ABSTRACT
Objective
Hyperuricemia, characterized by elevated serum uric acid levels without acute gout symptoms, may influence postoperative outcomes after total knee arthroplasty (TKA). This study aimed to evaluate the impact of hyperuricemia on postoperative inflammatory responses, complications, and mid‐term functional outcomes in patients undergoing primary TKA.
Methods
This was a retrospective cohort study. We identified all patients who had undergone primary TKA from April 1, 2015, to March 30, 2016. Patients were grouped by uric acid level. The knee society score (KSS) and hospital for special surgery knee score (HSS) before the surgery and 6 years after the surgery were recorded. Statistical analyses included t‐tests, chi‐square tests, and regression analyses to assess the influences of uric acid levels on C‐reactive protein (CRP) levels, body temperature, functional scores, and local inflammatory response. The influence of the uric acid level on the local inflammatory response was also analyzed.
Results
Of the 614 patients, 140 had hyperuricemia, and 474 had normal uric acid levels. The hyperuricemia group had a higher unplanned readmission rate (11.4% vs. 5.7%, p < 0.05) and longer hospital stay (10.75 vs. 9.54 days, p = 0.002). CRP levels were significantly greater in the hyperuricemia group (OR = 34.64, 95% CI: 27.99–41.30, p < 0.001), and the incidence of the local inflammatory response was greater (42.1% vs. 9.5%, p < 0.01). The diagnostic accuracy for uric acid in the local inflammatory response was 0.742 (AUC). Improvements in the KSS clinical score (p < 0.01), KSS functional score (p < 0.01), and HSS score (p < 0.01) were lower in the hyperuricemia group.
Conclusions
Hyperuricemia is associated with significantly elevated postoperative CRP levels, a higher unplanned readmission rate, and substantially poorer mid‐term functional outcomes after TKA. These patients also demonstrate increased inflammatory complications. These findings support preoperative uric acid screening to identify high‐risk patients for targeted management.
Clinical Relevance
Level III.
Trial Registration: ClinicalTrials.gov identifier: NCT05476367.
Keywords: HSS score, hyperuricemia, inflammatory response, knee society score, total knee arthroplasty
Hyperuricemia elevates CRP and impairs mid‐term functional outcomes in TKA patients, with no impact on postoperative temperature.
Abbreviations
- AUC
area under the curve
- BMI
body mass index
- CRP
C‐reactive protein
- HSS score
hospital for special surgery knee score
- KSS score
knee society score
- PJI
prosthetic joint infection
- PJI
prosthetic joint infection
- ROC
receiver operator characteristic
- SD
standard deviation
- TKA
total knee arthroplasty
- ULT
urate‐lowering treatment
- USA
the United States
1. Introduction
Hyperuricemia, defined as elevated serum uric acid levels without acute gout symptoms, is distinct from gouty arthritis, which involves painful inflammatory flares due to urate crystal deposition [1]. To our knowledge, the prevalence of hyperuricemia is approximately 20% in Western countries [2]. In China, the age‐standardized prevalence of hyperuricemia is 12.6% [3]. While gouty arthritis is a known risk factor for complications after total knee arthroplasty (TKA), the impact of asymptomatic hyperuricemia on postoperative inflammatory responses, complications, and long‐term functional outcomes remains poorly understood, with few studies beyond case reports on gout‐related complications [4]. This knowledge gap hinders the optimal perioperative management of TKA patients with hyperuricemia.
TKA is a common procedure for treating end‐stage arthritis, with three million cases projected annually in the United States by 2030 [5]. However, studies on TKA in patients with gout or hyperuricemia are still rare. Most existing studies are only case reports [6]. Bradley et al. reviewed 1,135,749 patients who underwent TKA in the USA. They reported a 5.7% prevalence of gout in patients undergoing primary TKA. Univariate analysis revealed that patients with a history of gout were more likely to develop prosthetic joint infection (PJI) and experience revision within 1 year after surgery. However, such correlations disappeared after matching for confounders [7].
Patients with asymptomatic hyperuricemia and osteoarthritis typically undergo TKA, as they lack the acute inflammatory symptoms of gout that complicate surgery. An acute inflammatory response can occur after TKA surgery in patients with hyperuricemia. Jeffrey et al. reported a case of a 39‐year‐old man who developed pain, swelling, and erythema in the joint 2 years after TKA [8]. This patient was misdiagnosed with periprosthetic infection and finally underwent arthrotomy. A recent population‐based study in Taiwan, China and the UK confirmed that gout is an independent risk factor for total joint replacements [9]. However, studies on the influence of hyperuricemia and its related inflammatory process after TKA are rare. No studies have reported the incidence and clinical features of postoperative acute inflammatory symptoms in patients with hyperuricemia. This study aimed to: (i) compare postoperative local inflammatory responses, complications (e.g., infections, prosthesis issues), and midterm functional outcomes (assessed via KSS and HSS scores) between hyperuricemic patients and those with normal uric acid levels following primary TKA; (ii) analyze the dose–response relationship between serum uric acid levels and postoperative inflammatory markers, particularly C‐reactive protein (CRP); and (iii) evaluate the diagnostic accuracy of uric acid in predicting local inflammatory responses after TKA.
