What Are the Targets in CKD-MBD?

Transcription

1 Knowledge Exchange 2016 Paris, France, September 30, 2016 Date of preparation: Nov 2016 Item job code: INTSP/C-ANPROM/FOS/16/0025 Cristina Ortiz Jorge B Cannata-Andía Bone and Mineral Research Unit Hospital Universitario Central de Asturias Universidad de Oviedo, Spain Universidad de Oviedo

2 Declaration of Transparency Research Grants: Amgen, Shire Advisory Boards: Amgen, Kerix, Servier Honorarium: Amgen, Bayer, Shire, Fresenius/Vifor

3 Why Are the Targets So Important? Are They Useful? Are We Treating the Patients or Are We Just Correcting Numbers? Are We Influencing Outcomes?

4 Cannata-Andia JB. Nefrologica Clinica. Ed Hernando What Are the Targets in CKD-MBD? Why Are the Targets So Important? During the Last 50 Years Abnormalities PTH Calcium Poor Clinical Outcomes Calcitriol Phosphorus

5 Where Did the KDOQI & the KDIGO Targets Come From? What Kind of Scientific Evidences Support These Targets? Since 2000: Several Guidelines Appeared Worldwide KDIGO 2009 Founda=on Both Set Targets K/DOQI Clinical practice guideline for bone metabolism and disease in chronic kidney disease. Am J Kidney Dis. 2003;42(4 suppl 3):S Moe et al. Kidney Int. 2005;67(2):760 71

6 Recommended CKD-BMD Serum Target Levels Phosphorus 1,2,3,4 Calcium 1,2,3, Opinion Based Small Studies mg/dl mmol/l mmol/l PTH Bone Biopsy: Bone Turnover pg/ml or ng/l 1. K/DOQI Clinical practice guidelines for bone metabolism and disease in chronic kidney disease. Am J Kidney Dis. 2003;42(4 suppl 3):S Moe et al. Kidney Int. 2005;67(2): KDIGO Clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of Chronic Kidney Disease-Mineral Bone Disorder (CKD-MBD). Kidney Int. 2009;76(S113):S KDIGO Clinical practice guideline for the evaluation and management of Chronic Kidney Disease. Kidney Int. 2013;3(1): Cavalier et al. Nephrol Dial Trans. 2012;27(5): Adapted from Fernández-Martín et al. Nephrol Dial Transplant. 2015;30:

7 Recommended CKD-BMD Serum Target Levels Phosphorus 1,2,3,4 Calcium 1,2,3, Opinion Based Small Studies NORMAL VALUES Insufficient Evidence NORMAL VALUES mg/dl mmol/l mmol/l PTH Bone Biopsy: Bone Turnover 2 TO 9 TIMES THE UPPER LIMIT OF THE ASSAY 5 Based on Mortality Risk Studies pg/ml or ng/l 1. K/DOQI Clinical practice guidelines for bone metabolism and disease in chronic kidney disease. Am J Kidney Dis. 2003;42(4 suppl 3):S Moe et al. Kidney Int. 2005;67(2): KDIGO Clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of Chronic Kidney Disease-Mineral Bone Disorder (CKD-MBD). Kidney Int. 2009;76(S113):S KDIGO Clinical practice guideline for the evaluation and management of Chronic Kidney Disease. Kidney Int. 2013;3(1): Cavalier et al. Nephrol Dial Trans. 2012;27(5): Adapted from Fernández-Martín et al. Nephrol Dial Transplant. 2015;30:

8 Why Are the Targets So Important? Are They Useful? The Targets Help Us to Maintain Patients in Pre-Determined Serum Ranges Are We Treating the Patients or Are We Just Correcting Numbers? Are We Influencing Outcomes?

9 Why Are the Targets So Important? Are They Useful? COSMOS NDT 2015 IMPROVEMENT OF CKD-MBD BIOCHEMICAL MARKERS IS ASSOCIATED WITH BETTER SURVIVAL IN HAEMODIALYSIS PATIENTS: THE COSMOS STUDY The Targets Help Us to Mantain Patients in Pre-Determined Serum Ranges Are We Treating the Patients or Are We Just Correcting Numbers? Are We Influencing Outcomes?

