What Is the Role of Surgery in Secondary and Tertiary Hyperparathyroidism?

Abstract

Secondary hyperparathyroidism (sHPT) contributes significantly to renal osteodystrophy, cardiovascular morbidity, and mortality. Pharmacological management includes phosphate-lowering treatments for persistent overt hyperphosphatemia, calcitriol and vitamin D analogs for hypocalcemia, and less frequent calcimimetics. Refractory sHPT, unresponsive to pharmacological treatments, necessitates an individualized approach to parathyroidectomy (PTx). PTx in refractory sHPT should be considered when parathyroid hormone levels progressively rise or sHPT-related symptoms persist. Subtotal PTx or total PTx with auto-transplantation is preferred for patients eligible for kidney transplantation. For those not considered for kidney transplantation, total PTx is an option. Additional thymectomy, mainly when the lower parathyroid glands cannot be located, may be performed. Tertiary hyperparathyroidism (tHPT) frequently persists at two years of follow-up after kidney transplantation. THPT often involves multiple glands, adversely affecting bone metabolism, cardiovascular risk, and kidney allograft function, thus warranting PTx. Subtotal PTx remains the preferred surgical approach. When glandular autonomy is suspected, the timing of PTx ideally precedes kidney transplantation. If PTx is required post-kidney transplantation, most centers delay surgery until one year after transplantation to improve kidney allograft outcomes. The decision for PTx and its extent and timing must be carefully individualized, balancing the risks and benefits to maximize patient outcomes in both sHPT and tHPT.

1. Introduction

The parathyroid glands are the primary regulators of calcium metabolism. Calcium plays a crucial role in nerve conduction, muscle contraction, and bone mineralization, underscoring the importance of the parathyroid glands. In secondary hyperparathyroidism (sHPT), the elevated serum parathyroid hormone (PTH) levels are not due to a malfunction within the parathyroid glands themselves. Instead, low serum calcium levels stimulate all parathyroid glands. Potential causes include vitamin D deficiency and chronic kidney disease (CKD), conditions where 25(OH) vitamin D is not converted to its active form, 1,25(OH)² calcitriol. SHPT is a major contributor to chronic kidney disease-mineral and bone disorder (CKD-MBD) [1]. CKD-MBD is a complex syndrome seen in CKD patients that includes renal osteodystrophy, disturbances in mineral metabolism, and cardiovascular disease [1]. Depending on the stage of CKD, the prevalence of sHPT ranges from 20 to 80% [2, 3, 4]. SHPT further increases the risk of vascular and valvular calcification [5, 6] and is associated with high cardiovascular morbidity and mortality in non-dialysis and dialysis patients [7, 8, 9, 10].

Refractory sHPT is characterized by progressively rising and persistently elevated PTH levels that do not adequately respond to medical treatments, such as phosphate-lowering treatments, calcitriol and vitamin D analogs, and calcimimetics, without causing hyperphosphatemia or hypercalcemia. In patients who experience improved glomerular filtration rate (GFR) following kidney transplantation, abnormalities in calcium, phosphate, and vitamin D metabolism often normalize, allowing PTH levels to return to physiological levels gradually. However, prolonged stimulation of the parathyroid glands can lead to tertiary hyperparathyroidism (tHPT), characterized by a persistent elevation of PTH due to parathyroid autonomy, resulting in mild to moderate hypercalcemia and hypophosphatemia. THPT after kidney transplantation has been found to impact bone quality negatively [11, 12], reduce kidney allograft function and survival [13], and increase cardiovascular and overall mortality [13].

This book chapter will focus on the pathophysiology of sHPT and tHPT and its treatments, particularly emphasizing the current surgical practices, including the extent and timing of parathyroidectomy (PTx).

2. Definition and pathogenesis of secondary and tertiary hyperparathyroidism

In advanced CKD, hyperphosphatemia, hypocalcemia, and decreased 1,25(OH)² calcitriol levels cause continuous stimulation of the parathyroid glands via direct and indirect mechanisms. This results in increased PTH production and release [14]. Persistently elevated PTH levels increase serum calcium levels through three primary mechanisms: First, PTH enhances vitamin D activation to 1,25(OH)² calcitriol, thereby improving intestinal calcium absorption. Second, PTH reduces renal calcium excretion, and third, PTH increases serum calcium levels by promoting bone resorption.

