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To find factors related to postoperative acute kidney injury and long-term significant renal function (RF) loss after partial nephrectomy (PN) in Chinese population.
Methods
The main outcome was significant RF loss during the last follow-up, which was defined as >25% decrease in estimated glomerular filtration rate.
Results
A total of 416 patients were included with median age as 57 (interquartile ranges,IQR 49.8-65.0) year with body mass index as 24.2 (IQR 22.0-26.5) kg/m2 and preoperative estimated glomerular filtration rate as 90.5 (IQR 79.8-101) mL/min. Summarily, 259 (62.3%) patients were male, 54 (13%) had diabetes, 180 (43.3%) hypertension and 80 (19.2%) hyperuricemia. Median (IQR) tumor diameter was 3.1 (2.4-4.1) cm. All patients underwent PN, in which 135 (32.5%) by open PN approach, 109 (26.2%) by laparoscopic PN and 172 (41.3%) by robot assisted PN. RF was followed up for 16.88 (10.15-36.37) months, where 58 (13.9%) patients suffered significant RF loss. Multivariable analysis showed age (P = .0039), body mass index (P = .0049), diabetes (P = .0351), operative time > 110 minutes (P = .0034), diameter classification by Diameter-Axial-Polar score (diameter 2.4 cm-4.4 cm, P = .0225: diameter > 4.4 cm, P = .0207), postoperative acute kidney injury (P < .001) to be predictors of RF loss with area under the curve as 0.850.
Conclusion
We prospectively found predictive factors of short and long-term significant RF loss in all operative methods and constructed a clinical nomogram for long-term Chinese patients RF loss.
Since introduction of partial nephrectomy (PN), it has become the most preferred choice for localized T1 and part of T2 renal lesions if technically feasible with the necessity of sufficient parenchymal volume to preserve for better renal function (RF) protection, especially in those with solitary kidney, bilateral tumors and kidney dysfunction.
With development in technology, laparoscopic PN (LPN) and robot-assisted PN (RAPN) are prevailing worldwide with smaller incision and clearer view. However, the prognostic factors about long-term RF loss are not yet clear.
Various scoring systems have been emerging since the first introduction of Radius-Exophytic/Endophytic-Nearness-Anterior/Posterior-Location (RENAL) score in 2009.
But most of the nephrometry systems were designed to evaluate the difficulty of the operations instead of predict RF outcomes. In 2021, a novel nomogram for the prediction of postoperative intermediate significant RF loss was brought up by Andrea Mari et al in a prospective way.
A Nomogram for the prediction of intermediate significant renal function loss after robot-assisted partial nephrectomy for localized renal tumors: a prospective multicenter observational study (RECORd2 Project).
However, the nomogram was only applicable to RAPN and European population, so we intended to prospectively explore the different factors in Chinese population related to acute kidney injury (AKI) and long-term RF loss separately, discuss the potential explanation and create a new predictive nomogram of long-term RF loss for PN of all surgical methods including open PN (OPN), LPN, and RAPN.
MATERIALS AND METHODS
Patients and Methods
With the approval from ethics committee, prospective recruitment of patients started from August 2016 to August 2020 in Zhongshan Hospital, Shanghai (Fig. 1). The inclusion criteria were listed as: (1) Renal lesion was localized without distant metastasis; (2) Renal lesion was classified as T1 and T2a stage; (3) Underwent PN in Urology Department regardless of operation methods; (4) With intact medical record. All the patients were followed up with repeated RF evaluation, including creatine, estimated glomerular filtration rate (eGFR) and uric acid as well as radiological examinations every 3 or 6 months after discharge. Corresponding information were collected with informed consents. Postoperative eGFR was collected on the first day after PN operation.
All the Computed Tomography scan or Magnetic Resonance Imaging images were independently evaluated by a urologist and a radiologist to get scores according to different scoring systems including Zhongshan Score, R.E.N.A.L. score, Preoperative Aspects and Dimensions Used for an Anatomical score (PADUA) score, Diameter-Axial-Polar (DAP) score, C-Index, Zonal Nearness-Physical-Radius-Organization (NePhRO) score and Invision Score. A third specialist would intervene by giving a final thought independently if different scores showed up. This research has been registered and approved by Chinese Clinical Trial Registry (Registration number: ChiCTR1900025167).
