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Postoperative Anemia Is Associated with Acute Kidney Injury in Patients Undergoing Total Hip Replacement Arthroplasty: A Retrospective Study

Choi, Yoon Ji MD, PhD; Kim, Seon-Ok MSc; Sim, Ji Hoon MD; Hahm, Kyung-Don MD, PhD

doi: 10.1213/ANE.0000000000001003
Critical Care, Trauma, and Resuscitation: Research Report

BACKGROUND: Chronic and acute anemia are both correlated with an increased risk of injury to major organs, such as the brain, heart, and kidney. We evaluated the association between postoperative anemia (hemoglobin [Hb] < 10 g/dL) and acute kidney injury (AKI) in patients undergoing total hip replacement arthroplasty (THRA).

METHODS: Patients who underwent THRA between January 2005 and February 2013 were retrospectively reviewed. We divided patients into 2 groups: Hb < 10 (n = 938) and Hb ≥ 10 (n = 1529). They were then categorized according to changes in plasma creatinine concentration within 48 hours of THRA using Acute Kidney Injury Network criteria. To evaluate the association between postoperative anemia and postoperative AKI, an inverse-probability-of-treatment weighted method was used and both univariate and multivariable analyses were performed.

RESULTS: Postoperative anemia was significantly associated with postoperative AKI (multivariate odds ratio, 2.036; 95% confidence interval, 1.369–3.028; P < 0.001; inverse probability-of-treatment weighted odds ratio, 1.817; 95% confidence interval, 1.169–2.826; P = 0.011). In patients with a normal glomerular filtration rate, postoperative AKI was also related to postoperative anemia (P = 0.010).

CONCLUSIONS: Postoperative anemia was associated with postoperative AKI after THRA. Although our study was limited by its retrospective design, our observation suggests that postoperative anemia may play a role in postoperative AKI.

Published ahead of print October 8, 2015

From the *Department of Dental Anesthesiology, Seoul National University Dental Hospital, Seoul, Korea; and Departments of Clinical Epidemiology and Biostatistics and Anesthesiology and Pain Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.

Accepted for publication July 24, 2015.

Published ahead of print October 8, 2015

Funding: None.

The authors declare no conflicts of interest.

Reprints will not be available from the authors.

Address correspondence to Kyung-Don Hahm, MD, PhD, Department of Anesthesiology and Pain Medicine, Asan Medical Center, University of Ulsan College of Medicine, 388-1 Pungnap 2-dong, Songpa-gu, Seoul 138-736, Korea. Address e-mail to kdhahm@gmail.com.

Acute kidney injury (AKI) occurs in 1% to 16% of patients after total hip replacement arthroplasty (THRA)1,2 and is associated with a longer inpatient stay and greater inpatient morbidity and mortality.2 Risk factors for the development of AKI after hip fracture include male sex, hypertension, diabetes mellitus, and premorbid chronic renal disease.2 AKI is also more likely in patients who develop acute perioperative complications, such as sepsis, acute myocardial infarction, heart failure, and massive pulmonary embolism.3 In addition, renal artery occlusion because of embolism or thrombus, radiocontrast agents, concurrent diuretic, and angiotensin-converting enzyme inhibitor, or angiotensin II receptor blocker use are associated with perioperative AKI.4–6

One potential factor in the pathogenesis of postoperative AKI is anemia.7 Postoperative anemia may affect renal function via either a higher incidence of hypotension or a decrease in oxygen-carrying capacity. The current literature8–10 is unclear regarding the effect of anemia on renal function. To clarify this issue, we evaluated the relationship between postoperative anemia (hemoglobin [Hb] < 10 g/dL) and AKI in patients undergoing THRA.

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METHODS

This study was approved by the IRB (2013-0567) and the Clinical Research Information Service (KCT0000796). The medical records of 3917 patients who had undergone THRA between January 2005 and February 2013 at our hospital were retrospectively reviewed. Baseline demographics, comorbidities, medications that affect kidney function, and preoperative laboratory findings were extracted from the computerized medical record. Patients were excluded if they had undergone repeat surgery, if they had been diagnosed with end-stage renal disease with hemodialysis, or if vasoactive agents (ephedrine, phenylephrine, norepinephrine, vasopressin, etc.) were used during perioperative period. Patients were also excluded if they had unstable vital signs (mean blood pressure <60 mm Hg or had received additional packed red blood cells [RBCs] or colloid in the postanesthesia care unit or ward) or during the 48 hours after surgery. Finally, patients were excluded if the Hb level crossed the 10 g/dL threshold during the 48 hours after surgery (e.g., if Hb increased from <10 to >10 g/dL or decreased from >10 to <10 g/dL). The final cohort consisted of 2467 patients and included 326 patients from a previously published study.1

