Cardiovascular and fracture events analysis and intervention strategies in patients undergoing parathyroidectomy with secondary hyperparathyroidism
Highlight box
Key findings
• A total of 119 patients who received parathyroidectomy (PTX) for secondary hyperparathyroidism (SHPT) were analyzed in our study. Place of residence, age, and duration of uremia were shown to be independent risk factors.
What is known and what is new?
• Chronic kidney disease, especially end-stage renal disease (ESRD), is the most common cause of SHPT, and SHPT is the most severe complication of ESRD.
• Compared with urban residents, rural residents had poorer economic conditions, a longer interval from disease onset to PTX, and a higher incidence of cardiovascular and fracture events and concurrent nephrolithiasis, all of which were statistically significant.
What is the implication, and what should change now?
• Outpatient nephrology services for ESRD should prioritize populations at high risk of adverse events such as SHPT-related cardiovascular and fracture incidents, promptly assess surgical intervention measures, and provide necessary management of complications and psychological interventions.
Introduction
Chronic kidney disease (CKD), especially end-stage renal disease (ESRD), is the most common cause of secondary hyperparathyroidism (SHPT), and SHPT is the most severe complication of ESRD.
The hyperphosphatemia, hypercalcemia, hyperkalemia, and excessive secretion of parathyroid hormone (PTH) caused by hyperparathyroidism are critical factors increased the rate of vascular calcification and acute cardiovascular events, which are the leading causes of death in patients with CKD (1-7). Studies have shown that parathyroidectomy (PTX) can improve symptoms in SHPT patients and provide better survival benefits (1,8).
In China, the high incidence of CKD and the large number of patients undergoing dialysis contribute to a high prevalence of SHPT. Issues such as standardization in managing CKD leading to SHPT and the high cost of using calcimimetics such as cinacalcet pose challenges in managing a large population of SHPT patients with severe complications. This implies a corresponding increase in the risks associated with PTX and places higher demands on surgical interventions for such patients (9).
With advancements in medical practices, precision medicine has increasingly demonstrated advantages in clinical settings. Guided by the concept of precision medicine, systematic interventions in SHPT patients undergoing PTX evaluate the actual condition of patients and design optimal treatment plans tailored to individual differences. This approach enhances patient compliance with treatment, improves clinical efficacy, provides higher quality services, and reduces the risk of complications (10). However, it is hard to find the big-sample studies with the rate of vascular calcification and acute cardiovascular events in the Chinese mainland.
Therefore, this study evaluated 119 patients treated with PTX for SHPT at The First Affiliated Hospital, Zhejiang University School of Medicine from September 2021 to April 2024. It assessed the comorbidities, socioeconomic status, and postoperative complications of SHPT patients before PTX, aiming to provide insights for precision medicine in the perioperative period of PTX, i.e., optimizing the timing of surgical intervention, enhancing management of surgical complications, implementing personalized psychological interventions, and so on. We present this article in accordance with the STROBE reporting checklist (available at https://gs.amegroups.com/article/view/10.21037/gs-24-391/rc).
Methods
Participants
The study was designed as an observational, cross-sectional study. A total of 138 patients with SHPT received PTX at The First Affiliated Hospital, Zhejiang University School of Medicine, from September 2021 to April 2024, comprising the potential object of our study. The inclusion criteria were as follows: (I) confirmed diagnosis of uremia with ongoing hemodialysis or peritoneal dialysis; (II) meeting the surgical indications for SHPT secondary to ESRD in China; (III) first-time PTX; (IV) severe symptoms affecting daily life such as bone pain, pruritus, and so on; (V) ineffective internal medicine treatment for persistent hypercalcemia or hyperphosphatemia; (VI) imaging report showing at least 1 enlarged parathyroid gland with a diameter >1 cm. The exclusion criteria were as follows: (I) severe cardiopulmonary functional impairment intolerant to anesthesia; (II) severe coagulation disorders; (III) previous parathyroid surgery or minimally invasive surgery (see Figure 1). Finally, 119 patients were included according to the above criteria. Then, their clinical data were collected and analyzed. Among them, there were 55 males and 64 females, aged 21–71 years, with a mean age of 45.28±11.91 years. The duration of dialysis ranged from 1 to 24 years, with an average of 8.04±4.26 years.
Sample size estimation
We assume the sample size of rural and urban were equal. The alpha was set to 0.1 while the power was set to 0.9, we estimate the occurrence of cardiovascular and bone fracture difference was 0.25, then each group need 51 patients. Based on the nature of the retrospective study, we enrolled all patients with the final sample group of 119.
