Abstract
Introduction:
Tertiary hyperparathyroidism (THPT) after kidney transplantation (KT) has been associated with graft dysfunction, cardiovascular morbidity, and osteopenia, yet its true prevalence is unclear. The objective of our study was to evaluate the prevalence of and risk factors for THPT.
Methods:
A prospective cohort of 849 adult KT recipients (12/2008-2/2020) was used to estimate the prevalence of hyperparathyroidism (HPT) 1-year post-KT. THPT was defined as hypercalcemia (≥10mg/dl) and HPT (PTH≥70pg/ml) 1-year post-KT. Modified Poisson regression models were utilized to evaluate risk factors associated with the development of both persistent HPT and THPT.
Results:
Among KT recipients, 524 (61.7%) had persistent HPT and 182 (21.5%) had THPT at 1-year post-KT. Calcimimetic use prior to KT was associated with 1.30-fold higher risk of persistent HPT (aPR=1.30,95%CI: 1.12-1.51) and 1.84-fold higher risk of THPT (aPR=1.84,95%CI: 1.25-2.72). Pre-KT PTH ≥300 pg/mL was associated with 1.49-fold higher risk of persistent HPT (aPR=1.49,95%CI=1.19-1.85) and 2.21-fold higher risk of THPT (aPR=2.21,95%CI=1.25-3.90). Pre-KT THPT was associated with an increased risk of post-KT THPT (aPR=1.71,95%CI=1.29-2.27), but not persistent HPT. Furthermore, 73.0% of patients with persistent HPT and 61.5% with THPT did not receive any treatment at 1-year post-KT.
Conclusions:
Persistent HPT affected 61.7% and THPT affected 21.5% of KT recipients, yet the majority of patients were not treated. Pre-KT PTH levels ≥300pg/ml and use of calcimimetics are associated with the development of THPT. These findings encourage the re-evaluation of recommended pre-KT PTH thresholds and reconsideration of pre-KT secondary HPT treatments to avoid the adverse sequelae of THPT in KT recipients.
Article Summary:
Persistent hyperparathyroidism affects 61.7% and tertiary hyperparathyroidism affects 21.5% of kidney transplant recipients, and risk factors for the development of both persistent and tertiary hyperparathyroidism include pre-transplant PTH levels ≥300pg/ml and use of calcimimetics. These findings importantly highlight the high prevalence and undertreatment of post-transplant hyperparathyroidism, as well as clinically modifiable risk factors for its development.
Introduction:
Persistent hyperparathyroidism (HPT) after successful kidney transplantation (KT) is associated with renal graft dysfunction, cardiovascular morbidity, bone loss, increased fracture risk, and worse quality of life1-6. Tertiary hyperparathyroidism (THPT) is additionally associated with nephrolithiasis, pancreatitis, soft tissue calcification, and peptic ulcer disease7. The definitive management of THPT is surgical with either a subtotal (3.5 gland) parathyroidectomy or total (4 gland) parathyroidectomy with auto-transplantation of parathyroid tissue in the forearm7-9. However, surgical referral is often delayed for patients with THPT, and most do not undergo definitive parathyroidectomy1, 10. The reasons for under-referral of THPT are multifactorial but include a lack of a consensus in the definition for diagnosis, optimal treatment modalities, and goals of treatment for THPT1, 2, 10, 11.
There is also wide variation in reported prevalence of both persistent HPT and THPT, ranging from 10-70% depending on the diagnostic thresholds for parathyroid hormone (PTH) and calcium, as well as timing of patient assessment post-KT1, 2, 11, 12. While the most dramatic fall in PTH occurs in the first 3 months post-KT, the diagnosis is often not established until up to two years post-KT, causing increased morbidity from subsequent delays in treatment 1, 7, 13. Therefore, the true prevalence of persistent HPT and THPT, as well as the patient and transplant factors that lead to their development, are largely unknown.
Some studies have demonstrated an association between severity of pre-KT secondary hyperparathyroidism (SHPT) and higher rates of post-KT graft failure and persistent hyperparathyroidism14-16. However, as treatment modalities for SHPT have continued to evolve over the past two decades, limited data exists regarding the impact of these treatments on the development of post-KT THPT. Additionally, quantitative thresholds for pre-KT PTH and calcium levels to minimize the risk for the development of THPT have not been established.
Therefore, we used a prospective cohort of patients who received a KT to characterize the course and treatment of hyperparathyroidism before and after KT. Our primary objectives were to evaluate the prevalence of THPT and to identify clinically relevant risk factors for its development. We hypothesized that increasing levels of PTH prior to KT as well as the pre-KT use of calcimimetics were associated with a higher risk of post-KT THPT.
Methods:
Study Design
Under IRB approval, study participants were identified from a prospective cohort of 1,243 adult (≥18 years old) KT recipients who underwent transplantation at a single institution between 12/2008-2/2020 (Figure 1). Recipients underwent informed consent and were enrolled at admission for KT. Patient characteristics were self-reported, measured, or abstracted from medical records at time of enrollment, including age, sex, race, ethnicity, body mass index (BMI), time on dialysis, and whether they attended college. Additional participant factors (cause of kidney failure, history of hypertension, history of diabetes, history of any malignancy, peak panel reactive antigen [PRA]), transplant factors (human leukocyte antigen [HLA] mismatch, ABO incompatibility, cold ischemia time, donor type, transplantation year), and donor characteristics (donor’s age, sex, race, ethnicity) were assessed from the Scientific Registry of Transplant Recipients (SRTR) and medical records.
