Maximal parathyroid gland diameter as a predictive factor for autograft-dependent recurrent secondary hyperparathyroidism after total parathyroidectomy.

Introduction: Following total parathyroidectomy (PTx), transcervical thymectomy, and forearm autograft for secondary hyperparathyroidism (SHPT), recurrent SHPT can occur in the autografted forearm. However, few studies have investigated the factors contributing to re-PTx due to autograft-dependent recurrent SHPT before the completion of the initial PTx. Methods: A total of 770 patients who had autografted parathyroid fragments derived from only one of the resected parathyroid glands (PTGs) and who had undergone successful initial total PTx and transcervical thymectomy-defined by serum intact parathyroid hormone level < 60 pg/mL on postoperative day 1-between January 2001 and December 2022 were included in this retrospective cohort study. Factors contributing to re-PTx due to graft-dependent recurrent SHPT before the completion of the initial PTx were investigated using multivariate Cox regression analysis. Receiver operating characteristic (ROC) curve analysis was performed to obtain the optimal maximum diameter of PTG for autograft. Results: Univariate analysis showed that dialysis vintage and maximum diameter and weight of the PTG for autograft were significant factors contributing to graft-dependent recurrent SHPT. However, multivariate analysis revealed that dialysis vintage (P=0.010; hazard ratio [HR], 0.995; 95% confidence interval [CI], 0.992-0.999) and the maximum diameter of the PTG for autograft (P=0.046; HR, 1.107; 95% CI, 1.002-1.224) significantly contributed to graft-dependent recurrent SHPT. ROC curve analysis showed that < 14 mm was the optimal maximum diameter of PTG for autograft (area under the curve, 0.628; 95% CI, 0.551-0.705). Conclusions: The dialysis vintage and maximum diameter of PTG for autograft may contribute to re-PTx due to autograft-dependent recurrent SHPT, which can be prevented by using PTGs with a maximum diameter of < 14 mm for autograft.

Treatment for secondary hyperparathyroidism focusing on parathyroidectomy.

Secondary hyperparathyroidism (SHPT) is a major problem for patients with chronic kidney disease and can cause many complications, including osteodystrophy, fractures, and cardiovascular diseases. Treatment for SHPT has changed radically with the advent of calcimimetics; however, parathyroidectomy (PTx) remains one of the most important treatments. For successful PTx, removing all parathyroid glands (PTGs) without complications is essential to prevent persistent or recurrent SHPT. Preoperative imaging studies for the localization of PTGs, such as ultrasonography, computed tomography, and 99mTc-Sestamibi scintigraphy, and intraoperative evaluation methods to confirm the removal of all PTGs, including, intraoperative intact parathyroid hormone monitoring and frozen section diagnosis, are useful. Functional and anatomical preservation of the recurrent laryngeal nerves can be confirmed via intraoperative nerve monitoring. Total or subtotal PTx with or without transcervical thymectomy and autotransplantation can also be performed. Appropriate operative methods for PTx should be selected according to the patients' need for kidney transplantation. In the case of persistent or recurrent SHPT after the initial PTx, localization of the causative PTGs with autotransplantation is challenging as causative PTGs can exist in the neck, mediastinum, or autotransplanted areas. Additionally, the efficacy and cost-effectiveness of calcimimetics and PTx are increasingly being discussed. In this review, medical and surgical treatments for SHPT are described.

Intraoperative intact parathyroid hormone monitoring and frozen section diagnosis are essential for successful parathyroidectomy in secondary hyperparathyroidism.

