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Similar to A nuclear magnetic resonance-based method for accurate assessment of glomerular filtration rate (GFR)
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A nuclear magnetic resonance-based method for accurate assessment of glomerular filtration rate (GFR)
- 1. -CONFIDENTIAL- 1 A NUCLEAR Real-time Precision Medicine. Mastering Metabolomic Networks. San Diego | ASN Kidney Week | October 2018 MAGNETIC RESONANCE-BASED OF GLOMERULAR FILTRATION RATE (GFR) METHOD FOR ACCURATE ASSESSMENT
- 2. -CONFIDENTIAL- 2 Gold standard • Measured GFR (mGFR), e.g. renal clearance of inulin or 125I-iothalamte • Very elaborate, expensive and/or associated with radiation • Rarely used in clinical routine Current routine: • GFR estimated based on serum creatinine (eGFR) • Creatinine depends on muscle mass, activity, age (biological variability) • Creatinine blind range of GFR 60-90 mL/min/1.73m² MacGregor NDT 2007 GFR: Current clinical practice eGFR (mL/min/1.73 m²) 125I-iothalamtemGFR(mL/min/1.73m²) Aim: New test for simple but precise estimation of GFR
- 3. -CONFIDENTIAL- 3 Retrospective samples from two European centers Hopital Edouard Herriot, Lyon • 139 samples • Adults and children University of Gothenburg • 77 samples • Exclusively children 216 samples 183 NMR spectra 33 had insufficient volume for preparation Discovery cohort (96) • Biomarker discovery • Modelling Test cohort (87) • Performance testing Study cohorts Data analysis
- 4. -CONFIDENTIAL- 4 Biomarker discovery in training cohort (n=96) Correlation of NMR signals with measured GFR 29 17 13 NMR signals found to be significantly correlated with mGFR Substances successfully verified (+ 7 unknown substances) Substances of physiological relevance remained for biostatistical modeling
- 5. -CONFIDENTIAL- 5 mGFR Hypofiltration Constellation �y𝐴𝐴 Hyperfiltration Constellation �y𝐵𝐵 Crea Val Myo Crea DMS Contribution Substance Pool Modelling Constellations Selection Selected constellations … Biomarker modelling and constellation selection +
- 6. -CONFIDENTIAL- 6 Filtration marker ROS Altered filtration, reabsorption, secretion Metabolic acidosis Oxidative stress Renalco-morbidityRenalfailure Biomarkers and their pathophysiology Creatinine Myo-Inositol Dimethyl sulfone Valine Accumulation of uremic toxins pH ↓ Uremia marker Oxidative stress marker Metabolic acidosis marker Clinicalmanifestation Increase when GFR declines to 50-60% Late marker Serum levels in renal impairment Impaired degradation in diseased kidneys Oxidative stress may increase serum levels Metabolic acidosis induces degradation Pathophysiological link
- 7. -CONFIDENTIAL- 7 CKD-EPI Creatinine eGFR(NMR) r = 0.848 RMSE =28.00 r = 0.880 RMSE =19.24 CKD-EPI Cystatin C r = 0.636 RMSE =32.81 eGFR(NMR) Test performance in independent cohort (n=87) In the “creatinine blind spot” eGFR(NMR) reduces variation from 24.5 to 11.0 compared to CKD-EPI Creatinine.
- 8. -CONFIDENTIAL- 8 Clinical need • Serum creatinine systematically overestimates renal organ reserve Utility Precise GFR estimation for detecting patients with renal involvement. Clinical need • Serum creatinine overestimates GFR • significantly decreased GFR is associated with AKI during or immediately after surgery. Utility Precise GFR estimation for selecting patients most likely benefitting from transplantation. Congestive heart failure Liver failure N=11 RMSE =15.64 N=11 RMSE =7.95 N=13 RMSE =26.41 N=13 RMSE =21.32 Pilot data for clinical utility: Subgroup analysis eGFR(NMR)eGFR(NMR)
- 9. -CONFIDENTIAL- 9 71% 95%82% 86% eGFR Blood sample Plasma clearance Tracer injection Blood samples Renal clearance Tracer injection Urine volume Urine sample Blood samples eGFR(NMR) Blood sample P30-Value Test performance continuum Am J Kidney Dis. 2014; 64(3): 411-424
- 10. -CONFIDENTIAL- 10 • As simple as serum creatinine testing • Outperforms creatinine and cystatin C-based estimations • With P30 > 80% almost as accurate as plasma clearance • Reduces variance in the creatinine blind spot between 60-90 ml/min/1.73 m² • Applicable to adults and children • Additional pathophysiological insights eGFR(NMR): Serum test for precise estimation of GFR Thank you for your attention! Interested? Email me at maulik.shah@numares.com