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DOI: 10.1055/a-2309-2240
Pretransplant Parathyroidectomy in Patients with Severe Secondary Hyperparathyroidism and Long-Term Effectiveness After Kidney Transplantation
Abstract
Kidney transplantation (KT) is the best option for patients with end-stage renal disease, but recipients still have legacy bone mineral disease from the pretransplant period, especially patients with severe secondary hyperparathyroidism (sHPT). Patients who had severe sHPT and underwent KT were analyzed retrospectively. Two groups were identified (patients with severe sHPT who had parathyroidectomy or calcimimetic before KT). Bone mineral density (BMD) was measured in the first year and last follow-up at the femoral neck, total hip, and lumbar spine using the dual-energy X-ray absorptiometry (DXA). Persistent hyperparathyroidism (perHPT) incidence was significantly higher in the calcimimetic group (75% vs. 40%, p=0.007). In patients with parathyroidectomy, BMDs were higher at femoral neck (0.818±0.114 vs. 0.744±0.134, p=0.04) and lumbar spine (1.005±0.170 vs. 0.897±0.151, p=0.01) at the first assessment. The BMD comparison between patients treated with parathyroidectomy and calcimimetic found a significant difference only in the femoral neck at second evaluation (0.835±0.118 vs. 0.758±0.129; p=0.03). In multivariate, linear regression revealed a positive association between the last BMD of the femoral neck with body mass index (CC: 0.297, 95% CI, 0.002–0.017) and parathyroidectomy (CC: 0.319, 95% CI, 0.021–0.156). Parathyroidectomy is associated with a significantly better femoral neck BMD and a lower incidence of perHPT in patients with severe sHPT.
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Keywords
kidney transplantation - hyperparathyroidism - calcium homeostasis - osteoporosis - parathyroidectomy - body mass indexIntroduction
Chronic kidney disease-mineral and bone disorders (CKD-MBD) is a complex disease that is caused by a disturbance in metabolic and hormone levels, including altered levels of calcium, phosphorus, parathyroid hormone (PTH), and vitamin D that impairs bone quality and bone remodelling.
Elevated PTH level is a crucial factor contributing to the development of osteodystrophy, vascular calcification, and anemia resistant to erythropoiesis-stimulating agents [1]. Also, studies demonstrated that a higher level of PTH correlated with osteopenia/osteoporosis and bone fracture risk in patients with chronic kidney disease treated by dialysis (CKD-G5D) [2] [3]. Optimization of the PTH levels should be the primary goal to reduce all these risks.
Current guidelines suggest maintaining intact PTH levels in the range of 2 to 9 times the normal upper limits in CKD-G5D patients and only recommend parathyroidectomy (PTX) in patients refractory to medical therapy [4]. In these patients, PTX was associated with improved survival in large observational dialysis cohorts, with a reported 20–37% and 33–41% reduction in all-cause and cardiovascular mortality, respectively [5] [6] [7]. Besides, it was found that CKD-G5D patients undergoing PTX have increased bone mineral density (BMD) and decreased fracture risk. [8] [9]. On the other hand, there was a significant decrease in the frequency of PTX after calcimimetics therapy was introduced in severe secondary hyperparathyroidism (sHPT) [10]. However, the effects of calcimimetics on major cardiovascular events, fractures or mortality are still controversial [11] [12]. In addition, side effects, patient adherence, calcium derangements, and drug cost significantly limit the use of these agents [13].
Although kidney transplantation (KT) is the best option for CKD-G5D patients and is associated with increased survival and health-related quality of life, the reduction in BMD within the first year is still observed, which could lead to adverse events [14] [15]. So, fracture rates in the first two years after transplantation have been reported to be 34% higher than in the previous year on dialysis, and the risk remains significantly higher even ten years after transplantation [16] [17]. Fracture outcomes are prominently worse, with higher hospitalization and mortality rates in KT recipients [18]. Additionally, sHPT can persist after KT in up to 66% of patients, despite an initial decrease in PTH levels, leading to hypophosphatemia, hypercalcemia, loss of bone mineral density (BMD), and increased risk of fractures [19] [20]. Although PTX after KT resolves electrolyte disturbances in patients with persistent hyperparathyroidism (perHPT), the BMD increase is lower than in CKD-G5D patients [21].
However, the long-term effect of PTX performed in KT recipients before transplantation remains unclear. The aim of this study was to compare the effects of PTX and calcimimetic agents used in severe sHPT before transplantation on the perHPT and long-term change in BMD after KT.
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Materials and Methods
Study population
We conducted a retrospective analysis of PTX and calcimimetic therapy for severe sHPT on long-term outcomes after KT. All patients who underwent kidney transplantation at our center between 2000 and 2017 were included. The inclusion criteria were as follows; age+≥+18 years at transplantation, patients treated with maintenance HD at least three times a week for+>+6 months before KT, and had plasma iPTH levels+>+800 pg/ml (at least three months) in the pre-transplantation period. Patients who received preemptive transplantation, an estimated glomerular filtration rate (eGFR)<30 ml/min/1.73 m2 on day 15 after KT, and patients with insufficient data and PTX after KT were excluded from the present study. Thus, the total eligible cohort for analysis was made of 68 patients ([Fig. 1]).
