End-Stage Renal Disease Related Hyperparathyroidism
van der Plas, Willemijn
DOI:
10.33612/diss.151471102
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Publication date: 2021
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van der Plas, W. (2021). End-Stage Renal Disease Related Hyperparathyroidism: Towards a Patient-Tailored Journey. University of Groningen. https://doi.org/10.33612/diss.151471102
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parathyroidectomy to total parathyroidectomy with
immediate parathyroid autograft
– a prospective randomized trial
W. Alves Filho1 W.Y van der Plas2 M.D.G. Brescia1 C.P. Nascimento Jr1 P.T. Goldenstein3 L.M. Massoni Neto1 S.S. Arap1 M.R. Custodio3 R.O. Bueno3 R.M.A. Moyses3 V. Jorgetti3 S. Kruijff2 F.L.M. Montenegro1
1 Department of Surgery, Hospital das Clinicas HCFMUSP, University of Sao Paulo, de Sao Paulo, Sao Paulo,
Brazil
2 Department of Surgery, University of Groningen, University Medical Center Groningen, Groningen,
the Netherlands
3 Department of Internal Medicine, Hospital das Clinicas HCFMUSP, University of Sao Paulo, Sao Paulo, Brazil
Abstract
Introduction
There is no prospective randomized data about the impact of different strategies of parathyroidectomy in secondary hyperparathyroidism patients on quality of life and its possible relationship with metabolic status after the operation.
Methods
In a prospective randomized trial, the Short Form 36 Health Survey Questionnaire (SF-36) was applied to 69 patients undergoing parathyroidectomy through different approaches: subtotal parathyroidectomy (ST, n=23), PTx with autotransplantation of 45 fragments (PTx-45, n=25) and PTx with autotransplantation of 90 fragments (PTx-90, n=21) at three different moments: (1) preoperatively, (2) 6 months and (3) 12 months after surgery Results
Quality of life improved significantly in physical component summary score (PCS) in all three groups [ST: from 30.6 (1) to 51.7 (2) and 53.7 (3); PTx-45: from 33.8 (1) to 52.6 (2) and 55.2 (3); and PTx-90 31.8 (1) to 50.5 (2) and 55.2 (3); all groups p<0,0001]. There was no significant difference in PCS change between the three groups. PCS was negatively correlated to age, parathormone and alkaline phosphatase preoperatively.
Conclusions
Parathyroidectomy significantly improves quality of life in hemodialysis patients with secondary hyperparathyroidism, regardless of the type of operation.
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Introduction
Among patients with end-stage renal disease (ESRD) undergoing dialysis, a true cure is not always possible. For this reason, mental and physical wellbeing should always figure among the main purposes of care.1 Complications of ESRD, such as secondary hyperparathyroidism (sHPT), should be treated accordingly, as they might increase mortality and have a major impact on quality of life (QoL) in such patients.2 Advanced sHPT includes symptoms such as fatigue, bone and joint pain, pruritus and headache. In addition, some patients can develop spontaneous fractures, ectopic calcifications and neuromuscular and psychiatrics manifestations.3 These problems may have an impact on QoL in sHPT patients.4,5
Surgical treatment for sHPT is indicated when clinical management becomes medically refractory.6,7 Parathyroidectomy corrects serum calcium, alkaline phosphatase and parathormone (PTH) levels and improves symptoms that can affect QoL, such as bone pain.3 Three approaches are available for the surgical management of sHPT: subtotal parathyroidectomy, total parathyroidectomy (PTx) and PTx with immediate heterotopic autograft.8–13 Less than subtotal parathyroid resection is not routinely considered as a satisfactory option in sHPT. In 1991, subtotal parathyroidectomy and PTx with immediate autograft were compared in a prospectively randomized study. Although the authors concluded that PTx with an autograft was superior to subtotal parathyroidectomy, they unfortunately did not compare PTH levels, which are currently a very important parameter in the evaluation of sHPT treatment.14 QoL was also not addressed in that study.
Previous studies have documented the use of tools to measure QoL in patients with ESRD. The Short Form 36 Health Survey Questionnaire (SF-36) is a valid instrument for these individuals1 and may also be a powerful predictor of morbidity and worse outcomes in dialysis patients.15 Even though various studies have assessed QoL in primary hyperparathyroidism, few studies have measured QoL in patients with sHPT.16–20 Although these studies indicate the improvement of QoL after the operation, they often have shortcomings, such as enrolling only a few patients, performing only one type of operation, or nonrandomized series.21–26
To the best of our knowledge, no clear information has been collected from a single prospective randomized study that compares QoL before and after parathyroidectomy, according to the various surgical approaches currently accepted.
