Secondary Hyperparathyroidism In Uremia Research Articles

Clinical Study of Percutaneous Puncture Radiofrequency Ablation Guided by CT Image Information Technology in Patients with Secondary Hyperparathyroidism of Uremia

Objective: To investigate the effectiveness and safety of CT-guided percutaneous radiofrequency ablation for the treatment of secondary hyperparathyroidism (SHPT) in chronic renal failure. Methods: Thirty patients with SHPT in our hospital were selected as the study subjects. Preoperative CT examinations confirmed that there were 1 to 4 hyperplastic parathyroid tissues. Under the guidance of CT, radiofrequency ablation of the hyperplastic parathyroid tissues was performed to detect ablation The levels of PTH, blood Ca, and blood P before and after 10 min, 1 d, 1 week, 1 month, 6 months, and 1 year of ablation were observed to observe the improvement of clinical symptoms and the occurrence of complications. Results: First, the patients' blood PTH levels at 10 min, 1 d, 1 week, 1 month, 6 months, and 1 year after ablation were significantly lower than those before the ablation (P < 0.05); 10 min, 1 d, Blood Ca levels at 1 week, 1 month, 6 months, and 1 year were significantly lower than those before ablation (P < 0.05); 10 min, 1 d, 1 week, 1 month, 6 months, and 1 month after ablation The blood P level in 2015 was significantly lower than that before ablation (P < 0.05). Second, the symptoms of bone pain, itching of the skin, muscle weakness, and anorexia were significantly improved after ablation, and hoarseness occurred in 3 cases. The rate was 10%, all of which remitted spontaneously within 1 week after operation; 2 cases of severe hypocalcemia occurred with a rate of 6.6%. All patients had remission after timely calcium supplementation, and all patients did not relapse. Conclusion: CT-guided percutaneous radiofrequency ablation is a safe and effective method for the treatment of SHPT, which can significantly improve the symptoms of renal bone disease and improve the quality of life.

Effect of etelcalcetide on parathyroid hormone secretion by primary hyperparathyroidism patient-derived primary parathyroid cells.

Etelcalcetide (Parsabiv®, AMG 416/ONO-5163) is a novel allosteric modulator for the calcium-sensing receptor approved for hemodialysis patients with secondary hyperparathyroidism of uremia. Etelcalcetide reduced parathyroid hormone levels in hemodialysis patients with secondary hyperparathyroidism of uremia in clinical studies. However, its direct effect on parathyroid hormone secretion in human parathyroid cells remains unknown. This study aimed to determine if etelcalcetide suppresses parathyroid hormone secretion by human parathyroid cells in vitro. We prepared primary cell cultures from human parathyroid tissue and determined calcium-sensing receptor expression levels by immunohistochemistry. Pathyroid tumors were removed from fourteen patients with primary hyperparathyrodism. Parathyroid tissue was dispersed with collagenase, resuspended in culture medium, incubated for 2h with etelcalcetide and Ca2+, and the medium was then collected. Final etelcalcetide concentrations in the medium were 0.005-50µmol/L. Levels of human parathyroid hormone in the medium were determined by enzyme-linked immunosorbent assay. In eight of the fourteen parathyroid cell cultures, extracellular Ca2+ reduced parathyroid hormone levels. In four of the eight parathyroid cell cultures which responded extracellular Ca2+, etelcalcetide reduced hormone secretion with the 50% effective concentrations of 0.57, 20.8, 0.42, and 0.57µmol/L. Expression levels of the calcium-sensing receptor were significantly lower in primary hyperparathyroidism patient-derived parathyroid tissues compared with controls. This is the first report that etelcalcetide directly reduced parathyroid hormone secretion from the primary cultured human parathyroid cells from patients with primary hyperparathyroidism. To verify this conclusion, further studies are needed using secondary hyperparathyroidism patient-derived parathyroid cells.

