The Volume of Nonneoplastic Parenchyma in a Minimally Invasive Partial Nephrectomy Specimen: Predictive Factors and Impact on Renal Function

Abstract

Purpose:

To identify predictors of nonneoplastic parenchymal volume excised during minimally invasive partial nephrectomy (PN) and determine the impact on postoperative renal function.

Patients and Methods:

A total of 206 patients underwent laparoscopic or robot-assisted PN between 2003 and 2011. Parenchymal volume was estimated by subtraction of calculated tumor volume from total specimen volume. Univariate and multivariate regression analyses were used to examine the association of parenchymal volume with tumor and surgical factors. Percent and absolute changes in estimated glomerular filtration rate (eGFR) on the day after surgery, 1 to 12 months, and >12 months after surgery were correlated with parenchymal volume.

Results:

Increased tumor size (P<0.001), earlier era of surgery (P=0.04), and longer ischemia time (P=0.05) were associated with higher parenchymal volume. Robotic surgery was not associated with better parenchymal preservation. Median percent change in eGFR at 1 to 12 months (mean=6.7 months) and >12 months (mean=28.3 months) was −10.9% and −12.1%, respectively. No association was found between the volume of parenchyma and change in eGFR. Longer ischemia time was associated with decrease in eGFR only the first day after surgery (P=0.005). Higher body mass index BMI and Charlson comorbidity index and lower preoperative eGFR were associated with decrease in eGFR 1 to 12 months after surgery (P=0.006, 0.04, 0.001, respectively).

Conclusions:

In our cohort, larger tumors, longer ischemia time, and earlier era of PN were associated with increased amount of nonneoplastic parenchyma excised during surgery. We did not observe a relationship between absolute volume of parenchyma and change in renal function after surgery. Baseline renal function and comorbidities were the strongest determinants of long-term renal function.

Introduction

The incidence of kidney cancer has been rising over recent decades, reaching an estimated 61,000 new cases in the United States during 2011.¹ With a downward stage migration, ∼60% of newly diagnosed lesions are 4 cm or less in diameter and termed small renal masses.² The ability to preserve normal renal parenchyma while maintaining oncologic outcomes comparable to those of radical nephrectomy has made partial nephrectomy (PN) a standard of care option for treating patients with SRMs.³

The impact of PN on long-term renal function may vary from no measurable deterioration to significant decline. Identification of modifiable determining factors is of paramount importance and continues to be the focus of ongoing research.^4
–6 Recent publications suggest that the extent of nonneoplastic renal parenchymal volume reduction during surgery is associated with long-term renal function.^7
–9 Simmons and associates⁸ found that immediately after PN, both ischemia time and parenchymal preservation were associated with renal function. In contrast, at late time points, only the percent functional volume preservation was associated with the decrease in glomerular filtration rate (GFR).

In previous studies, volume change after PN was estimated using indirect methods such as surgeon's impression or imaging-based calculations.^8

–11 We estimated the amount of nonneoplastic parenchyma resected during PN, based on pathologic specimen measurements. Potential determinants of parenchymal volume and its association with postoperative renal function were investigated.

Patients and Methods

Patients

Our prospectively maintained renal mass database is comprised of 337 patients who underwent laparoscopic or robot-assisted PN by two surgeons (ALS and SEE) between 2003 and 2011. We reviewed all pathologic reports and identified 212 (63%) patients for whom three dimensional descriptions of the tumor and total specimen free of fat were available. Of these patients, we excluded six with more than one resected tumor. This led to a total number of 206 eligible patients. Retrieved data included patient characteristics (eg, age, sex, body mass index [BMI], history of hypertension and diabetes mellitus), tumor characteristics (eg, laterality, size, depth, and polarity) and surgical parameters (eg, surgical approach, use of intraoperative ultrasonography, era of surgery, ischemia time, overall operative time). Era of surgery was evaluated as a continuous variable, in months after surgery. The study was approved by our Institutional Review Board.

