Yoshihiro Tominaga

Depressed expression of Klotho and FGF receptor 1 in hyperplastic parathyroid glands from uremic patients.

Fibroblast growth factor 23 (FGF23) exerts its effect by binding to its cognate FGF receptor 1 (FGFR1) in the presence of its co-receptor Klotho. Parathyroid glands express both FGFR1 and Klotho, and FGF23 decreases parathyroid hormone gene expression and hormone secretion directly. In uremic patients with secondary hyperparathyroidism (SHPT), however, parathyroid hormone secretion remains elevated despite extremely high FGF23 levels. To determine the mechanism of this resistance, we measured the expression of Klotho, FGFR1, and the proliferative marker Ki67 in 7 normal and 80 hyperplastic parathyroid glands from uremic patients by immunohistochemistry. All uremic patients had severe SHPT along with markedly high FGF23 levels. Quantitative real-time reverse transcription PCR showed that the mRNA levels for Klotho and FGFR1correlated significantly with their semi-quantitative immunohistochemical intensity. Compared with normal tissue, the immunohistochemical expression of Klotho and FGFR1 decreased, but Ki67 expression increased significantly in hyperplastic parathyroid glands, particularly in glands with nodular hyperplasia. These results suggest that the depressed expression of the Klotho-FGFR1 complex in hyperplastic glands underlies the pathogenesis of SHPT and its resistance to extremely high FGF23 levels in uremic patients.

Histopathology, pathophysiology, and indications for surgical treatment of renal hyperparathyroidism

Morphological changes in the parathyroid glands evidently occur early during renal failure. Histopathological investigations have suggested that parathyroid cells initially increase diffusely with a normal lobular structure (diffuse hyperplasia). The parathyroid glands then become hyperplastic with some nodules (nodular hyperplasia). Cells in nodules grow monoclonally and proliferate aggressively, possibly induced by some kind of genetic abnormality. Pathophysiologically, in cells consisting of hyperplastic nodules, suppression of parathyroid hormone (PTH) secretion under the influence of excess extracellular calcium is more deranged, possibly due to a reduction of calcium-sensing receptors. Vitamin D receptor density decreases more severely in these cells, possibly causing abnormal PTH synthesis, PTH secretion, and even parathyroid cell proliferation. According to histopathological and pathophysiological findings, patients with nodular hyperplasia during renal hyperparathyroidism may be refractory to medical treatments, including calcitriol pulse therapy, and parathyroidectomy will become necessary. There is a relationship between the pattern of parathyroid hyperplasia and glandular weight in which glands weighing more than 500 mg may be pathognomonic of nodular hyperplasia. Glandular volume, estimated by ultrasonography, is one of several important criteria indicating parathyroidectomy. In order to prevent a recurrence of hyperparathyroidism, all nodular hyperplastic tissue should be extirpated.

Clonal analysis of nodular parathyroid hyperplasia in renal hyperparathyroidism

Abstract. Although it is well known that chronic renal failure induces parathyroid hyperplasia, the pathogenesis and development of this parathyroid lesion in this disease are poorly understood. Histopathologically, there is progression from diffuse to nodular hyperplasia, and each nodule consists of a single cell type with aggressive proliferative potential. Pathophysiologic and clinical investigations have suggested that neoplastic tumors may emerge from nodular hyperplasia. In this study the clonality of parathyroid tissue in nodular and diffuse hyperplasia in renal hyperparathyroidism was analyzed by a method based on restriction fragment length polymorphism of the X chromosome-linked phosphoglycerokinase gene and on random inactivation of the gene by methylation. DNA of peripheral lymphocytes was screened in 43 women undergoing parathyroidectomy for advanced renal hyperparathyroidism, and 10 of these patients appeared to be heterozygous. Fourteen specimens from these patients were available for clonal analysis. The analysis showed that all four specimens of diffuse hyperplasia were polyclonal, whereas all seven specimens from nodules in nodular hyperplasia and all three samples representing parathyroid tissue removed from forearm because of graft-dependent recurrence were revealed to be monoclonal. It is likely that the clonal origin of each nodule is independent. These results suggest that in renal hyperparathyroidism parathyroid glands initially grow diffusely and polyclonally, and then the cells in the nodules are later transformed monoclonally and proliferate aggressively. From the present study it can be concluded that nodular hyperplasia represents monoclonal parathyroid neoplasia, which might explain why patients with nodular hyperplasia in renal hyperparathyroidism are refractory to medical treatment, requiring parathyroidectomy. To prevent recurrences, nodular hyperplastic tissue should not be left at surgery.

