Diagnostic value of contrast-enhanced ultrasound in judging the survival of graft after heteroautoplasty for secondary hyperparathyroidism

Abstract

BACKGROUND:

OBJECTIVE:

To investigate the value and advantages of contrast-enhanced ultrasound (CEUS) in evaluating the survival of autografts after parathyroidectomy $+$ parathyroid autotransplantation.

METHODS:

In this study, 125 patients with renal failure due to polycystic kidney disease, chronic nephritis, diabetic nephropathy, lupus nephritis, and atherosclerotic nephropathy were enrolled as the participants and each of them had 4 secondary hyperactive parathyroid glands and underwent parathyroid autotransplantation. One parathyroid gland was taken from each patient and equally divided into 4 parts and placed in the subcutaneous fat of one forearm for transplantation. CEUS was performed 14 days after the transplantation to observe the micro blood supply of the graft and assess the survival and secretory function of the transplanted parathyroid. The grafts were divided into the partial survival group and the total survival group based on the enhancement characteristics. The survival of the grafts was determined by comparing the parathyroid hormone level in bilateral elbow cephalic veins 1 month after surgery.

RESULTS:

Among the 125 patients, 112 had linear or punctate enhancement of 2–4 parathyroid glands 14 days after surgery, and 13 patients had linear or punctate enhancement of 0–1 parathyroid gland. There were statistically significant differences in the perfusion pattern, enhancement uniformity, and parathyroid hormone levels in the cephalic veins at the elbow on both the graft and non-graft sides among all groups ( $P<$ 0.05).

CONCLUSION:

Compared to the detection of the difference in the parathyroid hormone level in the cephalic vein of bilateral elbows 1 month after surgery, CEUS can reflect the parathyroid survival after transplantation more quickly and accurately 2 weeks later, and provide a more rapid and agile non-invasive clinical diagnosis method.

Keywords

Contrast-enhanced ultrasound (CEUS)parathyroid autotransplantation secondary hyperparathyroidism survival

1. Introduction

Secondary hyperparathyroidism (SHPT) is one of the common complications of end-stage renal disease-uremia, and is mainly manifested as parathyroid hyperplasia and abnormal secretion of parathyroid hormone (PTH), thereby causing calcium and phosphorus metabolism disorders, bone lesions, calcification of blood vessels and soft tissues, and other progressive aggravation. Severe SHPT can cause pathological fracture, depression and anxiety, cardiovascular and cerebrovascular abnormalities, and other multi-system diseases, significantly affecting the quality of life of patients [1, 2]. The current medical treatment of SHPT mainly includes phosphorus binders (e.g., Sevelamer, colestilan), colestilanactive vitamin D preparations (e.g., calcitriol, paliacalcitol) and calcium sensitive receptor agonists (e.g., Cinacalcet and Evocalcet). But surgery remains the most effective treatment option for patients with refractory or progressive SHPT that shows no response to internal medicinal treatment. Total parathyroidectomy often leads to permanent hypoparathyroidism, eventually leading to chronic renal impairment, reduced bone remodeling, basal ganglia calcification, and other multiple system impairments. Total parathyroidectomy with autotransplantation (tPTX $+$ AT), a surgical method commonly used by Chinese doctors, is a safe and mature surgical method that can significantly reduce the level of immunoreactive parathyroid hormone (iPTH) in uremic dialysis blood, correct high phosphorate levels, improve hyperparathyroidism, and maintain normal levels of serum calcium and phosphorus, thus significantly relieving symptoms such as skin pruritus, muscle weakness, and bone pain, and improving the quality of life of patients. tPTX $+$ AT has been widely popularized and applied, with reliable short-term and long-term efficacy in treating hyperparathyroidism secondary to uremia [3, 4, 5]. The survival and secretory function of the parathyroid gland after autologous transplantation are the final clinical indexes of surgical success. With the development of high frequency ultrasound and new ultrasound technology, such as contrast ultrasound also known as contrast enhanced ultrasound. Ultrasound contrast agents (UCA) were used to obtain contrast-enhanced images with strong backscattering in sound field. This technique provides better vascular spatial resolution. The main components of ultrasound contrast agent (UCA) are tiny bubbles of sulfur hexafluoride (SF6) that consist of microbubbles of heavy gas stabilized with a lipid, protein or lipoprotein shell. These agents vary in their gas content and shell structure. The bubbles are about the size of a red blood cell (1.5–2.5 $\mu$ m) but large enough to prevent their extravasation to the interstitium after intravenous (IV) injection. Thus, they are purely intravascular, do not have any interstitial phase and are not absorbed by somatic cells. They do not produce toxic side effects to the human body, do not increase the liver and kidney damage, and can easily pass through the smallest capillaries in the human body, inert gas bubbles, without any damage to the human body. They finally metabolize through the lung by breathing (almost all discharged after 15 minutes). A small amount of bubble shell is removed by the liver and gallbladder system. Therefore, contrast-enhanced ultrasound (CEUS) can be used to evaluate and detect blood perfusion in tissues, organs, or lesions in a safe, real-time, dynamic, and quantitative manner. It is especially advantageous in recognizing and displaying low-flow small vessels [6, 7]. Therefore, it is of significant diagnostic value in evaluating the survival of parathyroid glands after transplantation.