![](https://www.thieme-connect.de/media/hmr/202407/thumbnails/10-1055-a-2309-2240-ihmr-2023-06-0233-0001.jpg)
![Zoom Image](/products/assets/desktop/css/img/icon-figure-zoom.png)
All of the patients received induction therapy with basiliximab, daclizumab or anti-thymocyte globulin. An intravenous bolus of 500 mg on day 1 (D1), then 250 mg (D2) on day 2, then 20 mg/ day orally, the prednisolone dose was tapered by 5 mg every week until the dose was 5–10 mg. All patients were kept on a minimum of 5 mg of prednisolone. Maintenance therapy was with prednisolone as above and the calcineurin inhibitors cyclosporine or tacrolimus and the antimetabolite mycophenolate mofetil or azathioprine. In case of development of intolerable side effects, mammalian target of rapamaycin (mTOR) inbitors were used. Vitamin D supplementation was performed all patients who had vitamin D levels below 30 ng/ml according to “Kidney disease: improving global outcomes” (KDIGO) clinical practice guideline for the care of kidney transplant recipients [22]. Acute allograft rejection episodes are confirmed by renal biopsy and were treated in accordance with the KDIGO guideline [22].
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Data collection
Medical records were reviewed for patient data. Patient demographics were determined as age, sex, diabetes mellitus, cardiovascular disease (coronary artery or peripheral arterial disease), cause of ESRD (diabetes mellitus, hypertension, glomerulonephritis, urological abnormalities, unknown or “other” (including, amyloidosis, Alport syndrome, and polycystic kidney disease), dialysis vintage, dialysis types (hemodialysis, peritoneal dialysis or both modalities), baseline serum calcium, phosphate, and PTH. Kidney transplant data included donor type, delayed graft function (requiring dialysis within the first week after transplantation), rejection episodes (antibody-mediated or cellular rejection), allograft loss, and overall survival. Serum PTH, calcium, and phosphate levels at first, second and third year and last follow up post-transplantation were also collected.
We used bone mineral densitometry (BMD) at the hip (neck of the femur and total), and lumbar spine using dual-energy X-ray absorptiometry (DEXA Horizon; Hologic Inc., Marlborough, Massachusetts, USA) at first year after KT and at the last follow-up were noted. All the patients are followed up with BMD annually according to the KDIGO 2009 guideline in our clinic. BMD values were expressed in absolute values, g/cm2, as well as T-scores. Osteoporosis was defined as a T-score+≤+–2.5 at least one site, and osteopenia as a T-score between –1 and –2.5. Cases of symptomatic AVN were diagnosed by standard anterior-posterior X-ray views of the pelvis or magnetic resonance imaging (MRI) of the pelvis, hip, knee or shoulder. The presence of fractures was determined through a combination of electronic data base and medical records of the patients. Fractures associated with trauma were excluded.
The primary outcome was long-term changes in BMD measurements of patients with severe sHPT prior to KT. The secondary outcomes were serum PTH, calcium, and phosphate levels after kidney transplantation. Persistent HPT was defined as PTH+>+88 pg/ml after the first year of KT. Calcium (8.5–10.5 mg/dl) and phosphate (2.5–4.5 mg/dl) disturbances were defined as detecting values outside the reference ranges in the same direction on at least two consecutive visits.
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Statistical analysis
According to distribution, continuous data are presented as mean±standard deviation or median (interquartile range). Categorical data are presented as number (n) and percentage. Baseline characteristics were compared between groups using the Student t-test or non-parametric tests for continuous variables (according to distribution) and the chi-square test for categorical variables. Additionally, to identify independent risk factors for last femoral neck BMD, univariate and multivariate analysis was performed. Only variables with a p-value of<0.1 were considered for multivariate analysis. A p-value of<0.05 was considered significant. SPSS 16.0 (IBM Corp., Chicago, IL, USA) software was used for the statistical analyses.
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Results
A total of 68 patients were included in the analysis (20 received PTX and 48 received calcimimetic prior transplantation) with a mean 92.3±46.9 months follow-up time. The mean age of participants was 35.4±11.8 years, 47% were male and mean BMI of the cohort was 25.06±4.4 kg/m2. The PTX group had significantly more patients with female gender (p=0.004), whereas the baseline BMI value was higher in the calcimimetic group (p=0.02). Other demographic characteristics of the study population were similar and were demonstrated in [Table 1].
