Ann Surg Oncol DOI 10.1245/s10434-015-4444-0

ORIGINAL ARTICLE – UROLOGIC ONCOLOGY

Preoperative Chronic Kidney Disease Status is an Independent Prognostic Factor in Patients with Renal Cell Carcinoma Young-Won Kim, MD1, Won Tae Kim, MD, PhD1, Seok Joong Yun, MD, PhD1, Sang-Cheol Lee, MD, PhD1, Wun-Jae Kim, MD, PhD1, Yun-Sok Ha, MD, PhD2, Yong Hyun Park, MD, PhD3, Seok Ho Kang, MD, PhD4, Sung-Hoo Hong, MD, PhD3, Tae Gyun Kwon, MD, PhD2, Seok-Soo Byun, MD, PhD5, Cheol Kwak, MD, PhD6, and Yong-June Kim, MD, PhD1 Department of Urology, Chungbuk National University College of Medicine, Cheongju, Chungbuk, Korea; 2Department of Urology, Kyungpook National University College of Medicine, Daegu, Korea; 3Department of Urology, College of Medicine, The Catholic University of Korea, Seoul, Korea; 4Department of Urology, Korea University School of Medicine, Seoul, Korea; 5Department of Urology, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, Korea; 6Department of Urology, Seoul National University College of Medicine, Seoul, Korea 1

ABSTRACT Purpose. Preoperative chronic kidney disease (CKD) status may affect disease outcomes in patients with renal cell carcinoma (RCC). This study evaluated the influence of preoperative CKD status on clinicopathological features and prognosis in patients with RCC. Methods. Between 1999 and 2011, a total of 1855 patients underwent radical nephrectomy at various centers throughout Korea. Of these patients, 1655 had an estimated glomerular filtration rate (eGFR) C60 ml/min/1.73 m2 (non-CKD group) and 200 patients had an eGFR C30 but \60 ml/min/1.73 m2 (CKD group). To reduce the effects of selection bias and potential confounding factors, 600 patients in the non-CKD group were selected by propensity-score matching. Results. The median age of all patients was 57.3 years (range 20–94 years) and the median follow-up was 35.0 months (range 1–154 months). Comparisons of the propensity-score-matched cohorts showed that T and N stages were more advanced and tumor size was larger in the CKD group than in the non-CKD group (p \ 0.05 each). Kaplan–Meier analyses showed that recurrence-free

Ó Society of Surgical Oncology 2015 First Received: 30 December 2014 C. Kwak, MD, PhD e-mail: [email protected] Y.-J. Kim, MD, PhD e-mail: [email protected]

survival, cancer-specific survival (CSS), and overall survival (OS) were significantly lower in the CKD group (p \ 0.01 each). Multivariate regression analysis showed that preoperative CKD status was an independent predictor of CSS and OS in patients with RCC (p \ 0.05 each). Conclusions. Preoperative CKD may be associated with more aggressive features and poorer prognosis in patients with RCC. RCC patients with preoperative CKD should be carefully and frequently followed-up after nephrectomy.

Renal cell carcinoma (RCC) is the third most frequent type of urologic tumor.1 Its incidence has increased since 1970 because of early detection of asymptomatic tumors by advanced radiological modalities, such as ultrasonography and computed tomography (CT) scanning;2 however, despite increased detection of early-stage renal masses, the mortality rate has not decreased.2 Thus, identification of clinically prognostic factors may be valuable in improving management and follow-up strategies for patients with RCC. Smoking, obesity, chronic dialysis, family history of RCC, hypertension, and diabetes mellitus (DM) are among the risk factors associated with RCC.1,3 Moreover, several recent studies have analyzed the relationships between renal function and RCC.4–6 Earlier studies found that patients with RCC were at increased risk of reduced glomerular filtration rate (GFR) and new-onset chronic kidney disease (CKD) after radical nephrectomy (RN).7,8 Moreover, severe CKD in patients with end-stage renal disease (ESRD) was associated

Y. Kim et al.

with a greatly increased risk of RCC.9 Renal function in RCC patients with preoperative CKD will likely deteriorate after RN, and this may affect patient prognosis and risks of new RCC. Although previous studies identified a relationship between ESRD status and RCC, preoperative CKD status may also play an important role in disease features and outcomes in patients with RCC. This study was therefore designed to evaluate the effects of preoperative CKD status on clinicopathological features and the prognosis of patients with RCC after nephrectomy. To our knowledge, no previous study has assessed the effects of preoperative mild to moderate CKD status on RCC.

