CLB-09216; No. of pages: 6; 4C: Clinical Biochemistry xxx (2016) xxx–xxx
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Intra-operative parathyroid hormone monitoring through central laboratory is accurate in renal secondary hyperparathyroidism☆ Carlo Vulpio a,⁎, Maurizio Bossola a, Enrico Di Stasio b, Gilda Pepe a, Eda Nure a, Sabina Magalini a, Salvatore Agnes a a b
Division of General Surgery and Organ Transplantation, Catholic University of the Sacred Heart, Roma, Italy Institute of Biochemistry, Catholic University of the Sacred Heart, Roma, Italy
a r t i c l e
i n f o
Article history: Received 16 October 2015 Received in revised form 8 January 2016 Accepted 12 January 2016 Available online xxxx Keywords: Renal secondary hyperparathyroidism Intra-operative parathyroid hormone Parathyroidectomy Parathyroid glands Hemodialysis
a b s t r a c t Objective: The usefulness, the methods and the criteria of intra-operative monitoring of the parathyroid hormone (ioPTH) during parathyroidectomy (PTX) for renal secondary hyperparathyroidism (rSHPT) in patients on chronic hemodialysis remain still matter of debate. The present study aimed to evaluate the ability of a low cost central-laboratory second generation PTH assay to predict an incomplete resection of parathyroid glands (PTG). Methods: The ioPTH decay was determined In 42 consecutive patients undergoing PTX (15 subtotal and 27 total without auto-transplant of PTG) for rSHPT. The ioPTH monitoring included five samples: pre-intubation, post-manipulation of PTG and at 10, 20 and 30 min post-PTG excision. The patients with PTH exceeding the normal value (65 pg/ml) at the first postoperative week, 6 and 12 months were classified as persistent rSHPT. Results: The concentrations of ioPTH declined significantly over time in patients who received total or subtotal PTX; however, no difference was found between the two types of PTX. Irrespective of the type of PTX and the number of PTG removed, combining the absolute and percentage of ioPTH decay at 30 min after PTG excision, we found high sensitivity (100%), specificity (92%), negative predictive value (100%) and accuracy (93%) in predicting the persistence of rSHPT. Conclusions: The monitoring of the ioPTH decline by a low cost central-laboratory second generation assay is extremely accurate in predicting the persistence of disease in patients on maintenance hemodialysis undergoing surgery for rSHPT. © 2016 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.
1. Introduction The monitoring of intra-operative parathyroid hormone (ioPTH) has become a well recognized predictor of surgical success in primary hyperparathyroidism in which the diagnosis of uni- or multi-glandular disease is the crucial point for the choice of uni- or bilateral surgical access to the neck [1–3]. In this regard, the Miami criterion of a decrease of ioPTH to N50% of baseline within 10 min after excision has shown to be very accurate (93–98%) [4,5]. Conversely, in renal secondary hyperparathyroidism (rSHPT), in which the bilateral exploration of neck is always needed, the usefulness of ioPTH is less obvious. Abbreviations: rSHPT, renal secondary hyperparathyroidism; ioPTH, intra-operative parathyroid hormone; iPTH, intact PTH; wPTH, whole PTH; PTX, parathyroidectomy; PTG, parathyroid glands; TPTX, total PTX; SPTX, subtotal PTX. ☆ All authors designed and conducted the study and prepared and approved the manuscript. ⁎ Corresponding author at: Division of General Surgery and Organ Transplantation, Catholic University of the Sacred Heart, Largo A. Gemelli, 8, Roma 00168, Italy. E-mail address: [email protected] (C. Vulpio).
The criteria to define the early and late success of surgery in primary hyperparathyroidism are clear: serum calcium and PTH in the normal range. In rSHPT the choice of the type of surgery as well as a standard definition of surgical success have not been standardized [6–11] because the normal range of PTH among the patients with normal kidney function is not applicable to patients on chronic hemodialysis in which values of PTH within the 150–250 pg/ml range may still be acceptable [12]. Indeed, the metabolism of the intact (1–84) PTH and its fragments is delayed in rSHPT because of the impaired renal function [13–18], the kinetics of the elimination of the PTH and its fragments in relation to surgical procedures and to PTH assay used [i.e. second generation or intact PTH (iPTH) and third generation or whole PTH (wPTH)]. These issues have not been adequately elucidated and especially it still remains to be defined which criterion of ioPTH decline performs best in predicting postoperative outcome of rSHPT [19–30]. Furthermore, the intraoperative estimation of the quantity of parathyroid tissue to be removed and the decision to perform subtotal or total parathyroidectomy (PTX) with or without immediate or delayed auto-transplantation is still arduous [27–31].
http://dx.doi.org/10.1016/j.clinbiochem.2016.01.012 0009-9120/© 2016 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.
Please cite this article as: C. Vulpio, et al., Intra-operative parathyroid hormone monitoring through central laboratory is accurate in renal secondary hyperparathyroidism, Clin Biochem (2016), http://dx.doi.org/10.1016/j.clinbiochem.2016.01.012
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C. Vulpio et al. / Clinical Biochemistry xxx (2016) xxx–xxx
The present study aimed to evaluate the ability of a low cost centrallaboratory second generation PTH assay to predict an acceptable surgical outcome or an incomplete resection of parathyroid glands (PTG) in patients who underwent total or subtotal PTX for rSHPT. The diagnostic accuracy of several values of the absolute concentrations and percentage of ioPTH decay was assessed in relation to: (a) the time after excision; (b) the type of PTX and (c) the number of PTG removed. 2. Patients and methods 2.1. Patients and surgical strategy All patients who underwent parathyroidectomy for rSHPT with ioPTH monitoring at the Division of Transplantation and Hemodialysis of our University from 2007 to 2014 were included in this study. The study was approved by the local ethics committee, and written informed consent was obtained from all patients before the surgery. The surgical indication was based on K/DOQI guidelines (patients with PTH level N 800 pg/ml with hypercalcemia and/or hyperphosphoremia, refractory to medical treatment prolonged at least for 6–12 months and including paricalcitol, phosphate binders, cinacalcet; patients with calciphylaxis) [12] and on the PTG size. The ultrasonography of the neck and 99mTc-sestamibi scanning were routinely performed prior to the surgery [32]. Subtotal parathyroidectomy (SPTX) was preferred in young patients or in candidates for kidney transplantation, whereas total parathyroidectomy (TPTX) without auto transplant was performed in older patients not candidate for transplantation. A bilateral transcervical thymectomy was systematically performed in all patients. Neck dissection, opening of the retro-pharyngeal and retroesophageal space, and the carotid sheath, was not systematically performed in all patients. The surgery was deemed to be concluded if the percentage of ioPTH was b 20% at 20 and /or 30 min. Instead, the search of the remaining PTG proceeded if fewer than 4 PTG were detected or if the percentage of ioPTH remained N20% of basal value at 20 and 30 min after PTG excision (i.e. a decline b80%). Anyhow, extension to mediastinal exploration was not undertaken in primary surgery, but early postoperative localization measures were preferably undertaken to guide a planned re-intervention. Finally, a bilateral neck exploration was performed in all cases of recurrent rSHPT and the PTG detected by 99Tc-sestamibi scintigraphy and computed tomography were removed.