Total patients n=68 |
Parathyroidectomy n=20 (29%) |
Calcimimetic n=48 (71%) |
p-Value |
|
---|---|---|---|---|
Age at transplantation (years) |
35.4±11.8 |
35.45±12.25 |
35.44±11.8 |
0.9 |
BMI |
25.06±4.4 |
23.2±3.7 |
25.8±4.5 |
0.02 |
Gender (female/male) |
36 (53%)/32 (47%) |
16 (80%)/4 (20%) |
20 (42%)/28 (58%) |
0.004 |
Hypertension (n) |
49 (72%) |
12 (60%) |
37 (77%) |
0.1 |
CAD pre-transplantation (n) |
7 (10%) |
3 (15%) |
4 (8%) |
0.3 |
Pretranspl. glucocorticoid (n) |
19 (28%) |
5 (25%) |
14 (29%) |
0.4 |
NODAT (n) |
11 (16%) |
3 (15%) |
8 (17%) |
0.9 |
Cause of ESRD (n) |
||||
HT |
8 (12%) |
3 (15%) |
5 (10%) |
0.7 |
DM |
2 (3%) |
1 (5%) |
1 (2%) |
0.8 |
Glomerulonephritis |
17 (25%) |
3 (15%) |
14 (29%) |
0.5 |
Urological abnormalities |
6 (9%) |
3 (15%) |
3 (6%) |
0.3 |
Others |
20 (30%) |
6 (30%) |
14 (29%) |
0.9 |
Unknown |
15 (22%) |
4 (20%) |
11 (23%) |
0.9 |
Dialysis modality |
||||
PD |
11 (16%) |
3 (15%) |
8 (17%) |
0.9 |
HD |
36 (53%) |
10 (50%) |
26 (54%) |
0.9 |
PD and HD |
21 (31%) |
7 (35%) |
14 (29%) |
0.8 |
Dialysis vintage (years) |
9.2±4.4 |
10.4±5.3 |
8.7±4.0 |
0.1 |
Donor type (n) |
0.1 |
|||
Deceased donor |
35 (52%) |
13 (65%) |
22 (46%) |
0.1 |
Living donor |
33 (48%) |
7 (35%) |
26 (54%) |
|
Relative |
20 (61%) |
6 (86%) |
14 (54%) |
|
Induction with thymoglobulin (n) |
44 (65%) |
14 (70%) |
30 (63%) |
0.4 |
Delayed graft function (n) |
13 (19%) |
6 (30%) |
7 (15%) |
0.1 |
Immunosuppressive treatment |
||||
CNI (n) |
61 (90%) |
20 (100%) |
41 (85%) |
0.07 |
Antimetabolite (n) |
54 (79%) |
14 (70%) |
40 (83%) |
0.2 |
mTORi |
16 (24%) |
6 (30%) |
11 (23%) |
0.5 |
Steroid usage at last follow-up |
65 (96%) |
18 (90%) |
47 (98%) |
0.2 |
Follow-up time (months) |
92.3±46.9 |
84.9±44.4 |
95.4±48.1 |
0.4 |
BMI: Body mass index; CAD: Coronary artery disease; NODAT: New onset diabetes after transplantation; HT: Hypertension; DM: Diabetes mellitus; PD: Peritoneal dialysis; HD: Hemodialysis; CNI: Calcineurin inhibitors; mTORi: Mammalian target of rapamycin inhibitors.
PTH was significantly lower in the PTX group on the day of KT and most of the follow-up visits after KT ([Fig. 2a]). Mean serum calcium was lower in the PTX group only in the third month after KT (p=0.04) and the mean phosphate levels were similar over both groups during the follow-up ([Fig. 2b, c]). The incidence of hypercalcemia episodes was significantly higher in the group of patients who were treated with calcimimetic (50% vs. 22%, p=0.04). In contrast, hypocalcemia episodes were higher in the PTX group (17% vs 0%, p=0.02) ([Fig. 3a, b]). There were no differences in the incidence of hypophosphatemia or hyperphosphatemia episodes between groups ([Fig. 3c, d]).
![](https://www.thieme-connect.de/media/hmr/202407/thumbnails/10-1055-a-2309-2240-ihmr-2023-06-0233-0002.jpg)
![Zoom Image](/products/assets/desktop/css/img/icon-figure-zoom.png)
![](https://www.thieme-connect.de/media/hmr/202407/thumbnails/10-1055-a-2309-2240-ihmr-2023-06-0233-0003.jpg)
![Zoom Image](/products/assets/desktop/css/img/icon-figure-zoom.png)
Overall rates of allograft loss and death with functional allograft were comparable between the two groups. However, perHPT incidence was significantly higher in the calcimimetic group (75% vs. 40%, p=0.007). The DXA assessments were performed at a mean interval of 11.7±2.4 months for the first year and 7.2±2.9 years for the last follow-up after KT. At the first assessment, the overall rate of osteoporosis among the participants was 31%, whilst the proportion of people who had osteopenia was 37%. The median femoral neck, total hip and lumbar spine T-scores were –1.0 (–3.6 to 1.4), – 0.8 (–3.3 to 1.6), –1.6 (–3.7 to 2.1) respectively. In patients with PTX compared to the calcimimetic group, BMDs were significantly higher (T-scores) at all three measurement sites, that is, the femoral neck, total hip and lumbar spine, the median values of which were – 0.4 (–2.3 to 1.0) versus –1.2 (–3.6 to 1.36) (p=0.01); – 0.4 (–2.3 to 0.8) versus –1.0 (–3.3 to 1.6) (p=0.05); and 0.2 (–2.8 to 1.1) versuss –1.7 (–3.7 to 2.1) (p=0.02), respectively. The mean femoral neck, total hip and lumbar spine BMD measurements (g/cm2) of the patients were 0.766±0.131, 0.875±0.138, 0.929±0.163, respectively. In patients with PTX compared to calcimimetic group, BMD measurements (g/cm2) were higher at femoral neck and lumbar spine, the mean values of which were 0.818±0.114 versus 0.744±0.134 (p=0.04) and 1.005±0.170 versus 0.897±0.151 (p=0.01), respectively. At last follow-up, DXA showed osteoporosis in 9 patients (15%) and osteopenia in 33 patients (53%). The BMD comparison (T-score) between patients treated with PTX and calcimimetic prior KT found a significant difference only in the femoral neck [– 0.6 (–1.6 to 1.3) vs –1.2 (–3.1 to 1.4) (p=0.006), respectively]. Similar with that, BMD measurement (g/cm2) of femoral neck was significantly different between two groups (0.835±0.118 vs. 0.758±0.129; p=0.03). During an average of 94.1±49.2 follow-up time, 12% (8 patients) of the total study population sustained a fracture. Localization of the fracture sites were ankle (3/8; 38%), fibula (2/8; 25%), metacarpal bones (1/8; 13%), hip (1/8; 13%), and lumbar spine (1/8; 13%). Bone related parameters and clinical outcomes of the patients are summarized in [Table 2].