Volume estimation and renal function evaluation

Total specimen and tumor only volumes were calculated using the ellipsoid formula (ie, π/6×length×width×height), as described previously.¹² The volume of nonneoplastic parenchyma was estimated by subtraction of tumor volume from total specimen volume.

Renal function was evaluated using the abbreviated Modification of Diet and Renal Disease equation, based on serum creatinine, age, sex, and ethnicity.¹³ Serum creatinine was measured preoperatively, on the day after surgery, during 1 to 12 months after surgery, and >12 months after surgery. If more than one measurement was available, the latest measurement taken within each time group was used. The primary end point was percent change from baseline, calculated as (estimatedGFR [eGFR]_preoperative -eGFR_{postoperative})×100/eGFR_preoperative. Because preoperative eGFR is strongly associated with percent change in eGFR, we also calculated absolute change in eGFR. The latter was used in a separate multivariate analysis to evaluate the impact of preoperative eGFR.

Statistical analysis

Univariate and multivariate linear regression analyses were used to identify factors associated with the volume of nonneoplastic parenchyma. Patient, tumor, and surgical variables were included in the models. Next, we evaluated the association between nonneoplastic volume and the percent change in eGFR at different time points after surgery. All variables associated with a univariate P-value≤0.1 were included in the multivariate model as well as variables of interest, such as nonneoplastic parenchymal volume and comorbidities. Logistic transformation was applied to dependent variables having nonnormal distribution. Statistical tests were two-sided and were considered statistically significant when P<0.05. Analyses were performed with Stata 10 (Statacorp. College Station, TX).

Results

Demographics, tumor, and surgical parameters are presented in Table 1. Mean (standard deviation) volumes of total specimen, tumor, and nonneoplastic parenchyma were 22 (24), 9.4 (15.2) and 13.1 (13.5) cc, respectively.

Table 1.

Demographic, Tumor, and Surgical Parameters

Characteristic
Age, year, mean (SD)	56.9 (11.9)
Males, no. (%)	124 (60)
BMI, kg/m², mean (SD)	28.8 (6)
DM, no. (%)	32 (15)
HTN, no. (%)	103 (50)
Single kidney, no. (%)	4 (2)
Preoperative eGFR(mL/min/1.73 m²), no. (%)
≥90	60 (29)
60–89	108 (53)
30–59	35 (17)
15–29	3 (1)
Side, no. (%)
Right	115 (56)
Left	91 (44)
Polar location, no. (%)
Upper	70 (34)
Midpolar	72 (35)
Lower	64 (31)
Exophytic properties, no. (%)
>50% exophytic	109 (53)
≤50% exophytic	97 (47)
Hilar lesions, no. (%)	19 (9)
Cystic lesions, no. (%)	39 (19)
Malignant lesions, no. (%)	171 (83)
Procedure type, no. (%)
Laparoscopic	159 (77)
Robotic	47 (23)
Intraoperative U/S, no. (%)	161 (78)
Warm ischemia time, mean (SD)	27.7 (10.3)

SD=standard deviation; BMI=body mass index; DM=diabetes mellitus; HTN=hypertension; eGFR=estimated glomerular filtration rate.

On univariate analysis, increased tumor size (P<0.001), ≤50% exophytic rate (P=0.04), and longer ischemia time (P=0.04) were associated with higher volume of nonneoplastic parenchyma. Increased operative time, earlier era of surgery, and midpolar location of the tumor showed borderline significance (P=0.07, 0.08 and 0.08, respectively). Procedure type (robotic vs laparoscopic) and intraoperative ultrasonography use were not associated with parenchymal volume (P=0.43 and 0.46, respectively). Ischemia time was shorter in robot-assisted cases compared with laparoscopic-assisted (mean=24 vs 28 min, P=0.01), while no differences in tumor volume, depth, or location were found between these surgical approaches.

At multivariate regression analysis, increased tumor size (P<0.001), earlier era of surgery (P=0.04), longer ischemia time (P=0.05), and longer operative time (P=0.04) remained associated with higher nonneoplastic parenchymal volume (Table 2).

Table 2.

