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early treatment

The importance of treating SHPT early

The importance of treating SHPT early

Complications of SHPT and CKD–MBD

Secondary hyperparathyroidism (SHPT) is a component of the systemic syndrome chronic kidney disease–mineral and bone disorder (CKD–MBD), which is characterised by abnormalities in bone mineral and vitamin D metabolism, bone turnover and vascular calcification (Figure 1).1

Figure 1. Complications of CKD–MBD, the systemic syndrome that encompasses SHPT1–3
graph

Adapted from Moe S et al. 2006,1 Cunningham J et al. 20112 and Rodriguez M et al. 2005.3

 

Unmanaged or poorly controlled SHPT is associated with:

  • Cardiovascular calcification,2,4 resulting in cardiovascular events5–9
  • Bone disease,10–12 leading to bone fractures7,8,13
  • Therapeutic resistance,3,14–16 leading to parathyroidectomy2,17,18
  • Progression of chronic kidney disease (CKD)8,9,19 and death7,8,19,20

Cardiovascular events

SHPT is associated with increased risk of cardiovascular events5–9

  • After 10 years of follow-up in stage 3 or 4 CKD patients (N=5,108), parathyroid hormone (PTH) levels were shown to be an independent risk factor of vascular events.7 The risk was lowest at a baseline PTH level of 69 pg/mL (7.3 pmol/L; Figure 2)7
Figure 2. Ten-year probability of vascular events based on baseline PTH levels7
graph

An observational study of 5,108 stage 3 or 4 CKD patients investigating the relationships between PTH levels and subsequent ten-year probabilities of fractures, vascular events and death.

Adapted from Geng S et al. 2019.7

 
  • After four years of follow-up in CKD patients (N=2,445), SHPT was shown to be independently associated with risk of cardiovascular events (hazard ratio [HR]: 1.61; 95% confidence interval [CI]: 1.07, 2.43)*9
  • Development of SHPT has also been associated with a 2.2-fold (HR: 2.16; 95% CI: 1.42, 3.28) higher risk of major adverse cardiovascular events in CKD patients (N=2,556)†8
     

Bone fractures

SHPT is associated with increased risk of fractures7,8,13

  • After 10 years of follow-up in stage 3 or 4 CKD patients (N=5,108), PTH levels were shown to be an independent risk factor of fractures, regardless of CKD stage (Figure 3)7
Figure 3. Ten-year probability of fractures based on baseline PTH levels7
graph

An observational study of 5,108 stage 3 or 4 CKD patients investigating the relationships between PTH levels and subsequent ten-year probabilities of fractures, vascular events and death.

Reproduced from Geng S et al. 2019.7

 
  • Development of SHPT has also been associated with a 1.8-fold (95% CI: 1.5, 2.2) higher relative risk of fractures†8

Therapeutic resistance

The parathyroid glands become increasingly unresponsive to treatments as SHPT progresses3,14,15

  • In SHPT, prolonged parathyroid stimulation initially presents with polyclonal cell proliferation (i.e. diffuse hyperplasia) in one or more of the parathyroid glands3,17
  • If not managed appropriately, this can develop into monoclonal nodular hyperplasia with reduced expression of vitamin D receptors (VDRs) and calcium-sensing receptors (CaSRs; Figure 4).3,17 This decrease in VDR and CaSR expression results in an increase in resistance to vitamin D and calcimimetic therapies,3,14,15 leaving parathyroidectomy as the only available treatment option17,18
Figure 4. Progressive parathyroid gland hyperplasia and its effects on CaSR and VDR expression3
graph

Adapted from Rodriguez M et al. 2005.3

 
  • In an analysis of 2,728 haemodialysis patients, elevated PTH prior to haemodialysis was strongly associated with uncontrolled PTH during haemodialysis, despite more aggressive SHPT treatment with active vitamin D or calcimimetics (figures 5A and 5B)16
  • In the same analysis, the risk of having a PTH level greater than 600 pg/mL (63.6 pmol/L) 9 to 12 months after initiation of dialysis was 29% for patients who were initiated on dialysis with a PTH greater than 600 pg/mL and only 7% for patients who were initiated on dialysis with a PTH between 150 and 300 pg/mL (15.9 and 31.8 pmol/L).16 The adjusted risk difference between the two patient groups was 19%, demonstrating a robust association (Table 1)16
Figures 5A and 5B. Proportions of patients prescribed active vitamin D (A) and calcimimetics (B) over the first year of haemodialysis by PTH level prior to start of haemodialysis16
graph
graph
Table 1. Risk of PTH >600 pg/mL 9–12 months after haemodialysis start by PTH levels prior to haemodialysis16
graph

 

A descriptive analysis of 2,728 incident haemodialysis patients in Dialysis Outcomes and Practice Patterns Study (DOPPS) phases 4 to 6 (2009 to 2018). The analysis evaluated patient characteristics, treatment patterns and PTH control over the first year of haemodialysis by PTH level immediately prior to haemodialysis initiation. Intravenous or oral. §Adjusted for age, sex and black race.