Total patients n=68 |
Parathyroidectomy n=20 (29%) |
Calcimimetic n=48 (71%) |
p-Value |
|
---|---|---|---|---|
First DXA assessment after KT (months) |
11.7±2.4 |
11.1±2.2 |
12.0±2.4 |
0.9 |
First DXA T score |
||||
Femur neck |
– 1.0 (– 3.6 to 1.4) |
– 0.4 (– 2.3 to 1.0) |
– 1.2 (– 3.6 to 1.3) |
0.01 |
Total hip |
– 0.8 (– 3.3 to 1.6) |
– 0.4 (– 2.3 to 0.8) |
– 1.0 (– 3.3 to 1.6) |
0.05 |
Lumbar spine |
– 1.6 (– 3.7 to 2.1) |
0.2 (– 2.8 to 1.1) |
– 1.7 (– 3.7 to 2.1) |
0.02 |
First BMD measurement (g/cm2) |
||||
Femur neck |
0.766±0.131 |
0.818±0.114 |
0.744±0.134 |
0.04 |
Total hip |
0.875±0.138 |
0.925±0.137 |
0.854±0.135 |
0.06 |
Lumbar spine |
0.929±0.163 |
1.005±0.170 |
0.897±0.151 |
0.01 |
Last DXA assessment after KT (years) |
7.2±2.9 |
7.1±2.9 |
7.3±3.0 |
0.8 |
Last DXA T score * |
||||
Femur neck |
– 1.1 (– 3.1 to 1.4) |
– 0.6 (– 1.6 to 1.3) |
– 1.2 (– 3.1 to 1.4) |
0.006 |
Total hip |
– 0.5 (– 2.9 to 2.2) |
– 0.3 (– 2.8 to 0.8) |
– 0.8 (– 2.9 to 2.2) |
0.1 |
Lumbar spine |
– 1.2 (– 3.3 to 3.0) |
– 0.4 (– 2.5 to 3.0) |
– 1.4 (– 3.3 to 2.1) |
0.1 |
Last BMD measurement (g/cm2)* |
||||
Femur neck |
0.781±0.129 |
0.835±0.118 |
0.758±0.129 |
0.03 |
Total hip |
0.908±0.142 |
0.932±0.119 |
0.898±0.153 |
0.4 |
Lumbar spine |
0.965±0.158 |
1.015±0.178 |
0.943±0.147 |
0.09 |
First BMD category (n) |
||||
Normal |
22 (32%) |
9 (45%) |
13 (27%) |
|
Osteopenia |
25 (37%) |
7 (35%) |
18 (38%) |
1 |
Osteoporosis |
21 (31%) |
4 (20%) |
17 (35%) |
0.3 |
Last BMD category (n)* |
||||
Normal |
20 (32%) |
9 (50%) |
11 (25%) |
|
Osteopenia |
33 (53%) |
8 (44%) |
25 (57%) |
0.4 |
Osteoporosis |
9 (15%) |
1 (6%) |
8 (18%) |
0.3 |
MOF |
8 (12%) |
1 (5%) |
7 (15%) |
0.4 |
AVN (n) |
7 (10%) |
2 (10%) |
5 (10%) |
0.9 |
Bisphosphonates (n) |
6 (9%) |
2 (10%) |
4 (8%) |
0.6 |
perHPT (n) |
44 (65%) |
8 (40%) |
36 (75%) |
0.007 |
Cardiovascular events (n) |
7 (10%) |
2 (10%) |
5 (10%) |
0.9 |
eGFR at last follow-up (ml/min/1.73 m2) |
66.8±35.6 |
65.1±35.5 |
67.5±36.0 |
0.8 |
Rejection episode (n) |
8 (12%) |
2 (10%) |
6 (13%) |
0.8 |
ACR |
4 (50%) |
1 (50%) |
3 (50%) |
|
ABMR |
4 (50%) |
1 (50%) |
3 (50%) |
|
Allograft lost (n) |
13 (19%) |
3 (15%) |
10 (21%) |
0.4 |
Death with functional allograft (n) |
5 (7%) |
2 (10%) |
3 (6%) |
0.6 |
ACR: Acute cellular rejection; ABMR: Antibody mediated rejection; AVN: Avascular necrosis; BMD: Bone mineral density; DXA: Dual–energy X–ray absorptiometry; eGFR: Estimated glomerular filtration rate; MOF: Major osteoporotic fractures; perHPT: Persistent hyperparathyroidism. *Patients who used bisphosphonate were excluded from analysis.
Univariate and multivariate regression analysis was performed to determine the affecting factors for the last femoral neck BMD measurement (g/cm2). Linear regression revealed a positive association between the last BMD of femoral neck with BMI [Correlation coefficient (CC): 0.251, 95% confidence interval (CI), 0.001– 0.016] and PTX performed prior KT (CC: 0.276, 95% CI, 0.007– 0.146). Additionally, BMI and PTX prior KT maintained their statistical significance in multivariate analysis (CC: 0.297, 95% CI, 0.002– 0.017 and CC: 0.319, 95% CI, 0.021– 0.156, respectively) ([Table 3]).
