Kidney CaseCJASN Conference: ePress. Published on May 27, 2020 as doi: 10.2215/CJN.13411119 How I Treat Secondary Hyperparathyroidism in a Patient with CKD Ryyan Hyder and Stuart M. Sprague CJASN 15: ccc–ccc, 2020. doi: https://doi.org/10.2215/CJN.13411119 Introduction FGF23 also reduces 1,25(OH)2Dproductionin Secondary hyperparathyroidism is an almost univer- the kidney by inhibition of the 1-a-hydroxylase NorthShore University sal phenomenon of CKD that worsens as CKD (CYP27B1) and stimulates 1,25(OH)2D degradation Health progresses. It affects 40% of individuals with stage 3 by stimulating 24-hydroxylase (CYP24A1) (3). Be- System–Pritzker School of Medicine, CKD and 82% of individuals with stage 4 CKD (1). cause 1,25(OH)2D promotes intestinal absorption of University of Chicago Early management and treatment of secondary hy- calcium and phosphorus, this cascade of events leads Pritzker School of perparathyroidism are imperative to preserve bone to decreased gut absorption of these minerals. The Medicine, Chicago, health and decrease soft tissue and vascular calcifica- reduced serum calcium and calcitriol concentrations Illinois tions. Below is a discussion of the pathophysiology are sensed by the vitamin D receptors and calcium and treatment, including both pharmacologic and sensing receptors of the parathyroid cells, leading to Correspondence: Dr.StuartM.Sprague, surgical options for secondary hyperparathyroidism. cell proliferation and a rise in PTH production. In Division of addition, hyperphosphatemia also directly inhibits Nephrology and calcium sensing receptors and also stimulates PTH Hypertension, Patient production (4). Although FGF23 binds to the Klotho- NorthShore University A 61-year-old man with stage 4 CKD, autosomal Health FGF23 receptor in the parathyroid to inhibit PTH, System–Pritzker dominant polycystic kidney disease, and hypertension is there is decreased Klotho with worsening kidney School of Medicine, evaluated for management of mineral metabolism. His function, and thus, the ability of FGF23 to decrease University of Chicago, creatinine is 2.6 mg/dl, calcium is 9.2 mg/dl, phospho- PTH concentrations is lost (2). PTH promotes bone 2650 Ridge Avenue, rus is 4.2 mg/dl, albumin is 4.1 g/dl, parathyroid resorption with release of calcium and phosphate Evanston, IL 60201. Email: ssprague@ hormone (PTH) is 228 pg/ml, and 25-hydroxyvitamin D and increases CYP27B1 expression in the proximal northshore.org [25(OH)D] is 18 ng/ml. tubules in an attempt to maintain normal serum calcium concentrations. The ongoing phosphate re- tention and hypocalcemia lead to a sustained and Pathophysiology of Secondary progressive increase in PTH production, and ulti- Hyperparathyroidism mately, they lead to parathyroid gland hyperplasia Figure 1 illustrates that the pathophysiology of further augmenting secondary hyperparathyroidism. secondary hyperparathyroidism is complex. With As parathyroid gland hyperplasia progresses and decreasing kidney function, there is a decreased nodules develop, there is a progressive loss of both filtered load of phosphate, resulting in decreased the vitamin D and calcium sensing receptors causing phosphate excretion (2). The retained phosphate the loss of negative regulation of PTH production stimulates osteocytes and osteoblasts to synthesize resulting in tertiary hyperparathyroidism. fibroblast growth factor-23 (FGF23), one of the hor- mones involved in maintaining phosphate homeosta- sis. FGF23 binds to fibroblast growth factor receptor Treatment 1, and in the presence of the required coreceptor We recommend that therapy should be focused aKlotho, FGF23 decreases the type II sodium– on early management and prevention of hyperpara- dependent phosphate cotransporters NaPi2a and thyroidism. High phosphorus concentrations are NaPi2c in the proximal tubule of the kidney, thereby involved in the pathogenesis of secondary hyper- inhibiting phosphate reabsorption and promoting parathyroidism; therefore, reducing serum phospho- phosphaturia (3). Unfortunately, there is also de- rus concentrations by decreasing dietary intake can creased production of Klotho with progressive CKD; be used as a treatment strategy. The CKD Optimal thus, the effectiveness of FGF23/Klotho to correct Management with Binders and Nicotinamide trial phosphate retention is limited, and as CKD prog- showed that individuals with stage 3b–4 CKD on resses, there is the development of overt hyperphos- phosphate binders or nicotinamide, an inhibitor of phatemia, resulting in further stimulation of FGF23 intestinal phosphate transport, had no significant re- production. In addition, both 1,25-dihydroxyvitamin duction in serum phosphate or FGF23 levels at 1 year D [1,25(OH)2D] and PTH increase the production when taken either