Introduction
Chronic hypoparathyroidism is a rare endocrine disorder characterized by hypocalcemia, hyperphosphatemia, and absent or insufficient parathyroid hormone (PTH) production [
1,
2]. Hypoparathyroidism is most commonly caused by damage to or removal of the parathyroid glands during thyroid surgery but can also be of autoimmune or genetic origin [
1,
2]. In the absence of PTH, the mechanisms regulating calcium transport and phosphate reabsorption in the PTH receptor-rich renal tubule are deregulated resulting in disruption to the major role of the kidney in controlling calcium and phosphate homeostasis [
3].
Previous studies have found increased risk of renal complications in patients with chronic hypoparathyroidism managed with conventional therapy consisting of oral calcium and active vitamin D [
4,
5]. Recent studies have added to the body of evidence regarding renal complications in patients with chronic hypoparathyroidism [
6‐
10]. A Scottish study identified a significantly higher risk of renal failure, defined as estimated glomerular filtration rate (eGFR) < 30 ml/min, in patients with hypoparathyroidism compared with age- and gender-matched controls [
6]. In a cross-sectional Belgian study, kidney stones and/or nephrocalcinosis was present in 22% of patients on conventional therapy with available renal imaging from the prior 10 years; history of kidney stones did not differ between surgical and nonsurgical etiologies [
7]. Two Danish retrospective cohort studies found that nonsurgical hypoparathyroidism and postsurgical hypoparathyroidism were associated with increased risk of renal stones, renal insufficiency, and renal diseases, defined using diagnosis codes [
5,
8]. Patients with long-standing hypoparathyroidism treated with conventional therapy require close monitoring of symptoms of hypoparathyroidism and comorbidities, including development of chronic kidney disease (CKD), risk of renal stones, and renal calcifications [
2,
7,
9,
10]. Previous studies were limited by the small sample size and evaluated a limited range of kidney outcomes. Therefore, we conducted a large-scale retrospective study aiming to more comprehensively examine risks of development and progression of CKD and decline in eGFR in patients with chronic hypoparathyroidism.
Discussion
The current study demonstrated that patients with chronic hypoparathyroidism were at greater risk of incident CKD, CKD stage progression, progression to ESKD, and faster decline in eGFR compared with patients without hypoparathyroidism during the 5-year follow-up period. These results remained consistent after adjusting for a variety of potential outcome-relevant confounders.
Whereas previous research generally examined smaller cohorts with limited kidney outcomes, this study confirms and expands on the adverse associations between chronic hypoparathyroidism and renal complications in a large-scale cohort of nationally representative patients in the United States using both diagnostic codes and repeat eGFR values. For example, two Danish retrospective studies found that nonsurgical hypoparathyroidism (
N = 180) and postsurgical hypoparathyroidism (
N = 688) were associated with increased risk of any renal disease and renal insufficiency defined by diagnostic codes compared with age- and sex-matched controls [
5,
8]. Another study from the UK (
N = 280) identified a significantly higher risk of mortality and renal failure (defined as eGFR < 30 ml/min) in patients with hypoparathyroidism compared with age- and gender-matched control patients [
6]. Similarly, a long-term Massachusetts-based registry study of 120 patients with chronic hypoparathyroidism, most of whom were treated with conventional therapy (two patients also received teriparatide), reported a greater proportion of patients with hypoparathyroidism with eGFR < 60 ml/min/1.73 m
2 compared with age-adjusted norms [
4].