Parathyroid Diseases and Animal Models

Circulating calcium and phosphate are tightly regulated by three hormones: the active form of vitamin D (1,25-dihydroxyvitamin D), fibroblast growth factor (FGF)-23, and parathyroid hormone (PTH). PTH acts to stimulate a rapid increment in serum calcium and has a crucial role in calcium homeostasis. Major target organs of PTH are kidney and bone. The oversecretion of the hormone results in hypercalcemia, caused by increased intestinal calcium absorption, reduced renal calcium clearance, and mobilization of calcium from bone in primary hyperparathyroidism. In chronic kidney disease, secondary hyperparathyroidism of uremia is observed in its early stages, and this finally develops into the autonomous secretion of PTH during maintenance hemodialysis. Receptors in parathyroid cells, such as the calcium-sensing receptor, vitamin D receptor, and FGF receptor (FGFR)-Klotho complex have crucial roles in the regulation of PTH secretion. Genes such as Cyclin D1, RET, MEN1, HRPT2, and CDKN1B have been identified in parathyroid diseases. Genetically engineered animals with these receptors and the associated genes have provided us with valuable information on the patho-physiology of parathyroid diseases. The application of these animal models is significant for the development of new therapies.

1289: Percutaneous Bi-Polar Radiofrequency Ablation for Treating Secondary Hyperparathyroidism in Uremia

1289: Percutaneous Bi-Polar Radiofrequency Ablation for Treating Secondary Hyperparathyroidism in Uremia

Animal models of hyperfunctioning parathyroid diseases for drug development

Background: Disorders of mineral and bone metabolism have been implicated as a risk factor in the high mortality in patients with chronic kidney disease (CKD). Hyperphosphatemia, disorders of vitamin D metabolism and secondary hyperparathyroidism of uremia (SHPT) are therapeutic targets in these patients to improve the mortality. Animal models for CKD are indispensable and uremic rats produced by 5/6-nephrectomies are one of the most useful animal models for the development of new therapeutic agents. As there are limitations of uremic rats such as short lifespan and less severity of secondary hyperparathyroidism distinct from CKD patients on maintenance hemodialysis, the development of new model animals is expected. Objective: This review discusses the molecular pathogenesis of hyperfunctioning parathyroid diseases and the applications of animal models exhibiting hyperparathyroidisms in the aspect of the development of new therapeutics. Conclusion: PTH–cyclin D1 transgenic mice, with parathyroid-targeted overexpression of cyclin D1 oncogene, not only developed abnormal parathyroid cell proliferation but, notably, also developed biochemical hyperparathyroidism with characteristic abnormalities in bone. The mice exhibit age-dependent development of biochemical hyperparathyroidism, which enables testing of the drug precisely. In addition, the mice develop parathyroid cell hyperplasia, followed by monoclonal expansion, which is observed in refractory SHPT patients.

Direct in vitro evidence of the suppressive effect of cinacalcet HCl on parathyroid hormone secretion in human parathyroid cells with pathologically reduced calcium-sensing receptor levels

Clinical studies have been performed to determine the effect of cinacalcet HCl (cinacalcet), an allosteric modulator of the calcium-sensing receptor (CaR), on primary hyperparathyroidism (PHPT) and secondary hyperparathyroidism of uremia (SHPT). However, no in vitro studies on human parathyroid cells have been reported to date. In this study, the inhibitory effect of cinacalcet on PTH secretion was analyzed in primary cultured parathyroid cells obtained from patients. The investigation involved three PHPT and three SHPT patients subjected to therapeutic parathyroidectomy. Notably, all SHPT patients were resistant to intravenous vitamin D analogue therapy. Removed parathyroid tumors were used for immunohistochemistry and parathyroid cell primary culture. Immunohistochemical analyses revealed diminished expression of CaR and vitamin D receptor (VDR) in all parathyroid tumors. PTH secretion from cultured parathyroid cells of PHPT and SHPT patients was suppressed by extracellular Ca2+ and cinacalcet in a dose-dependent manner. Rates of suppression of PTH secretion in PHPT and SHPT by cinacalcet (1000 nmol/l) were 61% +/- 21% and 61% +/- 19%, respectively. Cinacalcet demonstrates significant potency in the suppression of PTH secretion in primary cultured human parathyroid cells in vitro, despite reduced levels of the target protein, CaR. Data from this in vitro analysis support the clinical application of cinacalcet in PHPT and SHPT therapy.