 

Reproduced (A and B) and adapted (C) from Tabibzadeh N et al. 2021.16

 

 

Parathyroidectomy is performed in suitable candidates if:2

  • They are refractory to medical therapy
  • Therapy is no longer effective (persistent PTH levels >1,000 pg/mL [106 pmol/L], associated with hypercalcaemia)
  • The volume of at least one hyperplastic gland is >500 mm3
 

Learn more about the available treatments for SHPT in CKD

Parathyroidectomy is associated with significant morbidity18

 

In a retrospective study evaluating clinical outcomes up to 1 year after parathyroidectomy in 7,707 CKD patients receiving haemodialysis, parathyroidectomy was associated with significant morbidity (Figure 6).18

Figure 6. All-cause hospitalisation events before and after parathyroidectomy18
graph

 

A retrospective study evaluating clinical outcomes up to 1 year after parathyroidectomy in 7,707 CKD patients receiving haemodialysis.

Reproduced from Ishani A et al. 2015.18

 

Compared with the preceding year:18

  • All-cause hospitalisations were higher by 39% (192.0 versus 138.6 per 100 patient-years; RR: 1.39; 95% CI: 1.34, 1.44)
  • Total number of hospital days was higher by 58% (1245.0 versus 789.3 per 100 patient-years; RR: 1.58; 95% CI: 1.56, 1.60)
  • Intensive care unit admission was higher by 69% (64.0 versus 37.9 per 100 patient-years; RR: 1.69; 95% CI: 1.59, 1.80)

CKD progression and death

SHPT is associated with CKD progression8,9,19 and higher risk of death7,8,19,20

  • After two years of follow-up in CKD patients (N=2,445), SHPT was shown to be independently associated with CKD progression (odds ratio [OR]: 2.75; 95% CI: 1.55, 4.88)*9
  • SHPT development was associated with a 5.0-fold (95% CI: 3.5, 7.2) risk of CKD progression and a 1.4-fold (HR: 1.38; 95% CI: 1.05, 1.83) higher risk of death in a cohort of 2,556 CKD patients†8
  • In a retrospective study, ND-CKD patients with SHPT (n=645) were over six times more likely to be initiated on dialysis (HR: 6.52) and over five times more likely to be initiated on dialysis or die (HR: 5.05) compared with ND-CKD patients without SHPT (n=2,422; Figure 7)19
Figure 7. Kaplan–Meier analysis of time to dialysis or death (matched cohort analysis)19
graph

A retrospective US study of insurance claims from 66,019 ND-CKD patients that compared the rate of resource utilisation and costs as well as risks of dialysis and mortality among patients with and without SHPT.

Reproduced from Schumock GT et al. 2008.19

 
  • Higher PTH levels were associated with higher all-cause mortality (p=0.028) after multivariable adjustments in 515 ND-CKD patients (Figure 8)20
Figure 8. Estimated all-cause mortality for continuous PTH in a multivariable regression spline model20
graph

A retrospective US study of 515 ND-CKD patients investigating the relationship between PTH levels and all-cause mortality.

Reproduced from Kovesdy CP et al. 2008.20

  • After 10 years of follow-up in stage 3 or 4 CKD patients (N=5,108), PTH levels were shown to be an independent risk factor of death.7 The risk of death was lowest at a baseline PTH level of 58 pg/mL (6.1 pmol/L; Figure 9)7
Figure 9. Ten-year probability of death based on baseline PTH levels7
graph

An observational study of 5,108 stage 3 or 4 CKD patients investigating the relationships between PTH levels and subsequent ten-year probabilities of fractures, vascular events and death.

Adapted from Geng S et al. 2019.7

 

Learn about the goal of SHPT treatment in CKD patients

Footnotes, abbreviations and references

*An observational prospective cohort study of 2,445 CKD patients that investigated the potential associations between SHPT, CKD progression and cardiovascular events, and their associated costs.9

 

An observational study of 2,556 CKD patients (stages 1 to 5) that explored the incidence and predictors of SHPT and the association between SHPT and the risks of fractures, CKD progression, major adverse cardiovascular events and death.8

 

CaSR: calcium-sensing receptor; CI: confidence interval; CKD: chronic kidney disease; CKD–MBD: chronic kidney disease–mineral and bone disorder; DOPPS: Dialysis Outcomes and Practice Patterns Study; FGF-23: fibroblast growth factor-23; HR: hazard ratio; ND-CKD: non-dialysis chronic kidney disease; OR: odds ratio; PTH: parathyroid hormone; RR: rate ratio; SHPT: secondary hyperparathyroidism; VDR: vitamin D receptor.

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