test as appropriate. After prequalification of demographics and clinicopathological parameters with univariate analysis, significant factors were evaluated using logistic regression analysis to determine the association of the independent variables with baseline pre-CKD and development of post-CKD. Null hypotheses of no difference were rejected if P values were ,0.05 (two-tailed). All data analyses were processed with SPSS 18.0 statistical software (SPSS, Inc., Chicago, IL, USA).
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16.1% of patients developed post-CKD (Tables 1 and 2). Among 1336 males and 592 females, renal tumors were found in males twice as often as females (69.3% vs. 30.7%), and CKD was detected more frequently in males (8.7%) than in females (1.3%) using the renal functional analysis with eGFR MDRD ,60 ml/min/1.76 m 2 (Table 1). Among the 447 patients .65 years of age, 87 (19.5%) patients were found to have indolent pre-CKD before surgery, and 102 (28.3%) out Table 1. Demographic and clinicopathological variables before surgery (n ¼ 1928) Pre-non-CKD
Pre-CKD
P value
Subjects, n (%)
1736 (90.0)
192 (10.0)
Age, mean + SD, years
54.3 + 12.5
60.7 + 12.4
,0.001
Sex, n (%)
1336 (69.3)
592 (30.7)
,0.001
1169 (60.6)/567 (29.4)
167 (8.7)/25 (1.3)
37.6 + 31.5
38.1 + 29.9
Male/Female, n (%) Duration of follow-up, mean + SD, months
Table 2. Demographic and clinicopathological variables associated with surgically incidental CKD (n ¼ 1676) Variables
Post-non-CKD
Post-CKD
P value
Subjects, n (%)
1407 (83.9)
269 (16.1)
Diagnostic age, mean + SD, years
53.3 + 12.4
60 + 11.7
,0.001 ,0.001
Sex, n (%)
1133 (67.6)
543 (32.4)
Male/female, n (%)
905 (54)/228 (13.6)
502 (30)/ 41 (2.4)
Body mass index, mean + SD, kg/m2
24.7 + 10.1
24.7 + 3.1
Follow-up duration, mean + SD, months
36.4 + 30.5
47.69 + 35.8
,0.001
,0.001
0.005
Comorbidities Diabetes, n (%)
153 (10.9)
59 (21.9)
Hypertension, n (%)
420 (29.9)
117 (43.5)
ECOG, n (%) 0.329
Comorbidities ,0.001
Group 0
587 (41.7)
120 (44.6)
Group 1
498 (35.4)
62 (23.1)
Group 2
303 (21.5)
73 (27.1)
Group 3
19 (1.4)
14 (5.2)
14.0 + 1.7
13.9 + 1.8
,0.001
Diabetes, n (%)
221 (12.7)
50 (26.0)
Hypertension, n (%)
557 (32.1)
116 (60.4)
Group 0
695 (40.0)
71 (37.0)
Group 1
602 (34.7)
36 (18.8)
ESR, mean + SD, mg/dl
13.1 + 24.5
13.1 + 24.5
0.491
Albumin, mean + SD, g/dl
4.3 + 0.5
4.3 + 0.5
0.001
Calcium, mean + SD, mg/
9.2 + 0.6
9.2 + 0.6
0.547
Creatinine, mean + SD, mg/dl
0.9 + 0.4
1.1 + 0.5
,0.001
,0.001
Laboratory findings
ECOG, n (%)
Group 2
404 (23.3)
65 (33.8)
Group 3
35 (2.0)
2 0(10.4)
Hemoglobin, mean + SD, g/dl
14.0 + 1.8
13.2 + 2.0
0.107
ESR, mean + SD, mg/dl
13.4 + 23.4
24.3 + 26.0
0.051
Albumin, mean + SD, g/dl
4.3 + 0.5
4.0 + 0.5
,0.001
Calcium, mean + SD, mg/dl
9.2 + 0.6
9.0 + 0.7
0.001
Creatinine, mean + SD, mg/dl
,0.001
1.0 + 0.4
2.1 + 3.6
95.1 + 28.1
41.7 + 20.2
Tumor size, mean + SD, cm
2.6 + 1.5
2.6 + 1.7
0.732
Type, n (%) Radical nephrectomy
620 (35.7)
111 (57.8)
Partial nephrectomy
1116 (64.3)
81 (42.2)
Pure laparoscopy
446 (25.7)
59 (30.7)
Hand-assisted laparoscopy
73 (4.2)
5 (2.6)
Open
471 (27.1)
83 (43.3)
Robot-assisted laparoscopy
746 (43.0)
640 (23.4)
0.608
dl
Laboratory findings
eGFRþ, mean + SD, ml/min/ 1.73 m2
Hemoglobin, mean + SD, g/dl
,0.001
NA
MDRD, mean + SD, ml/min/1.73 m2 Preoperative
97.6 + 28.8
77.3 + 13.6
Postoperative
93.3 + 28.5
49.7 + 10.1
Tumor size, mean + SD, cm
2.6 + 1.5
3.2 + 2.1
0.545
Volume of EBL, mean + SD, ml
294.0 + 294.7
300.1 + 238.7
0.714
170.5 + 65.5
184.9 + 67.9
0.001
35.2 + 15.4
34.4 + 15.7
0.452
Radical nephrectomy
394 (28.0)
211 (78.4)
Partial nephrectomy
1013 (72.0)
58 (21.6)
Pure laparoscopy
360 (25.6)
120 (44.6)
Hand-assisted laparoscopy
45 (3.2)
24 (8.9)
Open
362 (25.7)
82 (30.5)
Robot-assisted laparoscopy
640 (45.5)
43(16.0)
127 (9.0)
36 (13.4)
Operative time Total time, mean + SD, min Ischemic time, mean + SD, min
Method, n (%)
Type, n (%) NA
CKD, chronic kidney disease; ECOG, Eastern Cooperative Oncology Group; ESR, estimated sedimentation rate; þ, calculated by equation of MDRD (Modification of Diet in Renal Disease); SD, standard deviation; NA, not applicable.
,0.001
Method, n (%)
Transfusion, n (%)
0.206
0.033
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Variables
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DISCUSSION This retrospective multicenter study deals with the prevalence of both pre-CKD and newly developed post-CKD cases and with the RFs for patients with a single renal tumor 4 cm (clinical T1a) before and after PN or RN as a curative treatment at five Korean tertiary hospitals. It is the first study to report the incidence rate of CKD before and after nephrectomy in Korea.