Background: Total parathyroidectomy (PTx) is often performed to treat secondary hyperparathyroidism (SHPT). Successful PTx is essential to prevent recurrent and persistent SHPT because remnant parathyroid glands (PTGs) in the neck can be stimulated and may secrete excessive parathyroid hormone (PTH) in end-stage renal disease. However, to date, few studies have investigated factors contributing to successful PTx before the completion of surgery. Materials and methods: Between August 2010 and February 2020, 344 patients underwent total PTx, transcervical thymectomy, and forearm autograft for SHPT at our institute. Factors contributing to successful PTx before the completion of surgery were investigated. Preoperative imaging diagnoses, including computed tomography, ultrasonography, technetium-99m methoxyisobutylisonitrile (99mTc-MIBI) scintigraphy, intraoperative intact PTH (IOIPTH) monitoring, and frozen section histologic diagnosis, were performed. Successful PTx was defined as intact PTH level < 60 pg/mL on postoperative day 1. A sufficient decrease in IOIPTH level was defined as > 70% decrease in intact PTH levels measured 10 min after total PTx and transcervical thymectomy compared to intact PTH levels measured before skin incision. Logistic regression analysis was conducted to investigate factors contributing to PTx success. Results: Univariate analysis showed that the number of all PTGs identified preoperatively by imaging modalities and the specimens submitted for frozen section diagnosis, which surgeon presumed to be PTGs, were not significant factors contributing to successful PTx. However, multivariate analysis revealed that the number of PTGs identified by frozen section diagnosis (P < 0.001, odds ratio [OR] 4.356, 95% confidence interval [CI] 2.499-7.592) and sufficient decrease in IOIPTH levels (P = 0.001, OR 7.847, 95% CI 2.443-25.204) significantly contributed to successful PTx. Conclusion: Sufficient intact PTH level decrease observed on IOIPTH monitoring and the number of PTGs identified by frozen section diagnosis contributed to successful PTx for SHPT. IOIPTH monitoring and frozen section diagnosis are essential for achieving successful PTx for SHPT.

Renal hyperparathyroidism.

The number of the patients with chronic kidney disease is now increasing in the world. The pathophysiology of renal hyperparathyroidism is closely associated with Klotho-FGF-endocrine axes, which must be solved definitively as early as possible. It was revealed that the expression of fgf23 is activated by calciprotein particles, which induces vascular ossification. And it is well known that phosphorus overload directly increases parathyroid hormone and hyperparathyroid bone disease develops in those subjects. On the other hand, low turnover bone disease is often recently. Both the patients with chronic kidney disease suffering from hyperparathyroid bone disease or low turnover bone disease are associated with increased fracture risk. Micropetrosis may be one of the causes of increased fracture risk in the subjects with low turnover bone disease. In this chapter, we now describe the diagnosis, pathophysiology and treatments of renal hyperparathyroidism.

Elevated parathyroid hormone one year after kidney transplantation is an independent risk factor for graft loss even without hypercalcemia.

BACKGROUND: Hypercalcemic hyperparathyroidism has been associated with poor outcomes after kidney transplantation (KTx). However, the clinical implications of normocalcemic hyperparathyroidism after KTx are unclear. This retrospective cohort study attempted to identify these implications. METHODS: Normocalcemic recipients who underwent KTx between 2000 and 2016 without a history of parathyroidectomy were included in the study. Those who lost their graft within 1 year posttransplant were excluded. Normocalcemia was defined as total serum calcium levels of 8.5-10.5 mg/dL, while hyperparathyroidism was defined as when intact parathyroid hormone levels exceeded 80 pg/mL. The patients were divided into two groups based on the presence of hyperparathyroidism 1 year after KTx. The primary outcome was the risk of graft loss. RESULTS: Among the 892 consecutive patients, 493 did not have hyperparathyroidism (HPT-free group), and 399 had normocalcemic hyperparathyroidism (NC-HPT group). Ninety-five patients lost their grafts. Death-censored graft survival after KTx was significantly lower in the NC-HPT group than in the HPT-free group (96.7% vs. 99.6% after 5 years, respectively, P < 0.001). Cox hazard analysis revealed that normocalcemic hyperparathyroidism was an independent risk factor for graft loss (P = 0.002; hazard ratio, 1.94; 95% confidence interval, 1.27-2.98). CONCLUSIONS: Normocalcemic hyperparathyroidism 1 year after KTx was an independent risk factor for death-censored graft loss. Early intervention of elevated parathyroid hormone levels may lead to better graft outcomes, even without overt hypercalcemia.

Preservation of the nonrecurrent laryngeal nerve using intraoperative nerve monitoring during endoscopic thyroidectomy.

A 40-year-old woman underwent right lobe thyroidectomy for thyroid nodules that increased in size from 17 mm to 33.5 mm within 1 year. Identification of arteria lusoria using computed tomography suggested the presence of a right nonrecurrent laryngeal nerve (RNRLN). Endoscopic thyroidectomy was performed under general anesthesia. The right vagal nerve was first identified between the common carotid artery and jugular vein. A positive response was confirmed via intraoperative neuromonitoring (IONM), implying that the RNRLN did not branch from the central side of the stimulated point of the vagal nerve. The RNRLN was confirmed using IONM around the middle to lower pole of the right thyroid gland. The right thyroid lobe was successfully removed, with meticulous preservation of the RNRLN. The motion of the vocal cord, examined by an ear-nose-throat doctor postoperatively, was intact. We demonstrated the efficacy of IONM in patients with RNRLN who underwent endoscopic thyroidectomy.

