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Hyperparathyroidism at 1 year after kidney transplantation is associated with graft loss

Open AccessPublished:October 14, 2022DOI:https://doi.org/10.1016/j.surg.2022.07.031

      Abstract

      Background

      Hyperparathyroidism persists in many patients after kidney transplantation. The purpose of this study was to evaluate the association between post-transplant hyperparathyroidism and kidney transplantation outcomes.

      Methods

      We identified 824 participants from a prospective longitudinal cohort of adult patients who underwent kidney transplantation at a single institution between December 2008 and February 2020. Parathyroid hormone levels before and after kidney transplantation were abstracted from medical records. Post-transplant hyperparathyroidism was defined as parathyroid hormone level ≥70 pg/mL 1 year after kidney transplantation. Cox proportional hazards models were used to estimate the adjusted hazard ratios of mortality and death-censored graft loss by post-transplant hyperparathyroidism. Models were adjusted for age, sex, race/ethnicity, college education, parathyroid hormone level before kidney transplantation, cause of kidney failure, and years on dialysis before kidney transplantation. A Wald test for interactions was used to evaluate the risk of death-censored graft loss by age, sex, and race.

      Results

      Of 824 recipients, 60.9% had post-transplant hyperparathyroidism. Compared with non-hyperparathyroidism patients, those with post-transplant hyperparathyroidism were more likely to be Black (47.2% vs 32.6%), undergo dialysis before kidney transplantation (86.9% vs 76.6%), and have a parathyroid hormone level ≥300 pg/mL before kidney transplantation (26.8% vs 9.5%) (all P < .001). Patients with post-transplant hyperparathyroidism had a 1.6-fold higher risk of death-censored graft loss (adjusted hazard ratio = 1.60, 95% confidence interval: 1.02–2.49) compared with those without post-transplant hyperparathyroidism. This risk more than doubled in those with parathyroid hormone ≥300 pg/mL 1 year after kidney transplantation (adjusted hazard ratio = 4.19, 95% confidence interval: 1.95–9.03). The risk of death-censored graft loss did not differ by age, sex, or race (all Pinteraction > .05). There was no association between post-transplant hyperparathyroidism and mortality.

      Conclusion

      The risk of graft loss was significantly higher among patients with post-transplant hyperparathyroidism when compared with patients without post-transplant hyperparathyroidism.

      Introduction

      Hyperparathyroidism is present in the majority of patients at the time of kidney transplant (KT) and typically resolves within 1 year of successful KT in many patients.
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      However, recent studies have demonstrated that hyperparathyroidism can persist in ≤60% of patients at 1-year post-KT.
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      Prevalence and risk factors for tertiary hyperparathyroidism in kidney transplant recipients.
      Post-transplant hyperparathyroidism, or elevated parathyroid hormone (PTH) levels >1 year post-KT, is multifactorial and encompasses both secondary and tertiary hyperparathyroidism. Pretransplant risk factors for developing post-transplant hyperparathyroidism include prolonged length of dialysis, obesity, calcimimetic use, pretransplant PTH levels ≥300 pg/mL, and hypercalcemia at the time of KT.
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      How well does renal transplantation cure hyperparathyroidism?.
      Data regarding the impact of post-transplant hyperparathyroidism on KT outcomes are conflicting. Although several studies have found that normalization of PTH levels post-KT may be associated with improved graft function,
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      Increased risk of all-cause mortality and renal graft loss in stable renal transplant recipients with hyperparathyroidism.
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      others have not identified a relationship between post-transplant hyperparathyroidism and transplant outcomes.
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      These mixed results may arise from varying definitions of post-transplant hyperparathyroidism, discrepancies in the timing of PTH measurement post-KT, differing sample sizes, variation in study populations, differentiation of types of hyperparathyroidism, and variations in post-KT outcomes assessed. Finally, limited evidence exists regarding whether the adverse transplant outcomes identified are mediated by calcium, vitamin D deficiency, or PTH.
      Recommendations from Kidney Disease: Improving Global Outcomes are vague regarding the length of time post-KT that PTH should be measured.
      Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD Work Group
      KDIGO clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of Chronic Kidney Disease–Mineral and Bone Disorder (CKD-MBD).
      Furthermore, Kidney Disease: Improving Global Outcomes cites a low quality of evidence provided for the guidelines regarding the treatment of hyperparathyroidism post-KT and does not offer recommendations for the management of hyperparathyroidism beyond the first 12 months after transplant.
      Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD Work Group
      KDIGO clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of Chronic Kidney Disease–Mineral and Bone Disorder (CKD-MBD).
      As a result, treatment for post-transplant hyperparathyroidism is often delayed.
      • Dream S.
      • Chen H.
      • Lindeman B.
      Tertiary hyperparathyroidism: why the delay?.
      Understanding the impact of elevated PTH levels on KT outcomes may help guide treatment for those patients who have post-transplant hyperparathyroidism. Therefore, the purpose of this study was to evaluate the association between post-transplant hyperparathyroidism, irrespective of calcium or vitamin D levels, on both graft loss and mortality. We also sought to identify the subgroups most at risk for these adverse outcomes.