Tumor Classification and Patient Management Tumors were staged pathologically13 and subtyped histologically,14 as described. Nuclear differentiation was graded by pathologists at each institution using the Fuhrman grading system.15 All patients were evaluated postoperatively, by physical examination and radiologic imaging, every 3 months for the first 2 years, every 6 months for the next 2 years, and yearly thereafter. Recurrence was defined as relapse, as determined by abdominal and thoracic methods (primarily CT). Statistical Analysis

MATERIALS AND METHODS Study Population This retrospective study included data from five academic centers in Korea. A total of 3567 patients were identified between 1999 and 2011. Patients with ESRD [GFR \30 ml/min/1.73 m2 or defined chronic renal failure (CRF) treated by dialysis or transplantation], pediatric patients (aged \18 years), patients with incomplete data or benign renal tumors, patients who underwent partial nephrectomy (PN), and patients with unclassified histologic subtype of tumors were excluded from the analysis. Overall, a total of 1855 patients with RCC who underwent RN were analyzed. Demographic and clinical features analyzed included age at surgery, sex, body mass index (BMI), symptoms at presentation, Eastern Cooperative Oncology Group performance status (ECOG-PS), and operative variables. In addition, chronic metabolic diseases such as hypertension and DM were assessed. Estimated GFR (eGFR) was calculated from the final preoperative serum creatinine concentration using the abbreviated Modification Diet of Renal Disease (MDRD) equation, with eGFR = 186.3 9 (serum creatinine - 1.154) 9 (age - 0.203) 9 0.742 (if female).10 Baseline GFR was categorized as stage I (C90 ml/min), II (60–89 ml/min), or III (30–59 ml/min/ 1.73 m2),11 with CKD defined as an eGFR \60 ml/min/ 1.73 m2. Patients were classified as having an eGFR C60 ml/min/1.73 m2 (non-CKD group; n = 1655) or C30 but \60 ml/min/1.73 m2 (CKD group; n = 200). To reduce the effects of selection bias and potential confounding factors, propensity-score-matching analysis was performed to adjust for covariates such as age, sex, and BMI.12 Of the 1655 patients in the non-CKD group, 600 were selected by propensity-score-matching analysis and compared with the 200 patients in the CKD group. The data collection and analysis of all subjects was approved by the individual academic center’s Institutional Review Board.

Baseline covariates were compared after propensityscore matching, with continuous variables compared using Student’s t tests and categorical variables using v2 tests. The effects of CKD on recurrence-free survival (RFS), cancer-specific survival (CSS), and overall survival (OS) were estimated using the Kaplan–Meier method, and compared using log-rank tests. Factors independently associated with RFS, CSS, and OS were determined by a multivariate Cox proportional hazard regression model, with hazard ratio (HR) and 95 % confidence interval (CI) computed for each factor. All statistical analyses were performed using SPSS version 20.0 (IBM Corporation, Armonk, NY, USA) and R version 2.12.1 software, with p values \0.05 considered statistically significant.

RESULTS Clinicopathological Characteristics Total Cohorts The median age of the 1855 patients with RCC was 57.3 years (range 20–94 years), and 69.8 % (1295/1855) were males. Of these patients, 200 (10.8 %) had CKD and 1655 (89.2 %) did not. The median followup was 35.0 months (range 1–154 months). Comparisons of the two groups showed that median age (64.8 vs. 56.4 years; p \ 0.01) and BMI (25.0 vs. 24.2 kg/m2; p = 0.004) were significantly higher in the CKD group, as was the proportion of males [90.5 % (181/200) vs. 67.3 % (1114/1655); p \ 0.01] (Table 1). The rates of DM and hypertension were significantly higher in the CKD group than in the non-CKD group (p \ 0.01 each). The proportions of patients with more advanced T and M stages and higher Fuhrman’s grade were significantly higher in the CKD group than in the non-CKD group (p \ 0.05 each). Other parameters, such as tumor size, N stage, ECOG-PS, and tumor histologic types, did not differ significantly in the two groups.