In the last decade, this understanding has been augmented by the discovery of the fibroblast growth factor 23 (FGF23), a phosphaturic protein produced in osteocytes and osteoblasts with multiple effects. FGF23 is stimulated early in CKD, preceding clinically evident hyperphosphatemia [15]. Together with the cofactor/coreceptor Klotho, which facilitates FGF23 binding to the FGF23 receptors in the kidneys, parathyroid glands, and bone, phosphate excretion is increased through different mechanisms: First, FGF23 increases renal phosphate excretion in the proximal tubule, second it decreases PTH excretion in the parathyroid glands, and third it inhibits vitamin D activation in the kidney [15]. However, in advanced CKD, the phosphaturic capacity of FGF23 becomes exhausted, so elevated FGF23 levels indirectly stimulate PTH and contribute to the progression of sHPT [15].

Ultimately, sHPT is characterized by (1) normal or decreased serum calcium levels, depending on the compensatory capacity of the parathyroid glands; (2) increased serum phosphate and FGF23 levels, and (3) decreased 1,25(OH)² calcitriol levels. Refractory sHPT is defined by progressively rising and persistently elevated PTH levels that do not adequately respond to medical treatments, such as phosphate-lowering treatments, calcitriol and vitamin D analogs, and calcimimetics, without resulting in significant hyperphosphatemia or hypercalcemia.

If end-stage CKD, as the cause of sHPT, is corrected by kidney transplantation, abnormalities in calcium, phosphate, and vitamin D metabolism often normalize, and PTH levels gradually return to physiological levels. However, it is assumed that in many individuals, the normalization of kidney function following kidney transplantation does not lead to the normalization of parathyroid function. SHPT has been shown to decrease from 70% at one year to 43% at two years after kidney transplantation [16]. Long-term stimulation of the parathyroid glands in CKD can lead to gland hyperplasia, and over time, polyclonal stimulation may result in nodular remodeling. From this point, somatic mutations can lead to predominantly monoclonal proliferation with reduced sensitivity of the calcium-sensing and vitamin D receptors on the parathyroid cells. At this stage, parathyroid cells no longer undergo normal regulation and do not respond to typical PTH-suppressive stimuli such as normalized serum calcium levels. Consequently, serum calcium levels rise, and parathyroid autonomy develops, a condition known as tHPT. Although the clinical manifestations of hypercalcemia and hypophosphatemia resemble primary hyperparathyroidism, multiglandular disease is common in tHPT.

3. Impact of secondary hyperparathyroidism on chronic kidney disease: Mineral and bone disorder

Clinically, patients with sHPT exhibit various signs and symptoms, primarily impacting the bone with bone and joint pain and incident fractures and the cardiovascular system with extra-skeletal calcifications of vasculature and valves and, in rare cases soft tissue resulting in calciphylaxis [17].

The decreased levels of 1,25(OH)² calcitriol in CKD lead to deficient bone mineralization, known as osteomalacia. Conversely, the PTH-stimulating effect enhances bone turnover, decreasing laminar bone and increasing trabecular bone volume, a condition termed osteitis fibrosa cystica. When bone turnover is reduced due to medical treatment, this is called adynamic bone disease. All three forms of skeletal involvement—osteomalacia, osteitis fibrosa cystica, and adynamic bone disease—are common in CKD and collectively known as renal osteodystrophy [11, 18]. Unlike osteoporosis, where trabecular bone is primarily affected, renal osteodystrophy predominantly impacts cortical bone [18]. PTH increases bone volume but not the mass of trabecular bone, leaving the mechanically strong lamellar bone less affected. An iliac crest biopsy remains the gold standard for diagnosing and classifying renal osteodystrophy. While bone mineral density (BMD) assessments by dual-energy X-ray absorptiometry (DXA) are designed to evaluate osteoporosis and are not ideal for assessing renal osteodystrophy, they are less invasive. Therefore, low and declining BMD, in combination with increasing serum alkaline phosphatase levels, used as indicators of elevated bone turnover, are reasonable biomarkers to predict incident fracture risk in CKD patients with renal osteodystrophy and to support the use of osteoporosis medications [19].