      Methods

      Study population and design

      Under institutional review board approval, we leveraged a longitudinal prospective cohort study of 1,236 adult (age ≥18 years) KT recipients enrolled at admission for KT at the Johns Hopkins Hospital, Baltimore, Maryland (Dec 2008 to Feb 2020). Patient characteristics including age, sex, race, ethnicity, education, body mass index, dialysis pre-KT, and years on dialysis were self-reported, measured, or abstracted from medical records at time of enrollment. All recipients were linked to the Scientific Registry of Transplant Recipients (SRTR) to ascertain post-transplant outcomes of graft loss and death. The SRTR includes data on all donor and transplant recipients in the United States, submitted by members of the Organ Procurement and Transplant Network.
      • Massie A.B.
      • Kucirka L.M.
      • Segev D.L.
      Big data in organ transplantation: registries and administrative claims.
      Additional characteristics ascertained from SRTR included cause of end-stage renal disease (ESRD) and donor type.
      We retrospectively abstracted lab results of PTH, calcium, and vitamin D levels pre-KT and at 1-year post-KT for each recipient from medical records. After a chart review, a total of 845 recipients had a PTH level measured at a median of 1-year post-KT (IQR = 0.9–1.2 years). In order to include only those with functioning grafts at 1-year post-KT, we excluded recipients who had graft loss within 1 year of KT (n = 21) for a final sample size of 824 participants. These patients were followed for a median of 6.9 (IQR = 5.2–9.0) years.

      Definitions

      A PTH level <70 pg/mL is considered normal at the health care system where transplants took place. Therefore, post-transplant hyperparathyroidism was defined as PTH ≥70 pg/mL at 1-year post-KT. This definition encompassed patients with both secondary hyperparathyroidism, defined as PTH ≥70 pg/mL and calcium <10 mg/dL; and tertiary hyperparathyroidism, defined as patients with PTH ≥70 pg/mL and calcium ≥10 mg/dL. Patients with both secondary and tertiary hyperparathyroidism were included to be consistent with nephrology literature. Those without post-transplant hyperparathyroidism were defined as patients with a PTH level <70 pg/mL at 1-year post-KT. This included patients with preoperative hyperparathyroidism who subsequently experienced normalization of PTH levels to <70 pg/mL within 1-year post-KT. Hypercalcemia was defined as calcium level ≥10 mg/dL, and vitamin D deficiency was defined as vitamin D 25-OH level ≤30 ng/mL.
      All recipients were followed for graft loss until death or administrative censoring (Oct 2021). The primary exposure was the presence of post-transplant hyperparathyroidism, classified as a binary variable. Because several nephrology guidelines recommend maintaining a pretransplant PTH level <300 pg/mL in patients with ESRD,
      K/DOQI clinical practice guidelines for bone metabolism and disease in chronic kidney disease.
      ,
      • Kazama J.J.
      Japanese Society of Dialysis Therapy treatment guidelines for secondary hyperparathyroidism.
      a secondary analysis was performed in which those with post-transplant hyperparathyroidism were further stratified as having a PTH level either 70 to 299 pg/mL or ≥300 pg/mL. The outcomes of interest were all-cause mortality, all-cause graft loss, and death-censored graft loss (DCGL). All-cause graft loss was defined as graft loss for any cause (including return to dialysis, retransplant, and death), and DCGL was defined as graft loss due to any cause other than death. Each of these outcomes was ascertained through SRTR. The time to event was defined as the period from receipt of KT to date of event or end of follow-up.

