Tetsuhiko Sato

Surgical Indications and Procedures of Parathyroidectomy in Patients with Chronic Kidney Disease

Abstract:  The Kidney Foundation of the USA proposed clinical practice guidelines for bone metabolism and disease in chronic kidney disease including parathyroidectomy (PTx). We performed PTx in a total of 1725 patients with advanced secondary hyperparathyroidism (2HPT) and evaluated the K/DOQI guideline concerning PTx, comparing it with our surgical strategy. The guidelines emphasize the avoidance of ectopic calcification and cardiovascular complications which may be induced by hypercalcemia, hyperphosphatemia, and persistent high parathyroid hormone level. We agree with the attitude of the K/DOQI guideline. To decide surgical indications, we emphasize that the size of parathyroid gland is one of the important factors. The guideline recommends subtotal PTx and total PTx with autotransplantation. We prefer total PTx with forearm autograft, mainly because it is easier and safer to remove the residual parathyroid tissue from the forearm at recurrence compared to neck re‐exploration. In Japan, almost all patients require long‐term hemodialysis after PTx because of the very small opportunity of kidney transplantation. The risk of recurrence is not negligible. Based on our huge experience we believe our strategy for advanced secondary hyperparathyroidism can be accepted at least in Japan.  

Diabetes mellitus after transplant: relationship to pretransplant glucose metabolism and tacrolimus or cyclosporine A-based therapy.

Objective. The purpose of this study was to identify pretransplantation and posttransplantation indicators for the development of diabetes mellitus in the first 2 months after renal transplantation and to examine the influence of a cyclosporine A (CsA)-based versus a tacrolimus-based immunosuppressive regimen on these risk factors. Methods. Key variables associated with the development of posttransplant diabetes mellitus (PTDM) in the first 2 months after transplantation were assessed in 48 patients who underwent living-related renal transplantation and who were treated with a CsA-based or a tacrolimus-based immunosuppressive regimen. The insulinogenic index (I Index) and glucose infusion rate (GIR) were measures of insulin secretion and insulin sensitivity, respectively. Results. Eight patients developed PTDM. I Index (odds ratio, 0.000384) and GIR (odds ratio, 0.349) were significant risk factors for PTDM development. The cumulative steroid dose had a borderline association. PTDM developed in 4 of 28 CsA-treated patients and in 4 of 20 tacrolimus-treated patients. CsA therapy increased the mean I Index from 0.713±0.071 preoperatively to 1.130±0.140 postoperatively (P <0.01), whereas in tacrolimus-treated patients, I Index remained unchanged (1.09±0.264 preoperatively and 0.949±0.296 postoperatively; P =not significant). Age, duration of pretransplant dialysis, and body mass index did not predict PTDM development. All eight patients with PTDM had hypertension. Conclusions. Pre- and posttransplant abnormalities of insulin secretion and sensitivity are significant predictors of PTDM. Corticosteroid cumulative dose may affect the incidence of PTDM during the first 2 months after transplantation. CsA treatment increases insulin secretion in patients with a high pretransplant risk of PTDM.

EGFR Activation Increases Parathyroid Hyperplasia and Calcitriol Resistance in Kidney Disease

Calcitriol, acting through vitamin D receptors (VDR) in the parathyroid, suppresses parathyroid hormone synthesis and cell proliferation. In secondary hyperparathyroidism (SH), VDR content is reduced as hyperplasia becomes more severe, limiting the efficacy of calcitriol. In a rat model of SH, activation of the EGF receptor (EGFR) by TGF-alpha is required for the development of parathyroid hyperplasia, but the relationship between EGFR activation and reduced VDR content is unknown. With the use of the same rat model, it was found that pharmacologic inhibition of EGFR activation with erlotinib prevented the upregulation of parathyroid TGF-alpha, the progression of growth, and the reduction of VDR. Increased TGF-alpha/EGFR activation induced the synthesis of liver-enriched inhibitory protein, a potent mitogen and the dominant negative isoform of the transcription factor CCAAT enhancer binding protein-beta, in human hyperplastic parathyroid glands and in the human epidermoid carcinoma cell line A431, which mimics hyperplastic parathyroid cells. Increases in liver-enriched inhibitory protein directly correlated with proliferating activity and, in A431 cells, reduced VDR expression by antagonizing CCAAT enhancer binding protein-beta transactivation of the VDR gene. Similarly, in nodular hyperplasia, which is the most severe form of SH and the most resistant to calcitriol therapy, higher TGF-alpha activation of the EGFR was associated with an 80% reduction in VDR mRNA levels. Thus, in SH, EGFR activation is the cause of both hyperplastic growth and VDR reduction and therefore influences the efficacy of therapy with calcitriol.