The early surgical outcome and the definitive cure of patients were respectively assessed on the basis of PTH concentrations within the first postoperative week (t1stw), after 6 months and at the end of 1 year follow-up. The surgical outcome was classified as follows: when the PTH value exceeds 65 pg/ml on first postoperative week and at 6 and 12 months, we considered that the patient had persistent SHPT; when PTH decreased to a value under 65 pg/ml on first postoperative week and then increased after sixth months, recurrent rSHPT was present [8,9,33,34]. 2.3. Statistical analysis Data were analyzed by MedCalc Software (Belgium Version 12.5 for Microsoft Windows). Continuous variables were first tested for normality and equality of variances using the Kolmogorov–Smirnov test. Continuous variables were expressed as mean ± standard deviation (SD) and categorical and interval variables as frequencies or median and interquartile range (IQR). The appropriate parametric or non-parametric tests were used when comparing groups [t test, analysis of variance (ANOVA), Friedman's test, Mann–Whitney and chi-square test). Receiver operating characteristic (ROC) analysis and Area Under Curve (AUC) with 95% confidential interval [95%CI] were used in order to determine the ioPTH cut-off value corresponding to 100% sensitivity with the higher specificity. Once identified the values of absolute and relative ioPTH cut-off by ROC curve analysis, the sensitivity, specificity, positive (PPV) and negative predictive value (NPV) and accuracy of test were calculated using the following definitions: TN (True Negative) = true decline: a sufficient decline of ioPTH and a t1stw lower or within the normal range; FN (False Negative) = false decline: a sufficient decline of ioPTH and a high t1stw; TP (True Positive) = true failure to decline: an insufficient decline of ioPTH and a high t1stw; FP (False Positive) = false failure to decline: an insufficient decline of ioPTH and a normal t1stw. Moreover, we also evaluated the accuracy of the simultaneous achievement of the absolute and percentage decline of ioPTH: the test was defined TP (true positive for persistence of rSHPT) if both criteria were inadequate (i.e. true failure to decline: both the concentration and the percentage of remaining ioPTH more than the cut-off identified by ROC curve analysis). P b 0.05 was considered statistically significant. 3. Results
2.2. Blood sampling, i.o. PTH monitoring and surgical outcome 3.1. Surgical procedures, PTG removed and persistence of rSHPT The blood samples, drawn from the saphenous vein at the level of malleolus, were collected: before tracheal intubation (t0), after all PTG have been identified (post-manipulation), but before any tissue has been excised (t1). Further samples were collected after the removal of the last PTG every 10 min over a maximal period of 30 min. The ioPTH monitoring was expressed as absolute concentrations (t10–30) and as remaining percentage (%t10–30) of pre-excision values using the highest of the two pre-excision values (t0 or t1). For intra-operative measurements, the samples were promptly analyzed in the central laboratory located in the same floor of the operating room. The serum PTH concentrations were determined using a second generation intact-PTH electrochemiluminescence immunoassay (Roche Intact PTH) assay running on a Roche Modular E 170 analyzer. The uses a biotinylated monoclonal antibody, which reacts with amino acids 26–32, and a capture ruthenium-complexed monoclonal antibody, which reacts with amino acids 55–64. Normal PTH values range from 15 to 65 pg/ml and the intra-assay CV was 2.9% and the inter-assay CV was 5.8% at concentrations of 35.0 and 180.0 ng/l, respectively. These systems are routinely used in our institution and the turnaround time (TAT) was 25 min including 18 for the assay.
We studied 42 patients (12 females, 30 males) who underwent surgery for rSHPT (37) or its recurrence (5). The mean age (mean ± SD) of patients was 53.9 ± 14.8 years and the mean dialysis duration was 4.7 ± 2.5 years. In all patients the diuresis was null. In the 37 patients who underwent for the first time PTX, 15 subtototal and 22 total PTX without auto-transplant of PTG were performed. In patients with recurrent rSHPT, we removed a hyperplastic remnant of an orthotopic PTG in 1 patient, an ectopic retroesophageal PTG in 2 patients and 3 or 6 multifocal nests of hyperplastic parathyroid tissue infiltrating the sternocleidomastoid muscle in the remaining two. These surgical procedures were considered as total PTX. Mortality was null. A temporary recurrent nerve palsy, was observed in one patient. In the 37 patients who underwent parathyroidectomy for the first time, we detected 3 PTG in 7 patients (19%), 4 PTG in 26 (70%) and more than 4 PTG in 4 (11%) [6 PTG in 2, 5 PTG in 2]. Fifteen (9%) out of 159 PTG removed were ectopic (7 intra-thymic, 3 retro-jugular, 3 retro-esophageal, 1 intra-thyroidal and 1 in the carotid sheath). Table 1 shows the pre- and post-operative metabolic parameters in patients who underwent total and subtotal PTX.
Please cite this article as: C. Vulpio, et al., Intra-operative parathyroid hormone monitoring through central laboratory is accurate in renal secondary hyperparathyroidism, Clin Biochem (2016), http://dx.doi.org/10.1016/j.clinbiochem.2016.01.012
C. Vulpio et al. / Clinical Biochemistry xxx (2016) xxx–xxx Table 1 Pre- and post-operative clinical and metabolic parameters in patients who underwent total (TPTX) or subtotal parathyroidectomy (SPTX).(Ca = calcium, Pi = phosphates, AlP = alkaline phosphatases, Mg = magnesium), Pre- and post-operative metabolic parameters in total or subtotal parathyroidectomy TPTX n = 27
SPTX n = 15
Mean ± SD
Mean ± SD
p value
Pre-operative Age (years) Dialysis vintage (years) Ca pre (mg/dl) Pi pre (mg/dl) AlP pre (UI/l) Mg pre (mg/dl)
58.1 ± 15.7 4.9 ± 2.6 10.7 ± 1.5 5.3 ± 2.2 669 ± 399 2.6 ± 0.8
48.2 ± 12.2 4.7 ± 2.7 10.2 ± 1.4 5.8 ± 2.6 543 ± 258 2.4 ± 0.3
0.041 0.891 0.296 0.512 0.290 0.120
Postoperative Ca post Pi post AlP post Mg post
8.2 ± 1.7 4.5 ± 2.1 313 ± 61 2.4 ± 0.6
8.1 ± 1.4 4.1 ± 0.4 328 ± 121 2.3 ± 0.3
0.849 0.486 0.573 0.560
3
3.2. Accuracy of ioPTH monitoring The mean ± SD concentrations of ioPTH pre-intubation (t0) and post surgical manipulation (t1) were similar (t0 = 1236 ± 497; t1 = 1250 ± 548, p = 0.825) and significantly correlated (Coefficient R2 = 0.87,p b 0.001). The t0 and t1 ioPTH were not correlated with total weight and number of PTG detected. After total and subtotal PTX, a statistically significant difference of absolute and percentage decline of ioPTH concentrations was observed over the time. However, no difference was found between the two types of PTX (Fig. 1A, B). The number and the total weight of the PTG removed were not significantly correlated with the absolute and percentage decline of ioPTH. Table 2 shows the absolute and the percentage of ioPTH concentrations remaining at 20 and 30 min after surgery. They were significantly higher in patients with persistence of rSHPT rather than in those without persistence of rSHPT (Fig. 1C, D).