      Statistical analysis

      The differences in patient and clinical characteristics by post-transplant hyperparathyroidism were tested using analysis of variance tests for normally distributed continuous variables, Kruskal-Wallis tests for non-normally distributed continuous variables, and Fisher exact tests for the categorical variables.
      The cumulative incidence of each outcome of interest was estimated using the Kaplan-Meier method, and the unadjusted survival curves were compared using log-rank tests. After verifying the proportional hazard assumptions by visually inspecting log-log plots, the association between hyperparathyroidism and post-KT outcomes was assessed using adjusted Cox proportional hazard models. Models were adjusted for older age (≥65 years), sex, Black race, college education, high PTH level pre-KT (≥300 pg/mL), cause of ESRD, and years on dialysis. The primary analysis evaluated post-transplant hyperparathyroidism as a binary variable, whereas the secondary analysis evaluated categorical PTH levels <70 pg/mL, 70 to 299 pg/mL, and ≥300 pg/mL. We tested whether associations between post-transplant hyperparathyroidism and transplant outcomes differed by age, sex, or race by including an interaction term between post-transplant hyperparathyroidism and each factor in separate models; a Wald test was used to determine whether these associations were significant. Furthermore, we estimated the association between post-transplant hyperparathyroidism and each outcome within age, sex, and race subgroups.
      We imputed the missing values for all covariates using multiple imputation method with 10 iterations for all regression analyses. All analyses were performed using Stata version 15 (StataCorp, College Station, TX).

      Results

      Participant characteristics

      The 824 KT recipients had a mean age of 53.2 years (SD = 13.6) at the time of KT. Of these patients, 39.8% were female, 41.5% were Black, 2.8% were Hispanic, and 68.6% had a college education. The most common cause of ESRD was hypertension (31.9%), followed by glomerulonephritis (26.2%). A majority of the cohort (82.9%) underwent dialysis pre-KT with a median time on dialysis of 2.7 years (IQR = 0.6–5.5). Most of the patients (65.2%) received a deceased donor KT. Pre- KT, 15.3% of patients had PTH levels <100 pg/mL, and 36.2% had PTH levels ≥300 pg/mL (Table I).
      Table ICharacteristics of KT recipients at admission for KT by post-KT post-transplant HPT
      CharacteristicOverall (n = 824)HPT status 1-year post-KTP value
      No post-transplant HPT (n = 322)Post-transplant HPT (n = 502)
      Age at KT, mean (SD)53.2 (13.6)53.0 (14.1)53.4 (13.3).69
      Female, %328 (39.8%)137 (42.5%)191 (38.0%).20
      Race/ethnicity, %
       White405 (49.2%)177 (55.0%)228 (45.4%)< .001
       Black342 (41.5%)105 (32.6%)237 (47.2%)
       Hispanic23 (2.8%)9 (2.8%)14 (2.8%)
       Other54 (6.6%)31 (9.6%)23 (4.6%)
       College education, %565 (68.6%)217 (67.4%)348 (69.3%).56
       BMI, mean (SD)27.2 (5.5)26.4 (5.2)27.7 (5.6)< .001
      Cause of ESRD, %
       Glomerulonephritis215 (26.2%)90 (28.0%)125 (25.0%).005
       Diabetes mellitus136 (16.5%)51 (15.9%)85 (17.0%)
       Hypertension262 (31.9%)82 (25.5%)180 (35.9%)
       Other209 (25.4%)98 (30.5%)111 (22.2%)
       Pre-KT dialysis, %682 (82.9%)246 (76.6%)436 (86.9%)< .001
       Years on dialysis, median (IQR)2.7 (0.6, 5.5)1.6 (0.1, 4.1)3.6 (1.2, 6.2)< .001
       Deceased donor KT, %537 (65.2%)201 (62.4%)336 (66.9%).18
      Pre-KT PTH level, %
       <100 pg/mL118 (15.3%)70 (23.1%)48 (10.2%)< .001
       100–299 pg/mL355 (46.0%)155 (51.2%)200 (42.6%)
       300–599 pg/mL203 (26.3%)57 (18.8%)146 (31.1%)
       ≥600 pg/mL96 (12.4%)21 (6.9%)75 (16.0%)
       Pre-KT hypercalcemia,
      Post-KT hypercalcemia was defined as calcium level ≥10 mg/dL at 1-year post-KT.
      %
      132 (16.4%)43 (13.4%)89 (18.4%).061
       Pre-KT vitamin D deficiency,
      Post-KT vitamin D deficiency was defined as vitamin D level ≤30 ng/mL at 1-year post-KT.
      %
      152 (71.4%)58 (64.4%)94 (76.4%).056
       Pre-KT parathyroidectomy, %25 (3.0%)6 (1.9%)19 (3.8%).12
       Post-KT hypercalcemia,
      Post-KT hypercalcemia was defined as calcium level ≥10 mg/dL at 1-year post-KT.
      %
      243 (29.5%)63 (19.6%)180 (35.9%)< .001
       Post-KT vitamin D deficiency,
      Post-KT vitamin D deficiency was defined as vitamin D level ≤30 ng/mL at 1-year post-KT.
      %
      448 (56.5%)135 (43.1%)313 (65.2%)< .001
      Post-KT treatment for HPT, %
       None673 (81.8%)302 (93.8%)371 (74.1%)< .001
       Calcimimetics132 (16.0%)16 (5.0%)116 (23.2%)
       Parathyroidectomy10 (1.2%)3 (0.9%)7 (1.4%)
       Both8 (1.0%)1 (0.3%)7 (1.4%)
      Post-transplant HPT was defined as PTH level ≥70 pg/mL at 1-year post-KT.
      BMI, body mass index; ESRD, end-stage renal disease; HPT, hyperparathyroidism; KT, kidney transplant; PTH, parathyroid hormone.
      Post-KT hypercalcemia was defined as calcium level ≥10 mg/dL at 1-year post-KT.
      Post-KT vitamin D deficiency was defined as vitamin D level ≤30 ng/mL at 1-year post-KT.
      Among the entire cohort, 60.9% of patients had post-transplant hyperparathyroidism, or PTH level ≥70 pg/mL at 1-year post-KT. Compared to those without post-transplant hyperparathyroidism, patients with post-transplant hyperparathyroidism were more likely to be Black (47.2% vs 32.6%, P < .001), have a higher body mass index (27.7 vs 26.4 kg/m2, P < .001), receive dialysis pre-KT (86.9% vs 76.6%, P < .001), and have hypertension as the cause of ESRD (35.9% vs 25.5%, P = .005). Additionally, 3.8% of patients with post-transplant hyperparathyroidism and 1.9% of patients without post-transplant hyperparathyroidism underwent parathyroidectomy pre-KT (P = .12). Patients with post-transplant hyperparathyroidism had higher PTH levels pre-KT and were more likely to have hypercalcemia (35.9% vs 19.6%, P < .001) and vitamin D deficiency (65.2% vs 43.1%, P < .001) at 1-year post-KT. Compared to patients without post-transplant hyperparathyroidism, patients with post-transplant hyperparathyroidism were more likely to undergo treatment with calcimimetics (23.3% vs 5.0%), parathyroidectomy (1.4% vs 0.9%), or both (1.4% vs. 0.3%) post-KT (all P < .001) (Table I).

