The Treatment of Renal Hyperparathyroidism

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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, ff chronic kidney disease cardiovascular disease and death. It is treated medically, but when medical therapy ff hyperparathyroidism cannot control the hyperparathyroidism, surgical parathyroidectomy is an option. In ff parathyroid hormone this review, we summarize the pathophysiology, diagnosis, and medical treatment; we ff vitamin D describe the effects of renal transplantation; and discuss the indications and strategies in ff 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

-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

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. 2008). The positive renal failure FGF23 increases first, followed by a decrease in phosphate balance leads to elevated levels of FGF23.

1,25 dihydroxyvitamin D3 after which levels of parathyroid Phosphate also stimulates the release of PTH. The hormone increase. Usually phosphate levels are affected phosphaturic actions of PTH together with FGF23 keep last and start to rise in CKD stage 5. Thus, FGF23 probably phosphate levels regulated in early CKD (Sneddon et al. has primary responsibility for maintaining phosphaturia, 2016). Phosphate levels in the blood remain normal until while the rise in PTH is most likely a direct response to CKD stages 4–5, when hyperphosphatemia is common the decrease in 1,25 dihydroxyvitamin D3 and a decrease in (Levin et al. 2007). This is due to the loss of functioning plasma calcium concentration. Finally, plasma phosphate nephrons and because tubular reabsorption is already further stimulates hyperparathyroidism (Isakova et al. maximally inhibited by FGF23 and PTH. In almost all 2011, Kuro 2019). other situations involving phosphate retention, the Vitamin D comprises a group of lipid-soluble skeleton pools excessive phosphate to keep blood levels molecules. 25-Hydroxyvitamin D (25(OH)D) is unchanged. In CKD, due to bone disease, the phosphate the major form in circulation and is activated to reservoir is shifted to soft tissue (e.g. vasculature), a process 1,25-dihydroxyvitamin D by 1-α-hydoxylase, which is driven by multiple bone-specific signaling pathways, expressed in the proximal tubule. 25(OH)D has a half-life many of them directly activated by phosphate itself of 3 weeks, which is the longest in the group. FGF23 limits (Hruska et al. 2008). Long-lasting hyperphosphatemia the production of 1,25-dihydroxyvitamin D by suppressing thus leads to vascular calcifications (Mathew et al. 2008) 1-α-hydoxylase, while 1,25-dihydroxyvitamin D stimulates and is a central element of the development of CKD-MBD FGF23, creating a feedback loop (Goldsmith 2016). and rHPT, see also Fig. 1.

