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Dr Musarrat Hussain . MD ,FAAP Diplomat American Board of Pediatrics.

Dr Musarrat Hussain . MD ,FAAP Diplomat American Board of Pediatrics. Fellow Pediatric Nephrology SUNNY at stony Brook USA. Pediatric Nephrologist , Shifa International Hospital Islamabad. ROLE OF BIOMARKERS IN THE FUTURE MANAGEMENT OF ACUTE KIDNEY

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Dr Musarrat Hussain . MD ,FAAP Diplomat American Board of Pediatrics.

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  1. DrMusarratHussain. MD ,FAAP Diplomat American Board of Pediatrics. Fellow Pediatric Nephrology SUNNY at stony Brook USA. Pediatric Nephrologist , Shifa International Hospital Islamabad

  2. ROLE OF BIOMARKERS IN THE FUTURE MANAGEMENT OF ACUTE KIDNEY INJURY IN CHILDREN

  3. AKI • Acute kidney injury (AKI) is a serious condition characterized by the sudden onset of renal dysfunction, leading to impaired control of acidbase, electrolyte and fluid balance. • Common in children admitted to the PICU. Etiology has shifted from primary renal diseases to being multifactorial in origin, particularly in hospitalized children. • incidence 5 % in hospitalized patients • 30–50 % in intensive care units • . Xue JL, Daniels F, Star RA, Kimmel PL, Eggers PW,Molitoris BA,Himmelfarb J, Collins AJ (2006) Incidence and mortality of acute renal failure in Medicare beneficiaries, 1992 to 2001. J Am Soc Nephrol 17:1135–1142

  4. AKI • 10–18 % children in ICUs develop AKI , app half developing with in 24 h and 75 % within 7 days after acute illness. • AKI occurs in up to 82 % of the most critically ill children (ventilated and on vasopressors) • Evidence of progression of AKI-to-CKD is currently evolving . • 3 to 5 Year Post AKI patient survival of 57 % only • 9 % of surviving AKI developing ESRD BY 5 Years • Askenazi DJ, Feig DI, Graham NM, Hui-Stickle S, Goldstein SL (2006). Kidney Int 69:184–189 • Akcan-Arikan A, Zappitelli M, Loftis LL,Washburn KK, Jefferson LS, Goldstein SL (2007) Kidney Int 71:1028–1035 • Nat Clin Pract Nephrol 4:510–514 • Pediatr Crit Care Med 8:29–35 • PediatrCrit Care Med 38:933–939

  5. AKI Clinicians now recognize that patients are dying “of ” and not just “with” AKI.

  6. AKI Etiology • Intrinsic AKI : concomitant ischemic, nephrotoxic, and septic components . • Multiple organ dysfunction syndrome • Complex cardiac repair • in developing countries , volume depletion, infections, and primary kidney D. • NSAIDs injury : PG maintain GFR by mediating afferent arteriolar dilatation, NSAIDs inhibit this response and can pptintrinsic AKI in prerenal states. • 14.. Crit Care 12:R47 15. Loza R, Estremadoyro L, Loza C, Cieza J (2006)

  7. Definition of AKI • The term AKI has replaced ARF • Change in S.Cr remains the gold standard for Dx of AKI. • There are limitation of using S.Cr as measure of AKI. • S.Cr is a measure of function ,not a measure of injury

  8. LIMITATION OF SERUM CREATININ • Increase in S.Cr can be delayed by as much as 48 hours. • S.Cr may not change until about 50 % function has been lost • S.Cr is affected by age, sex, and muscle mass • unable to differentiate among the various causes of AKI.

