The Treatment of Renal Hyperparathyroidism

27 1 Endocrine-Related M Almquist et al. The treatment of renal 27:1 R21–R34 Cancer hyperparathyroidism REVIEW The treatment of renal hyperparathyroidism Martin Almquist1, Elin Isaksson2 and Naomi Clyne3 1Department of Clinical Sciences Lund, Department of Surgery Section of Endocrine and Sarcoma Lund, Skåne University Hospital, Lund University, Lund, Sweden 2Department of Clinical Sciences Malmö, Urology Malmö, Faculty of Medicine, Skåne University Hospital, Lund University, Malmö, Sweden 3Department of Clinical Sciences Lund, Nephrology Lund, Faculty of Medicine, Skåne University Hospital, Lund University, Lund, Sweden Correspondence should be addressed to M Almquist: [email protected] Abstract Renal hyperparathyroidism (rHPT) is a complex and challenging disorder. It develops Key Words early in the course of renal failure and is associated with increased risks of fractures, f chronic kidney disease cardiovascular disease and death. It is treated medically, but when medical therapy f hyperparathyroidism cannot control the hyperparathyroidism, surgical parathyroidectomy is an option. In f parathyroid hormone this review, we summarize the pathophysiology, diagnosis, and medical treatment; we f vitamin D describe the effects of renal transplantation; and discuss the indications and strategies in f parathyroidectomy parathyroidectomy for rHPT. Renal hyperparathyroidism develops early in renal failure, mainly as a consequence of lower levels of vitamin D, hypocalcemia, diminished excretion of phosphate and inability to activate vitamin D. Treatment consists of supplying vitamin D and reducing phosphate intake. In later stages calcimimetics might be added. RHPT refractory to medical treatment can be managed surgically with parathyroidectomy. Risks of surgery are small but not negligible. Parathyroidectomy should likely not be too radical, especially if the patient is a candidate for future renal transplantation. Subtotal or total parathyroidectomy with autotransplantation are recognized surgical options. Renal transplantation improves rHPT but does not cure it. Endocrine-Related Cancer (2020) 27, R21–R34 Introduction Pathophysiology Hyperparathyroidism is relatively common. Primary Chronic kidney disease hyperparathyroidism is the third most common endocrine disorder with a lifetime risk of 1% (Shindo et al. 2016). Chronic kidney disease, CKD, is defined as abnormalities Secondary hyperparathyroidism has an external etiology of kidney structure or function, present for more than and can be caused by vitamin D deficiency, liver disease, 3 months, with implications for health (KDIGO 2013). lithium therapy or, most commonly, chronic kidney disease It is a general term that includes many heterogenous (CKD). Typical of secondary hyperparathyroidism in CKD is disorders that all affect kidney structure and function that it is driven by hypocalcemia and hyperphosphatemia. (KDIGO 2013). Due to the heterogenous origin of renal Eventually the parathyroid glands become unresponsive disease, CKD can range from a mild asymptomatic to plasma calcium levels and autonomously produce decrease in renal function that remains stable for decades high levels of parathyroid hormone in the presence to a rapidly decreasing renal function with multiple of hypercalcemia; this condition is defined as tertiary complications and finally end-stage renal disease hyperparathyroidism. The hyperparathyroidism of CKD (ESRD). A failing kidney has a widespread impact on the is the focus of this review and we will refer to it as renal organism and affects almost all organs in the human hyperparathyroidism (rHPT). body. Patients with ESRD have 10–20 times higher https://erc.bioscientifica.com © 2020 Society for Endocrinology https://doi.org/10.1530/ERC-19-0284 Published by Bioscientifica Ltd. Printed in Great Britain Downloaded from Bioscientifica.com at 09/27/2021 01:17:47PM via free access -19-0284 Endocrine-Related M Almquist et al. The treatment of renal 27:1 R22 Cancer hyperparathyroidism Figure 1 Schematic image of the pathophysiology of renal hyperparathyroidism. CaSR, calcium-sensing receptor; FGF23, fibroblast growth factor 23; PTH, parathyroid hormone; VDR, vitamin D receptor. mortality rates compared to the general population and FGF23 and klotho the major cause of mortality is cardiovascular (Foley et al. 1998). Patients with ESRD also develop bone disease. The A central hormone in the rHPT process is fibroblast complex relation between vascular calcifications, bone growth factor 23 (FGF23), produced by osteoblasts and and kidney has led Kidney Disease Improving Global osteocytes. It is the major phosphate regulatory hormone Outcomes (KDIGO) to produce clinical guidelines for the (Isakova et al. 2011). FGF23 is induced by high levels of management of chronic kidney disease – mineral and phosphate, active vitamin D and PTH (Meir et al. 2014, bone disorder (CKD-MBD) (KDIGO 2009). An outline of Bon et al. 2018) and increases early in CKD (Isakova et al. these relations is presented in Fig. 1. 