Recurrent renal hyperparathyroidism caused by parathyromatosis.

BackgroundParathyromatosis is defined as multiple foci of benign hyperfunctioning parathyroid tissue in the neck or mediastinum. Parathyromatosis is a problematic cause of recurrent hyperparathyroidism (HPT). In renal HPT, the stimuli of the parathyroid cells persist after parathyroidectomy (PTx), and for this reason, parathyromatosis might be important in renal HPT.MethodsBetween July 1973 and December 2005, 1,932 patients underwent PTx for advanced renal HPT in our department. We evaluated the frequency, clinical findings and the prognosis of this kind of parathyroid disorder.ResultsAfter total PTx with forearm autograft for renal HPT, which was performed initially in our department, the risk for developing parathyromatosis was 0.11% (2/1837); after sub-total PTx, it was 5% (1/20). The risk for developing parathyromatosis was lower after total PTx with forearm autograft than after sub-total PTx (P < 0.05). In patients who developed persistent or recurrent HPT and were referred to our department for neck re-operation, parathyromatosis occurred in 12.1% (7/58); in those originally operated on at our hospital, the corresponding figure was 7.1% (3/42). This difference was not significant (P = 0.42). Only in 4 of 10 patients was parathyromatosis suggested before re-operation. However, in spite of several re-operations, high parathyroid hormone (PTH) levels persisted in 6 of 10 patients with parathyromatosis.ConclusionParathyromatosis is a non-negligible cause of recurrent renal HPT in patients who require neck re-exploration. Parathyromatosis is difficult to diagnose pre-operatively and completely controlled by re-operation. Parathyromatosis should be kept in mind when performing neck re-exploration for recurrent renal HPT.

Clinical Features and Hyperplastic Patterns of Parathyroid Glands in Hemodialysis Patients With Advanced Secondary Hyperparathyroidism Refractory to Maxacalcitol Treatment and Required Parathyroidectomy

Abstract:  We have previously suggested that when parathyroid glands progress to nodular hyperplasia, secondary hyperparathyroidism (2HPT) may be refractory to medical treatments, including treatment with Maxacalcitol (OCT). In the present study we evaluated the clinical features and hyperplastic patterns of parathyroid glands in patients who underwent parathyroidectomy (PTx) after being withdrawn from OCT. One hundred and eighty‐seven advanced 2HPT patients who had been withdrawn from OCT and required PTx were enrolled. At the start of OCT treatment, the patients had a mean age of 55.3 years and had been receiving hemodialysis (HD) for a mean period of 149 months. At the start of OCT treatment and at PTx, the mean intact PTH (i‐PTH) levels were 772.8 ± 446.0 and 855.5 ± 420.5 pg/mL, respectively. The main reasons for withdrawal of OCT treatment were persistently high PTH (n = 148), hypercalcemia (n = 79), hyperphosphatemia (n = 65), and progressive symptoms (n = 60). We classified the parathyroid glands by hyperplastic pattern into four categories: diffuse hyperplastic gland (D), early nodularity in diffuse hyperplastic gland (EN), nodular hyperplastic gland (N), and single nodular gland (SN). The mean total excised gland weight was 2592.6 mg. Out of a total of 706 glands, 118 were classified as D, 66 as EN, 436 as N, and 86 as SN. All patients had at least one nodular hyperplastic gland or single nodular gland. The mean number of nodular hyperplastic glands and/or single nodular glands was 2.9. All hemodialysis patients with advanced OCT‐refractory 2HPT who underwent PTx had at least one nodular hyperplastic gland or single nodular gland.