3.3. Criteria of i.o.PTH monitoring Overall, 7 out 42 patients showed persistence of rSHPT (5 out of 37 patients who underwent for the first time PTX and 2 out 5 patients who underwent surgery for recurrent rSHPT). After one year followup no recurrence of rSHPT was observed.
Table 3 shows the sensitivity, specificity, and accuracy of several criteria of absolute and percentage of remaining ioPTH predictive of persistence of rSHPT.
Fig. 1. Panels A and B show the absolute [median and IQR concentrations (pg/ml)] and percentage of ioPTH at 10, 20 and 30 min after excision of PTG in patients who underwent total PTX and subtotal PTX, respectively.Panels C and D show the same parameters in patients with (blacks triangles) and without (white circles) persistence of rSHPT. The concentrations and percentage of ioPTH at 20 and 30 min are significantly different (test of Mann–Whitney p b 0.01).
Please cite this article as: C. Vulpio, et al., Intra-operative parathyroid hormone monitoring through central laboratory is accurate in renal secondary hyperparathyroidism, Clin Biochem (2016), http://dx.doi.org/10.1016/j.clinbiochem.2016.01.012
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C. Vulpio et al. / Clinical Biochemistry xxx (2016) xxx–xxx
Table 2 Concentrations (pg/ml) and percentage of remaining ioPTH at 10, 20 and 30 min after PTG excision, in patients with and without persistence of rSHPT. The ioPTH concentrations and the percentage of remaining ioPTH at 20 and 30 min after surgery were significantly higher in patients with persistence of rSHPT. * Mann–Whitney t-test; † Friedman test. Absolute and percentage of ioPTH decay in patients without and with persistence of rSHPT p value†
Without persistence n = 35
10 min 20 min 30 min % 10 min % 20 min % 30 min
Median (IQR)
Median (IQR)
273 (215–497) 168 (122–210) 129 (88–158) 13 (27–38) 13 (10–18) 11 (8–13)
448 (236–1172) 339 (219–344) 293 (200–328) 27 (20–29) 19 (15–27) 19 (14–23)
0.001
0.001
The sensitivity of the classic Miami criterion (i.e. test positive for persistence of rSHPT if ioPTH remaining at 10 min N 50%) was very low (29%). According to the criterion of Barczyński M. et al. (i.e. test positive for persistence of rSHPT if ioPTH remaining N20% at 20 or 30 min), the test was negative in 35 patients and positive in the remaining seven. In these 7 patients, surgical exploration was extended opening of the retro-pharyngeal and retro-esophageal space, and the carotid sheath. In six patients the surgical exploration was negative while in one patient a fifth supernumerary PTG was detected in the retro-esophageal space. Among the six patients with negative surgical exploration, four showed a normal post operative iPTH (false positive) and three a persistence of rSHPT (true positive). Only one out 35 patients with negative test presented persistence of rSHPT (1 false negative). Therefore, overall, on the bases of this criterion, we observed 31 true negative, 4 false negative, 3 true positive and 4 false positive (Table 3). Then, we calculated the Area Under the ROC Curve (AUC) of the absolute and percentage of remaining ioPTH concentrations predictive of persistence of rSHPT corresponding to the 100% sensitivity combined to the best specificity (Fig. 2A, B). Twenty minutes after surgery, a concentration N 169 pg/ml and a percentage of remaining ioPTH N 14% predict the persistence of rSHPT with 100% sensitivity and 51% and 60% of specificity. Thirty minutes after surgery, a concentration N 166 pg/ml and a percentage of remaining ioPTH N12% were the best predictive cut off with 100% sensitivity and 77% specificity. Finally, the two criteria (concentration and percentage of remaining ioPTH at 30 min) were simultaneously considered and the test was Table 3 Criteria of ioPTH monitoring predictive of persistence of rSHPT (Test positive = predictive for persistence of rSHPT) based on the absolute concentrations or percentage of ioPTH remaining at 10, 20 and 30 min after excision. The table show the “Miami Criterion” (1) [≥50% decay from highest pre-excision value 10 min after excision], the Barczyński et al. criterion (2) [≥80% decay at 20 min after excision) and the criteria adopted in the present study (i.e. the cut-off of concentration and a percentage of ioPTH, identified by ROC curves analysis, corresponding to 100% sensitivity with higher specificity). TN (true negative), FN (false negative), TP (true positive), FP( false positive), PPV (positive predictive value), NPV (negative predictive value). SENS (sensitivity); SPEC (specificity); ACC (accuracy). Predictive criteria for persistence of rSHPT TN
FN
TP
FP
SENS
SPEC
PPV
NPV
ACC
31 31
5 4
2 3
4 4
29 57
86 89
33 50
86 89
79 83
Criteria of present study Single criterion 20 min N169 pg/ml 18 30 min N166 pg/ml 27 % 20 min N14 21 % 30 min N12 25
0 0 0 0
7 7 7 7
17 8 14 10
100 100 100 100
51 77 60 71
28 47 50 41
100 100 100 100
60 81 67 76
Classic criteria % 10 min N50% (1) % 20 min N20% (2)
With persistence n = 7
Double criterion (test positive = both absolute and percentage criteria fulfilled) 20 min 30 0 7 5 100 86 58 100 30 min 32 0 7 3 100 92 70 100
88 93
p value†
0.001
0.001
p value*
0.188 0.004 0.001 0.253 0.009 0.001
defined true positive for persistence of rSHPT if both criteria were fulfilled. As result of double criterion a sensitivity, specificity and accuracy of 100%, 92%, 93% were observed.(Fig. 3).