  9. LIMITATION OF SERUM CREATININ • By the time a change is observed in S.Cr, a critical therapeutic window may have been missed. • In NB interpretation of S Cr is difficult as it reflects maternal S.Cr in first wk of life ,base line S Cr is rarely available in children • it is an insensitive and delayed measure of kidney function following AKI

  10. Sepsis-induced AKI VS NON SEPTIC AKI • Has less favorable outcome • Higher risk of death, and long-term risk of CKD. • Has increased hospital mortality , longer ICU stay • SAKI is most common cause of death in critically ill children • Clin J Am Soc Nephrol 2:431–439 • Pediatr Nephrol 20:1177–1181 • Intensive Care Med 37:241–248

  11. Pathophysiologic interaction between sepsis and AKI

  12. Defining AKI Definition of AKI remains challenging ,many definitions has evolved RIFLE criteria -2004, revolutionized our approach to AKI research pRIFLE criteria- 2007 AKIN definition KDIGO -2012, AKIN, and pRIFLE were harmonized into a single definition by the Kidney Disease Improving Global Outcomes(KDIGO) AKI Consensus Conference  

  13. Pediatric-modified RIFLE criteriaa (pRIFLE) pediatric risk, injury, failure, loss, end- stage renal disease Akcan-Arikan A, Zappitelli M, Loftis LL, Washburn KK, Jefferson LS, Goldstein SL (2007) Modified RIFLE criteria in critically ill children with acute kidney injury. Kidney Int 71:1028–1035

  14. AKI AKIN definition (Acute Kidney Injury Network), which relies on an increase in creatinine from a previous trough level, pRIFLE was refined by the recommendations of the AKIN (Acute Kidney Injury Network) group [4], 4. Mehta RL, Kellum JA, Shah SV, Molitoris BA, Ronco C, Warnock DG, Levin A (2007) Acute Kidney Injury Network: report of an initiative to improve outcomes in acute kidney injury. Crit Care 11:R31

  15. AKI 2012 KDIGO (Kidney Disease Improving Global Outcomes) Guidelines finally unified the pRIFLE and AKIN for the diagnosis and management of AKI in adults and children. Despite limitations of SCr, the KDIGO AKI definition and staging should be used to guide clinical care. Kidney Disease: Improving Global Outcomes (KDIGO) (2012) KDIGO clinical practice guideline for acute kidney injury. Kidney Int Suppl 2:1–138

  16. AKI-KDIGO GUIDE LINE 2012 Kidney Disease: Improving Global Outcomes (KDIGO) (2012) KDIGO clinical practice guideline for acute kidney injury. Kidney Int Suppl 2:1–138

  17. Necrosis Vs Apoptosis Necrosis is caused by factors external to the cell or tissue, such as infection, toxins, or trauma that result in the unregulated digestion of cell components. Apoptosis is a naturally occurring programmed and targeted cause of cellular death.

  18.  Pathophysiology of intrinsic and structural acute kidney injury: hemodynamic alterations and their consequences. GFR, glomerular filtration rate.

  19. Figure 30.6 Structural consequences of acute ischemia and reperfusion injury to kidney tubule cells. Novel therapeutic approaches in acute kidney injury have targeted prevention of cell death, inhibition of inflammation, and acceleration of the endogenous recovery process. PMN, polymorphonuclear leukocyte.

  20. Brief Review of AKI Management • Adequate intravascular volume • Restoration of arterial filling • Restoration of C 0 , MAP, and oxygen carrying capacity • Vasoactive support (i.e. inotropic, vasopressor, vasodilator) • Norepinephrine is preferential over dopamine.

  21. The initial approach for suspected AKI • Identifying the underlying cause • Distinguishing prerenal (functional), intrinsic (structural), and postrenal • Determining the severity of AKI • Rapid response to fluid repletion is considered to be the ‘gold standard’ for the differentiation between transient volume-responsive prerenal AKI and persistent intrinsic AKI. • Some forms of prerenal AKI (liver failure, heart failure, and nephrotic syndrome) require fluid restriction rather than repletion

  22. Fluid overload and AKI

  23. Proven measures to prevent AKI • Avoidance of hypotension • Treatment of the underlying cause • Fluid and electrolyte management • Nutritional support • Adjustment of drug dosing • Renal replacement therapy

  24. Diagnosing AKI Decreasing urinary output and increasing S Cr remains the gold standard for AKI diagnosis. Process of Necrosis and apoptosis at the cellular level can not be detected by present investigatory tools. The renal injury evolves over periods of hours to days after renal insult. Renal Biomarkers have potential to Dx AKI before the GFR fall

  25. Nature of Biomarker A biomarker is defined as a characteristic that can be objectively measured and evaluated as an indicator of normal biological or pathogenic processes or pharmacological responses to a therapeutic intervention.