2. Participants and methods

2.1 Participants

A total of 125 SHPT patients were enrolled and transferred from the Department of Nephrology to the Department of General Surgery of our hospital for total parathyoidectomy with autoteans-plantation from 2015 to 2022. The patients were aged 24–70 years, with an average age of 50 years. They were all dialysis patients, including hemodialysis, peritoneal dialysis, with a dialysis length of dialysis of 5–20 years, averaging (13 $\pm$ 5) years. Each patient had a continuously increased parathyroid hormone level, with all of the 4 parathyroid tissues hyperplastic. The diagnosis was made by CT examination and color Doppler ultrasound before operation. Postoperative pathology confirmed that all 4 parathyroid glands were hyperplastic.

This study was approved by the Ethics Committee of The 983th Hospital of Joint Logistic Support Force of PLA (no. 2022-YK-030-01) and conducted in accordance with the Declaration of Helsinki. Written informed consent was obtained from all participants.

2.2 Equipment and methods

2.2.1 tPTX $+$ AT

After successful anesthesia, hyperplastic parathyroid glands were found on the dorsal side of the thyroid gland bilaterally and excised completely along the capsule. Intraoperative rapid cryopathological examination confirmed that the patient had 4 parathyroid hyperplasia, and some of the soft parathyroid glands were divided from 4 granular tissues (about 1 mm * 1 mm * 1 mm). In order to prevent the central ischemic necrosis of the transplanted tissue and to increase the expression of vascular endothelial growth factor, it is conducive to the formation of neovascularization so as to play the role of the transplanted tissue. A four-point incision was then made on the skin of the forearm on the non-arteriovenous fistula side of the dialysis patient, with a length of about 0.5 cm and the distance between the dots of about 4 cm to form a square. The transplantation position is about 5 cm below the elbow joint of the forearm (Fig. 1) and the graft was located between the skin and the fat layer. The whole layer was sutured with non-absorbent sutures to increase the convenience in looking for signs of parathyroid re-resection after postoperative recurrence, followed by pressure bandaging with elastic bandage [8].

Figure 1.

The site of the parathyroid transplant.

2.2.2 Contrast-enhanced ultrasound (CEUS)

The four transplanted parathyroid remnant tissue were set as 4 points, respectively: the proximal radial end as point a, the distal radial end as point b, the proximal ulnar end as point c, and the distal ulnar end as point d. CEUS was performed 14 days after surgery. Philips EPIQ 7 color ultrasonic diagnostic system was used for detection (probe type L12-5, frequency 7.5 MHz, mechanical index 0.07). Fixed ultrasound examiner is a senior title, with more than 10 years of experience in CEUS. The contrast agent was SonoVue (Bracco, Italy). After transplantation, the parathyroid gland was examined by 2D ultrasound and recorded for the location, morphology, boundary, and internal echo (Fig. 2). The color Doppler ultrasound was used to observe the blood supply of the remnant graft (Fig. 3). The best display section was selected and the probe position was fixed to start the CEUS mode. The microvascular enhancement of each graft was observed successively (Fig. 4). It is filled with sulfur hexafluoride gas and phosphine fat composition, which is white lyophilized powder. Before use, it was diluted with 5 ml normal saline and shaken for 20 s, and became a milky sulfur hexafluoride microbubble suspension with an average diameter of 2.5 $\mu$ m and a density of (2 $\sim$ 5) 10⁸ cells/ml. After reconstructing the ultrasound agent, 2.5 ml of the implanted median cubital vein was injected quickly. After the injection, another 5 to 10 mL of normal saline irrigation was injected. While injecting contrast agent the timer button of the device was pressed to observe the blood perfusion of the tissue in real-time continuously. The dynamic storage button was pressed throughout the scanning process to record all dynamic images [9, 10, 11]. The duration of CEUS was about 3 to 6 min, and then the cyclic playback analysis was performed. During this process, the patient was instructed to avoid swallowing, coughing, and speaking, and to keep quiet and breathe evenly and slowly [11]. All patients were divided into the minority survival group and the majority survival group based on the number of survived grafts observed by CEUS, namely, the majority survival group: linear or punctate enhancement of 2–4 parathyroid tissues after transplantation and the minority survival group: linear or punctate enhancement of 0–1 parathyroid tissue after transplantation.