Correlation coefficient |
95% Confidence interval |
p-Value |
|
---|---|---|---|
Univariate analysis |
|||
Age |
– 0.158 |
– 0.004 and 0.001 |
0.2 |
BMI |
0.251 |
0.000 and 0.016 |
0.05 |
Male gender |
0.065 |
– 0.050 and 0.083 |
0.6 |
Dialysis vintage |
– 0.004 |
– 0.008 and 0.007 |
0.9 |
Delayed graft function |
0.098 |
– 0.054 and 0.119 |
0.5 |
NODAT |
– 0.162 |
– 0.152 and 0.034 |
0.2 |
Smoking |
– 0.091 |
– 0.091 and 0.044 |
0.5 |
CNI |
– 0.099 |
– 0.108and 0.049 |
0.4 |
Anti metabolite |
– 0.132 |
– 0.130 and 0.042 |
0.3 |
mTORi |
0.102 |
– 0.047 and 0.108 |
0.4 |
perPHP |
– 0.086 |
– 0.093 and 0.047 |
0.5 |
eGFR (last follow-up) |
0.147 |
– 0.003 and 0.012 |
0.3 |
PTX |
0.276 |
0.007 and 0.146 |
0.03 |
Multivariate analysis |
|||
BMI |
0.297 |
0.002 and 0.017 |
0.02 |
PTX |
0.319 |
0.021 and 0.156 |
0.01 |
BMI: Body mass index; NODAT: New onset diabetes after transplantation; CNI: Calcineurin inhibitors; eGFR: Estimated glomerular filtration rate; mTORi: Mammalian target of rapamycin inhibitors; perHPT: Persistent hyperparathyroidism; PTX: Parathyroidectomy.
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Discussion
The aim of our study was to evaluate changes in BMD in patients with severe sHPT who were treated with PTX or calcimimetic before KT. Our result showed that DXA assessment the first year after KT was significantly better in patients with PTX than those with calcimimetics. Besides, DXA assessment at the last follow-up revealed femoral neck BMD better in the PTX group and significantly associated with PTX.
Secondary hyperparathyroidism is a common problem in CKD-G5D patients, and the main factors for the development of sHPT were hypocalcemia, hyperphosphatemia, low 1,25D3, and high FGF23 levels [23]. sHPT is characterized by increased PTH synthesis and secretion accompanied by parathyroid cell hyperplasia. After introducing calcimimetics, the management of sHPT has changed, and utilization of PTX has decreased over time. Calcimimetics improved phosphate, PTH levels, and BMD in patients with sHPT, but many patients have treatment adherence issues [24]. If severe sHPT cannot be controlled in the pre-transplant period, it could lead to perHPT, increased risk of graft failure and bone loss after KT [25] [26] [27].
Our study showed that 65% of the patients had perHPT after KT, similar to other studies [19]. The percentage of the perHPT is significantly lower in the PTX group (40%) than in the calcimimetic treated group (75%) prior to KT. Previous studies reported high pre-transplant PTH levels along with calcium, phosphate and, dialysis vintage are risk factors for perHPT [28]. Besides, during the entire follow-up period after KT, patients with PTX had lower PTH levels than the calcimimetic treated group. A single-center study conducted by Callender et al. suggested that PTX prior to KT was associated with a lesser risk of graft failure. However, allograft loss in our study was similar in patients with or without PTX [25]. In addition, we found no difference in rejection episodes, cardiovascular events, or death with functional graft between the two groups. As expected, more hypercalcemia episodes were seen in the calcimimetic-treated group, compatible with the previous study [29].
Osteoporosis is one of the significant problems in kidney transplant recepients (KTRs). However, the clinical focus is on allograft function after KT and bone disease management is usually neglected. In this study, the percentage of patients with osteoporosis and osteopenia in the first DXA assessment was 31% and 37%, respectively. In a French cohort study, Segaud et al. reported 41% and 43% incidences of osteoporosis and osteopenia at the first assessment, respectively [30]. However, our study population was younger than this study, and we may attribute this difference to the lower mean age of our cohort.
KTRs have legacy bone mineral disease from chronic kidney disease that worsens with the drugs used after transplantation. Julian et al. reported a loss of 6.8±5.6% in the lumbar spine in BMD 6 to 12 months after KT, suggesting that it was due to the toxic effect of glucocorticoids [31]. Other associated risk factors with bone loss after KT were duration of dialysis before transplantation, age at transplantation, vitamin D deficiency, BMI<23 kg/m2, and higher initial parathyroid hormone level [27] [31] [32]. Modifiable risk factors such as perHPT, BMI, and early transplantation should be managed and treated promptly, as glucocorticoid therapy is mandatory in a patient with KT. In this context, we found that patients with a history of PTX had significantly better femoral neck, total hip or lumbar spine T scores in the first DXA assessments than those treated with calcimimetics. Chandran et al. found that patients with PTX prior to KT have better BMD and trabecular bone scores at the time of transplantation than patients with tertiary hyperparathyroidism [33]. That may explain the better BMD of these patients after the first year of KT, and it could be thought that controlling PTH levels before transplantation may contribute to preventing bone loss in the early period after KT.
In this study, we also examined the long-term effect of PTX performed before transplantation on BMD, and we found that the femoral neck T score and BMD at the last follow-up were better in the PTX group than those with calcimimetic. Also, we showed in the multivariate analysis that PTX and BMI are the independent factors correlated with better femoral neck BMD. There is no study in the literature that examines the impacts of PTX prior to KT on BMD. However, the only randomized, controlled trial investigating the role of PTX for perHPT revealed that PTX was superior to cinacalcet for increasing femoral neck BMD, but, the long-term effectiveness remains unclear [34]. Our results can be interpreted that surgical interventions before transplantation in severe sHPT will have an additional contribution in the long term in this particular patient group. In the general population, higher BMI has been shown to be protective against osteoporosis. Similarly to previous studies, we observed that BMI correlates with the better femoral neck BMD of the patients. [32] [35]. On the other hand, Akaberi et al. demonstrated high persistent PTH values correlated with significant bone loss at the hip after KT [36]. The last femoral neck BMD was not correlated with perHPT in our cohort; however, the presence of patients treated for perHPT in both groups after KT may have impacted this outcome.