In addition to renal osteodystrophy, sHPT is associated with high cardiovascular morbidity and mortality [8, 9, 10, 13]. Given that most patients with sHPT have elevated phosphate levels, it cannot be excluded that hyperphosphatemia contributes significantly to the high cardiovascular risk. In addition, elevated FGF23 levels in advanced CKD have deleterious effects on vascular and valvular calcification [20], and left ventricular hypertrophy (LVH), putting those patients at the highest cardiovascular risk.

This complex syndrome associated with CKD is termed CKD-MBD [17, 21]. It encompasses mineral metabolism abnormalities, bone abnormalities (renal osteodystrophy), and vascular calcification. SHPT is the predominant driver of CKD-MBD.

4. Medical treatment options for secondary hyperparathyroidism and tertiary hyperparathyroidism

The only causative treatment for refractory sHPT in patients with CKD is kidney transplantation. All other treatments aim to improve dysregulation and reduce morbidity, serving as symptomatic treatments. General recommendations for CKD patients on dialysis are to maintain PTH levels in the range of approximately two to nine times the upper normal limit of the assay (i.e., 585 pg./mL if the upper range of normal is 65 pg./mL). PTH levels of around 300 pg./mL are considered compensatory and represent an appropriate adaptive response due to phosphaturic effects and increasing bone resistance to PTH. Patients with progressively rising and persistently elevated PTH levels, alongside hyperphosphatemia or hypercalcemia despite optimized medical treatment, are considered refractory, and PTx may be evaluated [21]. In addition to optimizing dialysis dose and adequacy, medical treatments include phosphate-lowering treatments, calcitriol and vitamin D analogs, calcimimetics, or a combination thereof.

4.1 Phosphate-lowering treatments

High phosphate levels are associated with increased mortality in advanced CKD patients (CKD 3a-5) [9]. This has led to the widespread use of phosphate-restrictive diets and phosphate binders in CKD patients. However, phosphate-lowering treatments may suppress PTH, potentially leading to adynamic bone disease. Calcium-based phosphate binders may increase vascular and valvular calcification [22], and aluminum-containing phosphate binders have shown toxicity due to aluminum accumulation [23]. Despite the clear association between high phosphate levels and mortality, there is no proof that phosphate restriction or phosphate-lowering treatments improve cardiovascular morbidity. Consequently, the use of phosphate-lowering treatments has become more restrictive, particularly calcium-based preparations, with the recommendation to treat hyperphosphatemia only if phosphate levels are repeatedly high (e.g., above 1.8 mmol/L) and not to treat CKD patients prophylactically [21].

4.2 Calcitriol and vitamin D analogs

In advanced CKD patients, low levels of 1,25(OH)² calcitriol stimulate parathyroid glands due to decreased intestinal calcium uptake and subsequent serum calcium drop, suggesting vitamin D supplementation as a potential solution. Two randomized controlled trials (RCTs) examined the effects of calcitriol or vitamin D analogs on cardiac endpoints [24, 25], revealing a significant increase in hypercalcemia without beneficial effects on surrogate cardiac endpoints. Given the morbidity associated with hypercalcemia and the related increase in phosphate and FGF23 levels, the risk-benefit ratio of treating moderate PTH elevations using calcitriol or vitamin D analogs is not clearly favorable. Routine use of calcitriol or vitamin D analogs is not recommended and should be reserved for severe and progressive sHPT, administered in low doses titrated based on PTH response while avoiding hypercalcemia [19].

4.3 Calcimimetics

Calcimimetics such as cinacalcet allosterically activate the calcium-binding site of PTH receptors in the parathyroid glands, lowering PTH and calcium levels, often resulting in hypocalcemia. In a well-designed RCT with 3383 dialysis patients randomized to either calcimimetics or placebo, calcimimetics significantly reduced PTH levels without affecting mortality, non-fatal cardiovascular events, or fracture rate [26, 27]. This has led to discussions about whether cinacalcet should be a first-line option for all patients with sHPT and advanced CKD requiring PTH-lowering treatment. Currently, there is no clear recommendation, but calcimimetics remain an option when PTH is markedly elevated and resulting mild hypocalcemia could be tolerated [21]. The potential of newer calcimimetic agents to reduce PTx rates among dialysis patients remains uncertain. In dialysis patients, the intravenous calcimimetic etelcalcetide has been shown to lower PTH levels more effectively than cinacalcet [9, 14].