Ethical statement
The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). This study was approved by the Ethics Committee of The First Affiliated Hospital, Zhejiang University School of Medicine (No. 20230601) and individual consent for this retrospective analysis was waived.
Pathway
Upon admission, baseline data were assessed. Detailed information regarding patients’ socioeconomic status, CKD treatment history, management of SHPT complications, and plans for kidney transplantation was obtained. Basic treatment for uremia prior to surgery included dietary control, blood pressure management, erythropoiesis-stimulating agents, and regular dialysis. A follow-up plan was formulated based on this foundation, providing personalized guidance including health education, individualized psychological intervention, postoperative rehabilitation guidance, and community and family interventions. A post-discharge follow-up model was implemented to monitor patient recovery progress.
Observation indicators
To understand the preoperative quality of life and analyze their socioeconomic status, patients were categorized into rural and urban residents for comparison. The analysis included preoperative complications such as osteoporosis, fractures, and cardiovascular event diagnosed by radiography (see Figures 2,3). Postoperative complications, long-term outcomes, and their relationships with dialysis duration, treatment duration for hyperparathyroidism, blood calcium, phosphorus levels, and PTH levels were also analyzed. All patients received cardiovascular computed tomography angiography (CTA) and X-ray for bone fracture before surgery to reveal the complications. A cardiovascular event was defined as major coronary artery stenosis over 75% and the need for specialized intervention. A skeletal event was defined as a bone fracture, diagnosed by a radiologist via X-ray. All complications were diagnosed by 2 specialists to decrease diagnosis bias. Major outcomes were defined as the occurrence of skeletal and cardiovascular events. The data were recorded well with no missing data.
Statistical methods
Statistical analysis was conducted using SPSS 22.0 software (IBM Corp., Armonk, NY, USA). Due to the standardized pre-operative checklist, there were no common clinical data missing in the statistical analysis. For normally distributed and homogenous variance metric data, results are presented as mean ± standard deviation, and independent sample t-tests were performed. For non-normally distributed data, median values are presented, and χ2 tests were used. A significance level of P<0.05 was considered statistically significant. Baseline data of rural and urban group patients were analyzed, and variables showing significant differences in baseline data were included in a multivariate regression analysis. Univariate analysis associated with occurrence of cardiovascular and fracture events with P<0.10 were enrolled in logistic regression analysis for better model representation. Binary logistic regression was used to identify independent risk factors for cardiovascular/fracture events based on the entering method (P<0.05 was considered statistically significant).
Results
Surgery and postoperative complications
A total of 119 patients underwent total PTX with autotransplantation of parathyroid tissue from the forearm; all surgeries were successfully completed. There were no deaths during the perioperative period, and postoperative PTH levels met the criteria for surgical success. The incidence of severe hypocalcemia postoperatively was 2.5% (3/119). There was one patient who developed gastrointestinal perforation postoperatively, another with acute pancreatitis which improved with aggressive treatment, and one patient who experienced recurrent laryngeal nerve injury (see Table 1). There were no cases of surgical site infection.
Table 1
| Items | Cases, n | Incidence (%) |
|---|---|---|
| Hoarseness (including one case of recurrent laryngeal nerve injury) | 2 | 1.7 |
| Arthralgia | 2 | 1.7 |
| Numbness of the limbs | 2 | 1.7 |
| Hyperkalemia | 3 | 2.5 |
| Hypocalcemia | 3 | 2.5 |
| Nausea (including 1 case of pancreatitis) | 3 | 2.5 |
| Weakness | 4 | 3.4 |
| Gastrointestinal perforation | 1 | 0.8 |
| Clavien-Dindo classification | ||
| Grade I | 4 | 3.4 |
| Grade II | 15 | 12.6 |
| Grade III | 1 | 0.8 |
Postoperative follow-up
Follow-up was conducted via telephone and outpatient visits, with no loss to follow up among the 119 patients. During the follow-up period, two patients died, one from lung cancer and the other from abdominal infection. Permanent hypoparathyroidism requiring calcium supplementation developed in one patient (0.84%). During follow-up, no patients required reoperation due to recurrence.
Baseline characteristics and the incidence of events
A total of 119 patients were enrolled in the study, 64 (53.8%) were female. The mean age was 51.7±11.0 years, with 8.2±4.5 years of uremia duration and 2.6±2.7 years of SHPT duration. Twenty-seven (22.7%) had cardiovascular events and 18 (15.1%) had fracture events.