Methods
Subjects were enrolled from a current clinical research trial developed at the University of Sao Paulo Medical School, entitled “Subtotal Parathyroidectomy or Total Parathyroidectomy With Autograft in Chronic Kidney Disease Patients Under Dialysis”, a randomized clinical trial comparing various parathyroidectomy strategies registered at Clinicaltrials.gov (NCT02464072). This is a parallel group trial with a 1:1:1 allocation. This main study has three arms: subtotal parathyroidectomy, and two variants of PTx with immediate autograft in the forearm, one group with autograft of 45 fragments of parathyroid tissue, and the other group with twice the number of parathyroid fragments implanted (90 fragments). The primary end point of this study was survival after the operation. To disclose a difference of 0.3 in survival at 5 years after the operation and considering a 15% rate of patients missing follow-up, we estimated the inclusion of approximately 41 patients in each of the three arms for a statistical power of 80% and a significance level of 5%. The same group of surgeons performed the three types of surgical techniques for sHPT. These techniques were widely established as adequate for treating the condition, but there was no information available on the best approach regarding overall survival and adequate PTH levels after surgery. Randomization was generated by computer software (MS-Excel 2007, Microsoft, Redmond, WA, USA)) and the operation type was stored in a concealed opaque envelope that was opened at the induction of anesthesia.
The present study is part of this study and it has its own approval of the University of Sao Paulo Medical School’s institutional review board. The primary end point is QoL, by determining whether there is a significant difference in change of QoL among patients with sHPT undergoing subtotal parathyroidectomy or PTx with immediate autograft. For this end point no new sample estimates were calculated. In addition, we evaluated the degree of change in QoL after surgery, degree of improvement, and its possible relation to biochemical markers, before and after the procedures.
Eligible patients were those with ESRD on dialysis who had an indication for surgical treatment of sHPT, fulfilling one or more of the following criteria: (1) high PTH levels (>500 pg/mL), (2) the detection of one or more enlarged parathyroid gland (>500 mm3 or diameter greater than 1 cm), (3) hypercalcemia (>10.2 mg/dL) and/or hyperphosphatemia (>6 mg/dL). Subjects with severe symptoms, ectopic calcifications, erythropoietin resistant anemia, or dilated myocardiopathy were also referred to surgery. These patients were followed at the Renal Osteodystrophy Unit, Section of Nephrology
6
of the Department of Internal Medicine of the University of Sao Paulo Medical School. The decision for surgical referral was made solely by nephrologists. All dialysis patients with indications for parathyroidectomy were invited to participate in the study by the surgeons. Patients who agreed to participate signed the informed consent form. Subjects who did not agree to participate, those who underwent a successful kidney transplant after parathyroidectomy, or those who demonstrated immediate failure to surgical treatment of sHPT (persistence, represented by an insufficient decrease of PTH few days after the procedure) or late recurrence of sHPT (defined as PTH levels higher than 9 times the upper limit of normality after 6 months postoperatively), were excluded from the study.27
After hospital admission for surgery, patients were interviewed by the main investigator, using the SF-36 questionnaire to assess QoL preoperatively. Patients were randomly allocated to one of the three types of operation: subtotal parathyroidectomy, PTx with 45 fragments autograft, and PTx with 90 fragments autograft. PTx consists in the removal of all parathyroid glands, confirmed by frozen section histopathological analysis. We select one of the glands to be the source of the parathyroid fragments that will be immediately implanted in the forearm. Each parathyroid fragment consists in a 2 x 1 x 1 mm tissue of the macroscopically non-nodular parathyroid gland. Subtotal parathyroidectomy, on the other hand, consists in the removal of parathyroid glands, while preserving an amount of parathyroid tissue of approximately 2 times the size of a normal gland, with its vascular pedicle also preserved. The same surgical team performed all operations. It consisted of residents, staff, and attending surgeons, including the main investigator, who followed a detailed protocol. All surgeons participating in the study were personally instructed by the principal investigator and adequately trained to perform the three types of operation. Postoperative care and hospital discharge were left to the discretion of the attending physician.