4.4 Bone-directed therapies

Renal osteodystrophy encompasses three main forms: osteomalacia, osteitis fibrosa cystica, and adynamic bone disease with low bone turnover. Adynamic bone disease, which is particularly detrimental, should be avoided if possible. Low bone turnover can be disease-related (e.g., malnutrition, diabetes, and hyperphosphatemia in CKD leading to PTH hyporesponsiveness) or triggered by medical treatments [28]. Specifically, calcium supplementation, calcitriol, vitamin D analogs, calcimimetics, and PTx can lead to adynamic bone disease due to over-suppression of PTH in the parathyroid glands [28]. Bone-directed treatments aim to shift the bone mineral balance toward a positive state, including antiresorptive and osteoanabolic treatments. Antiresorptive therapies inhibit osteoclasts, which cause bone resorption as counterplayers to osteoblasts. As antiresorptive agents, bisphosphonates induce osteoclast apoptosis, while denosumab decreases osteoclast development. Both are associated with atypical femur fractures and are not recommended for adynamic bone disease or hypocalcemic patients, as they can exacerbate hypocalcemia. They may be considered in patients with high bone turnover, weighing the risk of antiresorptive use against the accuracy of diagnosing the underlying bone phenotype.

Abaloparatide and romosozumab, as osteoanabolic agents, offer the benefit of stimulating osteoblast activity, which can be particularly advantageous in addressing adynamic bone disease with low bone turnover. However, their use must be carefully monitored to prevent potential complications such as hypercalcemia. Achieving a balance between their anabolic effects and minimizing the risk of exacerbating adynamic bone disease is crucial for optimizing patient outcomes.

5. The indication for parathyroidectomy in secondary hyperparathyroidism and its potential benefits

If medical treatment cannot control severe refractory sHPT, PTx must be evaluated. According to the KDIGO guidelines, this is indicated when PTH remains progressively rising and persistently above nine times the normal range despite treatment with calcitriol, vitamin D analogs, calcimimetics, or a combination thereof [21]. However, PTx is rarely performed at this level in the absence of sHPT-related symptoms such as bone and joint pain, myopathy, or severe extra-skeletal calcifications.

The German guidelines recommend starting with a phosphate-lowering treatment if phosphate levels are repeatedly elevated (e.g., above 1.8 mmol/l). If PTH rises above 300 pg./mL, vitamin D analogs or calcimimetics should be administered. Vitamin D analogs are preferred in hypocalcemic patients to correct vitamin D deficiency. At the same time, calcimimetics can be an option in hypercalcemic patients, although the KDIGO 2017 does not explicitly recommend their use. If these medical treatments and optimizing dialysis dose and adequacy are unsuccessful, PTx may be recommended [1].

However, the indication for PTx must be individualized based on factors such as age, cardiovascular risk, other comorbidities, and preparation for possible kidney transplantation. In severely symptomatic patients, the indication for PTx exists independent of these factors. In asymptomatic patients, while there is no consensus on a PTH level that mandates PTx, progressively rising PTH levels above 1000 pg./mL may be considered an indication.

The rationale is clear: elevated PTH levels significantly raise morbidity by increasing cardiovascular risk, incident fracture risk, and overall mortality. Therefore, removing the source of PTH production should mitigate these effects.

Regarding renal osteodystrophy, a matched retrospective study on nearly 6000 hemodialysis patients showed that PTx reduced the risk of hip fractures by 32% [29]. This could be because patients with PTx experienced less pain and, therefore, moved more freely, positively impacting bone strength. Another study examined cardiovascular mortality in over 114,000 hemodialysis patients in Japan. In over 4000 hemodialysis patients matched with just as many who underwent PTx, not having had a PTx was a risk factor for all-cause and cardiovascular mortality [7].

In terms of future kidney allograft function, Callender et al. retrospectively examined 900 kidney transplant recipients, 57 of whom had a PTx before transplantation. They found that a six-fold increase in PTH at the time of transplantation was associated with kidney allograft loss. PTx before transplantation was associated with a lower risk of kidney allograft loss [30].