Figure 1: Sample Selection Process of Study Population.
The figure displays the number of kidney transplant (KT) recipients enrolled and included in analysis.
KT: kidney transplant; PTH: parathyroid hormone.
The lab results for PTH, calcium, and vitamin D prior to KT and at approximately one-year post-KT were abstracted from medical records. The treatment methods used for pre-KT HPT were recorded including calcimimetics, parathyroidectomy, and supplementation (vitamin D analogs, phosphate binders, and/or calcium). The use of calcimimetics and/or parathyroidectomy post-KT for treatment of THPT was also recorded.
A total of 849 patients had a PTH level recorded at least 6 months post-KT (median: 1.0 years post-KT, IQR: 0.6-1.1). These 849 patients were included in the analysis for persistent HPT, and 848 patients of these patients also had a post-KT calcium level recorded and were included in THPT analysis.
Definitions of Hyperparathyroidism
For categorization of hyperparathyroidism prior to KT, SHPT was defined as PTH ≥70 and calcium <10mg/dl, and pre-KT THPT was defined as PTH ≥70 and calcium ≥10 mg/dL.
For categorization of hyperparathyroidism post-KT, persistent HPT was defined as an elevated PTH level ≥70 pg/ml one-year post-KT with or without hypercalcemia, which includes patients with both SHPT and THPT. Post-KT THPT was a subset of patients with post-KT HPT, defined as both elevated PTH level (≥70 pg/ml) and hypercalcemia (serum calcium ≥10 mg/dL) at one-year post-KT.
Statistical Analysis
Differences in characteristics by persistent HPT or THPT were tested using ANOVA tests for normally distributed continuous variables, Kruskal-Wallis tests for non-normally distributed continuous variables, and Fisher’s exact tests for categorical variables.
Prevalence ratios (PRs) of persistent HPT and THPT by risk factors were estimated using modified Poisson regression models. Risk factors were identified based upon literature review, and the base model included participant age, sex, and race. We then used the Akaike’s information criterion (AIC) in a step-wise approach to select additional risk factors and determine the model with the best fit.17 The selected variables included: pre-KT THPT, pre-KT treatment for SHPT, pre-KT PTH level, low vitamin D post-KT, college education, BMI, cause of kidney failure, time on dialysis, history of hypertension, peak PRA, and cold ischemia time. All the selected risk factors in addition to the base model were included in a single model.
All analyses were performed using Stata version 15 (StataCorp, College Station, TX). Two-sided p-values < 0.05 were considered statistically significant.
Sensitivity Analysis
A sensitivity analysis was conducted to quantify the total number of patients that may have had post-KT THPT that was being masked by treatment with calcium-lowering calcimimetics, and to evaluate the association between risk factors and development of THPT in this group. The sensitivity analysis included patients with THPT based on our initial definition (PTH ≥70 pg/ml and calcium ≥10 mg/dl) as well as patients with “possibly masked THPT”, defined as patients with normocalcemic, persistent HPT (PTH ≥70 pg/ml and calcium <10 mg/dl) who were prescribed calcimimetics at one-year post-KT.
Results:
Characteristics of the Cohort
Among the 849 patients included in the study, the mean age was 53.1 (Standard Deviation (SD): 13.7) years, 39.6% were female, 48.5% were Black, 42.3% were White, and 2.8% were Hispanic. The mean BMI among the cohort was 27.2 (SD: 5.5) kg/m2 and 68.9% attended college. The leading cause of kidney failure was hypertension in 31.8% of patients, followed by glomerulonephritis in 25.9%, and diabetes mellitus in 17.1%. The majority of patients (92.4%) had a history of hypertension. Most patients (88.0%) were on dialysis and the median time on dialysis was 2.7 years prior to KT (interquartile range (IQR): 0.6-5.5). Treatment for SHPT prior to KT included supplementations in 53.0%, calcimimetics in 26.4%, parathyroidectomy in only 3.1%, and 17.6% received no treatment. The pre-KT PTH level measured <100 pg/mL in 15.2% of patients, 100-299 pg/mL in 45.3%, 300-599 pg/mL in 27.0%, and ≥600 pg/mL in 12.5% of patients. A total of 16.7% of patients had pre-KT hypercalcemia (calcium ≥10mg/dl) and 14.7% patients had pre-KT THPT. The majority of patients had SHPT prior to KT (77.3%). Additionally, 71.7% of patients had a vitamin D level ≤30 ng/ml prior to KT, and 57.2% patients had a vitamin D level ≤30 ng/ml post-KT. Most patients (65.5%) underwent deceased donor kidney transplants, and mean donor age was 38.5 (SD: 15.1) years.
Prevalence and Treatment of Hyperparathyroidism Post-Kidney Transplant
Of 849 KT recipients with post-KT PTH level, 524 (61.7%) had persistent HPT one-year post-KT, and 182 (21.5%) had THPT (Figure 2).
Figure 2: Prevalence of Persistent Hyperparathyroidism (HPT) and Tertiary Hyperparathyroidism (THPT) Among Kidney Transplant Recipients (n=849).
Persistent HPT was defined as parathyroid hormone (PTH) level ≥70 pg/ml at 1-year post-KT. THPT was defined as PTH level ≥70 pg/ml (hyperparathyroidism) and calcium ≥10 mg/dl (hypercalcemia) at 1-year post-KT.