Vitamin D and calcium the expression of p21 independent of vitamin D, which is why phosphate also contributes to parathyroid cell Vitamin D plays an important role in mineral homeostasis. proliferation (Dusso et al. 2001). In early CKD the Native vitamin D (25-hydroxyvitamin D) is activated in parathyroid gland often shows polyclonal proliferation, the kidney via 1- -hydroxylase (Brunette et al. 1978) α and in late CKD monoclonal/nodular proliferation is to the active form 1,25-dihydroxyvitamin D. Activated more common. However, different pathological changes vitamin D acts via the vitamin D receptor (VDR) in the often coexist in the same parathyroid gland (Basile et al. intestines to stimulate calcium and phosphate uptake 2006). With more severe rHPT the expression of VDR CaSR (Xue & Fleet 2009). Vitamin D receptors are also present and α-klotho is reduced (Fukuda et al. 1993, Komaba et al. in the parathyroid gland where, if activated they lead to 2010, Lee et al. 2013). reduced production and release of PTH and a suppression of parathyroid gland proliferation (Silver et al. 1986). The elevated levels of FGF23 in early CKD contribute Tertiary hyperparathyroidism to low levels of activated vitamin D, and later on, loss Long-standing CKD with rHPT leads to polyclonal and of nephrons also contribute to a deficiency of active eventually monoclonal proliferation of parathyroid tissue vitamin D (Levin et al. 2007). Patients with CKD also with a loss of regulatory receptors (van der Plas et al. have low levels of native vitamin D due to albuminuria, 2019). This condition is generally defined as tertiary low exposure to sunlight, and poor dietary intake hyperparathyroidism due to general hyperplasia of (Obi et al. 2015). The result of vitamin D deficiency is the parathyroid gland or autonomous adenoma. Both hypocalcemia. In late CKD both high phosphate and conditions are characterized by high levels of PTH in the vitamin D deficiency leads to hypocalcemia which is the presence of persistent hypercalcemia (Pitt et al. 2009). most potent stimulator of PTH release via the calcium- A histological finding of severe hyperplasia or parathyroid sensing receptor in the parathyroid gland (CaSR) adenomas with high levels of parathyroid hormone and (Brown et al. 1993). Apart from other effects of PTH persistent hypercalcemia and often also hyperphosphatemia described earlier, the most potent effect is to increase in patients with rHPT is associated with failure to respond serum calcium levels by enhancing renal tubular to medical treatment (Tominaga et al. 2007). Tertiary HPT calcium reabsorption, stimulating net bone resorption is a complication of long-term CKD most often after many and increasing the production of activated vitamin years of dialysis treatment and can persist after successful D (1,25(OH)2D3) (Pocotte et al. 1991). Low levels of renal transplantation. Two years after renal transplantation active vitamin D also directly result in PTH release and an incidence of about 30% has been reported (Shindo et al. parathyroid cell proliferation. 2016). It is noteworthy, however, that some authors define tertiary hyperparathyroidism as a persistent HPT after renal transplantation (Dulfer et al. 2017). In this review Parathyroid gland hyperplasia we have chosen to define tertiary hyperparathyroidism as The leading factors for parathyroid gland hyperplasia are refractory rHPT. active vitamin D, calcium and phosphate. Transforming growth factor-alpha (TGF-α) has been shown to be a Symptoms and signs potent proliferative agent for parathyroid cells via the activation of EGF receptor (EGFR). Activation of EGFR RHPT is not only manifested by deranged laboratory both leads to proliferation of parathyroid cells and analyses. It also affects patient well-being, see Table 2 for to lesser expression of VDR (Arcidiacono et al. 2008). some common signs and symptoms. Initial symptoms are The anti-proliferation pathway is mediated via cyclin- pruritus and thirst. As rHPT becomes more pronounced, dependent kinase inhibitor p21 and also reduced muscle weakness and tiring easily become prominent. expression of TGF-α. Both active vitamin D and high levels Albeit, that all these symptoms are also typical during the of calcium inhibit parathyroid cell proliferation through later stages of CKD. Findings such as vascular calcification this pathway (Cozzolino et al. 2001, Cordero et al. 2002). and osteodystrophy can occur already during CKD stage 3 Thus, low levels of active vitamin D in CKD contribute and evolve as GFR declines, due to an increased imbalance to parathyroid cell proliferation (Tokumoto et al. 2002). in the FGF23–calcium–phosphate–vitamin D-PTH axis. In uremic rats, high dietary intake of phosphate increases Once rHPT advances to tertiary hyperparathyroidism TGF-α and low dietary intake of phosphate enhances patients can experience mood swings, conjunctivitis

Table 2 Some signs and symptoms in rHPT. Vitamin D: ergocalciferol or cholecalciferol In accordance with the described sequence of Pruritus Thirst pathophysiological events, the first line of treatment Headaches should be medical, aiming to compensate for the Muscle weakness dwindling number of nephrons. Thus, supplementation Bone pain with calciferol is recommended as the first line of Joint pain Tiring easily treatment in non-dialysis patients with CKD stages 3a to Abdominal pain 5 (KDIGO 2009, Goldsmith 2016). 25(OH) insufficiency Mood swings and/or depression or deficiency in patients with CKD stages 3 to 5 should be Conjunctivitis – red eye syndrome treated according to the recommendations for the general Vascular calcification Osteodystrophy population (KDIGO 2009). The same treatment strategy Brown tumors in the mandible should be employed in patients with CKD stage 5D Brown tumors in the bones of the extremities (KDIGO 2009, Goldsmith 2016). There is still controversy Low bone mineral density regarding the long-term effects of this treatment, mainly Fragility fractures due to the fact that there is insufficient evidence from Data from Pasieka & Parsons (2000). solid, long-term randomized controlled trials comparing vitamin D with other treatment modalities. However, as well as bone and joint pain. Eventually they develop in a recent randomized controlled trial in patients with brown tumors in their bones. CKD stages 3 and 4, 12 weeks of supplementation with cholecalciferol resulted in a decrease in PTH with stable levels of plasma calcium (Westerberg et al. 2018). Diagnosis

