Total parathyroidectomy versus total parathyroidectomy with autotransplantation for secondary hyperparathyroidism: systematic review and meta-analysis

Abstract Background: Total parathyroidectomy (tPTX) and total parathyroidectomy with autotransplantation (tPTX + AT) are effective and inexpensive treatments for secondary hyperparathyroidism (sHPT), but we do not know which one is the optimal approach. Therefore, we undertook a meta-analysis to compare the safety and efficacy of these two surgical procedures. Methodology: Studies published in English on PubMed, Embase and the Cochrane Library from inception to 27 September 2016 were searched systematically. Eligible studies comparing tPTX with tPTX + AT for sHPT were included and Review Manager v5.3 was used. Results: Eleven studies were included in this meta-analysis. Ten cohort studies and one randomized controlled trial (RCT) involving 1108 patients with sHPT were identified. There was no significant difference in the prevalence of surgical complications (relative risk [RR], 1.71; 95% confidence interval [CI], 0.77–3.79; p = .19), all-cause mortality (RR, 0.68; 95% CI, 0.33–1.39; p = .29), sHPT persistence (RR, 3.81; 95% CI, 0.56–25.95; p = .17) or symptomatic improvement (RR, 1.02; 95% CI, 0.91–1.13; p = .79). tPTX could reduce the risk of sHPT recurrence (RR, 0.19; 95% CI, 0.09–0.41; p < .0001) and reoperation because of recurrence or persistence of sHPT (RR, 0.46; 95% CI 0.24–0.86; p = .01) compared with tPTX + AT. Simultaneously, tPTX increased the risk of hypoparathyroidism (RR, 2.63; 95% CI, 1.06–6.51; p = .04). Conclusions: We found tPTX and tPTX + AT to be useful methods for sHPT treatment. tPTX was superior for reducing the risk of sHPT recurrence and reoperation than tPTX + AT but, due to a lack of high statistical-power RCTs, comparative studies will be needed in the future.


Background
Chronic kidney disease (CKD) has become a worldwide public-health problem [1]. Secondary (renal) hyperparathyroidism (sHPT) is a prevalent complication of CKD [2]. Persistently elevated levels of parathyroid hormone (PTH) and parathyroid hyperplasia are features of sHPT. Hypocalcemia, hyperphosphatemia, and 1,25(OH) 2 D 3 deficiency play important roles in sHTP [3]. The only way to cure sHPT is kidney transplantation but the number of available kidneys for transplantation is limited. Hence, medical and surgical treatments are the only ways to combat sHPT.
In the early stages, patients can be treated by a lowphosphate diet, phosphate binders, vitamin-D analogs, and calcimimetic agents, whereas more advanced stages often require surgical treatment [4]. The calcimimetic agent cinacalcet can achieve identical results to those elicited by surgery. In Germany, the annual cost for cinacalcet (60 mg/day) is e5828.4, whereas the cost of surgery for one person is about e3755.38 [5]. The cost is one disadvantage of cinacalcet. Furthermore, it does not always work. Therefore, surgery is needed in the most advanced stages of sHPT and would be acceptable.
There are three surgical approaches for parathyroidectomy: subtotal parathyroidectomy (sPTX), total parathyroidectomy (tPTX) and total parathyroidectomy with autotransplantation (tPTX þ AT). sPTX is resection of 3.5 parathyroid glands, leaving 40-80 mg of the most normal-appearing parathyroid gland in situ [6]. tPTX was first described in 1967, and involves identification and resection of all parathyroid glands. tPTX þ AT comprises resection and AT. All parathyroid glands are resected, then the most normal-appearing glands are 'minced' into 10-201 mm 3 pieces for AT. The sternocleidomastoid muscle and brachioradialis muscle of the non-dominant forearm as potential sites for AT. Guidelines set by the kidney disease outcomes quality initiative (K/DOQI) [7] and most experts recommend sPTX and tPTX þ AT for sHPT, but a consensus on the best operative management is lacking. K/DOQI [7] guidelines recommend that patients with severe hyperparathyroidism (persistent serum levels of intact PTH >800 pg/mL [88.0 pmol/L]), accompanied with hypercalcemia and/or hyperphosphatemia refractory to medical therapy should receive PTX. However, guidelines set by the Japanese society for dialysis therapy (JSDT) recommend that patients with severe hyperparathyroidism (persistent serum levels of intact PTH >500 pg/mL), accompanied with hypercalcemia (serum calcium >10.0 mg/dL) and/or hyperphosphatemia (serum phosphate >6.0 mg/dL) refractory to medical therapy should receive PTX [8].
Secondary hyperparathyroidism patients usually suffer from bone pain, pruritus, fractures, sleep disorders, restless leg syndrome and 'shrinking man syndrome'. PTX can reduce the prevalence of all-cause mortality and cardiovascular mortality, and can improve the quality of life (QoL) simultaneously. Jia et al. [9] compared the two procedures up to December 2013, and new articles on this issue have been published since then. The aim of the present study was to compare tPTX with tPTX þ AT by carrying out a systematic review and meta-analysis.