Of 524 patients with persistent HPT at one-year post-KT, 381 (73.0%) patients received no treatment. After KT, 125 (23.9%) patients received calcimimetics and only 16 (3.0%) patients underwent parathyroidectomy. Of 182 patients with THPT at one-year post-KT, 112 (61.5%) patients received no treatment. After KT, 59 (32.4%) patients received calcimimetics and only 11 (6.0%) patients underwent parathyroidectomy (Figure 3).
Figure 3: Post-Transplant Treatments at One Year for Kidney Transplant Recipients with Persistent Hyperparathyroidism (HPT) (n=524) and Recipients with Tertiary Hyperparathyroidism (THPT) (n=182).
Persistent HPT was defined as parathyroid hormone (PTH) level ≥70 pg/ml at 1-year post-KT. THPT was defined as PTH level ≥70 pg/ml (hyperparathyroidism) and calcium ≥10 mg/dl (hypercalcemia) at 1-year post-KT.
Characteristics of Patients with Hyperparathyroidism
Among patients with persistent HPT or THPT, 37.6% were female with mean age of 53.1 (SD: 13.5) years. A larger proportion of those with persistent HPT (48.1%) and THPT (47.8%) were Black when compared to those without HPT (32.9%), and the mean BMI was higher (27.7kg/m2, SD: 5.5; and 27.3kg/m2, SD: 5.0; vs. 26.4kg/m2, SD: 5.2). Patients with persistent HPT and THPT had a higher median dialysis vintage compared to those without HPT (3.5 years, IQR: 1.3-6.1; and 4.1 years, IQR: 2.1-6.8; vs. 1.7 years, IQR: 0.2-4.1). A larger proportion of patients with persistent HPT and THPT had pre-KT PTH ≥600pg/ml (16.3% and 23.1% vs. 6.9%) and 300-599pg/ml (32.0% and 38.2% vs. 19.0%). Additionally, compared to those without post-KT HPT, a higher proportion of patients who developed post-KT persistent HPT and THPT had pre-KT hypercalcemia (18.9% and 26.4% vs. 13.3%), and pre-KT THPT (17.3% and 26.4% vs. 10.5%). The rates of pre-KT SHPT were similar across the three groups (77.4% and 72.7% vs. 77.0%). More patients with post-KT persistent HPT and THPT received pre-KT treatment for HPT with calcimimetics (36.1% and 48.9% vs. 10.8%) or parathyroidectomy (3.8% and 2.7% vs. 1.8%) compared to those without HPT. Patients with post-KT persistent HPT and THPT were also more likely to have Vitamin D deficiency (≤30 ng/ml) prior to KT (76.7% and 72.3% vs. 64.4%) and post-KT (65.9% and 72.4% vs. 43.4%). There was no difference between the groups for peak PRA or transplant characteristics including percentage of deceased donor KT, donor age, or cold ischemia time (Tables 1a & 1b).
Table 1a: Characteristics of Kidney Transplant Recipients (n=849) with Persistent Hyperparathyroidism (HPT) Compared to Those without HPT at One-Year Post-Transplant.
Persistent HPT was defined as a PTH level ≥70 pg/ml. Differences that are statistically significant at p<0.05 are bolded.
| Persistent Hyperparathyroidism (n=524) |
Non- hyperparathyroidism (n=325) |
P value | |
|---|---|---|---|
| Patient Characteristics | |||
| Age at KT (years), mean (SD) | 53.1 (13.5) | 53.0 (14.1) | 0.92 |
| Female | 37.6% | 42.8% | 0.13 |
| Race/ethnicity | |||
| White | 44.8% | 54.5% | <0.001 |
| Black | 48.1% | 32.9% | |
| Hispanic | 2.9% | 2.8% | |
| Other | 4.2% | 9.8% | |
| Attended college | 69.3% | 68.2% | 0.74 |
| BMI (kg/m2), mean (SD) | 27.7 (5.5) | 26.4 (5.2) | <0.001 |
| Cause of kidney failure | |||
| Glomerulonephritis | 24.5% | 28.1% | 0.006 |
| Diabetes mellitus | 18.0% | 15.7% | |
| Hypertension | 35.4% | 25.9% | |
| Other | 22.2% | 30.2% | |
| History of hypertension | 93.2% | 91.1% | 0.32 |
| Pre-KT dialysis | 90.3% | 84.2% | 0.008 |
| Years on dialysis, median (IQR) | 3.5 (1.3, 6.1) | 1.7 (0.2, 4.1) | <0.001 |
| Pre-KT treatment for HPT | |||
| Calcimimetics | 36.1% | 10.8% | <0.001 |
| Parathyroidectomy | 3.8% | 1.8% | |
| Supplementation | 43.5% | 68.3% | |
| None | 16.6% | 19.1% | |
| Pre-KT THPT | 17.3% | 10.5% | 0.008 |
| Pre-KT SHPT | 77.4% | 77.0% | 0.93 |
| Pre-KT PTH level | |||
| <100 pg/ml | 10.2% | 23.2% | <0.001 |
| 100-299 pg/ml | 41.8% | 51.0% | |
| 300-599 pg/ml | 32.0% | 19.0% | |
| ≥600 pg/ml | 16.1% | 6.9% | |
| Pre-KT calcium ≥10 mg/dl | 18.9% | 13.3% | 0.036 |
| Pre-KT vitamin D ≤30 ng/ml | 76.7% | 64.4% | 0.050 |
| Post-KT vitamin D ≤30 ng/ml | 65.9% | 43.4% | <0.001 |
| Peak PRA (%), median (IQR) | 6.0 (0.0, 63.0) | 4.0 (0.0, 33.0) | 0.064 |
| Transplant Characteristics | |||
| Deceased donor | 67.2% | 62.8% | 0.19 |
| Donor age (years), mean (SD) | 39.2 (14.6) | 37.4 (15.8) | 0.092 |
| Cold ischemia time (hours), median (IQR) | 18.0 (3.1, 29.0) | 18.0 (2.0, 29.0) | 0.44 |
| Transplantation year | |||
| 2008-2011 | 28.1% | 27.4% | 0.88 |
| 2012-2015 | 48.1% | 49.8% | |
| 2016-2019 | 23.9% | 22.8% |
KT, kidney transplant; PTH, parathyroid hormone; SHPT, secondary hyperparathyroidism; BMI, body mass index; PRA, panel reactive antigen; SD, standard deviation; IQR, interquartile range.