Genetics in secondary hyperparathyroidism of uremia

Little is known about genetic alterations in parathyroid hyperplasias in uremic patients. Although overexpression of cyclin D1 and inactivation of MEN1 gene are found in subsets of common parathyroid adenomas, specific oncogenes or tumor suppressor genes contributing to monoclonal uremic hyperparathyroidism have not yet been identified. On the other hand, some candidate gene polymorphisms have been suggested to play a key role in the pathogenesis of this disease.

Genetic aspects of secondary hyperparathyroidism in uremia

In addition to the well-known uremia-related factors calcium, phosphate, and vitamin D, genetic polymorphisms and gene mutations appear to have a role as well in modulating parathyroid function. Allelic polymorphisms of the vitamin D receptor gene have been most often examined but to date their precise place is not yet certain in patients with chronic renal failure. The frequent transformation of parathyroid cell proliferation from polyclonal to monoclonal growth in patients with severe secondary hyperparathyroidism must be attributed to mutations or deletions of various tumor-suppressor genes, and probably more rarely also to an activation of tumor-enhancer genes. © 2001 by the National Kidney Foundation, Inc.

Rare Somatic Inactivation of the Multiple Endocrine Neoplasia Type 1 Gene in Secondary Hyperparathyroidism of Uremia

Rare Somatic Inactivation of the Multiple Endocrine Neoplasia Type 1 Gene in Secondary Hyperparathyroidism of Uremia

Rare somatic inactivation of the multiple endocrine neoplasia type 1 gene in secondary hyperparathyroidism of uremia.

The molecular pathway of autonomous growth of the parathyroid glands in uremic patients is poorly understood. Loss of heterozygosity at the recently identified multiple endocrine neoplasia type 1 (MEN1) gene locus on chromosome 11q13 has been found in a subset of parathyroid glands from patients with refractory hyperparathyroidism. To clarify the role of the MEN1 gene in parathyroid tumorigenesis, we analyzed 81 parathyroid glands from 22 Japanese uremic patients for allelic loss on chromosomal arm 11q13 DNA using 3 flanking markers (PYGM, D11S4946, and D11S449) and for mutations of the MEN1-coding exons by PCR-based single strand conformation polymorphism analysis and sequencing. Allelic loss on 11q13 was observed in 6 glands (7%), and 1 of 6 demonstrated a previously unrecognized somatic frameshift deletion (331delG) of the MEN1 gene. This mutation would probably result in a nonfunctional menin protein, consistent with a tumor suppressor mechanism. Clinical and pathological characteristics of hyperparathyroidism were unrelated to the presence or absence of loss of heterozygosity on 11q13 and MEN1 gene mutations. These observations indicate that somatic inactivation of the MEN1 gene contributes to the pathogenesis of uremia-associated parathyroid tumors, but its role in this disease appears to be very limited.