      Mortality

      Among the entire cohort, 19.1% (n = 157) of patients died during the follow-up period. The cumulative incidence of mortality was similar when comparing patients with and without post-transplant hyperparathyroidism (log-rank P = .13) (Figure 1, A). After adjusting for all covariates, post-transplant hyperparathyroidism was not associated with all-cause mortality (aHR = 1.35, 95% CI: 0.96–1.91) (Table II).
      Figure thumbnail gr1
      Figure 1Cumulative incidence of (A) all-cause mortality, (B) all-cause graft loss, and (C) death-censored graft loss by post-transplant hyperparathyroidism among kidney transplant recipients (n = 824). Post-transplant hyperparathyroidism was defined as parathyroid hormone level ≥70 pg/mL at 1-year post-KT; as such, the cumulative incidence was calculated starting at 1-year post-KT. KT, kidney transplant; HPT, hyperparathyroidism.
      Table IIRisks of all-cause mortality, all-cause graft loss, and death-censored graft loss by post-transplant HPT among the entire cohort (n = 824)
      Post-transplant HPTAll-cause mortalityAll-cause graft lossDeath-censored graft loss
      aHR (95% CI)aHR (95% CI)aHR (95% CI)
      NoReferenceReferenceReference
      Yes1.35 (0.96−1.91)1.37 (1.04−1.82)1.60 (1.02−2.49)
      Post-transplant HPT was defined as PTH level ≥70 pg/mL at 1-year post-KT.
      The aHRs with 95% CIs are presented from Cox proportional hazards models adjusted for older age (≥65 years), sex, Black race, college education, high pre-KT PTH level (≥300 pg/mL), cause of ESRD, and years on dialysis.
      ESRD, end-stage renal disease; HPT, hyperparathyroidism; KT, kidney transplant; PTH, parathyroid hormone.