Definition of Factors Related
The primary outcome was significant RF loss. RF was classified according to CKD staging system. EGFR was calculated by Chronic Kidney Disease Epidemiology Collaboration equation. AKI and long-term significant RF loss was defined as >25% drop in eGFR on the first postoperative day and the last time of follow-up compared with preoperative value according to RIFLE criteria.
Acute renal failure - definition, outcome measures, animal models, fluid therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group.
Dyslipidemia was diagnosed if any of the following conditions was met: (1) Total cholesterol > 6.2 mmol/L; (2) Triglyceride > 2.3 mmol/L; (3) Low density lipoprotein cholesterol > 4.1 mmol/L; (4) Non-high-density lipoprotein cholesterol > 4.9 mmol/L. Hyperuricemia was defined as > 428 μmol/L in male and > 357 μmol/L in female.
Statistical Analysis
All the statistical analysis was performed processed on the platform of R (version 3.6.3 2020-02-29). Continuous variables were reported as medians and interquartile ranges (IQRs) and categorical variables as numbers and proportions. Uni- and multivariable regression analyses were performed with “glmnet” package. The predictive nomogram was generated based on multivariable logistic regression. Both the nomogram and calibration curve were generated by with “rms” package. The validation of the predictive model by receiver operator characteristic (ROC) curve and area under the curve (AUC) was achieved by “pROC” package. All P values are 2 sided and considered significant when P < .05.
RESULTS
General Information of the Study
Flowchart of our study was shown in Figure 1. Overall, 451 consecutive patients were planned to undergo PN. However, according to inclusion criteria, 12 of them were excluded with absence of radiological information in 10 patients and conversion to radical nephrectomy in 2 patients. During follow-up of RF, 23 patients were lost. A total of 416 patients were included in this study. Descriptive features of all the patients were listed in Supplementary table 1. The median age was 57 (IQR 49.8-65.0) years old, with median body mass index (BMI) as 24.2 (IQR 22.0-26.5) kg/m2, in which 259 (62.3%) patients were male, 54 (13%) patients were diagnosed as diabetes, 180 (43.3%) as hypertension and 80 (19.2%) patients as hyperuricemia. Median preoperative uric acid was 338 (IQR 273-389) μmol/L and median preoperative eGFR was 90.5 (IQR 79.8-101) mL/min. As for evaluation of tumors, median (IQR) tumor diameter was 3.1 (2.4-4.1) cm, and a median of 7.3 (6.0-8.5) points was reached in Zhongshan score, 7 (6-9) points in R.E.N.A.L score, 9 (8-10) points in PADUA score, 6 (5-7) points in DAP score, 2.3 points in C-Index, 9 (7-10) points in NePhRO score and 9 (8-11) points in Invision score. All the patients underwent PN with 50 (20-100) mL estimated blood loss (EBL), in which 135 (32.5%) operated by OPN approach, 109 (26.2%) by LPN and 172 (41.3%) by RAPN. In the OPN group, 85 (63.0%) patients underwent cold ischemic PN, also known as renal artery clamping with ice. Postoperative eGFR dropped to a median of 77 (60-93) mL/min with 100 (24.0%) patients suffered from AKI. RF of patients was followed up for a median of 16.88 (10.15-36.37) months, in which 58 (13.9%) patients underwent significant RF loss, defined as >25% drop of eGFR compared with preoperative eGFR.