During 10-year follow-ups (at least a minimum 6-month follow-up) on 1928 patients enrolled in this study, 10.0% had untreated pre-CKD. This prevalence of pre-CKD among patients with a renal tumor is lower than that of other reports, showing that 22 – 30% of patients presenting for surgery had baseline pre-CKD (7,9 – 11). This discrepancy in the prevalence of pre-CKD may be explained by the baseline demographics of enrolled patients. Most enrolled patients in this study were young, with a mean age of 55.0 (+12.4) years, and had a low BMI (median 24.7 cm/m2 ) with a good performance status (,ECOG 3 [80.8%]). This rationale presumes that there is a lesser risk of severe metabolic disease and cardiovascular disease negatively affecting renal function that would result in a lower prevalence of pre-CKD (Table 1). However, similar to our results, many other reports also indicate a low pre-CKD prevalence (10.0 – 16.1%) among the general population (7,12 – 15). In addition, for patients .65 years of age, this study showed a 19.5% prevalence of pre-CKD, which is higher than the overall prevalence rate; thus, more attention should be paid to renal function in older people presenting with a renal mass for surgery. To evaluate the characteristics of pre-CKD and to define any predisposing RFs, male gender, age at diagnosis, hypertension and serum albumin and calcium levels were shown to be significant, independent RFs (P , 0.01) and major influential parameters on renal function between pre-CKD and pre-non-CKD groups before surgery in this study (Table 3). An older age at diagnosis of a renal mass (OR 1.04), male gender (OR 3.55), hypertension (OR 0.46) and serum calcium levels (OR 2.06) and lower serum albumin levels (OR 0.23) significantly increased the prevalence of pre-CKD. These pre-CKD RFs, including increasing age, have already been identified as being associated with renal function (4,5,13,16,17). The higher prevalence of CKD and mortality in males have been reported in many animal and clinical studies, and are attributed to many biological and social factors, such as sex hormones (18 – 20), social activities, including drinking alcohol and smoking, occupational stress and lack of physical activity (21,22). Hypertension is also a wellknown predisposing factor for the development of CKD because of the increasing risk of damage to the cardiovasculature, which results in impaired renal function (7,9,10,13,15). Other RFs for pre-CKD are serum albumin and calcium levels, which are known as functional renal markers, as well
Table 3. Predictive factors of pre-CKD in multivariate analysis Table 4. Predictive factors of post-CKD development in multivariate analysis
Male sex
P value
Odds ratio
95% confidence interval
,0.001
3.55
1.763– 7.059
P value
OR
95% confidence interval
Diagnostic age
0.002
1.04
1.015– 1.065
PN vs. RN
,0.001
11.89
7.984–17.696
Hypertension
0.006
0.46
0.263– 0.808
Diagnostic age
,0.001
1.05
1.037–1.072
Albumin
,0.001
0.23
0.110– 0.467
Male sex
,0.001
3.78
2.120–6.748
Calcium
0.015
2.06
1.149– 3.675
Preoperative Cr
0.023
1.90
1.093–3.311
OR, odds ratio.
PN, partial nephrectomy; RN, radical nephrectomy; Cr, creatinine level.
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of 360 pre-non-CKD patients developed post-CKD (data not shown in Tables 1 and 2). Among the pre-CKD (n ¼ 192, 10.0%) and pre-non-CKD groups (n ¼ 1736, 90.0%), gender, diagnostic age, existence of underlying diseases that raise the risk of CKD (diabetes and hypertension), ECOG group and laboratory results (albumin, calcium and creatinine levels) differed significantly in terms of pre-CKD risk in univariate analysis (P , 0.05, Table 1). Among the 1676 patients after PN or RN, most patients (n ¼ 1232, 73.5%) underwent laparoscopic treatments, including pure transperitoneal and retroperitoneal approaches, and hand-assisted or robot-assisted methods; the remainder underwent open methods (n ¼ 444, 26.5%, Table 2). PN was performed more frequently than RN (PN 72.0% vs. RN 28.0%), especially in post-non-CKD groups, and RN (78.4%) was performed more often in the post-CKD groups (PN 21.6%). In the post-non-CKD (n ¼ 1407, 83.9%) and post-CKD groups (n ¼ 269, 16.1%), statistically different RFs for post-CKD were male gender, BMI, diagnostic age, diabetes, hypertension, ECOG, tumor size, preoperative albumin level, operating time, surgical type (PN or RN) and transfusion in univariate analysis (P , 0.05, Table 2). After multivariate analyses, significantly different RFs for CKD before and after surgery were male gender (OR 3.55 vs. OR 3.78, P , 0.001, respectively), and diagnostic age (OR 1.04, P ¼ 0.002 vs. OR 1.05, P , 0.001). In addition, hypertension (OR 0.46, P ¼ 0.006), serum albumin (OR 0.23, P , 0.001) and calcium (OR 2.06, P ¼ 0.015) were significant RFs for pre-CKD, and preoperative serum creatinine levels (OR 1.90, P ¼ 0.023), and surgical type (either RP or PN) were RFs for post-CKD (OR 11.89, P , 0.001) (Tables 3 and 4).
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function after surgery. Another explanation is that the surgical type of RN has a major influential effect, with an OR of 11.89, such that pre-existing, chronic diseases do not affect the early development of post-CKD. However, one would expect that hypertension and diabetes would become influential RFs for CKD over time. Our study has some limitations. First, despite this being the first meaningful report of the Korean baseline incidence of CKD, further randomized prospective studies with a larger sample size, including a non-surgical control group, is needed to evaluate RFs for CKD. Second, the CKD equation, MDRD and serum creatinine levels are not very accurate tools for defining actual kidney function. More accurate tools are needed to evaluate renal function, such as 24 h creatinine clearance, serum cystatin-C or the CKD epidemiology equation (CKD-EPI) (6,26,27). Third, the RFs in this study were observed at two specific time points, so that the laboratory results might be influenced by other factors such as medications and nutritional states. More data from different time points are needed to evaluate the actual influence of the RFs we suggested. Finally, this study did not deal with sequelae or metabolically associated post-CKD (28– 30).
CONCLUSIONS This study shows that patients with a small renal mass and a normal contralateral kidney should be carefully evaluated in terms of preoperative renal function to prevent post-CKD, especially if they are males with a history of hypertension. In addition, PN should be first considered rather than RN to reduce the risk of post-CKD.