Data sources and search strategy
Two experienced reviewers designed and carried out the search strategy. We searched PubMed, Embase and Cochrane databases using the following keywords: 'parathyroidectomy', 'hyperparathyroidism, secondary', 'hyperparathyroidism, renal' and 'kidney disease'. Searching was carried out from the inception of each database to 27 September 2016. In addition, references and cited articles were searched manually to identify other studies meeting the inclusion criteria.

Inclusion and exclusion criteria
Inclusion criteria were: (i) randomized controlled trials (RCTs), cohorts or case-control studies; (ii) comparison of short-term and long-term (follow-up duration 6 months) outcomes between tPTX and tPTX þ AT in sHPT; (iii) outcomes included at least one of the following endpoints: all-cause mortality, surgical complications (bleeding and/or voice hoarseness), reoperation prevalence, persistent and/or recurrent hyperparathyroidism, hypoparathyroidism; (iv) results were published in English.
Exclusion criteria were: (i) enrolled patients with primary hyperparathyroidism or tertiary hyperparathyroidism; (ii) enrolled patients underwent repeated surgical procedures; (iii) articles were letters, case reports, reviews, comments, editorials or proceedings. In particular, if one surgical team or institution published more than one article, then repetitive publication was identified. If such duplicated articles could not be distinguished, then the article published most recently or the longest article was selected.

Data extraction and quality assessment
Two reviewers working independently examined and selected all potentially eligible articles. Disagreements were resolved by discussion with a third reviewer. The following information was extracted in standardized forms: name of the first author; year of publication; location of study; study type; population characteristics (age, sex, number); surgical indications and procedures; duration of follow-up; outcomes. The Newcastle-Ottawa scale (NOS) was used to assess the quality of non-randomized studies, whereas the Cochrane assessment tool was used to assess RCTs. The NOS consists of three quality parameters: 'selection', 'comparability' and 'outcome'. 'Quality' is assessed using a star system: four in the selection domain, two in comparability and three in outcome, making a total of nine stars. A study graded with 5 stars is considered 'high quality', whereas that with <5 stars is considered 'low quality'. Two reviewers assessed the quality of each study independently and disagreements were resolved by a third reviewer.

Statistical analyses
Data were analyzed using Review Manager v5.3.0 (Cochrane Collaboration). For dichotomous scales, data are expressed as relative risk (RR) along with a 95% confidence interval (CI). If there were continuous data of outcomes, then data are presented as the mean difference (MD). We used the v 2 test and I 2 statistic to assess heterogeneity among studies. p < .1 [10] and I 2 > 50% [11] indicated heterogeneity to be significant. Data that were not significantly heterogeneous (p > .1, I 2 50%) were calculated using a fixed-effects model, whereas heterogeneous data (p < .1, I 2 > 50%) were calculated using a random-effects model. Publication bias was assessed using a funnel plot for standard error by effect size (log RR). p < .05 was considered significant.