Micropetrosis in hemodialysis patients.

Micropetrosis develops as a result of stagnation of calcium, phosphorus and bone fluid, which appears as highly mineralized bone area in the osteocytic perilacunar/canalicular system regardless of bone turnover of the patients. And microcracks are predisposed to increase in these areas, which leads to increased bone fragility. However, micropetrosis of hemodialysis (HD) patients has not been discussed at all. Micropetrosis area per bone area (Mp.Ar/B·Ar) and osteocyte number per micropetrosis area (Ot.N/Mp.Ar) were measured in nine HD patients with renal hyperparathyroidism (Group I), twelve patients with hypoparathyroidism within 1 year after the treatment of renal hyperparathyroidism (Group II) and seven patients suffering from hypoparathyroidism for over two years (Group III). And bone mineral density (BMD) and tissue mineral density (TMD) were calculated using µCT to evaluate bone mineral content of iliac bone of the patients. These parameters were compared among the three groups. Only Mp.Ar/B·Ar was statistically greater in Group II and III compared to Group I in the parameters of bone mineral content and micropetrosis. However, the other parameters were not statistically different among the three groups. In long-term HD patients, BMD and TMD may be modified by the causes of renal insufficiency and the treatment of renal bone disease. We concluded that Mp.Ar/B·Ar was greater in patients with long-term hypoparathyroidism than both those with short-term hypoparathyroidism and with renal hyperparathyroidism. Special attention should be paid to avoid long-term hypoparathyroidism of the patients from the view point of increased fracture risk caused by increased micropetrosis area.

Predictors of Bone Mineral Density Improvement after Parathyroidectomy for Secondary Hyperparathyroidism: A Retrospective Single-Center Analysis.

BACKGROUND: Parathyroidectomy (PTx) reportedly increases bone mineral density (BMD) in patients with severe secondary hyperparathyroidism (SHPT). To date, however, there has not been sufficient evidence on predictors of BMD improvement post-PTx for SHPT, an issue the present retrospective cohort study aimed to address. METHODS: A total of 173 SHPT patients who underwent total PTx with forearm autograft between 2009 and 2017 were included in the present study. Demographic information, perioperative laboratory data and pre- and post-PTx BMD values (measured by dual-energy X-ray absorptiometry) were collected from their medical records. The change in BMD post-PTx in the lumbar spine was evaluated as the primary outcome. Then, a multivariate logistic regression analysis was performed for a ≥ 10% increase in BMD post-PTx. RESULTS: Overall, the median BMD in the lumbar spine was increased by 8.7% post-PTx. The multivariate logistic regression analysis revealed that age ≥ 70 years (P = 0.005; odds ratio [OR], 0.138; 95% confidence interval [CI]: 0.034-0.555), serum Ca level (P = 0.017; OR, 0.598; 95% CI: 0.392-0.911) and pre-PTx BMD in the lumbar spine (P = 0.003; OR, 0.013; 95% CI: 0.001-0.229) were negatively associated with a ≥ 10% increase in BMD post-PTx. CONCLUSION: Our study demonstrated that presurgical age, serum Ca levels and BMD values could better predict an improvement in BMD post-PTx in SHPT patients.

Intact parathyroid hormone levels localize causative glands in persistent or recurrent renal hyperparathyroidism: A retrospective cohort study.