Conflict of interest statement None declared.
References 1. Campbell SC, Novick AC, Belldegrun A, et al. Guideline for management of the clinical T1 renal mass. J Urol 2009;182:1271–9. 2. Huang WC, Elkin EB, Levey AS, Jang TL, Russo P. Partial nephrectomy versus radical nephrectomy in patients with small renal tumors—is there a difference in mortality and cardiovascular outcomes? J Urol 2009;181:55– 61; discussion 2. 3. Go AS, Chertow GM, Fan D, McCulloch CE, Hsu CY. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med 2004;351:1296– 305. 4. Lucas SM, Stern JM, Adibi M, Zeltser IS, Cadeddu JA, Raj GV. Renal function outcomes in patients treated for renal masses smaller than 4 cm by ablative and extirpative techniques. J Urol 2008;179:75 – 9; discussion 9 –80. 5. Lane BR, Poggio ED, Herts BR, Novick AC, Campbell SC. Renal function assessment in the era of chronic kidney disease: renewed emphasis on renal function centered patient care. J Urol 2009;182: 435– 43; discussion 43–4. 6. Lane BR, Demirjian S, Weight CJ, Larson BT, Poggio ED, Campbell SC. Performance of the chronic kidney disease-epidemiology study equations for estimating glomerular filtration rate before and after nephrectomy. J Urol 2010;183:896– 901.
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as markers of end-stage renal disease, renal tubular acidosis, diabetes and other diseases (16,17,23). Therefore, clinicians should be aware of pre-CKD in patients with these RFs if they plan to undergo treatment for a small renal mass (cT1a) and should focus on the patient’s preoperative renal function and demographical parameters to evaluate the risk for post-CKD. Among 1676 non-CKD patients before surgery, 16.1% of the patients developed post-CKD (28.3% for .65-year-old patients) with significant RFs, including male gender (OR 3.78), age at diagnosis (OR 1.05), preoperative serum creatinine levels (OR 1.90) and surgical type (OR 11.89, P , 0.05, Table 4). The incidence of post-CKD is also relatively low compared with 30 – 50% for other reported events due to the aforementioned differences in baseline demographics of enrolled patients (2,4,11,16). Among the significant RFs for post-CKD, the strongest RF is surgical type of RN, which influences kidney function with an odds ratio (OR) of 11.8 (Table 4), suggesting that PN should be recommended first to prevent post-CKD after considering the factors and thorough discussions with patients and responsible caregivers. However, two recent papers suggested that PN showed a significant benefit for CKD patients but was unlikely to prevent surgical CKD compared with RN after considering its oncologic control and morbidity (11,24,25). These authors also admitted that in the past, insufficient numbers of patients who underwent PN were enrolled to compare with patients who underwent RN. Patients with PN should be enrolled with further long-term follow-up because the surgical techniques and instruments for use in PN improved compared with the past. Another study from Lane et al. suggested that the benefits of PN were lower risks of progression and mortality compared with medically induced CKD (11). The generally accepted post-CKD RFs after nephrectomy, such as diabetes, hypertension and operating time including ischemic time for PN, have not been statistically proven to affect the development of CKD (P . 0.05) (3 – 5,7). In particular, operative time including the ischemic time is not a significant RF for CKD because renal masses 4 cm are not large enough to affect postoperative changes in renal function and minimal parenchymal and vascular injury during PN. Less than 30 min of ischemic time is required to avoid renal ischemic injury in PN; operating time in this study was tolerably short, with a median time of 160 min, including a median ischemic time of 23 min (total mean operating time 170.1 + 62.2 min; total mean ischemic time 25.1 + 14.0 min; data not shown). Additionally, the resected renal parenchyma of the renal tumor is too small to affect postoperative renal function, so renal function is preserved after PN to a large extent. Another parameter that negatively affects renal function is chronic renovascular disease, such as diabetes and hypertension, and they are not found to be significant RFs for incident post-CKD after either PN or RN. This observation is likely because the patients are young with good performance status (ECOG 1 or 2, 97.2%), and few patients have had hypertension or diabetes .5 years that would negatively affect renal
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19. Mulroney SE, Woda C, Johnson M, Pesce C. Gender differences in renal growth and function after uninephrectomy in adult rats. Kidney Int 1999;56:944– 53. 20. Sakemi T, Baba N. Castration attenuates proteinuria and glomerular injury in unilaterally nephrectomized male Sprague – Dawley rats. Lab Invest 1993;69:51 –7. 21. Robine JM, Michel JP, Herrmann FR. Excess male mortality and age-specific mortality trajectories under different mortality conditions: a lesson from the heat wave of summer 2003. Mech Ageing Dev 2012;133:378 –86. 22. Bobak M. Relative and absolute gender gap in all-cause mortality in Europe and the contribution of smoking. Eur J Epidemiol 2003;18:15 –8. 23. Foley RN, Parfrey PS, Harnett JD, et al. Hypocalcemia, morbidity, and mortality in end-stage renal disease. Am J Nephrol 1996;16:386–93. 24. Van Poppel H, Da Pozzo L, Albrecht W, et al. A prospective, randomised EORTC intergroup phase 3 study comparing the oncologic outcome of elective nephron-sparing surgery and radical nephrectomy for low-stage renal cell carcinoma. Eur Urol 2011;59:543– 52. 25. Van Poppel H, Becker F, Cadeddu JA, et al. Treatment of localised renal cell carcinoma. Eur Urol 2011;60:662–72. 26. Inker LA, Okparavero A. Cystatin C as a marker of glomerular filtration rate: prospects and limitations. Curr Opin Nephrol Hypertens 2011;20:631– 9. 27. Matsushita K, Mahmoodi BK, Woodward M, et al. Comparison of risk prediction using the CKD-EPI equation and the MDRD study equation for estimated glomerular filtration rate. JAMA 2012;307:1941– 51. 28. Malcolm JB, Bagrodia A, Derweesh IH, et al. Comparison of rates and risk factors for developing chronic renal insufficiency, proteinuria and metabolic acidosis after radical or partial nephrectomy. BJU Int 2009;104:476– 81. 29. Bagrodia A, Mehrazin R, Bazzi WM, et al. Comparison of rates and risk factors for development of osteoporosis and fractures after radical or partial nephrectomy. Urology 2011;78:614–9. 30. Weight CJ, Larson BT, Fergany AF, et al. Nephrectomy induced chronic renal insufficiency is associated with increased risk of cardiovascular death and death from any cause in patients with localized cT1b renal masses. J Urol 2010;183:1317– 23.