Univariable Logistic Regression Analysis
The univariable analysis was applied to AKI and long-term RF loss. According to univariable analysis (Table 1), age (OR 1.04, 95% CI 1.01-1.07; P = .004), male gender (OR 2.61, 95% CI 1.38-5.31; P = .005), BMI (OR 1.25, 95% CI 1.14-1.38; P < .001), diabetes (OR 4.03, 95% CI 2.06-7.69; P < .001), hypertension (OR 2.43, 95% CI 1.38-4.36, 1.07; P = .002), operative time (OT) (OR 1.01, 95% CI 1.00-1.02; P = .002), preoperative eGFR (OR 0.98, 95% CI 0.964-0.991; P = .0012), postoperative eGFR (OR 0.96, 95% CI 0.944-0.971; P < .001), Zhongshan score (OR 1.27, 95% CI 1.11-1.46; P < .001), DAP score (OR 1.39, 95% CI 1.05-1.87; P = .003) and NePhRO score (OR 1.27, 95% CI 1.09-1.49; P = .003) were all strong predictors of long-term RF loss with p value less than 0.01. As for AKI, diabetes (OR 1.39, CI 0.72-1.29; P = .3), hypertension (OR 1.29, CI 0.82-2.02; P = .27) showed no significance, while ischemia time (OR 1.04, 95% CI 1.01-1.06; P = .002), WIT > 20 minutes in LPN and RAPN (OR 1.99, 95% CI 1.08-3.85; P = .03), preoperative uric acid (OR 1.00, 95% CI 1.00-1.01; P < .001), RENAL score (OR 1.51, 95% CI 1.31-1.76; P < .001), PADUA score (OR 1.52, 95% CI 1.32-1.77; P < .001), diameter (OR 1.69, 95% CI 1.44-2.00; P < .001) and Invision score (OR 1.29, 95% CI 01.16-1.44; P < .001) were significantly related. For further exploration, we selected the cutoff values for OT as 110 minutes and 100 minutes considering median OT. Univariable analysis showed that both cutoff values were significant (P < .001) while 110 minutes showed higher OR.
Table 1Univariate logistic regression analysis to predict renal function variation
Late > 25% Loss of eGFR
AKI
Variable
OR
95%CI
P value
OR
95%CI
P value
Age
1.04
1.01, 1.07
.004
1.00
0.98, 1.02
.72
Gender
Female
Ref.
Ref.
Male
2.61
1.38, 5.31
.005
3.06
1.82, 5.36
<.001
BMI
1.25
1.14, 1.38
<.001
1.19
1.11, 1.29
<.001
Diabetes
Absent
Ref.
Ref.
Present
4.03
2.06, 7.69
<.001
1.39
0.72, 2.58
.30
Hypertension
Absent
Ref.
Ref.
Present
2.43
1.38, 4.36
.002
1.29
0.82, 2.02
.27
Dyslipidemia
Absent
Ref.
Ref.
Present
1.93
1.07, 3.44
.03
1.00
0.59, 1.66
.99
Operative time
1.01
1.00, 1.02
.002
1.02
1.01, 1.02
<.001
OT >100
3.32
1.83, 6.29
<.001
5.64
3.39, 9.71
<.001
OT >110
4.17
2.35, 7.62
<.001
3.36
2.12, 5.38
<.001
EBL
1.00
0.998, 1.001
.96
1.00
1.00, 1.00
.14
Ischemia time
1.00
0.995, 1.014
.40
1.04
1.01, 1.06
.002
WIT>20 min in LPN and RAPN
1.76
0.807, 4.161
.17
1.99
1.08, 3.85
.03
Uric acid preoperative
1.00
1.000, 1.006
.02
1.00
1.00, 1.01
<.001
eGFR preoperative
0.98
0.964, 0.991
.0012
0.98
0.96, 0.99
<.001
eGFR 1-d postoperative
0.96
0.944,0.971
<.001
AKI
7.52
4.18, 13.81
<.001
ZS score
1.27
1.11,1.46
<.001
1.52
1.34, 1.74
<.001
RENAL score
1.13
0.96, 1.33
.15
1.51
1.31, 1.76
<.001
PADUA score
1.09
0.93, 1.29
.29
1.52
1.32, 1.77
<.001
Diameter
1.29
1.09, 1.52
.035
1.69
1.44, 2.00
<.001
DAP score
1.39
1.05, 1.87
.003
1.84
1.53, 2.23
<.001
DAP diameter level
< 2.4 cm
Ref.
Ref.
2.4 cm - 4.4 cm
4.52
1.73, 15.49
.006
1.82
0.97, 3.59
.07
> 4.4 cm
8.17
2.97, 28.85
<.001
5.16
2.63, 10.66
<.001
C-Index
0.58
0.42,0.78
<.001
0.44
0.33, 0.58
<.001
Invision score
1.15
1.01, 1.31
.03
1.29
1.16, 1.44
<.001
NePhRO score
1.27
1.09, 1.49
.003
1.46
1.27, 1.68
<.001
BMI, body mass index; DAP, Diameter-Axial-Polar score; EBL, estimated blood loss; eGFR, estimated glomerular filtration rate; NePhRO, zonal nearness-physical-radius-organization; OT, operative time; PADUA, preoperative aspects and dimensions used for an anatomical score; RENAL, radius-exophytic/endophytic-nearness-anterior/posterior-location; ZS, Zhongshan.
