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- 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 concentrations Illinois tions. Below is a discussion of the pathophysiology are sensed by the 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, also directly inhibits Nephrology and calcium sensing receptors and also stimulates PTH , 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 lead to a sustained and Pathophysiology of Secondary progressive increase in PTH production, and ulti- Hyperparathyroidism mately, they lead to 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, . 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 (10). fi (vitamin D2) and (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 [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 , such as , 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 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 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 25(OH)D concentrations. In addition, pg/ml, and vitamin D of 68 ng/ml. In conclusion, sec- calcitriol and other vitamin D receptor agonists may cause ondary hyperparathyroidism is important to treat early in hypercalcemia, , and hyperphosphatemia, patients with CKD to prevent mineral bone disease and which can lead to vascular calcifications. Therefore, we maintain vascular health. Medical management may ini- recommend that calcitriol should be used as adjunctive tially consist of correcting 25(OH)D deficiency with ergo- therapy in patients who cannot be controlled with ergo- calciferol or cholecalciferol, although these therapies calciferol or cholecalciferol with careful monitoring for generally do not effectively decrease PTH in later stages hypercalcemia and hyperphosphatemia. Other vitamin D of CKD. If 25(OH)D deficiency persists, a trial with analogs include doxercalciferol and paricalcitol. These extended release calcifediol may be warranted. If PTH CJASN 15: ccc–ccc, July, 2020 Hyperparathyroidism in CKD, Hyder and Sprague 3

remains elevated after 25(OH)D is corrected, vitamin D 4. Centeno PP, Herberger A, Mun HC, Tu C, Nemeth EF, Chang W, receptor agonists could be added but will need to closely Conigrave AD, Ward DT: Phosphate acts directly on the calcium- sensing receptor to stimulate parathyroid hormone secretion. Nat monitor for possible hypercalcemia and hyperphosphate- Commun 10: 4693, 2019 mia. If medical management is not successful in treating 5. IxJH, IsakovaT,LariveB,RaphaelKL,Raj DS, Cheung AK, Sprague secondary hyperparathyroidism, parathyroidectomy may SM, Fried LF, Gassman JJ, Middleton JP, Flessner MF, Block GA, be an alternative. Further clinical trials that evaluate clinical Wolf M: Effects of nicotinamide and lanthanum carbonate on outcomes, such as fractures, cardiovascular disease, and serum phosphate and fibroblast growth factor-23 in CKD: The COMBINE trial. J Am Soc Nephrol 30: 1096–1108, 2019 mortality, are necessary to determine the best treatment 6. Zisman AL, Hristova M, Ho LT, Sprague SM: Impact of ergo- regimen for secondary hyperparathyroidism in CKD. calciferol treatment of vitamin D deficiency on serum parathyroid hormone concentrations in . Am J Nephrol Disclosures 27: 36–43, 2007 ¨ Dr. Sprague reports grants and personal fees from Amgen, grants 7. Westerberg PA, Sterner G, Ljunggren O, Isaksson E, Elvarson F, Dezfoolian H, Linde T: High doses of cholecalciferol alleviate the and personal fees from Opko, grants and personal fees from Vifor, progression of hyperparathyroidismin patientswith CKD stages 3- and grants and personal fees from Fresenius outside the submitted 4: Results of a 12-week double-blind, randomized, controlled work. Dr. Hyder has nothing to disclose. study. Nephrol Dial Transplant 33: 466–471, 2018 8. Ennis JL, Worcester EM, Coe FL, Sprague SM: Current recom- Funding mended 25-hydroxyvitamin D targets for chronic kidney disease management may be too low. J Nephrol 29: 63–70, 2016 None. 9. Sprague SM, Coyne D: Control of secondary hyperparathyroidism by vitamin D receptor agonists in chronic kidney disease. Clin J Am Soc Nephrol 5: 512–518, 2010 References 10. Coyne DW, Goldberg S, Faber M, Ghossein C, Sprague SM: A 1. Sprague SM, Crawford PW, Melnick J, Strugnell SA, Ali S, randomized multicenter trial of paricalcitol versus calcitriol for Mangoo-Karim R, Lee S, Petkovich PM, Bishop CW: Use of secondary hyperparathyroidism in stages 3-4 CKD. Clin J Am Soc extended-release calcifediol to treat secondary hyperparathy- Nephrol 9: 1620–1626, 2014 roidism in stages 3 and 4 chronickidney disease. Am J Nephrol 44: 11. Lau WL, Obi Y, Kalantar-Zadeh K: Parathyroidectomy in the 316–325, 2016 management of secondary hyperparathyroidism. Clin J Am Soc 2. Cunningham J, Locatelli F, Rodriguez M: Secondary hyperpara- Nephrol 13: 952–961, 2018 thyroidism: Pathogenesis, disease progression, and therapeutic options. Clin J Am Soc Nephrol 6: 913–921, 2011 3. Martin A, David V, Quarles LD: Regulation and function of the Published online ahead of print. Publication date available at FGF23/klotho endocrine pathways. Physiol Rev 92: 131–155, 2012 www.cjasn.org.