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7. Coresh J, Selvin E, Stevens LA, et al. Prevalence of chronic kidney disease in the United States. JAMA 2007;298:2038– 47. 8. Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med 1999;130:461– 70. 9. Canter D, Kutikov A, Sirohi M, et al. Prevalence of baseline chronic kidney disease in patients presenting with solid renal tumors. Urology 2011;77:781– 5. 10. Crews DC, Plantinga LC, Miller ER, et al. Prevalence of chronic kidney disease in persons with undiagnosed or prehypertension in the United States. Hypertension 2010;55:1102– 9. 11. Lane BR, Campbell SC, Demirjian S, Fergany AF. Surgically-induced chronic kidney disease may be associated with lesser risk of progression and mortality than medical chronic kidney disease. J Urol 2013;189:1649–55. 12. Chadban SJ, Briganti EM, Kerr PG, et al. Prevalence of kidney damage in Australian adults: The AusDiab kidney study. J Am Soc Nephrol 2003;14:S131–8. 13. Prevalence of chronic kidney disease and associated risk factors—United States, 1999 – 2004. Prevalence of chronic kidney disease and associated risk factors—United States, 1999– 2004. JAMA 2007;297:1767– 8. 14. Hallan SI, Coresh J, Astor BC, et al. International comparison of the relationship of chronic kidney disease prevalence and ESRD risk. J Am Soc Nephrol 2006;17:2275– 84. 15. Perkovic V, Cass A, Patel AA, et al. High prevalence of chronic kidney disease in Thailand. Kidney Int 2008;73:473– 9. 16. Foley RN, Parfrey PS, Harnett JD, Kent GM, Murray DC, Barre PE. Hypoalbuminemia, cardiac morbidity, and mortality in end-stage renal disease. J Am Soc Nephrol 1996;7:728–36. 17. Schwarz S, Trivedi BK, Kalantar-Zadeh K, Kovesdy CP. Association of disorders in mineral metabolism with progression of chronic kidney disease. Clin J Am Soc Nephrol 2006;1:825– 31. 18. Kasimay O, Sener G, Cakir B, et al. Estrogen protects against oxidative multiorgan damage in rats with chronic renal failure. Renal Fail 2009;31:711– 25.
Incidence and Risk Factors of Chronic Kidney Disease in Korean Patients with T1a Renal Cell Carcinoma Before and After Radical or Partial Nephrectomy Sung Han Kim1, Sang Eun Lee2, Sung Kyu Hong2, Chang Wook Jeong2, Yong Hyun Park1, Yong-June Kim3, Seok Ho Kang4, Sung-Hoo Hong5, Won Suk Choi6 and Seok-Soo Byun2,* Department of Urology, Seoul National University College of Medicine, Seoul, 2Department of Urology, Seoul National University Bundang Hospital, Seongnam, 3Department of Urology, Chungbuk National University College of Medicine, Cheongju, 4Department of Urology, College of Medicine, Korea University, Seoul, 5Department of Urology, College of Medicine, the Catholic University of Korea, Seoul and 6Urologic Clinic, Yongin, Korea *For reprints and all correspondence: Seok Soo Byun, Department of Urology, Seoul National University Bundang Hospital, 82 Gumi-ro 173 Beon-gil, Bundang-gu, Seongnam 463-707, Korea. E-mail: [email protected] Received May 9, 2013; accepted September 5, 2013
Objective: The aim of the study was to investigate the incidence of chronic kidney disease in patients with T1a renal cell carcinoma both before and after partial or radical nephrectomy, and to assess risk factors for chronic kidney disease. Methods: From January 2001 to December 2011, 1928 patients with a single renal mass 4 cm undergoing partial nephrectomy or radical nephrectomy with the existence of a normal contralateral kidney were retrospectively reviewed for the evaluation of preoperative chronic kidney disease, and reviewed only 1676 patients for the postoperative chronic kidney disease. The estimated glomerular filtration rates were used to define chronic kidney disease ,60 ml/ min/1.73 m2 by the Modification of Diet in Renal Disease equation. Demographics and clinicopathological parameters were evaluated to determine the risk factors with the development of chronic kidney disease both before and after surgery. Results: Chronic kidney disease was found preoperatively in 10.0% (n ¼ 192) of patients; 16.1% (n ¼ 269) of patients developed chronic kidney disease postoperatively, including 102 (6.1%) chronic kidney disease patients .65 years of age. Between the non-chronic kidney disease and chronic kidney disease patients, male gender (odds ratio 3.55 vs. 3.78, respectively) and diagnostic age (odds ratio 1.04 vs. 1.05) were significantly distinctive common risk factors for chronic kidney disease both before and after surgery (P , 0.002). In addition, hypertension (odds ratio 0.46), serum albumin (odds ratio 0.23) and calcium (odds ratio 2.06) were significant as preoperative risk factors (P , 0.015), and preoperative serum creatinine (odds ratio 1.90) and surgical type ( partial nephrectomy or radical nephrectomy; odds ratio 11.89) were significant as postoperative risk factors (P , 0.030). Conclusions: Old, male hypertensive patients with a small renal mass would be better candidates for partial nephrectomy to prevent postoperative chronic kidney disease. Key words: carcinoma – renal cell – nephrectomy – renal insufficiency – chronic – incidence – risk factors
# The Author 2013. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected]
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INTRODUCTION
PATIENTS AND METHODS Approval of the study was obtained from the Institutional Review Board (IRB No. B-1202/145-102). A total of 1982 patients with sporadic RCC ,4 cm and non-metastatic RCC (pathologic T1aN0M0, International Union Against Cancer/ American Joint Committee on Cancer, 2009) at the time of surgery were collected from five institutions between January 2001 and December 2011 in the Republic of Korea. After excluding patients with a solitary kidney, metastatic disease, bilateral disease or previous renal surgery, 1928 patients were enrolled in the study. The patients’ clinicopathological information was retrospectively reviewed. All patients had undergone PN or RN with a curative intent and had a follow-up of at least 6 months. Follow-up consisted of a history, physical examination, routine blood work and serum chemistry, chest radiography and abdomen computed tomography (CT) every 6 months for 3 years, and then yearly in most patients. Other radiographic evaluations, including bone scan, MRI or positron emission tomography – CT, were performed when clinically indicated. Patients were divided into CKD and non-CKD groups before ( pre-CKD vs. pre-non-CKD) and after surgery
RESULTS Among the 1928 patients with a single small renal mass 4 cm, pre-CKD was found in 10.0% of patients, whereas
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Improvements in imaging modalities have made the detection of small, localized, renal masses considerably easier. There is, therefore, a corresponding rise in treatment, with radical nephrectomy (RN), partial nephrectomy (PN), thermal ablation or active surveillance among the treatments recommended by the American Urological Association (1). Recent studies have suggested that PN showed an equivalent oncological outcome for renal masses ,4 cm in size, and better postoperative preservation of overall renal function than RN to reduce the prevalence of chronic kidney disease (CKD) (2). Patients with CKD [defined as an estimated glomerular filtration rate (eGFR) , 60 ml/min/1.73 m2] often develop and progress to kidney failure, complications from decreased renal function, cardiovascular disease or death (3,4). As more incidental, small renal masses are increasingly detected, and the negative relationship between long-term CKD and morbidity/mortality is uncovered, the preservation of kidney function and its related aggravating factors will continue to be emphasized, because conservative serum creatinine levels do not exactly reflect renal function and its degree of impairment (5,6). According to Coresh’s study, 25% of patients with normal serum creatinine levels in the study had CKD (7). Therefore, it is important to determine the parameters of renal function and aggravating factors of CKD after renal treatment. In this multicenter, retrospective study, we estimated the incidence of baseline CKD and postoperative development of CKD in patients with a single, small renal mass 4 cm of renal cell carcinoma (RCC), and assessed the parameters of renal function before and after either PN or RN.
