A Roadmap To Parathyroidectomy For Kidney Transplant Candidates

Post-transplant HPT

Successful KT was considered to reduce CKD-MBD to a large extent, but MBDs are common in KTRs, changing only the CKDMBD phenotype. High PTH levels are observed in up to 80% of patients throughout the first year after KT [26]. Complete resolution of SHPT was observed in only 30% and 57% of recipients within the first and second years post-transplantation, respectively [27]. In 1000 consecutive KTRs, nearly 17% of patients were hypercalcemic at 12 months post-transplant and 10% were hypercalcemic at 48 months. In addition, ∼50% and ∼40% of patients had high PTH levels at months 12 and 48 post-transplant, respectively [6]. The main predictive factors of persistent SHPT are dialysis vintage, high pre-KT PTH levels, and the size of the parathyroid glands. The rapid growth of kidney failure prevalence is prolonging dialysis vintage before KT and this contributes to increasing the prevalence of persistent HPT in those on the KT waiting list [28–30]. In living donor KT, which is usually characterized by a shorter dialysis vintage before KT, mineral metabolism normalizes faster than in deceased donor KT [31]. Different definitions of persistent HPT may explain differences in prevalence, the assessment time point as well as the study era [27, 32–35]. The ideal range of PTH and calcium levels after transplantation is not yet well defined.

Posttransplant HPT can be differentiated into persistent HPT (maladaptive response) versus de novo HPT (compensatory adaptive response). Persistent HPT results from preexisting CKDMBD with SHPT, while de novo HPT results from decreasing graft function, leading to elevated PTH levels to maintain normalphosphatemia and normo-calcemia [31], reproducing the pathophysiology of CKD-MBD as observed in progressive CKD in native kidneys.

PTH levels. 

There is no consensus about the safe level of PTH, the PTH cut-off level that identifies persistent HPT, or the 'ideal' timing of PTH assessment after transplantation. Most nephrologists wait up to 12 months after transplantation for PTH to normalize. Beyond 12 months, a PTH level >100 pg/mL [36, 37] or 70 pg/mL [32] is consistent with persistent HPT. The Kidney Disease: Improving Global Outcomes (KDIGO) guidelines recommend that KTRs should have the same therapeutic approach for CKD-MBD abnormalities, including PTH, as for patients with CKD stages 3–5. This implies having PTH levels within the reference range defined by each assay [38].

THPT. 

THPT is a misleading term that originally denoted the occurrence in the same patient of adenoma and hyperplasia in different glands, but classifying a gland as an adenoma in a patient with four enlarged parathyroid glands is questionable [33]. Some authors consider THPT to be a distinct though less frequent (21.5%) phenotype of persistent HPT, detectable in a subset of KTRs with both elevated PTH (>70 pg/mL) and hypercalcemia (serum calcium >10 mg/dL) at 1-year post-KT [32, 39].

Pre-KT PTH levels >300 pg/mL, high serum calcium (before and after KT), the use of calcimimetics, dialysis vintage, or enlarged parathyroid glands pre-KT have been associated with the development of persistent HPT and THPT [32, 36, 40–42].

Parathyroid gland size. 

The proportion of parathyroid tissue that develops nodular hyperplasia increases as gland weight/size increases, despite diffuse hyperplasia often being observed in small glands in patients with SHPT [43, 44]. In enlarged parathyroid glands (volume ≥500 mm3 or diameter ≥10 mm), nodular hyperplastic lesions are likely present and associated with a poor response to treatment with vitamin D receptor activators (VDRAs) and cinacalcet in dialysis-dependent patients [25, 45–52], likely as a consequence of reduced expression of both VDR and CaSR in nodular hyperplastic lesions in the transition from polyclonal to monoclonal proliferation that leads to nodular hyperplasia [23]. Thus long-term drug therapy with VDRA alone or VDRA plus cinacalcet may be helpful in patients with parathyroid glands <10 mm but useless if the size is >10 mm [48, 50]. Few studies have analyzed the predictive value of enlarged parathyroid glands, assessed pre-KT, in the development of persistent HPT after transplantation [42, 53, 54]. Parathyroid glands of patients with persistent HPT after renal transplantation contained more than one nodular hyperplasia and restoration of VDR and CaSR expression after transplantation was observed only in diffuse hyperplasia. Therefore, in KT candidates, one enlarged parathyroid gland likely reflects nodular hyperplasia that is unlikely to regress [55]. Previous studies have demonstrated that therapy for persistent HPT should be started 3 months after KT since the most significant reduction of PTH occurs within the first 3 months after KT and PTH levels are unlikely to return to normal when elevated between 6 months and 1-year post-KT [33, 56–58]. However, the diagnosis is often not established until up to 2 years post-KT, causing increased morbidity from delayed treatment [32].