Enrolled patients were anesthetized by either spinal or general anesthesia at the discretion of the attending anesthesiologist. Spinal anesthesia was performed using a midline or paramedian approach with a 23- to 25-gauge Quincke needle at the L3−4 or L4−5 intervertebral space in the lateral or sitting position. After identifying free-flowing cerebrospinal fluid, 10 to 15 mg of 0.5% hyperbaric bupivacaine was injected. When a sensory dermatome at T7 or higher was blocked, we considered the patient to be satisfactorily anesthetized. Midazolam was administered IV for sedation if required. General anesthesia was performed using sevoflurane with 3 L/min of fresh gas flow, IV fentanyl, and either rocuronium or atracurium as a muscle relaxant. Intraoperative monitoring was performed with electrocardiography, invasive surveillance of arterial blood pressure, and pulse oximetry.

During surgery, crystalloid (normal saline or Hartmann’s solution) or colloid (10% pentastarch; Pentaspan®; Jeil, Seoul, Korea) was given when either mean arterial pressure <60 mm Hg or urine output <0.5 mL/kg/h. Packed RBCs were considered only when the Hb concentration decreased <10 g/dL and were then transfused at the discretion of the attending anesthesiologist.

After the completion of surgery, patients receiving general anesthesia were tracheally extubated and transferred to the postanesthesia care unit. Laboratory data, including Hb concentrations, were measured before surgery, within the first 2 hours after surgery, and 48 hours after surgery.

The flow diagram of patients through the study is shown in Figure 1. The 2467 patients included in our analysis were divided into 2 groups: those with postoperative Hb <10 (n = 938) and those with postoperative Hb ≥10 (n = 1529). Anesthetic type and duration, fluids, and RBCs administered during surgery and estimated blood loss were collected for each patient.

Figure 1

Figure 1

AKI in the postoperative period was diagnosed according to Acute Kidney Injury Network (AKIN) criteria11: stage I was defined as an increase from baseline of ≥0.3 mg/dL (normal reference range, 0.7−1.4 g/dL at our institution) or an increase from baseline between 150% and 200%; stage II as an increase from baseline between 200% and 300%; and stage III as an increase from baseline >300%, or an increase from baseline ≥4.0 mg/dL accompanied by an acute increase from baseline ≥0.5 mg/L, or the need for renal replacement therapy irrespective of other criteria.11 Urine output data were not included because they were not recorded intraoperatively for all patients: the urine output of some patients who were expected to have only a small volume of blood loss during THRA was not monitored.

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Statistical Analysis

Continuous variables were expressed as mean ± SDs and categorical variables as numbers and percentages. Baseline and intraoperative characteristics and variables for postoperative outcomes were compared using the t test or the Mann-Whitney rank sum test for continuous variables and the χ2 test or Fisher exact test for categorical variables.

To reduce potential confounding from baseline and intraoperative variables that may affect the incidence of AKI, we performed propensity score analysis. The sample size resulting from this technique was very low (n = 300). We then performed weighted logistic regression analysis with an inverse-probability-of-treatment weighted (IPTW) technique. Factors with the potential to affect renal function4,7–11 were incorporated into the logistic regression (Table 1 [patient characteristics], Table 2 [perioperative care factors]) and included age, body mass index (BMI), sex, use of insulin, hypoalbuminemia, and use of 10% pentastarch. The effect of Hb >10 g/dL on AKI was evaluated using weighted logistic regression analysis with an IPTW technique, calculated by the propensity scores. Using IPTW, Hb <10 patients were assigned a weighting of the inverse of 1 minus the propensity score, and Hb ≥10 patients were assigned a weighting of the inverse of the propensity score. By using the weighting, we compared the baseline covariates between the 2 groups. Model discrimination was assessed using c statistics (equal to 0.715), and model calibration was assessed using Hosmer-Lemeshow statistics (χ2 = 5.166, df = 8, P = 0.740).