QoL was investigated using the SF-36 questionnaire and applied to subjects at three time points: (1) preoperatively, (2) 6 months after surgery, and (3) 12 months after surgery. Data were collected through direct interview (during hospital admission to surgery) and by telephone (6 and 12 months postoperatively). All interviews (preoperative and postoperative) were conducted by the main investigator.
SF-36 consists of 36 objective questions to assess patients’ well-being through eight dimensions: physical functioning (PF), role-functioning physical (RP), bodily pain (BP), general health (GH), vitality (VT), social functioning (SF), role-functioning emotional
(RE), and mental health (MH). The scores varied from 0 to 100, and the higher the score, the better the QoL in terms of the dimensions studied. Two summary scores were also used: the physical component summary Score (PCS) – calculated as the mean of the PF, RP, BP, and GH scores – and the mental component summary Score (MCS) – calculated as the mean of the VT, SF, RE, and MH scores. Formulae for calculation of the SF-36 scores can be found at http://www.rand.org/health/surveys_tools/mos/36-item-short-form/scoring.html. The absolute change of PCS (∆PCS) and the absolute change of MCS (∆MCS) were calculated by subtracting the preoperative measurements from each value of PCS and MCS postoperatively, which then represented the degree of improvement on those scores.
The biochemical parameters evaluated were the serum levels of total calcium [calcium, reference range (RR): 8.6 – 10.2 mg/dL], phosphorus (P, RR: 2.7 – 4.5 mg/dL), and total alkaline phosphatase (ALP, RR: 35-130 UI/L). Intact parathyroid hormone levels (iPTH, RR: 10 – 65 pg/mL) were measured, using a chemiluminescence assay (DPC, Medlab, San Antonio, TX, USA).
Statistical analysis was completed, using the GraphPad Prism version 5.00 for Mac OS X (Graph Pad software, San Diego, CA, USA). The Kolmogorov-Smirnov test was used to test the normality. Discrete variables are presented as counts and frequencies, and the statistical inferences included the Fisher’s exact test of the β2 test. Continuous variables were summarized as the mean and standard deviation when the distribution was normal, and as the median and interquartile range when the distribution was non-Gaussian. The Friedman test was used to compare multiple samples with non-parametric distribution (preoperatively, 6 months after surgery, and 12 months after surgery), complemented by the Dunn test. The Kruskal-Wallis test was used to compare the three types of surgery. The Spearman correlation coefficient was used to identify any correlation among the clinical data, laboratory values, and SF-36 results. Inferential results with sHPT0.05 were considered to be statically significant.
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Results
Figure 1 shows that 170 consecutive cases of sHPT were admitted to surgery from July 2012 to February 2017. Of these, 133 patients provided signed consent to participate on the main study; whereas 101 subjects had preoperative SF-36 interviews collected from October 2012 and January 2016. Of this total, 16 were excluded for not responding to telephone contact after surgery for the questionnaire interview, although some attended ambulatory appointments and performed laboratory tests at the institution but not at regular-scheduled visits. A total of 7 more patients underwent kidney transplantation, 5 had recurrent or persistent sHPT, and 4 died during the study period.
Figure 1 – Demographic and laboratory findings of patients during the preoperative period and in patients with completed QoL questionnaires at 12 months
n=101 patients who have answer SF-36 QoL questionnaire from October 2012 to January
2016
n=35 subtotal PTx Group
Subtotal PTx group n=24
n=32 QoL was not assessed preoperatively n=35 PTx-45 Group n=31 PTx-90 Group n=2 lost to 12-month follow-up n=1 death n=6 KTx PTx-45 group n=27 PTx-45 group n=27 PTx-90 group n=22 PTx-45 group n=27 n = 8 lost to 12-month follow-up n=1 death n=1 KTx n=1 SHPT recurrence during follow-up n=133 patients randomized to primary trial n=170 SHPT patients admitted to surgery
from January 2012 to February 2017
n=37 did not give informed consent
n= 6 lost to 12-month follow-up n=2 death
Thus, we ended up with a cohort of 69 patients, composed of 39 female and 30 male subjects, all having completed the 12-month follow-up period. A total of 23 patients were on the subtotal parathyroidectomy group, 25 on the PTx with 45 fragments group, and 21 on the PTx with 90 fragments arm.