Cardiovascular complications caused by advanced secondary hyperparathyroidism in chronic dialysis patients; special focus on dilated cardiomyopathy.

BackgroundThe frequency and prognosis of dilated cardiomyopathy (DCM) caused by secondary hyperparathyroidism (2°HPT) is not known. The purpose of this study was to determine the morbidity of DCM caused by 2°HPT and the efficacy of parathyroidectomy (PTx) in chronic dialysis patients with advanced 2°HPT was analyzed prospectively.MethodsBetween November 2000 and January 2003, 237 dialysis patients who underwent total PTx with forearm autograft at our department were enrolled in this study. Cardiac complications that existed before PTx were examined. Ten patients (4%) had DCM without valvular disease (VD) or ischemic heart disease (IHD). In these 10 patients with DCM before operation, we estimated left ventricular (LV) function at 6 months after PTx, according to echocardiography findings and clinical symptoms.ResultsSix months after PTx, left ventricular ejection fraction (LVEF) in these 10 patients was significantly improved, from 31.0 ± 9.8% before PTx, to 56.8 ± 13.5% (P = 0.0003), and left ventricular end-diastolic dimension (LVDd) was reduced, from 59.8 ± 9.7 mm to 46.3 ± 7.0 mm (P = 0.0014). The symptoms due to DCM and the fall of blood pressure that had occurred during dialysis were clearly improved after PTx.ConclusionsAdvanced 2°HPT can influence LV function, and in patients who suffered from DCM, LV function was dramatically improved by PTx. PTx should be performed immediately in patients with DCM caused by 2°HPT.

Reoperation for renal hyperparathyroidism

Abstract Reoperation for secondary hyperparathyroidism (HPT) due to uremia (2HPT) may be required among patients with persistent renal failure if not all parathyroid glands are removed at the initial operation. Between March 1981 and July 2001, altogether 1110 patients underwent total parathyroidectomy with forearm autograft for advanced 2HPT in our department. In this study, we evaluated the clinical features of patients who required reoperation and classified them into persistent HPT [the lowest intact parathyroid (PTH) level after initial operation remained higher than 60 pg/ml] and recurrent HPT (the lowest intact PTH level was normalized after surgery but reelevated became high enough to require reoperation). Removal of residual glands was indicated in 30 (2.7%) cases for persistent or recurrent HPT. All remaining glands were detected by preoperative imaging diagnoses. In 44 (4.0%) patients persistent HPT was recognized and in 15 of them (1.4% of all cases) reoperation was required. In 11 cases, the responsible glands were supernumerary ones removed from the mediastinum. In 4 cases, the glands were resected from the neck. In 15 cases (1.4%), reoperation was performed for recurrent HPT when residual glands were left either in the neck or in the thymic tongue. In all but one case, the missed glands were supernumerary. This study reveals that it is often difficult to avoid persistent HPT induced by mediastinal supernumerary glands and recurrent HPT caused by small glands left in the neck. Our findings indicate that patients with uremia should be closely followed considering the possibility that persistent or recurrent HPT may occur after parathyroidectomy.

Parathyroidectomy for Secondary Hyperparathyroidism in the Era of Calcimimetics

Secondary hyperparathyroidism (SHPT) is one of the major complications experienced by patients with renal failure. Cinacalcet hydrochloride, a calcimimetic, is a new modality for the treatment of SHPT and is able to suppress a high parathyroid hormone level remarkably well. However, for patients with uncontrollable SHPT while on cinacalcet, those with severe SHPT symptoms and those with difficulty being treated with cinacalcet because of side‐effects, parathyroidectomy (PTx) may be indicated as usual. PTx can induce a remarkable improvement in SHPT: postoperative serum phosphorus and calcium levels are easily maintained within their target ranges, quality of life is improved, survival rates are improved and the procedure has high cost‐effectiveness, so for the patients with SHPT refractory to conventional vitamin D or vitamin D analog treatment in whom long‐term survival is expected, PTx might be a more preferable treatment. On the other hand, cinacalcet is the first choice for patients in whom it is difficult to manage SHPT with PTx. Indications are patients (i) for whom surgery under general anesthesia would be highly invasive; (ii) whose parathyroid glands are located in an area making resection difficult; (iii) in whom the affected parathyroid tissues are difficult to identify; (iv) in whom it is difficult to resect all affected parathyroid tissues; and (v) who have undergone repeated surgery or percutaneous ethanol injection therapy and may develop serious complications such as bilateral recurrent laryngeal nerve paralysis. Cinacalcet may be a rescuer treatment for these patients.