Table 1b: Characteristics of Kidney Transplant Recipients (n=848) with Tertiary Hyperparathyroidism (THPT) Compared to Those without THPT at One-Year Post-Transplant.
THPT was defined as PTH level ≥70 pg/ml (hyperparathyroidism) and calcium ≥10 mg/dl (hypercalcemia). Differences that are statistically significant at p<0.05 are bolded.
| THPT (n=182) |
Non-THPT (n=666) |
P value | |
|---|---|---|---|
| Patient Characteristics | |||
| Age at KT (years), mean (SD) | 52.7 (13.8) | 53.2 (13.7) | 0.67 |
| Female | 33.5% | 41.3% | 0.057 |
| Race/ethnicity | |||
| White | 45.6% | 49.4% | 0.12 |
| Black | 47.8% | 40.7% | |
| Hispanic | 3.3% | 2.7% | |
| Other | 3.3% | 7.2% | |
| Attended college | 70.9% | 68.3% | 0.49 |
| BMI (kg/m2), mean (SD) | 27.3 (5.0) | 27.2 (5.6) | 0.95 |
| Cause of kidney failure | |||
| Glomerulonephritis | 21.5% | 26.9% | 0.10 |
| Diabetes mellitus | 16.0% | 17.4% | |
| Hypertension | 39.2% | 29.8% | |
| Other | 23.2% | 25.9% | |
| History of hypertension | 96.4% | 91.3% | 0.045 |
| Pre-KT dialysis | 92.3% | 87.0% | 0.051 |
| Years on dialysis, median (IQR) | 4.1 (2.1, 6.8) | 2.2 (0.5, 4.8) | <0.001 |
| Pre-KT treatment for HPT | |||
| Calcimimetics | 48.9% | 20.3% | <0.001 |
| Parathyroidectomy | 2.7% | 3.2% | |
| Supplementation | 34.1% | 58.1% | |
| None | 14.3% | 18.5% | |
| Pre-KT THPT | 24.9% | 11.9% | <0.001 |
| Pre-KT SHPT | 72.7% | 78.5% | 0.12 |
| Pre-KT PTH level | |||
| <100 pg/ml | 6.9% | 17.5% | <0.001 |
| 100-299 pg/ml | 31.8% | 49.0% | |
| 300-599 pg/ml | 38.2% | 23.9% | |
| ≥600 pg/ml | 23.1% | 9.6% | |
| Pre-KT calcium ≥10 mg/dl | 26.4% | 14.2% | <0.001 |
| Pre-KT vitamin D ≤30 ng/ml | 72.3% | 71.5% | 1.00 |
| Post-KT vitamin D ≤30 ng/ml | 72.4% | 53.2% | <0.001 |
| Peak PRA (%), median (IQR) | 4.0 (0.0, 60.0) | 6.0 (0.0, 48.0) | 0.76 |
| Transplant Characteristics | |||
| Deceased donor | 69.2% | 64.6% | 0.24 |
| Donor age (years), mean (SD) | 37.6 (13.8) | 38.8 (15.4) | 0.33 |
| Cold ischemia time (hours), median (IQR) | 18.0 (4.6, 30.0) | 18.0 (2.5, 28.7) | 0.35 |
| Transplantation year | |||
| 2008-2011 | 24.2% | 28.7% | 0.11 |
| 2012-2015 | 46.7% | 49.4% | |
| 2016-2019 | 29.1% | 21.9% |
KT, kidney transplant; PTH, parathyroid hormone; THPT, tertiary hyperparathyroidism; SHPT, secondary hyperparathyroidism; BMI, body mass index; PRA, panel reactive antigen; SD, standard deviation; IQR, interquartile range.
Risk Factors for THPT Among KT Recipients
Patients who were treated with calcimimetics for HPT prior to KT had a 1.30-fold higher risk of developing persistent HPT (aPR=1.30, 95%CI: 1.12-1.51) and a 1.84-fold higher risk of developing THPT (aPR=1.84, 95%CI: 1.25-2.72) at one-year post-KT. Patients with a pre-KT PTH level of 300-599pg/ml were more likely to develop persistent HPT and THPT (aPR=1.49, 95%CI: 1.19-1.85 and aPR=2.21, 95%CI: 1.19-3.90, respectively), as were patients with a pre-KT level ≥600pg/ml (aPR=1.44, 95%CI: 1.14-1.81 and aPR=2.21, 95%CI: 1.19-4.08, respectively). Patients with post-KT Vitamin D ≤30 ng/ml had a 1.30-fold increased risk of developing persistent HPT (aPR=1.30, 95%CI: 1.15-1.46) and a 1.61-fold increased risk of developing THPT (aPR-1.61, 95%CI: 1.18-2.18). College education was found to be associated with persistent HPT and THPT (aPR=1.13, 95%CI: 1.01-1.27 and aPR=1.38, 95%CI: 1.05-1.83, respectively).