  26. Nature of Biomarker Biomarkerare proteins , either secreted in urine as a result of renal tubular cellular injury and extrusion from the cell cytoplasm or are somehow involved in AKI pathophysiology or cellular repair, allowing for early identification of tissue injury before function is impaired.

  27. Phases of Biomarker discovery • Discovery • Qualification • Verification • Research assay optimization • Clinical validation • Commercialization • Protein biomarker discovery and validation: the long and uncertain path to clinical utility. • Nat Biotechnol.  2006; 24(8):971-83 (ISSN: 1087-0156)

  28. Criteriaforideal biomarker • Validation in different settings of AKI eg : cardiac surgery, sepsis, contrast NP • Devoid of interference with other substances present in biological fluid • Development of a panel of biomarkers . • Measurable by a rapid test of readily available samples (urine or blood) • Should be cost-effective, with high sensitivity and specificity • Has dynamic and rapidly changing levels correlating disease progression/improvement • Has prognostic value • Edelstein C. Biomarkers of kidney disease. Boston (MA):Elsevier; 2016. • Makris K, Spanou L. Acute kidney injury: diagnostic approaches and controversies. Clin Biochem Rev 2016;37(4):153–75 • Nguyen MT, Devarajan P. Biomarkers for the early detection of acute kidney injury. Pediatr Nephrol 2008; 23:2151.

  29. Pioneering studies from the past 2 decades have identified candidate biomarkers of AKI with considerable potential in translational medicine. These biomarkers can be subdivided into 5 categories (Table 2) (15).article Makris K, Spanou L. Acute kidney injury: diagnostic approaches and controversies. Clin Biochem Rev 2016;37(4):153–75.

  30. Biomarkers investigated for various renal conditions • AKI • Chronic kidney disease (CKD) • Various forms of glomerulonephritis (GN) • Autosomal dominant polycystic kidney disease (ADPKD)

  31. Most promising novel biomarkers of AKI:. • Neutrophil gelatinase-associated lipocalin (NGAL) • kidney injury molecule 1 (KIM-1) • interleukin 18 (lL-18) • liver-type fatty-acid-binding protein (L-FABP) • insulin-like-growth-factor-binding protein 7 (IGFBP7) • and tissue inhibitor of metalloproteinase 2 (TIMP-2)

  32. A number of candidate biomarkers were identified following the discovery and identification of renal genes that are rapidly upregulated following a period of renal ischaemia : • Neutrophil gelatinase-associated lipocalin (NGAL)Approved -canada ,europe • Interleukin-18 (IL-18) • Kidney injury molecule 1 (KIM-1) Aproved by FDA USA • Liver-type fatty acid–binding protein (L-FABP) Approved in Japan for clinical use • Insulinlike growth factor–binding protein 7 (IGFBP7) 2014 Approved by FDA –USA • x tissue inhibitor of metalloproteinases–2 (TIMP-2) 2014 Approved by FDA –USA • Calprotectin • Urinary angiotensinogen • Urinary microRNA

  33. Novel Biomarkers of Nephrotoxicity • N-acetyl-glucosaminidase (NAG) • Glutathione-s-transferase (GST) • Gamma-glutamyl transpeptidase (GGT) • Alanine aminopeptidase (AAP) • Lactate dehydrogenase (LDH) • Kidney injury molecule 1 (KIM-1

