Management of Secondary Hyperparathyroidism: The Importance and the Challenge of Controlling Parathyroid Hormone Levels without Elevating Calcium, Phosphorus, and Calcium-Phosphorus Product

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Abstract

Secondary hyperparathyroidism (HPT) is a common complication of chronic kidney disease (CKD) that can lead to clinically significant bone disease. Additional consequences of secondary HPT, such as soft-tissue and vascular calcification, cardiovascular disease, and calcific uremic arteriolopathy, may contribute to the increased risk of cardiovascular morbidity and mortality among CKD patients. Secondary HPT arises from disturbances in calcium, phosphorus, vitamin D and parathyroid hormone metabolism, which develop early in the course of CKD and become more prominent as kidney function declines. The standard therapies currently recommended to correct mineral metabolism and bone disease in these patients include calcium supplementation, dietary phosphorus restriction, phosphate-binding agents, and treatment with vitamin D sterols. However, such medications often have significant effects on the serum levels of calcium and phosphorus, which result in exacerbation of the disease and significant extraskeletal morbidity and mortality. Thus, there is a need to identify more effective treatment approaches. This review discusses the pathophysiology of secondary HPT, the challenges faced in the management of this disorder, and the impact of current treatment options on patients’ risks of morbidity and mortality. In addition, the development of new, more physiologically relevant therapies, which may lead to successful management of secondary HPT, is reviewed.

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Retinoid X receptor interacts with nuclear receptors in retinoic acid, thyroid hormone and vitamin D3 signalling.

K Umesono, Jane R. Evans, S Kliewer … (1992)

Cellular responsiveness to retinoic acid and its metabolites is conferred through two structurally and pharmacologically distinct families of receptors: the retinoic acid receptors (RAR) and the retinoid X receptors (RXR). Here we report that the transcriptional activity of RAR and RXR can be reciprocally modulated by direct interactions between the two proteins. RAR and RXR have a high degree of cooperativity in binding to target DNA, consistent with previous reports indicating that the binding of either RAR or RXR to their cognate response elements is enhanced by factors present in nuclear extracts. RXR also interacts directly with and enhances the binding of nuclear receptors conferring responsiveness to vitamin D3 and thyroid hormone T3; the DNA-binding activities of these receptors are also stimulated by the presence of nuclear extracts. Together these data indicate that RXR has a central role in multiple hormonal signalling pathways.

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Cardiovascular mortality in end-stage renal disease.

V Collins (2003)

Cardiovascular disease accounts for more than 50% of end-stage renal disease (ESRD) deaths. The reported cardiovascular death rates in patients receiving dialysis are substantially higher than in the general population. Cardiovascular mortality in ESRD is particularly high after acute myocardial infarction, but it is also elevated in ESRD patients with other forms of atherosclerotic vascular disease (eg, chronic coronary artery disease, strokes, transient ischemic attacks, and peripheral arterial disease). Left ventricular hypertrophy and dilation are associated with increased cardiovascular mortality, as is congestive heart failure. One of the major reasons for such high cardiovascular mortality in ESRD is the large burden of cardiovascular disease present in patients with chronic artery disease before renal replacement therapy. These observations mandate not only aggressive diagnosis and treatment of cardiovascular disease in patients with ESRD, but also active screening, diagnosis, and treatment in those with chronic kidney disease before renal replacement therapy.

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The calcimimetic AMG 073 reduces parathyroid hormone and calcium x phosphorus in secondary hyperparathyroidism.

Jessica Turner, Brian J Coburn, Sharon Moe … (2002)

A need exists for a therapy that lowers parathyroid hormone (PTH) without increasing calcium x phosphorus in patients with secondary hyperparathyroidism. The calcimimetic AMG 073 increases the sensitivity of the parathyroid calcium-sensing receptor to extracellular calcium, thereby reducing PTH secretion. Consequently, AMG 073 may provide a novel therapy for secondary hyperparathyroidism. Seventy-eight hemodialysis patients with secondary hyperparathyroidism were enrolled into this 18-week, double-blind, randomized, placebo-controlled, dose titration study. Daily oral AMG 073 doses were administered to determine the effect on PTH, serum calcium, phosphorus, and calcium x phosphorus. The mean baseline PTH was similar in patients administered AMG 073 or placebo (632 +/- 280.1 pg/mL vs. 637 +/- 455.9 pg/mL, respectively). PTH decreased by 26.0% in the AMG 073-treated group, compared with an increase of 22.0% in the placebo group (P or=30%, compared with the placebo group (8%) (P = 0.001). Decreases in PTH were independent of baseline vitamin D usage. Patients receiving AMG 073 had an 11.9% decrease in calcium x phosphorus compared with a 10.9% increase in the placebo group (P < 0.001). Use of vitamin D sterols, as well as both calcium and noncalcium-containing phosphate binders. were similar between treatment groups. Administration of AMG 073 was safe and well tolerated in this 18-week study. The calcimimetic AMG 073 decreases both PTH and calcium x phosphorus levels in hemodialysis patients with secondary hyperparathyroidism.

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Author and article information

Journal

Journal ID (publisher-id): AJN

Journal ID (nlm-ta): Am J Nephrol

Journal ID (doi): 10.1159/issn.0250-8095

Title: American Journal of Nephrology

Publisher: S. Karger AG

ISSN (Print): 0250-8095

ISSN (Electronic): 1421-9670

Publication date Subscription-year: 2003

Publication date (Print): December 2003

Publication date (Electronic): 21 November 2003

Volume: 23

Issue: 6

Pages: 369-379

Affiliations

^aDepartment of Medicine, Division of Nephrology, Indiana University School of Medicine and Roudebush Veterans Affairs Medical Center, Indianapolis, Ind., USA; ^bInserm Unité 507, Division of Nephrology, Hôpital Necker, Paris, France

Article

Publisher ID: 73945 Other ID: Am J Nephrol 2003;23:369–379

DOI: 10.1159/000073945

PubMed ID: 14551461

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