Additionally, PTx has been shown to significantly improve symptoms in patients with primary, sHPT, and tHPT. Patients with sHPT had the most prominent symptoms and were not entirely symptom-free after surgery. Symptom improvement in patients with primary and tHPT was similar. Symptoms were measured using the median symptom index score (MSIS), which includes 13 items, such as bone pain, depressive mood, and memory impairments [31]. For sHPT, symptom improvement after PTx was confirmed in another study using the parathyroidectomy assessment of symptoms (PAS) score [32].

PTx in patients with sHPT has notable perioperative morbidity. Besides the small risk of recurrent laryngeal nerve palsy and bleeding, mortality is increased in the postoperative period. A study of over 4500 hemodialysis patients with PTx, compared with just as many without PTx, showed that mortality was significantly higher in the PTx group until 90 days postoperatively. However, after 587 days, the mortality risk decreased for patients who underwent PTx [33]. Thus, while perioperative mortality is higher, long-term mortality is lower in hemodialysis patients who undergo PTx.

Overall, PTx in patients with refractory sHPT appears to benefit bone integrity, cardiovascular morbidity, and mortality, particularly in dialysis patients, and may also impact future kidney allograft survival.

6. Parathyroidectomy for secondary hyperparathyroidism

Various surgical options are available when discussing PTx for sHPT. These include (1) total PTx with resection of all four parathyroid glands with auto-transplantation, (2) total PTx without auto-transplantation, and (3) subtotal PTx, which involves leaving half of the most normal-looking gland in situ. Additionally, a thymectomy can be performed as part of the procedure. Determining the optimal treatment requires careful consideration of multiple studies comparing these surgical approaches. Some studies compare total PTx with auto-transplantation to subtotal PTx [34, 35, 36], while others compare total PTx with or without auto-transplantation (Table 1), [39, 40, 41, 42].

Publication	Study design	Compared groups	Outcome
Schneider et al. [37]	Retrospective	Total PTx + AT (n = 504) Subtotal PTx (n = 32) Total PTx -AT (n = 21) Incomplete PTx (n = 49)	PTx-AT: Lowest recurrence, ns Lowest persistence, ns
Isaksson [38]	Retrospective Sweedish registry data	Total PTx (n = 388) Subtotal PTx (n = 436)	Subtotal PTx: Lower kardiovascular risk Higher risk for recurrence
Chen et al. [34]	Systematic review and meta-analysis (13 studies, n = 1589)	Total PTx + AT (n = 1064) Subtotal PTx (n = 621)	Recurrence ns Persistence ns Reoperation rate ns
Rothmund et al. [35]	RCT	Subtotal PTx (n = 20) Total PTx + AT (n = 20)	PTx + AT: Clinical improvement↗
Yuan et al. [36]	Systematic review and meta-analysis (18 studies, n = 3656)	Subtotal PTx (n = 1864) Total PTx + AT (n = 1792)	ns: Symptoms Hypocalcemia rate Persistence Recurrence Reoperation rate Total PTx + AT Prolonged in-hospital stay Serum calcium 1 mo FU ↘
Schlosser et al. [39]	Multicenter prosp. RCT	Total PTx + AT + thymectomy (n = 48) Total PTx (n = 52)	Total PTx + AT+thymectomy at 3 y FU Calcium ns, PTH levels ↗ Recurrence ↗ (8.3% vs. 0% without AT)
Jia et al. [40]	Meta-analysis (7 cohort studies, n = 931)	Total PTx + AT (n = 621) Total PTx –AT (n = 150) Other PTx (n = 160)	Total PTx-AT Persistence↘ Recurrence ↘ Reoperation rate↘
Li et al. [41]	Meta-analysis (10 cohort studies, 1 RCT; n = 1108)	Total PTx + AT (n = 833) Total PTx-AT (n = 275)	Hypoparathyroidism rate↗ No patients recorded with severe hypocalcemia or adynamic bone disease
Liu et al. [42]	Meta-analysis (9 cohort studies, 1 RCT; n = 1283)	Total PTx + AT Total PTx-AT

Table 1.

Studies on extent of parathyroidectomy in sHPT.

In summary, (1) subtotal PTx has the lowest hypoparathyroidism rate but the highest reoperation rate due to recurrence or persistence. (2) Total PTx with auto-transplantation has a higher hypoparathyroidism rate than subtotal PTx but a lower need for potentially less challenging reoperations. (3) Total PTx without auto-transplantation has the lowest reoperation rate but the highest risk of postoperative hypoparathyroidism (Table 2). This lower reoperation rate advantage comes at the cost of a greater lifelong need for calcium supplementation, risk of tetany, and risk of adynamic bone disease due to low PTH levels.