Comparison of population characteristics before surgery in different economic conditions
In this study, we defined severe coronary artery stenosis and fracture events as primary outcomes. A total of 35 (29.4%) patients experienced cardiovascular/fracture events. Compared to urban residents, rural residents with poorer economic conditions had a longer interval from onset to PTX (7.6±4.05 vs. 10.4±5.3 years, P=0.009), during which cardiovascular and fracture events were more likely to occur, with a higher incidence of nephrolithiasis, showing significant statistical significance (38.0% vs. 16.7%, P=0.01). By grouping cardiovascular and/or fracture events as a whole, further comparisons of cardiovascular/fracture events revealed associations with place of residence (P=0.01), age (P<0.001), duration of uremia (P=0.009), preoperative PTH levels (P=0.03), and blood phosphorus levels (P=0.07) (see Tables 2,3). Further multifactorial analysis of cardiovascular/fracture events identified residence [hazard ratio (HR) =0.352, P=0.045], age (HR =1.110, P<0.001), blood phosphorus levels (HR =2.556, P<0.001), and duration of uremia (HR =1.149, P=0.02) as independent risk factors (see Table 4, Figure 4).
Table 2
| Items | Rural (n=71) | Urban (n=48) | P value |
|---|---|---|---|
| Age (years) | 52.1±11.2 | 51.2±10.7 | 0.66 |
| Gender | 0.94 | ||
| Male | 33 (46.5) | 22 (45.8) | |
| Female | 38 (53.5) | 26 (54.2) | |
| Bone pain symptoms | 25 (35.2) | 17 (35.4) | 0.98 |
| Kidney stone symptoms | 4 (5.6) | 0 (0.0) | 0.03 |
| Fatigue symptoms | 14 (19.7) | 7 (14.6) | 0.47 |
| Mental symptoms | 1 (1.4) | 1 (2.1) | 0.34 |
| Duration of uremia (years) | 7.6±4.05 | 10.4±5.3 | 0.009 |
| Duration of secondary hyperparathyroidism (years) | 2.3±2.5 | 3.6±3.0 | 0.81 |
| Cardiovascular events | 21 (29.6) | 6 (12.5) | 0.043 |
| Fracture events | 13 (18.3) | 5 (10.4) | 0.30 |
| Cardiovascular and/or fracture events | 27 (38.0) | 8 (16.7) | 0.01 |
| Preoperative latest PTH (pg/mL) | 1,497±1,271 | 1,123±825 | 0.08 |
| Serum calcium (mmol/L) | 2.3±0.3 | 2.4±0.3 | 0.10 |
| Serum phosphate (mmol/L) | 1.9±0.7 | 1.7±0.5 | 0.16 |
Continuous data are presented as average ± standard deviation and counting data are presented as numbers (percentage). PTH, parathyroid hormone.
Table 3
| Items | Non-event group (n=84) | Cardiovascular/fracture event group (n=35) | P value |
|---|---|---|---|
| Age (years) | 49.2±11.1 | 57.8±8.1 | <0.001 |
| Gender | >0.99 | ||
| Male | 39 (46.4) | 16 (45.7) | |
| Female | 45 (53.6) | 19 (54.3) | |
| Residence | 0.01 | ||
| Rural | 44 (52.4) | 27 (77.1) | |
| Urban | 40 (47.6) | 8 (22.9) | |
| Duration of uremia (years) | 7.5±4.1 | 9.9±4.9 | 0.009 |
| Duration of secondary hyperparathyroidism (years) | 2.5±2.4 | 2.6±2.6 | 0.81 |
| Preoperative latest PTH (pg/mL) | 1,202±955 | 1,692±1,406 | 0.03 |
| Serum calcium (mmol/L) | 2.4±0.3 | 2.4±0.4 | 0.71 |
| Serum phosphate (mmol/L) | 1.8±0.6 | 2.0±0.7 | 0.07 |
Continuous data are presented as average ± standard deviation and counting data are presented as numbers (percentage). PTH, parathyroid hormone.
Table 4
| Items | Univariate analysis | Multivariate analysis | ||||
|---|---|---|---|---|---|---|
| P value | RR (95% CI) | B | Significance | HR (95% CI) | ||
| Residence (rural vs. urban) | 0.01 | 0.326 (0.133–0.800) | −1.345 | 0.045 | 0.352 (0.127–0.976) | |
| Age | <0.001 | 1.096 (1.043–1.151) | 0.105 | <0.001 | 1.110 (1.049–1.175) | |
| Duration of uremia | 0.01 | 1.123 (1.026–1.229) | 0.139 | 0.02 | 1.149 (1.024–1.289) | |
| Recent preoperative PTH | 0.044 | 1.000 (1.000–1.001) | 0.000 | 0.29 | 1.000 (1.000–1.001) | |
| Serum phosphorus levels | 0.07 | 1.790 (0.955–3.353) | 0.938 | <0.001 | 2.556 (1.105–5.911) | |
RR, risk ratio; CI, confidence interval; HR, hazard ratio; PTH, parathyroid hormone.
