Transcript No Slide Title

NUOVE ACQUISIZIONI NELLA
TERAPIA DELL’IPERPARATIROIDISMO
SECONDARIO IN DIALISI
PERITONEALE
Mario Cozzolino, MD, PhD
XV CONVEGNO del
Gruppo di Studio di Dialisi Peritoneale
Palermo, 19 Marzo 2010
NUOVE ACQUISIZIONI NELLA
FISIOPATOLOGIA
DELL’IPERPARATIROIDISMO
SECONDARIO
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
Ca
PTH
P
Vit.D
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.



Reduce elevated phosphate levels toward the normal
range
Maintain normal calcium levels
Use a dialysate calcium concentration between 1.25 and
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
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.


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 Pbinder takes into account:
-
CKD stage
-
Presence of other components of CKD-MBD
(Ca, PTH, ALP, Vascular Calcification)
-
Concomitant therapies (VDRAs, Cinacalcet)
-
Side effect profile
Use of P-Binders
In CKD stages 3-5D and hyperphosphatemia:


Restricting the dose of calcium-based phosphate binders in the
presence of hypercalcemia (1B), arterial calcification (2C), and/or
adynamic bone disease (2C), and/or if serum PTH levels are
persistently low (2C).
Avoiding the long-term use of aluminum-containing phosphate binders
(1C).

Limiting dietary phosphate intake (2D)

Increasing dialytic phosphate removal (2C)
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
DIALYSIS
Optimizing the Treatment of
Hyperphosphatemia
Sevelamer Hydrochloride in Peritoneal
Dialysis Patients: Results of a Multicenter
Cross-sectional Study
Rosa Ramos, et al.
Peritoneal Dialysis International 2007;
27:697-701
22% of Sevelamer-treated pts showed a blood
HCO3- levels <22.0 mmol/L
Structure of Sevelamer HCl and Carbonate
Sevelamer HCl
NH2-nHCI
a
Sevelamer Carbonate
NH-nHCI
NH3+
HCO3OH
NH2-nHCI
NH-nHCI
b
a, b
c
n
m
=
=
=
=
NH
a
NH2
c
m
OH
NH
b
c
m
number of primary amine groups a + b = 9
number of cross-linking groups c = 1
fraction of protonated amines n = 0.4
large number to indicate extended polymer network
• Same polymer backbone: Retains similar phosphate-binding capacity
• Salt change: Potentially improves buffering capacity
Structures adapted from Renagel and Renvela Package Inserts.
Sevelamer Carbonate: Significance
of Improving Buffering 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 blood
HCO3- levels <22.0 mmol/L
CKD-MBD
Ca
P
PTH
Vit.D
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.
–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 KDIGO Guidelines:
Target Range for PTH
150
100
K/DOQI
PTH
Target
300
(pg/mL)
500
KDIGO
2-9 times
– Low bone turnover
– Adynamic bone disease
–
–
–
–
High bone turnover
Bone pain
Cardiovascular disease
Cognitive impairment
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 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
CKD-MBD and PERITONEAL
DIALYSIS
Optimizing the Treatment
of SHPT
Cinacalcet HCl, an Oral Calcimimetic Agent
for the Treatment of SHPT in HD and PD:
a Randomized, Double-Blind, Multicenter
Study
Jill Lindberg, et al.
JASN 2005; 16: 800-807
Safety and Efficacy of Pulse and Daily
Calcitriol in Patients on CAPD: a
Randomized Trial
Sharon Moe, et al.
NDT 1998; 13: 1234-1241
Oral Paricalcitol for the Treatment of
Secondary Hyperparathyroidism in Patients
on Hemodialysis or Peritoneal Dialysis
Edward A. Ross, et al
Am 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
baseline
 Safety: 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 paricalcitol
120
100 *
Patients (%)
100
88 *
83 *
80
60
40
16
13
20
0
0
All patients
PD
HD
Paricalcitol
*p<0.001
Change from baseline to
last on-treatment visit
Mean % Δ from baseline in iPTH
Primary endpoint: % patients with 2 consecutive
≥30% decreases in iPTH from baseline
30
22,4
20,4
20
14,1
10
0
-10
-20
-21
-30
-27,8
*
*
-40
-43,9
-50
All patients
Placebo
PD
*
HD
Observed mean values of iPTH, Ca and
P during treatment phase
Paricalcitol
Placebo
• 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
Mean iPTH (pg/mL)
1000
900
800
700
600
500
400
500
0
2
4
6
8
10
12
p<0.001 at each timepoint
10
9
Calcium
10
8
9
7
8
6
7
5
6
4
Phosphorus
5
3
0
2
4
6
8
10
Weeks since first dose of study drug
12
Mean sP (mg/dL)
Mean sCa (mg/dL)
11
The Role of Paricalcitol beyond
PTH Suppression
Cardio-protection
 Renal protection
 Reduction of inflammatory markers
 Prevention of vascular calcification
 Prevention of oxidative stress

SUMMARY
Cinacalcet
Ca Bath
PTH
FGF23
Calcium
CKD-MBD
in PD
P Binders
Paricalcitol
Vitamin D
Phosphate
THANKS for your
ATTENTION!