Patients with renal masses are at risk for having or developing chronic kidney disease (CKD) stage 3 (glomerular filtration rate [GFR] <60 mL per minute/1.73 m2). In this study, the authors investigated whether the Screening for Occult Renal Disease (SCORED) model could identify patients with renal masses who were at risk for having or developing CKD.
Two hundred forty-two consecutive patients with unilateral T1a renal masses who underwent treatment were reviewed retrospectively. The GFR was estimated by using the Modification of Diet in Renal Disease equation. SCORED values were stratified as low (<4) or high (≥4). Kaplan-Meier survival curves (with log-rank comparison) were used to compute the risk of developing CKD.
Before intervention, 65 of 242 patients (27%) with T1a renal masses had CKD, including 10 of 98 patients (10%) with low SCORED values and 55 of 144 patients (38%) with high SCORED values. Interventions included radical nephrectomy (RN) in 71 patients (29%) and nephron-sparing approaches (NSA) in 171 patients (71%). Among patients with normal preoperative renal function, those with low SCORED values were less likely to develop CKD than those with high SCORED values, whether they underwent RN (38% vs 82%; P < .001) or NSA (14% vs 22%; P = .01). Multivariate analyses revealed that high SCORED values (hazard ratio [HR], 2.9; P = .02) and RN (HR, 7.0; P < .001) were significant predictors of developing CKD.
It has been estimated that chronic kidney disease stage 3 (glomerular filtration rate [GFR] < 60 mL/minute/1.73m2) (CKD) is prevalent in 11% of the general population, including 16% of the population aged >60 years.1 Recently, we and others demonstrated that CKD is present in 25% of patients with small unilateral renal masses at the time of their initial diagnosis despite a normal contralateral kidney.2, 3 The etiology of this higher incidence of CKD in patients with small unilateral renal masses even before intervention is not clear, because a small T1a renal mass occupies < 5% of the total renal volume.
Furthermore, among patients with normal preoperative renal function, we and others have demonstrated that nephron-sparing approaches (NSA) can help patients preserve renal function and avoid CKD better than radical nephrectomy (RN).2–4 At 4 years after intervention, 25% of patients who underwent partial nephrectomy (PN) developed CKD compared with 73% of patients who underwent RN. Unlike transplantation donors5—another group of patients undergoing unilateral nephrectomy—an increasing body of evidence indicates that RN in patients with small renal masses appears to be associated with a higher risk of having or developing CKD.
This higher proclivity toward the development of CKD in patients with small unilateral renal masses is of concern, because CKD represents an independent graded and staged risk factor for cardiovascular morbidity, hospitalization from any cause, and death.6–9 Recent analyses of both the SEER data and the Mayo Clinic data confirmed that patients who undergo RN for small unilateral renal masses have a significantly lower overall survival (hazard ratio, 2.2 for patients aged < 65 years) than patients who undergo NSA.10, 11
In an effort to understand the higher rates of CKD in patients with a small renal mass, we sought to examine the impact of comorbidities on renal outcomes using the Screening of Occult Renal Disease (SCORED) method, a predictive algorithm that includes factors such as age, proteinuria, anemia, and cardiovascular comorbidities.12 It has been demonstrated that a SCORED value ≥4 correlates with an increased risk of having or developing CKD.12 In the current study, we examined whether stratification by preoperative SCORED values could help identify patients who are at risk for having or developing CKD.