Persistent or recurrent renal hyperparathyroidism may occur after total parathyroidectomy and transcervical thymectomy with forearm autograft under continuous stimulation due to uremia. Parathyroid hormone (PTH) levels may reflect persistent or recurrent renal hyperparathyroidism because of the enlarged autografted parathyroid glands in the forearm or remnant parathyroid glands in the neck or mediastinum. Detailed imaging requires predictive localization of causative parathyroid glands. Casanova and simplified Casanova tests may be convenient. However, these methods require avascularization of the autografted forearm for >10 min with a tourniquet or Esmarch. The heavy pressure during avascularization can be incredibly painful and result in nerve damage. An easier method that minimizes the burden on patients in addition to predicting the localization of causative parathyroid glands was developed in this study. Ninety patients who underwent successful re-parathyroidectomy for persistent or recurrent renal hyperparathyroidism after parathyroidectomy between January 2000 and July 2019 were classified according to the localization of causative parathyroid glands (63 and 27 patients in the autografted forearm and the neck or mediastinum groups, respectively). Preoperatively, intact PTH levels were measured from bilateral forearm blood samples following a 5-min avascularization of the autografted forearm. Cutoff values of the intact PTH ratio (intact PTH level obtained from the non-autografted forearm before re-parathyroidectomy/intact PTH level obtained from the autografted forearm before re-parathyroidectomy) were investigated with receiver operating characteristic curves to localize the causative parathyroid glands. Intact PTH ratios of <0.310 with an area under the curve (AUC) of 0.913 (95% confidence interval [CI]: 0.856-0.970; P < 0.001) and >0.859 with an AUC 0.744 (95% CI: 0.587-0.901; P = 0.013) could predict causative parathyroid glands in the autografted forearm and the neck or mediastinum with diagnostic accuracies of 81.1% and 83.3%, respectively. Therefore, we propose that the intact PTH ratio is useful for predicting the localization of causative parathyroid glands for re-parathyroidectomy.

Intraoperative recurrent laryngeal nerve monitoring using endotracheal electromyography during parathyroidectomy for secondary hyperparathyroidism.

OBJECTIVE: To investigate the factors associated with adherence of an enlarged parathyroid gland to the recurrent laryngeal nerve (RLN) and the effectiveness of intraoperative neural monitoring (IONM). METHODS: This single-center retrospective study involved samples from 197 consecutive patients (394 RLNs; 733 parathyroid glands) who underwent parathyroidectomy and transcervical thymectomy between September 2010 and December 2014. The presence of parathyroid gland adhesion to the RLN and the clinical characteristics of patients with and without nerve adhesion were recorded. All patients underwent intraoperative monitoring of the electromyographic responses of the vocal cords using the endotracheal NIM-Response 3.0 system. The patients' postoperative clinical outcomes were recorded. RESULTS: Parathyroid gland adhesion to the RLN was significantly associated with maximum gland diameter (>15 mm), weight (>500 mg), and the presence of nodular hyperplasia. IONM demonstrated a sensitivity of 97.8%, specificity of 43.5%, and accuracy of 94.7% for detecting nerve damage. Parathyroid gland adhesion to 17 RLNs occurred in 3 cases (17.6%) of vocal cord paralysis, whereas the 377 glands without nerve adhesion resulted in vocal cord paralysis in 20 cases (5.3%). CONCLUSION: Our findings demonstrated the effectiveness of IONM using endotracheal electromyography in patients who underwent parathyroidectomy for secondary hyperparathyroidism.

Surgical outcomes of parathyroidectomy for secondary hyperparathyroidism resistant to calcimimetic treatment: A retrospective single-center cohort study.

To evaluate the surgical outcomes of parathyroidectomy (PTx) for secondary hyperparathyroidism (SHPT) resistant to calcimimetic treatment, we retrospectively studied 187 patients with SHPT who had no history of calcimimetic treatment (NCMT) (NCMT group) and 186 patients with SHPT who were resistant to calcimimetic treatment (RCMT) (RCMT group). Success rate and operative time of PTx were compared among the two groups. Operative time was significantly longer in the RCMT group than in the NCMT group (180 vs 158 minutes, P < .001), but the difference was attenuated after multivariate adjustment including the weight of the largest parathyroid gland. No significant differences were observed in success rate of PTx (90.9% vs 91.4%, P = 1.000) between the two groups. In patients with SHPT who are resistant to calcimimetic treatment, operative time could be elongated but success rate of PTx remains unchanged.

Comparison of Pre- and Post-transplant Parathyroidectomy in Renal Transplant Recipients and the Impact of Parathyroidectomy Timing on Calcium Metabolism and Renal Allograft Function: A Retrospective Single-Center Analysis.