Literature search and characteristics
A flow chart of the selection process is shown in Figure 1. Finally, eleven studies [12][13][14][15][16][17][18][19][20][21][22] were included for studies comparing tPTX with tPTX þ AT published between 1991 and 2016. A total of 275 patients were in the tPTX group and 833 patients were in the tPTX þ AT group. The baseline characteristics of these included studies and NOS assessments are listed in Tables 1  and 2, respectively. For RCTs, the Cochrane assessment is listed in Table 3.
There were eight retrospective cohort studies, two prospective cohort studies and one RCT. The follow-up period was from 4 months to 13 years. The sample size of these included studies ranged from 20 to 585. Three studies were conducted in Germany, three in China, two in UK, two in Italy, one in Argentina. Ten studies [12][13][14][15][16][17][18][19][20][21] described the indications for PTX. Only one study [22] described the etiology of sHPT. The NOS score of 10 studies was >5 stars, which were considered high quality for admission.

All-cause mortality
Data regarding to all-cause mortality were reported in four studies [14,15,19,21], nine patients in tPTX group and 19 patients in tPTX þ AT group. Prevalence of mortality in the tPTX group and tPTX þ AT group was 9.78% (9/92) and 14.84% (19/128), respectively. Although the all-cause mortality in the tPTX þ AT group was higher than that of the tPTX group, meta-analysis showed no significant difference (RR, 0.68; 95% CI, 0.33-1.39; p ¼ .29). There was no substantial heterogeneity  between the studies (p ¼ .31, I 2 ¼ 16%), so a fixedeffects model was used for the meta-analysis (Figure 3).

Persistence of sHPT
Data about persistence of the disease were reported in five articles [13,14,18,20,22]. Twelve events were noted in the tPTX group, whereas four events were observed in the tPTX þ AT group. The meta-analysis showed no significant difference (RR, 3.81; 95% CI, 0.56-25.95; p ¼ .17). The heterogeneity between the   two groups was substantial (p ¼ .06, I 2 ¼ 56%), so we accepted a random-effects model for the analysis ( Figure 5).

Publication bias
A funnel plot was used to assess publication bias. There was no evidence of publication bias because the funnel   plot of standard error by effect estimate of recurrence showed all studies lay within the limits (Figure 9).

Sensitivity analyses
A sensitivity analysis for disease persistence were used to determine the dependability of our results by accepting the leave-one-out approach. The heterogeneity of all five studies was significant (p ¼ .06, I 2 ¼ 56%), and the heterogeneity disappeared (p ¼ .70, I 2 ¼ 0) when the study by Jofr e et al. [18] was excluded. The result continued to show no significant difference. When we removed each studies back, the pooled result indicating that no study dominated the analysis.