Diagnosis of rHPT is a process. Initially plasma calcium Control of calcium and phosphate (low to normal), phosphate (elevated), PTH (elevated) and vitamin D (low) are sufficient for the diagnosis of Restriction of dietary intake As plasma phosphate rHPTH. Moreover, in patients with evidence of CKD-MBD starts to rise, a restriction of dietary phosphate intake is or osteoporosis monitoring of bone mineral density with recommended. This is not always easy for the patient to dual-energy X-ray absorptiometry (DEXA) is recommended adhere to. There are usually high levels of phosphate in (KDIGO). As long as rHPT can be controlled with the therapy processed foods, which can add an extra burden for the options described in sections ‘Vitamin D: ergocalciferol patient if they are unaccustomed to preparing their meals or cholecalciferol’ to ‘Active vitamin D analogs’ further using fresh and whole ingredients. In patients with CKD investigations are generally not required. However, when stages 4 and 5, protein restriction per se will provide a PTH, plasma calcium and phosphate no longer can be certain phosphate restriction, but in patients on dialysis controlled and the question of tertiary hyperparathyroidism the increased protein requirements can make phosphate arises, further investigation is necessary. Firstly, patient restriction more complicated. Thus, most patients will to symptoms should be explored in order to guide the extent some degree require treatment with phosphate binders. of the investigation. Once, the nephrologist is convinced that the patient has tertiary rHPT, that is, renal HPT resistant Treatment with phosphate binders Phosphate binders to medical treatment, contact with an endocrine surgeon is are central to the treatment of hyperphosphatemia, established. Secondly, if the patient has bone and/or joint usually starting during CKD stages 4 and 5 and continuing pain an X-ray, scintigraphy or CT of the mandible, hands, through stage 5D. Numerous studies have shown that legs and arms are recommended. The degree of vascular increased levels of phosphate are associated with increased calcification can be investigated by a lumbar X-ray to mortality (Tentori et al. 2008, 2015). Hypercalcemia is determine the abdominal aortic calcification score. associated with increased morbidity and mortality mainly due to valvular, coronary artery, and aortic calcification (Floege & Ketteler 2004, Ogawa & Nitta 2018). The oldest Treatment phosphate binder is aluminum hydroxide and should not be used due to the deleterious effects of aluminum Medical overload. Calcium-based phosphate binders, usually Treatment options are summarized in Table 3. calcium carbonate, can be used, but it is essential to

Table 3 An overview of medical treatment options for renal HPT.

Restriction of Non-selective vitamin Selective vitamin D Vitamin D phosphate intake Phosphate binders D receptor activators receptor activators Calcimimetics Ergocalciferol Avoid processed Sevelamer Calcitriol Paricalcitrol Cinacalcet foods hydrochloride Cholecalciferol Avoid drinks with Lanthanum Alfacalcidol Maxacalcitol Etelcalcide (only i.v. high phosphate carbonate administration) Avoid certain Ferric citrate Doxecalciferol foods with high phosphate content Sucroferric oxyhydroxide Calcium carbonate