BACKGROUND: The effect of parathyroidectomy (PTx) timing on serum calcium (Ca) levels and renal functions in renal transplant recipients with severe hyperparathyroidism (HPT) remains unclear. We retrospectively aimed to investigate and compare the clinical data of patients who underwent pre- and post-transplant PTx and elucidated the impact of PTx timing on serum Ca levels and renal graft outcomes after renal transplantation (RTx). METHODS: During January 2000-December 2016, 53 and 55 patients underwent post-transplant PTx (Post-RTx group) and pretransplant PTx (Pre-RTx group), respectively. The serum Ca levels and estimated glomerular filtration rate (eGFR) were assessed in both groups. RESULTS: At the end of the follow-up, the serum Ca levels were significantly higher and the incidence of hypocalcemia was significantly lower in the Pre-RTx group than in the Post-RTx group [9.5 vs. 8.9 mg/dL, P < 0.001; 14.5% vs. 34.0%, P = 0.024]. The decrease in the eGFR 12-36 months after RTx was more significant in the Post-RTx group than in the Pre-RTx group (-13.8% vs. -0.9%; P = 0.001). A logistic regression involving age, sex, dialysis period, and serum parathormone level revealed that post-transplant PTx is an independent risk factor for persistent hypocalcemia at the end of the follow-up (P = 0.034) and for a >20% decrease in the eGFR 12-36 months after RTx (P = 0.029). CONCLUSIONS: In renal transplant candidates with severe HPT, pretransplant PTx should be considered to prevent persistent hypocalcemia and deterioration of the renal graft function.

The Importance of Biologically Active Vitamin D for Mineralization by Osteocytes After Parathyroidectomy for Renal Hyperparathyroidism.

Hypomineralized matrix is a factor determining bone mineral density. Increased perilacunar hypomineralized bone area is caused by reduced mineralization by osteocytes. The importance of vitamin D in the mineralization by osteocytes was investigated in hemodialysis patients who underwent total parathyroidectomy (PTX) with immediate autotransplantation of diffuse hyperplastic parathyroid tissue. No previous reports on this subject exist. The study was conducted in 19 patients with renal hyperparathyroidism treated with PTX. In 15 patients, the serum calcium levels were maintained by subsequent administration of alfacalcidol (2.0 µg/day), i.v. calcium gluconate, and oral calcium carbonate for 4 weeks after PTX (group I). This was followed in a subset of 4 patients in group I by a reduced dose of 0.5 µg/day until 1 year following PTX; this was defined as group II. In the remaining 4 patients, who were not in group I, the serum calcium (Ca) levels were maintained without subsequent administration of alfacalcidol (group III). Transiliac bone biopsy specimens were obtained in all groups before and 3 or 4 weeks after PTX to evaluate the change of the hypomineralized bone area. In addition, patients from group II underwent a third bone biopsy 1 year following PTX. A significant decrease of perilacunar hypomineralized bone area was observed 3 or 4 weeks after PTX in all group I and II patients. The area was increased again in the group II patients 1 year following PTX. In group III patients, an increase of the hypomineralized bone area was observed 4 weeks after PTX. The maintenance of a proper dose of vitamin D is necessary for mineralization by osteocytes, which is important to increase bone mineral density after PTX for renal hyperparathyroidism. © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

Disrupted tubular parathyroid hormone/parathyroid hormone receptor signaling and damaged tubular cell viability possibly trigger postsurgical kidney injury in patients with advanced hyperparathyroidism.

