Perioperative Anaemia is a Risk Factor of Acute Kidney Injury in Patients Undergoing Partial Nephrectomy


 Background Acute kidney injury (AKI) secondary to partial nephrectomy (PN) is a challenging clinical issue. During PN anaemia develops due to haemodilution and blood loss, which decreases oxygen transfer and provokes tissue hypoxia, leading to postoperative adverse outcomes. The aim of this study was to investigate the impact of perioperative anaemia on postoperative AKI after PN.Methods This retrospective cohort study included 68 adult patients undergoing PN for a single nonmetastatic renal tumor. Detailed clinical information was systematically reviewed and analyzed. Serum concentrations of neutrophil gelatinase-associated lipocalin (NGAL) and creatinine (sCr) were tested before, 2 hours and 1 day after PN surgery. Perioperative anaemia was assessed according to haematocrit (Ht) value at the same timepoint. Association between perioperative anaemia and postoperative AKI were explored by logistic regression analyses and pearson correlation analysis. Results The rate of perioperative anaemia in patients undergoing PN was 35.3% when the criteria of Ht < 30% was adopted. AKI developed in 32.4% of the patients when KDIGO criteria was applicated and in 51.5% of the patients when the criteria of serum NGAL >150 ng/mL was used. The incidence of AKI in patients with perioperative anaemia was higher than that in patients without anaemia. Univariate logistic regression analyses showed perioperative anaemia was a relevant factor of postoperative AKI in patients undergoing PN.Conclusions Perioperative anaemia might be a risk factor of postoperative AKI after PN. But the detailed interrelation still needs to be verified by large-scale prospective studies.

positive correlation with perioperative haemodilutional anaemia [4,7,8]. However, whether perioperative anaemia also an indicator of AKI after PN is still unknown. As a result, we conducted this retrospective observational study to investigate the association between perioperative anaemia and postoperative AKI in a cohort of patients underwent PN.

Methods
This was a retrospective cohort study conducted on patients who underwent PN for a single nonmetastatic renal tumor between April 2019 and June 2020 at our institution. Exclusion criteria were (1) anatomic or functional solitary kidney; (2) abnormal contralateral renal function; (3) abnormal preoperative sCr or serum NGAL; (4) preoperative anaemia; (5) venous tumor thrombus; (6) systemic autoimmune disease; (7) sepsis or urinary tract infection; (8) urolithiasis; (9) hydronephrosis; (10) diabetes mellitus or uncontrolled hypertension. A total of 68 patients were reviewed. Detailed information of age, gender, R.E.N.A.L. score, operation (laparoscopic or open surgical approaches, ischemia time, blood loss and blood transfusion) were recorded and analyzed.
Perioperative anaemia was assessed according to Ht values before PN and 2 hours and 1 day after the surgery. Some researchers suggested Ht < 25% as the standard of anaemia, while others recommended Ht < 30% [9,10]. In general, it is agreed that tissue oxygen supply won't be in uenced obviously when Ht > 30%. Therefore, the criteria of Ht < 30% was chosen in our research.
AKI was assessed according to the sCr and serum concentrations of NGAL, which was recorded in the baseline, 2 hours and 1 day after PN. NGAL is a lipocalin located in the distal renal tubular cells and can be rapidly released after renal insults. Increases in NGAL levels predict AKI 24 to 72 hours before diagnostic sCr increases and are of prognostic value in response to renal injury [11,12]. In a meta-analysis of 2538 patients, Haase et al. found that the NGAL cutoff value for predicting AKI was > 150 ng/mL [13]. Therefore, serum NGAL > 150 ng/mL was used as the standard for postoperative AKI diagnosis in our research. Patients were classi ed into the AKI group when at least one postoperative serum NGAL was > 150 ng/mL or the sCr concentration increased at least by 50% or 26.5µ mol/L according to the KDIGO criteria [14].

Statistical analysis
Statistical comparisons were performed using the statistical software GraphPad Prism 5 (GraphPad Software, CA, USA) and PASW Statistics 18.0 (IBM Corp., NY, USA). Continuous variables were expressed as mean ± standard deviation (SD). The intergroup differences were tested using the Student's t test.
Categorical variables were expressed as frequency (percentage), and Chi square test was used to test the intergroup differences. Pearson correlation analysis was used to analyze the interdependency between variables. Logistic regression analyses were used to investigate the relevant factors of postoperative AKI and perioperative anaemia. Statistical signi cance was de ned as p < 0.05.

Results
Preoperatively, the values of Ht, sCr, and serum NGAL were all within normal ranges in all patients. Moreover, sCr and serum NGAL before PN were not statistically different in patients who developed AKI postoperatively and those who did not.
A total of 24/68 (35.29%) patients developed perioperative anaemia when the criteria of at least one of the postoperative Ht < 30% was adopted. Patients with or without perioperative anaemia were comparable in terms of demographic and biochemical characteristics, including age, gender, baseline Ht, baseline sCr, and baseline serum NGAL, as well as R.E.N.A.L. Score (Table 1). score were all con rmed as relevant factors of postoperative AKI in patients undergoing PN (Table 2). Meanwhile, perioperative anaemia was associated with ischemia time, blood loss, blood transfusion and surgical approaches (Table 3). Abbreviations AKI acute kidney injury, CI con dence interval, OR odds ratio, SE standard error † Binary univariate logistic regression analysis *** meant p < 0.001, ** meant p < 0.01, * meant p < 0.05, were assumed as statistically signi cant.  When the variate was changed from variation of sCr to serum NGAL 1d after PN, the semblable relationships were observed (Fig. 1).

