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?

12–33% 25–57% 40–82%

CKD: chronic kidney disease; SHPT: secondary hyperparathyroidism.

CKD: chronic kidney disease; GFR: glomerular filtration rate; PTH: parathyroid hormone; SHPT: secondary hyperparathyroidism.

SHPT AFFECTS 40–82% OF PATIENTS WITH STAGE 3 OR 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 observed from stage 3 CKD2

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

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.

SHPT IS A MALADAPTIVE RESPONSE TO DISRUPTED MINERAL AND VITAMIN D HOMEOSTASIS DUE TO RENAL FUNCTION DECLINE3

Parathyroid gland hyperplasia Parathyroidectomy Therapeutic resistanceAdapted 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

Loss of mineral homeostasis due to renal failure leads to:3,4

Parathyroid gland hyperplasia

Bone and cardiovascular complications

CKD: chronic kidney disease; ND-CKD: non-dialysis chronic kidney disease; SHPT: secondary hyperparathyroidism.

COMPARED WITH PATIENTS WITHOUT SHPT, PATIENTSWITH SHPT ARE >5X MORE LIKELY TO BE INITIATED ON DIALYSIS OR DIE7

A retrospective study of insurance claims from 66,644 ND-CKD patients with or without SHPT.

Reproduced from Schumock G et al. 2008.7

Kaplan–Meier analysis of time to dialysis or death7

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

SHPT is associated with increased morbidity, mortality and disease progression in patients with ND-CKD7

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 and59 pg/mL (7.3 and 6.3 pmol/L), respectively.8

CKD: chronic kidney disease; PTH: parathyroid hormone.

PTH LEVELS INDEPENDENTLY PREDICT FRACTURES, VASCULAR EVENTS AND DEATH IN STAGE 3 AND 4 CKD PATIENTS8

Observational study of 5,108 stage 3 or 4 CKD patients. The study investigated the relationships between baseline PTH levels and subsequent ten-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 probability of fractures (A), vascular events and death (B) based on baseline PTH levels8

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

CKD: chronic kidney disease; SHPT: secondary hyperparathyroidism.

AT WHICH STAGE OF CKD DO YOU TYPICALLY INITIATE SHPT TREATMENT?

STAGE 1 STAGE 2 STAGE 3

STAGE 4 STAGE 5

1,25(OH)2D: 1,25-dihydroxyvitamin D; CKD: chronic kidney disease; FGF-23: fibroblast growth factor-23; PTH: parathyroid hormone; SHPT: secondary hyperparathyroidism.

EARLY DIAGNOSIS AND TREATMENT ARE CRUCIAL IN THE MANAGEMENT OF SHPT1,9,10

Progressively more severe1,9,11,12

Without prompt and effective treatment, SHPT becomes:

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

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

Disturbances in mineral metabolism with progression of CKD,11 highlighting the need for early treatment

25(OH)D: 25-hydroxyvitamin D; FGF-23: fibroblast growth factor-23; PTH: parathyroid hormone.

THE OPTIMAL TREATMENT APPROACH WOULD HAVE WHICH PRIMARY CHARACTERISTIC?

Increases25(OH)D levels 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

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.

THE GOALS OF SHPT TREATMENT ARE TO REGAIN MINERAL HOMEOSTASIS AND POTENTIALLY REDUCE THE RISKS OF BONE AND CARDIOVASCULAR COMPLICATIONS9,10,12

Increase 25(OH)D

Minimally change calcium, phosphate and FGF-23 levels

The ideal treatment approach would:1

Reduce PTH

Beneficial Detrimental No/Minimal change Small change Large change

Optimal treatment approach1

25(OH)D Calcium Phosphate PTH FGF-23

Effects on key CKD–MBD parameters

Adapted from Sprague SM et al. 2017.1

Correction of SHPT requires a holistic approach that takes into account all CKD–MBD parameters1

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.

LIMITATIONS OF NUTRITIONAL VITAMIN D, ACTIVE VITAMIN D AND ACTIVE ANALOGUES

Do not correct 25(OH)D1

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:

Increase the risks of hypercalcaemia and hyperphosphataemia1,16–18

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

CKD: chronic kidney disease; CKD–MBD: chronic kidney disease–mineral and bone disorder;KDIGO: Kidney Disease—Improving Global Outcomes; PTH: parathyroid hormone.

THE LIMITATIONS OF CURRENT TREATMENT OPTIONS ARE ACKNOWLEDGED IN KDIGO 2017 GUIDELINES12

“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 CKD G4–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.”

The full KDIGO 2017 clinical practice guidelines are available online.

View guidelines

25(OH)D: 25-hydroxyvitamin D; CKD: chronic kidney disease; PTH: parathyroid hormone;SHPT: secondary hyperparathyroidism.

TO CONTROL SHPT, A 25(OH)D LEVEL OF 42–48 NG/ML(105–120 NMOL/L) IS REQUIRED20

Associated with lower PTH concentrations

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

Not associated with increased rates of hypercalcaemia or hyperphosphataemia

PTH by 25(OH)D level and CKD stage20

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

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

CAN YOU REGAIN CONTROL?

To learn more about the unmet needs inSHPT treatment, please contact a Vifor

medical representative.

SHPT: secondary hyperparathyroidism.

REFERENCES

1. 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.