Discussion
The relationship between sHPT and CKD has been well established [23]. sHPT is a common sequel of CKD that causes electrolyte disturbance and results in pathological fractures, cardiovascular disease and even death [24,25]. Despite recent advances in drug therapy, many patients still require surgery. The prevalence of surgery to treat sHPT with maintenance dialysis over 10-20 years is 15-38% [13]. PTX can improve the survival from sHPT as well as symptomatology and QoL [26,27]. Our systematic review was carried out by a comprehensive search for studies to appraise the safety and efficacy of two surgical approaches (tPTX and tPTX þ AT) in sHPT. Finally, 11 studies involving 1108 patients with sHPT met the inclusion criteria and were enrolled in our meta-analysis. Our findings showed that both approaches were equally effective with regard to avoidance of surgical complications (bleeding and voice hoarseness), all-cause mortality, persistence of disease and symptomatic improvement. However, there were significantly fewer episodes of recurrence and reoperation because of recurrence/persistence of disease in the tPTX group compared with the tPTX þ AT group. The tPTX group had an increased risk of hypoparathyroidism according to our meta-analysis.
The results of this meta-analysis showed no difference in the prevalence of surgical complications (bleeding and voice hoarseness) between the two groups. Both surgical procedures included removal of all parathyroid glands. After resection, tPTX þ AT required another procedure: AT. The sites used for AT were the sternocleidomastoid muscle, brachioradialis muscle and tibialis anterior muscle [20,28,29]. Most surgeons chose the brachioradialis muscle for AT because this site is simple for reoperation. The AT site chosen would not increase the prevalence of bleeding and voice hoarseness.
The aim of every treatment is to improve survival or QoL. These two approaches had an identical effect on symptomatic improvement. Almost all patients suffered from bone pain and pruritus before surgery. Some studies indicated that these symptoms were relieved or disappeared the day after surgery regardless of the surgical approach. Also, the level of PTH in serum decreased dramatically after surgery. When the PTH level was >495 pg/mL, the mortality risk was increased by 25% [30]. PTX can reduce the prevalence of mortality in renal hyperparathyroidism [31]. However, the evidence from our study does not explain which one was better.
Persistent hyperparathyroidism is a common complication of surgery. There was no difference in persistence of hyperparathyroidism in our meta-analysis. The reasons for persistence can be ectopic and supernumerary parathyroid glands. Identification of ectopic parathyroid gland is challenging because parathyroid glands are not always in the same anatomic position. Gomes et al. [32] described the most common sites to be thyroid parenchyma (33.3%), thyroid-thymus conduit (18.5%) and thymus (14.8%).The prevalence of supernumerary parathyroid glands by random autopsies was 13% [33]. Akerstrom et al. [34] reported that 3% of patients had three parathyroid glands, 84% had four parathyroid glands and 13% had supernumerary glands. Many supernumerary glands were located in thymus tissue. The prevalence of persistent hyperparathyroidism could not be improved by surgical methods alone.
Recurrent hyperparathyroidism was a serious complication after PTX. Results showed that tPTX could reduce the risk of recurrence better than tPTX þ AT. Recurrent hyperparathyroidism could not be avoided in patients undergoing maintenance dialysis with time. In 80% of patients after TPTX þ AT, disease recurrence was in the graft, and the other 20% was in the neck [35]. Zhong et al. [36] reported that tPTX þ AT is associated with sHPT recurrence. Melck et al. [37] suggested that tPTX þ AT should be abandoned as sHPT treatment because of frequent recurrence. Tominaga et al. [38] stated that graft-dependent recurrence could be controlled by removing the autograft.
The pooled result of included studies suggested that tPTX could increase the risk of hypoparathyroidism. However, adynamic bone disease or hypocalcemia were absent. This procedure was conducted by removal of all parathyroid glands. However, PTH levels could be measured in many patients after tPTX because PTH may be secreted from the thymus gland [39]. Conzo et al. [40] suggested that hypoparathyroidism could be treated by pharmacological means.

Strengths and limitations of our meta-analysis
The strengths of our meta-analysis were explicit inclusion criteria, broad search strategy and independent assessment of eligibility by two reviewers. This metaanalysis had three main limitations. First, most of the included studies had small sample-sized cohort studies, so the results of our study may not be adequate to judge the safety and efficacy of tPTX and tPTX þ AT. Second, some studies reported recurrent and persistent hyperparathyroidism, but the definitions of recurrence and persistence were not mentioned in most of them. Third, some studies described long-term serum levels of calcium, phosphate, alkaline phosphatase and PTH, but the authors presented them in different ways (histogram, line graphs), so we could not draw conclusions on changes in biochemistry.

Conclusions
Our meta-analysis suggests that tPTX and tPTX þ AT are effective surgical approaches to the treatment of sHTP. They also show the apparent benefits of tPTX on sHPT recurrence and reoperation. Hence, tPTX could be the best way to treat uncontrolled sHPT. Nevertheless, tPTX increases the risk of hypoparathyroidism compared with tPTX þ AT. Surgeons counseling patients should consider the benefits and disadvantages of tPTX versus tPTX þ AT. To guide future work in this area, large multicenter RCTs comparing the two approaches are necessary.

Disclosure statement
No potential conflict of interest was reported by the authors.