MATERIALS AND METHODS
After approval from out Institutional Review Board, a retrospective review was performed to identify consecutive patients with renal masses < 4 cm, a normal contralateral kidney, and no prior evidence of renal masses who underwent intervention for their renal masses between July 1995 and March 2005. All patients in this study underwent intervention for a small, solid enhancing renal mass suggestive of malignancy. Patients with bilateral renal masses, known metastatic disease at presentation, congenital solitary kidney, or previous renal extirpative or ablative renal surgery were excluded. Preoperative data, including patient demographics and comorbidities, preoperative characteristics of the renal mass, serum creatinine chemistries, and urinalysis, were obtained. Postoperative data included all available serum creatinine values starting from those collected at least 1 month after surgery. The GFR was calculated by using the Modification of Diet in Renal Disease (MDRD) equation, which was modified in 200513, 14:
The SCORED value was calculated for each patient in the manner described previously.12 Briefly, points were assigned for each decade of age >50 years (ages 50–59 years, 2 points; ages 60–69 years, 3 points; aged ≥70 years, 4 points), sex (woman, 1 point), anemia (presence, 1 point), proteinuria (presence, 1 point), presence of cardiovascular disease (1 point), congestive heart failure (1 point), diabetes (1 point), and peripheral vascular disease (1 point). SCORED values were stratified into low (<4) or high (≥4) categories. In the National Health and Nutrition Examination Surveys (NHANES) study, patients with SCORED values ≥4 had a 20% risk of having CKD, whereas those with SCORED values < 4 had a very low risk of CKD.12 Patients who underwent a secondary procedure were censored from postoperative GFR analysis at the time of the second treatment. Patients with CKD at the time of treatment were excluded from regression analysis concerning the development of CKD after treatment.
The choice of therapeutic intervention generally was based on renal mass location, patient comorbidity profile, and patient and physician preference. Because of the retrospective nature of this study, the factors that influenced the choice of therapeutic intervention could not be ascertained adequately. This cohort of patients included patients who underwent RN since 1995, open PN since 1996, laparoscopic PN since 2000, and radiofrequency ablation (RFA) since 2001. Because our prior data indicated that patients undergoing PN or RFA had comparable CKD outcomes, we evaluated these patients as a single cohort of patients undergoing nephron-sparing approaches in comparison to those undergoing RN.2 All patients underwent preoperative contrast-enhanced computed tomography (CT) or magnetic-resonance imaging of the abdomen and pelvis.
The median preoperative differences between the NSA and RN treatment groups for GFR, size on CT scan, and age were compared using the Mann-Whitney U test. Patient characteristics and SCORED values were compared by using Kruskal-Wallis or chi-square tests as appropriate. Survival analysis was calculated by using life tables and the Kaplan-Meier method. Two-sided tests of significance were used, the log-rank statistic was used to compare survival rates, and the P value set at .05, between patients with low SCORED values and high SCORED values. An event was defined as a decline in GFR < 60 mL/minute/1.73 m2 (CKD stage 3) on 2 consecutive measures >3 months apart, in keeping with the definition of CKD.15 Although estimated GFR levels may fluctuate over time, and GFR declines below a designated threshold may be temporary, in our study population, almost all patients who had GFR declines below a threshold remained below that threshold.2 In only 5 patients, the estimated GFR returned to normal after a temporary decline below a GFR < 60 mL/minute/1.73 m.2 Finally, Cox proportional-hazards analysis was used to evaluate multiple variables and determine which had an impact on renal function postoperatively. All analyses were performed with SPSS software (version 13.0; SPSS Inc., Chicago, Ill).
Our cohort consisted of 242 patients who underwent intervention for clinical T1a unilateral renal lesions and a normal contralateral kidney (Table 1). Before the intervention, 65 patients (27%) had CKD (Table 1). SCORED values were calculated in all patients and included 98 patients (40%) with low SCORED values and 144 (60%) with high SCORED values (Table 2). Patients with higher SCORED values were at a significantly higher risk of having CKD before any intervention compared with those who had lower SCORED values (38% vs 10%, respectively; P < .001) (Table 3).
Table 1. Demographics of the Cohort Stratified by Type of Procedure
Table 3. Characteristics of Patients With Unilateral, Small Renal Masses Who Had Chronic Kidney Disease (CKD) Before Intervention or No CKD Before Intervention Stratified by Screening for Occult Renal Disease Value or Type of Intervention
All 242 patients underwent intervention with either RN (71% or 29%) or NSA (171 or 71%; 86 RFA [36%] and 85 PN [35%]). Demographics, median preoperative GFR, and comorbidities for patients who underwent RN or NSA were comparable (Table 1). The median size of the renal mass was significantly larger in patients who underwent RN (RN, 3.2 cm; IQR = 1 vs NSA, 2.4 cm; IQR = 1; P < .001). The median follow-up for all patients in the cohort was 35 months. Among the patients who underwent RN, 40 of 71 patients (56%) had a high SCORED value compared with 104 of 171 patients (60%) who received NSA.