Table 1

Table 1

Table 2

Table 2

In addition, patients were divided into 2 groups based on estimated preoperative glomerular filtration rate (GFR): reduced (≤60 mL/min/1.73 m2 [n = 2390]) or normal (>60 mL/min/1.73 m2 [n = 77]). Model discrimination was assessed using c statistics (equal to 0.707 and 0.907), and model calibration was assessed using Hosmer-Lemeshow statistics (χ2 = 9.290 and 7.180, df = 8 and 8, P = 0.320 and 0.520). Using crude, multivariable, and IPTW analysis, the association between postoperative anemia and AKI was then evaluated in patients with normal and reduced GFR.

To identify factors significantly predictive of postoperative AKI, univariate and multivariable logistic regression analyses were performed. Also, the interaction terms between postoperative Hb and the other covariates were assessed on pairwise analyses. After selecting the factors that yielded a P value <0.2, a backward elimination process was used to develop the final multivariable model. Adjusted odds ratios with 95% confidence intervals were then calculated.

All statistical analyses were conducted using SAS® ver. 9.2 (SAS Institute, Cary, NC). A P value <0.05 was considered statistically significant.

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RESULTS

Our final data set included 938 patients with postoperative Hb <10 and 1529 patients with postoperative Hb ≥10. Mean serum Hb concentrations immediately after surgery were 8.90 ± 0.84 and 11.42 ± 1.08 g/dL in the Hb < 10 and Hb ≥ 10 groups, respectively. Hb concentrations 48 hours after surgery were 8.89 ± 0.85 and 11.41 ± 1.07 g/dL in the Hb < 10 and Hb ≥ 10 groups, respectively. Hb groups also differed in patient characteristics, including age, BMI, sex, use of insulin, hypoalbuminemia, and use of 10% pentastarch (Tables 1 and 2).

The mean serum Cr levels before surgery were 0.87 ± 0.63 and 0.83 ± 0.29 mg/dL in the Hb < 10 and Hb ≥ 10 groups, respectively. The number (percentage) of patients in each group who were not transfused with RBCs intraoperatively and up to 48 hours after surgery were 454 (48.40) and 753 (49.25) in the Hb < 10 and Hb ≥ 10 groups, respectively. The number (percentage) of patients in each group who had completed transfusions in the operating room were 471 (97.31) and 742 (95.61) in the Hb < 10 and Hb ≥ 10 groups, respectively.

After propensity adjustment using the IPTW, the 2 Hb groups did not differ in any of the parameters in Table 1 or 2. In particular, estimated blood loss or RBC units given did not differ between the 2 groups. The crude AKI incidence is shown in Tables 3 and 4 and was higher in the Hb < 10 group (P < 0.001). This difference persisted after multivariable and IPTW analysis (Tables 3 and 4; odds ratio, 2.036; 95% confidence interval, 1.369–3.028).

Table 3

Table 3

Table 4

Table 4

In addition, we analyzed the effect of postoperative anemia in patients with normal (≤60 mL/min/1.73 m2) and reduced GFR (>60 mL/min/1.73 m2) preoperatively. In patients with normal GFR, postoperative AKI occurred in 93 (38%) of patients and was associated with postoperative anemia (P = 0.010; Table 5).

Table 5

Table 5

Table 6

Table 6

Using univariate analysis, postoperative anemia, serum albumin level, age, sex, the use of diuretics or insulin, ischemic heart disease, hypertension, diabetes mellitus, and cerebrovascular disease were associated with postoperative AKI. In multivariable analysis, postoperative anemia, age, sex, BMI (<22 vs >25), and diabetes mellitus were identified as risk factors for postoperative AKI (Table 6). The interaction between postoperative Hb and RBC transfusion was not a significant contributor (P = 0.064) in multivariable analysis.

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DISCUSSION

In THRA patients, perioperative AKI is associated with increased morbidity and mortality, prolonged hospital stays, and poorer outcomes.2,12 We found that in THRA patients, postoperative anemia was associated with postoperative AKI.

Several mechanisms may explain the link between postoperative anemia and AKI that we observed. Reduced oxygen delivery and harmful effects of transfusions may both affect kidney function. In patients with renal failure, low Hb levels correlated with oliguria and higher urea levels.13 However, the effects of anemia can be patient-specific and thus highly variable.