FIGURE 3: PTH resistance. The target organs' responses to the action of PTH are progressively impaired in CKD, a condition commonly referred to as PTH resistance. Multiple factors are involved, including phosphate loading, calcitriol deficiency, oxidative stress, PTH1R downregulation and dysfunction, accumulation of PTH fragments, antagonists of the Wnt/β-catenin pathway, and uremic toxins, and accumulation of PTH fragments and uremic toxins.

FIGURE 4: Pathophysiology of secondary hyperparathyroidism in CKD. Initially in SHPT, the parathyroid glands grow diffusely with polyclonal parathyroid cell proliferation (diffuse hyperplasia). At this stage, VDRA activators and calcimimetics are effective in lowering PTH concentrations. Afterward, cells in the nodules are transformed monoclonal and proliferate. In parallel are four patterns of parathyroid hyperplasia: diffuse hyperplasia, early nodularity in diffuse hyperplasia, nodular hyperplasia, and single nodular glands. In the advanced stages of SHPT, downregulation of calcium-sensing receptor (CaSR), VDR, and Klotho-FGFR 1 makes parathyroid cells resistant to the inhibitory effect of calcimimetics, calcitriol, and FGF-23.

Persistent HPT and graft and patient outcomes 

Persistent HPT contributes to posttransplant complications such as hypercalcemia, hypophosphatemia, high FGF-23, and nephroncalcinosis and is associated with unfavorable graft and patient outcomes [5, 26, 33, 59]. Studies on the impact of persistent HPT on graft and patient outcomes are marred by different definitions of persistent HPT based on PTH thresholds and timing of assessment, with most studies assessing PTH 10 weeks–12 months after transplantation. Bone density and fractures. Persistent HPT in KTRs is associated with decreased bone density and an increased fracture rate [60–62]. Moderate bone mineral density (BMD) losses or BMD changes are observed in the first year after transplantation in the peripheral skeleton but not in the central skeleton. Steroid withdrawal and/or steroid minimization regimens decrease the negative effects of steroid therapy on bone health and persistent HPT is emerging as the main risk factor for bone fragility in KTRs [63, 64]. In particular, persistent HPT and high remodeling rates result in cortical and trabecular bone loss and decreased bone strength in the peripheral skeleton [65, 66]. Graft and patient survival. Studies on the association between persistent HPT and long-term graft and patient survival are limited, and results are contradictory. The pathways linking persistent HPT to graft dysfunction are not well known. Potential mechanisms include excessive vasoconstriction and turbulent interstitial calcification [36, 67]. Studies focused on pre-KT PTH values have reported divergent results. High pre-KT PTH levels have been linked to an increased risk of graft failure censored for death [36, 68]. However, a retrospective analysis of > 10,000 primary KTRs found no link between pre-KT PTH levels and death or graft loss after transplantation [69]. In 984 KTRs, FGF-23 was a strong and independent risk factor for the composite endpoint of death and graft loss, but the association between PTH and outcome was significant only in univariate analyses and disappeared when adjusting for estimated glomerular filtration rate (eGFR) [70]. The association of persistent HPT, defined as PTH >1.5 times the upper limit of the assay (100 pg/mL) 1 year after KT, with long-term graft outcomes, was evaluated in 911 KTRs. Persistent HPT was an independent risk factor for graft loss. Moreover, a PTH level >150 pg/mL at 6 months predicted 1-year persistent HPT with 92% specificity [36].