After intervention, among patients with a normal preoperative GFR (n = 177), CKD developed in 28 of 52 patients who underwent RN compared with 13 of 125 patients who underwent with NSA (P < .001). Stratification by preoperative SCORED value was predictive of a decline in GFR after treatment (Figs. 1, 2). Among the subset of patients with low preoperative SCORED values (n = 88), 6 of 22 patients who underwent RN and 3 of 66 patients who received NSA developed CKD (P = .004). In patients with high SCORED values (n = 89), 22 of 30 who underwent RN and 10 of 59 who received NSA developed CKD (P < .001). Regardless of the type of intervention, a higher SCORED value was associated with a significantly greater risk of CKD. The 3-year actuarial freedom from development of CKD was significantly higher in patients with low SCORED values than those with high SCORED values (NSA: 88.1 ± 6.6% vs 79.4 ± 7.8%; RN: 61.5 ± 13.5% vs 17.7 ± 10.8%). In multivariate analysis that included preoperative GFR, mass size, SCORED values, and procedure type, patients with high preoperative SCORED values were more likely to develop CKD after intervention for the renal masses (P = .021). Similarly, patients who underwent RN were more likely to develop CKD than those who received NSA (P < .001) (Table 4). Because the strongest predictor of renal function outcome was the type of intervention, the addition of SCORED value to a model that used intervention increased the area under the receiver operating characteristic curve from 0.74 (95%CI, 0.64–0.85) to 0.79 (95%CI, 0.69–0.9). Other variables, including mass size and preoperative GFR, did not add significantly to the predictive model.
Table 4. Multivariate Analyses of Renal Function Outcomes After Treatment for Unilateral T1a Renal Masses
Oncologic outcomes were comparable between patients with low and high preoperative SCORED values. Among those who received NSA, 78 of 86 patients (90.7%) underwent biopsy during RFA (55 renal cell carcinomas [RCCs], 8 indeterminate lesions, and 15 benign lesions), 85 patients who underwent PN had 69 RCCs and 16 benign lesions, and 71 patients who underwent RN had 62 RCCs and 9 benign lesions. In the NSA group, there were 8 local recurrences among 171 patients, including 6 recurrences after RFA (3 de novo tumors and 3 recurrences at the primary ablation site) and 2 recurrences after PN. These recurrences were managed by either repeat ablation in 3 patients or RN in 5 patients. In contrast, among the patients who underwent RN, there were no local recurrences, and there was 1 metachronous tumor in the contralateral kidney. No metastases were noted among the patients who received NSA; however, 2 patients who underwent RN developed metastatic disease shortly after surgery.
Preoperatively, >25% of our cohort with unilateral T1a renal masses and normal contralateral kidneys had significant CKD. These findings mirror those reported from multiple institutions, including our own, and suggest that >25% of patients with small renal masses had CKD stage ≥3 disease before any intervention.2, 3 This rate of CKD in patients with small unilateral renal masses is significantly higher than the 12% to 17% reported for the general population of patients aged >60 years.1 These data suggest that patients with renal masses may have a physiologic basis for a higher risk for CKD.
The physiologic basis of this higher risk for CKD may be attributed at least in part to the higher preoperative SCORED values in patients with renal masses. In this study, a majority of patients (60%) with a small unilateral renal mass had a preoperative SCORED value ≥4. In contrast, only 36% of 2864 patients who participated in the NHANES had SCORED values ≥4.12 It is noteworthy that, whereas in the NHANES study, a higher SCORED value predicted the development of CKD in only 18% of patients;, in our series, nearly 38% patients with a high SCORED value had CKD. It is important to note that the cohort of patients with renal cancer has several differences compared with the population in the NHANES study. Our patients were older (mean age, 60 years vs 46 years in the NHANES study) and had higher rates of hypertension and diabetes (44% vs 34% and 18% vs 8%. respectively). Thus, it is not surprising that the positive predictive value of a high SCORED value was higher in renal cancer patients than in the NHANES study. Taken together, these data indicate that patients with unilateral renal masses have a higher predilection for having CKD.