	Subtotal PTx	Total PTx + AT	Total PTx - AT
Postoperative hypocalcemia	↘	→	→
Reoperation rate	↗	→	→
Persistence and Recurrence	→	→	↘
Advantages	Cardiovascular risk↘1 Graft function2↗	Morbidity of revisional surgery risk↘	Persistence ↘ Recurrence ↘
Disadvantages	Cervical seeding Morbidity of revisional surgery↗	Longer postoperative hypocalcemia Seeding at implantation localization	Lifelong calcium substitution Risk for tetany↗ Risk for adynamic bone disease↗

Table 2.

Advantages and disadvantages of different parathyroidectomy extents in sHPT.

¹

Isaksson et al. [38].

²

Schwarz et al. [43].

Interestingly, patients undergoing subtotal PTx seem to have a lower cardiovascular risk and may have better kidney allograft function than those undergoing total PTx. Hypocalcemia and a significant PTH drop are detrimental to kidney allograft function. Studies indicate hypocalcemia and pronounced PTH drops are risk factors for decreased kidney allograft function [43]. Patients with no parathyroid tissue left will have lower serum calcium levels and a more significant PTH drop. Since PTH has a vasodilatory effect on preglomerular vessels and a potent action on renal plasma flow [44], a pronounced PTH drop after PTx may lead to reduced renal plasma flow and acute deterioration of kidney function. However, long-term animal studies suggest that treating sHPT might protect the kidney from the progression of chronic renal failure despite the acute risks associated with PTH drops post-PTx [45, 46].

The current recommendation for CKD patients with severe refractory sHPT and an indication for PTx is to leave some parathyroid tissue behind, especially in patients who are or might be listed for kidney transplantation, to potentially enable normal parathyroid function and avoid hypoparathyroidism. In elderly patients without the option of kidney transplantation, total PTx without auto-transplantation can be considered. Since the lower parathyroid glands can lie within the thymus in up to 39% of patients [37, 47], a thymectomy is indicated whenever the lower parathyroid gland cannot be found and can also be performed routinely to reduce persistency or recurrence rates. It might even be recommended for patients who will never be transplanted.

7. The indication for parathyroidectomy in tertiary hyperparathyroidism and its potential benefits

SHPT can resolve with PTH normalization in approximately 30% of cases within one year and 57% within two years after kidney transplantation [16]. However, almost 50% of patients develop parathyroid autonomy, known as tHPT, which often leads to mild or moderate hypercalcemia. This condition is considered irreversible, even when the glomerular filtration rate (GFR) remains normalized in the long-term post-kidney transplantation. Unlike patients with sHPT undergoing dialysis, kidney transplant recipients generally do not exhibit severe symptoms, as tHPT is less severe.

What impact does tHPT have after kidney transplantation (Table 3)? Similar to primary hyperparathyroidism, elevated PTH levels in kidney transplant recipients negatively affect bone density. A PTH level above 150 pg./mL, three times the normal level, has been shown to decrease bone density significantly [11]. Additionally, elevated PTH levels increase the fracture rate. The fracture incidence was 8% one year and as high as 15% two years post-transplantation if PTH levels remained elevated [12]. Persisting tHPT has also been shown to increase kidney allograft calcification within six months post-transplantation, associated with worse kidney allograft function [48]. Other studies have confirmed decreased kidney allograft function in the presence of tHPT [13, 16]. In one study, 43% of patients with persistent HPT two years after kidney transplantation had lower kidney allograft survival and overall patient survival, prompting the authors to advocate for early surgical intervention post-transplantation [16]. Pihlstrom et al. found an 85% increased risk of kidney allograft loss and a 46% higher mortality risk when PTH levels were above 65 ng/L (Table 3), [13]. However, the exact mechanism by which tHPT contributes to kidney allograft loss still remains unknown.