BACKGROUND: Parathyroidectomy (PTX) that alleviates clinical manifestations of advanced hyperparathyroidism, including hypercalcemia and hypophosphatemia, is considered the best protection from calcium overload in the kidney. However, little is known about the relationship between postsurgical robust parathyroid hormone (PTH) reduction and perisurgical renal tubular cell viability. Post-PTX kidney function is still a crucial issue for primary hyperparathyroidism (PHPT) and tertiary hyperparathyroidism after kidney transplantation (THPT). METHODS: As a clinical study, we examined data from 52 consecutive patients (45 with PHPT, 7 with THPT) who underwent PTX in our center between 2015 and 2017 to identify post-PTX kidney injury. Their clinical data, including urinary liver-type fatty acid-binding protein (L-FABP), a tubular biomarker for acute kidney injury (AKI), were obtained from patient charts. An absolute change in serum creatinine level of 0.3 mg/dL (26.5 µmol/L) on Day 2 after PTX defines AKI. Post-PTX calcium supplement dose adjustment was performed to strictly maintain serum calcium at the lower half of the normal range. To mimic post-PTX-related kidney status, a unique parathyroidectomized rat model was produced as follows: 13-week-old rats underwent thyroparathyroidectomy (TPTX) and/or 5/6 subtotal nephrectomy (NX). Indicated TPTX rats were given continuous infusion of a physiological level of 1-34 PTH using a subcutaneously implanted osmotic minipump. Immunofluorescence analyses were performed by polyclonal antibodies against PTH receptor (PTHR) and a possible key modulator of kidney injury, Klotho. RESULTS: Patients' estimated glomerular filtration rate (eGFR) did not have any clinically relevant change (62.5 ± 22.0 versus 59.4 ± 21.9 mL/min/1.73 m2, NS), whereas serum calcium (2.7 ± 0.18 versus 2.2 ± 0.16 mmol/L, P < 0.0001) and phosphorus levels (0.87 ± 0.19 versus 1.1 ± 0.23 mmol/L, P < 0.0001) were normalized and PTH decreased robustly (181 ± 99.1 versus 23.7 ± 16.8 pg/mL, P < 0.0001) after successful PTX. However, six patients who met postsurgical AKI criteria had lower eGFR and greater L-FABP than those without AKI. Receiver operating characteristics (ROC) analysis revealed eGFR <35 mL/min/1.73 m2 had 83% accuracy. Strikingly, L-FABP >9.8 µg/g creatinine had 100% accuracy in predicting post-PTX-related AKI. Rat kidney PTHR expression was lower in TPTX. PTH infusion (+PTH) restored tubular PTHR expression in rats that underwent TPTX. Rats with TPTX, +PTH and 5/6 NX had decreased PTHR expression compared with those without 5/6 NX. 5/6 NX partially cancelled tubular PTHR upregulation driven by +PTH. Tubular Klotho was modestly expressed in normal rat kidneys, whereas enhanced patchy tubular expression was identified in 5/6 NX rat kidneys. This Klotho and expression and localization pattern was absolutely canceled in TPTX, suggesting that PTH indirectly modulated the Klotho expression pattern. TPTX +PTH recovered tubular Klotho expression and even triggered diffusely abundant Klotho expression. 5/6 NX decreased viable tubular cells and eventually downregulated tubular Klotho expression and localization. CONCLUSIONS: Preexisting tubular damage is a potential risk factor for AKI after PTX although, overall patients with hyperparathyroidism are expected to keep favorable kidney function after PTX. Patients with elevated tubular cell biomarker levels may suffer post-PTX kidney impairment even though calcium supplement is meticulously adjusted after PTX. Our unique experimental rat model suggests that blunted tubular PTH/PTHR signaling may damage tubular cell viability and deteriorate kidney function through a Klotho-linked pathway.

Pre-operative Localisation of the Parathyroid Glands in Secondary Hyperparathyroidism: A Retrospective Cohort Study.

Complete parathyroidectomy (PTx) is essential during total PTx for secondary hyperparathyroidism (SHPT) to prevent recurrent and persistent hyperparathyroidism. Pre-operative imaging evaluations, including computed tomography (CT), ultrasonography (US), and Tc-99m sestamibi (MIBI) scans, are commonly performed. Between June 2009 and January 2016, 291 patients underwent PTx for SHPT after pre-operative evaluations involving CT, US, and MIBI scans, and the diagnostic accuracies of these imaging modalities for identifying the parathyroid glands were evaluated in 177 patients whose intact parathyroid hormone (PTH) levels were <9 pg/mL after the initial PTx. Additional PTx procedures were performed on 7 of 114 patients whose intact PTH levels were >9 ng/mL after PTx, and the diagnostic validities of the imaging modalities for the remnant parathyroid glands were evaluated. A combination of CT, US, and MIBI scans achieved the highest diagnostic accuracy (75%) for locating bilateral upper and lower parathyroid glands before initial PTx. The accuracies of CT, US, and MIBI scans with respect to locating remnant parathyroid glands before additional PTx were 100%, 28.6%, and 100%, respectively. A combination of CT, US, and MIBI scans is useful for initial PTx for SHPT, and CT and MIBI scans are useful imaging modalities for additional PTx procedures.

Effect of Oral Alfacalcidol on Clinical Outcomes in Patients Without Secondary Hyperparathyroidism Receiving Maintenance Hemodialysis: The J-DAVID Randomized Clinical Trial.