Prior studies demonstrated that the rate of de novo development of CKD after intervention was significantly greater in patients who underwent RN than in patients who received NSA.2–4, 16 In our series, >66% of patients who underwent RN developed CKD within 3 years of follow-up, compared with 10% of patients who received NSA. These data validate the importance of NSA whenever possible.
It is noteworthy that our data appear to identify a subset of patients undergoing either NSA or RN who are more susceptible to developing CKD. Among patients undergoing RN, those with a high preoperative SCORED value (80% risk of CKD) were twice as likely to develop CKD at 3 years as those with a low preoperative SCORED value (40% risk of CKD). Similarly, among patients undergoing NSA, those with a high preoperative SCORED value (22% risk of CKD) were more likely to develop CKD at 3 years than those with a low preoperative SCORED value (14% risk of CKD). Because there is a graded and increased risk of mortality and cardiovascular events with CKD, stratification by the SCORED model helps identify a subset of patients at higher risk of developing CKD and, thus, potentially may reduce survival.6–10
The findings in this study also may help explain the discrepancy between the outcomes of patients undergoing nephrectomy for renal masses or those undergoing nephrectomy as transplantation donors. Transplantation donors typically are healthy, likely have low preoperative SCORED values, and have excellent preservation of renal function after removal of a kidney. In contrast, patients with renal masses are at a distinctly higher risk for having or developing CKD after nephrectomy, because they have higher preoperative SCORED values. Currently, we are validating this hypothesis.
Our study has several limitations that must be explored further. Patients in this study were selected for each treatment modality based on clinical and tumor characteristics and the preferences of the patient and surgeon, which potentially created selection biases between the treatment groups. The retrospective nature of this report limits further clarification of the reasons why some patients with T1a renal masses underwent RN or PN. Generally, the majority of patients who underwent RN for T1a renal masses had central renal masses. Although patients undergoing NSA tended to have more comorbidities and smaller masses that were likely more peripheral than those in patients who underwent RN, the exact reasons for selecting a particular management strategy, including surgeon and patient preference and surgeon experience, cannot be controlled.
Another limitation of this study was that serum creatinine levels were not calibrated to the methods used by the MDRD research laboratory. The procedure for measuring creatinine is based on the clinic assay, which may differ from the assay used to update the MDRD equation.13 Although this softens the conclusion, the frequency of CKD and the rate of de novo CKD were comparable to what have been reported in previous studies.3 Furthermore, the recent adjustment of the MDRD equation, which was made to match the more widely used calibration assays in the clinical setting rather than the MDRD laboratory, was used to estimate GFR.15
Finally, without validation in either an internal or external cohort, it is possible that the higher frequency of higher SCORED values in patients with renal masses may represent a selection bias. A true propensity score analysis to minimize bias also would need to include patient preference and surgeon experience and could not be done for the current retrospective cohort. A patient with more comorbidities, including CKD, may be more likely to be screened with abdominal imaging than another patient with fewer or no comorbidities. Recently published evidence suggests an association between renal cancer and CKD, including an association between hypertension and renal cancer.17 However, the true cause-effect relation between the 2 needs to be elucidated further. Additional ongoing studies that include comparisons with the transplantation donor pool may help elucidate the true physiologic contribution of renal masses to renal dysfunction.
Overall, this study helped to identify the patients at highest risk for having or developing CKD after intervention for small unilateral renal masses. Patients with high preoperative SCORED values should be counseled about this risk, the parameters that affect renal function should be optimized, and NSA should be used whenever feasible. These findings require external validation before general adoption.
In conclusion, patients with unilateral T1a renal masses and high preoperative SCORED values had a greater prevalence of CKD before any intervention. Furthermore, high SCORED values were associated with a higher risk of developing CKD after either NSA or RN. Patients with high preoperative SCORED values should be counseled about their risk for CKD.