4. Discussion The present study shows that, using a central-laboratory second generation ioPTH assay, the combined concentrations ≥166 pg/ml and percentage N 12% of ioPTH remaining at 30 min after PTG excision is extremely accurate to predict the persistence of rSHPT (sensitivity 100%, specificity 71%, negative predictive value 100% and accuracy 76%). Moreover, when both criteria of absolute and percentage decline of ioPTH concentrations at 30 min are met, the sensitivity, specificity, negative predictive value and accuracy are even higher (100%, 92%, 100% and 93% respectively). Our findings suggest that, during PTX for rSHPT, the ioPTH monitoring trough a low cost central-laboratory PTH assay is useful and accurate to define whether PTX is complete, irrespective of the number of glands removed and the types of PTX performed. However more delayed and stricter criteria are required for success. In addition, PTH measurements made at 10 min by a central-laboratory analysis are not predictive and thus they should be avoided, whereas if the criteria at 30 min above-mentioned are obtained at 20 min, the further measurement at 30 min could be avoided. Actually, no consensus exists on the optimal ioPTH assay, the timing of acquisition of the baseline and subsequent levels following excision of PTG, and the thresholds for procedure termination. With regard to the target of surgery, most of the authors believe that the surgical cure is usually established on the basis of the early postoperative PTH, which should be within the normal values [8,19,29], whereas few other authors [11,20,30] consider acceptable PTH values less than 4 times the normal range or below the upper limit (b 250 pg/ml) of PTH suggested by K-DOQI guidelines [12]. Therefore, it is difficult to compare the different criteria of ioPTH decline used to predict the surgical outcome and no consensus yet exist in the literature. [9,15,18–26,34–36]. In addition, other potentially confounding factors are the kinetic and the half-life of the ioPTH in the cases of rSHPT and conflicting results have been reported [1,13–16,29]. It has been suggested that the reduced clearance of the cross-reacting PTH fragments leads to overestimation of the PTH levels using the iPTH assay (cross-reacting with PTH fragments) [37] whereas the wPTH assay (cross-reacting only with 1–84 PTH molecules) provides more accurate data to conduct the surgery [38]. Indeed, some authors [15,16] showed that the wPTH decreased more rapidly than iPTH after parathyroidectomy and that the half-life of wPTH is identical both primary and renal secondary hyperparathyroidism. Therefore, they suggested using the same predictive criterion (50% reduction of wPTH at 10 min). In truth, ioPTH monitoring in rSHPT with the intact and whole PTH assays identified surgical failure with the same frequency [16]. Recently, Freriks et al. [20] also showed that the results obtained by the use of the
Please cite this article as: C. Vulpio, et al., Intra-operative parathyroid hormone monitoring through central laboratory is accurate in renal secondary hyperparathyroidism, Clin Biochem (2016), http://dx.doi.org/10.1016/j.clinbiochem.2016.01.012
C. Vulpio et al. / Clinical Biochemistry xxx (2016) xxx–xxx
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Fig. 2. ROC curve analysis of absolute (A) and percentage (B) of ioPTH decline at 10, 20, 30 min predictive of persistence of rSHPT: a statistically significant difference was found between 20 and 30 min.
iPTH assay and the wPTH assay were comparable and that there is no need to switch to the more expensive wPTH assay. Indeed, also the results of present study are very similar to those of Barczyńskis et al. who, using a quick determinations of intact PTH within the surgical suite, reported an accuracy of 96% for ioPTH b 60% at 10 min and of 100% for ioPTH b80% at 20 min. With respect to a quick test used by Barczyńskis et al., our test required more time of assay
Fig. 3. Scatter diagram with regression line (Coefficient R2 = 0.6, p b 0001) of concentrations (pg/ml) and percentage of ioPTH remaining at 30 min after PTG excision in the patients with (black triangle) and without (white circle) persistence of rSHPT. The additional horizontal and vertical reference lines show the cut-off identified by ROC curve analysis of the absolute (166 pg/ml) and percentage (12%) of the ioPTH remaining at 30 min after excision.
(18′ with respect to 5–10′ of the quick test), but it is accurate as well at 30 min. In addition, the test used in present study is significantly cheaper [39,40]. In effect, the costs of a single measurement of PTH in our institution are respectively 6 euro for a conventional analysis in central laboratory and 30 euro for the direct measurement in the operating room. To the latter cost, the daily of a lab technician dedicated to operating room must be added. The sum of such costs should outweigh those arising from the prolonged acquisition time of central-laboratory PTH assay. Therefore, the ioPTH monitoring trough a central laboratory makes it usable also in settings where surgery of rSHPT is not common. The present study leads to two others interesting findings and considerations useful in the clinical practice. Firstly, in agreement with other authors [21,28], we have shown that there were not significantly differences of the ioPTH decay after total or subtotal PTX. This finding confirms that it is hard to determine which is the real immediate function of a gland's remnant in SPTX or TPTX with auto-transplantation and that ioPTH monitoring is not able to choose the type of PTX and do not help to select patients for immediate or delayed parathyroid auto-transplantation [41]. Secondly, the prevalence of persistent rSHPT did not differ significantly between patients with 4 or 3 PTG removed. In fact, it is well know that 84% of individuals in the healthy population show 4 PTG, 3% less than 4 and 13% more than 4. Moreover, supernumerary PTG may be present up to 30% of patients on maintenance hemodialysis [42–44]. Therefore, the detection of 4 PTG as well as of 3 PTG during neck exploration is unable to predict the success of the surgery, whereas, at this regard, the ioPTH monitoring may be helpful. In conclusion the present study demonstrates that, combining the absolute and percentage of ioPTH decline at 20 or 30 min after PTG excision, the monitoring of the ioPTH decay by a low cost central-laboratory ioPTH assay is extremely accurate in predicting the persistence of disease in patients on maintenance hemodialysis undergoing surgery for rSHPT.
Please cite this article as: C. Vulpio, et al., Intra-operative parathyroid hormone monitoring through central laboratory is accurate in renal secondary hyperparathyroidism, Clin Biochem (2016), http://dx.doi.org/10.1016/j.clinbiochem.2016.01.012
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C. Vulpio et al. / Clinical Biochemistry xxx (2016) xxx–xxx
Declaration of interest and funding All authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported and that this research did not receive any grant from any funding agency in the public, commercial or not-for-profit sector.