2. Materials and Methods
2.1. Study Design
This was a retrospective cohort study. All the operations were completed at a single institution. The work and manuscript have been reported in line with the STROCSS criteria. The institutional review board of our hospital approved this study (No. 2021‐1129). The average follow‐up time was 6 years (63–74 months), with patients contacted annually via telephone or in‐person clinic visits to assess functional outcomes and complications.
2.2. Grouping and Definitions
We identified all patients who had undergone primary TKA from April 1, 2015, to March 30, 2016. All operations were performed by one of four surgeons with standardized joint replacement training. Serum uric acid levels were measured once during routine preoperative screening (within 2 weeks before surgery) and used as the basis for grouping. Hyperuricemia was defined as a single preoperative measurement > 420 μmol/L in males or > 360 μmol/L in females [10], with patients stratified accordingly. Preoperative CRP was simultaneously measured. Postoperative CRP was assessed on day 3 via blood tests. Local inflammatory response (defined as concurrent presence of swelling, pain, and redness around the incision) was evaluated daily during hospitalization.
2.3. Inclusion and Exclusion Criteria
Inclusion criteria were: (1) Primary unilateral TKA; (2) Complete preoperative uric acid/CRP data; (3) Minimum 6‐year follow‐up. Exclusion criteria were applied as detailed below. Patients with elevated uric acid without clinical gout symptoms or crystal deposition signs were surgical candidates [11].
The exclusion criteria [12] were as follows: (1) infection, (2) rheumatoid arthritis, (3) ankylosing spondylitis, (4) revision surgery, (5) patients with unicondylar knee replacement, (6) patients who have been diagnosed with gout or previous gouty symptoms, (7) patients with preoperative redness or swelling, (8) patients complicated with spinal or hip diseases, and (9) patients with chronic respiratory or endocrine diseases (e.g., chronic obstructive pulmonary disease, diabetes mellitus) or who used hormones/immunosuppressants (e.g., corticosteroids, methotrexate) that could affect uric acid levels or inflammatory responses or lead to recurrent hospitalizations unrelated to TKA (Figure 1). We rigorously distinguished hyperuricemia from intercritical gout through comprehensive medical record review. Exclusion criterion (6) specifically applied to: (a) physician‐diagnosed gout; (b) self‐reported history of characteristic gout attacks (acute monoarthritis with rapid onset of severe pain, erythema, and swelling resolving within 7–14 days); and (c) documented urate‐lowering therapy use [13].
FIGURE 1.
Inclusion and exclusion flowchart.
2.4. Data Extraction and Definitions
The demographic, anthropometric, and clinical characteristics of all patients were collected. Unplanned readmissions were evaluated within 6 years post‐TKA for joint‐related complications (e.g., pain, swelling, suspected infection, or prosthesis failure) through medical record review and follow‐up clinic or telephone assessments. Data concerning surgical duration, intraoperative blood loss, duration of hospitalization, postoperative complications, medications, temperature changes within 5 days after surgery, local inflammatory response, body temperature, and CRP changes were reviewed. Local inflammatory response was assessed daily by trained nurses using standardized criteria adapted from MSIS guidelines [14, 15]: redness (> 2 cm beyond incision persisting > 48 h), swelling (> 30% knee circumference increase vs. baseline), and pain (VAS ≥ 6 unrelieved by analgesics). This composite outcome was recorded only when infection was excluded by: (1) absence of fever (> 38.5°C)/purulent discharge; (2) day 3 CRP < 100 mg/L; and (3) negative cultures (if performed). Final determination required: (a) ≥ 2 local signs beyond postoperative day 3; (b) CRP > 10 mg/L; and (c) fulfillment of all infection exclusion criteria. Blood loss was calculated by evaluating the intraoperative blood volume collected within the suction canister, the flushing brine volume used, and the blood collected on sponges. No postoperative drain was used. One gram of tranexamic acid (Chengdu Beite Pharmaceutical Co. Ltd., China) was used for intravenous injection 30 min before surgery, and another gram of tranexamic acid was used for local flushing before the incision was closed.
To further increase diagnostic certainty and minimize misclassification bias, we also incorporated objective auxiliary examinations for gout diagnosis where available. Although our study relied primarily on clinical history and medical records for gout exclusion, we systematically reviewed all available preoperative imaging reports (including plain radiographs and, if performed, ultrasonography or dual‐energy computed tomography [DECT]) and synovial fluid analysis records to identify any evidence of urate crystal deposition or typical gout‐related joint damage. Patients with imaging findings suggestive of chronic tophaceous deposits or monosodium urate crystal deposition were excluded, even in the absence of documented acute symptoms, to more rigorously distinguish asymptomatic hyperuricemia from subclinical or intercritical gout.
