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ACUTE KIDNEY INJURY Role of Novel Biomarkers

ACUTE KIDNEY INJURY Role of Novel Biomarkers. R Bhimma Department of Paediatrics and Child Health Nelson R Mandela School of Medicine University of KwaZulu-Natal. Definition of AKI. Sudden impairment of kidney function occurring over a period of hours to days.

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ACUTE KIDNEY INJURY Role of Novel Biomarkers

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  1. ACUTE KIDNEY INJURY Role of Novel Biomarkers R Bhimma Department of Paediatrics and Child Health Nelson R Mandela School of Medicine University of KwaZulu-Natal

  2. Definition of AKI Sudden impairment of kidney function occurring over a period of hours to days. Diagnosis Increase serum creatinine and/or blood urea nitrogen levels and/or decrease urine output

  3. Why is it important to detect AKI early? • A rise in serum creatinine of just 0.3mg/dl (26.5 mmol/l) has a four fold higher multivariable – adjusted risk of death. • Children with AKI may be at risk for long-term chronic kidney disease.

  4. Limitations of serum creatinine and BUN Change extracellular volume depletion decreased kidney blood flow Influenced by other factors, which are not directly related to kidney damage, such as: • age • sex • body mass • nutritional status

  5. Limitations of Serum creatinine and BUN cont… • Elevated serum creatinine concentrations are not specific for AKI and require differentiation from other pre-renal or extra-renal causes. • Serum creatinine concentrations are not specific for renal tubular lesions, pathogenetically related to AKI development. • Reflect the loss of glomerular filtration function, accompanying the development of AKI.

  6. Limitations of serum creatinine and BUN cont… • Increases in serum creatinine are detected later than the actual GFR changes as creatinine accumulates over time. • Serum creatinine is a poor marker of kidney dysfunction as changes in its concentrations are neither sensitive nor specific in response to slight GFR alterations. • Changes in serum creatinine become apparent only when the kidneys have lost ≥50% of their functional capacity.

  7. What is a biomarker? “a characteristics that is objectively measured and evaluated as an indicator of normal biological process, pathogenic process, or pharmacologic response to a therapeutic intervention”.

  8. Ideal Biomarker AKI • Non – invasive • Easily obtainable • Measurable using standardized assays • Fast results • Incur reasonable cost to perform

  9. Possible roles for novel kidney injury biomarkers Ismaili Z Al et al Ped Nephrol , 2010

  10. Pathophysiological mechanics of AKI and repair

  11. Proposed mechanisms for increased biomarker levels in plasma and urine (1) Increased synthesis in extrarenal tissues (2) Release from circulating immune cells (3) Glomerular filtration Increased biomarker levels in plasma (4) Impaired reabsorption in the proximal tubule (5) Increased synthesis in tubular cells (6) Release from infiltrating immune cells Increased biomarker levels in urine Martensson J et al BJA , 2012

  12. Proposed phase of biomarker development

  13. Summary of calculating diagnostic characteristics: sensitivity, specificity, positive predictive value, and negative predicative value.

  14. Hypothetical ROC: plot of the sensitivity of a test vs. 1-specificity for may different cut-off values of a biomarker

  15. Kidney Biomarkers • > 20 protein biomarkers have been intensively studied. • Urinary biomarkers are regarded as more non invasive, easy to measure, easily obtainable and provide earlier detection of AKI. • Depending on the time of appearance after AKI, urinary biomarkers many be classified as those of structural injury or functional injury.

  16. Biomarkers of structural injury

  17. Biomarkers of functional injury

  18. Others

  19. Neutrophilgelatinase – associated lipocalin (NGAL) • 25–kDa polypeptide covalently bound to gelatinase secreted from activated human neutrophils. • Most consistent biomarkers found during AKI. • Predominantly found in proliferating nuclear antigen–positive proximal tubule cells. • Predicts the occurrence of AKI in paediatric and adult patients after cardiac surgery. Cont…

  20. Neutrophilgelatinase – associated lipocalin (NGAL) • AUC- ROC for NGAL is 0,92 at 2 hours and 1,00 at 4 hours CBP. • Also predicts mobility and mortality in children who undergo cardiac surgery. • Also predicts development of DGF.

  21. Kidney Injury Molecule-1 (KIM-1) • Orphan trans-membrane receptor of unknown function. • Undetectable in normal kidney tissue or urine. • Markedly increased in ischaemic and nephrotoxic proximal tubular cell injury, and in renal cell carcinoma. • Higher urinary KIM-1 associated with worse outcome in established AKI. Cont… W. K. Han et al Advances in Clinical Chemistry, Vol. 49, 2009, pp. 73-97.

  22. Kidney Injury Molecule-1 (KIM-1) • AUC – ROC 0,57 at 2 hours, 0,83 at 12 hours, and 0,78 at 24 hours after cardiac surgery. • Also predicts graft loss in renal transplant patients. • Useful in some studies to differentiate between AKI, CKD and normal patients. W. K. Han et al Advances in Clinical Chemistry, Vol. 49, 2009, pp. 73-97.

  23. Interleukin (IL) -18 • Pro-inflammatory cytokine • Mediates inflammatory process during ischaemic, sepsis and nephrotic AKI. • Recruits neutrophils during ischaemic injury. • Can predict AKI 1 day ahead of serum creatinine. Cont…

  24. Interleukin (IL) -18 • AUC – ROC 0.73 for development of AKI in patients with acute respiratory distress syndrome. • Independent predictor of mortality in the above group of patients. • Also elevated after CPB --- ROC- AUC 0.61 at 4 hours, 0.75 at 12 hours and 0.73 at 24 hours.

  25. Cystatin C • 13 kDa cysteine protease inhibitor. • Secreted by all nucleated cells into plasma. • Freely filtered at the glomerulus and not secreted in the tubules. • Less influenced by factors other than GFR (e.g. age, sex, race, or muscle mass). • Therefore change in serum and urinary cystatin C is more sensitive than a change in serum Cr in predicting change in GFR. Cont…

  26. Cystatin C • Predicts the risk of AKI-associated CV morbidity. • Levels > 1.0mg/L also predict CV events and mortality in patients with a GFR >60mls/min/1.73m². • Increase urinary cystatin C and alpha 1 - microglobulin are predictors of an unfavourable outcome in ATN. • Has higher sensitivity and higher negative predictive value in determining GFR in CKD.

  27. Proposed Biomarker strategies for Renal Replacement Therapy (RRT)- initiation in AKI. • Some studies have shown better renal outcomes in patients who start RRT while in RIFLE-risk or injury compared to failure. • However some patients may recover spontaneously. • Biomarkers like NGAL, cystatin C, NAG, KIM-1 and alpha 1 - microglobulin can help distinguish patients in whom RRT will be needed.

  28. Proposed biomarkers – based strategy for RRT BM indicates RRT necessary Consider initiating RRT Severe AKI (AKIN stage 3) AKI present Measure BM BM Intermediate MILD/ MODERATE AKI (Akin stage 1-2) BM indicate RRT Unlikely Conservative treatment

  29. Conclusion • Need a ‘panel’ of biomarkers making it possible for early detection, treatment, and hopefully, preventing AKI. • As cardiology moved form LDH to troponins for the diagnosis of MI, intensive care nephrology will hopefully evolve from serum Cr to tissue specific injury biomarkers.

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