Mechanisms of CKD-MBD: New insights in the pathogenesis Jorge - PowerPoint PPT Presentation

Mechanisms in chronic kidney disease Mechanisms of CKD-MBD: New insights in the pathogenesis Jorge Cannata-Andia University of Oviedo Oviedo, Spain

Mechanisms of CKD-MBD: New Insights in the Pathogenesis • Role of Classic and New Players in the Pathogenesis of Secondary Hyperparathyroidism and CKD-MB Role of * Calcium (Calcimimetics) * Vitamin D Receptor Activators (VDRAs) * Phosphorus and FGF 23 * Phosphorus and FGF 23 * Genomic & Molecular Changes in the Severe and Refractory Secondary Hyperparathyroidism • The Links Between the Bone and Vascular Axis in CKD-MBD. Role of Phosphate in the Pathogenesis of Vascular Mineralization and Bone Demineralization. Possible Self-defensive Mechanisms Triggered by the Vascular System

Mechanisms of CKD-MBD: New Insights in the Pathogenesis 1943: Renal Osteodystrophy (RO) ( Liu et al, Medicine) • Secondary Hyperparathyroidism MEDICINE 22: 103-161; 1943 • Osteomalacia • Osteosclerosis • Osteoporosis 30 Following Years: Academic Concept With No Chance to be Applied in the Daily Clinical Management of CKD Patients 1970’s – 1980’s: PTH Assays and Bone Biopsy Diagnosis of ROD Useful in Clinical Practice (1980´s – 2007) In 2006 a New Term was Proposed with a Broader Scope

Mechanisms of CKD-MBD: New Insights in the Pathogenesis Kidney Disease Improving Global Outcomes Renal Secondary Hyperparathyroidism Osteodystrophy the Vessels & Bone Play Important Role

Parathyroid Regulation in Chronic Kidney Disease • Aluminium • Estrógenos • Magnesio PTH • Acidosis • Otros…… FGF23/Klotho FGF23/Klotho Calcium Calcitriol Phosphorus 25(OH)D Cannata –Andía JBy Rodriguez M.. Nefrología Clínica . Ed L Hernando, 2008,

Parathyroid Regulation in Chronic Kidney Disease CaSR Discover and Cloned in 1993 CaSR G Protein-Coupled Receptor (GPCR) Cell Surface Receptor PTH Able to Recognize and Respond to Extracellular Calcium and Others: Al, La, Sr, Ga, ....... FGF23/Klotho FGF23/Klotho Calcium Calcitriol Phosphorus Cannata –Andía JBy Rodriguez M.. Nefrología Clínica . Ed L Hernando, 2008,

Calcium Sensing Receptor (CaSR) Tissue Distribution Parathyroids Parathyroid and C cells Renal proximal tubule Nephron segments Gastrointestinal tract Gastrointestinal tract Osteoblast/Osteoclast Monocytes/macrophages Nervous system Bone marrow Cardiovascular

Calcium Sensing Receptor (CaSR) Signaling Pathways Activated by the CaSR NH 2 Phospholipase C Phospholipase C Phospholipase C Phospholipase C (Inositol triphosphate, Ca 2+ (Inositol triphosphate, Ca 2+ i ) 7 Phospholipase A2 Phospholipase A2 1 2 3 4 6 5 P (Arachidonic acid) (Arachidonic acid) P P P Phospholipase D (Phosphatidic acid) Phospholipase D (Phosphatidic acid) MAP Kinase MAP Kinase Inhibition of Adenylate Cyclase Inhibition of Adenylate Cyclase HCOO Spurney RF, et al. Kidney Int 1999;55(5):1750-8.

How Calcium Influence Parathyroid Hormone Synthesis ? DNA Transcripcion Low Calcium mRNA mRNA Storage Storage Translation Translation Low Calcium preproPTH Increases the Stability PTH of PTH mRNA Degradacion Secretion The Stability of PTHmRNA Post-transcriptional may vary from 5 minutes to 3 hours Silver et al, 2000-2002

The Calcium Sensing Receptor in CKD In CKD There is a Reduction of N H 2 Expression of CaSR (40-60%) 1 6 7 2 3 4 5 P Reduction in Capacity of the P P P Parathyroid Gland to Sense Ca HCOO

Changes in the PTH Response to Calcium with the Progression of Secondary Hyperparathyroidism ¿ Is the Decrease of Refractory Hiperparathyroidism Sensitivity of the Parathyroid Severe Hyperparathyroidism Glands to Calcium 110 Moderate Hyperparathyroidism 100 “ Clinically Relevant”? Normal 90 80 70 70 PTH (%) 60 50 40 Set point Increments in 30 20 “Non Suppressible” 10 PTH Secretion Due to 0 Gland Growth 0 1 1.1 1.2 1.3 1.4 1.5 1.6 Ionized Ca (mmol/L)

Parathyroid Gland Response to Calcium Changes in CKD 5 COSMOS Study: 4600 patients / 20 Countries PTH Response to Calcium Changes in CKD 5 TH (pg / ml) Progression of CKD-MBD Severely Affect the Response 95% IC PTH of the Parathyroid Glands of the Parathyroid Glands to Calcium 6-7 9.5-10 >12 8-9 10.5-11 Serum Calcium May Influence Serum Calcium (mg/dL) Outcomes in Dialysis Patients JL Fernández et al , ERA-EDTA, Stocholm, 2008

COSMOS: Una Fotografía del Escenario Europeo en CKD-MBD • Multi-centre, Open Cohort and Observational Study. • Prospective: 3-year of follow-up. • European Focused (20 countries) • Size of the Sample: 4,500 HD Patients from 227 Centres Spread Geographically (medium-large Centres Spread Geographically (medium-large hospitals and satellite units) • Sites and Patients (±20 per centre) Randomly selected Oviedo