Medical Management of Secondary Hyperparathyroidism in Uremia

The prevention and treatment of the secondary hyperparathyroidism of chronic renal failure by medical means relies on a number of different possible approaches, which should be tailored to each patient's individual needs. Schematically, prevention should start early during the course of chronic renal failure (ie, when plasma intact parathyroid hormone is normal or only slightly elevated). Small calcium supplements prevent the development of a calcium deficit and may prevent parathyroid hormone oversecretion. The various therapeutic options that are available at present include: oral or intravenous vitamin D and vitamin D derivatives, in particular the 1alpha-hydroxylated vitamin D compounds; oral calcium supplements (calcium carbonate and calcium acetate) to avoid calcium depletion and also to bind phosphate in the intestinal lumen; aluminum-containing phosphate binders, the use of which should be restricted; oral magnesium salts (magnesium carbonate and magnesium hydroxide), which often are not well tolerated; general measures, such as dietary restriction of phosphate intake; and, in the case of resistance to all these approaches, the possibility of attempting ultrasound-guided ethanol injection of grossly hyperplastic parathyroid glands. Finally, it is encouraging to know that new drugs are in development, including calcium-free, aluminum-free, nonabsorbable oral phosphate binders, potentially nonhypercalcemic vitamin D derivatives, and calcimimetics. Some of them already have entered the stage of clinical evaluation, and preliminary results are promising.

Surgical Management of Secondary Hyperparathyroidism in Uremia

Advanced secondary (renal) hyperparathyroidism (HPT) induced by uremia is one of the most serious complications for long-term hemodialysis patients. Parathyroidectomy (PTx) is indicated in patients with severely advanced renal HPT that is refractory to medical treatment, including calcitriol pulse therapy. The clinical effect of PTx is striking. However, skeletal deformity, vessel calcification, and remarkable reduction of bone content is irreversible. Therefore, it is important to perform PTx at the right time. Based on histopathological and pathophysiological investigations, nodular hyperplasia is monoclonal neoplasia with abnormal parathyroid hormone response to extracellular calcium and vitamin D. When parathyroid hyperplasia progresses to nodular hyperplasia, PTx should be required. Total PTx with forearm autograft is the preferred procedure for renal HPT, especially for patients who need to continue hemodialysis treatment after PTx. 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 HPT. In this series of 782 patients, the function of autografted parathyroid tissue is almost satisfactory and no retransplantation of cryopreserved parathyroid tissue was necessary; however, graft-dependent recurrent HPT was not negligible. In conclusion, total PTx with forearm autograft is very effective and adequate treatment for advanced renal HPT and parathyroid function can be controlled after PTx.

Medical Management of Secondary Hyperparathyroidism in Uremia

Medical Management of Secondary Hyperparathyroidism in Uremia

Surgical management of secondary hyperparathyroidism in uremia.

Advanced secondary (renal) hyperparathyroidism (HPT) induced by uremia is one of the most serious complications for long-term hemodialysis patients. Parathyroidectomy (PTx) is indicated in patients with severely advanced renal HPT that is refractory to medical treatment, including calcitriol pulse therapy. The clinical effect of PTx is striking. However, skeletal deformity, vessel calcification, and remarkable reduction of bone content is irreversible. Therefore, it is important to perform PTx at the right time. Based on histopathological and pathophysiological investigations, nodular hyperplasia is monoclonal neoplasia with abnormal parathyroid hormone response to extracellular calcium and vitamin D. When parathyroid hyperplasia progresses to nodular hyperplasia, PTx should be required. Total PTx with forearm autograft is the preferred procedure for renal HPT, especially for patients who need to continue hemodialysis treatment after PTx. 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 HPT. In this series of 782 patients, the function of autografted parathyroid tissue is almost satisfactory and no retransplantation of cryopreserved parathyroid tissue was necessary; however, graft-dependent recurrent HPT was not negligible. In conclusion, total PTx with forearm autograft is very effective and adequate treatment for advanced renal HPT and parathyroid function can be controlled after PTx.

The dilemma of parathyroidectomy in chronic renal failure.