Discussion
Emphasizing high-risk factors of adverse events in SHPT, optimizing the timing of surgical intervention
In China, there is a considerable number of CKD patients undergoing dialysis, yet the usage rate of PTX in clinical practice remains low. This discrepancy is attributed to factors such as socioeconomic conditions of patients, inadequate assessment of patient conditions by medical staff, concerns over multiple comorbidities in these patients leading to higher surgical risks, and insufficient overall disease management awareness among healthcare professionals. Consequently, there is a high prevalence of SHPT patients in China experiencing inadequate, delayed, or excessive treatments. A multicenter study, the Dialysis Outcomes and Practice Patterns Study (DOPPS), revealed that only 2.0% of dialysis patients in major cities such as Beijing, Shanghai, and Guangzhou undergo PTX (11).
From our study findings, it is evident that patients often undergo surgical treatment only when severe complications arise. Among all patients in our study, 38% experienced severe complications such as cardiac events and fractures. Rural patients, in particular, exhibited significantly longer preoperative hesitation periods and higher incidences of cardiovascular diseases and fractures.
In a previous similar study, the high efficacy of etelcalcetide in the treatment of SHPT in hemodialysis patients is recommended (12). In the study, the proportion of cardiovascular events in the mortality structure is more than 70% higher in the historical group than in the group of patients treated with etelcalcetide, and is 69.2% vs. 40.0%, respectively. The frequency of fractures is almost three times higher in the historical than in the main group of patients. Patients with multiple preoperative complications ultimately face higher rates of perioperative complications, poorer surgical outcomes, and increased surgical risks. This underscores the need for higher standards from the healthcare team during the perioperative period. Therefore, for SHPT patients at high risk of cardiovascular/fracture events, timely assessment by surgical teams to evaluate the necessity and feasibility of PTX or minimally invasive treatments is crucial (13).
Enhancing management of surgical complications
ESRD is a long-term chronic disease process. When performing PTX due to SHPT, specialized perioperative management must be provided based on dialysis treatment, especially in cases with severe complications and multiple surgical complications, posing a significant challenge to the healthcare team.
Therefore, in the perioperative management of PTX in SHPT patients, based on a comprehensive understanding of patient health needs, emphasis should be placed on comprehensive diagnosis and treatment. This includes anticipating and addressing potential preoperative and postoperative issues, enhancing observation and management of complications such as preoperative psychological intervention, management of preoperative comorbidities, postoperative bleeding, hypocalcemia, and other surgical complications, as well as preventing issues such as heparin-free dialysis, venous thrombosis, and fistula dysfunction. Timely assessment and dynamic adjustment of diagnostic and therapeutic measures are essential throughout the process.
Implementing personalized psychological interventions
During the long-term hemodialysis process of ESRD, anxiety and depression are the most serious psychological issues. This is particularly pronounced among elderly patients, exacerbating disease progression and increasing the risk of complications such as cardiovascular diseases and fractures. Our study indicates that rural patients, besides facing inherent psychological issues associated with the disease, also contend with greater economic burdens, feelings of guilt due to lost work capacity, and inadequate disease awareness compared to urban patients. These factors contribute to delayed treatment, resulting in more severe conditions during PTX and posing greater challenges for perioperative management (14).
Therefore, implementing targeted psychological intervention strategies can reduce anxiety and depression in SHPT patients undergoing PTX, enhance patient compliance, effectively lower the incidence of complications, improve clinical outcomes, and enhance overall quality of life.
Limitations
Certainly, this study has limitations, as it only conducted a retrospective analysis of a subset of PTX postoperative patients from The First Affiliated Hospital of Zhejiang University School of Medicine, with a relatively small sample size. Therefore, future research should focus on multicenter, large-sample longitudinal studies to comprehensively evaluate factors influencing major adverse events in SHPT patients, establish assessment models for surgical intervention timing, and guide clinical diagnosis and treatment.
Conclusions
Residence, age, and duration of uremia are independent risk factors for cardiovascular and fracture events in SHPT patients. ESRD patients should have better surveillance especially for rural, elder and poor phosphorus control patients. Outpatient nephrology services for ESRD should prioritize populations at high risk of adverse events such as SHPT-related cardiovascular and fracture incidents, promptly assessing surgical intervention measures, and providing necessary management of complications and psychological interventions.