      All-cause graft loss

      Among the entire cohort, the incidence of all-cause graft loss during the follow-up period was 29.4% (n = 242). The cumulative incidence of all-cause graft loss was higher among recipients with post-transplant hyperparathyroidism compared with those without hyperparathyroidism (log-rank P = .02) (Figure 1, B).
      Compared with those without post-transplant hyperparathyroidism, patients with post-transplant hyperparathyroidism had a 1.37-fold higher risk of all-cause graft loss (aHR = 1.37, 95% CI: 1.04–1.82) (Table II). This association did not differ by age (Pinteraction = .85), sex (Pinteraction = .67), or race (Pinteraction = .43). When stratified by PTH level at 1-year post-KT, patients with a PTH 70 to 299 pg/mL did not have an increased risk of all-cause graft loss. However, the risk of all-cause graft loss was 2.46-fold higher among patients with a PTH level ≥300 pg/mL when compared to those with a PTH <70 pg/mL (aHR = 2.46, 95% CI: 1.38–4.40) (Table III).
      Table IIIRisks of all-cause graft loss and death-censored graft loss among KT recipients by PTH level at 1-year post-KT (n = 824)
      PTH level at 1-year post-KT (pg/mL)All-cause graft lossDeath-censored graft loss
      aHR (95% CI)aHR (95% CI)
      <70ReferenceReference
      70–2991.33 (1.00−1.76)1.50 (0.96−2.36)
      ≥3002.46 (1.38−4.40)4.21 (1.90−9.30)
      Post-transplant PTH was stratified into 3 categories: <70, pg/mL, 70 to 299 pg/mL, and ≥300 pg/mL.
      The aHRs with 95% CIs are presented from Cox Proportional Hazards models adjusted for older age (≥65 years), sex, Black race, college education, high preKT PTH level (≥300 pg/mL), cause of ESRD, and years on dialysis.
      ESRD, end-stage renal disease; HPT, hyperparathyroidism; KT, kidney transplant; PTH, parathyroid hormone.

      Death-censored graft loss

      Among the entire cohort, the incidence of DCGL during the follow-up period was 12.6% (n = 104). The cumulative incidence of DCGL was higher among recipients with post-transplant hyperparathyroidism compared with those without hyperparathyroidism (log-rank P = .01) (Figure 1, C).
      Compared with those without post-transplant hyperparathyroidism, patients with post-transplant hyperparathyroidism had a 1.6-fold higher risk of DCGL (aHR = 1.60, 95% CI: 1.02–2.49) (Table II). This association did not differ by age (Pinteraction = .80), sex (Pinteraction = .06), or race (Pinteraction = .20). When stratified by PTH level at 1-year post-KT, patients with a PTH 70 to 299 pg/mL did not have an increased risk of DCGL. However, the risk of all-cause graft loss was 4.21-fold higher among patients with a PTH ≥300 pg/mL compared to those with a PTH <70 pg/mL (aHR = 4.21, 95% CI: 1.90–9.30) (Table III).

