Chronic kidney disease-mineral and bone disorder (CKD-MBD) is characterized by skeletal and cardiovascular abnormalities, including CKD-associated osteoporosis and vascular calcification. It is more likely to occur with more advanced CKD and has been linked with a reduced quality of life and premature mortality. A major biochemical hallmark of CKD-MBD is secondary hyperparathyroidism. Elevated levels of serum parathyroid hormone (PTH) in CKD are triggered by low serum calcium levels, a deficiency of active vitamin D, and high serum phosphate levels, all three of which are common biochemical abnormalities in CKD. Therapeutic approaches aimed at correction of vitamin D deficiency and lowering of serum phosphate levels are central to the management of CKD-MBD [1].
The 2017 update of the KDIGO CKD-MBD guidelines suggests that PTH lowering by calcitriol or vitamin D analogues should be reserved for CKD G4-5 patients with severe and progressive hyperparathyroidism [1]. In patients with CKD 3-5D and severe hyperparathyroidism who fail to respond to medical or pharmacological therapy, parathyroidectomy (PTX) is recommended. These recommendations are primarily based on the major adverse impact of CKD on bone turnover. While several observational studies have shown that elevated PTH levels and incident hyperparathyroidism are associated with CKD progression [2‒4], there are no convincing trial data to support that PTH-lowering interventions are able to slow kidney function decline, as will be discussed in more detail below. At the same time, new vitamin D formulations have become available.
Several forms of vitamin D have been developed, and their efficacy to increase serum 25-hydroxyvitamin D (25D) levels has been compared. Calcifediol (25-hydroxyvitamin D3) is approximately five times more efficient in increasing 25D levels than cholecalciferol [5]. Extended-release calcifediol (ERC) has been approved by the US Food and Drug Administration and the European Medicines Agency and is registered in some countries including the USA and Canada for the treatment of secondary hyperparathyroidism in patients with CKD G3–4 and serum total 25D <30 ng/mL. ERC was very effective in increasing serum 25D level and suppressing PTH in a trial in CKD stage 3–4 patients [6]. All patients randomized to ERC (60 μg/day) achieved a serum 25D level of >30 ng/L, while 44% of patients on cholecalciferol and 15% on paricalcitol (1–2 μg/day) combined with low-dose cholecalciferol (800 IU/day) reached this target. Intact PTH response rates at the end of the study (≥10, 20 or 30% below baseline) were similar for ERC and paricalcitol combined with low-dose cholecalciferol, while these rates were much lower for immediate-release calcifediol (266 μg/month) and high-dose cholecalciferol (300,000 IU/month) were much lower. A network meta-analysis including nine randomized controlled trials showed that ERC is comparable in lowering PTH levels with paricalcitol while having less impact on serum calcium [7]. Given these promising effects of ERC on biochemical endpoints, clinically relevant outcome data are eagerly awaited.
Against this background, in this issue of the American Journal of Nephrology, Bishop et al. [8] addressed the hypothesis that a sustained PTH reduction in patients treated with ERC is linked with slower kidney function decline. The investigators performed a post hoc analysis in 126 adults with SHPT, stage 3–4 CKD, and low serum 25D who had been treated for 1 year with ERC in pivotal trials. ERC was administered at 30 μg/day increasing, as needed, to 60 μg/day to achieve ≥30% reductions in PTH. In the current analysis, two subgroups were identified: patients who demonstrated a sustained ≥30% PTH reduction to ERC treatment, and patients who did not reach such reduction. Their key finding was that individuals who reached a persistent ≥30% decline in PTH demonstrated less kidney function decline (eGFR decline 0.6 ± 0.8 mL/min/1.73 m2) than those without such effect on PTH (eGFR decline 3.2 ± 0.7 mL/min/1.73 m2, p = 0.01). This result is of interest as it draws attention to the biochemical response to ERC treatment as a potential determinant of kidney function decline. While the title of the article suggests a causal relationship between PTH suppression by ERC and slower CKD progression, causality is still far from proven by the present observational study based on uncontrolled trial data. These findings should be considered in the context of other studies addressing the potential renoprotective effects of PTH-lowering interventions: PTX, cinacalcet, and (active) vitamin D.