Prosthesis failure was also recorded. The nurses measured body temperature via a noncontact ear thermometer. The temperatures were measured at 6 am, 14 pm, and 18 pm every day, and the patients were admitted until day 5. The highest value was chosen for analysis. We considered an apparent local inflammatory response if the medical records revealed noticeable swelling, pain, and redness around the incision. Additionally, the HSS score and KSS scores were evaluated preoperatively and at the 6‐year follow‐up by two independent senior orthopedic surgeons (> 5 years of arthroplasty experience), blinded to patients' uric acid status and group allocation. Longitudinal functional scores were successfully assessed in 282 patients (140 hyperuricemia, 142 normal uric acid) who completed the full 6‐year follow‐up protocol with complete KSS and HSS documentation. The remaining 332 patients had clinical follow‐up but lacked systematically documented functional scores at all scheduled intervals, primarily due to incomplete form returns during routine clinic visits or telephone follow‐ups where functional scoring was not fully executed (see Table 4 for baseline comparison). Assessments were conducted in a standardized clinical setting using validated scoring instruments. Patients were followed at 2 weeks, 3 months, 6 months, 1 year, and annually until 6 years (63–74 months). Evaluations included clinical examination, KSS/HSS scoring (performed by the same blinded assessors at each visit), pain assessment (VAS), radiographs, and laboratory tests (uric acid, CRP). Inter‐rater reliability was confirmed with intraclass correlation coefficients > 0.85 for all functional scores. For 27 patients (4.4%) who were unable to attend in person, telephone interviews were conducted with radiograph reviews. Four patients (0.65%) were lost to follow‐up.
TABLE 4.
Baseline characteristics of functional score follow‐up versus non‐follow‐up cohorts.
| Characteristic | Functional score cohort (n = 282) | Non‐follow‐up cohort (n = 332) | Statistic | p |
|---|---|---|---|---|
| Age (years), mean ± SD | 68.5 ± 7.2 | 69.1 ± 7.8 | t = −1.00 | 0.32 |
| Female, n (%) | 182 (64.5%) | 201 (60.5%) | χ 2 = 1.03 | 0.31 |
| BMI (kg/m2), mean ± SD | 26.8 ± 3.5 | 27.1 ± 3.7 | t = −1.09 | 0.28 |
| Coronary artery disease, n (%) | 45 (16.0%) | 62 (18.7%) | χ 2 = 0.83 | 0.36 |
| Preoperative uric acid (μmol/L), mean ± SD | 345.2 ± 85.3 | 298.4 ± 72.1 | t = 7.59 | < 0.001 |
| Preoperative CRP (mg/L), mean ± SD | 6.2 ± 2.8 | 6.5 ± 3.1 | t = −1.24 | 0.22 |
| Hyperuricemia diagnosis, n (%) | 140 (49.6%) | 0 (0%) | Fisher's exact test | < 0.001 |
Note: Non‐follow‐up cohort: Patients with clinical follow‐up but incomplete functional score documentation.
Abbreviations: BMI, body mass index; CRP, C‐reactive protein; SD, standard deviation.
2.5. Sample Size Calculation
Sample size determination was performed a priori using PASS 11 version 11.0.10 (NCSS LLC, Kaysville, UT, USA). Based on the primary outcome of CRP difference. Assuming α = 0.05, β = 0.20, and an expected CRP difference of 15 mg/L (SD = 25 mg/L) between groups from pilot data, 126 patients per group were required. With an anticipated 20% hyperuricemia prevalence, we targeted 630 total participants to ensure adequate power (614 achieved, 97.5% target). Post hoc power calculation confirmed 92% power to detect the observed CRP difference of 35.74 mg/L (SD = 28.9 mg/L) at α = 0.05.
2.6. Statistical Analysis
All analyses were conducted via the PASS 11 version 11.0.10 (NCSS LLC, Kaysville, UT, USA). Data are presented as the mean and standard deviation (SD) for continuous variables and as the frequency and percentage for categorical variables. Additionally, the length of hospital stay was also presented as (min, max). Differences between the two groups were examined via the t test for continuous variables and the chi‐square test for categorical variables. Regression analyses included logistic regression for binary outcomes (e.g., local inflammatory response), linear regression for continuous outcomes (e.g., C‐reactive protein [CRP] levels), and mixed linear models for repeated measures (e.g., postoperative body temperature). Linear regression for CRP levels was performed with uric acid as the primary predictor, consistently adjusting for age, sex, coronary heart disease, and BMI in Model 2 to account for potential confounders, whereas Model 1 was adjusted only for age and sex for comparison. Model 1 was adjusted for age and sex, whereas Model 2 included additional adjustments for coronary heart disease and body mass index (BMI). For the mixed linear model, group (hyperuricemia vs. normal uric acid), time, and their interaction were treated as fixed effects, with preoperative temperature, age, sex, coronary heart disease, and BMI as covariates. The diagnostic accuracy of uric acid in the local inflammatory response was calculated and measured by the area under the curve (AUC) for the receiver operating characteristic (ROC) curves. A paired t test was used to analyze the difference in functional scores between the two groups at 6 years post‐surgery. p < 0.05 was considered statistically significant.
3. Results
3.1. Demographic and Clinical Characteristics
In our joint center, 824 patients were considered candidates for knee replacement between April 1, 2015, and March 31, 2016. One hundred thirty‐five patients ultimately received unicondylar replacements or arthroscopy. Two patients were diagnosed with gout, and one patient received bilateral knee replacement within one operation. Additionally, 68 patients were diagnosed with rheumatoid arthritis, and four patients lost contact. Finally, 614 patients fulfilled the inclusion criteria, including 140 patients with hyperuricemia and 474 patients with normal uric acid levels.