      Sensitivity analyses

      Because our definition of post-transplant hyperparathyroidism encompassed patients with both secondary and tertiary hyperparathyroidism, several sensitivity analyses were carried out to better evaluate the impact that hypercalcemia may have on transplant outcomes. Three sensitivity analyses were performed in which patients with pretransplant hypercalcemia, post-transplant hypercalcemia, and either pre- or post-transplant hypercalcemia were excluded from the main analysis. When excluding patients with hypercalcemia pre-KT, those with post-transplant hyperparathyroidism had a 1.45-fold higher risk of all-cause graft loss and a 1.90-fold higher risk of DCGL compared with those without post-transplant hyperparathyroidism (aHR = 1.45, 95% CI: 1.07–1.97 and aHR = 1.90, 95% CI: 1.16–3.11). When excluding patients with hypercalcemia post-KT, those with post-transplant hyperparathyroidism had a 1.50-fold higher risk of all-cause graft loss and a 1.77-fold higher risk of DCGL compared with those without post-transplant hyperparathyroidism (aHR = 1.50, 95% CI: 1.08–2.08 and aHR = 1.77, 95% CI: 1.08–2.90). Finally, when excluding patients with hypercalcemia either pre- or post-KT, those with post-transplant hyperparathyroidism had a 1.51-fold higher risk of all-cause graft loss and a 2.13-fold higher risk of DCGL compared to those without post-transplant hyperparathyroidism (aHR = 1.51, 95% CI: 1.07–2.14 and aHR = 2.13, 95% CI: 1.25–3.64). Similar to the primary analysis, there was no association between post-transplant hyperparathyroidism and mortality in any of the three sensitivity analyses (Table IV).
      Table IVRisks of all-cause mortality, all-cause graft loss, and death-censored graft loss by post-transplant HPT when excluding patients with pretransplant hypercalcemia, post-transplant hypercalcemia, and pre- or post-transplant hypercalcemia
      Post-transplant HPTAll-cause graft lossDeath-censored graft loss
      aHR (95% CI)aHR (95% CI)
      NoReferenceReference
      Patients with pretransplant hypercalcemia excluded1.45 (1.07–1.97)1.90 (1.16–3.11)
      Patients with post-transplant hypercalcemia excluded1.50 (1.08–2.08)1.77 (1.08–2.90)
      Patients with either pre- or post-transplant hypercalcemia excluded1.51 (1.07–2.14)2.13 (1.25–3.64)
      Post-transplant HPT was defined as PTH level ≥70 pg/mL at 1-year post-KT. Hypercalcemia was defined as calcium ≥10 mg/dL.
      The aHRs with 95% CIs are presented from Cox proportional hazards models adjusted for older age (≥65 years), sex, Black race, college education, high pre-KT PTH level (≥300 pg/mL), cause of ESRD, and years on dialysis.
      ESRD, end-stage renal disease; HPT, hyperparathyroidism; KT, kidney transplant; PTH, parathyroid hormone.
      Six additional sensitivity analyses were also performed in which patients with pretransplant hypercalcemia, post-transplant hypercalcemia, and either pre- or post-transplant hypercalcemia were excluded when stratifying patients with post-transplant hyperparathyroidism by a PTH level either 70 to 299 pg/mL, or ≥300 pg/mL at 1-year post-KT. When excluding those with hypercalcemia, patients with a PTH 70 to 299 pg/mL at 1-year post-KT had a significantly increased risk of graft loss. Additionally, the risk of graft loss remained significant in those with a PTH ≥300 pg/mL at 1-year post-KT when patients with hypercalcemia were excluded (Table V).
      Table VRisks of all-cause graft loss and death-censored graft loss among KT recipients by PTH level at 1-year post-KT when excluding patients with pretransplant hypercalcemia, post-transplant hypercalcemia, or both
      PTH level at 1-year post-KT (pg/mL)All-cause graft lossDeath-censored graft loss
      aHR (95% CI)aHR (95% CI)
      <70ReferenceReference
       70–2991.33 (1.00−1.76)1.50 (0.96−2.36)
       ≥3002.46 (1.38−4.40)4.21 (1.90−9.30)
      Patients with pretransplant hypercalcemia excluded
       70–2991.39 (1.02−1.90)1.79 (1.09−2.96)
       ≥3002.88 (1.52−5.45)5.19 (2.14−12.58)
      Patients with post-transplant hypercalcemia excluded
       70–2991.45 (1.04−2.02)1.67 (1.01−2.76)
       ≥3002.48 (1.24−4.93)4.07 (1.62−10.22)
      Patients with either pre or post-transplant hypercalcemia excluded
       70–2991.46 (1.03−2.07)2.01 (1.16−3.46)
       ≥3002.56 (1.23−5.31)5.35 (2.05−13.95)
      Post-transplant PTH was stratified into 3 categories: <70, pg/mL, 70 to 299 pg/mL, and ≥300 pg/mL. Hypercalcemia was defined as calcium ≥10 mg/dL.
      The aHRs with 95% CIs are presented from Cox proportional hazards models adjusted for older age (≥65 years), sex, Black race, college education, high pre-KT PTH level (≥300 pg/mL), cause of ESRD, and years on dialysis.
      aHR, adjusted hazard ratios; ESRD, end-stage renal disease; HPT, hyperparathyroidism; KT, kidney transplant; PTH, parathyroid hormone.