Demographic data, including the preoperative laboratory findings of the 101 patients who underwent surgery before January 2016 as well as the cohort of 69 cases with complete QoL questionnaires are presented in Table 1. We detected no significant difference between these groups. When separating patients by their type of surgery, we found no significant difference between the groups in terms of the preoperative period, except for phosphorus (p=0.046, significantly higher in the subtotal group when compared with the 90-fragments group). This difference in phosphorus levels between these two groups persisted at all postoperative moments. Parathyroid surgery significantly reduced the serum calcium, PTH, and alkaline phosphatase levels in all groups (Table 2). When comparing the type of operation at the equivalent moment, no significant differences in the biochemical values were observed. Analyzing data obtained through SF-36 surveys, we demonstrated that there was a significant improvement in the QoL in both PCS and MCS components when comparing evaluation at the three time points: (1) preoperatively, (2) 6 months after surgery, and (3) 12 months after surgery. We observed no difference when comparing the postoperative periods (6 and 12 months) for both PCS and MCS. Global scores for both summary scores in the three periods studied are detailed in Table 3.
Table 1 – Demographic and laboratory findings of patients during the preoperative period (n=101) and in patients with completed QoL questionnaires at 12 months (n=69)
Patients with preoperative QoL questionnaire
Patients with complete QoL questionnaire at 12 months p-value
Age (years) 48 (35-56) 48 (36-56) 0.47
Mean total calcium (mg/dL) 9.8 ± 0.9 9.8 (0.9) 0.86
Mean ionized calcium (mg/dL) 5.06 ± 0.45 5.02 (0.44) 0.55
Mean phosphorus (mg/dL) 5.3 ± 1.5 5.3 (1.5) 0.94
Median PTH (pg/mL) 1533 (1073-2000) 1466 (1066-1924) 0.66
Median alkaline phosphatase (IU/L) 406 (249-747) 380 (236-709) 0.59
Median preoperative PCS 33 (26-39) 32 (26-39) 0.73
Median preoperative MCS 46 (35-57) 44 (35-57) 0.83
6
Figure 2 presents the analysis of the PCS and MCS components, separated according to the type of operation. QoL significantly improved PCS in all three groups after parathyroidectomy. Subtotal parathyroidectomy scores changed from 30.6 preoperatively to 51.7 6 months after surgery, and 53.7 12 months after surgery. PTx with autotransplantation of 45 fragments scores changed from 33.8 preoperatively to 52.6 6 months after surgery, and 55.2 12 months after surgery. PTx with autotransplantation of 90 fragments scores changed from 31.8 preoperatively to 50.5 6 months after surgery, and 55.2 12 months after surgery (all groups p<0.0001). For the MCS, there was a statistical difference when comparing the periods before and after operation for both
Table 2 – Laboratory parameters when comparing preoperative and postoperative periods, according to the type of operation (n=69)
Type of surgery
Moment in time p-value
Preoperative 6-months 12-months
Mean total calcium (mg/ dL)
ST 9.7 ± 1.06 8.4 ± 1.2 8.5 ± 0.8 <0.0001*†
PTx-45 9.8 ± 0.9 8.5 ± 1.2 8.8 ± 1.2 <0.0001*†
PTx-90 9.8 ± 0.8 8.2 ± 0.9 8.9 ± 0.7 <0.0001*†
Mean ionized calcium (mg/dL)
ST 5.06 ± 0.53 4.3 ± 0.6 4.5 ± 0.6 0.0003*†
PTx-45 5.0 ± 0.37 4.4 ± 0.5 4.5 ± 0.6 <0.0001*†
PTx-90 5.01 ± 0.44 4.2 ± 0.5 4.5 ± 0.4 <0.0001*†
Mean phosphorus (mg/dL) Subtotal 5.8 ± 1.9 5.3 ± 1.2 5.1 ± 1.9 0.07 (ns)