2011). FGF23 binds to its receptor FGF receptor 1 (FGFR1) Renal hyperparathyroidism, rHPT, with increasing which requires a co-receptor, α-klotho, to function (Kurosu levels of parathyroid hormone (PTH) and parathyroid & Kuro 2009). α-Klotho is expressed in the kidney and in gland hyperplasia, is a major part of CKD-MBD and parathyroid tissue (Lim et al. 2015). FGF23 decreases the develops in all patients with CKD as renal function phosphate reuptake in the distal tubuli and thus lowers deteriorates. CKD is divided into five stages based on blood levels of phosphate (Sneddon et al. 2016). FGF23 glomerular filtration rate (GFR), ranging from stage 1 also downregulates 1-α-hydroxylase and upregulates D-24- where the GFR is >90 mL/min/1.73 m2, to stage 5 where hydroxylase in the kidney with a net effect of lower levels GFR is <15 mL/min/1.73 m2 (Table 1) (KDIGO 2013). of active vitamin D and lower uptake of phosphate in In a recent review the global prevalence of CKD stages the intestines (Shimada et al. 2004). With declining renal 3–5 was found to be about 10% (Hill et al. 2016). Thus, function, the level of soluble α-klotho is reduced, which CKD is common and with an aging population with contributes to FGF23 resistance (Drew et al. 2017). Due to increasing prevalence of hypertension and diabetes it the FGF23 resistance, levels of FGF23 rise to compensate is a growing global problem (Coresh et al. 2007). Both (Sakan et al. 2014). Resistance to FGF23 leads to enhanced death and disability-adjusted life years lost due to CKD secretion of PTH from the parathyroid gland since PTH are increasing (Jager & Fraser 2017). The medical costs acts in a phosphaturic manner, in the same way as FGF23. attributable to CKD are substantial and increase as In early CKD and early stages of rHPT, high FGF23, low disease severity worsens, particularly if renal replacement soluble klotho, normo- or hyperphosphatemia and a slight therapy (RRT) has to be initiated (Honeycutt et al. 2013). increase in PTH are the usual findings Drueke( 2000). Renal hyperparathyroidism is a direct cause of vascular Thus, early in the course of declining renal function and bone-related outcomes as well as mortality in CKD there is a cascade of physiological changes due to the renal (Young et al. 2004). tubules’ failing ability to maintain homeostasis in the https://erc.bioscientifica.com © 2020 Society for Endocrinology https://doi.org/10.1530/ERC-19-0284 Published by Bioscientifica Ltd. Printed in Great Britain Downloaded from Bioscientifica.com at 09/27/2021 01:17:47PM via free access Endocrine-Related M Almquist et al. The treatment of renal 27:1 R23 Cancer hyperparathyroidism Table 1 Chronic kidney disease, CKD, is defined as Laboratory analyses abnormalities of kidney structure or function, present At present, FGF23 is not routinely analyzed in clinical for >3 months, with implications for health. practice. The latest KDIGO update on management of GFR stages GFR (mL/ CKD-MBD suggests that 25(OH)D might be analyzed 2 in CKD min/1.73 m ) Terms starting during CKD stage 3 (KDIGO 2009). In CKD consequence a cascade of pathophysiological events 1a ≥90 Normal 2a 60–89 Normal to mildly decreased go under the clinician’s radar. These changes become 3a 45–59 Mildly to moderately decreased apparent when plasma calcium levels decrease, PTH rises 3b 30–44 Moderately to severely and plasma phosphate increases. It is important to note decreased that there are diurnal variations and fluctuations in these 4 15–29 Severely decreased 5 <15 Kidney failure concentrations. Therefore, physicians are recommended not to act on a single value, but rather to analyze the aIn the absence of kidney damage neither of the categories qualifies trend in a series of laboratory results before starting or as CKD. CKD, chronic kidney disease; GFR, glomerular filtration rate. adjusting treatment (KDIGO 2009). calcium–phosphate–vitamin D axis, see also Fig. 1. This Phosphate retention is long before secondary hyperparathyroidism becomes manifest. In fact, the first sign that something is wrong A positive phosphate balance is another central factor in is a rise in FGF23. FGF23 exerts endocrine effects on the the development of rHPT. With declining renal function proximal tubules. However, due to the lack of heparin- the ability to maintain mineral homeostasis is impaired, binding sites on FGF23, it is dependent on both α and β both by reduced capacity to filter phosphate due to loss klotho as well as specific FGF receptors to exercise its effects. of renal function but also by disturbed function of the FGF23 has two key effects on calcium-phosphate- bone. In CKD various types of bone disease occur, all vitamin D homeostasis: it suppresses the activation of characterized by excessive bone resorption compared to vitamin D in the proximal tubules, functioning as a formation (Drueke & Massy 2016). This occurs early in counter-regulatory hormone for 1,25 dihydroxyvitamin D3 CKD and reduces the capacity for the skeleton to buffer (calcitriol) and it suppresses the reabsorption of phosphate, phosphate load. Instead, the skeleton contributes to thus inducing phosphaturia. In the course of progressive hyperphosphatemia (Hruska et al.

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