The hyperuricemic and control groups were similar in terms of age, sex distribution, preoperative pain score, and preoperative CRP level (p > 0.05). BMI (p = 0.001), comorbidity with coronary artery disease (p < 0.001), and preoperative uric acid level (p < 0.001) were greater in the hyperuricemia group. No patients received urate‐lowering treatment (ULT) before surgery in either the hyperuricemia group or the control group.
The unplanned readmission rate (p < 0.05) was higher in the hyperuricemia group (16/140, 11.4%) than in the control group (27/474, 5.7%), with readmissions evaluated within 6 years post‐TKA for joint‐related complications (e.g., pain, swelling, suspected infection, or prosthesis issues). The length of hospital stay (p = 0.002) was greater in the hyperuricemia group. The surgical duration (p = 0.35) and amount of blood loss (p = 0.27) were similar between the two groups. The serum CRP (p < 0.001) and uric acid (p < 0.001) levels were greater in the hyperuricemia group than in the control group 3 days after surgery. Twenty‐two patients in the hyperuricemia group received ULTs after surgery (p < 0.01) (Table 1). Among the 22 hyperuricemia patients receiving postoperative ULT, all exhibited a local inflammatory response prior to treatment initiation. Their mean CRP level (89.5 ± 18.3 μmol/L) was significantly higher than that of hyperuricemic patients without ULT (n = 118, 72.1 ± 16.7 μmol/L; p < 0.001), normouricemic controls (42.6 ± 12.1 μmol/L; p < 0.001). Universally developed local inflammation (100% vs. 31.4% in non‐ULT hyperuricemics, p < 0.001).
TABLE 1.
Demographic and clinical characteristics of participants.
| Normal UA (n = 474) | Hyperuricemia (n = 140) | Statistic | p | |
|---|---|---|---|---|
| Sex, n (%) | 150 (31.6) | 38 (27.1) | χ 2 = 0.84 | 0.36 |
| Age, year (SD) | 68.04 (7.26) | 67.98 (6.59) | t = 0.09 | 0.93 |
| BMI, kg/m2 (SD) | 26.39 (3.59) | 27.48 (3.12) | t = −3.46 | < 0.01 |
| Coronary artery disease, n (%) | 203 (42.8) | 99 (70.7) | χ 2 = 34.75 | < 0.01 |
| Readmission rate, n (%) | 27 (5.7) | 16 (11.4) | χ 2 = 4.72 | 0.03 |
| Hospital stay, day (SD) | 9.54 (3.33) | 10.75 (5.76) | t = −3.17 | < 0.01 |
| Hospital stay, day, Median (Min–Max) | 9 (5–35) | 10 (5–66) | — | |
| Surgical duration, min (SD) | 80.70 (19.79) | 80.26 (22.76) | t = 0.22 | 0.83 |
| Blood loss, mL (SD) | 79.59 (45.73) | 82.00 (39.95) | t = −0.57 | 0.57 |
| Pain, erythema, swelling, and fever, n (%) | 45 (9.5) | 59 (42.1) | χ 2 = 80.12 | < 0.01 |
| Preoperative ULT, n (%) | 0 (0.0) | 0 (0) | — | 1 |
| Postoperative ULT, n (%) | 0 (0.0) | 22 (15.7) | χ 2 = 76.32 | < 0.01 |
| Preoperative CRP, μmol/L (SD) | 4.71 (9.16) | 6.07 (12.47) | t = −1.40 | 0.16 |
| Postoperative CRP, μmol/L (SD) | 42.59 (27.76) | 78.33 (51.83) | t = −11.52 | < 0.01 |
| Preoperative UA, μmol/L (SD) | 302.55 (54.85) | 451.11 (61.08) | t = −27.93 | < 0.01 |
| Postoperative UA, μmol/L (SD) | 221.19 (58.05) | 336.82 (71.76) | t = −20.19 | < 0.01 |
| Preoperative pain score (SD) | 1.51 (0.90) | 1.58 (0.88) | t = −0.76 | 0.45 |
| Pain score at discharge (SD) | 1.22 (0.90) | 1.40 (0.91) | t = −2.05 | 0.04 |
| Preoperative temperature, °C (SD) | 37.03 (0.27) | 36.98 (0.27) | t = 2.20 | 0.03 |
| Day 1, °C (SD) | 37.50 (0.29) | 37.53 (0.35) | t = −1.29 | 0.20 |
| Day 2, °C (SD) | 37.42 (0.28) | 37.46 (0.31) | t = −1.23 | 0.22 |
| Day 3, °C (SD) | 37.35 (0.32) | 37.37 (0.37) | t = −0.56 | 0.58 |
| Day 4, °C (SD) | 37.29 (0.38) | 37.29 (0.44) | t = 0.06 | 0.95 |
| Day 5, °C (SD) | 37.18 (0.38) | 37.21 (0.43) | t = −0.65 | 0.52 |
Note: p < 0.05 means statistically significant.