(post-CKD vs. post-non-CKD), according to their renal function calculated by the Modification of Diet in Renal Disease (MDRD) equation (8). Pre-CKD and pre-non-CKD are groups of RCC patients who have detected indolent CKD and who have not detected CKD before nephrectomy, respectively. And post-CKD and post-non-CKD are groups of RCC patients who developed or who did not develop CKD after nephrectomy, respectively. The preoperative and postoperative CKD and non-CKD groups ([ pre-CKD vs. pre-non-CKD] and [ post-CKD vs. post-non-CKD]) were analyzed with the following demographic and perioperative parameters: age, sex, body mass index (BMI), diabetes, hypertension, blood tests [hemoglobin, platelet, creatinine, albumin, calcium, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), MDRD eGFR, Eastern Cooperative Oncology Group performance status (ECOG) group, tumor characteristics (size, laterality and location), surgical type (PN or RN), surgical method (laparoscopy or open), operative time, estimated blood loss (EBL), transfusion, pathologic data (included Fuhrman grade and surgical margin status), intra- and postoperative complications, recurrence and survival. The choice of a surgical approach was based on the referrals and the surgeon’s preference. To evaluate renal function and CKD, serum creatinine levels were measured preoperatively and at the 6-month follow-up postoperatively in all patients using the Jaffe´ method. The four-variable MDRD formula (eGFR ¼ 186.3 Pcr21.154 age20.203 0.742; if female) using serum creatinine levels and demographic variables was used to estimate the glomerular filtration rate (GFR). The outcome measure used in this study was the development of new onset CKD with an estimated GFR of ,60 ml/min/1.73 m2 after surgery, with an interval of at least 6 months after the operation. All patients with pre-CKD (n ¼ 192) and those with a deficiency of postoperative serum creatinine level (n ¼ 60) were excluded from the study when evaluating the incidence rate of developing post-CKD and post-CKD risk factors (RFs), yielding a total of 1676 patients. Comparisons of the qualitative and quantitative variables of the CKD and non-CKD groups before and after PN or RN were performed using a x 2 test or independent t test as appropriate. After prequalification of demographics and clinicopathological parameters with univariate analysis, significant factors were evaluated using logistic regression analysis to determine the association of the independent variables with baseline pre-CKD and development of post-CKD. Null hypotheses of no difference were rejected if P values were ,0.05 (two-tailed). All data analyses were processed with SPSS 18.0 statistical software (SPSS, Inc., Chicago, IL, USA).
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16.1% of patients developed post-CKD (Tables 1 and 2). Among 1336 males and 592 females, renal tumors were found in males twice as often as females (69.3% vs. 30.7%), and CKD was detected more frequently in males (8.7%) than in females (1.3%) using the renal functional analysis with eGFR MDRD ,60 ml/min/1.76 m 2 (Table 1). Among the 447 patients .65 years of age, 87 (19.5%) patients were found to have indolent pre-CKD before surgery, and 102 (28.3%) out Table 1. Demographic and clinicopathological variables before surgery (n ¼ 1928) Pre-non-CKD
Pre-CKD
P value
Subjects, n (%)
1736 (90.0)
192 (10.0)
Age, mean + SD, years
54.3 + 12.5
60.7 + 12.4
,0.001
Sex, n (%)
1336 (69.3)
592 (30.7)
,0.001
1169 (60.6)/567 (29.4)
167 (8.7)/25 (1.3)
37.6 + 31.5
38.1 + 29.9
Male/Female, n (%) Duration of follow-up, mean + SD, months
Table 2. Demographic and clinicopathological variables associated with surgically incidental CKD (n ¼ 1676) Variables
Post-non-CKD
Post-CKD
P value
Subjects, n (%)
1407 (83.9)
269 (16.1)
Diagnostic age, mean + SD, years
53.3 + 12.4
60 + 11.7
,0.001 ,0.001
Sex, n (%)
1133 (67.6)
543 (32.4)
Male/female, n (%)
905 (54)/228 (13.6)
502 (30)/ 41 (2.4)
Body mass index, mean + SD, kg/m2
24.7 + 10.1
24.7 + 3.1
Follow-up duration, mean + SD, months
36.4 + 30.5
47.69 + 35.8
,0.001
,0.001
0.005
Comorbidities Diabetes, n (%)
153 (10.9)
59 (21.9)
Hypertension, n (%)
420 (29.9)
117 (43.5)
ECOG, n (%) 0.329
Comorbidities ,0.001
Group 0
587 (41.7)
120 (44.6)
Group 1
498 (35.4)
62 (23.1)
Group 2
303 (21.5)
73 (27.1)
Group 3
19 (1.4)
14 (5.2)
14.0 + 1.7
13.9 + 1.8
,0.001
Diabetes, n (%)
221 (12.7)
50 (26.0)
Hypertension, n (%)
557 (32.1)
116 (60.4)
Group 0
695 (40.0)
71 (37.0)
Group 1
602 (34.7)
36 (18.8)
ESR, mean + SD, mg/dl
13.1 + 24.5
13.1 + 24.5
0.491
Albumin, mean + SD, g/dl
4.3 + 0.5
4.3 + 0.5
0.001
Calcium, mean + SD, mg/
9.2 + 0.6
9.2 + 0.6
0.547
Creatinine, mean + SD, mg/dl
0.9 + 0.4
1.1 + 0.5
,0.001
,0.001
Laboratory findings
ECOG, n (%)
Group 2
404 (23.3)
65 (33.8)
Group 3
35 (2.0)
2 0(10.4)
Hemoglobin, mean + SD, g/dl
14.0 + 1.8
13.2 + 2.0
0.107
ESR, mean + SD, mg/dl
13.4 + 23.4
24.3 + 26.0
0.051
Albumin, mean + SD, g/dl
4.3 + 0.5
4.0 + 0.5
,0.001
Calcium, mean + SD, mg/dl
9.2 + 0.6
