4/6/2017. Singapore? CKiD IPPN. Understanding pediatric CKD A Global Effort

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1 Biomarker mid-region pro-adrenomedullin is associated with diastolic dysfunction in children with end-stage renal failure Sharon Teo, Kar-Hui Ng, M Than, L Gong, JB Lunaria, TH Heng, C Chan, YWP Lau, WS Yeo, LH Ling, M Richards, YH Chan, ID Liu, HK Yap Shaw-NKF-NUH Children's Kidney Center, KTP-University Children's Medical Institute, National University Health System, Singapore National University of Singapore Annual Dialysis Conference, Long Beach, March 2017 Singapore? Understanding pediatric CKD A Global Effort CKiD 4C IPPN Singapore 1

2 We are giving good dialysis treatment Are we? CVS mortality is ~1000x more than peers! Dialysis Transplant n = 1380 cardiac deaths Mitsnefes M., Perit Dial Int 2005 Parekh RS et al., J Pediatr 2002 When does cardiovascular disease start? Dialysis Paediatric nephrologists set the balls rolling! Transplant n = 1380 cardiac deaths Mitsnefes M., Perit Dial Int 2005 Parekh RS et al., J Pediatr

3 To be GREAT, we can try to predict which patients are at risk of early CVS disease Predictors Early CVS disease Outcome What is early CVS disease? Predictors Early CVS disease Outcome CVS disease EARLY Arteriopathy Diastolic dysfunction LATE Changes in LV mass Systolic dysfunction 3

4 Ventricular filling during diastole: Two phases Early diastole Ventricular relaxation Passive filling Atrial contraction Active filling humanphysiology.academy. In diastolic dysfunction Early diastole Ventricles do not relax well filling Atrial contraction Atria contract harder filling humanphysiology.academy. What Doppler imaging parameters did we look at? 4

5 Transmitral Doppler LV inflow velocity E A Doppler imaging parameters E / A (Mitral valve) Blood flow (z scores referenced to age-appropriate norms) Doppler tissue velocity Muscle movement E A E / A (LV lateral wall) E / A (LV septal wall) Zile. Circulation. 2002;105: Colan SD. Echocardiography in Pediatric and Congenital Heart Disease, 2009 Transmitral Doppler LV inflow velocity Blood flow Doppler tissue velocity Tissue movement Normal E A A E Early diastolic dysfunction E A E/A E /A E A Zile. Circulation. 2002;105: Tissue Doppler imaging of the heart Predictors Early Diastolic CVS dysfunction disease Outcome 5

6 Renal-related Anemia Ca-phosphate imbalance Traditional Proteinuria Hypertension Inflammation and Dyslipidemia oxidative stress Diabetes Hyperhomocysteinemia Age Predictors Tissue Doppler imaging of the heart Early Diastolic CVS dysfunction disease Outcome Renal-related Anemia Ca-phosphate imbalance Traditional Proteinuria Hypertension Inflammation and Dyslipidemia oxidative stress Novel Diabetes Hyperhomocysteinemia biomarker with Age better prediction? Predictors Tissue Doppler imaging of the heart Early Diastolic CVS dysfunction disease Outcome Adrenomedullin (ADM) Circulating, autocrine and paracrine hormone Natriuretic, vasodilatory, and hypotensive effects Expressed in many organ systems Increased in hypertension, chronic renal disease, and heart failure. Medscape.com Peacock WF. Clin Chem Lab Med

7 But adrenomedullin is unstable in vitro Mid-regional pro-hormone fragment (MR-proADM) MR-proADM corresponds to ADM concentration Better than brain natriuretic peptide (BNP) and NT-proBNP in predicting mortality within 14 days (Biomarkers in Acute Heart Failure (BACH) trial) Peacock WF. Clin Chem Lab Med Aim of the study Renal-related Anemia Ca-phosphate imbalance Traditional Proteinuria Hypertension Inflammation and Dyslipidemia oxidative stress Diabetes Hyperhomocysteinemia MR-proADM Age Predictor Early Diastolic CVS dysfunction disease Outcome 7

8 Who are the patients we studied? n = 36 dialysis patients 17.9 yrs Years 4.7 yrs Age Duration of ESRD Slightly more males; More PD patients Male 55.6% Females 44.4% PD 80.6% HD 19.4% n = 36 dialysis patients 8

9 Majority had hypertension and dyslipidemia (11.1%) None (34.3%) Hypertension (88.8%) Dyslipidemia (65.7%) (ABP / clinic BP / meds) >50% have high calcium-phosphate products Ca x Phosphate product (mmol/l) (DKOQI cut off) So how many have cardiac dysfunction? (11 had missing TDI data) Remaining 25 patients 9

10 6 (24%) patients had diastolic dysfunction N (n = 25) How many had systolic dysfunction (FS<25%)? 2 (8%) patients z scores Lateral E /A Septal E /A Mitral E/A Diastolic dysfunction is defined as z-scores <-2 SD in any of the three parameters. How robust was our tissue Doppler imaging? Good correlation between the TDI parameters Septal E'/A' r = 0.49, p = Mitral E/A Lateral E'/A' r = 0.78, p < Septal E'/A' 10

11 So does MR-proADM correlate with TDI parameters? MR-proADM Early Diastolic CVS dysfunction disease MR-proADM correlates with diastolic dysfunction parameters r = p = MR-ADM (nmol/l) (n = 25) MR-ADM (nmol/l) r = p = Lateral E /A MR-ADM (nmol/l) r = p = Mitral E/A Septal E /A Does this association still hold true after adjustment for possible confounding factors? Age Hypertension Gender Dyslipidaemia Type of dialysis Ca-P product Duration of dialysis MR-proADM Septal E /A 11

12 This association remains significant after adjustments for age, gender, type of dialysis, duration of dialysis, presence of hypertension and dyslipidaemia and calcium-phosphate product. MRproADM Septal E /A standardized β = (95%CI to ) p = MR-proADM Early Diastolic CVS dysfunction disease Co-Investigators Paediatric Nephrology, NUH Dr Isaac Liu Dr. Sharon Teo Prof. Yap Hui Kim Dr. Perry Lau Dr. Yeo Wee Song Dr. Chee Qiao Zhi Dr. Mya Than Dr. Lourdes P. Resontoc Chloe Chan Xiaoyun Heng Teng Hiang Cardiovascular Research Institute, NUH Prof. Mark Richards Prof. Ling Lieng Hsi Gong Lingli Josephine Lunaria Berboso Prof. Quek Swee Chye Wang Ruifang Lab Medicine, NUH Dr. Sharon Saw Anastacia Pajarillaga Biostatistics Unit, NUS Dr. Chan Yiong Huak 12

13 Thank You This work was supported by the Venerable Yen Pei-NKF Research Fund grant. We are grateful to NKF for their support. 13