Our understanding of the pathogenesis of the secondary hyperparathyroidism of uremia is steadily evolving. New findings have been made and new interpretations provided as to the interaction between calcium, phosphorus, and calcitriol with the parathyroid gland cell, including the discovery of a calcium-sensing receptor in the parathyroid gland, the description of heterogenous distribution of the vitamin D receptor across the parathyroid gland, and the observation of a high prevalence of monoclonal, tumorlike growth of parathyroid tissue. These findings must be integrated into our current way of thinking with respect to the mechanisms involved in parathyroid hyperplasia, and to the potential practical consequences in terms of treatment and prevention. The development of new nonhypercalcemic vitamin D derivatives and specific calcium receptor agonists may help to elaborate more efficient treatment schedules. On the other hand, the occurrence of monoclonal parathyroid growth probably explains, at least in part, the frequently observed resistance to medical treatment. In such patients with severe secondary hyperparathyroidism, surgical parathyroidectomy often remains the only therapeutic alternative.

Down-regulation of the PTH/PTHrP receptor in uremia

Resistance to the action of PTH has been well characterized in the setting of chronic renal failure. Most evidence points to post-receptor abnormalities in its pathogenesis. The recent cloning of the PTH/PTHrP receptor (PTH-R) has permitted us to examine whether in a 5/6 nephrectomy rat model (CRF) the expression of the PTH-R gene is modified. First, we have found that the renal PTH-R mRNA expression is markedly decreased in CRF compared to normal rats. Diminished PTH-R transcripts were associated with a lower PTH-induced cAMP production in renal membranes in CRF suggesting a decrease in the PTH-R number or post-receptor modifications. Second, thyroparathyroidectomized (TPTX) rats with normal renal function had no change in the renal PTH-R expression whereas TPTX-CRF rats still showed a decreased renal PTH-R mRNA expression suggesting that high plasma PTH levels were not etiologically important in the observed down-regulation. Despite the renal PTH-R down-regulation, CRF rats had a normal renal handling of calcium. They also had a higher phosphate excretion than control rats. TPTX-CRF rats showed a decrease in renal tubular calcium reabsorption and a phosphate retention when compared with CRF animals with intact parathyroid glands. This suggests that a few available PTH-R in the kidney allow PTH to exert, to a certain extent, its physiological role in this experimental model of uremia. In conclusion, these findings indicate a down-regulation of the renal PTH-R expression in CRF which appears to be independent of parathyroid gland function. The relevance of this phenomenon in the setting of the secondary hyperparathyroidism of uremia remains to be elucidated.

1,25-Dihydroxyvitamin D 3 receptors in peripheral blood mononuclear cells from patients with primary and secondary hyperparathyroidism

A decreased number of calcitriol (1,25(OH) 2D 3) receptors has been observed in parathyroid glands of uremic animals. In humans, studies carried out in surgically removed parathyroid glands have shown that calcitriol binding is higher in primary than in secondary hyperparathyroidism. Since specific receptors for calcitriol have been described in peripheral blood mononuclear cells (PBMC), we have investigated the specific uptake of 3H-labelled l,25(OH) 2D 3 in PBMC of 12 women with primary hyperparathyroidism (PHP), 8 women with hyperparathyroidism secondary to chronic renal failure (SH), 9 women with renal transplant (RT), and 23 healthy women. The median dissociation constant ( K d) was similar in all three groups of patients and in healthy women (mean ± S.D. (range): PHP, 1.2 ± 1.0 (0.2–4) × 10 −10 M; SH, 0.6 ± 0.4 (0.2–1.2) × 10 −10 M; RT, 1.1 ± 0.5 (0.4–1.9) × 10 −10 M; controls, 1.0 ± 0.6 (0.3–2.6) × 10 −10 M). However, the maximal binding capacity ( N max) was significantly enhanced in PHP (3.9 ± 1.9 (1.3–7.6) fmol/10 7 cells vs. 2.3 ± 0.9 (1.1–4.4) fmol/10 7 cells in controls; P = 0.0006) and decreased in SH (0.8 ± 0.5 (0.2–1.6) fmol/10 7 cells vs. 2.3 ± 0.9 (1.1–4.4) fmol/10 7 cells in controls; P = 0.0001), whereas no changes were seen in RT (2.3 ± 0.7 (1.2–3.3) fmol/10 7 cells vs. 2.3 ± 0.9 (1.1–4.4) fmol/10 7 cells in controls). In three patients with PHP who were subjected to parathyroidectomy, the calcitriol number came down to normal. Changes of calcitriol receptors in primary and secondary hyperparathyroidism could magnify the consequences of disturbances in serum concentration of calcitriol itself and might play an important role in the development of secondary hyperparathyroidism in uremia.

