HOW STABLE ARE YOUR PATIENTS
WITH SHPT?Discover how your treatment
decision could affect your patients with SHPT
SHPT: secondary hyperparathyroidism.MED-HQ-NA-2000013Date of preparation: May 2020Vifor Fresenius Medical Care Renal Phama Ltd
WHAT PROPORTION OF YOUR PATIENTS WITH STAGE 3 OR 4 CKD DO YOU ESTIMATE ALSO HAVE SHPT?
CKD: chronic kidney disease;SHPT: secondary hyperparathyroidism.
25–57%
40–82%
12–33%
SHPT AFFECTS 40–82% OF PATIENTS WITH STAGE 3OR 4 CKD1
SHPT occurs in CKD as early as stage 22
The prevalence and severity of SHPT increase with declining kidney function2
SHPT and abnormal calcium and phosphorus are frequently observedfrom stage 3 CKD2
CKD: chronic kidney disease; GFR: glomerular filtration rate; PTH: parathyroid hormone; SHPT: secondary hyperparathyroidism.
Prevalence of abnormal PTH, calcium and phosphorus levels by worsening kidney function2
Patie
nts
(%)
Estimated GFR level (mL/min)
100
80
60
40
20
080
(n=61)79–70
(n=117)69–60
(n=230)59–50
(n=386)49–40
(n=355)39–30
(n=358)29–20
(n=204)6.9 pmol/L (>65 pg/mL)
Cross-sectional analysis of baseline data from 5,255 patients with CKD.
Adapted from Levin A et al. 2007.2
SHPT IS A MALADAPTIVE RESPONSE TO DISRUPTED MINERAL AND VITAMIN D HOMEOSTASIS DUE TO RENAL FUNCTION DECLINE3
Loss of mineral homeostasis due to renal failure leads to:3,4
Bone and cardiovascular complications
Parathyroid gland hyperplasia
1,25(OH)2D: 1,25-dihydroxyvitamin D;25(OH)D: 25-hydroxyvitamin D; CKD: chronic kidney disease; FGF-23: fibroblast growth factor-23; PO: phosphate; PTH: parathyroid hormone; sCa: serum calcium; SHPT: secondary hyperparathyroidism; sPO: serum phosphate.
Adapted from Cunningham J et al. 2011,3 Rodriguez M et al. 2005,4 Friedl C et al. 20175 and Wu W et al. 2018.6
Pathogenesis of SHPT3–6
Parathyroid gland hyperplasia ParathyroidectomyTherapeutic resistance
COMPARED WITH PATIENTS WITHOUT SHPT, PATIENTS WITH SHPT ARE >5X MORE LIKELY TO BE INITIATED ON DIALYSIS OR DIE7
SHPT is associated with increased morbidity, mortality and disease progression in patients withND-CKD7
CKD: chronic kidney disease; ND-CKD: non-dialysis chronic kidney disease; SHPT: secondary hyperparathyroidism.
Kaplan–Meier analysis of time to dialysis or death7
A retrospective study of insurance claims from 66,644 ND-CKD patients with or without SHPT.
Reproduced from Schumock G et al. 2008.7
Surv
ival
dis
trib
utio
n fu
nctio
n
Time to dialysis or death (days)
1.0
0.75
0.5
0.25
00
CKD w/o SHPT cohortCKD w SHPT cohort
250 500 750 1000 1250 1500
PTH LEVELS INDEPENDENTLY PREDICT FRACTURES, VASCULAR EVENTS AND DEATH IN STAGE 3 AND 4 CKD PATIENTS8
The risks of fractures, vascular events and death rise with increasing baseline PTH levels, with the probability of vascular events and death being lowest at 69 and 59 pg/mL (7.3 and 6.3 pmol/L), respectively.8
CKD: chronic kidney disease; PTH: parathyroid hormone.
Observational study of 5,108 stage 3 or 4 CKD patients. The study investigated the relationships between baseline PTH levels and subsequentten-year probabilities of fractures, vascular events and death.
Reproduced from Geng S et al. 2019.8
Ten-year prob
ability
1.0
0.9
0.8
0.7
0 50 200 350 400100 150 300250Baseline PTH level (pg/mL)
Death
Vascular events
Ten-year prob
ability
0.5
0.4
0.3
0.2
0 50 200 350 400100 150 300250Baseline PTH level (pg/mL)
Fractures
A
B
Ten-year probability of fractures (A), vascular events and death (B) based on baseline PTH levels8
AT WHICH STAGE OFCKD DO YOU TYPICALLY INITIATE SHPT TREATMENT?