Parathyroid Gland Response to Calcium Changes in CKD 5 COSMOS Study: 4600 patients / 21 Countries Calcimimetics Can Improve TH (pg / ml) the Poor Response of the Parathyroid Glands to Calcium Increasing the Sensivity 95% IC PTH of CaSR to Calcium of CaSR to Calcium 6-7 9.5-10 >12 8-9 10.5-11 Serum Calcium (mg/dL) JL Fernández et al , ERA-EDTA, 2007

Calcimimetics Reduce PTH Synthesis Calcimimetics Decrease Cell Proliferation DNA Transcription mRNA mRNA Translation preproPTH % Reduction in Size PTH PTH Degradation Calcimimetics 60% Upregulate CaSR and VDR –Interaction and Cooperation- < 500 mm3 > 500 mm3 Consequences of the Action of Calcimimetics

Effect of Calcimimetics Improvement in the Parathyroid Response Hiperparatiroidismo moderado 110 100 90 “Set Point” Shift 80 to the Left 70 PTH (%) 60 50 40 40 30 20 10 0 0 1 1.1 1.2 1.3 1.4 1.5 1.6 Ionized Ca (mmol/L)

Effect of Calcimimetics Improvement in the Parathyroid Response Hiperparatiroidismo moderado 110 100 90 “Set Point” Shift 80 to the Left 70 PTH (%) 60 50 40 40 30 Curve May 20 Be Push 10 Down 0 0 1 1.1 1.2 1.3 1.4 1.5 1.6 Ionized Ca (mmol/L)

Effects of VDR Activation Rapid Non-Genomic Response Slow Genomic Response 1,25-(OH) 2 D 1,25-(OH) 2 D Cell membrane Membrane Receptor 2 Messanger VDR VDR ? Ca 2+ , ?IP 3 , ? pH, PKC ? Ca 2+ , ?IP 3 , ? pH, PKC CITOPLASM CITOPLASM Transcription Factor Co-activators and co-represors Co-activators and co-represors - - - - - - - - Nuclear membrane NÚCLEUS NÚCLEUS VDRE VDRE VDRE Transcription Transcription ARNm ARNm ARNm ARNm Protein Protein

Effects of VDR Activation Slow Genomic Response 1,25-(OH) 2 D 1,25-(OH) 2 D Proteins Regulated by VDR Activation Cell membrane Down Regulated Membrane Receptor Cbf1 2 Messanger BMP-2 VDR VDR Osteopontin ? Ca 2+ , ?IP 3 , ? pH, PKC ? Ca 2+ , ?IP 3 , ? pH, PKC PTH Osteocalcin Collagen RANK-L CITOPLASMA CITOPLASM Transcription Factor 1 α hydroxilase VDR VDR Co-activators and co-represors Co-activators and co-represors Renin Renin - - - - - - - - 24-hydroxilase IFN- γ Calbindin IL-I β , IL-2, -6, - TRPV5-6 Nuclear membrane 12 IL-10, IL-4 Ciclin E Insulin Gen C-myc p-21, p-27 Up Regulated NÚCLEO NÚCLEUS VDRE VDRE VDRE Transcription Transcription Multiple Proteins are ARNm ARNm ARNm ARNm Regulated by VDR Activation Protein Proteina

Effects of VDR Activation � Bone and Mineral � Cardiovascular System � Intestine � Myocardial Structure � Parathyroid Glands � Myocardial Function � Vascular System � Bone - Arterial Pressure � Kidney - Vascular Function � � Immune System Immune System -Infections- � Inflammatory Response � Skin � Muscular System � Antiproliferative effect -Cancer- � Renoprotection Survival

VDR Activation and Survival CORES Relaytive Risk (RR) The Better Results Were 1,5 Obtained With Dose < 1 mcg/day Obtained With Dose < 1 mcg/day No vitamin D No vitamin D 1 0,74 (0,52-1,05) 0,66 (0,51-0,85) 0,75 0,60 (0,51-0,72) 0,54 (0,46-0,63) Vitamin D 0,50 > 1 µ g/d 0,25 < 0.25ug/d 0.25-0,50 µg/d > 0.50-1 µg/d (n=184) (n=1.304) (n=1.053) (n=432) Benefits of Oral Active VDR Activators on Survival

Mechanisms of CKD-MBD: New Insights in the Pathogenesis Main Factors Influencing the VDR Response � Adequate VDR Expression � Optimal Concentration of VDR Activator

VDR Expression in CKD No Inhibition of PTH DNA Calcitriol Transcription Gene Transcription Transcription mRNA Deficit mRNA Storage Storage Translation Translation preproPTH Decreased Expression of VDR Increase mRNA PTH PTH Degradation Synthesis VDR Secretion Transcriptional

VDR Expression in CKD Normalize Serum Administration Calcitriol Levels of Calcitriol Cooperation Between Expression mRNA VDR/18s (%) 300 DNA 218,7±42,6 of VDR VDR & CaSR Inhibition of PTH * 250 Transcription Gene Transcription mRNA 200 150 mRNA 100,0 100 Storage Storage Translation Translation Reduce Reduce 50 50 0 preproPTH PTH Calcitriol 10 -8 M Control Parathyroid Glands Culture Synthesis PTH Degradation Expression 300 mRNA CaR/18s (%) 212,8±39,9 of CaSR * 250 200 150 100,0 100 50 0 Control Calcitriol 10 -8 M

Mechanisms of CKD-MBD: New Insights in the Pathogenesis Main Factors Influencing the VDR Response � Adequate Concentration of VDR � Optimal Concentration of VDR Activator