Start treatment options by using medication in the left column and proceed toward the right as the severity of the condition progresses. avoid hypercalcemia. Modern phosphate binders, such as and hyperphosphatemia were similar for the non- sevelamer hydrochloride and lanthanum carbonate have selective VDRAs compared with the selective VDRAs been shown to be effective and safe (Patel et al. 2016). (Xie et al. 2017). Another meta-analysis in non-dialysis- The most recent additions are based on iron, such as ferric dependent patients with CKD compared paricalcitol citrate and sucroferric oxyhydroxide (Habbous et al. 2017). with placebo and found that paricalcitol effectively Moreover, sevelamer also seems to have positive effects decreased PTH levels (Han et al. 2013). They also found on arteriosclerosis which are not directly related to its a statistically nonsignificant trend toward hypercalcemia phosphate-binding capacity (Patel et al. 2016). Phosphate in the paricalcitol-treated patients compared to those on control is an important priority and levels should be placebo (Han et al. 2013). maintained within the normal range (KDIGO 2009). This is easier said than done. The burden of pills necessary Calcimimetics In some patients, hyperparathyroidism to control phosphate is usually high and can amount to is uncontrollable with the therapy options described around 15–20 extra tablets a day, which should be taken earlier. Before the advent of cinacalcet they would need with a meal. Moreover, many patients can experience surgical treatment to control their PTH and calcium mild gastrointestinal disturbances due to the phosphate levels. In 2002 cinacalcet was shown to successfully binders. The multi-professional nephrology team needs to lower PTH in patients on hemodialysis (Goodman et al. be involved to help motivate the patient and explain the 2002). A randomized controlled trial in 2004 showed that long-term advantages. cinacalcet could decrease PTH and induce lower plasma calcium and phosphate levels in patients on hemodialysis Active vitamin D analogs The active vitamin D (Block et al. 2004). Similar positive results were also analogs actively bind to the vitamin D receptors in reported in patients with CKD stages 3–4 (Charytan et al. many tissues such as the parathyroid gland and the 2005). Disappointingly, cinacalcet has not been as intestine. There are a number of non-selective vitamin effective as initially expected for long-term treatment D receptor activators: the first generation comprises of hyperparathyroidism in patients with CKD. In an calcitriol (1α25-dihydroxyvitamin D2), and the second observational study using French registry data the authors generation alfacalcidol (1α-hydroxyvitamin D3) and found that the use of cinacalcet did not significantly doxecalciferol (1α-hydroxyvitamin D2). They are effective impact PTH values compared with patients without the in controlling PTH but can cause hypercalcemia (Zand & treatment (Brunaud et al. 2016). The expectations that Kumar 2017). The third generation of vitamin D receptor cinacalcet treatment would reduce the risk of death or activators are selective and comprise paricalcitol (1,9-nor- major cardiovascular end points were not corroborated

1α25-dihydroxyvitamin D2) and maxacalcitol (22-oxa- in the EVOLVE trial (EVOLVE Trial Investigators 2012).

1,25-dihydroxyvitamin D3) (Darabian et al. 2012). In However, in a trial focusing on renal osteodystrophy, a meta-analysis calcitriol and alfacalcidol had similar cinacalcet significantly decreased high rates of bone efficacy in suppressing PTH compared with paricalcitol and formation and some biochemical markers of high-turnover maxacalcitol (Xie et al. 2017). The risks of hypercalcemia bone disease as PTH was reduced, with 26% of the patients