Discussion
The aim of this study was to nd out the relationship between perioperative anaemia and postoperative AKI after PN surgery. In present ndings, we found perioperative anaemia occurred in 35.29% of the patients undergoing PN for a single nonmetastatic renal tumor, and postoperative AKI developed in 32.4% of the patients when KDIGO criteria was applicated. In addition, we found that the patients with perioperative anaemia had a higher risk of AKI than those without anaemia (58.3% (14/24) vs. 18.2% (8/44)). Moreover, univariate logistic regression analyses revealed that anaemia was a risk factor of postoperative AKI.
Anaemia is a common complication within the surgical populations for various reasons. Numbers of studies suggested an association of anaemia in the perioperative period with postoperative adverse outcomes, like AKI, stroke and myocardial infarction [7,8]. Our data exhibited the high prevalence of postoperative anaemia in patients undergoing PN. Multifactorial in origin, preoperative anemia, perioperative blood loss (surgical bleeding, coagulopathy, phlebotomy, etc.) and progressive blunted erythropoiesis are the main factors that cause postoperative anaemia after clinical surgery [7]. Likewise, our univariate analysis results showed that the occurrence of postoperative anemia was related to the ischemia time, blood loss and surgical approaches. Furthermore, haemodilution caused by excessive infusion may lead to "dilutional" anemia or aggravate previous anaemia.
The incidence of postoperative AKI in our research was high. An important cause of AKI in PN surgery is cellular ischemia, which results in tubular epithelial and vascular endothelial injury and activation [15,16]. The higher NGAL level in the anaemia group con rmed this in our research. As reported, the decline in renal function after PN averages about 20% in the operative kidney [3]. In fact, the patients enrolled in our study underwent more complicated surgery (R.E.N.A.L. score was 6.7 ± 1.5 for patients in perioperative anaemia group and 6.1 ± 1.1 in non-anaemia group, which meant middle complexity and is concerned with outcome of PN [17]) and suffered more blood loss and longer ischemia time that culminated in renal hypoxaemia [1,8], which might increase the risk of postoperative anaemia and AKI. In the past, postoperative AKI was thought to be a transient injury, which had no effect on prognosis after recovery. However, studies have demonstrated that postoperative AKI, even short-term AKI (lasting 48-72 hours), could increase the risk of long-term functional impairment [18].
However, it is not clear whether the presence of anaemia is a direct contributor to AKI or simply a comorbid disease that indirectly leads to AKI through potential factors. In previous study, Hales [19] found that AKI could contribute to the development of anaemia as a result of reduced EPO production, an increased risk of bleeding and reduced red cell life span. It has also been demonstrated that anaemia was a risk factor of AKI in patients underwent major surgery, leading to increased postoperative adverse outcomes [7,20,21]. Postoperative anemia may affect renal function via either a higher incidence of hypotension or a decrease in oxygen-carrying capacity to enhance renal oxidative stress [22]. Although a blood transfusion might improve oxygen delivery, less transfusion is consistently related to a decreased risk of morbidity and mortality [23][24][25]. Moreover, red cell viability is impaired during storage, resulting in excess hemolysis after transfusion. As a result, transfusions may induce iron release from macrophages that results in oxidative renal injury [26,27]. Therefore, transfusion itself may have affected the incidence of AKI [28,29]. In our study, 3 patients had blood loss and adequate transfusion to correct their hematocrit to > 30%,of which 1 and 2 developed AKI when KDIGO and NGAL criteria was used respectively. The adverse consequences of anaemia are likely to be severer during PN surgery, during which, for reasons outlined earlier, postoperative AKI is more prone to occurrence.
Our results suggest that postoperative anaemia is a risk factor for the development of AKI in patients undergoing PN, though the correlation is weak, which is probably compromised by other stronger predictors of AKI, such as ischemia time and blood loss. Nevertheless, our study still has a few limitations: Firstly, it was a single-center retrospective study, which might undergo selection bias. Secondly, the sample size was small, so we cannot perform a multivariable analysis to determine the independent predictive ability of perioperative anemia. Thirdly, we did not evaluate the long-term effect on patient's kidney function and could not draw any conclusion if perioperative AKI can be reversed. As a result, further large-scale, long-term and prospective studies should be conducted in multi-centers to verify the detailed correlation between anaemia and postoperative AKI.

Conclusions
In conclusion, patients who suffered anaemia after PN presented a higher risk of developing AKI. Unanswered questions remain and further investigation is warranted. Since perioperative anaemia is a risk factor of postoperative AKI and could have long-term effects, efforts should be made to control the anaemia-related risk factors and thus avoid postoperative AKI. If anaemia occurs after operation, AKI should be on the alert. NGAL or other sensitive biomarkers need to be monitored to detect AKI in early stage. Jiao Tong University. Written informed consent was obtained from individual or guardian participants.

Consent for publication:
Written informed consent for publication was obtained from all participants.
Availability of data and material: The datasets used and analyzed during the current study are available from the corresponding author Subo Qian and Haibo Shen on reasonable request.
Competing interests: The authors declare that they have no competing interests.

Funding
Not applicable.
Authors' contributions SZ carried out the main part of the experiments, analyzed the data, wrote and edited the manuscript. HD carried out the main part of the experiments, analyzed the data and edited the manuscript as well. YW helped to analyze the data and was also a major contributor in editing the manuscript. JG and WX helped to perform the experiments and participated in the data analysis. SQ and HS designed and supervised the progress of this research and were also major contributors in writing and editing the manuscript. All the authors have read and approved the nal version of the manuscript.