      Discussion

      In this single-institution retrospective study of 824 KT recipients followed for a median of 6.9 years, we found that patients with post-transplant hyperparathyroidism, or PTH ≥70 pg/mL at 1-year post-KT, had a 1.37-fold higher risk of all-cause graft loss and a 1.6-fold higher risk of DCGL compared with patients without post-transplant hyperparathyroidism. When stratified by PTH levels at 1-year post-KT, this risk roughly doubled among those with a PTH level ≥300 pg/mL. The association between post-transplant hyperparathyroidism and graft loss persisted even when excluding patients with hypercalcemia. Our findings suggested that KT recipients with hyperparathyroidism after transplant should be closely monitored to optimize graft viability.
      Similar to our findings, others have demonstrated an association between post-transplant hyperparathyroidism and adverse transplant outcomes. Lou et al found that normalization of PTH within 1 year of KT was associated with improved overall graft survival on Kaplan-Meier analysis compared to those with post-transplant hyperparathyroidism.
      • Lou I.
      • Foley D.
      • Odorico S.K.
      • et al.
      How well does renal transplantation cure hyperparathyroidism?.
      Araujo et al found that ionized calcium >5.3 mg/dL or PTH >100 pg/mL at 1-year post-KT was associated with a shorter median time to graft loss compared with non-hyperparathyroidism patients.
      • Araujo M.
      • Ramalho J.A.M.
      • Elias R.M.
      • et al.
      Persistent hyperparathyroidism as a risk factor for long-term graft failure: the need to discuss indication for parathyroidectomy.
      In addition, Isakov et al reported that PTH >150 pg/mL at 3-months post-KT was an independent predictor for decreased GFR in KT recipients ≤3 years post-transplant.
      • Isakov O.
      • Ghinea R.
      • Beckerman P.
      • Mor E.
      • Riella L.V.
      • Hod T.
      Early persistent hyperparathyroidism post-renal transplantation as a predictor of worse graft function and mortality after transplantation.
      Our study was built on each of these previous findings by examining PTH thresholds at 1-year post-KT; we found that higher PTH levels were associated with a greater risk of graft loss.
      In contrast to our study, Wolf et al found no association between post-transplant hyperparathyroidism and graft loss; however, the time interval at which PTH levels were collected post-KT was variable.
      • Wolf M.
      • Molnar M.Z.
      • Amaral A.P.
      • et al.
      Elevated fibroblast growth factor 23 is a risk factor for kidney transplant loss and mortality.
      Similarly, Marcén et al found no association between post-transplant hyperparathyroidism and graft loss on univariate analysis, although this study did not use a multivariate analysis to control for any potential confounding effects.
      • Marcén R.
      • Jimenez S.
      • Fernández A.
      • et al.
      The effects of mineral metabolism markers on renal transplant outcomes.
      Pihlstrøm et al reported an association between post-transplant hyperparathyroidism and all-cause mortality, a finding that was not seen in our study.
      • Pihlstrøm H.
      • Dahle D.O.
      • Mjøen G.
      • et al.
      Increased risk of all-cause mortality and renal graft loss in stable renal transplant recipients with hyperparathyroidism.
      However, unlike our study, Pihlstrøm et al used PTH levels that were collected at an average of 5.1 years from KT, suggesting that a longer exposure to elevated PTH levels post-KT may result in an increased risk of mortality.
      The mechanism of graft loss in those with post-transplant hyperparathyroidism is unclear. Some data has suggested that hyperparathyroidism may indirectly lead to graft failure by causing hypercalcemia, which in turn may lead to calcium deposition in renal vasculature, nephrocalcinosis, and subsequent graft loss.
      • Gwinner W.
      • Suppa S.
      • Mengel M.
      • et al.
      Early calcification of renal allografts detected by protocol biopsies: causes and clinical implications.
      An association between elevated circulating calcium-phosphate product and graft loss has been reported previously.
      • Egbuna O.I.
      • Taylor J.G.
      • Bushinsky D.A.
      • Zand M.S.
      Elevated calcium phosphate product after renal transplantation is a risk factor for graft failure.
      In addition, PTH-mediated hypercalcemia may lead to systemic calciphylaxis, a rare complication that has devastating effects on both graft survival and overall mortality.
      • Lo Monte A.I.
      • Bellavia M.
      • Maione C.
      • et al.
      Sistemic calciphylaxis and thrombotic microangiopathy in a kidney transplant patient: two mixing fatal syndromes?.
      Conversely, there is some evidence to suggest that PTH levels may influence KT outcomes independent of calcium. Parathyroid hormone receptors have been found on cardiomyocytes, vascular smooth muscle cells, and endothelial cells, suggesting that PTH has a direct impact on vasculature.
      • Schlüter K.D.
      • Piper H.M.
      Cardiovascular actions of parathyroid hormone and parathyroid hormone-related peptide.
      ,
      • Pepe J.
      • Cipriani C.
      • Sonato C.
      • Raimo O.
      • Biamonte F.
      • Minisola S.
      Cardiovascular manifestations of primary hyperparathyroidism: a narrative review.
      Elevated PTH levels have been shown to cause structural changes to arteries, making them less responsive to vasodilatory changes.
      • Barenbrock M.
      • Hausberg M.
      • Kosch M.