A similar cut-off value (PTH ≥150 pg/mL) at 3 months after KT was associated with worse allograft function up to 3 years posttransplant and to increased risk for death or death with a functioning graft [71]. In a retrospective analysis of 522 KTRs, intact, PTH (iPTH) levels during the early posttransplant period (10 weeks) predicted a composite endpoint of cardiovascular events, graft loss, and death. Moreover, patients with the highest levels of iPTH had the highest risk for the composite endpoint, the highest levels of calcium, and the lowest levels of phosphate [72]. In a large cohort of 1840 KTRs from the ALERT trial, recruited with a mean of 5.1 years after KT and with a follow-up time of 6–7 years, persistent HPT after KT was significantly associated with all-cause mortality (4% increased risk) and allograft loss (5% increased risk) but not with major cardiovascular events [73]. No significant associations between PTH and serum calcium or phosphate were observed. These results are in agreement with another study showing that the correlation between serum PTH and serum calcium early after transplantation is gradually lost over time [58], but they differ from previous studies showing an association of hypercalcemia with graft loss and nephrocalcinoise [5, 74, 75].

Medical treatment versus parathyroidectomy before or after KT: association with outcomes 

Persistent HPT post-KT often requires parathyroidectomy with a prevalence range from 0.6 to 5.6% [76]. However, there are no clear guidelines on how to treat waitlisted dialysis patients to reduce the risk of persistent HPT post-KT [77]. Moreover, the appropriate strategy in KTRs is debated, with a particular focus on the risk of worsening graft function related to medical and surgical therapy [39]. SHPT before KT can be treated by medical (VDRAs, phosphate binders, and calcimimetics) or surgical (parathyroidectomy) approaches. Both reduce PTH values, although parathyroidectomy provides better long-term control of calcium and PTH values [77]. Medical treatment is generally the first step

Calcimimetics. 

Calcimimetics are positive allosteric modulators of CaSRs that increase the sensitivity of the parathyroid glands to circulating calcium and VDR expression [23]. Randomized studies on cinacalcet have demonstrated its efficacy in the control of SHPT in patients on dialysis compared with vitamin D analogs and placebo [78, 79]. The Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events study had a primary composite end point of time to death, myocardial infarction, hospitalization for unstable angina, heart failure, and peripheral vascular events. The unadjusted intention-to-treat analysis of the 3883 dialysis patients treated with cinacalcet and placebo did not demonstrate differences in the primary endpoint (48.2% of patients treated with cinacalcet and 49.2% of patients treated with placebo) [80]. A prespecified analysis by age categories (≥65 years and <65 years) showed a reduction in major cardiovascular events {hazard ratio [HR] 0.70 [95% confidence interval (CI) 0.60–0.81], P ≤ .001} and all-cause mortality [HR 0.68 (95% CI 0.58–0.81), P ≤ .001] in older patients [81]. Further analysis did not disclose differences in the risk of fractures, although after adjusting for baseline characteristics, multiple fractures, and discontinuation of therapy, cinacalcet reduced the frequency of clinically evident fractures by 16–29% [82].

The use of calcimimetics pre-KT is frequently associated with the onset of mild hypercalcemia after KT, although this is present in 30% of KTRs (treated in dialysis with cinacalcet or not) and is potentially related to the rebound of SHPT and nephroticcyanosis may develop months after KT [83]. In dialysis patients with PTH levels well controlled by cinacalcet, there is a direct relationship between cinacalcet dosage and the development of hypercalcemia after KT [83]. Etelcalcetide is an intravenous direct CaSR agonist to treat SHPT in hemodialysis patients. In two recent cases, severe hypercalcemia developed in KT patients who had been on etelcalcetide in dialysis, requiring parathyroidectomy about 1 month after KT [84].

Parathyroidectomy.

