Mario Cozzolino, MD, PhD NUOVE ACQUISIZIONI NELLA TERAPIA DELL’IPERPARATIROIDISMO SECONDARIO IN DIALISI PERITONEALE 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 P PTHCa 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, Reduce elevated phosphate levels toward the normal range Reduce elevated phosphate levels toward the normal range Maintain normal calcium levels Maintain normal calcium levels Use a dialysate calcium concentration between 1.25 and 1.50 mmol/L ( mEq/L) Use a dialysate calcium concentration between 1.25 and 1.50 mmol/L ( 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: 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). 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). Avoiding the long-term use of aluminum-containing phosphate 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 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:

22% of Sevelamer-treated pts showed a blood HCO 3 - levels <22.0 mmol/L

Structure of Sevelamer HCl and Carbonate Structures adapted from Renagel and Renvela Package Inserts. Same polymer backbone: Retains similar phosphate-binding capacity Salt change: Potentially improves buffering capacity Sevelamer HClSevelamer Carbonate NH 2 -nHCIaNH-nHCI NH 2 -nHCINH-nHCI bc m OH NH 3 + a NH NH 2 NH bc m OH HCO 3 - 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

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

3% of Lanthanum-treated pts showed a blood HCO 3 - levels <22.0 mmol/L

CKD-MBD PTH PCa 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, –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 K/DOQI PTH Target (pg/mL) – Low bone turnover – Adynamic bone disease – High bone turnover – Bone pain – Cardiovascular disease – Cognitive impairment KDIGO 2-9 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 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:

Safety and Efficacy of Pulse and Daily Calcitriol in Patients on CAPD: a Randomized Trial Sharon Moe, et al. NDT 1998; 13:

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 mg 2 /dL 2 ) 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 Patients (%) * * * *p<0.001 Primary endpoint: % patients with 2 consecutive ≥30% decreases in iPTH from baseline ParicalcitolPlacebo Mean % Δ from baseline in iPTH Change from baseline to last on-treatment visit * * *

Observed mean values of iPTH, Ca and P during treatment phase Weeks since first dose of study drug PlaceboParicalcitol Phosphorus Calcium Mean sP (mg/dL) Mean sCa (mg/dL) p<0.001 at each timepoint Mean iPTH (pg/mL) 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 mg 2 /dL 2 throughout

The Role of Paricalcitol beyond PTH Suppression Cardio-protection Cardio-protection Renal protection Renal protection Reduction of inflammatory markers Reduction of inflammatory markers Prevention of vascular calcification Prevention of vascular calcification Prevention of oxidative stress Prevention of oxidative stress

PTHCalciumPhosphateVitamin DFGF23 CKD-MBD in PDSUMMARY P Binders Ca Bath Paricalcitol Cinacalcet

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