PTX, Cinacalcet, and Kidney Outcomes
Most data regarding the effect of PTX on kidney function come from studies in patients with primary hyperparathyroidism. A recent very large study in 43,697 primary hyperparathyroidism patients used target trial emulation to estimate the effect of PTX on long-term kidney function [9]. While no effect was observed in the total population, a subgroup analysis suggested that PTX was associated with a reduced risk of a sustained eGFR decline by at least 50% from the pre-treatment eGFR among patients younger than 60 years. A secondary analysis of a randomized controlled trial in 150 patients that compared PTX with non-surgical treatment did not show any difference in kidney function after 10 years of follow-up [10]. A randomized trial comparing subtotal PTX with cinacalcet in kidney transplant recipients with persistent hyperparathyroidism showed that, while PTX had a stronger effect on PTH, calcium and phosphate, patients in the cinacalcet arm had a more pronounced reduction in eGFR (−9 mL/min/1.73 m2, p = 0.01 vs. baseline), compared with the PTX arm (−4 mL/min/1.73 m2, p = 0.1 vs. baseline) [11].
Vitamin D (Analogues) and Kidney Outcomes
The potential effect of nutritional vitamin D and vitamin D analogues on kidney outcomes has been addressed in several studies. While active vitamin D (analogue) likely has a small albuminuria-lowering effect [12], the clinical relevance is likely marginal [13]. In an ancillary study from the Vitamin D and Omega-3 Trial (VITAL), supplementation with vitamin D3 did not prevent the development or progression of CKD in 1,312 individuals with type 2 diabetes [14]. While most participants had normal kidney function at baseline, and vitamin D supplementation could not be considered PTH suppression in this context, this trial provides a strong argument against direct renoprotective effects of vitamin D in this population.
The potential effects of PTH-lowering interventions on kidney outcomes thus remain a topic of debate. Given the observational nature of this post hoc analysis by Bishop et al. [8], the question remains what could explain the suboptimal PTH response to ERC in a considerable part of the study population, and whether this factor may have also contributed to accelerated CKD progression. What discriminates those who showed a sustained PTH reduction from those who did not? While on average, both groups had an identical eGFR at baseline (30.7 mL/min/1.73 m2), the biochemical response to ERC was less pronounced in the subgroup with no ≥30% PTH reduction, with lower achieved serum 25D levels at end of treatment (72.1 ng/mL), compared to 89.1 ng/mL in the PTH responder group. There was no difference in albuminuria at baseline or the end of treatment, nor was there a difference in the change in albuminuria during the study between both subgroups. A relevant difference, as also highlighted by the authors, was that body mass index (BMI) was considerably higher in the group without a sustained PTH response (at mean 37.5 kg/m2 vs. 33.6 kg/m2, p < 0.05). Since obesity is a well-established risk factor for CKD progression [15], BMI could have been a confounder that explains the more pronounced loss of kidney function in the subgroup of patients without a sustained PTH response. Taken together, the present study by Bishop et al. [8] sets the stage for a randomized controlled trial with ERC to more definitively establish whether adequate suppression of PTH provides kidney protection in individuals with CKD stage 3–4 and secondary hyperparathyroidism.
Conflict of Interest Statement
M.H.d.B. has received a research grant from CSL Vifor; consulting fees from Astra Zeneca, Bayer, Pharmacosmos, and Sanofi Genzyme; and lecture fees from Amgen, Kyowa Kirin Pharma, and CSL Vifor (all to employer).
Funding Sources
This study was not supported by any sponsor or funder.
Author Contributions
M.H.d.B. wrote the manuscript.
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