  34. Asphyxiated NB with normal SCr have elevated • Serum neutrophil gelatinase-associated lipocalin (sNGAL) • urine neutrophil gelatinase-associated lipo- calin (uNGAL) • Krawczeski CD, Woo JG, Wang Y, Bennett MR, Ma Q, Devarajan P (2011) Neutrophil gelatinase-associated lipocalin concentrations predict development of acute kidney injury in neonates and children after cardiopulmonary bypass. J Pediatr 158:1009

  35. Tissue inhibitor of metalloproteinase 2 (TIMP2) plus insulin-like-growth-factor–binding protein 7 (IGFBP7) • TIMP -2 : Metaloproteinase inhibitor • IGFBP 7: insulin-like growth factor –binding protein • Discovery year : 2013 • AKI Population studied: Adult heterogeneous ,ICU ,CBP, high risk surgery and Pediatrics. • Mechanism of action upon injury :Expressed in renal tubular cell with injury leading to blocking the effect of cyclin-dependent protein kinase. • A point-of-care device measuring those two biomarkers was,approved by the US FDA in 2014 For CBP • Gunnerson KJ, Shaw AD, Chawla LS, Bihorac A, Al-KhafajiA, Kashani K, et al. TIMP2*IGFBP7 biomarker panelaccurately predicts acute kidney injury in high-risksurgical patients. J Trauma Acute Care Surg 2016;80(2):243–9 • . .

  36. NGAL( Neutrophil gelatinase-associated lipocalin ) Expression in KIDNEY : Proximal Tubule, Likely Distal. AKI Discovery Year :2001- Ischemia Reperfusion in Rats . 2003 - Plasma NGAL, Systemic Vasculitis ,Renal Damage 2003 Confirmed Ischemia Reperfusion+Nephrotoxic AKI AKI Population studied :Adult : Cardiac,Sepsis,Contrast ,Kidney Tx, ICU, Liver Tx, CKD Pediatric : Cardiac, PICU, Heart Tx, Kidney Tx , Contrast , Sepsis, CKD Mechanism of action upon Injury :Upregulated, released in Urine/Plasma . Action –unknown ,appears protective ,chelates iron from damaged tubules preventing free-radiclal formation and less cell death. currently approved in Canada and Europe for clinical use (41, 42). 41. Vijayan A, Faubel S, Askenazi DJ, Cerda J, Fissell WH,Heung M, et al. Clinical use of the urine biomarker [TIMP-2] Å~ [IGFBP7] for acute kidney injury risk assessment. AmJ Kidney Dis 2016;68(1):19 –28 .42. Schinstock CA, Semret MH, Wagner SJ, Borland TM,Bryant SC, Kashani KB, et al. Urinalysis is more specificand urinary neutrophil gelatinase-associated lipocalin ismore sensitive for early detection of acute kidney injury.Nephrol Dial Transplantation 2013;28(5):1175–85.

  37. NGAL pNGAL and uNGAL may peak before the onset of AKI, have the potential to predict AKI, needs to be caution with the use of pNGAL in sepsis. Pediatr Nephrol (2015) 30:1861–1871DOI 10.1007/s00467-015-3089-3 Towards a biomarker panel for the assessment of AKI in ch. NGAL may potentially be useful in differentiating pre-renal disease from ATN. Nat Med. Author manuscript; available in PMC 2011 Aug 1.Published in final edited form as:Nat Med. 2011 Feb; 17(2): 216–222. NGAL has excellent potential to diagnose AKI,when assessed by ROC analysis , measuring NGAL could be beneficial in clinical practice. Metaanalysis Pediatr Nephrol DOI 10.1007/s00467-017-3704-6 Accuracy of neutrophil gelatinase-associated lipocalin for acute kidney injury diagnosis in children: systematic review and meta-analysis Luís Taddeo Filho1 & Antonio Jose Grande1 & Tamy Colonetti 1 &Éverton Simon Possamai Della1 & Maria Inês da Rosa1