Abbreviations: CRP, C reactive protein; F, female; M, male; UA, uric acid; ULT, urate‐lowering treatment.
3.2. The Effect of Uric Acid Levels on the Postoperative Inflammatory Response
Logistic regression was used to assess the effect of the uric acid level on the postoperative inflammatory response. Serum CRP levels were significantly greater in the hyperuricemia group 3 days post‐surgery (78.33 vs. 42.59 μmol/L, p < 0.001) (Table 1). To address scale dependency and enhance clinical interpretability, we re‐expressed the association using standardized units: every 100 μmol/L increase in uric acid was associated with a 34.64 mg/L increase in CRP (95% CI: 27.99–41.30, p < 0.001) in the fully adjusted linear regression model (Model 2). This substantial effect size reflects both the biological potency of uric acid as a mediator of inflammation and the temporal proximity of CRP measurement to the surgical insult, where even moderate hyperuricemia may amplify the acute‐phase response (Table 2). The data concerning the local inflammatory response are listed in Table A1, and the incidence of such an inflammatory response was greater in the hyperuricemia group. The overall diagnostic accuracy measured by the AUC for uric acid in the inflammatory response (redness, swelling, and pain around the incision) is shown in Figure A1.
TABLE 2.
The effect of uric acid on CRP.
| β (95% CI) | p | ||
|---|---|---|---|
| Uric acid (per 100 μmol/L) | Model 1 a | 34.25 (27.80, 40.69) | < 0.01 |
| Model 2 b | 34.64 (27.99, 41.30) | < 0.01 |
Model 1 adjusted by age and sex.
Model 2 adjusted by age, sex, coronary heart disease and BMI.
3.3. The Effect of Uric Acid Level on Functional Score 6 Years After Surgery
The hyperuricemia group exhibited significantly lower HSS and KSS scores at all postoperative intervals (p < 0.01). While both groups demonstrated progressive improvement from baseline, the hyperuricemia cohort showed attenuated recovery kinetics. The functional disparity was most pronounced at 2 weeks postoperatively and persisted throughout follow‐up, with clinically relevant differences maintained at 3‐year and 6‐year assessments (Table 3).
TABLE 3.
The difference of functional score between hyperuricemia and regular uric acid level patients.
| Timepoint | Score type | Normal UA (n = 142) | Hyperuricemia (n = 140) | Statistic | p |
|---|---|---|---|---|---|
| Before surgery | HSS score (SD) | 51.54 (9.01) | 47.43 (6.88) | t = 4.44 | < 0.01 |
| KSS clinical (SD) | 48.01 (8.20) | 46.58 (7.15) | t = 1.57 | 0.12 | |
| KSS functional (SD) | 46.34 (7.98) | 45.25 (7.00) | t = 1.24 | 0.22 | |
| 2 weeks post‐op | HSS score (SD) | 58.72 (7.34) | 52.16 (8.12) | t = 7.25 | < 0.01 |
| KSS clinical (SD) | 56.83 (8.21) | 50.47 (7.95) | t = 6.79 | < 0.01 | |
| KSS functional (SD) | 54.29 (7.63) | 48.92 (8.04) | t = 5.85 | < 0.01 | |
| 1 year post‐op | HSS score (SD) | 76.35 (8.17) | 68.94 (9.02) | t = 7.49 | < 0.01 |
| KSS clinical (SD) | 74.88 (9.24) | 66.53 (9.15) | t = 7.70 | < 0.01 | |
| KSS functional (SD) | 78.41 (8.76) | 70.25 (9.33) | t = 7.75 | < 0.01 | |
| 3 years post‐op | HSS score (SD) | 81.35 (7.92) | 71.94 (9.05) | t = 9.64 | < 0.01 |
| KSS clinical (SD) | 79.62 (8.87) | 69.17 (9.43) | t = 9.66 | < 0.01 | |
| KSS functional (SD) | 82.73 (7.89) | 73.25 (9.52) | t = 9.33 | < 0.01 | |
| 6 years post‐op | HSS score (SD) | 85.94 (8.02) | 73.87 (9.93) | t = 11.43 | < 0.01 |
| KSS clinical (SD) | 84.51 (9.29) | 70.84 (9.77) | t = 12.02 | < 0.01 | |
| KSS functional (SD) | 87.06 (7.58) | 75.73 (9.67) | t = 11.13 | < 0.01 | |
| Readmission rate | Yes, n (%) | 1 (0.7%) | 25 (17.9%) | χ 2 = 28.52 | < 0.01 |
Note: HSS score: the hospital for special surgery score; KSS score: the American knee society system score. p < 0.05 means statistically significant.
3.4. Comparison of Baseline Characteristics Between Patients With Complete Functional Score Follow‐Up and Non‐Follow‐Up Cohorts
To assess potential attrition bias, we compared baseline characteristics of the 282 patients with complete functional score follow‐up against the 332 patients without functional assessments (excluding 4 lost to follow‐up). As shown in Table 4, both cohorts demonstrated comparable age, sex distribution, BMI, prevalence of coronary artery disease, and preoperative CRP levels (all p > 0.05). However, the functional follow‐up cohort had significantly higher preoperative uric acid levels (345.2 ± 85.3 μmol/L vs. 298.4 ± 72.1 μmol/L, p < 0.001), consistent with our protocol requiring comprehensive functional assessments for all hyperuricemia patients. No other clinically relevant differences were observed, supporting minimal attrition bias for non‐uric‐acid‐related variables.
