Key words
hypoparathyroidism - total thyroidectomy - calcitriol - renal insufficiency
Introduction
Hypoparathyroidism (hypoPT) is an endocrine disease characterized by inappropriately
low circulating parathyroid hormone (PTH) levels. The most common cause is surgery
of thyroid gland and/or parathyroid glands. Patients can present with a broad array
of symptoms and have a lower quality of life [1]
[2]. Standard treatment consists of a lifelong regimen of calcium and vitamin D supplements
(ergocalciferol or cholecalciferol), usually combined with active vitamin D analogues
(alfa-calcidiol or calcitriol) [3]
[4]
[5]
[6].
PTH raises serum calcium and lowers phosphate, whereas calcitriol raises both calcium
and phosphate, which can lead to a high calcium phosphate product. This is an important
contributor to the higher incidence of arterial calcifications, cardiovascular events,
and basal ganglia calcification, well-known complications of hypoPT [7]
[8]. Patients with hypoPT may be at an ever greater risk for renal complications, because
they lack the stimulatory effect of PTH on the reabsorption of calcium in the renal
tubules [9]
[10].
There are no large cohort studies looking into long term complications of calcitriol
therapy, therefore we performed a retrospective cohort study to observe, if long-term
treatment with calcitriol (1,25-dihydroxycholecalciferol=Rocaltrol®), has a negative effect on renal function.
Patients and Methods
Patients
We analyzed the records of all patients who underwent a total thyroidectomy at the
University Hospital of Brussels (UZ Brussel) between January 1st 1996 and December
31st 2016 (n=2664) (see [Fig. 1]). We included all patients with hypocalcemia and inappropriate low PTH-levels post-thyroidectomy
who were followed in our own academic center and were on continuous therapy with calcitriol
(n=359). We used the following exclusion criteria: patients without active calcitriol
treatment (n=165), patients who had insufficient data related to their illness and
renal function (n=63), patients who died during the course of follow-up (n=16), patients
who had an active malignant disease (n=9) and who had pre-existing renal insufficiency,
defined as eGFR<60 ml/min at the moment of operation (n=5). The 101 remaining patients
were identified as having post-surgical hypoparathyroidism and were included in the
study, which was approved by the Ethics Committee of the UZ Brussel.
Fig. 1 Flowchart describing the patient selection method for our study.
Outcomes
The primary outcome measure was renal function at the beginning and at the end of
the study. Secondary outcome measures included mean calcium phosphate product, calcitriol
dosage, urinary calcium excretion, serum intact PTH (iPTH), and vitamin D.
Analytical approach
All 101 patients were retrospectively analyzed comparing the present renal function
with renal function at the time of diagnosis of hypoPT. The onset of hypoPT was defined
as the date of surgery.
Renal function was assessed using the CKD-EPI equation at the onset of hypoPT and
compared to the renal function at the maximum duration of follow up [11]
[12]
[13]
[14]. This difference in renal function was calculated and used in a multivariate model.
The mean calcium phosphate product was calculated using the last measurement available
in the year of diagnosis of hypoPT and the last measurement at the maximum duration
of follow-up.
Measurements of iPTH, vitamin D and HbA1c were the most recent ones available in the
hospital electronic system. The 24-hour urine collection measuring calcium, phosphate,
and creatinine was used at the year of diagnosis of hypoPT and at the maximum duration
of follow-up.
Statistical analysis
Data are presented as (n) with percentages within group (%) for discrete variable,
and median with range (minimum-maximum) for continuous variables. A multiple linear
regression analysis was used to predict renal function evolution (eGFR Δ) values with
duration of disease, calcium phosphate product and age as independent variables. A
two sided p<0.05 was considered significant. All calculations were performed using
the IBM Statistical Package for Social Sciences (SPSS 23.0) (IBM, New York, USA) for
Windows.
Results
Cohort description
[Table 1] describes the full demographic data of our cohort, which was predominantly female
of Caucasian origin. The median age was 50 years at the beginning and 55 years at
the end of follow-up. Thyroidectomy for thyroid cancer was identified in 44 (43.6%)
patients, while 57 (56.4%) patients had a benign etiology. Mean duration of follow-up
was 6.6 years calculated as the time between the operation and the end of the study.
The iPTH median value of the cohort was 1.41 pmol/l (normal value: 1.06–6.90 pmol/l)
with an interquartile range (IQR) of 0.88–2.23 pmol/l. The median value of 25(OH)
vitamin D was 60 nmol/l (IQR 44–85 nmol/l) (n=94).
Table 1 Demographic of patient cohort.
|
Age (at operation, median, years)
|
50 (18–75)
|
|
Age (at end of study, median, years)
|
55 (28–85)
|
|
Follow-up (mean, years)
|
6.6
|
|
Sex
|
|
|
Male
|
21 (20.8%)
|
|
Female
|
80 (79.2%)
|
|
Race
|
|
|
Caucasian
|
85 (84.2%)
|
|
Black
|
2 (1.9%)
|
|
Mediterranean
|
14 (13.9%)
|
|
Surgical etiology
|
|
|
Benign
|
57 (56.4%)
|
|
Malignant
|
44 (43.6%)
|
Data are presented as (n) with percentages within group (%), median with range (minimum-maximum)
or mean.