tHPT associated morbidity	Study	Study design	Results
Renal Osteodystrophy	Heaf et al. [11]	Retrospective, 3 years FU, n = 114 Assoc. between MBD und PTH	PTH > 150 ng/L decreases bone density significantly
	Perrin et al. [12]	Retrospective, n = 143 KTRs Risk factors for fractures after kidney Tx	Elevated PTH after Kidney Tx is significant risk factor for fracture rate 8% after 1 year 15% after 2 years
Graft function	Gwinner et al. [48]	Retrospective, n = 213 KTRs Kidney biopsies at 6 weeks, 3 and 6 months after Tx	tHPT after Kidney Tx correlates with Graft calcifications within 6 months Decreased graft function
Mortality	Lou et al. [16]	Retrospective, n = 1609 KTRs PTH normalization at 1 and 2 years after Tx Graft- and overall survival	Early PTH normalization after Kidney Tx improves Graft- and overall survival
	Pihlstrom et al. [13]	Retrospective, n = 2102 KTRs; mean FU 5.1 yearsAssociation between PTH and Cardiovascular events Graft loss and mortality	PTH > 65 pg./ml: 85% higher risk of graft loss (p < 0.001) 46% higher risk of mortality (p = 0.006)

Table 3.

Morbidity associated with tHPT in kidney transplant recipients.

KTRs = Kidney transplant recipients.

Can elevated PTH levels after kidney transplantation be positively affected by PTx (Table 4)? Few studies have investigated the morbidity of kidney transplant recipients based on whether they had a PTx. Collaud et al. found improved bone mineral density in kidney transplant recipients after PTx compared to before PTx in a small patient sample [49]. Additionally, PTx for tHPT may benefit kidney allograft function in the mid to long term. However, a significant drop in PTH and subsequent hypocalcemia can be detrimental to kidney allograft function [43]. Other studies have reported deterioration of kidney allograft function after PTx [39, 51]. In a retrospective study comparing 100 kidney transplant recipients with tHPT treated with the calcimimetic cinacalcet to 33 patients treated with PTx, those treated with PTx had a higher rate of PTH normalization and significantly lower kidney allograft loss (Table 4), [50]. Despite representing an additional perioperative risk to kidney allograft function, treating tHPT with PTx benefits kidney allograft function in the long-term post-transplantation.

tHPT associated morbidity	Study	Study design	Improvement by PTx?
Renal Osteodystrophy	Collaud et al. [49]	Retrospective, PTx after Kidney Tx for tHPT n = 14, mean FU 26 months BMD before- and after PTx	PTx significantly increased BMD (p < 0.01)
Graft function	Finnerty et al. [50]	Retrospective Graft function in KTRs with tHPT n = 133, median FU 7 years Cinacalcet (n = 100) subtotal PTx and bilateral thymectomy (n = 33)	PTx PTH normalization ↗ Graft-failure ↘ (9% vs. 33%, p = 0.007)

Table 4.

Effect of PTx for tHPT in kidney transplant recipients.

Given the limited data on the indications for PTx in kidney transplant recipients with tHPT, decisions must be individualized based on factors such as age, cardiovascular risk, other comorbidities, the success of the kidney transplantation, and long-term prognosis. Although symptoms of tHPT are usually mild to moderate, the improvement of symptoms [31] and the long-term benefit for kidney allograft function may justify PTx in in a greater number of patients.

8. Parathyroidectomy for tertiary hyperparathyroidism

To determine the optimal extent of PTx for tHPT, it is essential to understand that 90% of tHPT patients present with multiglandular disease, with only 10% affected by a single parathyroid gland and 30% by two glands.

Ideally, only the autonomous parathyroid glands would be removed to maintain self-regulated calcium homeostasis. Achieving this requires excellent localization methods or a thorough four-gland exploration to identify and remove abnormal parathyroid glands. To date, no such ideal localization diagnostic exists. Sonography can localize enlarged parathyroid glands with a low sensitivity of around 62% for sHPT and tHPT [52]. Despite its limitations sonography remains important in renal hyperparathyroidism, also to exclude coexisting thyroid pathologies before parathyroid surgery. The sensitivity of scintigraphy for renal hyperparathyroidism is low (around 55%) [52]. To date, the Choline-PET /MRI or Choline-PET/CT is the best imaging modality with the highest specificity (93%) and sensitivity (86%) for detecting hyperplastic parathyroid glands in patients with secondary and tertiary HPT [52]. Data for Choline-PET in renal HPT is however still scarce, so that a recommendation for its regular use in renal HPT cannot yet be given. The four-gland exploration remains the best localization method for autonomous parathyroid glands in renal HPT. However, normal appearing glands may still be autonomous, and many patients may experience advanced CKD anew, again leading to stimulation of the parathyroid glands and potentially necessitating additional surgery.