Autonomic neuropathy and secondary hyperparathyroidism in uremia

To evaluate the relationship between autonomic neuropathy, and biochemical and radiological parameters of secondary hyperparathyroidism, we examined 19 predialysis and 24 hemodialysis non-diabetic uremic patients. Autonomic neuropathy was assessed using four cardiovascular tests. Ten predialysis and 15 hemodialysis patients showed abnormalities in one or more autonomic tests. Ca, Ca 2+, P, alkaline phosphatase, immunoreactive parathyroid hormone and osteocalcin did not significantly differ in uremic patients with and without abnormal autonomic test results. Radiological markers of hyperparathyroidism such as acro-osteolysis (score A) and subperiosteal resorption (score B) were more common in patients with abnormalities in autonomic tests than in patients without. When predialysis and hemodialysis patients were considered separately, the correlation between score A, score B and autonomic neuropathy was confirmed only in hemodialysis patients. In conclusion, autonomic neuropathy is not related to biochemical parameters of hyperparathyroidism, while it appears correlated with radiological signs of osteodystrophy, suggesting a possible pathogenetic link between autonomic neuropathy and secondary hyperparathyroidism.

Effect of inorganic phosphate on serum ionized calcium concentration in vitro: A reassessment of the “trade-off hypothesis”

The development of secondary hyperparathyroidism in uremia is thought to be due, in part, to the retention of inorganic phosphate which, as proposed by the "trade-off hypothesis", lowers serum ionized calcium by means of CaHPO4 complex formation. To study this hypothesis, free from hormonal or physiological influence, the effect of changes in inorganic phosphate concentration on calcium ion concentration was examined in vitro in serum and protein-free aqueous solutions. The findings of this study demonstrate that the mean change in ionized calcium in aqueous solution is -0.019 +/- 0.001 mM per 1 mM change in inorganic phosphate, and is not significantly different in serum where the mean change in ionized calcium is -0.018 +/- 0.003 mM per 1 mM change in inorganic phosphate. The results in both aqueous solutions and sera agree closely with values predicted from the K'CaHPO4. Based on these results, the serum inorganic phosphate would have to increase by 1.2 mM (3.7 mg%) before the serum ionized calcium would fall sufficiently (0.025 mM) to stimulate the parathyroid glands. These results indicate that an increase in serum inorganic phosphate to as great as 1 mM/liter does not produce a fall in serum ionized calcium by means of direct physicochemical CaHPO4 complex formation great enough to account for the development of secondary hyperparathyroidism.

Search for the Uremic Toxin

In a retrospective analysis to determine whether secondary hyperparathyroidism in uremia has a role in uremic peripheral neuropathy, we simultaneously measured motor-nerve conduction velocity and serum parathormone level in 42 uremic patients. We compared age-matched groups of nondiabetic uremic patients, divided into three groups according to serum parathyroid hormone, for degree of impairment of motor-nerve conduction velocity, and 12 diabetic patients with uremia. The group with highest levels had a significantly (P less than 0.01) lower conduction velocity (25.3 +/- 4.9 m per second) than the group with normal or slightly elevated parathyroid hormone, who had only mild depression of nerve conduction (45.1 +/- 1.3 m per second). Mean serum calcium and creatinine were not significantly different between groups. Nerve conduction velocity was similarly depressed in 17 patients on additional dialysis studied prospectively and divided into groups according to parathyroid hormone levels. These results suggest a relation between high parathormone levels and uremic neuropathy and implicate parathyroid hormone as a uremic toxin.