STAGE 2
STAGE 3
STAGE 4
STAGE 5
STAGE 1
CKD: chronic kidney disease; SHPT: secondary hyperparathyroidism.
EARLY DIAGNOSIS AND TREATMENT ARE CRUCIAL IN THE MANAGEMENT OF SHPT1,9,10
Disturbances in mineral metabolism with progression of CKD,11 highlighting the need for early treatment
The earliest alteration in mineral metabolism in CKD is an elevated FGF-23 level (1). This causes a decline in the level of 1,25(OH)2D (2), which leads to an increase in PTH secretion (3). All of these changes occur prior to elevations in phosphate levels (4).Colour-coded bands represent normal ranges.
Reproduced from Wolf M 2015.11
1,25(OH)2D: 1,25-dihydroxyvitamin D; CKD: chronic kidney disease; FGF-23: fibroblast growth factor-23; PTH: parathyroid hormone; SHPT: secondary hyperparathyroidism.
Without prompt and effective treatment,SHPT becomes:
Progressively more severe1,9,11,12
Increasingly unresponsive to medical treatment as the hyperplastic parathyroid glands become less sensitive to calcium and vitamin D hormone signalling1,4,13,14
Analyte conc
entration
1000
90
60
30
40
>90 75 60 45 30 15Glomerular filtration rate (mL/min/1.73m2)1,25(OH)
2D (pg/mL)
FGF-23 (RU/mL)
PTH (pg/mL)
Normal PTH range
Normal phosphate range
Phosphate (mg/dL)
23 4
1
Reduces PTH levels
Increases rates of vitamin D signalling
Avoids anundesirable increase in
FGF-23 levels
Avoids an undesirable increase in
phosphate levels
Avoids anundesirable increase in
calcium levels
THE OPTIMAL TREATMENT APPROACH WOULD HAVE WHICH PRIMARY CHARACTERISTIC?
25(OH)D: 25-hydroxyvitamin D; FGF-23: fibroblast growth factor-23; PTH: parathyroid hormone.
Increases25(OH)D levels
THE GOALS OF SHPT TREATMENT ARE TO REGAIN MINERAL HOMEOSTASIS AND POTENTIALLY REDUCE THE RISKS OF BONE AND CARDIOVASCULAR COMPLICATIONS9,10,12
Correction of SHPT requires a holistic approach that takes into account all key CKD–MBD parameters1
Increase 25(OH)D
The ideal treatment approach would:1
Reduce PTH
Minimally change calcium, phosphate and FGF-23 levels
25(OH)D: 25-hydroxyvitamin D; CKD–MBD: chronic kidney disease–mineral and bone disorder; FGF-23: fibroblast growth factor-23; PTH: parathyroid hormone; SHPT: secondary hyperparathyroidism.
Beneficial Detrimental No/Minimal change Small change Large change
Effects on key CKD–MBD parameters
Adapted from Sprague SM et al. 2017.1
LIMITATIONS OF NUTRITIONAL VITAMIN D, ACTIVE VITAMIN D AND ACTIVE ANALOGUES
Do not correct 25(OH)D1
Increase the risks of hypercalcaemia and hyperphosphataemia1,16–18
25(OH)D: 25-hydroxyvitamin D; CKD–MBD: chronic kidney disease–mineral and bone disorder; FGF-23: fibroblast growth factor-23; PTH: parathyroid hormone; RCT: randomised controlled trial.
Adapted from Sprague SM et al. 2017,1 Agarwal R et al. 2016,15 Li X et al. 2015,16 Coyne DW et al. 2013,17 Coyne DW et al. 201418 and Westerberg PA et al. 2018.19
Optimal treatment approach125(OH)D Calcium Phosphate PTH FGF-23
Effects on key CKD–MBD parameters
Active vitamin D andactive analogues1,16–18Nutritional vitamin D1,15,19
Beneficial Detrimental No/Minimal change Small change Large change
According to RCTs, nutritional vitamin D is ineffective at consistently reducing PTH and often delays effective therapy.1,15
In contrast, active vitamin D and active analogues can reduce PTH, but they:
THE LIMITATIONS OF CURRENT TREATMENT OPTIONS ARE ACKNOWLEDGED IN KDIGO 2017 GUIDELINES12
CKD: chronic kidney disease; CKD–MBD: chronic kidney disease–mineral and bone disorder; KDIGO: Kidney Disease—Improving Global Outcomes; PTH: parathyroid hormone.