Figure 2.

Two-dimensional ultrasound imaging showed the parathyroid glands after transplantation.

Figure 3.

CDFI (Color Doppler Flow Imaging) shows the parathyroid glands after transplantation.

Figure 4.

A. During contrast-enhanced ultrasound observation, the developer presented spot-like and linear enhanced graft images (as indicated by the white arrow). B. Two-dimensional ultrasound image of graft. Note: CEUS images of parathyroid tissue after subcutaneous transplantation in the forearm (CEUS image on the left and the conventional ultrasound image on the right), which were performed synchronously and in real time for observation.

2.2.3 Comparison of serum parathyroid hormone concentration in brachiocephalic veins

Serum PTH levels in the bilateral antecubital cephalic vein 4 weeks after surgery in 125 patients were compared and recorded. Before blood drawing, patients fasted for 8–12 h, blood samples were collected in the morning, EDTA anticoagulation, centrifuge, 2000 r/min, centrifuge for 10 min, and were given a unified place in the refrigerator. Roche cobas e411 automatic electrochemiluminescence immunoanalyzer was used. If the difference in the serum hormone levels between the graft and non-graft sides was more than 1.5 times by biochemical test, it was considered a functional graft [12]. Therefore, the inter-group parathyroid hormone levels in the graft and non-graft cephalic veins were detected. The patients were divided into two groups, namely, the positive group (secretion group) – the difference in the serum parathyroid hormone levels between the bilateral cubital cephalic veins was greater than 1.5 times; and the negative group (non-secretion group) – the difference in the serum parathyroid hormone levels between the bilateral cubital cephalic veins was less than 1.5 times.

2.3 Statistical processing

SPSS version 26.0 statistical software was used for statistical processing. The measurement data are expressed as $x\pm s$ , and an independent sample $t$ -test or one-way analysis of variance was used for inter-group comparison. The enumeration data are expressed as frequency or rate, and $\chi^{2}$ test or Fisher exact test was used for inter-group comparison. $P<$ 0.05 indicated that the difference was statistically significant.

3. Results

After 14 days, The developer presented spot-like and fine-line parathyroid grafts. There were 112 patients in the majority survival group and 13 patients in the minority survival group.

In the majority survival groups, the serum hormone levels in the biochemical tests performed 1 month after surgery showed positive results in 110 cases and negative in 2 cases.

In the minority survival groups, the serum hormone levels in the biochemical tests performed 1 month after surgery showed positive results in 4 cases and negative in 9 cases.

The results revealed that CEUS can display the condition of neovascularization 14 days after transplantation, and indicated a statistically significant difference from the serum parathyroid hormone levels in the bilateral cubital cephalic veins 4 weeks later ( $P<$ 0.05), as shown in Table 1. The sensitivity and specificity of CEUS in determining the survival rate after parathyroid transplantation were 90.6% and 70%, respectively.

Table 1
The formation of new microvessels after 14 days was compared with the secretion of parathyroid hormone after 4 weeks

		Negative (no secretion)	Positive (secretion)	Total
		Secretion results
New microvascular	Majority survival	2	110	112
	Minority survival	9	4	13
Total		11	114	125

