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Atorvastatin

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Title: Atorvastatin


1
NUOVE ACQUISIZIONI NELLA TERAPIA
DELLIPERPARATIROIDISMO SECONDARIO IN DIALISI
PERITONEALE
Mario Cozzolino, MD, PhD
XV CONVEGNO del Gruppo di Studio di Dialisi
Peritoneale Palermo, 19 Marzo 2010
2
NUOVE ACQUISIZIONI NELLA FISIOPATOLOGIA
DELLIPERPARATIROIDISMO SECONDARIO
FGF-23
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5
Dobbiamo dosare lFGF23 nei pazienti con CKD?
6
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
7
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8
CKD-MBD
PTH
Ca
P
Vit.D
9
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
10
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.

11
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

12
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.
13
CKD-MBD and PERITONEAL DIALYSIS
Optimizing the Treatment of Hyperphosphatemia
14
Sevelamer Hydrochloride in Peritoneal Dialysis
Patients Results of a Multicenter
Cross-sectional Study
  • Rosa Ramos, et al.
  • Peritoneal Dialysis International 2007 27697-701

15
22 of Sevelamer-treated pts showed a blood HCO3-
levels lt22.0 mmol/L
16
Structure of Sevelamer HCl and Carbonate
Sevelamer HCl
Sevelamer Carbonate
NH2-nHCI
a
NH-nHCI
NH3
NH
HCO3-
a
OH
OH
NH2-nHCI
NH-nHCI
NH2
NH
b
c
b
c
m
m
a, b number of primary amine groups a b
9 c number of cross-linking groups c
1 n fraction of protonated amines n
0.4 m 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.
17
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/K
DOQI/guidelines_bone/Guide15.htm Duggal A, Hanus
M, Zhorov E, et al. J Ren Nutr 200616(3)248-252
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3 of Lanthanum-treated pts showed a blood HCO3-
levels lt22.0 mmol/L
21
CKD-MBD
P
Ca
PTH
Vit.D
22
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

23
Proposed KDIGO Guidelines Target Range for PTH
K/DOQI PTHTarget (pg/mL)
150
300
100
500
KDIGO 2-9 times
  • High bone turnover
  • Bone pain
  • Cardiovascular disease
  • Cognitive impairment
  • Low bone turnover
  • Adynamic bone disease

24
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

25
CKD-MBD and PERITONEAL DIALYSIS
Optimizing the Treatment of SHPT
26
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

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29
Safety and Efficacy of Pulse and Daily Calcitriol
in Patients on CAPD a Randomized Trial
  • Sharon Moe, et al.
  • NDT 1998 13 1234-1241

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31
Oral Paricalcitol for the Treatment ofSecondary
Hyperparathyroidism in Patients on Hemodialysis
or Peritoneal Dialysis
  • Edward A. Ross, et al
  • Am J Nephrol 2008 2897106

32
Effects of oral paricalcitol in reducing PTH
Study design
  • 88 CKD Stage 5 pts with SHPT (iPTH 300 pg/mL
    sCa 8.010.5 mg/dL Ca x P 65 mg2/dL2) receiving
    chronic HD (n62) or PD (n26) 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 gt11.0 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)

33
Decreases in iPTH with paricalcitol
Primary endpoint patients with 2 consecutive
30 decreases in iPTH from baseline
Change from baseline to last on-treatment visit



Patients ()
Mean ? from baseline in iPTH



Paricalcitol
Placebo
plt0.001
34
Observed mean values of iPTH, Ca and P during
treatment phase
Placebo
Paricalcitol
  • Hypercalcemia (2 consecutive Ca gt11.0 mg/dL) 2
    paricalcitol 0 placebo
  • Ca in normal range throughout for both groups
  • No statistically significant differences in P
  • Ca x P lt55 mg2/dL2 throughout

1000
900
800
700
Mean iPTH (pg/mL)
600
500
400
500
0
2
4
6
8
10
12
plt0.001 at each timepoint
10
11
9
10
Calcium
8
9
7
Mean sP (mg/dL)
Mean sCa (mg/dL)
8
6
7
5
6
4
Phosphorus
5
3
0
2
4
6
8
10
12
Weeks since first dose of study drug
35
The Role of Paricalcitol beyond PTH Suppression
  • Cardio-protection
  • Renal protection
  • Reduction of inflammatory markers
  • Prevention of vascular calcification
  • Prevention of oxidative stress

36
SUMMARY
Cinacalcet
Ca Bath
CKD-MBD in PD
P Binders
Paricalcitol
37
THANKS for your ATTENTION!
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