CKD as a Prognostic Factor in RCC Patients TABLE 1 Baseline characteristics of total and propensity-score-matched cohorts of patients with renal cell carcinoma who underwent radical nephrectomy Total cohorts

Age (years)

Propensity-score-matched cohorts

Non-CKD group (n = 1655)

CKD group (n = 200)

56.4 ± 12.3

64.8 ± 9.9

p value

Non-CKD group (n = 600)

CKD group (n = 200)

\0.001

64.3 ± 9.8

64.5 ± 9.9

\0.001

Sex (%) Male

1114 (67.3)

181 (90.5)

Female

51 (32.7)

19 (9.5)

24.2 ± 3.3

25.0 ± 3.5

0.004

Preoperative e-GFR (mL/min/1.73 m2)

90.4 ± 23.5

52.7 ± 6.2

\0.001

Tumor size (cm)

5.0 ± 2.9

5.4 ± 3.0

No Yes Diabetes mellitus [n (%)]

0.055

181 (90.5)

58 (9.7)

19 (9.5)

24.9 ± 3.4

25.0 ± 3.5

0.590

81.3 ± 17.3

52.7 ± 6.2

\0.001

4.9 ± 2.8

5.4 ± 3.0

305 (50.8)

74 (37.0)

295 (49.2)

126 (63.0)

\0.001

Hypertension [n (%)] 1022 (61.8)

74 (37.0)

633 (38.2)

126 (63.0)

\0.001

No

1414 (85.4)

128 (64.0)

482 (80.3)

128 (64.0)

Yes

241 (14.6)

72 (36.0)

118 (19.7)

72 (36.0)

0.893

0.661

0

554 (33.5)

66 (33.0)

188 (31.3)

66 (33.0)

1–4

1101 (66.5)

134 (67.0)

412 (68.7)

134 (67.0)

T1

1042 (63.0)

100 (50.0)

370 (61.7)

100 (50.0)

T2

253 (15.3)

33 (16.5)

85 (14.2)

33 (16.5)

T3

330 (19.9)

54 (27.0)

135 (22.5)

54 (27.0)

T4

30 (1.8)

13 (6.5)

10 (1.7)

13 (6.5)

N0

1583 (95.6)

186 (93.0)

581 (96.8)

186 (93.0)

N1–2

72 (4.4)

14 (7.0)

19 (3.2)

14 (7.0)

\0.001

T stage [n (%)]

N stage [n (%)]

M stage [n (%)] M0

0.001

0.092

0.018

0.018

0.079

1541 (93.1)

177 (88.5)

555 (92.5)

177 (88.5)

114 (6.9)

23 (11.5)

45 (7.5)

23 (11.5)

Low (1–2)

826 (49.9)

84 (42.0)

274 (45.7)

84 (42.0)

High (3–4)

829 (50.1)

116 (58.0)

326 (54.3)

116 (58.0)

M1 Fuhrman’s grade [n (%)]

0.035

Tumor histological type [n (%)]

0.014 0.001

\0.001

ECOG-PS [n (%)]

0.908 0.945

542 (90.3)

BMI (kg/m2)

p value

0.366

0.936

0.252

Clear cell

1446 (87.7)

174 (87.4)

540 (90.3)

174 (87.4)

Non-clear cell

204 (12.4)

25 (12.6)

58 (9.7)

25 (12.6)

Data are expressed as mean ± SD unless otherwise indicated BMI body mass index, CKD chronic kidney disease, ECOG-PS European Cooperative Oncology Group performance score, e-GFR estimated glomerular filtration rate, SD standard deviation

Propensity-Score-Matched Cohorts Following propensityscore matching, covariates, including age, sex, BMI, ECOGPS, M stage, Fuhrman’s grade, and tumor histologic type, did not differ significantly between the 200 patients in the CKD group and the 600 patients in the non-CKD group (Table 1). However, the rates of DM and hypertension remained significantly higher in the CKD

group than in the non-CKD group (p \ 0.01 each), as did the proportions of patients with more advanced T and N stages (p \ 0.05 each). In addition, mean tumor size was larger in the CKD group than in the non-CKD group (p \ 0.05). The rates of comorbidities and more aggressive oncologic features were also higher in the CKD group.

Y. Kim et al.

Prognosis of Renal Cell Carcinoma According to the Chronic Kidney Disease Status of the PropensityScore-Matched Cohorts Kaplan–Meier analysis showed that RFS, CSS, and OS in the propensity-matched cohorts were greater in the non-CKD group than in the CKD group (log-rank test; p \ 0.010 each) (Fig. 1) performed to evaluate the ability of preoperative CKD status to predict RFS, CSS, and OS in propensity-score-matched cohorts. After additional adjustments for prognostic factors and clinical parameters, preoperative CKD status was found to be an independent predictive risk factor for CSS (HR 1.692; p = 0.023) and OS (HR 1.452; p = 0.049), but not RSS (p = 0.055), in patients with RCC (Table 2). DISCUSSION This study evaluated the impact of preoperative CKD status on clinicopathological features and prognosis of RCC using a propensity-score-matching analysis. Rates of DM and hypertension were higher and tumor size was larger in the CKD group than in the non-CKD group. Tumors in the CKD group had more aggressive features and patients in this group had a poorer prognosis compared with the non-CKD group. To our knowledge, this study is the first to report the impact of preoperative CKD status on disease outcomes in RCC patients who underwent RN. A recent multicenter analysis of RCC in patients with ESRD reported that asymptomatic, small, low-stage, and low-grade tumors were more frequent in patients with ESRD than those without.16 By contrast, age, tumor size, rate of incidental cancer, pathological T stage, and grade were found to be similar in RCC patients with and without ESRD.17 Our results showed that CKD status was associated with aggressive tumor characteristics and poor disease outcomes. More advanced T and N stages were more