alone or combined (5). Thus, further of FGF23 (2). data are required for evaluating the role of phosphate www.cjasn.org Vol 15 July, 2020 Copyright © 2020 by the American Society of Nephrology 1 2 CJASN Figure 1. | Pathophysiology of secondary hyperparathyroidism. FGF23, fibroblast growth factor-23; PTH, parathyroid hormone. binders on serum phosphate, FGF23, and PTH concentra- analogs also decrease PTH production but like calcitriol, tions in patients with CKD and normophosphatemia. at the risk of causing both hypercalcemia and hyperphos- Therefore, the mainstay of therapy would be correction phatemia. In the only comparative study, there was no of 25(OH)D deficiency. This can initially be approached difference in the development of hypercalcemia and hyper- with the use of the inactive compounds, ergocalciferol phosphatemia with calcitriol and paricalcitol (10). fi (vitamin D2) and cholecalciferol (vitamin D3). Ergocalci- The third option for correcting vitamin D de ciency ferol is derived from plant sources, and cholecalciferol is would be the use of extended release calcifediol [25(OH)D], derived from animal sources. Administration of these which has been shown to effectively increase both circu- compounds should result in increase of 25(OH)D, which lating 25(OH)D and 1,25(OH)2D concentrations while de- should increase 1,25(OH)2D; this should then stimulate the creasing PTH levels (1). This effect does not seem to be vitamin D receptor on parathyroid gland to suppress PTH dependent on CKD stage, and the development of hyper- production. As kidney function declines, the ability of these calcemia was similar to placebo-treated subjects (1). compounds to reduce PTH synthesis declines. Therapy Other options to treat refractory hyperparathyroidism with ergocalciferol resulted in a normalization of circulat- would include calcimimetics, such as cinacalcet, which ing 25(OH)D concentrations with a 13% decrease in PTH in activate calcium sensing receptors and increase sensitivity individuals with stage 3 CKD; however, there was not a of serum calcium to inhibit PTH production and release, statistically significant decrease in PTH for individuals resulting in a reduction in PTH within a few hours. Studies with stage 4 CKD (6). Another study using high-dose have shown that treatment of secondary hyperparathy- cholecalciferol for 12 weeks resulted in an almost threefold roidism with calcimimetics can decrease proliferation of increase in circulating 25(OH)D concentrations with stabi- parathyroid cells and subsequently suppress parathyroid lization of PTH concentrations, compared with placebo in hyperplasia (2). Unfortunately, calcimimetics can cause which circulating 25(OH)D concentrations remained stable hypocalcemia and in CKD, may result in hyperphospha- and there was a 16% increase in PTH (7). It seems that, as temia. Therefore, calcimimetics are currently not used for kidney function deteriorates, higher 25(OH)D concentra- patients with secondary hyperparathyroidism and CKD. tions may be required to maximally suppress PTH (8). If refractory hyperparathyroidism is not responsive to Thus, in many patients with advanced CKD in the absence medical therapy, then parathyroidectomy may be indi- of hypercalcemia, treatment with 1,25(OH)2Dorananalog cated. Indications for parathyroidectomy in appropriate may be required to suppress PTH (6,9). surgical candidates include serum PTH of .800 pg/ml Calcitriol is a biologically active nonselective vitamin D refractory to medical therapy, hyperplastic parathyroid receptor agonist that is used in the treatment of secondary gland measuring .500 mm3,orglands.1cmindiameter hyperparathyroidism. It decreases PTH synthesis and (11). It is important to monitor these patients because prevents parathyroid gland hyperplasia (9). Activation of secondary hyperparathyroidism can return due to hyper- vitamin D receptors also increases serum calcium, which functioning of the remaining or autotransplanted tissue. activates calcium sensing receptors in the parathyroid Potential benefits of parathyroidectomy include decreased gland, further decreasing PTH production (9). Calcitriol fracture risk, increased bone mineral density, and im- is usually started when vitamin D supplementation is no proved survival and quality of life (2,11). longer adequate. Unlike ergocalciferol and cholecalciferol, This patient was treated with extended release calcifediol calcitriol suppresses PTH regardless of CKD stage. Limi- 30 mg for 6 months. Repeat laboratory tests demonstrated tations of calcitriol include ineffective repletion of serum that creatinine is 2.8 mg/dl with calcium of 9.6 mg/dl, 25(OH)D and stimulation of CYP24A1 and FGF23, which phosphorus of 4.0 mg/dl, albumin of 3.9 g/dl, PTH of 144 will further decrease