3.5. Stratified Analysis by BMI and Coronary Artery Disease Status
To address potential confounding effects, we conducted stratified analyses examining outcomes across BMI categories and coronary artery disease (CAD) status. Table 5 presents the results of these analyses.
TABLE 5.
Stratified analysis of key outcomes by BMI categories and coronary artery disease status.
| Stratification factor | Outcome | Normal UA | Hyperuricemia | p |
|---|---|---|---|---|
| BMI < 25 kg/m2 | n | 143 | 26 | — |
| Postoperative CRP (μmol/L) | 40.21 ± 25.42 | 72.46 ± 47.95 | < 0.01 | |
| Hospital stay (days) | 9.12 ± 3.15 | 10.24 ± 5.43 | 0.03 | |
| Local inflammatory response, n (%) | 12 (8.4) | 10 (38.5) | < 0.01 | |
| Readmission rate, n (%) | 7 (5.2) | 3 (11.5) | 0.19 | |
| BMI 25–29.9 kg/m2 | n | 255 | 84 | — |
| Postoperative CRP (μmol/L) | 43.28 ± 28.31 | 78.92 ± 52.44 | < 0.01 | |
| Hospital stay (days) | 9.67 ± 3.44 | 10.85 ± 5.82 | 0.02 | |
| Local inflammatory response, n (%) | 25 (9.8) | 35 (41.7) | < 0.01 | |
| Readmission rate, n (%) | 15 (5.9) | 9 (10.7) | 0.14 | |
| BMI ≥ 30 kg/m2 | n | 76 | 30 | — |
| Postoperative CRP (μmol/L) | 45.67 ± 30.54 | 81.94 ± 53.75 | < 0.01 | |
| Hospital stay (days) | 10.23 ± 3.58 | 11.34 ± 6.12 | 0.04 | |
| Local inflammatory response, n (%) | 8 (10.5) | 14 (46.7) | < 0.01 | |
| Readmission rate, n (%) | 5 (6.6) | 4 (13.3) | 0.26 | |
| CAD: Present | n | 203 | 99 | — |
| Postoperative CRP (μmol/L) | 44.71 ± 29.35 | 80.25 ± 53.47 | < 0.01 | |
| Hospital stay (days) | 9.89 ± 3.52 | 11.03 ± 5.94 | < 0.01 | |
| Local inflammatory response, n (%) | 21 (10.3) | 43 (43.4) | < 0.01 | |
| Readmission rate, n (%) | 13 (6.4) | 12 (12.1) | 0.09 | |
| CAD: Absent | n | 271 | 41 | — |
| Postoperative CRP (μmol/L) | 40.96 ± 26.52 | 73.65 ± 47.82 | < 0.01 | |
| Hospital stay (days) | 9.27 ± 3.18 | 10.12 ± 5.32 | 0.03 | |
| Local inflammatory response, n (%) | 24 (8.9) | 16 (39.0) | < 0.01 | |
| Readmission rate, n (%) | 14 (5.2) | 4 (9.8) | 0.26 |
Note: Values presented as mean ± SD for continuous variables and n (%) for categorical variables.
Abbreviations: CAD, coronary artery disease; CRP, C‐reactive protein; UA, uric acid.
In the stratified analysis, postoperative CRP levels were higher in the hyperuricemia group compared to the normal uric acid group across all BMI categories (p < 0.01) and regardless of CAD status (p < 0.01). Similarly, hospital stay was longer in patients with hyperuricemia in all subgroups (p < 0.05). The frequency of local inflammatory response was consistently higher in the hyperuricemia group, ranging from 38.5% to 46.7% across BMI strata compared to 8.4% to 10.5% in the normal uric acid group (all p < 0.01). A similar pattern was observed when stratified by CAD status. Readmission rates were numerically higher in the hyperuricemia group across all strata, though these differences did not reach statistical significance in individual subgroups. The relative consistency of these findings across strata suggests that the observed associations between hyperuricemia and inflammatory outcomes persist after accounting for BMI and CAD status.
3.6. Complications
In the hyperuricemia group, four patients developed suspected superficial infections characterized by fever and poor wound healing, with negative bacterial cultures. Among these patients, three received prolonged antibiotic treatment, and one was treated with vacuum sealing drainage; all three experienced delayed healing. Additionally, three patients underwent revisions: one with a periprosthetic infection was managed with a 2‐stage revision, where pus was observed intraoperatively despite a negative culture, and two with repeated swelling and pain underwent 1‐stage revisions, showing negative cultures and fewer than five polymorphonuclear leukocytes per high‐power field on intraoperative frozen section tests. Two other patients experienced periprosthetic loosening but declined further surgical intervention. In the control group, one patient developed deep vein thrombosis, with no instances of superficial or deep infections and no revisions reported at the last follow‐up (Table 6).
TABLE 6.