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 R27 Cancer hyperparathyroidism achieving normal bone histology after 12 months of Cardiovascular disease is the leading cause of death treatment (Behets et al. 2015). There are some unwanted in renal transplant recipients (Kasiske et al. 1996) and side effects of treatment with cinacalcet. All studies report there are some data supporting an association with rHPT that hypocalcemia, nausea and vomiting were frequent (Bleskestad et al. 2014, Pihlstrom et al. 2015). The fracture and difficult side effects in patients treated with cinacalcet risk is high after renal transplantation (Naylor et al. 2013) (Block et al. 2004, EVOLVE Trial Investigators 2012, and renal transplant patients have varying patterns of Brunaud et al. 2016). The gastrointestinal symptoms were bone disease. Studies of bone biopsies in renal transplant often a reason that patients discontinued treatment. recipients show a marked decrease in bone turnover The latest calcimimetic, etelcalcide, is administered following transplantation and low bone turnover as the intravenously. In a randomized controlled trial in predominant pattern (Evenepoel et al. 2017, Keronen et al. hemodialysis patients the effects of etelcalcide on PTH 2019). Bone disease after renal transplantation is both were found to be non-inferior to cinacalcet (Block et al. due to rHPT but also to factors specific to transplantation 2017). The frequency of nausea and vomiting was similar such as corticosteroids and immunosuppressive agents in both treatment groups, but the etelcalcide group was (Julian et al. 1991, Weisinger et al. 2006). The correlation more likely to experience hypocalcemia compared with between bone histology and non-invasive diagnostic tools the cinacalcet group (Block et al. 2017). (bone mineral density, biomarkers) is weak (Keronen et al. In summary, medical treatment is not the sine qua 2019) and bone biopsies are infrequently used in clinical non for treatment of hyperparathyroidism in patients practice. Additionally, most findings regarding rHPT post- with CKD. A problem that has not been adequately transplantation are based on small observational studies. addressed when evaluating the efficacy of different Thus, recommendations of evaluation and treatment of treatment modalities is whether a patient only suffers post-transplant rHPT are not very specific. from an increased production of PTH or whether there is hyperplasia of or adenoma in the parathyroid glands. It is Surgical: parathyroidectomy likely that the boundary for success of medical treatment runs here, and when there are manifest anatomical Indications changes in the PTH glands, surgical treatment becomes As stated earlier, rHPT is initially a physiologic adaptation necessary. to the decreasing renal function. However, with time, hyperparathyroidism becomes deleterious, increasing the risk for cardiovascular and skeletal disease and can lead to Renal transplantation shortened survival in patients with CKD. Most patients After successful renal transplantation the mineral are successfully managed medically, as outlined above. homeostasis is completely changed. The remaining high However, in a small but important subset of patients, FGF23 and PTH now exert actions on a functioning medical treatment cannot control rHPT. In these patients, kidney that will increase the secretion of phosphate in the surgical treatment with parathyroidectomy (PTX) is an urine, resulting in hypophosphatemia (Bhan et al. 2006). option. KDIGO CKD-MBD guidelines state that PTX is Levels of FGF23 decrease and the expression of α-klotho indicated in ‘patients with ESRD and severe HPT who fail increases after transplantation (Kimura et al. 2015). Levels to respond to pharmacological treatment’. The European of vitamin D and calcium increase (Reinhardt et al. 1998). Society of Endocrine Surgeons published a consensus Hypercalcemia in the first 1–6 months is common and is report in 2015 stating that PTX is an option in any patient associated with high levels of PTH (Amin et al. 2016). Levels with rHPT, but that in most patients, the condition of PTH accumulate during ESRD thus a rapid decrease in can be managed medically. Specifically, PTX would PTH is seen immediately after transplantation. Thereafter, be indicated when medical treatment fails to correct levels of PTH keep decreasing slowly and stabilize metabolic parameters: PTH >85 pmol/L, hypercalcemia after the first 6 months (Isaksson & Sterner 2012). The and hyperphosphatemia. majority of patients have PTH levels above the reference There are no randomized trials comparing PTX to range 1 year after transplantation (Sprague et al. 2008). medical treatment. Hence, guideline recommendations Risk factors for post-transplant rHPT are pre-transplant rely on data from observational studies. Given the levels of PTH and calcium, time spent on dialysis heterogeneity of patients with rHPT, the differences before transplantation and nodular hyperplasia of the in types of dialysis, whether patients had or had not parathyroid glands (Taweesedt & Disthabanchong 2015). previously received a renal transplant, differences in