[22]
[23]
[24]
Author contribution The authors Carlo Vulpio and Enrico Di Stasio equally contributed to the present paper
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Please cite this article as: C. Vulpio, et al., Intra-operative parathyroid hormone monitoring through central laboratory is accurate in renal secondary hyperparathyroidism, Clin Biochem (2016), http://dx.doi.org/10.1016/j.clinbiochem.2016.01.012
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Intra-operative parathyroid hormone monitoring through central laboratory is accurate in renal secondary hyperparathyroidism☆ Carlo Vulpio a,⁎, Maurizio Bossola a, Enrico Di Stasio b, Gilda Pepe a, Eda Nure a, Sabina Magalini a, Salvatore Agnes a a b
Division of General Surgery and Organ Transplantation, Catholic University of the Sacred Heart, Roma, Italy Institute of Biochemistry, Catholic University of the Sacred Heart, Roma, Italy
a r t i c l e
i n f o
Article history: Received 16 October 2015 Received in revised form 8 January 2016 Accepted 12 January 2016 Available online xxxx Keywords: Renal secondary hyperparathyroidism Intra-operative parathyroid hormone Parathyroidectomy Parathyroid glands Hemodialysis
a b s t r a c t Objective: The usefulness, the methods and the criteria of intra-operative monitoring of the parathyroid hormone (ioPTH) during parathyroidectomy (PTX) for renal secondary hyperparathyroidism (rSHPT) in patients on chronic hemodialysis remain still matter of debate. The present study aimed to evaluate the ability of a low cost central-laboratory second generation PTH assay to predict an incomplete resection of parathyroid glands (PTG). Methods: The ioPTH decay was determined In 42 consecutive patients undergoing PTX (15 subtotal and 27 total without auto-transplant of PTG) for rSHPT. The ioPTH monitoring included five samples: pre-intubation, post-manipulation of PTG and at 10, 20 and 30 min post-PTG excision. The patients with PTH exceeding the normal value (65 pg/ml) at the first postoperative week, 6 and 12 months were classified as persistent rSHPT. Results: The concentrations of ioPTH declined significantly over time in patients who received total or subtotal PTX; however, no difference was found between the two types of PTX. Irrespective of the type of PTX and the number of PTG removed, combining the absolute and percentage of ioPTH decay at 30 min after PTG excision, we found high sensitivity (100%), specificity (92%), negative predictive value (100%) and accuracy (93%) in predicting the persistence of rSHPT. Conclusions: The monitoring of the ioPTH decline by a low cost central-laboratory second generation assay is extremely accurate in predicting the persistence of disease in patients on maintenance hemodialysis undergoing surgery for rSHPT. © 2016 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.
1. Introduction The monitoring of intra-operative parathyroid hormone (ioPTH) has become a well recognized predictor of surgical success in primary hyperparathyroidism in which the diagnosis of uni- or multi-glandular disease is the crucial point for the choice of uni- or bilateral surgical access to the neck [1–3]. In this regard, the Miami criterion of a decrease of ioPTH to N50% of baseline within 10 min after excision has shown to be very accurate (93–98%) [4,5]. Conversely, in renal secondary hyperparathyroidism (rSHPT), in which the bilateral exploration of neck is always needed, the usefulness of ioPTH is less obvious. Abbreviations: rSHPT, renal secondary hyperparathyroidism; ioPTH, intra-operative parathyroid hormone; iPTH, intact PTH; wPTH, whole PTH; PTX, parathyroidectomy; PTG, parathyroid glands; TPTX, total PTX; SPTX, subtotal PTX. ☆ All authors designed and conducted the study and prepared and approved the manuscript. ⁎ Corresponding author at: Division of General Surgery and Organ Transplantation, Catholic University of the Sacred Heart, Largo A. Gemelli, 8, Roma 00168, Italy. E-mail address: [email protected] (C. Vulpio).
The criteria to define the early and late success of surgery in primary hyperparathyroidism are clear: serum calcium and PTH in the normal range. In rSHPT the choice of the type of surgery as well as a standard definition of surgical success have not been standardized [6–11] because the normal range of PTH among the patients with normal kidney function is not applicable to patients on chronic hemodialysis in which values of PTH within the 150–250 pg/ml range may still be acceptable [12]. Indeed, the metabolism of the intact (1–84) PTH and its fragments is delayed in rSHPT because of the impaired renal function [13–18], the kinetics of the elimination of the PTH and its fragments in relation to surgical procedures and to PTH assay used [i.e. second generation or intact PTH (iPTH) and third generation or whole PTH (wPTH)]. These issues have not been adequately elucidated and especially it still remains to be defined which criterion of ioPTH decline performs best in predicting postoperative outcome of rSHPT [19–30]. Furthermore, the intraoperative estimation of the quantity of parathyroid tissue to be removed and the decision to perform subtotal or total parathyroidectomy (PTX) with or without immediate or delayed auto-transplantation is still arduous [27–31].
http://dx.doi.org/10.1016/j.clinbiochem.2016.01.012 0009-9120/© 2016 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.
Please cite this article as: C. Vulpio, et al., Intra-operative parathyroid hormone monitoring through central laboratory is accurate in renal secondary hyperparathyroidism, Clin Biochem (2016), http://dx.doi.org/10.1016/j.clinbiochem.2016.01.012
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C. Vulpio et al. / Clinical Biochemistry xxx (2016) xxx–xxx
The present study aimed to evaluate the ability of a low cost centrallaboratory second generation PTH assay to predict an acceptable surgical outcome or an incomplete resection of parathyroid glands (PTG) in patients who underwent total or subtotal PTX for rSHPT. The diagnostic accuracy of several values of the absolute concentrations and percentage of ioPTH decay was assessed in relation to: (a) the time after excision; (b) the type of PTX and (c) the number of PTG removed. 2. Patients and methods 2.1. Patients and surgical strategy All patients who underwent parathyroidectomy for rSHPT with ioPTH monitoring at the Division of Transplantation and Hemodialysis of our University from 2007 to 2014 were included in this study. The study was approved by the local ethics committee, and written informed consent was obtained from all patients before the surgery. The surgical indication was based on K/DOQI guidelines (patients with PTH level N 800 pg/ml with hypercalcemia and/or hyperphosphoremia, refractory to medical treatment prolonged at least for 6–12 months and including paricalcitol, phosphate binders, cinacalcet; patients with calciphylaxis) [12] and on the PTG size. The ultrasonography of the neck and 99mTc-sestamibi scanning were routinely performed prior to the surgery [32]. Subtotal parathyroidectomy (SPTX) was preferred in young patients or in candidates for kidney transplantation, whereas total parathyroidectomy (TPTX) without auto transplant was performed in older patients not candidate for transplantation. A bilateral transcervical thymectomy was systematically performed in all patients. Neck dissection, opening of the retro-pharyngeal and retroesophageal space, and the carotid sheath, was not systematically performed in all patients. The surgery was deemed to be concluded if the percentage of ioPTH was b 20% at 20 and /or 30 min. Instead, the search of the remaining PTG proceeded if fewer than 4 PTG were detected or if the percentage of ioPTH remained N20% of basal value at 20 and 30 min after PTG excision (i.e. a decline b80%). Anyhow, extension to mediastinal exploration was not undertaken in primary surgery, but early postoperative localization measures were preferably undertaken to guide a planned re-intervention. Finally, a bilateral neck exploration was performed in all cases of recurrent rSHPT and the PTG detected by 99Tc-sestamibi scintigraphy and computed tomography were removed.