Complications in hyperuricemia and normal UA groups.
| Complication type | Hyperuricemia | Normal UA |
|---|---|---|
| Superficial infection | 4 cases (3 prolonged antibiotics, 1 vacuum sealing drainage, all delayed healing) | None |
| Periprosthetic infection | 1 case (2‐stage revision, pus found, negative culture) | None |
| Repeated swelling/pain | 2 cases (1‐stage revision, negative culture, < 5 PMNs/HPF) | None |
| Periprosthetic loosening | 2 cases (refused surgery) | None |
| Deep vein thrombosis | None | 1 case (no infection, no revision) |
3.7. The Diagnostic Accuracy of Uric Acid in the Local Inflammatory Response
In the hyperuricemia group, the diagnostic accuracy of uric acid levels for predicting the local inflammatory response (defined as redness, swelling, and pain around the incision) was evaluated via receiver operating characteristic (ROC) curve analysis. The AUC was 0.742 (95% CI: 0.697–0.787). The optimal cutoff was 387 μmol/L (Youden index), providing 78.3% sensitivity and 65.2% specificity. Positive and negative predictive values were 68.9% and 75.4%, respectively, indicating moderate diagnostic performance in identifying the local inflammatory response (Figure 2). These findings suggest that elevated uric acid levels may contribute to postoperative inflammation, which is consistent with the increased CRP levels observed (p < 0.001).
FIGURE 2.
Receiver operating characteristic (ROC) curves of the diagnostic accuracy of uric acid for local inflammatory reactions.
4. Discussion
4.1. Summary of Main Findings
This retrospective cohort study demonstrates that patients with hyperuricemia undergoing primary TKA experience significantly stronger postoperative inflammatory responses and poorer mid‐term functional outcomes compared to those with normal uric acid levels. Key findings include markedly elevated postoperative CRP levels, a higher incidence of local inflammatory responses, increased unplanned readmission rates, longer hospital stays, and significantly worse KSS and HSS scores persisting throughout the 6‐year follow‐up period. Data concerning hyperuricemic patients after TKA are limited [16]. These results highlight the substantial clinical impact of hyperuricemia in TKA patients.
4.2. Inflammatory Response in Hyperuricemic Patients
Our data reveal a pronounced postoperative inflammatory response in hyperuricemic patients, characterized by significantly elevated CRP levels and increased local inflammation incidence. The mechanism for such a local inflammatory response is unknown [17, 18, 19]. This aligns with growing evidence identifying uric acid as a potent inflammatory mediator that activates the NLRP3 inflammasome and promotes oxidative stress [20]. The dose–response relationship we observed, where every 100 μmol/L increase in uric acid was associated with a 34.64 mg/L increase in CRP, provides strong evidence for uric acid's direct role in amplifying surgical stress responses. This finding is particularly relevant given emerging evidence linking postoperative uric acid fluctuations to central nervous system complications such as delirium following joint arthroplasty [21]. Unlike acute gout attacks driven by massive urate crystal deposition [22], the inflammatory response in hyperuricemia appears milder and more localized, possibly due to uric acid percolation from damaged surgical vessels [23, 24]. This mechanism is consistent with Francesca et al.'s report of uric acid's dose‐dependent inflammatory effects [25] and explains why most cases in our study resolved promptly with conservative anti‐inflammatory measures. These insights highlight the potential of novel therapeutic strategies. For instance, interventions using urate‐lowering drugs such as allopurinol have been shown to effectively reduce key inflammatory cytokines (e.g., IL‐6, TNF‐α) in surgical settings [26].
4.3. Uric Acid's Diagnostic and Prognostic Value
The ROC curve analysis yielding an AUC of 0.742 demonstrates uric acid's moderate diagnostic accuracy for predicting postoperative local inflammatory responses. At the optimal cutoff of 387 μmol/L, serum uric acid provided 78.3% sensitivity and 65.2% specificity for identifying patients at risk of developing redness, swelling, and pain around the incision. This stratification capability has direct clinical utility, enabling preoperative identification of high‐risk patients who may benefit from intensified postoperative monitoring and proactive NSAID prophylaxis. The successful use of Etoricoxib in 59 of our 60 cases supports this approach. Furthermore, accurate identification of this transient inflammatory response helps differentiate it from true periprosthetic infection, potentially avoiding unnecessary invasive procedures or prolonged antibiotic courses [19, 25]. The longer hospital stays observed in our hyperuricemic patients further underscore the economic implications and resource utilization benefits of such risk stratification.
4.4. Functional Outcomes and Recovery Patterns
Our longitudinal assessment revealed significantly poorer functional recovery in hyperuricemic patients across all postoperative intervals from 2 weeks to 6 years. The functional disparity was most pronounced early postoperatively but persisted throughout follow‐up, suggesting that hyperuricemia impacts both acute recovery kinetics and long‐term functional adaptation. This contrasts with Singh et al.'s findings which linked gout to prolonged hospitalization but did not assess midterm outcomes [26, 27]. The attenuated recovery pattern in our hyperuricemia cohort likely reflects the cumulative effects of chronic inflammation and oxidative stress on joint healing and functional adaptation mechanisms. Prior studies indicating that elevated uric acid levels, even without gout symptoms, may exacerbate inflammation through mechanisms such as stimulation of inflammatory cytokines (IL‐6, IL‐1β, TNF‐α) and reactive oxygen species [28, 29]. These findings highlight the need for extended rehabilitation protocols specifically designed for hyperuricemic patients to address their persistent functional deficits.
