Mario Cozzolino, MD, PhD

NUOVE ACQUISIZIONI NELLA NUOVE ACQUISIZIONI NELLA TERAPIA TERAPIA

DELL’DELL’IPERPARATIROIDISMO IPERPARATIROIDISMO SECONDARIO SECONDARIO IN DIALISI IN DIALISI

PERITONEALEPERITONEALE

XV CONVEGNO del Gruppo di Studio di Dialisi Peritoneale

Palermo, 19 Marzo 2010

NUOVE ACQUISIZIONI NELLA NUOVE ACQUISIZIONI NELLA FISIOPATOLOGIA FISIOPATOLOGIA

DELL’DELL’IPERPARATIROIDISMO IPERPARATIROIDISMO SECONDARIOSECONDARIO

FGF-23

Dobbiamo dosare l’FGF23

nei pazienti con CKD?

KDIGO Clinical Practice Guideline for the Diagnosis, Evaluation, Prevention, and Treatment of Chronic Kidney

Disease-Mineral and Bone Disorder (CKD-MBD)

VOLUME 76 | SUPPLEMENT 113 | AUGUST 2009

CKD-MBD

P

PTH

Ca

Vit.D

KDIGO Clinical Practice Guideline for the Diagnosis, KDIGO Clinical Practice Guideline for the Diagnosis, Evaluation, Prevention, andEvaluation, Prevention, and Treatment of Chronic Treatment of Chronic

Kidney Disease-Mineral and Bone Disorder (CKD-MBD).Kidney Disease-Mineral and Bone Disorder (CKD-MBD).Kidney IntKidney Int 76: S1-130, 2009. 76: S1-130, 2009.

Reduce elevated phosphate levels toward the normal rangeReduce elevated phosphate levels toward the normal range Maintain normal calcium levels Maintain normal calcium levels Use a dialysate Use a dialysate ccaalciumlcium concentration between 1.25 and concentration between 1.25 and

1.50 mmol/L (2.5-3.0 mEq/L)1.50 mmol/L (2.5-3.0 mEq/L)

In CKD patients receiving treatments for CKD-MBD or in whom biochemical abnormalities are identified, it is reasonable to increase the frequency of measurements to monitor for trends and treatment efficacy and side-effects

Lateral abdominal radiograph and echocardiogram to detect presence/absence respectively of vascular and/or valvular calcification.

Patients with VC should be considered at HIGHEST CV RISK. It is reasonable to use this information to guide the management of CKD-MBD.

KDIGO Clinical Practice Guideline for the Diagnosis, Evaluation, Prevention, and Treatment of Chronic Kidney Disease-Mineral and Bone Disorder (CKD-

MBD).Kidney Int 76: S1-130, 2009.

“We suggest” using P-binders in the treatment of hyperphosphatemia. It is reasonable that the CHOICE of P-binder takes into account:

- CKD stage

- Presence of other components of CKD-MBD (Ca, PTH, ALP, Vascular Calcification)

- Concomitant therapies (VDRAs, Cinacalcet)

- Side effect profile

KDIGO Clinical Practice Guideline for the Diagnosis, Evaluation, Prevention, and Treatment of Chronic Kidney Disease-Mineral and Bone Disorder (CKD-

MBD).Kidney Int 76: S1-130, 2009.

In CKD stages 3-5D and hyperphosphatemia:In CKD stages 3-5D and hyperphosphatemia:

Restricting the dose of cRestricting the dose of calciumalcium-based phosphate binders in the -based phosphate binders in the presence of hypercalcemia (1B), arterial calcification (2C), presence of hypercalcemia (1B), arterial calcification (2C), and/or adynamic bone disease (2C), and/or if serum PTH levels and/or adynamic bone disease (2C), and/or if serum PTH levels are persistently low (2C).are persistently low (2C).

Avoiding the long-term use of aluminum-containing phosphate Avoiding the long-term use of aluminum-containing phosphate binders (1C).binders (1C).

Limiting dietary phosphate intake (2D)Limiting dietary phosphate intake (2D)

Increasing dialytic phosphate removal (2C)Increasing dialytic phosphate removal (2C)

Use of P-Binders

KDIGO Clinical Practice Guideline for the Diagnosis, Evaluation, Prevention, and Treatment of Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD). Kidney Int 76: S1-130, 2009.