Exploration of Predictive Factors Based on Multivariable Analysis
Significant factors from univariable analysis were included in multivariable logistic regression analysis (Table 2), among which age (OR 1.05, 95% CI 1.02-1.09; P = .0039), BMI (OR 1.18, 95% CI 1.06-1.33; P = .0049), diabetes (OR 2.51, 95% CI 1.05-5.87; P = .0351), OT > 110 minutes (OR 2.82, 95% CI 1.42-5.75; P = .0034), diameter classification of DAP scoring system (diameter 2.4 cm - 4.4 cm OR 3.73, 95% CI 1.33-13.45; P = .0225; diameter > 4.4 cm OR 4.12, 95% CI 1.35-15.64; P = .0207), presence of AKI (OR 5.07, 95% CI 2.56-10.27; P < .001) were all significantly related to remarkable RF loss in a long term.
Table 2Predictive factors of >25% loss of eGFR in long term follow-up based on multivariable logistic regression analysis
Multivariable Model
Variable
OR (95%CI)
P value
Age
1.05(1.02, 1.09)
.0039
BMI
1.18(1.06, 1.33)
.0049
Diabetes
2.51(1.05, 5.87)
.0351
OT > 110 min
2.82(1.42, 5.75)
.0034
Diameter level of DAP score
< 2.4 cm
Ref.
2.4 cm-4.4 cm
3.73(1.33, 13.45)
.0225
> 4.4 cm
4.12(1.35, 15.64)
.0207
AKI
5.07(2.56, 10.27)
<.001
AKI, acute kidney injury; BMI, body mass index; DAP, Diameter-Axial-Polar score; eGFR, estimated glomerular filtration rate; OT, operative time.
Predictive nomogram was constructed based on aforementioned factors (Fig. 2A). The predictive system derived from multivariable analysis was verified by receiver operating characteristic curve with area under curve as 0.850 (Fig. 2B). Logistic calibration curve was generated with S:P = 0.886, Emax = 0.231 and Eavg = 0.028 (Fig. 2C).
Figure 2Parts A-C. Generation and validation of nomogram. (A) Predictive nomogram of long-term eGFR loss after all kinds of partial nephrectomy. (B) ROC curve of multivariable analysis. (C) Validation of predictive nomogram by calibration curve. AKI, acute kidney injury; BMI, body mass index; DM, diabetes mellitus; DAP, Diameter-Axial-Polar score; eGFR, estimated glomerular filtration rate; OT, operative time. Color version available online.
The predictive role of biomarkers for the detection of acute kidney injury after partial or radical nephrectomy: a systematic review of the literature.
and general information of patients have all been discussed but without further validation. As far as the studies have shown, PN is not so perfect in that it can preserve about 80% of the RF in operated kidney and 90% of overall function in patients with intact 2 kidneys.
In that case, there is actual need to dig into the predictive factors of long-term postoperative RF loss to better educate patients undergo RN with individualized plans.
In terms of nephrometry scoring systems, according to the meta-analysis by Alessandro Veccia et al, continuous and categorical RENAL scores were independent predictors of eGFR increase and DAP score and Peritumoral Artery Scoring System were independent predictors of RF variation regardless of operative methods.
The conclusion reached in our study is consistent with the systemic review in that DAP score also showed significant predictive value in RF variation based on univariable analysis. Alberto Martini et al brought up a nomogram consisting of age, gender, Charson comorbidity index, RENAL score as continuous variable, baseline eGFR, the presence of postoperative AKI in patients with normal RF to predict significant eGFR reduction after RAPN in a retrospective way in 2018.
Independent external validation of a nomogram to define risk categories for a significant decline in estimated glomerular filtration rate after robotic-assisted partial nephrectomy.
A Nomogram for the prediction of intermediate significant renal function loss after robot-assisted partial nephrectomy for localized renal tumors: a prospective multicenter observational study (RECORd2 Project).
