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Two key opinion leaders in SHPT management share the latest understanding of SHPT and how it develops in CKD
In a comprehensive interview that was first published online in the Emergency Medicine Journal (EMJ) in February 2021, professors Patrice Ambühl* and Jordi Bover† deliver a wealth of insights about secondary hyperparathyroidism (SHPT) in non-dialysis chronic kidney disease (CKD).1 The interview covers a wide range of subjects and includes practical lessons useful in clinical practice. In one of the many highlights of the interview, the professors elaborate on the latest understanding of the trade-off hypothesis of SHPT pathogenesis.
The old hypothesis
Parathyroid hormone (PTH) is one of the key regulators of serum calcium homeostasis.2 Whenever the level of calcium drops, PTH secretion increases to normalise it.2 Therefore, the development of SHPT in CKD was perceived to be largely calcium related.3
But this is not the whole story, according to Professor Ambühl: “Actually, PTH [and thus SHPT] is mainly regulated by phosphate.”1
Professor Ambühl went on to explain the most recent rendition of the trade-off hypothesis, which gives a prominent role to not only phosphate but also fibroblast growth factor-23 (FGF-23) and vitamin D.1
The trade-off hypothesis
According to Professor Ambühl, “The first [measurable] step in the development of SHPT within CKD is an increase in the level of FGF-23, a phosphaturic hormone, in order to compensate for the loss of the glomerular filtration of phosphate by supporting the excretion of excess phosphate.[1]
“FGF-23 [also] acts by inhibiting the activation of vitamin D [25(OH)D] to 1,25(OH)2D, the active form of vitamin D that increases the absorption of phosphate from the gut.[1]
“In turn, this leads to a decrease in calcium, as 1,25(OH)2D is the principal regulator for the intestinal absorption of calcium.[1]
“As a result, PTH levels start to increase to normalise the serum levels of calcium [Figure 1], an effect that is reinforced by loss of the direct inhibitory effect of 1,25(OH)2D on PTH release [as mediated by vitamin D receptors on the parathyroid glands].”1
Figure 1. The roles of FGF-23 and vitamin D insufficiency in SHPT pathogenesis1,4
The reduced functional renal mass characteristic of CKD leads to a decrease in phosphate clearance and consequential phosphate build-up. To reduce the phosphate level, the amount of FGF-23 released from bone increases. FGF-23 also reduces 1,25(OH)2D production by downregulating 1-alpha-hydroxylase (CYP27B1), the enzyme responsible for the synthesis of 1,25(OH)2D from 25(OH)D. 25(OH)D insufficiency, which often accompanies CKD, contributes to the low 1,25(OH)2D level. PTH increases to keep calcium and 1,25(OH)2D up and phosphate down, leading to SHPT.
Adapted from EMJ Nephrol. 20211 and Friedl C et al. 2017.4
“Unfortunately, this drive towards normocalcaemia is at the cost of hyperphosphataemia, as phosphate absorption from the gut is also increased. This is compensated [for], in part, through a PTH-induced inhibition of phosphate reabsorption from the renal tubule.”1
Expanding on the key role of vitamin D in this process, Professor Ambühl added: “If [the suppression of vitamin D activation] continues over a long timecourse, the patient develops hypocalcaemia, leading to an increase in PTH, parathyroid hyperplasia and the associated clinical consequences of uncontrolled SHPT.[1]
“Hypocalcaemia is [therefore] a late phenomenon in the clinical course of CKD. In fact, the usual spectrum in ND-CKD [non-dialysis CKD] is normal calcium, normal phosphate and high PTH because PTH drives calcium up and phosphate down.”1 Normocalcaemia and normophosphataemia are traded for hyper-FGF-23 levels and SHPT, hence the trade-off hypothesis of SHPT pathogenesis.1,5,6
The importance of treating SHPT early
As a low vitamin D level is a major trigger for the increase in PTH secretion in the trade-off hypothesis,1,4 Professor Ambühl stressed that, “from a pathological point of view, it makes sense to start vitamin D replacement very early”.1 Measuring and correcting vitamin D starting from stage 3A CKD is also suggested in the 2017 Kidney Disease: Improving Global Outcomes (KDIGO) guidelines.7
The call for early treatment was re-emphasised by Professor Bover: “We believe that early treatment is important. If patients are not properly followed and treated early, some will develop a progressive form of SHPT in which the parathyroid gland grows and becomes autonomous. If not treated until this stage, you have to use high doses of the different treatments for SHPT, which was the situation we had 50 years ago, [...]. We ended up doing parathyroidectomies, and this is not a solution, being too radical and exposing patients to additional morbidity.”1
Read the interview now
EMJ’s enlightening interview with professors Ambühl and Bover is available on the EMJ website. Read it now to learn more from the professors, including:
- What the three areas are in which more research is required
- Why it may not be appropriate to normalise PTH
- What new and exciting treatments are emerging, and how they might change the treatment landscape
Footnotes and references
*Institute for Nephrology, Stadtspital Waid and Triemli, Zurich, Switzerland.
†Department of Nephrology, Fundació Puigvert, Barcelona, Spain.
EMJ Nephrol. 2021;9(Suppl 1):2–9.
Ilahi A et al. Anatomy, Head and Neck, Parathyroid. [Updated 2020 August 10]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021 January–. Available from: https://www.ncbi.nlm.nih.gov/books/NBK537203/ [cited 2021 July 21].
Massry SG et al. Kidney Int. 1974;5:437–45.
Friedl C et al. Int J Nephrol Renovascular Dis. 2017;10:109–22.
Wolf M et al. J Am Soc Nephrol. 2010;21(9):1427−35.
Levin A et al. Kidney Int. 2007;71(1):31−8.
Kidney Disease: Improving Outcomes (KDIGO) Work Group. Kidney Int Suppl. 2017;7:1−59.
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© 2021 Vifor Fresenius Medical Care Renal Pharma
Vifor Fresenius Medical Care Renal Pharma (VFMCRP) Ltd., a company of the Vifor Pharma Group, is the partner of choice for renal pharmaceutical and innovative, patient-focused solutions. The Vifor Pharma Group is a global pharmaceuticals company. It aims to become the global leader in iron deficiency, nephrology …
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