View guidelines
The full KDIGO 2017 clinical practice guidelines areavailable online.
“In patients with CKD G3a–G5D, treatments of CKD–MBD should be based on serial assessments of phosphate, calcium, and PTH levels, considered together (Not Graded).”
“In patients with CKD G3a–G5 not on dialysis, the optimal PTH level is not known. However, we suggest that patients with levels of intact PTH progressively rising or persistently above the upper normal limit for the assay be evaluated for modifiable factors, including hyperphosphatemia, hypocalcemia, high phosphate intake, and vitamin D deficiency (2C).
“In adult patients with CKD G3a–G5 not on dialysis, we suggest that [active vitamin D and active analogues] not be routinely used (2C). It is reasonable to reserve the use of [active vitamin D and active analogues] for patients with CKDG4–G5 with severe and progressive hyperparathyroidism (Not Graded).”
KDIGO also mention that no studies of sufficient duration with nutritional vitamin D supplementation to suppress PTH could be identified, and “thus this therapy remains unproven.”
TO CONTROL SHPT, A 25(OH)D LEVEL OF 42–48 NG/ML(105–120 NMOL/L) IS REQUIRED20
Associated with lower PTH concentrations
Not associated with increased rates of hypercalcaemia or hyperphosphataemia
25(OH)D: 25-hydroxyvitamin D; CKD: chronic kidney disease; PTH: parathyroid hormone;SHPT: secondary hyperparathyroidism.
PTH by 25(OH)D level and CKD stage20
Plasma PTH
(pg/mL)
39
100
200
0
25(OH)D (ng/mL)
CKD stage 5
CKD stage 3CKD stage 2CKD stage 1
g
CKD stage 4
In CKD stages 3–5, progressively higher 25(OH)D levels are:20
The effect of 25(OH)D to reduce PTH does not decrease until 25(OH)D levels of 42–48 ng/mL (105–120 nmol/L).20
Cross-sectional analysis of 14,289 stage 1–5 CKD patients. The objective was to identify a therapeutic 25(OH)D target that optimally lowers PTH without producing excessive hypercalcaemia or hyperphosphataemia in CKD.
Reproduced from Ennis JL et al. 2016.20
To learn more about the unmet needs in SHPT
treatment, please contact a Vifor medical representative.
CAN YOU REGAIN CONTROL?
SHPT: secondary hyperparathyroidism.
REFERENCES1. Sprague SM et al. Exp Rev
Endocrinol Metab. 2017;12(5):289–301.2. Levin A et al. Kidney Int. 2007;71:31–8.3. Cunningham J et al. Clin J Am Soc
Nephrol. 2011;6:913–21.4. Rodriguez M et al. Am J Renal
Physiol. 2005;288:F253–64.5. Friedl C et al. Int J Nephrol
Renovascular Dis. 2017;10:109–22.6. Wu W et al. Exp Dermatol.
2018;27:1201–09.7. Schumock G et al. Curr Med Res
Opin. 2008;24:3037–48.8. Geng G et al. Osteoporos Int.
2019;30:2019–25.9. Tomasello S. Diabetes Spectrum.
2008;21(1):19–25.10. Locatelli F et al. Nephrol Dial
Transplant. 2002;17(5):723–31.11. Wolf M. JASN. 2010;21(9):1427–35.12. KDIGO Work Group. Kidney Int
Suppl. 2017;7:1–59.13. Fukuda N et al. J Clin Invest.
1993;92:1436–43. 14. Gogusev J et al. Kidney Int.
1997;51:328–36.15. Agarwal R et al. Nephrol Dial
Transplant. 2016;31:706–13.16. Li X et al. Nephrology. 2015;20:706–14. 17. Coyne DW et al. Nephrol Dial
Transplant. 2013;28:2260–8. 18. Coyne DW et al. Clin J Am Soc
Nephrol. 2014;9:1620–6.19. Westerberg PA et al. Nephrol Dial
Transplant. 2018;33(3):466–71.20. Ennis JL et al. J Nephrol.
2016;29:63–70.