Although a growing body of research supports an increased risk of renal complications in patients with chronic hypoparathyroidism [
4‐
6,
8], the underlying mechanism of this risk in the pathophysiology of hypoparathyroidism remains unknown. Chronic hypoparathyroidism is commonly managed with conventional therapy, which is aimed at maintaining a serum calcium concentration in the lower part of the normal range (i.e., 8.0–8.5 mg/dl) [
2,
13‐
15]. Conventional therapy corrects hypocalcemia by increasing intestinal calcium absorption but does not replace the actions of parathyroid hormone on the kidney that stimulate renal calcium reabsorption and urinary phosphate excretion [
15,
16]. Parathyroid hormone exerts calcium-sparing and phosphaturic effects on the kidney, and hormone loss leads to abnormal mineral homeostasis, resulting in unstable serum calcium levels, hyperphosphatemia, and hypercalciuria [
15]. In a Danish study of patients with hypoparathyroidism treated with conventional therapy, risk of renal disease was associated with an increased calcium-phosphate product level [
17]. In addition, two other studies linked elevated serum calcium concentrations with the risk of CKD [
4,
6]. Chen et al. recently reported that in a study of patients with chronic hypoparathyroidism, eGFR declined by 8.0 ml/min/1.73 m
2 in 53 patients treated without recombinant human parathyroid hormone (1–84), rhPTH(1–84), over a 5-year follow-up period [
18]. In contrast, eGFR remained stable among 69 patients treated with rhPTH(1–84), suggesting that hormone replacement therapy may ameliorate eGFR decline. However, this analysis was limited by differences in patient management between the cohorts (i.e., rhPTH [1–84]-treated patients were derived from clinical trial studies vs. the control cohort being obtained from an electronic health record database). A possible role for calcium-induced autophagy is suggested, but further research is needed to understand the mechanistic link with the pathogenesis of CKD and chronic hypoparathyroidism [
19].
Several limitations should be considered when interpreting findings from this study. Because of the observational study design, there may be unobserved and/or unmeasured differences between the cohorts with and without chronic hypoparathyroidism that were not accounted for in the analyses. As such, we cannot formally exclude the possibility that unknown confounding variables or pathological processes that are unevenly distributed between the cohorts may influence the risk associated with the development of CKD or decline in eGFR. Kidney transplantation was not an exclusion criterion so we cannot exclude the possibility that this was a confounding factor in the overall results. However, after adjusting for known relevant baseline demographic and clinical characteristics, we found similar results for all outcomes, including the development of incident CKD, CKD stage progression, progression to end stage, and eGFR decline compared with the unadjusted analyses. Unadjusted HR results of the Cox models should be interpreted with caution because of differences in demographic and baseline characteristics between patient cohorts.
In addition, a further potential limitation was the ability to discern whether the decline in CKD was chronic rather than temporary. Misclassification of the outcome is a potential concern in observational studies using administrative databases. Previous studies on the utility of billing codes for identifying CKD have shown relatively low sensitivity but high specificity [
20,
21], indicating that patients captured through billing code analysis are unlikely to be false-positives. To ensure that our data show true CKD progression, (1) the definition was based on diagnosis codes or a baseline eGFR measure indicating CKD stage 3 or 4 and (2) we required CKD diagnoses based on an eGFR value that was confirmed with a second eGFR value at least 3 months apart. With this comprehensive definition, we identified events based on both CKD diagnosis codes and by two eGFR values at least 3 months apart (to address the risk that some patients may not have diagnoses of CKD entered into their records). In addition, we conducted sensitivity analyses using CKD diagnosis codes alone to define CKD and CKD progression to address the potential limitation that eGFR values may fluctuate and thus may not indicate chronic renal decline. Results were similar across the main analyses and sensitivity analyses regardless of outcome, which strengthens our overall conclusion.
We used a claims database, which means there may be miscoded or missing data. Although this study was limited to the United States, the conclusions are unlikely to vary across different regions. However, the magnitude of the results may differ by country. Lastly, because of limited availability of patient-level data for treatments related to hypoparathyroidism (e.g., calcium, vitamins D2 and D3) or other conditions, etiology, duration of disease, and laboratory data, we were unable to assess potential biomarkers or treatments that may mediate the relationship between hypoparathyroidism and renal outcomes. The mechanism of the observed findings merits further research.
Our study has important strengths. Using a nationally representative insurance claims database of patients with chronic hypoparathyroidism, the study evaluated several critical renal outcomes, such as development and progression of CKD assessed by both diagnosis codes and eGFR. Subgroup analyses conducted in cohorts of patients both with and without renal function impairment at baseline also strengthen this study’s findings.