PTH Receptors and Skeletal Resistance to PTH Action

Secondary hyperparathyroidism (SHPT) is an integral component of chronic kidney disease-mineral and bone disorder (CKD-MBD). Many factors have been associated with its development and progression, but the presence of skeletal or calcemic resistance to the action of PTH in CKD has often gone unnoticed. The term hyporesponsiveness to PTH is currently preferred and, in this chapter, we will review not only the scientific history but also the factors linked to this impaired response to PTH in CKD. Decreased calcitriol levels, phosphate retention, down-regulation of PTH receptors, uremia per se, abnormal metabolism of PTH and PTH fragments, downstream competing signals, local factors (inflammation, cytokines, oxidative stress, ion concentration etc.), and systemic factors (age, race, diabetes, fibroblast growth factor-23, klotho, Wnt antagonists such as sclerostin, etc.) have all been implicated. Additionally, important clinical implications are reviewed since hyporesponsiveness to PTH explains not only progressive PTH hypersecretion and parathyroid hyperplasia but also the increasing prevalence of adynamic bone disease in the CKD population. Therefore, hyporesponsiveness to PTH should be taken into account when treating SHPT in CKD patients, and its significance underlines the importance of avoiding the normalization of PTH levels at any CKD stage. On the other hand, progressively increasing PTH levels may indicate a change from an adaptive to a maladaptive clinical situation requiring therapeutic decisions. Finally, resistance to the biological action of several other hormones is a well-known feature of CKD (uremia as a “receptor disease”), and consequently future additional studies at cellular and molecular levels may be of value beyond their significance for hyporesponsiveness to PTH.