Surgical Significance of Supernumerary Parathyroid Glands in Renal Hyperparathyroidism

Abstract. In secondary hyperparathyroidism (2HPT) fundamentally all parathyroid glands, including supernumerary glands, become hyperplastic, and stimulation of parathyroid glands continues after parathyroidectomy (PTx). Therefore supernumerary glands have special significance during surgery for 2HPT, whether persistent or recurrent HPT. In the present study 570 patients underwent initial total PTx with a forearm autograft. The frequency, type, location, histopathology, and clinical significance of the supernumerary glands were evaluated. At the initial operation 90 supernumerary glands were removed from 82 of 570 patients (14.4%); 12 patients (2.1%) required extirpation of supernumerary glands for persistent/recurrent HPT. Altogether 104 supernumerary glands were identified at operation in 94 of the 570 patients (16.5%). Among these 104 glands, 25 (24.0%) were of the rudimentary, or split, type and 79 (76.0%) of the proper type. Supernumerary glands were most frequently identified in the thymic tongue (53/104, 51.0%); 32 (60.4%) of these 53 glands were identified only microscopically. In 6 of the 570 cases (1.1%), reoperation was required for persistent HPT due to supernumerary glands located in the mediastinum, and 6 patients underwent neck reexploration for recurrence. Histopathologically, 61 of 104 (58.7%) supernumerary glands, including 36 glands recognized only microscopically, showed diffuse hyperplasia, and 43 (41.3%) displayed nodular hyperplasia. Residual small supernumerary glands with diffuse hyperplasia have the potential to be transformed to nodular hyperplasia during long-term hemodialysis. Therefore all parathyroid glands including supernumerary glands should, if possible, be removed at the initial operation. Routine removal of the thymic tongue and careful examination of the regions surrounding the lower poles of the thyroid, especially on the left side, are important steps in the surgical treatment.

Surgical treatment of renal hyperparathyroidism

Advanced secondary (renal) hyperparathyroidism induced by chronic renal disturbance is one of the most serious complications for long-term hemodialysis patients. Parathyroidectomy is indicated in patients with severely advanced renal hyperparathyroidism refractory to medical treatment (including calcitriol pulse therapy) and the clinical effect of parathyroidectomy is striking. However, skeletal deformity, vessel calcification, and remarkable reduction of bone content is irreversible, and it is important to perform parathyroidectomy at right time. Based on histopathological and pathophysiological investigations, nodular hyperplasia is monoclonal neoplasia with abnormal parathyroid hormone (PTH) response to extracellular calcium and vitamin D. When parathyroid hyperplasia progresses to nodular hyperplasia, parathyroidectomy should be required. Total parathyroidectomy with forearm autograft is the preferable procedure for renal hyperparathyroidism, especially for patients who need to continue hemodialysis treatment after parathyroidectomy. Removal of all parathyroid glands, including supernumerary glands, at the initial operation, and proper choice of adequate parathyroid tissue for autograft, are important to prevent persistent and recurrent hyperparathyroidism. Preoperative image diagnosis is useful for localization, and routine resection of thymic tissue is necessary to remove supernumerary glands. In our series of 548 patients, graft-dependent recurrent hyperparathyroidism was not negligible and the incidence was about 20% at the 5th year postoperatively. Enlarged autografts of parathyroid tissue could be removed from forearm under local anesthesia with fewer invasions. The function of autografted parathyroid tissue is nearly satisfactory and no re-transplantation of cryopreserved parathyroid tissue was necessary. To avoid adynamic bone disease, relatively high PTH level is required-over-suppression of PTH by excess of vitamin D and calcium salts should be avoided. In our experience, total parathyroidectomy with forearm autograft is very effective and adequate treatment for advanced renal hyperparathyroidism, and parathyroid function can be controlled after parathyroidectomy.