4. Discussion

End-stage renal disease-uremia often leads to secondary hyper-parathyroidism, which often requires surgical removal of the parathyroid gland along with ectopic transplantation. Parathyroid autotransplantation also plays an important role in reducing the incidence of permanent hypoparathyroidism after surgery. Parathyroid autotransplantation can be performed in many locations, including sternocleidomastoid, brachioradialis, pectoralis major, and forearm subcutaneous tissue. In the U.S., the parathyroid gland is usually transplanted into the sternocleidomastoid or sternohyoid muscle. Its advantage is that the transplantation site can be exposed simultaneously with the operation, without increasing the surgical incision and operation time. It is highly vascularized, and it is easy to form a pocket to hold the sliced parathyroid tissue during the operation. Its disadvantage is that the function and vitality of the graft cannot be measured and controlled, and there is a lack of detection methods to confirm its survival. We chose to transplant the excised parathyroid tissue into the subcutaneous area of the forearm and the adipose layer, which has the advantages of abundant subcutaneous vessels of the forearm, easy survival of the graft and high success rate of transplantation, and local anesthesia can be used for surgery. For hyperparathyroidism recurring after transplantation, a second surgical resection is required for recurrent graft operation, which is relatively simple and brings less surgical risk and pain to patients [13]. Traditionally, to judge the survival of the graft, the gradient difference of serum parathyroid hormone levels between the transplanted arm and the non-transplanted arm was measured 4 weeks after surgery, which was used as evidence to judge the success of the graft [14, 15, 16]. CEUS is an innovative detection method that can detect graft survival quickly, conveniently, repeatably and noninvasively. Previous scholars have found that the graft showed linear or spot-like enhancement when CEUS was performed 15–21 days after tPTX $+$ AT, indicating the presence of blood supply in the graft, which can be used as a marker of graft survival [9]. However, the time concept of this study is unclear and vague, the sample size is small, and the credibility of the conclusion is general. The main purpose of this study is to further evaluate the value of CEUS in determining the early survival rate after parathyroid transplantation, and to provide more accurate information for clinicians.

In this study, the gradient difference of parathyroid hormone levels in bilateral arms at 4 weeks after surgery was used as the criterion to judge the graft survival, which verified the feasibility of CEUS in judging the graft survival at 2 weeks after surgery. The sensitivity and specificity of CEUS in determining the survival rate after parathyroid transplantation were 96.4% and 81.8%, respectively, with a high accuracy. Results showed that neovascularization was detected with CEUS at 14 days after transplantation. Thus, CEUS can be used to evaluate the survival condition of the parathyroid tissue in the sternocleidomastoid, brachioradialis, pectoralis major, and forearm subcutaneous tissue after autotransplantation. If linear or punctate enhancement is present, the graft survival can be confirmed. CEUS can fully compensate for the shortcomings of conventional ultrasound in tissue vascularization and visualization of high dynamic blood flow. It can be used for early detection of parathyroid survival after transplantation, dynamic observation of parathyroid microcirculation after transplantation, monitoring of capillary perfusion, and real-time and continuous assessment of blood circulation distribution in the graft. It can shorten the time for clinicians to judge the survival of postoperative parathyroid transplantation, so as to timely determine the next treatment plan for patients, and further avoid the risk to patients caused by deviation of postoperative calcium and phosphorus plasma level.

There are certain limitations to this experimental study, such as a univariate center, small sample size, limited detection time, poor data integrity and homogeneity, lack of guarantee of the standardization of observation method units, and consistency of observation endpoint. Moreover, it may involve some selection bias, and the influences of age, drugs, dialysis, individual differences, and other factors on the research results cannot be excluded entirely. Therefore, it is necessary to continue expanding the sample size, extend the study phase in the future, and further refine the detection methods.

5. Conclusion

Through this study we found that CEUS can be used as an optimal diagnostic method for clinical assessment of survival after parathyroid autotransplantation, as compared with the previous method to detect the parathyroid hormone level in the head venous blood 1 month after surgery. Key is that in a much earlier time, the survival of the parathyroid glands is evident at 14 days after surgery, and CEUS can be repeated in a short time, can be safely used in patients with renal failure, and can also be performed in the emergency room, ICU or bedside [11]. To provide an earlier clinical selection of preoperative transplantation location and surgical methods, excessive preservation of postoperative parathyroid tissue must be avoided, as it affects the survival of grafts requiring re-transplantation.

Competing interests

The authors declare that they have no competing interests.

Funding

No external funding was received to conduct this study.

Availability of data and materials

All data generated or analysed during this study are included in this article. Further enquiries can be directed to the corresponding author.

Footnotes

Acknowledgments

The authors would like to acknowledge the hard and dedicated work of all staff that implemented the intervention and evaluation components of the study.

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Diagnostic value of contrast-enhanced ultrasound in judging the survival of graft after heteroautoplasty for secondary hyperparathyroidism

Abstract

BACKGROUND:

OBJECTIVE:

METHODS:

RESULTS:

CONCLUSION:

Keywords

1. Introduction

2. Participants and methods

2.1 Participants

2.2 Equipment and methods

2.2.1 tPTX + AT

2.3 Statistical processing

3. Results

Table 1 The formation of new microvessels after 14 days was compared with the secretion of parathyroid hormone after 4 weeks

5. Conclusion

Competing interests

Funding

Availability of data and materials

Footnotes

Acknowledgments

References

2.2.1 tPTX $+$ AT

Table 1
The formation of new microvessels after 14 days was compared with the secretion of parathyroid hormone after 4 weeks