Calcium phosphate product
The median calcium phosphate product was 2.56 mmol2/l2 (IQR 2.27–2.89 mmol2/l2) at the start and 2.81 mmol2/l2 (IQR 2.54–2.97 mmol2/l2) at the end of follow-up. The mean calcium phosphate product was 2.75 mmol2/l2 (IQR 2.54–2.97 mmol2/l2).
Urinary calcium excretion
Fifty-three patients (52.3%) had an at least one 24-hour urinary collection, but only
34 patients (33.7%) had a recorded 24-hour urinary calcium measurement. Median urinary
calcium was 6.54 mmol/24 h (IQR 4.76–8.65 mmol/24 h). Only 10 patients (29.4% of measured)
had a measurement of urinary calcium exceeding 7.5 mmol/24 h and were thus hypercalciuric.
Co-morbidities
Co-morbidities with possible effect on renal function (diabetes mellitus, arterial
hypertension, and renal stones) were recorded and are described in [Table 2]. Both arterial hypertension and diabetes mellitus were well controlled in all of
the patients.
Table 2 Co-morbidities.
|
Diabetes Mellitus
|
20 (19.8%)
|
|
HbA1c (mmol/mol)
|
44 (31–86)
|
|
Arterial hypertension
|
30 (29.7%)
|
|
Renal stones (total)
|
7 (6.9%)
|
|
Male
|
6 (28.6%)
|
|
Female
|
1 (1.3%)
|
Data are presented as (n) with percentages within group (%) or median with range (minimum-maximum).
Medical therapy
All the patients in the cohort were taking calcitriol therapy with a dosage varying
between 0.25 and 2.00 μg per day. The most frequent dosage used was 0.5 μg/day (n=46;
45.5%) ([Table 3]). Other medication used consisted of thyroid hormone replacement (n=99; 98%), calcium
supplementation (n=77; 76.2%), vitamin D supplementation (n=29; 28.7%), and other
treatments consisting of cholesterol-lowering therapy (n=27; 26.7%) and antihypertensive
therapy (n=30; 29.7%).
Table 3 Calcitriol dosage.
|
0.25 μg/day
|
31 (30.7%)
|
|
0.50 μg/day
|
46 (45.5%)
|
|
0.75 μg/day
|
13 (12.9%)
|
|
1.00 μg/day
|
9 (8.9%)
|
|
1.25 μg/day
|
1 (1.0%)
|
|
2.00 μg/day
|
1 (1.0%)
|
Data are presented as (n) with percentages within group (%).
Renal function analysis
Using a multivariate regression model correcting for patient age and mean calcium
phosphate product ([Fig. 2]), calcitriol therapy was found to be significantly correlated (p=0.027) with renal
function loss. When corrected for age and average calcium phosphate product, the patients
in our cohort lost 1.06 ml/min/1.73 m2 per year of calcitriol therapy ([Fig. 3]). There was also a significant correlation (p=0.023) between the average calcium
phosphate product and renal function loss. Age was not significantly correlated (p=0.126).
The dosage of calcitriol was not significantly correlated with renal function loss
or with mean calcium phosphate product or urinary calcium excretion.
Fig. 2 Multiple linear regression analysis with the renal function decline (eGFR Δ) as dependent
variable. Duration of calcitriol therapy, mean calcium phosphate product and age were
used as independent variables.
Fig. 3 Univariate relation between the eGFR decline (eGFR Δ) and the duration of calcitriol
therapy in years. Longer treatment is associated with a greater decline. R2 linear=0.034.
Only 7 patients (6.9%) underwent imaging studies of the kidneys, and none of them
showed signs of nephrocalcinosis. Out of the 101 patients, 7 (6.9%) developed renal
stones during the follow-up period. Six of them were male (28.6% of the male cohort),
one was female (1.3% of the female cohort).
Discussion
This is the first study describing a retrospective analysis of renal function evolution
in patients with postsurgical hypoPT on calcitriol therapy, demonstrating a statistically
significant correlation between long term calcitriol therapy and loss of renal function.
All patients in our cohort had acceptable calcium phosphate products<4.4 mmol2/l2, which is the recommendation of the current guidelines. The values of the mean calcium
phosphate product in our cohort were surprisingly low compared to values reported
by similar studies [2]
[10]. Despite this fact, 10 patients (29.4% of those with data) had hypercalciuria. Data
on nephrocalcinosis were not sufficient as only 7 patients (6.9%) underwent imaging
studies of the kidneys. Seven (6.9%) patients developed renal stones and our findings
of hypercalciuria and increased renal stone risk agree with previous studies [4]
[15]
[16].
One of the strengths of our study is that we identified a large cohort of 101 post-surgical
hypoPT patients with a suitable duration of follow up.
The major limitation of our study is the retrospective nature with some missing data,
specifically on magnesium levels. Only one study has prospectively evaluated the effect
of calcitriol versus recombinant human parathyroid hormone (rhPTH) on renal function
[2]. They found no noticeable worsening of renal insufficiency using a short period
of follow up of just 24 weeks.
In conclusion, this study is the first one to show a statistically significant correlation
between the cumulative calcitriol therapy and renal function decline at a rate of
1.06 ml/min/1.73 m2 per year of calcitriol therapy. This may have an impact on future guidelines and
prompt further research into other treatment options of chronic hypoPT, such as rhPTH.
Funding
This research did not receive any specific grant from any funding agency in the public,
commercial or not-for-profit sector.