Patients were more likely to develop THPT, but not persistent HPT, if they had biochemical evidence of THPT prior to KT (aPR=1.71, 95%CI: 1.29-2.27).
Patients were more likely to develop persistent HPT, but not THPT, if they were of Black race (aPR=1.14, 95%CI: 1.02-1.28) or had a pre-KT PTH 100-299 pg/ml (aPR=1.26, 95%CI: 1.01-1.56) (Table 2).
Table 2: Risk Factors for Development of Persistent Hyperparathyroidism (HPT) and Tertiary Hyperparathyroidism (THPT) among Kidney Transplant Recipients.
Persistent HPT was defined as PTH level ≥70 pg/ml at 1-year post-KT. THPT was defined as PTH level ≥70 pg/ml (hyperparathyroidism) and calcium ≥10 mg/dl (hypercalcemia) at 1-year post-KT. Adjusted prevalence ratios (aPRs) and 95% confidence intervals (CIs) are presented from modified Poisson models. Models adjusted for pre-KT THPT, pre-KT treatment (vs. no treatment), pre-KT PTH level (vs. <100 pg/ml), post-KT vitamin D ≤30 ng/ml, age at KT, sex, Black, college education, BMI, cause of kidney failure (vs. glomerulonephritis), time on dialysi history of hypertension, peak PRA, and cold ischemia time. Associations that are statistically significant at p<0.05 are bolded.
| Risk factors | Persistent HPT (n=849) aPR (95% CI) |
THPT (n=848) aPR (95% CI) |
|---|---|---|
| Pre-KT THPT | 1.13 (1.00, 1.28) | 1.71 (1.29, 2.27) |
| Pre-KT treatment for HPT | ||
| Calcimimetics | 1.30 (1.12, 1.51) | 1.84 (1.25, 2.72) |
| Parathyroidectomy | 1.29 (1.02, 1.63) | 0.94 (0.43, 2.07) |
| Supplementation | 0.91 (0.78, 1.06) | 0.87 (0.59, 1.28) |
| Pre-KT PTH level | ||
| 100-299 pg/ml | 1.26 (1.01, 1.56) | 1.24 (0.70, 2.19) |
| 300-599 pg/ml | 1.49 (1.19, 1.85) | 2.21 (1.25, 3.90) |
| ≥600 pg/ml | 1.44 (1.14, 1.81) | 2.21 (1.19, 4.08) |
| Post-KT vitamin D ≤30 ng/ml | 1.30 (1.15, 1.46) | 1.61 (1.18, 2.18) |
| Age at KT, per 5 years | 1.02 (1.00, 1.04) | 1.03 (0.98, 1.08) |
| Female | 0.91 (0.81, 1.02) | 0.75 (0.56, 1.00) |
| Black | 1.14 (1.02, 1.28) | 1.08 (0.82, 1.42) |
| Attended college | 1.13 (1.01, 1.27) | 1.38 (1.05, 1.83) |
| BMI, per 5 kg/m2 | 1.04 (0.99, 1.09) | 0.93 (0.83, 1.04) |
| Cause of kidney failure | ||
| Diabetes mellitus | 1.06 (0.89, 1.26) | 1.18 (0.76, 1.84) |
| Hypertension | 1.09 (0.94, 1.25) | 1.31 (0.91, 1.90) |
| Other | 0.98 (0.84, 1.14) | 1.20 (0.82, 1.75) |
| Time on dialysis, per 3 years | 1.00 (0.98, 1.03) | 1.03 (0.99, 1.09) |
| History of hypertension | 1.04 (0.82, 1.32) | 1.68 (0.73, 3.85) |
| Peak PRA, per 10% | 1.01 (0.99, 1.03) | 0.98 (0.94, 1.03) |
| Cold ischemia time, per 2 hours | 1.00 (0.99, 1.00) | 1.00 (0.98, 1.02) |
KT, kidney transplant; PTH, parathyroid hormone; THPT, tertiary hyperparathyroidism; SHPT, secondary hyperparathyroidism; BMI, body mass index; PRA, panel reactive
Patient Characteristics and Risk Factors for THPT in Sensitivity Analysis
There were 68 patients with possibly masked THPT. When added to the patients categorized as THPT on main analysis, it is estimated that up to 250 (29.5%) patients had THPT at one-year post-KT.
Similar to the findings in our main analysis, increased risk of development of THPT on sensitivity analysis was associated with pre-KT THPT (aPR=1.57, 95%CI: 1.27-1.95), use of calcimimetics (aPR=2.07, 95%CI: 1.51-2.84), and PTH level 300-599 pg/ml (aPR=2.23, 95%CI: 1.37-3.61) and ≥600 pg/ml (aPR=2.28, 95%CI: 1.37-3.80), as well as post-KT Vitamin D deficiency (aPR=1.51, 95%CI: 1.19-1.91), and college attendance (aPR=1.32, 95%CI: 1.06-1.64). Increased risk of development of THPT in the sensitivity analysis was additionally associated with male sex (aPR=1.30, 95%CI: 1.04-1.61), increased time on dialysis pre-KT (aPR=1.04, 95%CI: 1.002-1.07), and pre-KT parathyroidectomy (aPR=1.78, 95%CI: 1.18-2.68) (Supplemental Table 1).