10 What is COSMOS? Current Management Of Secondary Hyperparathyroidism: a Multicentre Observational Study Designed & Directed Oviedo Servicio de Metabolismo Óseo y Mineral Instituto Reina Sofía de Investigación Hospital Universitario Central de Asturias, Oviedo, España NDT- EDUCATIONAL Supported by an unrestricted educa1onal grant from Amgen Fundación Renal Iñigo Alvarez de Toledo

11 What is COSMOS? Multi-centre, Open Cohort Noninterventional/ Observational Prospective 3-year Follow up Study. European Focused (20 countries) Recruit 6797 HD Patients from 227 Centres Spread Geographically (Medium-large Hospitals and Satellite Units) Randomly Selected!!!!! The Greater the Country, the Larger the Number of HD Patients Since Baseline during 3 Years the Previous 6 Months Were Recorded (Time Dependent Variable) Country Sites Austria 5 Belgium 7 Croatia 3 Czech Republic 7 Denmark 3 Finland 2 France 38 Germany 73 Greece 10 Hungary 6 Italy 50 Netherlands 6 Poland 15 Portugal 10 Romania 7 Slovenia 2 Spain 22 Sweden 4 Switzerland 3 United Kingdom 20

12 What is COSMOS? COSMOS Can Be Analysed Either as One Study of 3 Years Follow Up Baseline Follow Up 3 Years

13 What is COSMOS? 6 Consecutive Studies of 6 Months in Order To Mimic a Clinical Trial to Investigate the Impact of Achieving CKD-MBD Targets on the Relative Risk of Mortality Baseline Follow Up 3 Years Baseline MONTHS

14 Phosphorus, Calcium and PTH 14 Hazard Ratio Univariate Serum Levels With Model 1 the Lowest RR of Model Mortality 2 N= Observa1ons distribu1on 95% CI (Model 3) 3 Models of Adjustments Full Line is Full Adjustment 22 Variables Demography & Comorbidities Treatments Biochemical Parameters Serum phosphorus (mg/dl)

15 15 Serum Phosphorus Overall Mortality Hazard Ratio Model mg/dl Observa1ons distribu1on 95% CI (Model 3) Penalized Spline Curves 0.0 N= Serum phosphorus (mg/dl)

16 Serum Calcium Overall Mortality % CI (Model 3) Penalized Spline Curves Hazard Ratio Model mg/dl N= Observa1ons distribu1on Serum calcium (mg/dl)

17 17 Serum PTH Overall Mortality pg/ml Model 2 95% CI (Model 3) Penalized Spline Curves Hazard Ratio 1.0 Model N= Observa1ons distribu1on Serum PTH (pg/ml)

18 1,4 What Are the Targets in CKD-MBD? COSMOS DATA: We Can Find New Serum Phosphorus, Calcium & PTH 1,5 Target Ranges Based in European HD Patients 18 1,3 1,2 1,1 1,0 0,9 0,

19 1,4 What Are the Targets in CKD-MBD? COSMOS DATA: We Can Find New Serum Phosphorus, Calcium & PTH 1,5 Target Ranges Based in European HD Patients Hazard Ra1os 1,3 1,2 1,1 1,0 Lowest Mortality 10% 10% 0,9 0,8 Optimal Target

20 20 Serum Phosphorus Serum Calcium Serum PTH BELOW OPTIMAL TARGET RANGES WITHIN OPTIMAL TARGET RANGES mg/dl Lowest Mortality mg/dl Lowest Mortality pg/ml ABOVE OPTIMAL TARGET RANGES

21 Recommended CKD-BMD Serum Targets Phosphorus 1,2,3,4 Calcium 1,2,3, mg/dl NORMAL VALUES NORMAL VALUES mg/dl mg/dl mg/dl mmol/l mmol/l PTH 2 TO 9 TIMES THE UPPER LIMIT OF THE ASSAY 5 Mortality Risk pg/ml pg/ml or ng/l 1. K/DOQI Clinical practice guidelines for bone metabolism and disease in chronic kidney disease. Am J Kidney Dis. 2003;42(4 suppl 3):S Moe et al. Kidney Int. 2005;67(2): KDIGO Clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of Chronic Kidney Disease-Mineral Bone Disorder (CKD-MBD). Kidney Int. 2009;76(S113):S KDIGO Clinical practice guideline for the evaluation and management of Chronic Kidney Disease. Kidney Int. 2013;3(1): Cavalier et al. Nephrol Dial Trans. 2012;27(5): Adapted from Fernández-Martín et al. Nephrol Dial Transplant. 2015;30:

22 22 Serum Phosphorus Serum Calcium Serum PTH BELOW OPTIMAL TARGET RANGES < 3.6 mg/dl N= 523 (8.3 %) < 7.9 mg/dl N= 326 (5.4 %) < 168 pg/ml N= 2529 (40.7 %) WITHIN OPTIMAL TARGET RANGES mg/dl N= 2569 (40.8 %) Lowest Mortality 7.9 mg/dl N= 4199 (69.0 %) Lowest Mortality 168 pg/ml N= 3079 (49.5 %) ABOVE OPTIMAL TARGET RANGES > 5.2 mg/dl N= 3199 (50.9 %) > 9.5 mg/dl N= 1562 (25.7 %) > 674 pg/ml N= 613 (9.9 %)

23 23 Serum Phosphorus Serum Calcium Serum PTH BELOW OPTIMAL TARGET RANGES WITHIN OPTIMAL TARGET RANGES mg/dl N= 2569 (40.8 %) 7.9 mg/dl N= 4199 (69.0 %) 168 pg/ml N= 3079 (49.5 %) ABOVE OPTIMAL TARGET RANGES

24 24 Serum Phosphorus BELOW OPTIMAL TARGET RANGES < 3.6 mg/dl N= 523 (8.3 %) WITHIN OPTIMAL TARGET RANGES mg/dl N= 2569 (40.8 %) ABOVE OPTIMAL TARGET RANGES > 5.2 mg/dl N= 3199 (50.9 %) Serum Calcium < 7.9 mg/dl N= 326 (5.4 %) 7.9 mg/dl N= 4199 (69.0 %) 9.5 > 9.5 mg/dl N= 1562 (25.7 %) Serum PTH < 168 pg/ml N= 2529 (40.7 %) 168 pg/ml N= 3079 (49.5 %) 674 > 674 pg/ml N= 613 (9.9 %)

25 Decrease of Serum Phosphorus and Risk of Mortality 25 Baseline serum phosphorus >5.2 mg/dl % CI (Model 3) 1.50 Hazard Ratio Decrease N= mg/dl Increase Observa1ons distribu1on Serum phosphorus change (mg/dl) Hazard Ratio % Model Decrease N= Increase Serum phosphorus change (mg/dl) 95% CI (Model 3) Observa1ons distribu1on mg/dl Mean Serum Value: 6.5 ± 1.1 mg/dl Mean Change: ± N= 3199 Patients (12729 Observations)

26 Decrease of Serum Calcium and Risk of Mortality 26 Baseline serum calcium >9.5 mg/dl Hazard Ratio % CI (Model 3) Decrease N= mg/dl Observa1ons distribu1on Increase Serum calcium change (mg/dl) Hazard Ratio % Univariate Model Decrease N= Serum calcium change (mg/dl) 95% CI (Model 3) Observa1ons distribu1on Increase mg/dl Mean Serum Value: 10 ± 0.3 mg/dl Mean Change: ± N= 1562 Patients. (6522 Observations)

27 Increase in Serum PTH and Risk of Mortality 27 Baseline serum PTH <168 pg/ml Hazard Ratio pg/ml Hazard Ratio % N=9 271 Model 3 Observa1ons distribu1on 95% CI (Model 3) Serum PTH (pg/ml) 200 Increase Decrease Serum PTH change (pg/ml) pg/ml Mean Serum Value: ± 46.5 pg/ml Mean Change: ± N= 2529 patients. (10096 Observations)

28 Why Are the Targets So Important? Are They Useful? For the First time, Using the COSMOS Results Mimicking As Much Are As We Possible Treating What the Patients Happens or in Are a Randomized We Just Correcting Clinical Trial, We Numbers Have Found? Are the We Correction Influencing of the Outcomes Main CKD-MBD? Serum Parameters was Associated with Significant Reduction in the Relative Risk of Mortality in CKD 5D Patients

29 ERA-EDTA Madrid 2017 Cristina Ortiz Many Thanks Universidad de Oviedo