Timing of Parathyroidectomy Does Not Influence Renal Function After Kidney Transplantation

We performed a multicenter retrospective cohort study in patients who underwent both KTx and PTx. The Dutch Hyperparathyroidism Study Group (DHSG) initiated a multicenter retrospective database with data from four academic centers in the Netherlands (University Medical Center Groningen [UMCG], Academic Medical Center Amsterdam [AMC], Erasmus Medical Center Rotterdam [EMC], and Leiden University Medical Center [LUMC]). We evaluated medical records of all patients who underwent both a KTx and a PTx in these centers between 1994 and 2015. All patients were ≥18 years and diagnosed with ESRD-related HPT. Patients were divided into two groups according to treatment sequence: the PTxKTx group, who underwent PTx before KTx, and the KTxPTx group, who underwent PTx after KTx. When patients received more than one kidney transplant, only the first KTx was taken into account.

This study was approved by the local medical ethical committee of all participating centers (METc 2014/077). The study was performed according to the Helsinki Ethical Principles.

For all patients, we collected cause of ESRD, pre-transplant dialysis status (preemptive or dialysis), history of diabetes mellitus, donor age and sex, cold and warm ischemia times, number of HLA mismatches, primary non-function (PNF), type of PTx (subtotal PTx or total PTx with autotransplantation), and biochemistry. PNF was defined as an eGFR <10 ml/min/1.73 m² at 3 months after KTx. Patients who reached ESRD (dialysis or re-transplantation) during follow-up were denoted as having an eGFR of 0 ml/min/1.73 m² until end of follow-up at 5 years; patients who died during follow-up were censored. The following biochemical measurements were recorded: serum calcium, PTH, albumin, and creatinine prior to KTx and PTx and at 3 months, 6 months, 1 year, 3 years, and 5 years after both KTx and PTx. For patients who underwent KTx after 2014, only 3-year follow-up data are available. eGFR was calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) in ml/min/1.73 m² [20]. Serum calcium and albumin were measured using routine laboratory techniques. Serum calcium was corrected for albumin levels according to the following formula: adjusted total calcium (mg/dL) = measured calcium (mg/dL) + (0.8 * 4 − [albumin (g/dL)]). Reference range for serum calcium was 2.20–2.60 mmol/L. Different PTH assays were used among the four centers. UMCG: until 2006: Nichols Institute Diagnostics, San Juan Capistrano, CA, USA; since February 2006: Immulite 2500, Siemens Healthcare Diagnostics, Deerfield, IL, USA; and the Cobas 3601 immunology analyzes Roche Diagnostics, Mannheim, Germany. PTH values were recalculated according to the conversion equation provided by the laboratory. Reference values were 1.8–9.6 pmol/L. EMC: Vitros ECi Assay, Ortho-Clinical Diagnostics, Inc., New Jersey, USA. Reference range was 1.4–7.3 pmol/L. AMC: Roche Cobas e602, Roche Diagnostics International Ltd, Rotkreuz, Switzerland, with a reference range of 2.00–7.00 pmol/L. LUMC: Immulite 1000, Siemens Healthcare Diagnostics, Deerfield, IL, USA, with a reference range of 0.7–8.0 pmol/L.

To analyze the impact of the timing of PTx on graft function, the primary endpoint was eGFR at 5 years after transplantation. We also analyzed serum-corrected calcium, and PTH, graft failure and post-PTx complications, including temporary palsy of the recurrent laryngeal nerve (RLN), surgical site problems (SSP, including hematoma and infection), hospital-acquired pneumonia (HAP), intensive care unit (ICU) admission, and temporary hypocalcaemia.

A power analysis was performed based on results of a previous comparable study [21]. With 80% power and a two-sided α = 0.05, a simple size of n = 120 is required to detect a 20% difference in eGFR post-KTx. Statistical analysis was performed using SPSS Statistics version 24.0 (IBM Corporation, Armonk, NY, USA); a P value of <0.05 was considered statistically significant.

Patient characteristics were compared between the two groups (PTxKTx vs. KTxPTx) using Mann–Whitney U test and Pearson’s Chi-square test where appropriate. Continuous variables were reported as mean ± standard error of the mean (SEM) or median with interquartile range (IQR). Categorical variables were expressed as number (n) and percentage (%).

To further study the impact of treatment sequence on graft function over time, we established generalized estimating equations (GEE) models with an exchangeable correlations structure. Based on previous literature, recipient age and sex, donor age and sex, type of donor (living vs. deceased), total number of HLA mismatches, type of PTx (total vs. subtotal), cold ischemia time, and pre-transplant dialysis status (preemptive or dialysis) were defined as potential important confounders prior to analysis and were adjusted for in the multivariable GEE model. Furthermore, baseline variables with P values <0.2 in the univariate GEE analyses were included in multivariable GEE model. Results of the GEE model are displayed as estimates of the effects (B) and 95% confidence interval (CI) with P value. In a sub-analysis, we also evaluated the impact on eGFR in patients who underwent PTx shortly after KTx (<1 year) or longer (≥1 year) after KTx.