Discussion:
In this longitudinal, prospective cohort study of adult KT recipients, 61.7% of patients had persistent HPT and 21.5% had THPT one-year post-KT. After KT, only 27.0% of patients with persistent HPT received any treatment, of which only 11.3% underwent parathyroidectomy; and only 38.5% of those with THPT received any treatment, of which only 15.7% underwent parathyroidectomy. Risk factors for the development of both persistent HPT and THPT post-KT included the use of calcimimetics to treat HPT prior to KT and pre-KT PTH level ≥300pg/ml. These findings elucidate the high prevalence and undertreatment of persistent and tertiary hyperparathyroidism in KT recipients and identify clinically modifiable pre-KT risk factors associated with development of THPT.
The reported prevalence of THPT varies widely across the literature, ranging from 10-70%1, 2, 11, 12. The large difference in reported prevalence is partially attributed to the range of definitions of THPT. In order to comprehensively examine the prevalence of post-KT hyperparathyroidism in our prospective cohort, we utilized two definitions: all patients with persistent hyperparathyroidism at one-year post-KT (61.7%) and patients with both hyperparathyroidism and hypercalcemia at one-year post-KT (21.5%). The importance of these findings is two-fold. First, given its associated morbidity and mortality, the prevalence of HPT in KT recipients is exceedingly high by both definitions3. Second, while the prevalence of both persistent HPT and THPT in our study fall within the range of prevalence reported by other studies, there is a three-fold difference in measured prevalence for the same cohort depending on the incorporation of hypercalcemia into the definition. Patients taking calcimimetics post-KT will have lower calcium measurements due to medication effect, and therefore may not be classified as or treated for THPT. In our study, there were an additional 8.0% of patients with normocalcemic, persistent HPT on calcimimetics that may be misclassified if calcimimetics were not held for diagnostic labs. This encourages the establishment of a clinically relevant, standardized characterization of THPT to reduce its underdiagnosis and subsequent undertreatment.
The gold standard treatment of THPT is parathyroidectomy, however management recommendations for normocalcemic KT recipients with persistent HPT is less clear. Strikingly, in our cohort, 73.0% of patients with persistent HPT at one-year post-KT were not treated, and only 3.0% eventually underwent parathyroidectomy, while the remainder received calcimimetics only. For patients with THPT, 61.5% received no treatment, 6.0% underwent parathyroidectomy, and 32.4% received calcimimetics only. These treatment patterns are similarly low to those reported in a recent study by Lou, et. al, who reported a 15% rate of parathyroidectomy for treatment18. Additionally, although calcimimetics were frequently used in this population, they are not approved by the Food and Drug Administration (FDA) for treatment of THPT. While we measured lab values for diagnosis of THPT at one-year post-KT, many transplant nephrologists historically waited at least one-year post-KT for normalization of PTH and calcium before considering treatment19. However, multiple studies have found that earlier surgical referral prior to one-year post-KT improves long-term allograft function. Isakov and colleagues demonstrated that persistently elevated PTH levels as early as three months post-KT portended worse allograft function1, 10, 20. Therefore, early detection and referral for THPT should be prioritized, as well as prevention if possible.
Prior to KT, 92.0% of study participants had HPT, of which 77.3% were SHPT and 14.7% were THPT. In patients with kidney failure, it is often assumed that elevated PTH values pre-KT are due to SHPT. However, while KT can cure some patients of SHPT, the only definitive management of THPT pre- or post-KT is parathyroidectomy1, 21. Pre-KT THPT is associated with a 1.71-fold increased risk of post-KT THPT, which could be prevented by its recognition and treatment prior to transplantation.
Similar to other studies, we found that increased pre-KT PTH levels were associated with a higher likelihood of persistent HPT and THPT post-KT22-24. While prior studies identified the relationship between increasing pre-KT PTH levels and THPT, we additionally identified a significant threshold value of pre-KT PTH ≥ 300pg/mL. Current practice guidelines by Kidney Diseases Improving Global Outcomes (KDIGO) recommend treatment of SHPT to maintain a PTH level at 2-9 times the normal range, which translates roughly to an upper limit of close to 600pg/mL25. However, titrating treatment for SHPT to maintain a lower PTH threshold may mitigate the development of THPT and its adverse sequelae.
The use of calcimimetics for treatment of HPT prior to KT was also associated with both persistent HPT and THPT at one-year post-KT. The use of calcimimetics to treat SHPT has progressively increased since the FDA approval of the first oral tablet in 2004 and the intravenous form in 2015. However, side effects from calcimimetics often hinder their utilization and subsequent effectiveness26. Only 43% of patients reach target PTH levels as recommended by KDIGO 26-28. Additionally, other studies have similarly found a “rebound” effect of cessation of calcimimetics at the time of KT that leads to subsequent hyperparathyroidism and hypercalcemia29, 30. For some patients, this rebound effect may have been a result of masked THPT prior to KT. In contrast, patients who underwent parathyroidectomy for, likely refractory, SHPT prior to KT were not more likely to develop THPT. Contrary to other studies, longer pre-KT dialysis vintage was not associated with persistent HPT or THPT23, 24.
Black patients were 1.14-fold more likely to develop persistent HPT one-year post-KT compared to patients of other races, representing a racial disparity for this disease that has been similarly described in prior studies31, 32. Black patients with and without end-stage renal disease have higher levels of circulating PTH compared to patients of other races, and our findings are consistent with this data31, 32. Interestingly, college education, as a surrogate measurement for socioeconomic status, was associated with an increased risk of developing both persistent HPT and THPT. This could be in part due to increased use of and adherence to cinacalcet pre-KT among patients of higher socioeconomic status, whereas patients of lower socioeconomic status more frequently undergo parathyroidectomy33, 34.