There are no clear guidelines on partythyroidectomy for patients on dialysis suffering from SHPT, beyond the notion that it is reserved for patients not responding to medical therapy [23]. Thus there are no clear indications on the optimal PTH targets to be achieved or the timing of parathyroidectomy. In the USA, between 2004 and 2016, the number of parathyroidectomies performed for SHPT in patients with kidney failure decreased by 40% [85]. In both KTRs and kidney failure patients, parathyroidectomy decreased from 7.9 to 5.4 per 1000 patients between 2002 and 2011, a major reduction being observed in 2004 (3.3 per 1000 patients), the year of cinacalcet release [85]. Evidence on the timing of parathyroidectomy in transplant candidates is also limited. Post-KT parathyroidectomy and graft function. Post-KT parathyroidectomy has been associated with worse graft function outcomes than pre-KT parathyroidectomy. In a retrospective single-center study of 123 patients (67 pre-KT parathyroidectomy and 56 post-KT parathyroidectomy), parathyroidectomy after KT was associated with a decrease in eGFR following surgery. Post-KT parathyroidectomy was an independent risk factor for recipient graft function worsening. The risk decreased when parathyroidectomy was performed 1 year post-KT or, even better, before KT [86]. Similarly, graft function decreased in transplant patients who underwent post-KT parathyroidectomy, but the lipid profile and blood pressure control improved [87]. The negative impact of partyiridectomy performed < 1-year post-KT on renal function persisted for 5 years after transplantation when compared with parathyroidectomy performed pre-KT or 1–5 years post-KT [88]. In 76 KT patients who underwent parathyroidectomy, worsening of renal function was related to the change in PTH decline before and after surgery: a reduction in PTH >80% was followed by an important reduction of creatinine clearance. A retrospective study of 108 patients did not observe differences in graft survival between pre-KT and post-KT parathyroidectomy. However, post-KT parathyroidectomy was an independent risk factor for persistent hypocalcemia, due to hungry bone disease or hypoparathyroidism, and for the reduction of eGFR by 20% 12–36 months after transplantation (P = .029) [67].

The reason for the deterioration of graft function is unclear, but a hemodynamic mechanism has been suggested [87]. Thus, PTH induces afferent arteriole vasodilatation and efferent vasoconstriction. This would result in glomerular hyperfiltration and the sudden removal of PTH may decrease GFR [59]. In this case, however, parathyroidectomy would also be expected to be protective in the long term, as is the case for nephroprotective ininterventions that decrease glomerular hyperfiltration.

Cinacalcet versus post-KT parathyroidectomy. 

To our knowledge, only a study compared cinacalcet and parathyroiditomy in KT patients. A 12-month prospective, multicenter, open-label, randomized study compared subtotal parathyroidectomy (n = 15) and cinacalcet (n = 15) in KT patients with hypercalcemia and HPT. The primary outcome was the normalization of calcium values, achieved in 100% of patients undergoing parathyroidectomy and in 67% of patients treated with cinacalcet (P = .04). Secondary outcomes included normalization of PTH values, which was achieved in 10 of 15 patients undergoing parathyroidectomy (P = .002) and in none of those receiving cinacalcet. Cinacalcet decreased PTH values, but they remained above the normal range: this was hypothesized to result from an increase in calcitonin with consequent hypocalcemia and persistence of HPT. BMD did not improve in patients treated with cinacalcet but increased in the femoral neck in patients undergoing parathyroidectomy (P = .01): BMD improvement was associated with the normalization of PTH and bone turnover marker values and the administration of calcium and vitamin D to avoid hungry bone syndrome. eGFR decreased in both groups and neithe treatment decreased vascular calcifications [90]. In a 5-year extension study, parathyroidectomy had a lower risk of recurrence of THPT [91]. In a retrospective study of 92 patients treated with parityiridectomy or cinacalcet pre-KT, parathyroidectomy resulted in better control of PTH and calcium values after transplantation (P < .01), although no statistically significant differences were observed in serum calcium, phosphate, and graft and overall survival at 10 years [92].

Safety.