Importance: Patients with chronic kidney disease have impaired vitamin D activation and elevated cardiovascular risk. Observational studies in patients treated with hemodialysis showed that the use of active vitamin D sterols was associated with lower risk of all-cause mortality, regardless of parathyroid hormone levels. Objective: To determine whether vitamin D receptor activators reduce cardiovascular events and mortality in patients without secondary hyperparathyroidism undergoing hemodialysis. Design, Setting, and Participants: Randomized, open-label, blinded end point multicenter study of 1289 patients in 207 dialysis centers in Japan. The study included 976 patients receiving maintenance hemodialysis with serum intact parathyroid hormone levels less than or equal to 180 pg/mL. The first and last participants were enrolled on August 18, 2008, and January 26, 2011, respectively. The final date of follow-up was April 4, 2015. Interventions: Treatment with 0.5 µg of oral alfacalcidol per day (intervention group; n = 495) vs treatment without vitamin D receptor activators (control group; n = 481). Main Outcomes and Measures: The primary outcome was a composite measure of fatal and nonfatal cardiovascular events, including myocardial infarctions, hospitalizations for congestive heart failure, stroke, aortic dissection/rupture, amputation of lower limb due to ischemia, and cardiac sudden death; coronary revascularization; and leg artery revascularization during 48 months of follow-up. The secondary outcome was all-cause death. Results: Among 976 patients who were randomized from 108 dialysis centers, 964 patients were included in the intention-to-treat analysis (median age, 65 years; 386 women [40.0%]), and 944 (97.9%) completed the trial. During follow-up (median, 4.0 years), the primary composite outcome of cardiovascular events occurred in 103 of 488 patients (21.1%) in the intervention group and 85 of 476 patients (17.9%) in the control group (absolute difference, 3.25% [95% CI, -1.75% to 8.24%]; hazard ratio, 1.25 [95% CI, 0.94-1.67]; P = .13). There was no significant difference in the secondary outcome of all-cause mortality between the groups (18.2% vs 16.8%, respectively; hazard ratio, 1.12 [95% CI, 0.83-1.52]; P = .46). Of the 488 participants in the intervention group, 199 (40.8%) experienced serious adverse events that were classified as cardiovascular, 64 (13.1%) experienced adverse events classified as infection, and 22 (4.5%) experienced malignancy-related serious adverse events. Of 476 participants in the control group, 191 (40.1%) experienced cardiovascular-related serious adverse events, 63 (13.2%) experienced infection-related serious adverse events, and 21 (4.4%) experienced malignancy-related adverse events. Conclusions and Relevance: Among patients without secondary hyperparathyroidism undergoing maintenance hemodialysis, oral alfacalcidol compared with usual care did not reduce the risk of a composite measure of select cardiovascular events. These findings do not support the use of vitamin D receptor activators for patients such as these. Trial Registration: UMIN-CTR Identifier: UMIN000001194.

Development of Severe Hyperparathyroidism Despite Short-Term Renal Replacement Therapy.

BACKGROUND: We occasionally experience cases of severe secondary hyperparathyroidism (SHPT) that require parathyroidectomy (PTX) despite undergoing short-term renal replacement therapy (RRT). Because the characteristics of such cases have never been discussed, we aimed to elucidate the pathophysiology of severe SHPT after short-term RRT by retrospectively analyzing clinical data. METHODS: A total of 1013 patients with severe SHPT underwent PTX between January 2007 and April 2016 at Nagoya Daini Red Cross Hospital. Of these patients, 570 underwent RRT for ≥10 years (long RRT group) and 23 for ≤1 year (short RRT group). We retrospectively investigated and compared patient characteristics, preoperative data, subjective symptoms, and bone lesion incidence between the two groups. RESULTS: A higher proportion of subjects with congenital or hereditary diseases as primary disease for chronic kidney disease (CKD) (21.7% (5/23) vs. 6.3% (36/570); P = 0.016) and longer predialysis period (21.2 ± 14.0 vs. 10.1 ± 9.2 years; P < 0.001) were observed in the short RRT group than in the long RRT group. Furthermore, lower serum calcium and phosphate levels, heavier parathyroid glands, and severe bone lesions were observed in the short RRT group than in the long RRT group. CONCLUSION: Severe SHPT after short-term RRT appeared to occur because of long-term CKD before initiating RRT. Therefore, treating mineral and bone disorders during the early CKD stage might prevent severe SHPT development before initiating RRT.

Cinacalcet hydrochloride relieves hypercalcemia in Japanese patients with parathyroid cancer and intractable primary hyperparathyroidism.