Expression of Parafibromin in Distant Metastatic Parathyroid Tumors in Patients with Advanced Secondary Hyperparathyroidism Due to Chronic Kidney Disease

BackgroundRecently, somatic inactivating mutations in HRPT2 have been reported in the majority of sporadic parathyroid carcinoma in primary hyperparathyroidism (HPT). Parafibromin is a tumor suppressor protein encoded by HRPT2, and loss of nuclear expression of parafibromin was found in approximately 70% of the carcinoma. In secondary HPT due to chronic kidney disease (CKD), parathyroid carcinoma is very rare and whether HRPT2 plays a role in the carcinogenesis in these cases is not clear. We evaluated the expression of parafibromin in hemodialysis patients with distant metastatic parathyroid tumors.MethodsBetween June 1973 and December 2006, 2,142 patients underwent parathyroidectomy (PTx) for secondary HPT in our department. We encountered five (0.23%) patients with distant metastatic parathyroid tumors. We evaluated the immunohistochemistry for parafibromin in eight primary parathyroid glands removed from the neck at the initial operation and/or at reoperation and seven distant metastatic tumors resected at reoperation.ResultsIn only one lung metastatic parathyroid tumor, negative staining for parafibromin was detected. In the other three lung, two regional node, and one chest wall metastatic parathyroid tumor, parafibromin was strongly stained in the nuclei of the parathyroid cells. Among eight primary glands, except for one with weakly positive staining, the expression of parafibromin was detected diffusely and strongly.ConclusionWe conclude that the inactivating mutations and/or allelic loss of the HRPT2 gene may not play a major role in parathyroid carcinogenesis in secondary HPT due to CKD, but in these cases cancer development may be associated with a heterogeneous genetic disorder.

QuiCk-IntraOperative Bio-Intact PTH Assay at Parathyroidectomy for Secondary Hyperparathyroidism

BackgroundIn uremic patients, metabolism of 1-84 parathyroid hormone (PTH) and fragments are delayed, and in these patients, the usefulness of intraoperative PTH assay may be problematic. We evaluated the usefulness of the QuiCk-IntraOperative Bio-Intact PTH (QPTH) assay for uremic patients with secondary hyperparathyroidism who required total parathyroidectomy (PTx) with forearm autograft. The purpose of our study was to recognize whether QPTH in uremic patients was useful to determine during operation whether complete PTx had been achieved.MethodsForty-four patients who underwent initial PTx were enrolled in this study. Blood samples were drawn just after induction of general anesthesia (basal samples), immediately after removal of the last gland, and at 5, 10, 15, and 30 minutes, and at the first morning after PTx. The assay was performed immediately after sample collection. Reductions of PTH levels were evaluated and expressed in percentage of basal levels.ResultsThe mean PTH levels in 41 patients, excluding 3 in whom the PTH level did not drop significantly (>60 pg/ml), measured by QPTH at anesthesia, 0, 5, 10, 15, and 30 minutes were 734.3, 104.7, 58.8, 37.4, 27.0, 16.3 pg/ml, corresponding to 100%, 17.1%, 9.3%, 5.8%, 4.1%, 2.4% of the preexcision values, respectively. If the cutoff value was defined as 10.8% at 10 minutes, the sensitivity was 100% and specificity 90%. When the QPTH level dropped to under 10.8% at 10 minutes, we could consider that all glands were removed.ConclusionsQPTH in uremic patients is very useful to determine whether complete PTx is achieved during operation.