Acknowledgments
This manuscript was polished by AME Collaborative Group. We are grateful to the patients and their families who contributed to this study. We also thank Dr. Zhenhua Tu, Dr. Fuqiang Li, and Dr. Pingbo Jin for editing the manuscript.
Funding: This work was supported by
Footnote
Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://gs.amegroups.com/article/view/10.21037/gs-24-391/rc
Data Sharing Statement: Available at https://gs.amegroups.com/article/view/10.21037/gs-24-391/dss
Peer Review File: Available at https://gs.amegroups.com/article/view/10.21037/gs-24-391/prf
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://gs.amegroups.com/article/view/10.21037/gs-24-391/coif). All authors report that this work was supported by China Association for Promotion of Health Science and Technology Research Project (No. JKHY-Z2023001-08) and Zhejiang Provincial Department of Education Research Project (No. Y202250769). The authors have no other conflicts of interest to declare.
Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by Ethics Committee of The First Affiliated Hospital, Zhejiang University School of Medicine (No. 20230601) and individual consent for this retrospective analysis was waived.
Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.
References
- Dream S, Kuo LE, Kuo JH, et al. The American Association of Endocrine Surgeons Guidelines for the Definitive Surgical Management of Secondary and Tertiary Renal Hyperparathyroidism. Ann Surg 2022;276:e141-76. [Crossref] [PubMed]
- Xu Y, Evans M, Soro M, et al. Secondary hyperparathyroidism and adverse health outcomes in adults with chronic kidney disease. Clin Kidney J 2021;14:2213-20. [Crossref] [PubMed]
- Inaguma D, Tatematsu Y, Okamoto N, et al. Multicentre, open-label, randomised, controlled trial to compare early intervention with calcimimetics and conventional therapy in preventing coronary artery calcification in patients with secondary hyperparathyroidism (UPCOMING): a study protocol. BMJ Open 2024;14:e076962. [Crossref] [PubMed]
- Rodzoń-Norwicz M, Norwicz S, Sowa-Kućma M, et al. Secondary hyperparathyroidism in chronic kidney disease: pathomechanism and current treatment possibilities. Endokrynol Pol 2023;74:490-8. [Crossref] [PubMed]
- Zhu X, Li Z, Xia X, et al. Predictors of hyperkalemia after total parathyroidectomy in patients with drug-refractory secondary hyperparathyroidism. Gland Surg 2022;11:702-9. [Crossref] [PubMed]
- Stack BC Jr. Hypercalcemia from primary hyperparathyroidism. Gland Surg 2024;13:274-6. [Crossref] [PubMed]
- Pang Y, Meng X. Surgical treatment of secondary hyperparathyroidism combined with Sagliker syndrome caused by chronic renal failure: a case report. Gland Surg 2022;11:1568-73. [Crossref] [PubMed]
- Rocha LAD, Neves MCD, Montenegro FLM. Parathyroidectomy in chronic kidney disease. J Bras Nefrol 2021;43:669-73. [Crossref] [PubMed]
- Song Z, Wu C, Wang R, et al. The Effects of Parathyroidectomy vs Medical Treatments for Secondary Hyperparathyroidism in Patients Undergoing Dialysis: A Meta-Analysis. Endocr Pract 2024;30:569-76. [Crossref] [PubMed]
- de Barbieri I, Baumann J, Casal MC, et al. An Over View of Nurses’ Management of Secondary Hyperparathyroidism: How is Europe Doing? J Ren Care 2015;41:202-10. [Crossref] [PubMed]
Dialysis Outcomes and Practice Patterns Study Practice Monitor - Dudar I, Shifris I, Dudar S, et al. Current therapeutic options for the treatment of secondary hyperparathyroidism in end-stage renal disease patients treated with hemodialysis: a 12-month comparative study. Pol Merkur Lekarski 2022;50:294-8.
- Konopnicki A, Cuellar S, Navid S, et al. Fragility Fractures Unveil the Hidden Dragon: A Case of Osteitis Fibrosa Cystica and Secondary Hyperparathyroidism in End-Stage Renal Disease Post-Trauma. Cureus 2024;16:e58208. [Crossref] [PubMed]
- Crepeau P, Fedorova T, Morris-Wiseman LF, et al. Secondary Hyperparathyroidism and Cognitive Decline. Curr Transplant Rep 2023;10:60-8. [Crossref] [PubMed]
(English Language Editor: J. Jones)