In critically ill patients with cardiovascular disease, the use of a low-threshold Hb strategy (transfusion Hb threshold = 7.0 g/dL) did not result in worse renal outcomes than a high-threshold Hb strategy (threshold, 10.0 g/dL of Hb; maintenance range, 10.0−12.0 g/dL of Hb) with normovolemia.8,14 In those studies, patients managed with a low-threshold Hb strategy required only 54% of RBC transfusions compared with controls and had reduced rates of cardiac complications and major organ dysfunction.8,14 Overall, a low-threshold Hb strategy also decreases the rate of adverse events, such as myocardial infarction, cardiac events, pneumonia, thromboembolism, and stroke.8 Although a transfusion might treat anemia and improve oxygen delivery, less transfusion is consistently related to a decreased risk of morbidity and mortality.10,15,16

In a 2011 study of patients undergoing hip surgery, Carson et al.17 found that a high-threshold Hb strategy (a Hb threshold of 10 g/dL) in patients >50 years who had either risk factors for or a history of cardiovascular disease did not reduce rates of death, inability to walk independently on 60-day follow-up, or in-hospital morbidity compared with a low-threshold Hb strategy (Hb level of <8 g/dL). In addition, the rates of in-hospital morbidity, including unstable angina, clinically recognized myocardial infarction, pneumonia, wound infection, stroke or transient ischemic attack, and thromboembolism were similar in the 2 groups (low- and high-threshold Hb).

Our study differs from that of Carson et al. in several ways. Whereas we found an effect of anemia on AKI, Carson et al. did not study renal outcomes. In addition, although patients in our study did not differ with respect to RBC transfusion, patients managed with a high-threshold Hb strategy (Hb > 10) in the study by Carson et al. received 3 times as many transfusions as those in the low-threshold Hb strategy. Transfusion itself may affect AKI,18–20 and the age of stored RBC may also have adverse effects.19,21 Transfusion itself may have affected the incidence of AKI after transfusion.20,22 In our study, postoperative anemia remained associated with AKI even when RBC transfusion was not a factor.

Our study has limitations. Most patients in both groups (79% in the Hb < 10 and 72% in the Hb > 10 group) received approximately 700 mL of 10% pentastarch, intraoperatively. These solutions have been associated with the development of AKI.23 However, the nephrotoxic effects of 10% pentastarch administration were unlikely to play a role in our study because a similar proportion (72% vs 79%) of patients in each group received the same volume of 10% pentastarch. In addition, all patients received prophylactic antibiotics before and after surgery. These antibiotics may also have affected kidney function. Finally, our study was not randomized with respect to transfusion. Patients in our study were managed at the discretion of the treating doctor. We also excluded all patients whose Hb moved from <10 to >10 g/dL or >10 to <10 g/dL during the postoperative period.

In conclusion, we found a correlation between Hb levels after hip replacement surgery and AKI. Our results suggest that postoperative anemia may be considered a risk factor for the development of AKI in patients undergoing THRA. In light of conflicting data from our study and that of Carson et al.,10 more research is needed to clarify the correlation between postoperative anemia and AKI using controlled prospective study.

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DISCLOSURES

Name: Yoon Ji Choi, MD, PhD.

Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.

Attestation: Yoon Ji Choi has seen the original study data, reviewed the analysis of the data, approved the final manuscript, and is the author responsible for archiving the study files.

Name: Seon-Ok Kim, MSc.

Contribution: This author helped conduct the study, analyze the data, writing the manuscript, and revision of the manuscript.

Attestation: Seon-Ok Kim has seen the original study data, reviewed the analysis of the data, approved the final manuscript, and is the author responsible for archiving the study files.

Name: Ji Hoon Sim, MD.

Contribution: This author helped conduct the study, analyze the data, writing the manuscript, and revision of the manuscript.

Attestation: Ji Hoon Sim has seen the original study data, reviewed the analysis of the data, approved the final manuscript, and is the author responsible for archiving the study files.

Name: Kyung-Don Hahm, MD, PhD.

Contribution: This author helped conduct the study and revision of manuscript.

Attestation: Kyung-Don Hahm has seen the original study data, reviewed the analysis of the data, approved the final manuscript, and is the author responsible for archiving the study files.

This manuscript was handled by: Avery Tung, MD.

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ACKNOWLEDGMENTS

This study was performed at Asan Medical Center, Seoul, Korea.

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