Effect of Pretransplant Use of Calcimimetic on Parathyroid Function after Renal Transplantation

Objective Persistence of hyperparathyroidism (HPT) after renal transplantation leads to undesirable outcomes such as increase in cardiovascular events, graft dysfunction, and increased mortality. Options for therapy include medical management with calcimimetic or operative management. The present study was undertaken to evaluate the natural history of HPT after renal transplantation and to determine risk factors for persistent HPT in the era of calcimimetic. Design The study is a retrospective review of data from 74 consecutive patients who underwent renal transplantation at our institution from April 2011 to November 2019. Methods The natural history of HPT after renal transplantation and associations between intact parathyroid hormone (PTH) level after transplantation and clinical variables such as age, sex, duration of pretransplant dialysis, and use of calcimimetic before transplantation were evaluated. Results Intact PTH decreased after renal transplantation in most of the patients without receiving parathyroidectomy. Known risk factors of persistent HPT did not associate with intact PTH level after renal transplantation in patients who had been receiving calcimimetic before transplantation. Conclusion In conclusion, we have found that HPT after renal transplantation could be managed successfully by medical treatments. When predicting the prognosis of HPT after transplantation, pretransplant use of calcimimetic should be taken into consideration.


Introduction
Secondary hyperparathyroidism (HPT) is a common complication in patients with chronic kidney disease. Main abnormalities responsible for secondary HPT are corrected in the first month after transplantation [1,2]. Up to 25% of patients with secondary HPT will have persistent HPT, 1 year after transplantation [3][4][5]. Persistence of elevated PTH levels leads to hypercalcemia, hypophosphatemia, and reduced bone mineral density with increased fractures, as well as vascular calcification, with an increased risk of cardiovascular events, graft dysfunction, and increased mortality [6][7][8][9][10]. Previous studies have reported that serum calcium, alkaline phosphatase, parathyroid hormone levels at the time of transplantation, enlarged parathyroid glands detected pretransplant, and pretransplant dialysis duration are the most important risk factors for persistent HPT [3,[11][12][13][14][15].
Options for therapy include medical management with calcimimetic or operative management with parathyroidectomy. In Japan, cinacalcet was approved for patients with secondary HPT under maintenance dialysis in 2008 and was later indicated for severe hypercalcemia in patients with primary HPT who are unable to undergo parathyroidectomy or relapsed after parathyroidectomy and patients with parathyroid carcinoma in 2014 and evocalcet in 2018 and 2019, respectively. Etelcalcetide was approved for patients with secondary HPT under maintenance dialysis in 2020. No consensus guidelines for parathyroidectomy versus calcimimetic yet exist for persistent HPT after renal transplantation. e use of calcimimetic may have influenced the known natural history of HPT and risk factors of persistent HPT. However, this issue remains to be elucidated. erefore, the present study was undertaken to evaluate the natural history of HPT after renal transplantation and to determine risk factors for persistent HPT in the era of calcimimetic.

Study Population and Design.
is study is a retrospective review of data from 74 consecutive patients who underwent renal transplantation at Tokyo Women's Medical University Hospital, from April 2011 to November 2019. Patients were excluded from study participation if they met any of the exclusion criteria: younger than 16 years, ineligibility judged by the principal investigator. e study was approved by the Ethical Review Committee of Tokyo Women's Medical University Hospital (No. 5606, May 28, 2020).
Clinical variables for analysis included age, sex, body mass index (BMI), etiology of end stage renal disease (ESRD), duration of pretransplant dialysis, cadaveric donor utilization, history of diabetes mellitus (DM) and hypertension (HTN), and smoking and drinking habits. Calcimimetic, vitamin D, bisphosphonate, and denosumab usage, total proximal femur bone mineral density (BMD), and biochemical markers including intact parathyroid hormone (PTH) (reference range: 10-65 pg/mL, electrochemiluminescence immunoassay) estimated glomerular filtration rate (eGFR), adjusted serum calcium (AdCa), and inorganic phosphate (IP) were analyzed before transplantation and at multiple posttransplant time points (12,24,36,48, 60, and 72 months). In patients who were on hemodialysis before transplantation, biochemical markers were measured before dialysis. e eGFR was reported in mL/ min/1.73 m 2 , using Modification of Diet in Renal Disease equation [16]. Persistent hyperparathyroidism was defined as hyperparathyroidism which needs either medication of calcimimetic, vitamin D, bisphosphonate, denosumab, and/ or parathyroidectomy after renal transplantation.