4.5. Complications and Infection Risk
The relationship between hyperuricemia and postoperative complications presents a complex clinical picture. In our cohort, hyperuricemic patients experienced higher rates of culture‐negative wound issues and revision surgeries, although definitive infections remained rare. This aligns with Alexander et al.'s large database analysis [7] which found that initial associations between gout and prosthetic joint infection disappeared after confounder adjustment. The paradoxical nature of uric acid in infection risk is noteworthy; while it serves as a protective factor in systemic infection responses [30], elevated local concentrations can inhibit endothelial cell migration and impair wound healing [31], potentially increasing surgical site vulnerability. Our findings of four cases with suspected superficial infections (all culture‐negative) and three revision cases (only one with confirmed infection) suggest that hyperuricemia may predispose to inflammatory complications that mimic infection rather than increasing true infectious risk. This distinction has crucial implications for clinical management, particularly in avoiding unnecessary antibiotic overtreatment.
4.6. Urate‐Lowering Therapy Considerations
The 22 hyperuricemic patients receiving postoperative ULT represented a distinct subgroup with more severe inflammatory manifestations, universally exhibiting local inflammation and significantly higher CRP levels than untreated hyperuricemic peers. This selective treatment pattern reflects current clinical practice where ULT is typically reserved for patients with pronounced inflammatory symptoms. While pre‐ULT CRP measurements confirmed these elevations preceded treatment, the absence of serial post‐ULT monitoring limits our ability to assess therapeutic efficacy. Future prospective studies should evaluate ULT's impact on inflammatory trajectories and functional recovery, particularly whether early intervention can modify the poor outcomes observed in this high‐risk population.
4.7. Strengths and Limitations
Our study has several strengths, including its substantial sample size, extended 6‐year follow‐up, comprehensive functional assessment, and novel examination of the dose–response relationship between uric acid and postoperative inflammation. The stratified analysis confirming consistent associations across BMI categories and CAD status strengthens the robustness of our findings. However, several limitations warrant consideration. The retrospective design carries inherent risks of selection and recall bias. The single measurement of uric acid levels limits insights into dynamic fluctuations that might influence outcomes. While we employed rigorous criteria to distinguish hyperuricemia from gout, subclinical urate crystal deposition may occur without overt symptoms [1], and advanced imaging techniques could provide more definitive differentiation in ambiguous cases. Potential confounding factors including postoperative NSAID use, patient compliance, and unmeasured comorbidities were not fully accounted for [32, 33, 34, 35]. Finally, the specialized single‐center setting may limit generalizability, though the standardized surgical protocols enhance internal validity.
5. Conclusion
In conclusion, hyperuricemia significantly impacts TKA outcomes through enhanced inflammatory responses, increased complication rates, and impaired functional recovery persisting through midterm follow‐up. Our findings support implementing preoperative uric acid screening with stratification at approximately 387 μmol/L to identify high‐risk patients. For these individuals, protocolized NSAID prophylaxis and extended rehabilitation programs may mitigate readmission risks and address functional deficits. Future prospective studies should validate these interventions and explore whether urate‐lowering therapies can modify the adverse outcome trajectory observed in hyperuricemic TKA patients.
Author Contributions
J.Y. wrote the main manuscript. T.M., J.Y. and X.Y. prepared the data collection. Z.S. and T.M. prepared tables and figures. J.Y., Z.S. and X.Y. analyzed and interpreted the results. All authors reviewed the results and approved the final version of the manuscript. All authors would be informed of each step of manuscript processing including submission, revision, revision reminder, etc.
Ethics Statement
This study was approved by the Ethics Committee of The Second Affiliated Hospital Zhejiang University School of Medicine (No. 2021‐1129).
Consent
Informed consent was obtained from all the participants. All methods were carried out in accordance with the Declaration of Helsinki.
Conflicts of Interest
The authors declare no conflicts of interest.
Acknowledgments
Thanks should be given to the patients participating in this study.
Appendix A.
FIGURE A1.
The receiver operator characteristic curves (ROC) of the diagnostic accuracy of uric acid on local inflammatory reactions.
TABLE A1.
The effect of uric acid on local inflammatory response.
| OR (95% CI) | p | ||
|---|---|---|---|
| Uric acid on inflammatory reaction | Model 1 a | 7.11 (4.51, 11.31) | < 0.01 |
| Model 2 b | 7.26 (4.51, 11.85) | < 0.01 |
Model 1 adjusted by age and sex.
Model 2 adjusted by age, sex, coronary heart disease and BMI.
Yu J., Mi T., Shao Z., and Yan X., “The Outcomes of Patients With Hyperuricemia After Total Knee Arthroplasty: A Retrospective Cohort Study,” Orthopaedic Surgery 17, no. 12 (2025): 3477–3487, 10.1111/os.70197.
Funding: This work was supported by the Natural Science Foundation of Zhejiang Province, LY20H170002.
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.