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 R28 Cancer hyperparathyroidism medication, and so forth, it is hard to define specific usually performed with open surgery through a Kocher indications for surgery in a given patient. It is likely that cervical incision in general anesthesia (Lorenz et al. 2015), indications differ according to sex, age, type of underlying although there have been reports on minimally invasive renal disease, whether the patient has a functioning PTX (Barbaros et al. 2009, Sun et al. 2009, Alesina et al. transplant and/or the chance of receiving a transplant. 2010). Subtotal and total PTX can both be combined Epidemiologic studies indicate that parathyroidectomy with transcervical thymus resection and/or parathyroid rates decreased in the first years after the introduction of autotransplantation. The lower parathyroids are often calcimimetics, but have since risen again (Akaberi et al. found in or close to the thymus, and nests of parathyroid 2014). They also point to regional differences within tissue are also often found in normal thymic tissue. Hence, and between countries, probably due to different access many authors recommend performing transcervical to nephrologists and/or endocrine surgeons, and to thymectomy together with PTX (Schneider et al. 2013, different therapy strategies between institutions. Multiple Lorenz et al. 2015). regression models suggest that women, younger patients There has been a debate among endocrine surgeons as and non-diabetic patients have a greater probability of to whether less (subtotal/focused) or more (total) radical undergoing PTX (Akaberi et al. 2014). surgery is optimal in rHPT. Large population-based studies Evidence indicates that PTX is associated with reduced (Isaksson et al. 2019) and meta-analysis (Chen et al. 2015) risk of fractures (Isaksson et al. 2017), cardiovascular have not found any evidence of differences in long-term disease (Ivarsson et al. 2019) and mortality (Ivarsson et al. outcomes such as risk of fracture, cardiovascular disease 2015). Studies also show that PTX is related to improved and mortality between the two types of procedures. quality of life (van der Plas et al. 2017) and that is more Furthermore, there has been a misunderstanding in cost-efficient than calcimimetics in most patients with that some authors believe that rHPT can be cured ESRD (Narayan et al. 2007). Unless the patient has a (Burgstaller et al. 2018), analogous to primary HPT high risk of dying soon or an imminent transplantation (pHPT), which has very high cure rates with the resection is expected, PTX is more cost-effective, given the high of one or more parathyroid glands (Bergenfelz et al. costs of maintenance treatment with calcimimetics 2009). However, pHPT and rHPT are different entities. (Narayan et al. 2007). However, perioperative morbidity It is evident from the discussion above that rHPT also and even mortality is not insignificant Kestenbaum( et al. persists even in mild renal dysfunction, if the patient 2004, Ishani et al. 2015); hence, in all patients, surgical receives a renal transplant (Lou et al. 2015). Hence, PTX risk must be weighed against potential long-term can never cure rHPT. Instead, the aim of PTX is to reduce improvement in outcomes. the amount of parathyroid tissue to such an extent that Even if most of these studies tried to adjust for an optimal level of PTH post-PTX is achieved. This is confounders, a selection bias cannot be completely ruled similar to the situation in hereditary pHPT, for example, out. Patients that are referred for parathyroidectomy multiple endocrine neoplasia type 1 (MEN1), which also are likely healthier and with a better expected outcome cannot be cured, and the goal of surgery is to give the than patients who do not get referred for surgery, all patient as many years with normocalcemia as possible other things equal. Unfortunately, it is unlikely that a (Schreinemakers et al. 2011). randomized trial comparing medical treatment to PTX The optimal level of PTH after PTX for rHPT is will ever be performed, given the large number of centers unknown. Probably, profound hypoparathyroidism is just that would be needed to perform such a study. as detrimental as severe hyperparathyroidism – in patients Whether to perform PTX or not is also influenced with rHPT, as we have seen earlier, the initial adaptation by potential future or previous renal transplantation. As of the parathyroids is physiological, helping the body get discussed earlier, renal transplantation can be expected to rid of excess phosphate not cleared by the kidneys. Hence, ameliorate some but not all renal hyperparathyroidism. leaving too little viable parathyroid tissue is probably not optimal. On the other hand, leaving too much increases the risk of reoperation (due to persistent and/or recurrent Surgical technique disease). Thus, the question for the endocrine surgeon is PTX is performed as either subtotal PTX, where the not how much to remove, but how much to leave behind. aim is to keep parathyroid tissue corresponding to one In this regard, there have been studies examining the normal gland, and total parathyroidectomy, aiming at correlation between PTH levels and long-term outcomes removing all parathyroid tissue. Parathyroidectomy is in patients with ESRD. Thus, a report from the DOPPS