9.0 + 0.7
0.001
Creatinine, mean + SD, mg/dl
,0.001
1.0 + 0.4
2.1 + 3.6
95.1 + 28.1
41.7 + 20.2
Tumor size, mean + SD, cm
2.6 + 1.5
2.6 + 1.7
0.732
Type, n (%) Radical nephrectomy
620 (35.7)
111 (57.8)
Partial nephrectomy
1116 (64.3)
81 (42.2)
Pure laparoscopy
446 (25.7)
59 (30.7)
Hand-assisted laparoscopy
73 (4.2)
5 (2.6)
Open
471 (27.1)
83 (43.3)
Robot-assisted laparoscopy
746 (43.0)
640 (23.4)
0.608
dl
Laboratory findings
eGFRþ, mean + SD, ml/min/ 1.73 m2
Hemoglobin, mean + SD, g/dl
,0.001
NA
MDRD, mean + SD, ml/min/1.73 m2 Preoperative
97.6 + 28.8
77.3 + 13.6
Postoperative
93.3 + 28.5
49.7 + 10.1
Tumor size, mean + SD, cm
2.6 + 1.5
3.2 + 2.1
0.545
Volume of EBL, mean + SD, ml
294.0 + 294.7
300.1 + 238.7
0.714
170.5 + 65.5
184.9 + 67.9
0.001
35.2 + 15.4
34.4 + 15.7
0.452
Radical nephrectomy
394 (28.0)
211 (78.4)
Partial nephrectomy
1013 (72.0)
58 (21.6)
Pure laparoscopy
360 (25.6)
120 (44.6)
Hand-assisted laparoscopy
45 (3.2)
24 (8.9)
Open
362 (25.7)
82 (30.5)
Robot-assisted laparoscopy
640 (45.5)
43(16.0)
127 (9.0)
36 (13.4)
Operative time Total time, mean + SD, min Ischemic time, mean + SD, min
Method, n (%)
Type, n (%) NA
CKD, chronic kidney disease; ECOG, Eastern Cooperative Oncology Group; ESR, estimated sedimentation rate; þ, calculated by equation of MDRD (Modification of Diet in Renal Disease); SD, standard deviation; NA, not applicable.
,0.001
Method, n (%)
Transfusion, n (%)
0.206
0.033
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Variables
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DISCUSSION This retrospective multicenter study deals with the prevalence of both pre-CKD and newly developed post-CKD cases and with the RFs for patients with a single renal tumor 4 cm (clinical T1a) before and after PN or RN as a curative treatment at five Korean tertiary hospitals. It is the first study to report the incidence rate of CKD before and after nephrectomy in Korea.
During 10-year follow-ups (at least a minimum 6-month follow-up) on 1928 patients enrolled in this study, 10.0% had untreated pre-CKD. This prevalence of pre-CKD among patients with a renal tumor is lower than that of other reports, showing that 22 – 30% of patients presenting for surgery had baseline pre-CKD (7,9 – 11). This discrepancy in the prevalence of pre-CKD may be explained by the baseline demographics of enrolled patients. Most enrolled patients in this study were young, with a mean age of 55.0 (+12.4) years, and had a low BMI (median 24.7 cm/m2 ) with a good performance status (,ECOG 3 [80.8%]). This rationale presumes that there is a lesser risk of severe metabolic disease and cardiovascular disease negatively affecting renal function that would result in a lower prevalence of pre-CKD (Table 1). However, similar to our results, many other reports also indicate a low pre-CKD prevalence (10.0 – 16.1%) among the general population (7,12 – 15). In addition, for patients .65 years of age, this study showed a 19.5% prevalence of pre-CKD, which is higher than the overall prevalence rate; thus, more attention should be paid to renal function in older people presenting with a renal mass for surgery. To evaluate the characteristics of pre-CKD and to define any predisposing RFs, male gender, age at diagnosis, hypertension and serum albumin and calcium levels were shown to be significant, independent RFs (P , 0.01) and major influential parameters on renal function between pre-CKD and pre-non-CKD groups before surgery in this study (Table 3). An older age at diagnosis of a renal mass (OR 1.04), male gender (OR 3.55), hypertension (OR 0.46) and serum calcium levels (OR 2.06) and lower serum albumin levels (OR 0.23) significantly increased the prevalence of pre-CKD. These pre-CKD RFs, including increasing age, have already been identified as being associated with renal function (4,5,13,16,17). The higher prevalence of CKD and mortality in males have been reported in many animal and clinical studies, and are attributed to many biological and social factors, such as sex hormones (18 – 20), social activities, including drinking alcohol and smoking, occupational stress and lack of physical activity (21,22). Hypertension is also a wellknown predisposing factor for the development of CKD because of the increasing risk of damage to the cardiovasculature, which results in impaired renal function (7,9,10,13,15). Other RFs for pre-CKD are serum albumin and calcium levels, which are known as functional renal markers, as well
Table 3. Predictive factors of pre-CKD in multivariate analysis Table 4. Predictive factors of post-CKD development in multivariate analysis
Male sex
P value
Odds ratio
95% confidence interval
,0.001
3.55
1.763– 7.059
P value
OR
95% confidence interval
Diagnostic age
0.002
1.04
1.015– 1.065
PN vs. RN
,0.001
11.89
7.984–17.696
Hypertension
0.006
0.46
0.263– 0.808
Diagnostic age
,0.001
1.05
1.037–1.072
Albumin
,0.001
0.23
0.110– 0.467
Male sex
,0.001
3.78
2.120–6.748
Calcium
0.015
2.06
1.149– 3.675
Preoperative Cr
0.023
1.90
1.093–3.311
OR, odds ratio.