Slight differences showed up in that instead of postoperative AKI and RENAL score, this RECORd2 nomogram introduced diabetes, peripheral vascular disease, surgical indication and PADUA score. However, though with convincing scale and prospective study type, the common limitation of these research is that the nomograms are only applicable to RAPN and suitable for most Caucasian population without extension to all kinds of PNs and all human races.
With the aim of creating a nomogram that suits all methods of operations and covers Chinese population, we constructed the nomogram consisting of age, BMI, diabetes mellitus, whether OT exceeded 110 minutes, diameter levels from DAP score and the presence of AKI. Long term was defined as at least 3 months since operation and >25% decrease in eGFR as significant RF loss.
In our study, the emphasis was put on the impacts of various scoring systems and metabolic situations of patients including uric acid, lipid and diabetes on the prognosis of long-term RF. According to the analysis, among all the scoring systems, ZS score, DAP score, C-Index score, Invision score and NePhRO score were related to long-term RF loss. Further analysis showed that DAP diameter level was significantly related to long term RF loss both in uni- and multivariable analysis. The underlying reason may be attribute to the early detection of renal lesions with the widespread health examination in Shanghai, which makes renal lesions greater than 7 cm based on RENAL and PADUA score less common. Besides, we also found that the presence of AKI could strongly indicate RF loss in the future, which was consistent with previous studies.
In clinical practice, if PN patients experienced significant decrease in eGFR, special attentions should be paid to avoidance of nephrotoxic drugs and closer follow-up of RF to avoid further deterioration of RF. According to previous studies, debates remained considering the role of shortened ischemia time in RF preservation.
Besides, another important conclusion was reached that no significant relationship was found between ischemia time and late RF loss. Therefore, we explored the role of ischemia time in AKI and figured that impact of ischemia time was greater on short-term drop in eGFR, which was proved before.
Consistent with RECORd2 project, ischemia time in our study was not significantly related to RF loss but OT mattered. The possible explanation could attribute to systemic influences caused by operation and anesthesia that may be more important than local ischemia time in the long run, which needs further exploration and validation.
There are several limitations in our study. First was the follow-up time. According to the hypothesis raised up by Andrea Mari et al, the impacts of factors on future RF may vary with prolonged follow-up time,
A Nomogram for the prediction of intermediate significant renal function loss after robot-assisted partial nephrectomy for localized renal tumors: a prospective multicenter observational study (RECORd2 Project).
so studies with longer follow-up time was expected. Secondly, our study did not dig into the vascular situations which may influence RF initially and ischemic pattern,
including the differences between zero ischemia and ischemic PN, as well as the ones between cold ischemic and warm ischemic PN due to lack of technique to cool down the operated kidney in RAPN and LPN. Additional limitations include the different surgical techniques among surgeons. Further external validation studies are expected to minimize bias.
CONCLUSION
We found factors that mattered to AKI and long-term RF loss and developed a perioperative nomogram for prediction of late RF loss after PN of all operative methods in a prospective way. This nomogram could help early identify the Chinese patients that would suffer from significant RF loss in the future for timely intervention.
Author Contributions
H. Wang had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Trial Registration
Registration number: ChiCTR1900025167.Name: A prospective study for different scoring systems on different kinds of nephron sparing surgery which is based on the major data. http://www.chictr.org.cn/showproj.aspx?proj=37394
A Nomogram for the prediction of intermediate significant renal function loss after robot-assisted partial nephrectomy for localized renal tumors: a prospective multicenter observational study (RECORd2 Project).
Acute renal failure - definition, outcome measures, animal models, fluid therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group.
The predictive role of biomarkers for the detection of acute kidney injury after partial or radical nephrectomy: a systematic review of the literature.
Independent external validation of a nomogram to define risk categories for a significant decline in estimated glomerular filtration rate after robotic-assisted partial nephrectomy.
Funding Support:This study was funded by grants from Shanghai Municipal Health Commission (2019SY073), Zhongshan Hospital Science Foundation (2020ZHZS20, 2020ZSLC16),National Natural Science Foundation of China (62273099) and Science and Technology Commission of Shanghai Municipality (22ZR1458000, 22Y11905300). All these study sponsors have no roles in the study design, in the collection, analysis, and in the interpretation of data.
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