The primary and major limitation is that this is a single-center study with a retrospective design. Within the limits of a single center, the study population was localized and included a small number of patients, which limited the analytic possibilities. Second, PTX time before KT was not standardized in this study. Also, bone turnover biomarkers were not available. Last, another limitation is that BMD values provide limited information on bone microarchitecture.
Our study has several strengths. First, to the best of our knowledge, this is the first study to demonstrate the long-term efficacy of PTX in femoral neck BMD measurements. Second, it is a study with an average mean follow-up time of 8 years after KT. Although this study includes a small number of patients, it was designed to evaluate a specific subgroup of patients with sHPT before KT.
#
Conclusion
In conclusion, pre-transplant PTX was associated with a significantly lower incidence of perHPT in patients with severe sHPT and better femoral neck BMD measurements (g/cm2) and T scores in the final DXA assessments. Therefore, further studies with a prospective manner are needed to define the impact of PTX performed before KT on the BMD of patients after transplantation.
#
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Conflict of Interest
The authors declare that they have no conflict of interest.
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References
- 1 Lau WL, Obi Y, Kalantar-Zadeh K. Parathyroidectomy in the management of secondary hyperparathyroidism. Clin J Am Soc Nephrol 2018; 13: 952-961
- 2 Brancaccio D, Di Leo C, Bestetti A. et al. Severe cortical and trabecular osteopenia in secondary hyperparathyroidism. Hemodial Int 2003; 7: 122-129
- 3 Nazzal Z, Khader S, Zawyani H. et al. Bone mineral density in Palestinian patients with end-stage renal disease and the related clinical and biochemical factors: Cross-sectional study. PLoS One 2020; 15: e0241201
- 4 Ketteler M, Block GA, Evenepoel P. et al. Executive summary of the 2017 KDIGO chronic kidney disease-mineral and bone disorder (CKD-MBD) guideline update: what's changed and why it matters. Kidney Int 2017; 92: 26-36
- 5 Sharma J, Raggi P, Kutner N. et al Improved long-term survival of dialysis patients after near-total parathyroidectomy. J Am Coll Surg 2012; 214: 400-407 discussion 407–408
- 6 Komaba H, Taniguchi M, Wada A. et al. Parathyroidectomy and survival among Japanese hemodialysis patients with secondary hyperparathyroidism. Kidney Int 2015; 88: 350-359
- 7 Ivarsson KM, Akaberi S, Isaksson E. et al. The effect of parathyroidectomy on patient survival in secondary hyperparathyroidism. Nephrol Dial Transplant 2015; 30: 2027-2033
- 8 Rudser KD, de Boer IH, Dooley A. et al. Fracture risk after parathyroidectomy among chronic hemodialysis patients. J Am Soc Nephrol 2007; 18: 2401-2407
- 9 Chou FF, Chen JB, Lee CH. et al. Parathyroidectomy can improve bone mineral density in patients with symptomatic secondary hyperparathyroidism. Arch Surg 2001; 136: 1064-1068
- 10 Kim SM, Long J, Montez-Rath ME. et al. Rates and outcomes of parathyroidectomy for secondary hyperparathyroidism in the United States. Clin J Am Soc Nephrol 2016; 11: 1260-1267
- 11 Chertow GM, Block GA, Correa-Rotter R. et al. Effect of cinacalcet on cardiovascular disease in patients undergoing dialysis. N Engl J Med 2012; 367: 2482-2494
- 12 Sekercioglu N, Busse JW, Sekercioglu MF. et al. Cinacalcet versus standard treatment for chronic kidney disease: a systematic review and meta-analysis. Ren Fail 2016; 38: 857-874
- 13 Shireman TI, Almehmi A, Wetmore JB. et al. Economic analysis of cinacalcet in combination with low-dose vitamin D versus flexible-dose vitamin D in treating secondary hyperparathyroidism in hemodialysis patients. Am J Kidney Dis 2010; 56: 1108-1116
- 14 Brandenburg VM, Politt D, Ketteler M. et al. Early rapid loss followed by long-term consolidation characterizes the development of lumbar bone mineral density after kidney transplantation. Transplantation 2004; 77: 1566-1571
- 15 Bouquegneau A, Salam S, Delanaye P. et al. Bone disease after kidney transplantation. Clin J Am Soc Nephrol 2016; 11: 1282-1296
- 16 Ball AM, Gillen DL, Sherrard D. et al. Risk of hip fracture among dialysis and renal transplant recipients. Jama 2002; 288: 3014-3018
- 17 Nair SS, Lenihan CR, Montez-Rath ME. et al. Temporal trends in the incidence, treatment and outcomes of hip fracture after first kidney transplantation in the United States. Am J Transplant 2014; 14: 943-951
- 18 Abbott KC, Oglesby RJ, Hypolite IO. et al. Hospitalizations for fractures after renal transplantation in the United States. Ann Epidemiol 2001; 11: 450-457
- 19 Bleskestad IH, Bergrem H, Leivestad T. et al. Intact parathyroid hormone levels in renal transplant patients with normal transplant function. Clin Transplant 2011; 25: E566-E570