PN, partial nephrectomy; RN, radical nephrectomy; Cr, creatinine level.
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of 360 pre-non-CKD patients developed post-CKD (data not shown in Tables 1 and 2). Among the pre-CKD (n ¼ 192, 10.0%) and pre-non-CKD groups (n ¼ 1736, 90.0%), gender, diagnostic age, existence of underlying diseases that raise the risk of CKD (diabetes and hypertension), ECOG group and laboratory results (albumin, calcium and creatinine levels) differed significantly in terms of pre-CKD risk in univariate analysis (P , 0.05, Table 1). Among the 1676 patients after PN or RN, most patients (n ¼ 1232, 73.5%) underwent laparoscopic treatments, including pure transperitoneal and retroperitoneal approaches, and hand-assisted or robot-assisted methods; the remainder underwent open methods (n ¼ 444, 26.5%, Table 2). PN was performed more frequently than RN (PN 72.0% vs. RN 28.0%), especially in post-non-CKD groups, and RN (78.4%) was performed more often in the post-CKD groups (PN 21.6%). In the post-non-CKD (n ¼ 1407, 83.9%) and post-CKD groups (n ¼ 269, 16.1%), statistically different RFs for post-CKD were male gender, BMI, diagnostic age, diabetes, hypertension, ECOG, tumor size, preoperative albumin level, operating time, surgical type (PN or RN) and transfusion in univariate analysis (P , 0.05, Table 2). After multivariate analyses, significantly different RFs for CKD before and after surgery were male gender (OR 3.55 vs. OR 3.78, P , 0.001, respectively), and diagnostic age (OR 1.04, P ¼ 0.002 vs. OR 1.05, P , 0.001). In addition, hypertension (OR 0.46, P ¼ 0.006), serum albumin (OR 0.23, P , 0.001) and calcium (OR 2.06, P ¼ 0.015) were significant RFs for pre-CKD, and preoperative serum creatinine levels (OR 1.90, P ¼ 0.023), and surgical type (either RP or PN) were RFs for post-CKD (OR 11.89, P , 0.001) (Tables 3 and 4).
Jpn J Clin Oncol 2013;43(12)
function after surgery. Another explanation is that the surgical type of RN has a major influential effect, with an OR of 11.89, such that pre-existing, chronic diseases do not affect the early development of post-CKD. However, one would expect that hypertension and diabetes would become influential RFs for CKD over time. Our study has some limitations. First, despite this being the first meaningful report of the Korean baseline incidence of CKD, further randomized prospective studies with a larger sample size, including a non-surgical control group, is needed to evaluate RFs for CKD. Second, the CKD equation, MDRD and serum creatinine levels are not very accurate tools for defining actual kidney function. More accurate tools are needed to evaluate renal function, such as 24 h creatinine clearance, serum cystatin-C or the CKD epidemiology equation (CKD-EPI) (6,26,27). Third, the RFs in this study were observed at two specific time points, so that the laboratory results might be influenced by other factors such as medications and nutritional states. More data from different time points are needed to evaluate the actual influence of the RFs we suggested. Finally, this study did not deal with sequelae or metabolically associated post-CKD (28– 30).
CONCLUSIONS This study shows that patients with a small renal mass and a normal contralateral kidney should be carefully evaluated in terms of preoperative renal function to prevent post-CKD, especially if they are males with a history of hypertension. In addition, PN should be first considered rather than RN to reduce the risk of post-CKD.
Conflict of interest statement None declared.
References 1. Campbell SC, Novick AC, Belldegrun A, et al. Guideline for management of the clinical T1 renal mass. J Urol 2009;182:1271–9. 2. Huang WC, Elkin EB, Levey AS, Jang TL, Russo P. Partial nephrectomy versus radical nephrectomy in patients with small renal tumors—is there a difference in mortality and cardiovascular outcomes? J Urol 2009;181:55– 61; discussion 2. 3. Go AS, Chertow GM, Fan D, McCulloch CE, Hsu CY. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med 2004;351:1296– 305. 4. Lucas SM, Stern JM, Adibi M, Zeltser IS, Cadeddu JA, Raj GV. Renal function outcomes in patients treated for renal masses smaller than 4 cm by ablative and extirpative techniques. J Urol 2008;179:75 – 9; discussion 9 –80. 5. Lane BR, Poggio ED, Herts BR, Novick AC, Campbell SC. Renal function assessment in the era of chronic kidney disease: renewed emphasis on renal function centered patient care. J Urol 2009;182: 435– 43; discussion 43–4. 6. Lane BR, Demirjian S, Weight CJ, Larson BT, Poggio ED, Campbell SC. Performance of the chronic kidney disease-epidemiology study equations for estimating glomerular filtration rate before and after nephrectomy. J Urol 2010;183:896– 901.