Effects of Serum Calcium, Phosphorous, and Intact Parathyroid Hormone Levels on Survival in Chronic Hemodialysis Patients in Japan

Abstract:  Disturbances in bone mineral metabolism are common in chronic hemodialysis (HD) patients and often underlie morbid conditions and mortality; however, no large epidemiological study for Asian dialysis patients has been performed. We analyzed the database of the Japanese Society for Dialysis Therapy registry. In this study, data from patients who were on HD at the end of 2000 was compiled. The Coxs proportional hazard analysis was carried out to evaluate the significance of the impact of variables related to bone mineral metabolism on survival after adjusting for possible confounding variables. The study period was three years, and a cohort of 27 404 HD patients was studied. The hazard ratios were 1.098 (P = 0.0129) for serum calcium levels ranging 10.0–10.9 mg/dL, and 1.243 (P = 0.0001) for serum calcium levels >11.0 mg/dL when the reference serum calcium level range was 9.0–9.9 mg/dL. Similarly, the hazard ratios were significantly higher in a serum phosphorous level of 5.0 mg/dL than for the reference serum phosphorous level range of 4.0–4.9 mg/dL. For intact parathyroid hormone (iPTH), the hazard ratios were significantly small (<119 pg/mL) when the reference iPTH level range was 180–359 pg/mL. However, the hazard ratio did not increase when the iPTH level increased to >360 pg/mL. Results showed that disturbances in bone mineral metabolism, such as those involving serum calcium, phosphorous, and iPTH, have a significant impact on survival in Japanese dialysis patients.

Subtotal versus total parathyroidectomy with forearm autograft for secondary hyperparathyroidism in chronic renal failure

Forty-three patients with chronic renal failure and secondary hyperparathyroidism underwent parathyroidectomy; 20 of the 43 underwent subtotal parathyroidectomy (Group A) and 23 patients underwent total parathyroidectomy and parathyroid autotransplant in the forearm (Group B). Postoperative clinical improvement was similar in both groups. In the immediate postoperative period eight patients in Group A who had severe bone changes and 21 patients in Group B needed supplemental calcium administration. The grafted tissues in all cases functioned well; ***relmplantation of the cryopreserved parathyroid tissues was unnecessary. One case in each group showed a recurrence. One patient in Group A was submitted to reexploration of the neck with a lateral approach. The other patient in Group B underwent excisions of the transplanted parathyroid tissues on three separate occasions under local anesthesia. The second operation was definitely easier and safer to manage after a total parathyroidectomy with autotransplantation to the forearm.

Molecular genetics of hyperparathyroid disease.

Information on genetic abnormalities in primary hyperparathyroidism has accumulated gradually. Genetic alterations responsible for tumorigenesis have been identified in multiple endocrine neoplasia types 1 and 2. Point mutations in a calcium-sensing receptor gene were recently found to be responsible for familial hypocalciuric hypercalcaemia and neonatal severe hyperparathyroidism. Evidence has been provided that abnormalities of cell cycle regulation participate at tumorigenesis in parathyroid adenoma and carcinoma. Clonal analysis has shown that in renal hyperparathyroidism the parathyroid glands initially grow diffusely and polyclonally, after which foci of nodular hyperplasia are transformed to monoclonal neoplasia. Somatic changes of specific genes have been suspected of being responsible for parathyroid tumorigenesis in renal hyperparathyroidism. However, the genetic loci responsible for the frequent monoclonality largely remain to be identified, and heterogeneous genetic abnormalities may contribute to the progression of secondary parathyroid hyperplasia.

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.