frequent and tumor size was larger in the CKD group than in the non-CKD group. The difference between our results and previous studies may be due in part to our inclusion, in the CKD group only, of patients with GFR 30–59 ml/min/ 1.73 m2, not those with ESRD. Most previous studies evaluated the association between RCC and GFR between patients with and without ESRD. To our knowledge, no previous studies have explored the association between mild to moderate CKD and the oncologic features of RCC. In a previous study, RCC patients with ESRD had low tumor stage and grade.18 Because ESRD patients are screened more frequently than the general population, early diagnosis may have been responsible, at least in part, for their less aggressive oncologic features.19 By contrast, the present study did not enroll any patients with ESRD, which may have affected the percentage with aggressive clinical features. Our study also differed from previous studies in that we assessed only patients who underwent RN, whereas previous studies included patients who underwent both RN and PN. Indications for PN include less aggressive clinical features of RCC, with the standard treatment for small renal masses shifting from RN to PN.20 Although the precise mechanisms by which relative renal insufficiency leads to kidney cancer, and possibly more virulent kidney cancer, is unknown, there is some evidence in a population-based cohort study that demonstrates the association between decreased renal function and risk of kidney cancer.21,22 Christensson et al. found that moderately impaired renal function at baseline is significantly associated with an increased risk of kidney cancer during the 28-year median follow-up period.21 Similarly, the risk of incidence renal cancer is gradually increased with the severity of renal function deterioration in a large-scale, retrospective study.22 CKD was found to

TABLE 2 Multivariate Cox regression analysis of factors predictive of prognosis in propensity-score-matched cohorts with renal cell carcinoma after radical nephrectomy Variables

Recurrence-free survival HR (95 % CI)

Age

0.986 (0.968–1.004)

Cancer-specific survival p value 0.128

HR (95 % CI) 1.010 (0.984–1.036)

Overall survival p value 0.461

HR (95 % CI) 1.017 (0.996–1.038)

p value 0.107

Sex (male vs. female)

0.654 (0.327–1.307)

0.230

0.335 (0.103–1.089)

0.069

0.395 (0.170–0.916)

0.030

BMI

0.856 (0.807–0.909)

\0.0001

0.889 (0.821–0.963)

0.004

0.864 (0.812–0.920)

\0.0001

ECOG-PS (0 vs. 1–4) Fuhrman grade (low vs. high)

1.197 (0.790–1.812) 3.428 (2.221–5.293)

0.396 \0.0001

1.546 (0.843–2.835) 2.942 (1.626–5.324)

0.159 \0.0001

1.437 (0.917–2.252) 1.701 (1.143–2.530)

0.114 0.009

Tumor size

1.057 (0.977–1.145)

0.168

1.090 (0.982–1.209)

0.106

1.039 (0.953–1.133)

0.389

T stage (T1 vs. T2–4)

3.446 (1.999–5.942)

\0.0001

4.398 (2.025–9.552)

\0.0001

2.388 (1.380–4.132)

0.002

CKD (no vs. yes)

1.402 (0.993–1.979)

0.055

1.692 (1.076–2.661)

0.023

1.452 (1.000–2.108)

0.049

CKD chronic kidney disease, BMI body mass index, ECOG-PS European Cooperative Oncology Group performance score, HR hazard ratio, CI confidence interval

CKD as a Prognostic Factor in RCC Patients

B 80 60 40 20

Non-CKD group CKD group

Log-rank test, p=0.005

0 0

20

40

60

80

100

120

140

C 100

100 80 60 40 20

Non-CKD group CKD group

Log-rank test, p=0.001

0 0

20

40

60

80

100

120

140

80 60 40 20

163

98

44

9

47

22

8

4

Number at risk Group: Non-CKD group 571 359 Group: CKD group 190 127

Non-CKD group CKD group

Log-rank test, p=0.009

0 0

20

40

Time (months)