There are no prospective randomized controlled trials (RCTs) on the ideal surgical approach for tHPT. In a multicenter retrospective study, 61 kidney transplant recipients who underwent subtotal PTx were compared to 44 kidney transplant recipients who underwent total PTx with auto-transplantation. At six months follow-up, the hypoparathyroidism rate was significantly lower in the subtotal PTx group, while the cure rate was the same in both groups [53]. The authors concluded that subtotal PTx was superior to total PTx with auto-transplantation in kidney transplant recipients.

The question remains whether less than subtotal PTx might be sufficient for kidney transplant recipients with tHPT. Data in this area is sparse and inconsistent. One retrospective study with 19 kidney transplant recipients who underwent less than subtotal PTx and 52 kidney transplant recipients who underwent subtotal PTx found no differences in recurrence rates. The transient hypocalcemia rate was higher in the subtotal group, but no patient experienced permanent hypocalcemia. The authors concluded that the more focused procedure had the same success rate as subtotal PTx [54]. This conclusion, however, is debated. Triponez et al. retrospectively examined a similar patient set with 83 kidney transplant recipients who received subtotal or less than subtotal PTx, removing only the enlarged glands. After a mean follow-up of 5.4 years, the group with less than subtotal surgery had a 5.2 times higher risk of persistent or recurrent disease, leading Triponez et al. to recommend against less than subtotal surgery [55].

Currently, most endocrine surgeons will explore all four glands and perform a subtotal PTx for tHPT.

9. Timing for parathyroidectomy

The timing of PTx in relation to kidney transplantation has been investigated retrospectively. A study analyzing 190 kidney transplant recipients examined three time points: PTx before kidney transplantation, PTx within one year after kidney transplantation, and PTx more than one year after kidney transplantation [56]. The findings indicated that undergoing PTx after kidney transplantation was associated with decreased kidney allograft function. Specifically, if PTx was performed after kidney transplantation, the GFR dropped post-surgery. For kidney transplant recipients who underwent PTx within one year of kidney transplantation, kidney allograft function did not recover, whereas if PTx was performed more than one year after kidney transplantation, kidney allograft function improved. Based on these results, the authors concluded that PTx should ideally be performed before kidney transplantation if parathyroid autonomy is suspected. If hyperparathyroidism persists after kidney transplantation, PTx should not be performed within one year to protect the graft [56].

Contradicting these findings, another study demonstrated that early post-transplantation PTx (within 278 days) for patients with tHPT was associated with significantly better kidney allograft function compared to late referral (after 278 days) in a small cohort (n = 19 vs. 19) [57]. This data, along with evidence of kidney graft calcification within 6 months of kidney transplantation if hyperparathyroidism persists, supports earlier surgical intervention for tHPT.

10. Conclusion

The differentiation between sHPT and tHPT is critical, especially when it comes to surgical interventions by PTx. For refractory sHPT, PTx becomes necessary when medical therapies fail, offering significant benefits in reducing cardiovascular morbidity and mortality and improving bone integrity. On the other hand, tHPT often develops post-kidney transplantation, where prolonged stimulation of the parathyroid glands leads to parathyroid autonomy. Surgical intervention for tHPT, particularly subtotal PTx, is crucial to enhance kidney allograft function and mitigate complications such as hypercalcemia, cardiovascular risk, and bone density loss. The surgical indication for PTx, extent, and timing must be carefully individualized according to the patient’s age, cardiovascular risk, other comorbidities, and the overall prognosis. Balancing the risks and benefits to optimize patient outcomes in both sHPT and tHPT remains challenging but should be evaluated more liberally concerning PTx.

Conflict of interest

The authors declare no conflict of interest.

Acronyms and abbreviations

sHPT	secondary hyperparathyroidism
PTH	parathyroid hormone
FGF23	fibroblast growth factor 23
CKD	chronic kidney disease
tHPT	tertiary hyperparathyroidism
CKD-MBD	chronic kidney disease-mineral bone disorder
BMD	bone mineral density
LVH	left ventricular hypertrophy
PTx	parathyroidectomy
GFR	glomerular filtration rate