Regression Analysis of Factors Associated with the Volume of Nonneoplastic Parenchyma in PN Surgical Specimen

	Univariate		Multivariate
Factor	β (95% CI)	P-value	β (95% CI)	P-value
Tumor side (reference: right)	0.20 (−0.09, 0.50)	0.17	0.23 (−0.05, 0.50)	0.11
Tumor volume, cc	0.02 (0.02, 0.04)	<0.001	0.02 (0.01, 0.03)	<0.001
Exophytic rate (reference: >50%)	0.2 (0.00, 0.40)	0.04	0.09 (−0.10, 0.30)	0.3
Polar location (reference: midpolar)	−0.16 (−0.34, 0.02)	0.08	−0.15 (−0.30, 0.20)	0.09
Era of surgery, months	−0.00 (−0.01, −0.00)	0.08	−0.00 (−0.01, −0.00)	0.04
Operative time, min	0.00 (−0.00, 0.006)	0.07	0.00 (0.00, 0.006)	0.04
Warm ischemia time, min	0.01 (0.00, 0.03)	0.04	0.01 (−0.00, 0.02)	0.05

PN=partial nephrectomy; CI=confidence interval.

Serum creatinine level on the day after surgery, 1 to 12 months after surgery (mean 6.7±2.3) and >12 months after surgery (mean 28.3±12.3) were available for 190 (92%), 145 (70%), and 107 (52%) patients. The median (interquartile range) preoperative eGFR was 80 (65, 92) mL/min/1.73 m². Median percent change in eGFR was −14.7%, −10.9%, and −12.1% at first postoperative day, 1 to 12 months, and >12 months, respectively. During the first year after surgery, new onset stage III chronic kidney disease (CKD) developed in 11 of 145 (7.5%) patients, all of whom had stage II CKD preoperatively. New onset stage IV–V CKD developed in none of the patients.

On univariate analysis, nonneoplastic parenchymal volume was not associated with renal function 1 to 12 months and >12 months after surgery (P=0.4 and 0.9, respectively). Borderline significance was observed the first day after surgery (P=0.07). Longer ischemia time was associated with a decline in eGFR the first day after surgery (P=0.003) but not at 1 to 12 months (P=0.9) or >12 months (P=0.7). Higher BMI was associated with a more significant eGFR percent decline at all time periods (P=0.006, 0.001, and 0.05 at the first day after surgery, 1 to 12 months, and >12 months, respectively).

Multivariate regression analysis of potential factors predicting percent change in eGFR is shown in Table 3. Higher BMI and Charlson comorbidity index were associated with decreases in percent eGFR 1 to 12 months after surgery (P=0.006 and 0.045, respectively). When absolute eGFR change was used as the dependent variable in multivariate analysis, preoperative eGFR was strongly associated with postoperative eGFR at all time periods (P<0.001) (analysis not shown).

Table 3.

Multiple Regression Analysis of Factors Determining % Change in eGFR After Partial Nephrectomy

	POD 1		1–12 months after surgery		>12 months after surgery
Factor	β (95% CI)	P-value	β (95% CI)	P-value	β (95% CI)	P-value
BMI, kg/m²	−0.007 (−0.01, −0.001)	0.05	−0.007 (−0.01, −0.002)	0.006	−0.006 (−0.01, −0.00)	0.06
Diabetes	0.04 (−0.07, 0.17)	0.5	−0.003 (−0.09, 0.08)	0.9	0.002 (−0.1, 0.1)	0.9
HTN	−0.03 (−0.12, 0.05)	0.4	0.009 (−0.06, 0.08)	0.8	0.02 (−0.05, 0.1)	0.5
Charlson comorbidity index	−0.001 (−0.03, 0.03)	0.9	−0.02 (−0.05, −0.000)	0.04	−0.005 (−0.03, −0.02)	0.7
Non-neoplastic parenchyma, cc	−0.001 (−0.004, 0.001)	0.4	0.000 (−0.002, 0.002)	0.9	0.00 (−0.002, 0.002)	0.8
WIT, min	−0.005 (−0.01, −0.001)	0.005	0.000 (−0.002, 0.003)	0.8	−0.00 (−0.003, 0.003)	0.8

eGFR=estimated glomerular filtration rate; CI=confidence interval; BMI=body mass index; HTN=hypertension; WIT=warm ischemia time.