Time (months) Number at risk Group: Non-CKD group 571 359 248 Group: CKD group 190 127 87

Overall survival (%)

100

Cancer specific survival (%)

Recurrence-free survival (%)

A

60

80

100

120

140

Time (months)

248

163

98

44

9

0

87

47

22

8

4

0

Number at risk Group: Non-CKD group 571 359 Group: CKD group 190 127

248

163

98

44

9

0

87

47

22

8

4

0

FIG. 1 Kaplan–Meier analysis of a recurrence-free survival, b cancer-specific survival, and c overall survival following radical nephrectomy in propensity-score-matched cohorts of patients with and without preoperative CKD. CKD chronic kidney disease

be an independent risk factor for the development of cardiovascular diseases, number of hospitalizations, and death.23 ESRD increases the risk of kidney cancer up to 100-fold, and CRF is a strong risk factor for RCC.4,24 Strong associations have been observed between preoperative GFR and RCC, with many RCC patients with preoperative CKD having unfavorable risk factors, including smoking, hypertension, and DM.25 DM and hypertension are especially important risk factors for the decline of renal function in patients with RCC.26–28 A study assessing the long-term impact of hypertension and DM on GFR in 488 patients found that hypertension was associated with new-onset CRF only in patients who underwent RN (HR 1.39, 95 % CI 1.02–1.89).28 Another study found that hypertension was an independent predictor of CKD upstaging.26 DM has also been associated with CKD, such as in patients with diabetic renal disease, and is the most important cause of ESRD.27 We found that both DM and hypertension were more frequent in the CKD group than in the non-CKD group, in agreement with studies showing that chronic diseases such as metabolic syndrome may be important causes of CKD.26–28 Decreased preoperative GFR may aggravate CKD status or induce the development of new-onset severe CKD such as ESRD after nephrectomy in patients with RCC.5,7 Thus, appropriate medications should be selected and serum creatinine level monitored frequently to prevent degeneration of renal function after nephrectomy. Baseline GFR was found to independently affect OS after nephrectomy.6 In addition, severe CKD was shown to be an independent prognostic factor for tumor recurrence in RCC patients after surgery, suggesting that patients with ESRD are at higher risk of tumor progression.17 Similarly, our results indicated that preoperative CKD (not severe CKD) was independently predictive of CSS and OS, and was associated with poorer RFS, CSS, and OS. Preoperative CKD status may be rapidly exacerbated after nephrectomy due to reduced renal function in the

remaining kidney. Patients who underwent RN were found to be 1.9-fold more likely to experience CKD.7 Moreover, patients who undergo RN are significantly more likely to develop new-onset stage IV CKD (HR 4.23; p \ 0.001).5 New-onset severe CKD may be a risk factor for occurrence of a second RCC. Previous studies showed that patients with CRF have a high incidence of malignant tumors because uremia markedly suppresses the immune system.29 In addition, pathologic changes in the kidney related to a decline in renal function (e.g. renal fibrosis, tubular atrophy, interstitial inflammation, and acquired cystic kidney disease) may lead to RCC development.30 Declines in renal function and occurrence of a second RCC owing to histological changes in the remnant kidney and immune suppression are more likely to affect the prognosis of RCC patients with preoperative CKD after RN. Thus, frequent and careful monitoring for recurrence and progression after RN is necessary in RCC patients with preoperative CKD.

CONCLUSIONS These results suggest that preoperative CKD may be associated with aggressive features and poor prognosis of RCC. RCC patients with preoperative CKD should be carefully and frequently followed-up after nephrectomy. In addition, treatment modalities before nephrectomy should be carefully evaluated in CKD patients with RCC to prevent the aggravation of CKD status. ACKNOWLEDGMENT This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (2011-0023308) and Ministry of Science, ICT and Future Planning (NRF2014R1A2A1 A09006983). DISCLOSURE Young-Won Kim, Won Tae Kim, Seok Joong Yun, Sang-Cheol Lee, Wun-Jae Kim, Yun-Sok Ha, Yong Hyun Park, Seok Ho Kang, Sung-Hoo Hong, Tae Gyun Kwon, Seok-Soo Byun, Cheol

Y. Kim et al. Kwak, and Yong-June Kim declare that they have no conflicts of interest.

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Preoperative Chronic Kidney Disease Status is an Independent Prognostic Factor in Patients with Renal Cell Carcinoma.

Preoperative chronic kidney disease (CKD) status may affect disease outcomes in patients with renal cell carcinoma (RCC). This study evaluated the inf...
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