1. ¹Renal Division, Washington University School of Medicine, St Louis, Missouri, USA
2. ²Renal Center, Nagoya Second Red Cross Hospital, Nagoya, Aichi, Japan

Correspondence: AS Dusso, Renal Division, Washington University School of Medicine, Campus Box 8126, 660 S. Euclid Avenue, St Louis, Missouri 63110, USA. E-mail: adusso@im.wustl.edu

Abstract

Parathyroid hyperplasia is the cause of parathyroid gland enlargement in kidney disease (KD). Hypocalcemia, hyperphosphatemia, and vitamin D deficiency are critical contributors to the worsening of the hyperplastic parathyroid growth induced by KD. Reproduction of the features of human KD in the 5/6 nephrectomized rat model has shown that 80% of the mitogenic signals induced by KD in parathyroid cells that are aggravated by either high phosphate (P) or low calcium (Ca) diets occurred within 5 days after the onset of KD. Enhanced parathyroid expression of the potent growth promoter transforming growth factor alpha (TGF) and its receptor, the epidermal growth factor receptor (EGFR), was identified as the main cause of parathyroid hyperplasia in experimental KD. Indeed, administration of highly specific EGFR-tyrosine kinase inhibitors (TKI), which block downstream signaling from TGF-activated EGFR, completely prevented high P- and low Ca-induced parathyroid hyperplasia in early KD, as well as the severe progression of high P-induced parathyroid growth in established secondary hyperparathyroidism, the latter characterized by marked TGF and EGFR overexpression in the parathyroid glands. More importantly, the suppression of signals downstream from TGF binding to EGFR with EGFR-TKI treatment also revealed that TGF self-upregulation in the parathyroid glands is the main determinant of the severity of the hyperplastic growth, and that enhanced TGF activation of EGFR mediates the reduction in parathyroid vitamin D receptor levels thereby causing resistance to both the antiproliferative and parathyroid hormone-suppressive properties of calcitriol therapy.