In studies that compared cinacalcet and parathyroidectomy, the most frequent side effect of cinacalcet was gastric in tolerance, which may have limited dosing and compliance [88]. Complications after parathyroidectomy include surgical wound infection, temporary or permanent recurrent laryngeal nerve palsy, and transient or permanent hypocalcemia, the most frequent being transient hypocalcemia related to hungry bone syndrome [93, 94]. Other parathyroidectomy complications include mortality during hospitalization or within 1 month of parathyroidectomy (2%), rehospitalization (24% required), the need for intensive care (29%), and a 39% increase in 1-year hospitalizations, according to the United States Renal Data System information on parathyroidectomies performed from 2007 to 2009. The most frequent disorders were hypocalcemia, myocardial infarction, and arrhythmias. The number of adverse events varied significantly based on the patient's clinical history [93]. In conclusion, there are no long-term studies on the impact of parathyroidectomy or medical therapy for HPT, especially in kidney failure patients awaiting KT. However, available studies show that parathyroidectomy is more effective in controlling HPT. Pre-KT parathyroidectomy is preferable to decrease the risk of persistent HPT and protect graft outcomes [86].

Table 1. Main guidelines since 2001 for parathyroidectomy in kidney transplant candidates

There are no clear guidelines on the indication and timing of parathyroidectomy versus pharmacological treatment, therapeutic targets, or primary outcomes [95]. In the 2001 American Society of Transplantation Guideline, serum calcium, phosphate, and PTH should be evaluated periodically in patients waitlisted for KT and parathyroidectomy should be considered when medical management fails and/or patients have severe, persistent, complications of HPT [96]. Similarly, the 2005 Canadian Society of Transplantation Consensus Guidelines on eligibility for KT suggested assessing calcium, phosphate, and PTH levels as part of the pre-KT evaluation (Grade A) and partythyroidectomy for patients not responding to medical therapy or those with severe, persistent, complications of HPT (Grade B) [97]. The 2006 Caring for Australians and New Zealanders with Kidney Impairment guidelines on the management of CKD-MBD suggest considering parathyroidectomy for patients in whom cinacalcet does not achieve target levels of calcium, phosphate, and PTH (<800 pg/mL) without mentioning patients waitlisted for KT [98]. Instead, more recent 2011 UK Renal Association and British Transplant Society Guidelines on KTRs give no advice about CKD-MBD and parathyroidectomy during evaluation for KT eligibility [99], as well as 2013 Kidney Health Australia-Caring for Australians and New Zealanders with Kidney Impairment Guidelines [100]. In 2015, the European Renal Best Practice Guideline on kidney donor and recipient evaluation recommends not refusing a cadaveric graft only because of uncontrolled HPT in the recipient (1D). However, it also recommends that for patients on the waiting list, efforts should be made to comply with existing CKDMBD guidelines, including parathyroidectomy, when indicated (ungraded statement) [101]. The 2017 KDIGO CKD-MBD guidelines advise parathyroidectomy in patients with G3a–G5D with severe HPT who fail to respond to medical or pharmacological therapy (2B) [102]. The UK Renal Association commentary on the KDIGO 2017 CKD-MBD guidelines agrees on the indication of parathyroidectomy but does not mention preparation for KT [103].

Only the 2019 Chinese guidelines for CKD-MBD considered radiological parathyroid gland enlargement as a parameter to be considered before parathyroidectomy, although no suggestion is made for KTRs despite dealing with transplant bone disease [104].

The 2020 KDIGO clinical practice guidelines on the evaluation of candidates for KT contain a chapter dedicated to the preparation of the KT candidate with CKD-MBD. The rationale is that severe HPT needs to be treated before KT, and if medical therapy fails, pre-KT parathyroidectomy is indicated. These new guidelines suggest measuring serum PTH at the time of transplant evaluation and not transplanting patients with severe SHPT until they are adequately treated (medically or surgically) as per the 2017 KDIGO CKD-MBD guidelines (2D) [38]. Nevertheless, in the National Kidney Foundation Kidney Disease Outcomes Quality Initiative (KDOQI) US Commentary on the 2020 KDIGO guidelines on the evaluation of candidates for KT, there is no comment on the management of pre-KT parathyroidectomy [105]. From the analysis of different guidelines emerges the need for new guidelines that clarify the indications for pre-KT parathyroidectomy and its role in the prevention of graft failure and transplant bone disease.