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Kidney Week

Abstract: TH-PO158

Calcium Sensing Receptor and Klotho Expression of Advanced Dialysis-Dependent Hyperparathyroidism

Session Information

  • CKD-MBD: Targets and Outcomes
    November 03, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
    Abstract Time: 10:00 AM - 12:00 PM

Category: Bone and Mineral Metabolism

  • 402 Bone and Mineral Metabolism: Clinical

Authors

  • Sato, Tetsuhiko, JRC Aichi Medical Center, Nagoya Daini Hospital, Nagoya, Aichi, Japan
  • Kikkawa, Yamato, Tokyo University of Pharmacy and Life Sciences, Hachioji, Japan
  • Okada, Manabu, JRC Aichi Medical Center, Nagoya Daini Hospital, Nagoya, Aichi, Japan
  • Fukagawa, Masafumi, Tokai University, School of Medicine, Isehara, Japan
Background

Advanced parathyroid hyperplasia is often caused by long-term dialysis-dependent chronic kidney disease, resulted in more aggressive pathological pattern called nodular formation. Each intra-parathyroid gland nodule is thought to have monoclonal proliferation. Calcimimetics are expected to upregulate calcium sensing receptor (CaSR) expression and inhibit PTH synthesis and secretion. However, our surgical center has experienced over 20 parathyroidectomies in each year, although second-generation calcimimetics (intravenous and/or oral) are voluntarily used to control systemic PTH levels. The question remains how enlarged parathyroid glands develop calcimimetics-resistant phenotype, and eventually need surgical resection during this recent calcimimetics-era.

Methods

We hypothesized that Klotho expression in each parathyroid nodule may play a key role of advanced hyperparathyroidism, conducted the study of immunofluorescence of CaSR and Klotho expression, and examined the relation of enlarged parathyroid gland weight with immunoreactivity of CaSR and Klotho. We utilized surgically resected enlarged parathyroid glands to perform immunohistochemistry using primary antibodies to CaSR and Klotho.

Results

Presurgical PTH levels and total glandular weight on surgery was 520+/-278 pg/mL and 2307+/-1140 mg, respectively (mean+/-SD). Interestingly, parathyroid gland, ranging from 100 to 1000 mg weight possessed heterogenous CaSR (3+ positive to negative) and Klotho expression pattern. Each intra-gland nodule had a wide spectrum of immunoreactivity of CaSR with relatively weaker Klotho expression. In contrast, enlarged single-nodular parathyroid gland, ranging 1000 mg or greater did not harbor remarkable CaSR and Klotho expression.

Conclusion

In conclusion, profound use of “second-generation” calcimimetics may enhance CaSR in earlier phase of hyperplastic parathyroid glands, followed by Klotho downregulation, sugggesting that multiple nodules of parathyroid hyperplasia have diverse CaSR response to calcimimetics. Aggressively progressed parathyroid glands ended up with overwhelmingly marked downregulation of both CaSR and Klotho. CaSR and Klotho interaction may play a key role of advanced dialysis-dependent hyperparathyroidism.