CKD-MBD and PERITONEAL CKD-MBD and PERITONEAL DIALYSISDIALYSIS

Optimizing the Treatment of Hyperphosphatemia

Sevelamer Hydrochloride in Sevelamer Hydrochloride in Peritoneal Dialysis Patients: Results Peritoneal Dialysis Patients: Results

of a Multicenter Cross-sectional of a Multicenter Cross-sectional StudyStudy

Rosa Ramos, et al. Rosa Ramos, et al.

Peritoneal Dialysis International Peritoneal Dialysis International 2007; 27:697-7012007; 27:697-701

22% of Sevelamer-treated pts showed a blood22% of Sevelamer-treated pts showed a bloodHCOHCO33

-- levels <22.0 mmol/L levels <22.0 mmol/L

Structure of Sevelamer HCl and Structure of Sevelamer HCl and Carbonate Carbonate

Structures adapted from Renagel and Renvela Package Inserts.

• Same polymer backbone: Retains similar phosphate-binding capacity

• Salt change: Potentially improves buffering capacity

Sevelamer HCl Sevelamer Carbonate

NH2-nHCI a NH-nHCI

NH2-nHCI NH-nHCI

b cm

OH

NH3+

a

NH

NH2 NH

b cm

OH

HCO3-

a, b = number of primary amine groups a + b = 9c = number of cross-linking groups c = 1n = fraction of protonated amines n = 0.4m = large number to indicate extended polymer network

Sevelamer Carbonate: Sevelamer Carbonate: Significance of Improving Significance of Improving

Buffering CapacityBuffering Capacity Low bicarbonate levels are common in

CKD patients, regardless of phosphate binder choice

Removal of hydrochloride from Sevelamer HCl and the addition of carbonate from Sevelamer Carbonate to the GI tract may facilitate maintaining bicarbonate levels within recommended guidelines ranges

KDOQI Clinical Practice Guidelines for Bone Metabolism and Disease in Chronic Kidney Disease. Available at http://www.kidney.org/professionals/KDOQI/guidelines_bone/Guide15.htm

Duggal A, Hanus M, Zhorov E, et al. J Ren Nutr 2006;16(3):248-252

3% of Lanthanum-treated pts showed a blood3% of Lanthanum-treated pts showed a bloodHCOHCO33

-- levels <22.0 mmol/L levels <22.0 mmol/L

CKD-MBD

PTH

PCa

Vit.D

KDIGO Clinical Practice Guideline for the Diagnosis, KDIGO Clinical Practice Guideline for the Diagnosis, Evaluation, Prevention, andEvaluation, Prevention, and Treatment of Chronic Treatment of Chronic

Kidney Disease-Mineral and Bone Disorder (CKD-MBD).Kidney Disease-Mineral and Bone Disorder (CKD-MBD).Kidney IntKidney Int 76: S1-130, 2009. 76: S1-130, 2009.

–Maintain iPTH levels in the range of approximately 2 to 9 times the upper normal limit for the assay.

Mark changes in iPTH levels in either direction within this range prompt an initiation or change in therapy to avoid progression to levels outside of this range

Proposed KProposed KDIGODIGO Guidelines: Guidelines: Target Range for PTHTarget Range for PTH

K/DOQIPTH

Target(pg/mL)

100

150 300

500

– Low bone turnover– Adynamic bone disease

– High bone turnover– Bone pain– Cardiovascular disease– Cognitive impairment

KDIGO2-9 times

“We suggest” using VDRAs and/or cinacalcet in patients with CKD stage 5D and elevated or rising PTH. It is reasonable that INTIAL DRUG SELECTION for the treatment of elevated PTH be based on:

- Serum Ca and P levels

- Other aspects of CKD-MBD (ALP, Vascular Calcification)

- Concomitant therapies (Calcium containing P binders)

- Side effect profile

KDIGO Clinical Practice Guideline for the Diagnosis, Evaluation, Prevention, and Treatment of Chronic Kidney Disease-Mineral

and Bone Disorder (CKD-MBD).Kidney Int 76: S1-130, 2009.