The early surgical outcome and the definitive cure of patients were respectively assessed on the basis of PTH concentrations within the first postoperative week (t1stw), after 6 months and at the end of 1 year follow-up. The surgical outcome was classified as follows: when the PTH value exceeds 65 pg/ml on first postoperative week and at 6 and 12 months, we considered that the patient had persistent SHPT; when PTH decreased to a value under 65 pg/ml on first postoperative week and then increased after sixth months, recurrent rSHPT was present [8,9,33,34]. 2.3. Statistical analysis Data were analyzed by MedCalc Software (Belgium Version 12.5 for Microsoft Windows). Continuous variables were first tested for normality and equality of variances using the Kolmogorov–Smirnov test. Continuous variables were expressed as mean ± standard deviation (SD) and categorical and interval variables as frequencies or median and interquartile range (IQR). The appropriate parametric or non-parametric tests were used when comparing groups [t test, analysis of variance (ANOVA), Friedman's test, Mann–Whitney and chi-square test). Receiver operating characteristic (ROC) analysis and Area Under Curve (AUC) with 95% confidential interval [95%CI] were used in order to determine the ioPTH cut-off value corresponding to 100% sensitivity with the higher specificity. Once identified the values of absolute and relative ioPTH cut-off by ROC curve analysis, the sensitivity, specificity, positive (PPV) and negative predictive value (NPV) and accuracy of test were calculated using the following definitions: TN (True Negative) = true decline: a sufficient decline of ioPTH and a t1stw lower or within the normal range; FN (False Negative) = false decline: a sufficient decline of ioPTH and a high t1stw; TP (True Positive) = true failure to decline: an insufficient decline of ioPTH and a high t1stw; FP (False Positive) = false failure to decline: an insufficient decline of ioPTH and a normal t1stw. Moreover, we also evaluated the accuracy of the simultaneous achievement of the absolute and percentage decline of ioPTH: the test was defined TP (true positive for persistence of rSHPT) if both criteria were inadequate (i.e. true failure to decline: both the concentration and the percentage of remaining ioPTH more than the cut-off identified by ROC curve analysis). P b 0.05 was considered statistically significant. 3. Results
2.2. Blood sampling, i.o. PTH monitoring and surgical outcome 3.1. Surgical procedures, PTG removed and persistence of rSHPT The blood samples, drawn from the saphenous vein at the level of malleolus, were collected: before tracheal intubation (t0), after all PTG have been identified (post-manipulation), but before any tissue has been excised (t1). Further samples were collected after the removal of the last PTG every 10 min over a maximal period of 30 min. The ioPTH monitoring was expressed as absolute concentrations (t10–30) and as remaining percentage (%t10–30) of pre-excision values using the highest of the two pre-excision values (t0 or t1). For intra-operative measurements, the samples were promptly analyzed in the central laboratory located in the same floor of the operating room. The serum PTH concentrations were determined using a second generation intact-PTH electrochemiluminescence immunoassay (Roche Intact PTH) assay running on a Roche Modular E 170 analyzer. The uses a biotinylated monoclonal antibody, which reacts with amino acids 26–32, and a capture ruthenium-complexed monoclonal antibody, which reacts with amino acids 55–64. Normal PTH values range from 15 to 65 pg/ml and the intra-assay CV was 2.9% and the inter-assay CV was 5.8% at concentrations of 35.0 and 180.0 ng/l, respectively. These systems are routinely used in our institution and the turnaround time (TAT) was 25 min including 18 for the assay.
We studied 42 patients (12 females, 30 males) who underwent surgery for rSHPT (37) or its recurrence (5). The mean age (mean ± SD) of patients was 53.9 ± 14.8 years and the mean dialysis duration was 4.7 ± 2.5 years. In all patients the diuresis was null. In the 37 patients who underwent for the first time PTX, 15 subtototal and 22 total PTX without auto-transplant of PTG were performed. In patients with recurrent rSHPT, we removed a hyperplastic remnant of an orthotopic PTG in 1 patient, an ectopic retroesophageal PTG in 2 patients and 3 or 6 multifocal nests of hyperplastic parathyroid tissue infiltrating the sternocleidomastoid muscle in the remaining two. These surgical procedures were considered as total PTX. Mortality was null. A temporary recurrent nerve palsy, was observed in one patient. In the 37 patients who underwent parathyroidectomy for the first time, we detected 3 PTG in 7 patients (19%), 4 PTG in 26 (70%) and more than 4 PTG in 4 (11%) [6 PTG in 2, 5 PTG in 2]. Fifteen (9%) out of 159 PTG removed were ectopic (7 intra-thymic, 3 retro-jugular, 3 retro-esophageal, 1 intra-thyroidal and 1 in the carotid sheath). Table 1 shows the pre- and post-operative metabolic parameters in patients who underwent total and subtotal PTX.