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as markers of end-stage renal disease, renal tubular acidosis, diabetes and other diseases (16,17,23). Therefore, clinicians should be aware of pre-CKD in patients with these RFs if they plan to undergo treatment for a small renal mass (cT1a) and should focus on the patient’s preoperative renal function and demographical parameters to evaluate the risk for post-CKD. Among 1676 non-CKD patients before surgery, 16.1% of the patients developed post-CKD (28.3% for .65-year-old patients) with significant RFs, including male gender (OR 3.78), age at diagnosis (OR 1.05), preoperative serum creatinine levels (OR 1.90) and surgical type (OR 11.89, P , 0.05, Table 4). The incidence of post-CKD is also relatively low compared with 30 – 50% for other reported events due to the aforementioned differences in baseline demographics of enrolled patients (2,4,11,16). Among the significant RFs for post-CKD, the strongest RF is surgical type of RN, which influences kidney function with an odds ratio (OR) of 11.8 (Table 4), suggesting that PN should be recommended first to prevent post-CKD after considering the factors and thorough discussions with patients and responsible caregivers. However, two recent papers suggested that PN showed a significant benefit for CKD patients but was unlikely to prevent surgical CKD compared with RN after considering its oncologic control and morbidity (11,24,25). These authors also admitted that in the past, insufficient numbers of patients who underwent PN were enrolled to compare with patients who underwent RN. Patients with PN should be enrolled with further long-term follow-up because the surgical techniques and instruments for use in PN improved compared with the past. Another study from Lane et al. suggested that the benefits of PN were lower risks of progression and mortality compared with medically induced CKD (11). The generally accepted post-CKD RFs after nephrectomy, such as diabetes, hypertension and operating time including ischemic time for PN, have not been statistically proven to affect the development of CKD (P . 0.05) (3 – 5,7). In particular, operative time including the ischemic time is not a significant RF for CKD because renal masses 4 cm are not large enough to affect postoperative changes in renal function and minimal parenchymal and vascular injury during PN. Less than 30 min of ischemic time is required to avoid renal ischemic injury in PN; operating time in this study was tolerably short, with a median time of 160 min, including a median ischemic time of 23 min (total mean operating time 170.1 + 62.2 min; total mean ischemic time 25.1 + 14.0 min; data not shown). Additionally, the resected renal parenchyma of the renal tumor is too small to affect postoperative renal function, so renal function is preserved after PN to a large extent. Another parameter that negatively affects renal function is chronic renovascular disease, such as diabetes and hypertension, and they are not found to be significant RFs for incident post-CKD after either PN or RN. This observation is likely because the patients are young with good performance status (ECOG 1 or 2, 97.2%), and few patients have had hypertension or diabetes .5 years that would negatively affect renal
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19. Mulroney SE, Woda C, Johnson M, Pesce C. Gender differences in renal growth and function after uninephrectomy in adult rats. Kidney Int 1999;56:944– 53. 20. Sakemi T, Baba N. Castration attenuates proteinuria and glomerular injury in unilaterally nephrectomized male Sprague – Dawley rats. Lab Invest 1993;69:51 –7. 21. Robine JM, Michel JP, Herrmann FR. Excess male mortality and age-specific mortality trajectories under different mortality conditions: a lesson from the heat wave of summer 2003. Mech Ageing Dev 2012;133:378 –86. 22. Bobak M. Relative and absolute gender gap in all-cause mortality in Europe and the contribution of smoking. Eur J Epidemiol 2003;18:15 –8. 23. Foley RN, Parfrey PS, Harnett JD, et al. Hypocalcemia, morbidity, and mortality in end-stage renal disease. Am J Nephrol 1996;16:386–93. 24. Van Poppel H, Da Pozzo L, Albrecht W, et al. A prospective, randomised EORTC intergroup phase 3 study comparing the oncologic outcome of elective nephron-sparing surgery and radical nephrectomy for low-stage renal cell carcinoma. Eur Urol 2011;59:543– 52. 25. Van Poppel H, Becker F, Cadeddu JA, et al. Treatment of localised renal cell carcinoma. Eur Urol 2011;60:662–72. 26. Inker LA, Okparavero A. Cystatin C as a marker of glomerular filtration rate: prospects and limitations. Curr Opin Nephrol Hypertens 2011;20:631– 9. 27. Matsushita K, Mahmoodi BK, Woodward M, et al. Comparison of risk prediction using the CKD-EPI equation and the MDRD study equation for estimated glomerular filtration rate. JAMA 2012;307:1941– 51. 28. Malcolm JB, Bagrodia A, Derweesh IH, et al. Comparison of rates and risk factors for developing chronic renal insufficiency, proteinuria and metabolic acidosis after radical or partial nephrectomy. BJU Int 2009;104:476– 81. 29. Bagrodia A, Mehrazin R, Bazzi WM, et al. Comparison of rates and risk factors for development of osteoporosis and fractures after radical or partial nephrectomy. Urology 2011;78:614–9. 30. Weight CJ, Larson BT, Fergany AF, et al. Nephrectomy induced chronic renal insufficiency is associated with increased risk of cardiovascular death and death from any cause in patients with localized cT1b renal masses. J Urol 2010;183:1317– 23.
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7. Coresh J, Selvin E, Stevens LA, et al. Prevalence of chronic kidney disease in the United States. JAMA 2007;298:2038– 47. 8. Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med 1999;130:461– 70. 9. Canter D, Kutikov A, Sirohi M, et al. Prevalence of baseline chronic kidney disease in patients presenting with solid renal tumors. Urology 2011;77:781– 5. 10. Crews DC, Plantinga LC, Miller ER, et al. Prevalence of chronic kidney disease in persons with undiagnosed or prehypertension in the United States. Hypertension 2010;55:1102– 9. 11. Lane BR, Campbell SC, Demirjian S, Fergany AF. Surgically-induced chronic kidney disease may be associated with lesser risk of progression and mortality than medical chronic kidney disease. J Urol 2013;189:1649–55. 12. Chadban SJ, Briganti EM, Kerr PG, et al. Prevalence of kidney damage in Australian adults: The AusDiab kidney study. J Am Soc Nephrol 2003;14:S131–8. 13. Prevalence of chronic kidney disease and associated risk factors—United States, 1999 – 2004. Prevalence of chronic kidney disease and associated risk factors—United States, 1999– 2004. JAMA 2007;297:1767– 8. 14. Hallan SI, Coresh J, Astor BC, et al. International comparison of the relationship of chronic kidney disease prevalence and ESRD risk. J Am Soc Nephrol 2006;17:2275– 84. 15. Perkovic V, Cass A, Patel AA, et al. High prevalence of chronic kidney disease in Thailand. Kidney Int 2008;73:473– 9. 16. Foley RN, Parfrey PS, Harnett JD, Kent GM, Murray DC, Barre PE. Hypoalbuminemia, cardiac morbidity, and mortality in end-stage renal disease. J Am Soc Nephrol 1996;7:728–36. 17. Schwarz S, Trivedi BK, Kalantar-Zadeh K, Kovesdy CP. Association of disorders in mineral metabolism with progression of chronic kidney disease. Clin J Am Soc Nephrol 2006;1:825– 31. 18. Kasimay O, Sener G, Cakir B, et al. Estrogen protects against oxidative multiorgan damage in rats with chronic renal failure. Renal Fail 2009;31:711– 25.