Discussion

Based on pathologic specimen measurements, we identified tumor size, earlier era of surgery, and ischemia time as the strongest determinants of nonneoplastic parenchymal volume in PN specimen. In a cohort comprised mostly of patients with two functioning kidneys, however, this volume did not predict the percent change in overall renal function. Baseline nonmodifiable patient characteristics, such as preoperative eGFR, Charlson comorbidity index, and BMI were associated with renal function during the year after surgery.

To our knowledge, this study is the first to investigate which factors determine the amount of uninvolved parenchyma in PN pathologic specimens. The only tumor feature significantly associated with parenchymal volume was tumor size. Despite that, the association of longer operative and ischemia times with parenchymal volume implies that for surgically complex tumors, an increased amount of noncancerous tissue is resected. Supporting this, Simmons and colleagues⁸ found an association between ischemia time, tumor size, central location, and renal volume loss. Looking at era of surgery, we found that the ability to preserve parenchyma improved over the years. This trend was not related to technologic advances such as intraoperative ultrasonography. We assume that growing surgical experience contributed to this trend.

Not only has robot use in PN expanded in recent years, but it has also contributed to the overall increased use of PN.^14,15 Shorter ischemia time has been reported for robot-assisted PN compared with laparoscopy.^16
–18 Furthermore, using imaging based calculations, it has been recently claimed that higher volume of nonneoplastic parenchyma can be preserved with the robotic approach.¹⁹ Our data show reduced ischemia time with the robotic approach; however, we found no difference in parenchymal preservation between robotic and laparoscopic surgeries.

As use of PN expands,²⁰ data about renal function after surgery accumulate. Using volumetric methods, the percent reduction in parenchymal volume is estimable and found to be associated with renal function.^8,10 We calculated the absolute parenchymal volume resected during PN based on pathologic specimen. Similar to our findings, Propiglia and coworkers²¹ did not find an association between net amount of parenchyma (thickness of uninvolved parenchyma in PN specimen) and long-term renal function.

The impact of warm ischemia time (WIT) on functional results of PN has been widely investigated in previous studies. We found that WIT as a continuous variable was not associated with long-term change in renal function. As previously suggested, this might be a result of 98% of our cohort having two functioning kidneys and the majority (65%) with WIT ≤30 minutes.^{8,9,22

–25}

It is recognized that baseline patient characteristics, related to the quality of renal parenchyma, influence functional recovery after PN.^5,7,8,11,23 In our study, lower preoperative eGFR and higher Charlson comorbidity index independently predicted worsening postoperative eGFR. Moreover, new onset stage III CKD was observed only in patients with stage II CKD before surgery. These findings support a leading role of baseline features in predicting renal function after PN.

Conclusions of this study are tempered by several limitations: (1) Volume estimations were subjected to measurement error by the reliance on retrospectively collected pathologic data and approximation to a sphere shape; (2) surgical results represent the experience of two surgeons in a single institution and may not be generalizable to other surgeons or setting; (3) because preoperative volume of the operated kidney was not available, percent change in nonneoplastic parenchyma could not be estimated. Proportional estimates might have been a more comprehensive parameter to assess the effect on renal function; (4) follow-up of renal function was highly variable, and the number of patients in the late follow-up subgroup (>12 months) was relatively small.

Conclusions

In minimally invasive PN, larger tumors and longer ischemia time are associated with an increased amount of nonneoplastic parenchyma excised along with the tumor. While the amount of resected parenchyma in contemporary surgeries has decreased, we did not observe a relationship between absolute volume of resected nonneoplastic parenchyma and change in renal function after PN. In a cohort of patients with two functioning kidneys, baseline renal function and comorbidities were the strongest determinants of long-term change in renal function after PN.

Footnotes

Disclosure Statement

No competing financial interests exist.

Abbreviations Used

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