Please cite this article as: C. Vulpio, et al., Intra-operative parathyroid hormone monitoring through central laboratory is accurate in renal secondary hyperparathyroidism, Clin Biochem (2016), http://dx.doi.org/10.1016/j.clinbiochem.2016.01.012
C. Vulpio et al. / Clinical Biochemistry xxx (2016) xxx–xxx Table 1 Pre- and post-operative clinical and metabolic parameters in patients who underwent total (TPTX) or subtotal parathyroidectomy (SPTX).(Ca = calcium, Pi = phosphates, AlP = alkaline phosphatases, Mg = magnesium), Pre- and post-operative metabolic parameters in total or subtotal parathyroidectomy TPTX n = 27
SPTX n = 15
Mean ± SD
Mean ± SD
p value
Pre-operative Age (years) Dialysis vintage (years) Ca pre (mg/dl) Pi pre (mg/dl) AlP pre (UI/l) Mg pre (mg/dl)
58.1 ± 15.7 4.9 ± 2.6 10.7 ± 1.5 5.3 ± 2.2 669 ± 399 2.6 ± 0.8
48.2 ± 12.2 4.7 ± 2.7 10.2 ± 1.4 5.8 ± 2.6 543 ± 258 2.4 ± 0.3
0.041 0.891 0.296 0.512 0.290 0.120
Postoperative Ca post Pi post AlP post Mg post
8.2 ± 1.7 4.5 ± 2.1 313 ± 61 2.4 ± 0.6
8.1 ± 1.4 4.1 ± 0.4 328 ± 121 2.3 ± 0.3
0.849 0.486 0.573 0.560
3
3.2. Accuracy of ioPTH monitoring The mean ± SD concentrations of ioPTH pre-intubation (t0) and post surgical manipulation (t1) were similar (t0 = 1236 ± 497; t1 = 1250 ± 548, p = 0.825) and significantly correlated (Coefficient R2 = 0.87,p b 0.001). The t0 and t1 ioPTH were not correlated with total weight and number of PTG detected. After total and subtotal PTX, a statistically significant difference of absolute and percentage decline of ioPTH concentrations was observed over the time. However, no difference was found between the two types of PTX (Fig. 1A, B). The number and the total weight of the PTG removed were not significantly correlated with the absolute and percentage decline of ioPTH. Table 2 shows the absolute and the percentage of ioPTH concentrations remaining at 20 and 30 min after surgery. They were significantly higher in patients with persistence of rSHPT rather than in those without persistence of rSHPT (Fig. 1C, D).
3.3. Criteria of i.o.PTH monitoring Overall, 7 out 42 patients showed persistence of rSHPT (5 out of 37 patients who underwent for the first time PTX and 2 out 5 patients who underwent surgery for recurrent rSHPT). After one year followup no recurrence of rSHPT was observed.
Table 3 shows the sensitivity, specificity, and accuracy of several criteria of absolute and percentage of remaining ioPTH predictive of persistence of rSHPT.
Fig. 1. Panels A and B show the absolute [median and IQR concentrations (pg/ml)] and percentage of ioPTH at 10, 20 and 30 min after excision of PTG in patients who underwent total PTX and subtotal PTX, respectively.Panels C and D show the same parameters in patients with (blacks triangles) and without (white circles) persistence of rSHPT. The concentrations and percentage of ioPTH at 20 and 30 min are significantly different (test of Mann–Whitney p b 0.01).
Please cite this article as: C. Vulpio, et al., Intra-operative parathyroid hormone monitoring through central laboratory is accurate in renal secondary hyperparathyroidism, Clin Biochem (2016), http://dx.doi.org/10.1016/j.clinbiochem.2016.01.012
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Table 2 Concentrations (pg/ml) and percentage of remaining ioPTH at 10, 20 and 30 min after PTG excision, in patients with and without persistence of rSHPT. The ioPTH concentrations and the percentage of remaining ioPTH at 20 and 30 min after surgery were significantly higher in patients with persistence of rSHPT. * Mann–Whitney t-test; † Friedman test. Absolute and percentage of ioPTH decay in patients without and with persistence of rSHPT p value†
Without persistence n = 35
10 min 20 min 30 min % 10 min % 20 min % 30 min
Median (IQR)
Median (IQR)
273 (215–497) 168 (122–210) 129 (88–158) 13 (27–38) 13 (10–18) 11 (8–13)
448 (236–1172) 339 (219–344) 293 (200–328) 27 (20–29) 19 (15–27) 19 (14–23)
0.001
0.001
The sensitivity of the classic Miami criterion (i.e. test positive for persistence of rSHPT if ioPTH remaining at 10 min N 50%) was very low (29%). According to the criterion of Barczyński M. et al. (i.e. test positive for persistence of rSHPT if ioPTH remaining N20% at 20 or 30 min), the test was negative in 35 patients and positive in the remaining seven. In these 7 patients, surgical exploration was extended opening of the retro-pharyngeal and retro-esophageal space, and the carotid sheath. In six patients the surgical exploration was negative while in one patient a fifth supernumerary PTG was detected in the retro-esophageal space. Among the six patients with negative surgical exploration, four showed a normal post operative iPTH (false positive) and three a persistence of rSHPT (true positive). Only one out 35 patients with negative test presented persistence of rSHPT (1 false negative). Therefore, overall, on the bases of this criterion, we observed 31 true negative, 4 false negative, 3 true positive and 4 false positive (Table 3). Then, we calculated the Area Under the ROC Curve (AUC) of the absolute and percentage of remaining ioPTH concentrations predictive of persistence of rSHPT corresponding to the 100% sensitivity combined to the best specificity (Fig. 2A, B). Twenty minutes after surgery, a concentration N 169 pg/ml and a percentage of remaining ioPTH N 14% predict the persistence of rSHPT with 100% sensitivity and 51% and 60% of specificity. Thirty minutes after surgery, a concentration N 166 pg/ml and a percentage of remaining ioPTH N12% were the best predictive cut off with 100% sensitivity and 77% specificity. Finally, the two criteria (concentration and percentage of remaining ioPTH at 30 min) were simultaneously considered and the test was Table 3 Criteria of ioPTH monitoring predictive of persistence of rSHPT (Test positive = predictive for persistence of rSHPT) based on the absolute concentrations or percentage of ioPTH remaining at 10, 20 and 30 min after excision. The table show the “Miami Criterion” (1) [≥50% decay from highest pre-excision value 10 min after excision], the Barczyński et al. criterion (2) [≥80% decay at 20 min after excision) and the criteria adopted in the present study (i.e. the cut-off of concentration and a percentage of ioPTH, identified by ROC curves analysis, corresponding to 100% sensitivity with higher specificity). TN (true negative), FN (false negative), TP (true positive), FP( false positive), PPV (positive predictive value), NPV (negative predictive value). SENS (sensitivity); SPEC (specificity); ACC (accuracy). Predictive criteria for persistence of rSHPT TN
FN
TP
FP
SENS
SPEC
PPV
NPV
ACC
31 31
5 4
2 3
4 4
29 57
86 89
33 50
86 89
79 83
Criteria of present study Single criterion 20 min N169 pg/ml 18 30 min N166 pg/ml 27 % 20 min N14 21 % 30 min N12 25
0 0 0 0
7 7 7 7
17 8 14 10
100 100 100 100
51 77 60 71
28 47 50 41
100 100 100 100
60 81 67 76
Classic criteria % 10 min N50% (1) % 20 min N20% (2)
With persistence n = 7
Double criterion (test positive = both absolute and percentage criteria fulfilled) 20 min 30 0 7 5 100 86 58 100 30 min 32 0 7 3 100 92 70 100
88 93
p value†
0.001
0.001
p value*
0.188 0.004 0.001 0.253 0.009 0.001
defined true positive for persistence of rSHPT if both criteria were fulfilled. As result of double criterion a sensitivity, specificity and accuracy of 100%, 92%, 93% were observed.(Fig. 3).
