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30 August 2021
Published online in the Journal of Nephrology in June 2021, a detailed review by professors Ketteler* and Ambühl† explores the challenges, unanswered questions, unmet needs, latest data and opportunities associated with managing secondary hyperparathyroidism (SHPT) in non-dialysis chronic kidney disease (ND-CKD) patients.1 The review includes a detailed look at the optimal 25-hydroxyvitamin D (25(OH)D) level required to reliably reduce parathyroid hormone (PTH) levels in stage 3 and 4 CKD patients without producing clinically meaningful increases in serum calcium and phosphate.1
Common in chronic kidney disease (CKD),4 SHPT can increase the risks of bone and cardiovascular complications,5,6 therapeutic resistance,7–10 parathyroidectomy,11 accelerated CKD progression6,12,13 and death.5,6,13,14 These complications make early diagnosis and effective treatment essential.4,15
Correction of low vitamin D levels is a well-recognised treatment approach,2 but the target PTH level and the level of 25(OH)D required to induce PTH-lowering effects are still unclear.2,3
Two widely recognised clinical thresholds for serum 25(OH)D sufficiency are ≥20 ng/mL (≥49.9 nmol/L) and ≥30 ng/mL (≥74.9 nmol/L), which were both defined in 2011 by the Institute of Medicine and the Endocrine Society, respectively.16,17 However, these thresholds were intended for the general population.16,17 Recent evidence suggests that these levels may be too low for patients with CKD, with levels more than double the amount defined by the Institute of Medicine now being put forward as the target for clinically meaningful reductions in PTH.3
A large cross-sectional analysis of 14,289 stage 3 to 5 CKD patients sought to identify a potential therapeutic 25(OH)D target that optimally reduces PTH without producing excessive hypercalcaemia or hyperphosphataemia.3 Progressively higher 25(OH)D levels were found to be associated with progressively lower mean PTH levels, with no evidence of a decreasing effect of 25(OH)D to reduce PTH until 25(OH)D levels of 42 to 48 ng/mL (105 to 120 nmol/L).3 The higher 25(OH)D concentrations were not associated with increased rates of hypercalcaemia or hyperphosphataemia.3
Further support for a higher target 25(OH)D level comes from the VITALE study, which assessed the skeletal and extra-skeletal effects of high doses versus low doses of cholecalciferol in 536 renal transplantation patients.18 At the end of the study, the high- and low-dose groups had mean 25(OH)D levels of 43.1 ng/mL (107.6 nmol/L) and 25.1 ng/mL (62.6 nmol/L), respectively, but only the high-dose group demonstrated a reduction in PTH.18 The number of patients with incident hypercalcaemia or hyperphosphataemia did not differ between the groups.18
The vitamin D therapies widely used for the treatment of SHPT in ND-CKD are nutritional vitamin D (NVD), active vitamin D (AVD) and AVD analogues.15 Immediate-release (IR) calcifediol is also used, though it is available in a limited number of countries, such as France28 and Spain.29
All these vitamin D products fail to reliably deliver the desired clinical effects, which are to:4
NVD supplements do not consistently and reliably reduce PTH levels in ND-CKD patients, even at higher doses.19–22
IR calcifediol is not able to provide clinically meaningful reductions in PTH in ND-CKD patients.27
AVD and its analogues can suppress PTH;26 however, they are associated with a significantly increased risk of hypercalcaemia,23,24 prompting KDIGO to suggest that they no longer be routinely used in the treatment of SHPT in stages 3 to 5 CKD.2
Kidney Disease: Improving Global Outcomes (KDIGO) recommends regular monitoring of PTH levels starting from stage 3A CKD in order to identify patients with progressively rising or persistently elevated PTH levels.2 This emphasises the view that SHPT treatment should be based on trends rather than on a single elevated value. Patients who are identified can then be evaluated for modifiable risk factors, such as vitamin D deficiency.2 However, rates of testing for SHPT are lower than is recommended by KDIGO.30
In an investigation of the consistency with which US nephrologists follow KDIGO’s 2017 guidelines on testing and retesting for abnormalities in analytes associated with chronic kidney disease–mineral and bone disorder (CKD–MBD), the number of patients tested for abnormalities was found to be suboptimal.30 The lowest number of tests were ordered for PTH, 25(OH)D and phosphorus.30 As a result, opportunities to treat SHPT and potentially prevent the complications with which it is associated are being missed.