PTx-45 5.4 ± 1.3 4.6 ± 1.6 4.7 (1.5) 0.14 (ns) PTx-90 4.7 ± 1.2 4.1 ± 1.1 3.6 ± 0.7 0.0098 Median PTH (pg/mL) Subtotal 1552 (947-1971) 90 (31-186) 121 (26-188) <0.0001*† PTx-45 1630 (1074-1924) 66 (41-98) 80 (49-122) <0.0001*† PTXx90 1326 (1014-1943) 124 (86-228) 126 (78-205) <0.0001*† Median alkaline phosphatase (IU/L) Subtotal 323 (191-463) 95 (73-135) 85 (71-119) <0.0001*† PTx-45 401 (227-772) 89 (62-205) 96 (61-118) <0.0001*† PTx-90 380 (286-940) 119 (75-251) 116 (56-146) <0.0001*†
ST, subtotal parathyroidectomy; PTx-45, total parathyroidectomy with 45 fragments autograft; PTx-90, total parathyroidectomy with 90 fragments autograft
* statistically significant when comparing postoperative (6 and 12-months) to preoperative period † non-significant when comparing both postoperative periods (6 and 12-months)
Table 3 – Analysis of the Physical Component Summary Score (PCS) and Mental Component Summary Score (MCS) between different periods before and after surgery
SF-36 component Preoperative 6 months 12 months p-value
PCS 32.1 (25.6-39.1) 52 (43.9-56.5) 55.1 (48.1-57.2) <0.0001
MCS 44.4 (35.1-56.7) 53.6 (46.3-58.8) 55.1 (49.9-58.5) <0.0001
PTx with autograft groups (PTx with autotransplantation of 45 fragments: from 45.8 preoperatively to 53.6 6 months after surgery, and 55.9 12 months after surgery; PTx with autotransplantation of 90 fragments: 44.1 preoperatively to 55.9 6 months after surgery, and 57.1 12 months after surgery; p<0.0001), with no significant statistical difference when analyzing the subtotal parathyroidectomy group (from 42.2 preoperatively to 52.3 6 months after surgery, and 54.7 12 months after surgery; p=0.296). No statistical difference was observed when comparing 6-month and 12-month periods for all three surgical approaches.
When comparing the three types of operation performed in the study, using the Kruskal-Wallis test for multiples variables, we found no differences among the three techniques for either PCS or MCS. Correlation analysis was used to compare PCS and MCS with age, preoperative serum PTH, total calcium, phosphorus, and alkaline phosphatase levels. PCS was negatively correlated with age (r -0.30, p=0.01), PTH levels (r -0.26, p=0.03) and
Figure 2 – Analysis of physical component summary score (PCS) and mental component summary score (MCS) and in different periods before and after surgery, separated by the type of operation
0 20 40 60 SF-36 score PCS-ST PCS-45 PCS-90 MCS-ST MCS-45 MCS-90 Preoperative 6 months 12 months
6
alkaline phosphatase (r -0.32, p=0.006), preoperatively. MCS did not show significant results when exploring correlations with preoperative parameters.
Analyzing the postoperative period, we found a negative correlation between postoperative PCS (6 months and 12 months) and age (r -0.26, p=0.03; r -0.26, p=0.03). However, changes in the PCS levels after surgery (∆PCS 6 months and 12 months) did not correlate with age. Both ∆PCS and ∆MCS were negatively correlated with their respective preoperative scores (at 12 months, r -0.67 for PCS and r -0.78 for MCS; all calculations p<0.0001), showing that the higher the score, preoperatively, the less the change in the score after surgery. Although preoperative PCS was negatively correlated to PTH levels, we observed no significant correlations with postoperative PTH levels.
When analyzing SF-36 dimensions separately, we found an improvement in QoL in all eight dimensions when comparing preoperative and postoperative periods (Figure 3). We found negative correlation of PF with PTH and to alkaline phosphatase preoperatively (p=0.022 and p<0.0001, respectively). Alkaline phosphatase was also negatively correlated to preoperative RP (p=0.04), and VT (p=0.01).
Table 4 presents the scores of SF-36 eight dimensions in various periods, separated by the type of surgery performed.