A total of 185 patients were included: 102 (55.1%) patients underwent PTx before KTx (PTxKTx group), while 83 (44.9%) underwent PTx after KTx (KTxPTx group) (Fig. 1). Baseline patient and transplant characteristics are presented in Table 1. Patients within the KTxPTx group were significantly younger at the time of KTx than patients in the PTxKTx group. Eight patients (4.3%) underwent preemptive KTx; these patients were well equally distributed among the groups (n = 3 vs. n = 5, p = 0.31). Median time from start dialysis until KTx was significantly longer in the PTxKTx group compared to the KTxPTx group (61 months [46–83 months] versus 36 months [14–57 months], p <0.01). In the KTxPTx group, living donor KTx was more common compared to the PTxKTx group (26.5% vs. 6.9%, p = 0.006). Pre-KTx PTH levels were significantly higher in the KTxPTx group (66 [34–127] pmol/L vs. 15 [4–35] pmol/L, p <0.001). Calcimimetics were used at some point during follow-up in 31.4% of the patients in the PTxKTx group, compared to 20.5% of the patients in de KTxPTx group (p = 0.18). Ten patients (10.1%) developed primary non-function after KTx in the PTxKTx group, compared to 17.9% in the KTxPTx group (p = 0.13), and were excluded from further analysis.

Patients in the PTxKTx group had a median pre-PTx serum PTH level of 120 (73–186) pmol/L. Postoperatively, PTH dropped with a median of 96 (83–99)% within 3 months. Serum calcium levels corrected for albumin changed after PTx from 10.1 (9.3–10.7) mg/dL to 9.1 (8.1–10.0) mg/dL (p <0.01). Median time from PTx to KTx was 23 (11–38) months (Fig. 2). Median PTH levels increased from 5.4 (2.2–14.7) pmol/L post-PTx to 15 (4–35) pmol/L at day of admission for KTx (p = 0.006). Three months after KTx, PTH levels dropped significantly to 11 (6–24) pmol/L (p = 0.02). The course of eGFR after KTx is presented in Fig. 3. In the PTxKTx group, 8.1% of patients had a complication following PTx (Supplementary Table 1).

Patients in the KTxPTx group underwent PTx at median 30 (15–74) months after KTx (Fig. 2). Fifteen of the 83 patients (18.1%) underwent PTx within 1 year after KTx. Median pre-PTx PTH levels were significantly lower in the KTxPTX group compared to the PTxKTX group (50 [26–122] pmol/L vs. 120 [73–186] pmol/L, p <0.001). The median postoperative PTH drop three months after PTx was 88 (63–96)% to 7.7 [2.7–17.1] pmol/L. Serum calcium levels corrected for albumin also decreased significantly after PTx, from 10.7 (9.8–11.6) mg/dL to 9.2 (8.4–9.9) mg/dL (p <0.01). The eGFR course after KTx is depicted in Fig. 3. eGFR before and after PTx is shown in Fig. 4. Fifteen (18.1%) of patients in the KTxPTx group had a ≥25% decrease of eGFR at 3 months after PTx. (20.7 ± 5.4 ml/min/1.73 m² vs. 37.9 ± 3.2 ml/min/1.73 m², p = 0.01). At 1 year after PTx, eGFR was similar to pre-PTx values. There were no significant differences in baseline characteristics between patients with ≥25% decrease in eGFR versus patients with stable eGFR after PTx (Supplementary Table 2). The complication rate in the KTxPTx group was 5.0% and not significantly different compared to the PTxKTx group (p = 0.42).

The unadjusted GEE model showed that the timing of PTx was not associated with graft function over time (mean difference −1.0 ml/min/1.73 m², 95% confidence interval [CI] −8.4 to 6.4, p = 0.79), Table 2). In a model adjusted for donor variables including donor type, donor gender, total number of HLA mismatches, whether the transplantation was preemptive or post-dialysis, donor age, and cold ischemia time, the mean difference in eGFR was −4.8 ml/min/1.73 m² (96% CI −15.4 to 5.7, p = 0.37). Finally, we constructed a third model adjusted for pre-defined potentially relevant covariates and all baseline variables with a P value of <0.2 in univariate analysis. This analysis also showed that the course of eGFR over time was not significantly different between patients who underwent PTx before KTx or after KTx (Table 2).