4. Discussion The present study shows that, using a central-laboratory second generation ioPTH assay, the combined concentrations ≥166 pg/ml and percentage N 12% of ioPTH remaining at 30 min after PTG excision is extremely accurate to predict the persistence of rSHPT (sensitivity 100%, specificity 71%, negative predictive value 100% and accuracy 76%). Moreover, when both criteria of absolute and percentage decline of ioPTH concentrations at 30 min are met, the sensitivity, specificity, negative predictive value and accuracy are even higher (100%, 92%, 100% and 93% respectively). Our findings suggest that, during PTX for rSHPT, the ioPTH monitoring trough a low cost central-laboratory PTH assay is useful and accurate to define whether PTX is complete, irrespective of the number of glands removed and the types of PTX performed. However more delayed and stricter criteria are required for success. In addition, PTH measurements made at 10 min by a central-laboratory analysis are not predictive and thus they should be avoided, whereas if the criteria at 30 min above-mentioned are obtained at 20 min, the further measurement at 30 min could be avoided. Actually, no consensus exists on the optimal ioPTH assay, the timing of acquisition of the baseline and subsequent levels following excision of PTG, and the thresholds for procedure termination. With regard to the target of surgery, most of the authors believe that the surgical cure is usually established on the basis of the early postoperative PTH, which should be within the normal values [8,19,29], whereas few other authors [11,20,30] consider acceptable PTH values less than 4 times the normal range or below the upper limit (b 250 pg/ml) of PTH suggested by K-DOQI guidelines [12]. Therefore, it is difficult to compare the different criteria of ioPTH decline used to predict the surgical outcome and no consensus yet exist in the literature. [9,15,18–26,34–36]. In addition, other potentially confounding factors are the kinetic and the half-life of the ioPTH in the cases of rSHPT and conflicting results have been reported [1,13–16,29]. It has been suggested that the reduced clearance of the cross-reacting PTH fragments leads to overestimation of the PTH levels using the iPTH assay (cross-reacting with PTH fragments) [37] whereas the wPTH assay (cross-reacting only with 1–84 PTH molecules) provides more accurate data to conduct the surgery [38]. Indeed, some authors [15,16] showed that the wPTH decreased more rapidly than iPTH after parathyroidectomy and that the half-life of wPTH is identical both primary and renal secondary hyperparathyroidism. Therefore, they suggested using the same predictive criterion (50% reduction of wPTH at 10 min). In truth, ioPTH monitoring in rSHPT with the intact and whole PTH assays identified surgical failure with the same frequency [16]. Recently, Freriks et al. [20] also showed that the results obtained by the use of the
Please cite this article as: C. Vulpio, et al., Intra-operative parathyroid hormone monitoring through central laboratory is accurate in renal secondary hyperparathyroidism, Clin Biochem (2016), http://dx.doi.org/10.1016/j.clinbiochem.2016.01.012
C. Vulpio et al. / Clinical Biochemistry xxx (2016) xxx–xxx
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Fig. 2. ROC curve analysis of absolute (A) and percentage (B) of ioPTH decline at 10, 20, 30 min predictive of persistence of rSHPT: a statistically significant difference was found between 20 and 30 min.
iPTH assay and the wPTH assay were comparable and that there is no need to switch to the more expensive wPTH assay. Indeed, also the results of present study are very similar to those of Barczyńskis et al. who, using a quick determinations of intact PTH within the surgical suite, reported an accuracy of 96% for ioPTH b 60% at 10 min and of 100% for ioPTH b80% at 20 min. With respect to a quick test used by Barczyńskis et al., our test required more time of assay
Fig. 3. Scatter diagram with regression line (Coefficient R2 = 0.6, p b 0001) of concentrations (pg/ml) and percentage of ioPTH remaining at 30 min after PTG excision in the patients with (black triangle) and without (white circle) persistence of rSHPT. The additional horizontal and vertical reference lines show the cut-off identified by ROC curve analysis of the absolute (166 pg/ml) and percentage (12%) of the ioPTH remaining at 30 min after excision.
(18′ with respect to 5–10′ of the quick test), but it is accurate as well at 30 min. In addition, the test used in present study is significantly cheaper [39,40]. In effect, the costs of a single measurement of PTH in our institution are respectively 6 euro for a conventional analysis in central laboratory and 30 euro for the direct measurement in the operating room. To the latter cost, the daily of a lab technician dedicated to operating room must be added. The sum of such costs should outweigh those arising from the prolonged acquisition time of central-laboratory PTH assay. Therefore, the ioPTH monitoring trough a central laboratory makes it usable also in settings where surgery of rSHPT is not common. The present study leads to two others interesting findings and considerations useful in the clinical practice. Firstly, in agreement with other authors [21,28], we have shown that there were not significantly differences of the ioPTH decay after total or subtotal PTX. This finding confirms that it is hard to determine which is the real immediate function of a gland's remnant in SPTX or TPTX with auto-transplantation and that ioPTH monitoring is not able to choose the type of PTX and do not help to select patients for immediate or delayed parathyroid auto-transplantation [41]. Secondly, the prevalence of persistent rSHPT did not differ significantly between patients with 4 or 3 PTG removed. In fact, it is well know that 84% of individuals in the healthy population show 4 PTG, 3% less than 4 and 13% more than 4. Moreover, supernumerary PTG may be present up to 30% of patients on maintenance hemodialysis [42–44]. Therefore, the detection of 4 PTG as well as of 3 PTG during neck exploration is unable to predict the success of the surgery, whereas, at this regard, the ioPTH monitoring may be helpful. In conclusion the present study demonstrates that, combining the absolute and percentage of ioPTH decline at 20 or 30 min after PTG excision, the monitoring of the ioPTH decay by a low cost central-laboratory ioPTH assay is extremely accurate in predicting the persistence of disease in patients on maintenance hemodialysis undergoing surgery for rSHPT.
Please cite this article as: C. Vulpio, et al., Intra-operative parathyroid hormone monitoring through central laboratory is accurate in renal secondary hyperparathyroidism, Clin Biochem (2016), http://dx.doi.org/10.1016/j.clinbiochem.2016.01.012
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C. Vulpio et al. / Clinical Biochemistry xxx (2016) xxx–xxx
Declaration of interest and funding All authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported and that this research did not receive any grant from any funding agency in the public, commercial or not-for-profit sector.
[22]
[23]
[24]
Author contribution The authors Carlo Vulpio and Enrico Di Stasio equally contributed to the present paper
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