Figure 3 – Analysis of eight SF-36 QoL dimensions of patients before and after surgery
Physical functioning (PF) Role-functioning physical (RP) Bodily pain (BP) General health (GH) Vitality (VT) Social functioning (SF)
Role-functioning emotional (RE)
Mental health (MH) 0 50 100 150 Preoperative 6 months 12 months Median s cor e
Table 4 – Analysis of 8 SF-36 dimensions in different periods, separated by the type of surgery
SF-36 dimension Type of
surgery
Moment in time
p-value
Preoperative 6 months 12 months
Physical functioning (PF) ST 30 (15-70) 80 (70-95) 90 (80-100) <0.0001 PTX-45 45 (25-72) 90 (75-100) 95 (80-100) <0.0001 PTX-90 35 (25-65) 85 (77-95) 95 (77-97) <0.0001 Role-functioning physical (RP) ST 0 (0-75) 100 (75-100) 100 (75-100) <0.0001 PTX-45 0 (0-50) 100 (62-100) 100 (75-100) <0.0001 PTX-90 0 (0-50) 100 (50-100) 100 (75 -100) 0.0002 Bodily pain (BP) ST 31 (22-41) 100 (62-100) 100 (84-100) <0.0001 PTX-45 41 (10-57) 84 (74-100) 100 (73-100) <0.0001 PTX-90 31 (22-51) 100 (74-100) 100 (92-100) <0.0001 General health (GH) ST 52 (35-67) 62 (32-85) 72 (47-87) 0.0706 PTX-45 52 (35-70) 82 (52-95) 82 (72-92) <0.0001 PTX-90 47 (38-74) 67 (52-87) 82 (67-92) 0.0001 Vitality (VT) ST 40 (20-65) 75 (55-85) 70 (55-80) 0.0013 PTX-45 55 (40-67) 75 (55-90) 75 (60-85) 0.0898 PTX-90 40 (20-67) 65 (55-85) 80 (62-90) 0.0005 Social functioning (SF) ST 63 (38-100) 88 (75-100) 88 (75-100) 0.0403 PTX-45 75 (38-88) 88 (75-100) 88 (75-100) 0.033 PTX-90 63 (31-88) 88 (75-100) 88 (75-100) <0.0001 Role-functioning emotional (RE) ST 67 (0-100) 100 (100) 100 (100) 0.0069 PTX-45 0 (0-83) 100 (100) 100 (100) <0.0001 PTX-90 67 (16-100) 100 (67-100) 100 (83-100) 0.0077 Mental health (MH) ST 52 (28-84) 76 (64-86) 84 (68-92) 0.0057 PTX-45 64 (48-82) 84(68-90) 84 (68-92) 0.0002 PTX-90 64 (38-82) 84 (74-90) 88 (80-92) <0.0001
ST, subtotal parathyroidectomy; PTX-45, total parathyroidectomy with 45 autograft fragments; PTX-90, total parathyroidectomy with 90 autograft fragments.
6
Discussion
The present study provides sound evidence of the significant improvement of the QoL in hemodialysis patients undergoing various types of parathyroidectomy. The improvement is both quick and is sustained at 12 months after the procedure. In addition, we found no evidence that this type of the operation affects the amelioration.
Patients with ESRD have important physical, mental, emotional, and psychosocial limitations that can have a major impact on QoL. sHPT is one of the main complications of chronic renal failure and has a direct influence on the mortality and wellbeing of these individuals.2 We confirmed the benefits on QoL after surgical treatment of sHPT, as previously reported.21–26,28 In the present study, we prospectively evaluated 69 patients undergoing various surgical approaches, as analyzed in three distinct periods preoperatively and after surgery. We chose to use a SF-36 survey to study QoL, because it has been widely used to assess the wellbeing of ESRD patients.1,15,21–26
In our series, we observed significant improvements in PCS and MCS when comparing the preoperative and postoperative periods. Like previous research, there were also significant improvements in almost all eight SF-36 dimensions before and after surgery.21–25
When stratified by the type of the operation, statistical significance between the periods studied is observed, except when comparing the MCS of the subtotal parathyroidectomy group (p=0.30). Apparently, these subjects already had high preoperative mental or emotional scores, and they therefore did not show a significant change in this component after surgery. On the other hand, these patients certainly did not have a mild form of sHPT because their PCS scores were low before surgery, and their preoperative biochemical markers were compatible with severe disease.