Statistics.
All statistical analyses were performed with JMP ® Pro 13.0.0 software (SAS Institute Inc, Cary, NC, USA). Patient characteristics were compared and analyzed using the Wilcoxon rank sum test for continuous data, while Pearson's chi-square test was used for categorical data. e changes in variables were analyzed by one-way analysis of variance for repeated measures and for comparison of 0 month vs. and 12 months vs. each time point, Tukey's honestly significant difference test was used. Multiple linear regression was used to test the associations between intact PTH after renal transplantation and clinical variables. Multivariate logistic regression was performed to evaluate association of clinical variables with persistent hyperparathyroidism. A p value of <0.05 was considered significant.

Patient Characteristics.
Patient characteristics are summarized in Table 1. A total of 74 patients were included in the analysis. e median age of the entire cohort at the time of transplantation was 51 years (intraquartile range (IQR) 18). In the cohort, 49% of patients were male and median BMI was 21.5 kg/m 2 (IQR 4.7). Etiology of ESRD was most commonly chronic glomerulonephritis (52%); type 2 DM (12%); nephrosclerosis (7%); and more rarely, type 1 diabetes mellitus, and polycystic kidney disease, among others. Patients spent a median of 3 years (IQR 11) on dialysis before renal transplantation. e type of the kidney used during transplantation was 14 cadaveric (19%) and 60 living (81%) donors.
ere were no significant differences in age, sex, BMI, history of DM and HTN, smoking and alcohol habit, intact PTH, and adjusted serum calcium before transplantation between patients who had been receiving calcimimetic and not. Duration of dialysis before transplantation was significantly longer in patients who had been receiving calcimimetic (calcimimetic + vs. −, 12 years (IQR 9) vs. 1 year (IQR 3), p value ≤0.0001).

Associations between Intact PTH after Renal Transplantation and Clinical Variables.
Multiple linear regression was used to test the associations between intact PTH after renal transplantation (intact PTH level at the end of each case's observation period) and clinical variables ( Table 2). Duration of dialysis before renal transplantation (p � 0.171), intact PTH before renal transplantation (p � 0.0352), and medication of calcimimetic (p � 0.420) is significantly positively correlated with intact PTH level after renal transplantation.
e EGFR and history of parathyroidectomy after renal transplantation (p � 0.0169) are significantly negatively correlated.
ere were no significant correlations between age, month after renal transplantation, and adjusted serum Ca level with the intact PTH level after renal transplantation.
Subgroup analysis on associations between the intact PTH level after renal transplantation and clinical variables by with/without medication of calcimimetic before transplantation was done (Table 3).
ere were no significant associations between duration of dialysis, level of intact PTH pretransplantation, and eGFR and level of intact PTH posttransplantation in patients who had been receiving calcimimetic before transplantation. Table 4 provides odds ratios for the association of each variable within the predictive model to persistent hyperparathyroidism. Duration of dialysis pretransplantation is significantly related to the risk of persistent hyperparathyroidism (odds ratio: 5.1, p � 0.0033).

Percentage of Patients Treated with Medications Affecting
Bone and Mineral Metabolism.