- 20 Perrin P, Caillard S, Javier RM. et al. Persistent hyperparathyroidism is a major risk factor for fractures in the five years after kidney transplantation. Am J Transplant 2013; 13: 2653-2663
- 21 Coyne DW, Delos Santos R. Evaluating the safety and rationale for cinacalcet posttransplant hyperparathyroidism and hypercalcemia. Am J Transplant 2014; 14: 2446-2447
- 22 [Anonymous] KDIGO clinical practice guideline for the care of kidney transplant recipients. Am J Transplant. 2009 9. S1-S155
- 23 Rodríguez-Ortiz ME, Rodríguez M. Recent advances in understanding and managing secondary hyperparathyroidism in chronic kidney disease. F1000Res. 2020 9. F1000 Faculty Rev-1077; oi DOI: 10.12688/f1000research.22636.1; eCollection 2020
- 24 Lien YH, Silva AL, Whittman D. Effects of cinacalcet on bone mineral density in patients with secondary hyperparathyroidism. Nephrol Dial Transplant 2005; 20: 1232-1237
- 25 Callender GG, Malinowski J, Javid M. et al. Parathyroidectomy prior to kidney transplant decreases graft failure. Surgery 2017; 161: 44-50
- 26 Nakai K, Fujii H, Ishimura T. et al. Incidence and risk factors of persistent hyperparathyroidism after kidney transplantation. Transplant Proc 2017; 49: 53-56
- 27 Grotz WH, Mundinger FA, Rasenack J. et al. Bone loss after kidney transplantation: a longitudinal study in 115 graft recipients. Nephrol Dial Transplant 1995; 10: 2096-2100
- 28 Cohen E, Korah M, Callender G. et al. Metabolic disorders with kidney transplant. Clin J Am Soc Nephrol 2020; 15: 732-742
- 29 Koh EY, van der Plas WY, Dulfer RR. et al. Outcomes of parathyroidectomy versus calcimimetics for secondary hyperparathyroidism and kidney transplantation: a propensity-matched analysis. Langenbecks Arch Surg 2020; 405: 851-859
- 30 Segaud N, Legroux I, Hazzan M. et al. Changes in bone mineral density after kidney transplantation: 2-year assessment of a French cohort. Osteoporos Int 2018; 29: 1165-1175
- 31 Julian BA, Laskow DA, Dubovsky J. et al. Rapid loss of vertebral mineral density after renal transplantation. N Engl J Med 1991; 325: 544-550
- 32 Unal A, Kocyigit I, Sipahioglu MH. et al. Loss of bone mineral density in renal transplantation recipients. Transplant Proc 2010; 42: 3550-3553
- 33 Chandran M, Hao Y, Kwee AK. et al. Addressing bone quality and bone density after renal transplantation: a prospective evaluation of the evolution of trabecular bone score and bone mineral density over the first 5 years following renal transplantation in Asian patients. Clin Transplant 2019; 33: e13671
- 34 Cruzado JM, Moreno P, Torregrosa JV. et al. A randomized study comparing parathyroidectomy with cinacalcet for treating hypercalcemia in kidney allograft recipients with hyperparathyroidism. J Am Soc Nephrol 2016; 27: 2487-2494
- 35 Gupta AK, Huang M, Prasad GV. Determinants of bone mineral density in stable kidney transplant recipients. J Nephrol 2012; 25: 373-383
- 36 Akaberi S, Lindergård B, Simonsen O. et al. Impact of parathyroid hormone on bone density in long-term renal transplant patients with good graft function. Transplantation 2006; 82: 749-752
Correspondence
Publication History
Received: 06 June 2023
Accepted after revision: 13 April 2024
Article published online:
13 May 2024
© 2024. Thieme. All rights reserved.
Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany
-
References
- 1 Lau WL, Obi Y, Kalantar-Zadeh K. Parathyroidectomy in the management of secondary hyperparathyroidism. Clin J Am Soc Nephrol 2018; 13: 952-961
- 2 Brancaccio D, Di Leo C, Bestetti A. et al. Severe cortical and trabecular osteopenia in secondary hyperparathyroidism. Hemodial Int 2003; 7: 122-129
- 3 Nazzal Z, Khader S, Zawyani H. et al. Bone mineral density in Palestinian patients with end-stage renal disease and the related clinical and biochemical factors: Cross-sectional study. PLoS One 2020; 15: e0241201
- 4 Ketteler M, Block GA, Evenepoel P. et al. Executive summary of the 2017 KDIGO chronic kidney disease-mineral and bone disorder (CKD-MBD) guideline update: what's changed and why it matters. Kidney Int 2017; 92: 26-36
- 5 Sharma J, Raggi P, Kutner N. et al Improved long-term survival of dialysis patients after near-total parathyroidectomy. J Am Coll Surg 2012; 214: 400-407 discussion 407–408
- 6 Komaba H, Taniguchi M, Wada A. et al. Parathyroidectomy and survival among Japanese hemodialysis patients with secondary hyperparathyroidism. Kidney Int 2015; 88: 350-359
- 7 Ivarsson KM, Akaberi S, Isaksson E. et al. The effect of parathyroidectomy on patient survival in secondary hyperparathyroidism. Nephrol Dial Transplant 2015; 30: 2027-2033
- 8 Rudser KD, de Boer IH, Dooley A. et al. Fracture risk after parathyroidectomy among chronic hemodialysis patients. J Am Soc Nephrol 2007; 18: 2401-2407
- 9 Chou FF, Chen JB, Lee CH. et al. Parathyroidectomy can improve bone mineral density in patients with symptomatic secondary hyperparathyroidism. Arch Surg 2001; 136: 1064-1068