CKD-MBD and PERITONEAL CKD-MBD and PERITONEAL DIALYSISDIALYSIS

Optimizing the Treatment of SHPT

Cinacalcet HCl, an Oral Calcimimetic Cinacalcet HCl, an Oral Calcimimetic Agent for the Treatment of SHPT in Agent for the Treatment of SHPT in HD and PD: a Randomized, Double-HD and PD: a Randomized, Double-

Blind, Multicenter StudyBlind, Multicenter Study

Jill Lindberg, et al. Jill Lindberg, et al.

JASN 2005; 16: 800-807JASN 2005; 16: 800-807

Safety and Efficacy of Pulse and Daily Safety and Efficacy of Pulse and Daily Calcitriol in Patients on CAPD: a Calcitriol in Patients on CAPD: a

Randomized TrialRandomized Trial

Sharon Moe, et al. Sharon Moe, et al.

NDT 1998; 13: 1234-1241NDT 1998; 13: 1234-1241

Oral Paricalcitol for the Treatment ofOral Paricalcitol for the Treatment ofSecondary Hyperparathyroidism in Secondary Hyperparathyroidism in

Patients on Hemodialysis or Patients on Hemodialysis or Peritoneal DialysisPeritoneal Dialysis

Edward A. Ross, et alEdward A. Ross, et al

Am J Nephrol 2008; 28:97–106Am J Nephrol 2008; 28:97–106

Effects of oral paricalcitol in reducing PTH Study design

88 CKD Stage 5 pts with SHPT (iPTH ≥300 pg/mL; sCa 8.0–10.5 mg/dL; Ca x P ≤65 mg2/dL2) receiving chronic HD (n=62) or PD (n=26) randomised to oral paricalcitol or placebo for 12 weeks

Primary endpoints:Efficacy: 2 consecutive iPTH decreases ≥30% from

baselineSafety: Development of hypercalcemia (2 consecutive Ca

measurements >11.0 mg/dL)

Secondary endpoints:Absolute and percentage changes in iPTH and markers of

biochemical bone activity (BSAP, osteocalcin, collagen C-telopeptides (CTx), tartrate resistant acid phosphatase isoform 5b (TRAP-5b)

Decreases in iPTH with Decreases in iPTH with paricalcitolparicalcitol

88

100

83

13

0

16

0

20

40

60

80

100

120

All patients PD HD

Pat

ien

ts (

%)

**

*

*p<0.001

Primary endpoint: % patients with 2 consecutive ≥30% decreases in iPTH from baseline

-27,8

-21

-43,9

20,4 22,4

14,1

-50

-40

-30

-20

-10

0

10

20

30

All patients PD HD

Paricalcitol Placebo

Mea

n %

Δ f

rom

bas

elin

e in

iPT

H

Change from baseline to last on-treatment visit

**

*

Observed mean values of iPTH, Ca Observed mean values of iPTH, Ca and P during treatment phaseand P during treatment phase

Weeks since first dose of study drug

PlaceboParicalcitol

10

9

8

7

6

5

0 2 4 6 8 10 12

5

4

3

8

7

6

10

9

Phosphorus

Calcium

Me

an

sP

(m

g/d

L)

Me

an

sC

a (

mg

/dL

)

p<0.001 at each timepoint

1000

900

800

700

600

500

0 2 4 6 8 10 12

Me

an

iP

TH

(p

g/m

L)

400

500

11

• Hypercalcemia (≥2 consecutive Ca >11.0 mg/dL): 2% paricalcitol; 0% placebo

• Ca in normal range throughout for both groups

• No statistically significant differences in P

• Ca x P <55 mg2/dL2 throughout

The Role of Paricalcitol beyond The Role of Paricalcitol beyond PTH Suppression PTH Suppression

Cardio-protectionCardio-protectionRenal protectionRenal protectionReduction of inflammatory markersReduction of inflammatory markersPrevention of vascular calcificationPrevention of vascular calcificationPrevention of oxidative stressPrevention of oxidative stress

CKD-MBDin PD

SUMMARYSUMMARY

P Binders

Ca Bath

Paricalcitol

Cinacalcet

THANKS for your ATTENTION!