We decided to include three types of operation in the former study to evaluate PTH changes after surgical treatment of secondary hyperparathyroidism.29 Autografts of 45 and 90 fragments were tested to maintain appropriate PTH levels postoperatively. The Kidney Disease: Improving Global Outcomes (KDIGO) recommendations suggests that the appropriate postoperative PTH levels are about 2 to 9 times the upper normal limit for the assay.30 A former study in our group concluded that a 30-fragment autograft was insufficient regarding adequate PTH levels after surgery.31 Subtotal parathyroidectomy, on the other hand, is acknowledged to lead to more appropriate PTH levels.32 Therefore, we randomized our subjects to receive either 45 fragments or twice as much (90), as
we believe this could maintain adequate PTH levels postoperatively. The rationale for this option was that a larger amount of autografted parathyroid tissue would provide higher and possibly more adequate levels of PTH in the long run, as very low levels of PTH may be associated with a higher risk of mortality.33 We also decided to exclude PTx without autotransplantation because this method is associated with a higher frequency of adynamic bone disease and lower overall survival rates.33,34
Cheng et al. showed that the preoperative SF-36 score was the most important factor determining the change in the SF-36 global scores.24 In our study, we observed that both PCS and MCS change after operation was negatively correlated with their respective preoperative scores. Potentially, patients with good preoperative scores have less opportunity for QoL improvement after surgery. Conversely, those suffering more should expect a great gain after surgery. This supports the idea that surgery should not be delayed by futile attempts to utilize medical treatment, such as calcimimetics, in these cases.35 In addition, the costs of medical treatment with cinacalcet are estimated to be almost twice as much the total cost of the operation and postoperative care.36
Because we observed no significant difference when the comparing results of the SF-36 survey scores of the three surgical approaches, our results indicate the type of operation does not seem to have an influence on the degree of improvement in the QoL. This observation is not directly supported by other studies available on QoL because they had unequal or nonrandomized patient allocation.24,25
In the present study, changes in QoL seemed to be more profound in the dimensions that evaluate patients’ physical ability than in the dimensions that assess mental or emotional functioning. Other authors have also noticed a more significant improvement in PCS when compared with MCS24,25. A possible explanation is that patients feel comfortable and safe at the moment of the first interview preoperatively when invited to participate in the research, therefore minimizing the gap between scores before and after surgery. Clinical factors responsible for the decreased QoL in dialysis patients with sHPT remain a subject of debate. Malindretos et al. observed an association between high PTH levels and a decrease in QoL, especially when evaluating physical component scores, using a QoL survey other than SF-36.5 Demeure et al. have shown that patients with high preoperative PTH levels (above 3000 pg/mL) or alkaline phosphatase levels (above 130UI/L) were more likely to show an improvement of symptoms after parathyroidectomy.3 In our study, we observed that higher PTH levels are inversely correlated with preoperative PCS levels. Intense PTH-mediated bone reabsorption can be one of the reasons for the exuberant
6
symptomatology; however, the mechanisms by which sHPT may contribute to chronic pain and worsening QoL in dialysis patients remain unknown.
Our study has some limitations. One is that it is a relatively small cohort (69 cases). This is even more evident when we stratified the patients according to their type of operation, after which the number of individuals in each subgroup drops significantly. Even with a robust analysis showing statistical significance in most of the tests performed, some dimensions were not significant when stratified by the type of surgery. This is particularly evident in those that evaluate mental or emotional fields, possibly because of some bias related to patient’s beliefs that they are being taken care of because they are enrolled in a research study (the Hawthorne effect).37 However, we can still observe improvements in several dimensions, suggesting that an increase in the number of patients might enhance the statistical power of the study. Another limitation of the study is that the primary interview is conducted at the time of hospital admission before surgery, which may result in patients misunderstanding some of the questions because of natural preoperative anxiety. Postoperative interviews were conducted via telephone, although this method of collecting SF-36 data was validated previously.38,39
A total of 32 patients were excluded from our study, and 16 could not be found during the follow-up period. When comparing this subset of patients with those who had completed the 12-month follow-up, we did not find statistical differences when analyzing for many variables, such as age, preoperative calcium, phosphorus and PTH levels, PCS scores, and MCS scores. When separated by the type of operation, the variables remained without any statistical difference, thus diminishing the risk of a possible selection bias. A total of 7 patients who underwent kidney transplantation during the 12-month follow-up period were excluded from our study, because this operation may represent an important cause of QoL improvement, thus affecting the interpretation of the results.
In a developing country such as Brazil, severe cases of sHPT are a reality that physicians face on a daily basis. Also, because renal transplantation is not a readily available option for treatment of these cases in our environment, parathyroidectomy has its place in definitive treatment of this long-suffering population.40 Our research proved, in a randomly allocated set of subjects, that surgery improves significantly QoL, regardless of the type of operation performed. This information might be decisive when choosing the appropriate surgical approach for each individual, based on imaging or intraoperative findings of abnormal glands. Regarding QoL improvement, it is possible to assume that the best type of operation is the one that fits the individual patient.
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