      • Kisters K.
      • Hoeks A.P.
      • Rahn K.H.
      Effect of hyperparathyroidism on arterial distensibility in renal transplant recipients.
      ,
      • Suwelack B.
      • Gerhardt U.
      • Witta J.
      • Hillebrandt U.
      • Hohage H.
      Effect of parathyroid hormone levels on carotid intima-media thickness after renal transplantation.
      This has led some to believe that PTH-mediated structural changes within the renal vasculature may lead to micro- and macrovascular complications within the renal allograft, placing KT recipients with hyperparathyroidism at higher risk for graft loss.
      • Cohen E.
      • Korah M.
      • Callender G.
      • Belfort de Aguiar R.
      • Haakinson D.
      Metabolic disorders with kidney transplant.
      To be consistent with the nephrology literature, our definition of post-transplant hyperparathyroidism did not differentiate between the various etiologies of elevated PTH; as such, our analyses included patients with both secondary and tertiary hyperparathyroidism. To better evaluate the role of hypercalcemia in adverse KT outcomes, multiple additional sensitivity analyses were performed in which the relationship between post-transplant hyperparathyroidism and graft loss was determined when excluding patients with pretransplant hypercalcemia, post-transplant hypercalcemia, and either pre- or post-transplant hypercalcemia. When excluding hypercalcemic patients, the association between post-transplant hyperparathyroidism and graft loss did not change significantly when compared with the primary and secondary analyses. Additionally, in the group of patients with a post-transplant PTH 70 to 299 pg/mL, the risk of graft loss increased significantly, a finding that was not seen when patients with hypercalcemia were included. These findings suggested that graft loss in those with post-transplant hyperparathyroidism may be a PTH-mediated phenomena. However, further research is needed to elucidate the mechanisms between hyperparathyroidism and graft loss.
      The strengths of the study included the large sample size, the leverage of an ongoing longitudinal prospective cohort, and the close follow-up of each patient using data from SRTR. Our study had several limitations inherent to database and electronic medical record abstraction, including missing values and human error in data collection. In addition, the PTH levels may naturally fluctuate over the course of several years after transplant, and the type of PTH assay used may have differed across patients, both of which may have led to inaccurate PTH levels and misclassification of hyperparathyroidism. Similarly, PTH levels may vary based on renal function, and because data regarding renal function is not available in SRTR, we were not able to control for this in our model. However, all grafts were deemed to be functioning by each patient’s nephrologist. The current study did not address risk factors for post-transplant hyperparathyroidism that can be addressed pre-KT, as previous studies have suggested that improved control of secondary hyperparathyroidism before surgery may help mitigate post-transplant hyperparathyroidism post-KT.
      • Mathur A.
      • Sutton W.
      • Ahn J.B.
      • et al.
      Association between treatment of secondary hyperparathyroidism and posttransplant outcomes.
      • Callender G.G.
      • Malinowski J.
      • Javid M.
      • et al.
      Parathyroidectomy prior to kidney transplant decreases graft failure.
      • Roodnat J.I.
      • van Gurp E.A.
      • Mulder P.G.
      • et al.
      High pretransplant parathyroid hormone levels increase the risk for graft failure after renal transplantation.
      Although we found an association between post-transplant hyperparathyroidism and graft loss, this study was not designed to determine the most appropriate treatment for post-transplant hyperparathyroidism or to determine the timing of such treatment. Because KT recipients were managed by a wide range of transplant nephrologists after surgery, we were not able to comment on the specific rationale for choosing calcimimetics for treatment of post-transplant hyperparathyroidism in 23% of these patients. Finally, these data were collected from patients who underwent transplant at a single institution, which may limit the generalizability of our findings.
      In conclusion, post-transplant hyperparathyroidism post-KT was associated with an increased risk of graft loss compared with patients without post-transplant hyperparathyroidism, and higher PTH levels at 1-year post-KT were associated with an even greater risk of graft loss. This association persisted even when excluding patients with hypercalcemia. These findings suggested that KT recipients should undergo close monitoring of PTH levels after transplant to optimize graft viability. Future studies are warranted to better understand the mechanism of graft loss in patients with post-transplant hyperparathyroidism and to determine the most appropriate treatment for these patients.

      Funding/Support

      Funding for this study was provided in part by the National Cancer Institute (NCI), National Institute of Diabetes and Digestive and Kidney Disease (NIDDK), and the National Institute on Aging (NIA); grant numbers T32CA126607 (Philip Crepeau), K23AG053429 (PI: Aarti Mathur), R01DK120518 (PI: Mara McAdams-DeMarco), and R01AG055781 (PI: Mara McAdams-DeMarco), and K24DK101828 (PI: Dorry Segev).

      Conflict of interest/Disclosure

      The authors have no conflicts of interests or disclosures to report.

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