Discussion
e present study demonstrated two major findings. First, intact PTH decreased after renal transplantation in most of the patients without receiving parathyroidectomy. Second, long duration of dialysis and elevated intact PTH level before transplantation and posttransplant decreased eGFR, known risk factors of persistent HPT, did not associate with intact PTH level after renal transplantation in patients who had been receiving calcimimetic before transplantation.
Mean renal allograft eGFR at the end of the observational period was 41.0 ± 17.5 mL/min/1.73 m 2 in our cohort. In patients with chronic kidney disease G3a-G5 not on dialysis,  the optimal intact PTH level is not known [17]. In the present study, except for 4 patients who needed to have parathyroidectomy, the intact PTH level significantly decreased without performing parathyroidectomy but persisted above the upper normal limit. Prolonged HPT has been known to be associated with hypercalcemia and hypophosphatemia, but serum AdCa and IP were controlled to normal range after transplantation in our study.   [18]. However, in patients managed medically with cinacalcet alone, renal allograft failure was associated with increased PTH within 12 months posttransplant compared with patients with a functioning allograft (348 pg/mL vs. 195 pg/mL) [18]. Median PTH level in our subject (who did not receive parathyroidectomy) at 12month posttransplant was 165 pg/mL (IQR 140), with 11 patients receiving calcimimetic and 63 patients not. Also, though allograft renal function slightly decreased, the decrease was comparable to that of Japanese general population with an initial GFR of 40-49 mL/min/1.73 m 2 [19]. Heaf et al. reported that in patients with the high intact PTH level (>150 ng/L) after transplantation, although lumbar spine BMD stabilized after renal transplantation, there was a continuous loss of femoral neck BMD [20]. Total proximal femur BMD in our study remained unchanged. Overall, these evidences indicate that HPT after renal transplantation could be successfully managed without performing parathyroidectomy, regarding allograft renal function and BMD.    International Journal of Endocrinology We have analyzed the associations between the intact PTH level after renal transplantation (intact PTH level at the end of each case's observational period) and clinical variables. Consistent with the previous reports, duration of dialysis before renal transplantation and intact PTH before renal transplantation were risk factors for the increased intact PTH level after RT. Contrary to our expectation, medication of calcimimetic was also an independent risk factor for the persistence of HPT. It is speculated that this was because in the first place, calcimimetic was given selectively to patients with higher persistent PTH level. Conversely, having parathyroidectomy is negatively correlated with posttransplant PTH level. is might indicate that parathyroidectomy is superior to calcimimetic with respect to lowering PTH level.
Subgroup analysis showed no significant associations between duration of dialysis, level of intact PTH pretransplantation, and eGFR and level of intact PTH posttransplantation, in patients who had been receiving calcimimetic before transplantation. Actually, though calcimimetic is not covered by insurance for persistent HPT after renal transplantation in Japan, it is used in clinical practice, and we observed the course retrospectively. e variables known to be the most important risk factors for tertiary HPT [3,[11][12][13][14][15] lost relevance in the group with calcimimetic. Duration of dialysis lost relevance both in the groups with and without calcimimetic. Since the duration was significantly longer in the group with calcimimetic, within-group variance might have been too small for the duration of dialysis to be an independent risk for tertiary HPT in each subgroup. Level of intact PTH pretransplantation was not an independent risk factor in the group with calcimimetic. Although the intact PTH level had been successfully decreased by calcimimetic before transplantation in patients with HPT, it might not have cured HPT. It is speculated that since most of the patients discontinued receiving calcimimetic after transplantation, masked HPT manifested after transplantation and pretransplant and posttransplant level of PTH are no longer associated. is study has several limitations. e first is that it was based on retrospective data analysis. Although prospective validation would be ideal, since all the variables evaluated were objective clinical information and we also had a high rate of complete data collection, it is unlikely that the results would greatly change even if analyzed prospectively. Furthermore, because of the size limitation of the study, we were unable to include adequate factors in the multivariate analyses, particularly in subgroup analysis. Also, since it was a single-center study, selection of medication for HPT might have been biased. Finally, since we defined persistent HPT as HPT which needed either medication of calcimimetic, vitamin D, bisphosphonate, denosumab, and/or parathyroidectomy after renal transplantation, two different states with different pathophysiology, secondary, and tertiary HPT might have been mixed in our cohort. To fully explore the influence of calcimimetic, given before transplantation, on persistent HPT, implementation of a prospective, randomized controlled study is needed.
In conclusion, we have found that HPT after renal transplantation could be managed without surgical treatment in the era of calcimimetic. When predicting the prognosis of HPT after transplantation, pretransplant use of calcimimetic should be taken into consideration.

Data Availability
e data used to support the findings of this study are included within the article.

Conflicts of Interest
e authors declare that they have no conflicts of interest.

Acknowledgments
is study was supported in part by JSPS KAKENHI (19K08497 to S.M. and 16H05316 to A.I). 8 International Journal of Endocrinology