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 R29 Cancer hyperparathyroidism study in 2008 showed that PTH levels between 100 pg/mL HPT, preoperative imaging, with modalities such as and 600 pg/mL were associated with the lowest risk of ultrasonography, 99-Technetium sestamibi scintigraphy, mortality (Tentori et al. 2008). The authors re-examined and four-dimensional CT (4D-CT), has been evaluated but this topic and in 2015 reported similar findings. In their has not been shown to have greater accuracy in finding all multivariate analysis, patients in the reference group with parathyroid glands than traditional surgical exploration. levels of PTH between 150 and 300 pg/mL had the lowest A meta-analysis (Caldarella et al. 2012) reported that the mortality risk (Tentori et al. 2015). Data also show that sensitivity of 99mTc-sestamibi scan in secondary HPT was PTH levels vary significantly after both subtotal and total only 58%. They concluded that 99mTc-sestamibi is not PTX (Burgstaller et al. 2018, Isaksson et al. 2019). a first-line diagnostic imaging method in this situation. Sensitivity of US for detection of enlarged parathyroid glands has been reported to be 46–81% in patients with Intraoperative measurement of parathyroid secondary HPT (Sukan et al. 2008, Yuan et al. 2016, Li et al. hormone (ioPTH) 2017). The combination of US with 99mTc-sestamibi In primary HPT, intraoperative measurement of PTH SPECT/CT had a higher sensitivity than US or 99mTc- (ioPTH) helps the surgeon to determine if there is more sestamibi SPECT/CT alone (Yuan et al. 2016). Most authors hyperfunctioning tissue left after resection or whether thus conclude that ultrasound and sestamibi scintigraphy the operation can be terminated. There has been offer little benefit in localizing ectopic glands and rarely numerous studies investigating whether ioPTH also helps change the conduct of a standard four-gland exploration in PTX for rHPT (Lokey et al. 2000, Seehofer et al. 2001, (Alkhalili et al. 2015, Karipineni et al. 2018, van der Haustein et al. 2005, Weber et al. 2005, Meyer et al. 2009, Plas et al. 2019). However, some authors have found that Freriks et al. 2010, Sohn et al. 2015, El-Husseini et al. 2018, SPECT-CT offered useful information (Taieb et al. 2013). Marcadis et al. 2018). Most but not all of these studies On the contrary, in the setting of re-PTX, that is, surgery indicate that there is a correlation between ioPTH and for persistent or recurrent HPT after previous PTX, imaging postoperative PTH and that ioPTH is helpful. Since PTH studies are mandatory (Lorenz et al. 2015). is cleared by the kidneys, the half-life of PTH, and hence, the time needed to wait for a drop in intraoperative PTH, is longer after PTX for renal HPT. Probably, PTH should Intraoperative angiography be measured no earlier than 15–20 min post resection. A further issue complicating PTX is that it is difficult to Different criteria on the optimal level of ioPTH post be certain that the parathyroid tissue left in the neck at resection have been proposed, but there is no consensus surgery is viable: devascularization of the parathyroid on what level of ioPTH yields the best outcomes. glands is common. Recently, intraoperative angiography of the parathyroids using indocyanine green has shown great promise in aiding the surgeon to determine whether Preoperative localization parathyroid glands are functioning or not (Cui et al. 2017). The outcome of PTX is highly dependent on the skills Combined with ioPTH and possibly with cross-sectional and experience of the surgeon. In experienced hands, imaging, these tools might enable the surgeon to deliver a the main cause of persistent or recurrent rHPT after PTX more precise PTX, yielding an optimal postoperative level is the inability to localize ectopic parathyroid glands of PTH. (Dotzenrath et al. 2003). From a surgical point of view, a distinction exists between a minor ectopy (such as in the thyrothymic horn and upper anterior mediastinum, or Surgical complications beneath thyroid capsule) and a major ectopy (such as low Risks of PTX include damage to the recurrent laryngeal mediastinal, retro esophageal, above the level of the hyoid, nerve, bleeding and infection. These risks are small in in the carotid sheath, or within the thyroid parenchyma - the hands of experienced surgeons, and nationwide truly intrathyroidal) (Taieb et al. 2013). Ectopic and/or studies have shown these complications to be rare (van supernumerary glands are common in rHPT (Lorenz et al. der Plas et al. 2018). However, complications related to 2015), and it is essential that the surgeon has identified abnormal mineral metabolism are common and expected. all parathyroid glands. The experienced surgeon will usually find all non-ectopic glands; preoperative Postoperative management localization should therefore positively and accurately Patients undergoing PTX for renal hyperparathyroidism localize all ectopic parathyroid glands. Similar to primary are best managed by nephrologists, with input from 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 R30 Cancer hyperparathyroidism endocrine surgeon if needed. Profound postoperative References hypocalcemia is not uncommon, and perhaps ameliorated with preoperative calcitriol loading (Alsafran et al. 2019). Akaberi S, Clyne N, Sterner G, Rippe B, Reihner E, Wagner P, Rylance R, Prutz KG & Almquist M 2014 Temporal trends and risk factors for Admissions to intensive care units for hypocalcemia, and parathyroidectomy in the Swedish dialysis and transplant population re-admissions due to mineral metabolism imbalances are – a nationwide, population-based study 1991–2009. BMC Nephrology common. However, as stated earlier, data indicate that 15 75. 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Received in final form 25 October 2019 Accepted 5 November 2019 Accepted Manuscript published online 6 November 2019