There are several limitations to this study in addition to those inherent to electronic medical record and database abstraction including missing values and PTH assay variability, although the highly elevated levels of PTH and categorization of lab values minimize the risk of misclassification. There may have been confounding by indication in the treatment of pre-KT HPT, and post-KT HPT and THPT, as the factors that led to treatment decisions may not have been accounted for, such as severity of symptoms. Additionally, study participants are from a single institution and therefore generalizability of these findings cannot be certain, and the demographics of our cohort must be taken into consideration. This study additionally has several important strengths including large sample size, prospective data collection, and patient-specific follow-up utilizing data from SRTR and medical records, allowing for the incorporation of both patient and transplant-related factors in our analysis.
In conclusion, the prevalence of persistent HPT and THPT at one-year post-KT was 61.7% and 21.5%, respectively, and the majority of patients were not treated despite the increased risk of graft failure, cardiovascular morbidity, bone loss, and mortality. These findings encourage the re-evaluation of recommended pre-KT PTH thresholds and the consideration of pre-KT parathyroidectomy to avoid the adverse sequelae of THPT in KT recipients.
Supplementary Material
Funding/Support:
The data collection and analytic staff were supported by Dr. Mara McAdams-DeMarco’s NIH grant, R01AG055781. Additional funding and support were provided by T32CA126607 (Sutton), K23AG053429 (Mathur), R01DK120518 (McAdams-DeMarco), R01DK114074 (McAdams-DeMarco), R01DK111233 (Segev), and K24AI144954 (Segev).
Footnotes
COI/Disclosures:
The authors have no conflicts of interest nor other funding sources to report.
Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
References:
- 1.Lou I, Foley D, Odorico SK, Leverson G, Schneider DF, Sippel R, et al. How Well Does Renal Transplantation Cure Hyperparathyroidism? Ann Surg. 2015;262:653–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Evenepoel P Recovery versus persistence of disordered mineral metabolism in kidney transplant recipients. Semin Nephrol. 2013;33:191–203. [DOI] [PubMed] [Google Scholar]
- 3.Pihlstrom H, Dahle DO, Mjoen G, Pilz S, Marz W, Abedini S, et al. Increased risk of all-cause mortality and renal graft loss in stable renal transplant recipients with hyperparathyroidism. Transplantation. 2015;99:351–9. [DOI] [PubMed] [Google Scholar]
- 4.Araujo M, Ramalho JAM, Elias RM, Jorgetti V, Nahas W, Custodio M, et al. Persistent hyperparathyroidism as a risk factor for long-term graft failure: the need to discuss indication for parathyroidectomy. Surgery. 2018;163:1144–50. [DOI] [PubMed] [Google Scholar]
- 5.Cruzado JM, Moreno P, Torregrosa JV, Taco O, Mast R, Gomez-Vaquero C, et al. A Randomized Study Comparing Parathyroidectomy with Cinacalcet for Treating Hypercalcemia in Kidney Allograft Recipients with Hyperparathyroidism. J Am Soc Nephrol. 2016;27:2487–94. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.See A, Lim AEL, Wong J, Choong HL, Iyer NG, Tan HK, et al. The effect of parathyroidectomy on patients' symptoms in tertiary hyperparathyroidism. Head Neck. 2019;41:2748–55. [DOI] [PubMed] [Google Scholar]
- 7.Pitt SC, Sippel RS, Chen H. Secondary and tertiary hyperparathyroidism, state of the art surgical management. Surg Clin North Am. 2009;89:1227–39. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Pitt SC, Panneerselvan R, Chen H, Sippel RS. Tertiary hyperparathyroidism: is less than a subtotal resection ever appropriate? A study of long-term outcomes. Surgery. 2009;146:1130–7. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Pitt SC, Panneerselvan R, Chen H, Sippel RS. Secondary and tertiary hyperparathyroidism: the utility of ioPTH monitoring. World J Surg. 2010;34:1343–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Dream S, Chen H, Lindeman B. Tertiary Hyperparathyroidism: Why the Delay? Ann Surg. 2020. [DOI] [PubMed] [Google Scholar]
- 11.Dulfer RR, Franssen GJH, Hesselink DA, Hoorn EJ, van Eijck CHJ, van Ginhoven TM. Systematic review of surgical and medical treatment for tertiary hyperparathyroidism. Br J Surg. 2017;104:804–13. [DOI] [PubMed] [Google Scholar]
- 12.Tseng PY, Yang WC, Yang CY, Tarng DC. Long-term Outcomes of Parathyroidectomy in Kidney Transplant Recipients with Persistent Hyperparathyroidism. Kidney Blood Press Res. 2015;40:386–94. [DOI] [PubMed] [Google Scholar]
- 13.Evenepoel P, Claes K, Kuypers D, Maes B, Bammens B, Vanrenterghem Y. Natural history of parathyroid function and calcium metabolism after kidney transplantation: a single-centre study. Nephrol Dial Transplant. 2004;19:1281–7. [DOI] [PubMed] [Google Scholar]
- 14.Finnerty BM, Chan TW, Jones G, Khader T, Moore M, Gray KD, et al. Parathyroidectomy versus Cinacalcet in the Management of Tertiary Hyperparathyroidism: Surgery Improves Renal Transplant Allograft Survival. Surgery. 2019;165:129–34. [DOI] [PubMed] [Google Scholar]