- 10 Kim SM, Long J, Montez-Rath ME. et al. Rates and outcomes of parathyroidectomy for secondary hyperparathyroidism in the United States. Clin J Am Soc Nephrol 2016; 11: 1260-1267
- 11 Chertow GM, Block GA, Correa-Rotter R. et al. Effect of cinacalcet on cardiovascular disease in patients undergoing dialysis. N Engl J Med 2012; 367: 2482-2494
- 12 Sekercioglu N, Busse JW, Sekercioglu MF. et al. Cinacalcet versus standard treatment for chronic kidney disease: a systematic review and meta-analysis. Ren Fail 2016; 38: 857-874
- 13 Shireman TI, Almehmi A, Wetmore JB. et al. Economic analysis of cinacalcet in combination with low-dose vitamin D versus flexible-dose vitamin D in treating secondary hyperparathyroidism in hemodialysis patients. Am J Kidney Dis 2010; 56: 1108-1116
- 14 Brandenburg VM, Politt D, Ketteler M. et al. Early rapid loss followed by long-term consolidation characterizes the development of lumbar bone mineral density after kidney transplantation. Transplantation 2004; 77: 1566-1571
- 15 Bouquegneau A, Salam S, Delanaye P. et al. Bone disease after kidney transplantation. Clin J Am Soc Nephrol 2016; 11: 1282-1296
- 16 Ball AM, Gillen DL, Sherrard D. et al. Risk of hip fracture among dialysis and renal transplant recipients. Jama 2002; 288: 3014-3018
- 17 Nair SS, Lenihan CR, Montez-Rath ME. et al. Temporal trends in the incidence, treatment and outcomes of hip fracture after first kidney transplantation in the United States. Am J Transplant 2014; 14: 943-951
- 18 Abbott KC, Oglesby RJ, Hypolite IO. et al. Hospitalizations for fractures after renal transplantation in the United States. Ann Epidemiol 2001; 11: 450-457
- 19 Bleskestad IH, Bergrem H, Leivestad T. et al. Intact parathyroid hormone levels in renal transplant patients with normal transplant function. Clin Transplant 2011; 25: E566-E570
- 20 Perrin P, Caillard S, Javier RM. et al. Persistent hyperparathyroidism is a major risk factor for fractures in the five years after kidney transplantation. Am J Transplant 2013; 13: 2653-2663
- 21 Coyne DW, Delos Santos R. Evaluating the safety and rationale for cinacalcet posttransplant hyperparathyroidism and hypercalcemia. Am J Transplant 2014; 14: 2446-2447
- 22 [Anonymous] KDIGO clinical practice guideline for the care of kidney transplant recipients. Am J Transplant. 2009 9. S1-S155
- 23 Rodríguez-Ortiz ME, Rodríguez M. Recent advances in understanding and managing secondary hyperparathyroidism in chronic kidney disease. F1000Res. 2020 9. F1000 Faculty Rev-1077; oi DOI: 10.12688/f1000research.22636.1; eCollection 2020
- 24 Lien YH, Silva AL, Whittman D. Effects of cinacalcet on bone mineral density in patients with secondary hyperparathyroidism. Nephrol Dial Transplant 2005; 20: 1232-1237
- 25 Callender GG, Malinowski J, Javid M. et al. Parathyroidectomy prior to kidney transplant decreases graft failure. Surgery 2017; 161: 44-50
- 26 Nakai K, Fujii H, Ishimura T. et al. Incidence and risk factors of persistent hyperparathyroidism after kidney transplantation. Transplant Proc 2017; 49: 53-56
- 27 Grotz WH, Mundinger FA, Rasenack J. et al. Bone loss after kidney transplantation: a longitudinal study in 115 graft recipients. Nephrol Dial Transplant 1995; 10: 2096-2100
- 28 Cohen E, Korah M, Callender G. et al. Metabolic disorders with kidney transplant. Clin J Am Soc Nephrol 2020; 15: 732-742
- 29 Koh EY, van der Plas WY, Dulfer RR. et al. Outcomes of parathyroidectomy versus calcimimetics for secondary hyperparathyroidism and kidney transplantation: a propensity-matched analysis. Langenbecks Arch Surg 2020; 405: 851-859
- 30 Segaud N, Legroux I, Hazzan M. et al. Changes in bone mineral density after kidney transplantation: 2-year assessment of a French cohort. Osteoporos Int 2018; 29: 1165-1175
- 31 Julian BA, Laskow DA, Dubovsky J. et al. Rapid loss of vertebral mineral density after renal transplantation. N Engl J Med 1991; 325: 544-550
- 32 Unal A, Kocyigit I, Sipahioglu MH. et al. Loss of bone mineral density in renal transplantation recipients. Transplant Proc 2010; 42: 3550-3553
- 33 Chandran M, Hao Y, Kwee AK. et al. Addressing bone quality and bone density after renal transplantation: a prospective evaluation of the evolution of trabecular bone score and bone mineral density over the first 5 years following renal transplantation in Asian patients. Clin Transplant 2019; 33: e13671
- 34 Cruzado JM, Moreno P, Torregrosa JV. et al. A randomized study comparing parathyroidectomy with cinacalcet for treating hypercalcemia in kidney allograft recipients with hyperparathyroidism. J Am Soc Nephrol 2016; 27: 2487-2494
- 35 Gupta AK, Huang M, Prasad GV. Determinants of bone mineral density in stable kidney transplant recipients. J Nephrol 2012; 25: 373-383
- 36 Akaberi S, Lindergård B, Simonsen O. et al. Impact of parathyroid hormone on bone density in long-term renal transplant patients with good graft function. Transplantation 2006; 82: 749-752
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