Pharmacological treatment of hypercalcemia is essential for patients with parathyroid carcinoma and intractable primary hyperparathyroidism (PHPT). Use of the calcimimetic cinacalcet hydrochloride (cinacalcet) is an option to treat such patients. We investigated the efficacy and safety of cinacalcet in Japanese patients with parathyroid carcinoma and intractable PHPT. Five Japanese patients with parathyroid carcinoma and two with intractable PHPT were enrolled in an open-label, single-arm study consisting of titration and maintenance phases. Cinacalcet doses were titrated until the albumin-corrected serum calcium concentration decreased to 10.0 mg/dL or less or until dose escalation was considered not necessary or feasible. Serum calcium concentration at the baseline was 12.1 ± 1.3 mg/dL (mean ± standard deviation; range 10.4-14.6 mg/dL) and decreased to 10.1 ± 1.6 mg/dL (range 8.6-13.3 mg/dL) at the end of the titration phase with cinacalcet at a dosage of up to 75 mg three times a day. At the end of the titration phase, at least a 1 mg/dL reduction in serum calcium concentration from the baseline was observed in five patients (three with carcinoma and two with PHPT), and it decreased to the normocalcemic range in five patients (three with carcinoma and two with PHPT). Common adverse events were nausea and vomiting. One patient discontinued participation in the study because of an adverse event, liver disorder. Cinacalcet effectively relieved hypercalcemia in 60% of the Japanese patients with parathyroid carcinoma and might be effective in those with intractable PHPT. The drug might be tolerable and safe at a dosage of at most 75 mg three times a day.

Evaluation of Parathyroidectomy for Secondary and Tertiary Hyperparathyroidism by the Parathyroid Surgeons' Society of Japan.

Secondary hyperparathyroidism (SHPT) remains a serious complication in patients with chronic kidney disease, and some patients require parathyroidectomy. The Parathyroid Surgeons' Society of Japan (PSSJ) evaluated parathyroidectomy for SHPT and tertiary hyperparathyroidism (THPT) in Japan. The annual numbers of parathyroidectomies between 2004 and 2013 were evaluated using questionnaires. Since 2010, the PSSJ has registered the patients. In total, 826 patients from 42 institutions were registered. The annual number of parathyroidectomies for SHPT and THPT in Japan increased from 2004 to 2007 and then decreased markedly after 2007, with 296 operations performed in 2013. The number of women and men was almost equal (397/427). Median (interquartile range) age of these patients was 59.0 (24-87) years, the duration of hemodialysis before parathyroidectomy was 10.83 (0.0-38.7) years, and diabetic nephropathy was 87/826 (10.5%). Of these patients 59.6% were treated with cinacalcet at undergoing parathyroidectomy. In 75.3% of patients, a total parathyroidectomy with forearm autograft was performed. In 77.7% of patients, four or more parathyroid glands were removed during the initial operation. The incidences of husky voice and wound hemorrhage were 2.9% and 1.1%, respectively. The number of parathyroidectomies for SHPT in Japan decreased markedly after the introduction of cinacalcet. Based on the evaluation of registered patients, parathyroidectomies have been successfully performed at the institutions participating in the PSSJ.

Location Frequency of Missed Parathyroid Glands After Parathyroidectomy in Patients with Persistent or Recurrent Secondary Hyperparathyroidism.

BACKGROUND: Reoperative parathyroidectomy (RPTX) because parathyroid glands have been missed is frequently required in patients with secondary hyperparathyroidism (SHPT). The usual locations of these missed glands in patients with SHPT are yet to be fully elucidated. METHODS: We retrospectively investigated the locations of missed glands in 165 patients who underwent RPTX for persistent or recurrent SHPT at our institution from August 1982 to July 2014. At our institution, total parathyroidectomy with forearm autograft is the routine operative procedure for SHPT. We also routinely resect the thymic tongue. RESULTS: Of 165 patients, 82 underwent initial parathyroidectomy at our institution (Group A), and the remaining 83 underwent initial parathyroidectomy at other institutions (Group B). A total of 239 parathyroid glands were resected (Group A, 93; Group B, 146). Missed glands were most commonly located in the mediastinum (Group A, 22/93) and the thymic tongue (Group B, 31/146). CONCLUSIONS: In patients with persistent or recurrent SHPT, ectopic parathyroid glands are frequently located in the mediastinum and thymic tongue. Therefore, resecting the thymic tongue during the initial operation may reduce the need for RPTX.