- 15.Roodnat JI, van Gurp EA, Mulder PG, van Gelder T, de Rijke YB, de Herder WW, et al. High pretransplant parathyroid hormone levels increase the risk for graft failure after renal transplantation. Transplantation. 2006;82:362–7. [DOI] [PubMed] [Google Scholar]
- 16.Callender GG, Malinowski J, Javid M, Zhang Y, Huang H, Quinn CE, et al. Parathyroidectomy prior to kidney transplant decreases graft failure. Surgery. 2017;161:44–50. [DOI] [PubMed] [Google Scholar]
- 17.Bozdogan H Akaike's Information Criterion and Recent Developments in Information Complexity. J Math Psychol. 2000;44:62–91. [DOI] [PubMed] [Google Scholar]
- 18.Lou I, Schneider DF, Leverson G, Foley D, Sippel R, Chen H. Parathyroidectomy is underused in patients with tertiary hyperparathyroidism after renal transplantation. Surgery. 2016;159:172–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Triponez F, Clark OH, Vanrenthergem Y, Evenepoel P. Surgical treatment of persistent hyperparathyroidism after renal transplantation. Ann Surg. 2008;248:18–30. [DOI] [PubMed] [Google Scholar]
- 20.Isakov O, Ghinea R, Beckerman P, Mor E, Riella LV, Hod T. Early persistent hyperparathyroidism post-renal transplantation as a predictor of worse graft function and mortality after transplantation. Clin Transplant. 2020;34:e14085. [DOI] [PubMed] [Google Scholar]
- 21.Callender GG, Carling T, Christison-Lagay E, Udelsman R. Chapter 65 - Surgical Management of Hyperparathyroidism. Endocrinology: Adult and Pediatric. 7th ed: Elsevier Inc.; 2016. p. 1135–46. [Google Scholar]
- 22.Dewberry LC, Tata S, Graves S, Weber CJ, Sharma J. Predictors of tertiary hyperparathyroidism: Who will benefit from parathyroidectomy? Surgery. 2014;156:1631–6; discussion 6-7. [DOI] [PubMed] [Google Scholar]
- 23.Kirnap NG, Kirnap M, Sayin B, Akdur A, Bascil Tutuncu N, Haberal M. Risk Factors and Treatment Options for Persistent Hyperparathyroidism After Kidney Transplantation. Transplant Proc. 2020;52:157–61. [DOI] [PubMed] [Google Scholar]
- 24.Yamamoto T, Tominaga Y, Okada M, Hiramitsu T, Tsujita M, Goto N, et al. Characteristics of Persistent Hyperparathyroidism After Renal Transplantation. World J Surg. 2016;40:600–6. [DOI] [PubMed] [Google Scholar]
- 25.Kidney Disease: Improving Global Outcomes CKDMBDUWG. KDIGO 2017 Clinical Practice Guideline Update for the Diagnosis, Evaluation, Prevention, and Treatment of Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD). Kidney Int Suppl (2011). 2017;7:1–59. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Roggeri A, Conte F, Rossi C, Cozzolino M, Zocchetti C, Roggeri DP. Cinacalcet adherence in dialysis patients with secondary hyperparathyroidism in Lombardy Region: clinical implications and costs. Drugs Context. 2020;9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Block GA, Martin KJ, de Francisco AL, Turner SA, Avram MM, Suranyi MG, et al. Cinacalcet for secondary hyperparathyroidism in patients receiving hemodialysis. N Engl J Med. 2004;350:1516–25. [DOI] [PubMed] [Google Scholar]
- 28.Block GA, Bushinsky DA, Cheng S, Cunningham J, Dehmel B, Drueke TB, et al. Effect of Etelcalcetide vs Cinacalcet on Serum Parathyroid Hormone in Patients Receiving Hemodialysis With Secondary Hyperparathyroidism: A Randomized Clinical Trial. JAMA. 2017;317:156–64. [DOI] [PubMed] [Google Scholar]
- 29.Sharma AK, Masterson R, Holt SG, Tan SJ, Hughes PD, Chu M, et al. Impact of cinacalcet pre-transplantation on mineral metabolism in renal transplant recipients. Nephrology (Carlton). 2016;21:46–54. [DOI] [PubMed] [Google Scholar]
- 30.Evenepoel P, Sprangers B, Lerut E, Bammens B, Claes K, Kuypers D, et al. Mineral metabolism in renal transplant recipients discontinuing cinacalcet at the time of transplantation: a prospective observational study. Clin Transplant. 2012;26:393–402. [DOI] [PubMed] [Google Scholar]
- 31.Omije D, Norris K, Wang J, Pan D, Kermah D, Gupta A. Race is a major determinant of secondary hyperparathyroidism in uremic patients: comparative study of Blacks and Hispanics. Clin Nephrol. 2008;70:312–8. [DOI] [PubMed] [Google Scholar]
- 32.Kalantar-Zadeh K, Miller JE, Kovesdy CP, Mehrotra R, Lukowsky LR, Streja E, et al. Impact of race on hyperparathyroidism, mineral disarrays, administered vitamin D mimetic, and survival in hemodialysis patients. J Bone Miner Res. 2010;25:2724–34. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33.Greene B, Kim SJ, McCarthy EP, Pasternak JD. Effects of Social Disparities on Management and Surgical Outcomes for Patients with Secondary Hyperparathyroidism. World J Surg. 2020;44:537–43. [DOI] [PubMed] [Google Scholar]
- 34.Reams BD, Dluzniewski PJ, Do TP, Yue SV, Bradbury BD, Kshirsagar AV, et al. Dynamics of cinacalcet use and biochemical control in hemodialysis patients: a retrospective New-user cohort design. BMC Nephrol. 2015;16:175. [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.