  38. BIOMARKER ALPHA -GST Expression in Kidney : Proximal Tubule AKI Discovery Year : 1977- Ligandinuria 1988- Low Alpha GST with cortical damage and GSTs urine loss Nephrotoxic AKI 1994 – Human Nephrotoxic AKI AKI population studied: Adult : Cardiac, , Sepsis , Kidney Tx ,ICU ,Liver Tx Nephrotoxic Pediatric : Cardiac Mechanism of action upon Injury :Found in urine by passive release, higher urine concentration indicative of proximal tubular injury

  39. BIOMARKER Pi -GST Expression in Kidney : Thin limb of the loope of henley, collecting duct ,distal Tubule AKI Discovery Year : 1977 Nephrotoxic AKI 1992 Expressed in renal cell tumors 1994 Human Nephrotoxic AKI AKI population studied: Adult : Cardiac, , ICU ,SEPSIS ,Liver Tx , .Nephrotoxic Pediatric : Non Mechanism of action upon Injury : Found in urine by passive release , higher concentration indicative of distal tubular injury

  40. BIOMARKER Hep25 Expression in Kidney : Thick ascending limb,collecting duct, Cellular : Apical cell pole AKI Discovery Year : 2006 - Detection in renal failure 2008 -Lupus Nephritis Urine , 2009 - AKI Biomarker AKI population studied: Adult :Cardiac, , CKD Pediatric :CKD Mechanism of action upon Injury :Inhibits intestinal iron absorption and release from macrophage /hepatocytes ,upregulated by inflammation

  41. BIOMARKER L-FABP(Liver-type fatty acid–binding protein) Expression in Kidney : Proximal Tubule AKI Discovery Year : 2003 – Urine biomarker of CKD AKI population studied: Adult : Cardiac, , contrast, Kidney Tx ,ICU ,Liver Tx , .Nephrotoxic Pediatric : Cardiac ,ICU Mechanism of action upon Injury :upregulated ,binds lipids hydroperoxides and other reactive oxygen species Approved in Japan for clinical use

  42. BIOMARKER IL-18 (Interleukin-18) Expression in Kidney :Proximal Tubule AKI Discovery Year : 2001- Ischemic AKI in mice AKI population studied: Adult : ATN,CKD, Pre renal Azotemia, UTI Cardiac, Sepsis, cardiac contrast, Kidney Tx ,ICU ,Liver Tx Pediatric : Cardiac ,Sepsis, PICU ,Kidney Tx Mechanism of action upon Injury : Produce by Prox,Tubules upon injury , Caspase 1 cleaves pro IL-18 inactive form to active form which exhibit proinflammatory properties

  43. KIM 1 (Kidney injury molecule 1) • Expression in Kidney : Proximal Tubule • AKI Discovery Year 1998 Upregulated in renal cells after injury (post ischemic • kidney , Nephrotoxicity) • AKI population studied: Adult: ATN,CKD Pre renal Azotemia,Urinary infection , • Cardiac, Sepsis, contrast, Nephrotoxic • Kidney Tx ,ICU ,Liver Tx • Pediatric :Cardiac ,Kidney Tx .Nephrotoxic • Mechanism of action upon Injury :Promotes apoptotic and necrotic cell clearance • upregulated and shed in to the urine and extra • cellular space • Its diagnostic and prognostic value needs to be further validated • optimal cutoff values for clinical use currently are undetermined • KIM-1 approved by the US FDA as a biomarker for preclinical drug development (48) • Parikh CR, Thiessen-Philbrook H, Garg AX, Kadiyala D,Shlipak MG, Koyner JL, et al. Performance of kidney injurymolecule-1 and liver fatty acid-binding protein andcombined biomarkers of AKI after cardiac surgery. Clin JAm Soc Nephrol 2013;8(7):1079–88..

  44. Human KIM-1 • A rapid direct 15 min assay for the detection of KIM-1 has been developed . • The extracellular domain of KIM-1 appears in the urine shortly after ischemic injury and can be readily detected by aKIM-1 urinary dipstick • . • Vaidya VS, Ford GM, Waikar SS, et al. A rapid urine test for early detection of kidney injury. Kidney Int 2009; 76:108..

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