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29 September 2021
In this video presentation, which was hosted by Kidney Disease: Improving Global Outcomes (KDIGO) in May 2021, Professor Markus Ketteler* revisits some of the 2017 KDIGO chronic kidney disease–mineral and bone disorder (CKD–MBD) guidelines, which he helped to formulate,1 and asks whether they are supported or refuted by recent data. KDIGO guidelines consist of either suggestions or recommendations, with recommendations being supported by stronger evidence.1 Professor Ketteler evaluates the strength of one recommendation and four suggestions, two of which are discussed below. The suggestions concern the management of abnormally high parathyroid hormone (PTH) levels in non-dialysis chronic kidney disease (ND-CKD) patients.
One of the most important of KDIGO’s 2017 CKD–MBD suggestions in terms of treating ND-CKD patients with abnormally high PTH levels is 4.2.1.:
Since the publication of this suggestion, the optimal PTH level in ND-CKD patients is still unknown, and the act of addressing modifiable risk factors (such as vitamin D insufficiency/deficiency) as early as stage 3A CKD has received support.
A 2021 retrospective study (N=2,728) evaluated patient characteristics, treatment patterns and PTH control over the first year of haemodialysis by PTH level immediately prior to initiation of haemodialysis.2 The data came from phases 4 to 6 (2009 to 2018) of the Dialysis Outcomes and Practice Patterns Study (DOPPS).2
Elevated PTH prior to haemodialysis was found to be strongly associated with uncontrolled PTH during haemodialysis, despite more aggressive treatment with active vitamin D (AVD) or calcimimetics.2
As the results of this retrospective study clearly illustrate the importance of treating secondary hyperparathyroidism (SHPT) early, Professor Ketteler next turns his attention to an important treatment-related suggestion.
One of the suggestions that was fully revised in 2017 was 4.2.2.:1
The basis for 4.2.2. was that calcitriol and AVD analogues were associated with a significantly increased risk of hypercalcaemia and no improvements in clinically relevant outcomes in the PRIMO and OPERA trials.1,3,4 These associations remain and have been emphasised by subsequent meta-analyses.5,6
For example, in a meta-analysis of five studies (N=738), including PRIMO and OPERA, ND-CKD patients with SHPT who were treated with AVD analogues (paricalcitol in four of the studies and alfacalcidol in one of the studies) were found to have a 7.2-fold greater risk of developing hypercalcaemia than patients treated with placebo (Figure 1).6 The objective of the meta-analysis was to evaluate the effect of AVD analogues on hypercalcaemia in ND-CKD patients with SHPT.6
CI: confidence interval. Reproduced from Cozzolino M et al. 2021.6
Since PRIMO (Thadhani et al.) and OPERA (Wang et al.) accounted for a large proportion of the hypercalcaemia events, a secondary sensitivity analysis excluding these studies was conducted and found that the risk of hypercalcaemia was still 3.0-fold greater in patients receiving an AVD analogue vs placebo.6
This, then, raises an important question: which vitamin D therapy should be used in stage 3 and 4 CKD patients without severe SHPT if AVD and AVD analogues should be reserved for stage 4 and 5 CKD patients with severe SHPT?
In the video presentation, Professor Ketteler reviews both old and new treatment options, comparing them against a figurative optimal therapy. He also explores the question of how high 25-hydroxyvitamin D (25(OH)D) needs to be increased to ensure sustained PTH suppression.
Based on recent findings, Professor Ketteler concludes that a level between 50 and 90 ng/mL (125 and 225 nmol/L) may need to be targeted, which is much higher than the sufficiency levels that have been recommended for the general population (≥20 and ≥30 ng/mL [≥49.9 and ≥74.9 nmol/L]).7,8
You can watch the full presentation by Professor Ketteler on KDIGO’s website. The talk is followed by a presentation about controlling phosphate and calcium levels in CKD patients by Professor Marc Vervloet,‡ who is another member of the work group that formulated the 2017 guidelines.1
Footnotes and references
*Director of the Department of General Internal Medicine and Nephrology at the Robert-Bosch-Hospital in Stuttgart, Germany.
†2C = A suggestion rather than a recommendation (2), with low quality of evidence (C).1
‡Professor of Nephrology in the Department of Nephrology, Amsterdam University Medical Center, Amsterdam, The Netherlands.
1. Kidney Disease: Improving Global Outcomes (KDIGO) Work Group. Kidney Int Suppl. 2017;1–59.
2. Tabibzadeh N et al. Nephrol Dial Transplant. 2021;36(1):160–9.
3. Thadhani R et al. JAMA. 2012;307(7):674–84.
4. Wang AY-M et al. JASN. 2014;25(1):175–86.
5. Li X et al. Nephrology. 2015;20:706–14.
6. Cozzolino M et al. Clin Kidney J. 2021;sfab091.
7. Ross AC et al. J Clin Endocrinol Metab. 2011;96(1):53–8.
8. Holick MF et al. J Clin Endocrinol Metab. 2011;96:1911–30.
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