You can read the full and comprehensive review by professors Ketteler and Ambühl on the Springer website.
Footnotes and references
*General Internal Medicine and Nephrology, Robert-Bosch-Krankenhaus, Stuttgart, Germany.
†Clinic and Polyclinic for Internal Medicine, Universitätsspital Zürich, Zürich, Switzerland.
1. Ketteler M et al. J Nephrol. 2021;DOI:10.1007/s40620-021-01082-2.
2. Kidney Disease: Improving Global Outcomes (KDIGO) Work Group. Kidney Int Suppl. 2017;7:1–59.
3. Ennis JL et al. J Nephrol. 2016;29(1):63–70.
4. Sprague SM et al. Exp Rev Endocrinol Metab. 2017;12(5):289–301.
5. Geng S et al. Osteoporos Int. 2019;30:2019–25.
6. Xu Y et al. Clin Kidney J. 2021;sfab006.
7. Rodriguez M et al. Am J Renal Physiol. 2005;288:F253–64.
8. Fukuda N et al. J Clin Invest. 1993;92:1436–43.
9. Gogusev J et al. Kidney Int. 1997;51:328–36.
10. Tabibzadeh N et al. Nephrol Dial Transplant. 2021;36(1):160–69.
11. Cunningham J et al. Clin J Am Soc Nephrol. 2011;6:913–21.
12. Bermudez-Lopez M et al. Abstract presented at: 57th ERA–EDTA Congress; 2020 June 6–9; virtual.
13. Schumock G et al. Curr Med Res Opin. 2008;24:3037–48.
14. Kovesdy CP et al. Kidney Int. 2008;73:1296–302.
15. Tomasello S. Diabetes Spectr. 2008;21:19–25.
16. Ross AC et al. J Clin Endocrinol Metab. 2011;96(1):53–8.
17. Holick MF et al. J Clin Endocrinol Metab. 2011;96:1911–30.
18. Courbebaisse M et al. Abstract presented at: 56th ERA–EDTA Congress; 2019 June 13–16; Budapest, Hungary.
19. Agarwal R et al. Nephrol Dial Transplant. 2016;31:706–13. Erratum in: Nephrol Dial Transplant. 2021;36(3):566–7.
20. Agarwal R et al. Nephrol Dial Transplant. 2021;36(3):566–7. Erratum for: Nephrol Dial Transplant. 2016;31:706–13.
21. Westerberg PA et al. Nephrol Dial Transplant. 2018;33(3):466–71.
22. Bover J et al. Clin Kidney J. 2021;sfab035.
23. Li X et al. Nephrology. 2015;20:706–14.
24. Csomor P et al. Poster presented at: ISPOR Europe; 2019 November 2–6; Copenhagen, Denmark.
25. Coyne DW et al. Nephrol Dial Transplant. 2013;28:2260–8.
26. Coyne DW et al. Clin J Am Soc Nephrol. 2014;9:1620–6.
27. Petkovich M et al. J Steroid Biochem Mol Biol. 2015;148:283–9.
28. Desma Pharma. Dedrogyl 15 mg/100 mL Solution Buvable en Gouttes Résumé des Caractéristiques du Produit; 2021 March 30.
29. Faes Farma SA. Hidroferol 0.266 mg soft capsules Summary of Product Characteristics; 2015 August.
30. Wetmore JB et al. Kidney Int Rep. 2021;DOI:10.1016/j.ekir.2020.12.036.
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