novel diagnostics and treatments of aki
DESCRIPTION
Novel Diagnostics and Treatments of AKI. Paul J. Scheel, Jr., M.D. Director, Division of Nephrology The Johns Hopkins University School of Medicine. Learning Objectives. Understand increasing incidence of AKI Identify the new definitions of AKI - PowerPoint PPT PresentationTRANSCRIPT
Novel Diagnostics and Treatments of AKI
Paul J. Scheel, Jr., M.D.Director, Division of Nephrology
The Johns Hopkins University School of Medicine
Learning Objectives
• Understand increasing incidence of AKI• Identify the new definitions of AKI• Understand use and limitations of new
biomarkers for AKI• Review recent treatment trials of AKI
Incidence: AKI
Hsu et al , JASN 2013, 24:37-42
Incidence: AKI By Age
Hsu et al , JASN 2013, 24:37-42
Does AKI Lead to CKD ?
• The higher the serum creatinine• The longer the duration of AKI• Recurrent AKI
* Strongly Associated with CKD and Death
AKI and Survival
Chawla et al. Kid Int. 2012;82: 516-524
KDIGO Definition of AKIKDIGO STAGE
Serum Creatinine Increase Urine Output Criteria
1 1.5-1.9 x baseline or >0.3 mg/dl increase < 0.5 ml/kg per hr for 6-12h
2 2-2.9 x baseline < 0.5 ml/kg per hr for > 12 hrs
3 3x baseline or increase serum creatinine > 4 mg/dl or Initiation of Dialysis
< 0.3 ml/kg per hr for > 24 hrsOr anuria for > 12 hrs
Diagnosis
• Based on Change in Serum Creatinine– Assay Interference– Altered metabolism of creatinine in AKI– Dilution by volume overload– Alteration in secretion by drugs ( cimetidine)– Late and Indirect Marker
Bio-Markers of AKI
• Predict and Diagnose AKI• Identify Location of Injury• Identify Type and Etiology of Injury• Predict Outcomes
Biomarkers of AKIFunctional Biomarkers Tubular Enzymes Upregulated Proteins
Creatinine Alanine Amino Peptidase KIM-1
Cystatin C Alkaline Phosphatase Clusterin
Β-2 Microglobulin α-Glutathione-S-Transferase NGAL
Retinol-binding Protein ϒ-Glutamyl Transpeptidase IL-18
Microalbumin N-Acetyl-β-Glucosamidase Cysteine-Rich Protein
AKI Bio-Markers
• Cystatin C• Microalbumin• N-Acety-β-Glucose-Amidase (NAG)• Kidney Injury Molecule-1 ( KIM-1)• Neutrophil Gelatinase-Associated Lipocalcin (NGAL)• IL-18• Liver Fatty Acid Binding Protein
Charlton et al. NDT ( 2014) 0:1-11
Cystatin C
- Found in all nucleated cells- Freely filtered - Not protein bound- Not normally secreted in urine- Competes with albumin for
endocytic reabsorbtion- Analysis affected by:
- DM- Corticosteroids- Hyperthyroidism- Elevated Bilirubin- Inflammation
MicroAblbumin
• Normal < 30 mg/L• ↑Albuminuria secondary to
tubular dysfunction• Non specific as to site of
injury• Need to know baseline• Can be non pathologic ( fever, exercise)
MicroAlbuminuria and AKI
Adults AKI /Cardiac Surgery Children AKI /Cardiac Surgery
Age 1 month to 2 years Age > 2 years
Molnar et al. CJASN 2012;7:1749-1760 Zappitelli et al. CJASN;2012;7:1761-1769
N-Acetyl-β-D-Glucose AmidaseNAG
• Proximal Tubule Protein• Appears in Urine with
proximal tubular injury• Appears 12h to 4 days
before rise in serum creatinine
• Inhibited by Urea• False + : Glucose
intolerance,RA, Hyperthyroid
Charlton et al. NDT ( 2014) 0:1-11
Charlton et al. NDT ( 2014) 0:1-11
KIM-1
• Increased more than any other gene in AKI
• Shed from proximal tubular cells into urine
• Urine KIM-1 ↑within 12hrs of ischemic injury
Parikh et al. CJASN 2013; 8:1079-1088
Charlton et al. NDT ( 2014) 0:1-11
NGAL
• Produced by tubular epith cells and neutrophils
• Filtered at glomerulus• Filtered NGAL captured by
proximal tubular cells• Rise in serum and urine
NGAL predictor of AKI• Infusion of NGAL may
prevent AKI ?
NGAL in Diagnosis and Prognosis of AKI
Predict AKI Predict Initiation of RRT
Haase et al. Am J Kid Dis 2009;54(6):1012-1024
Charlton et al. NDT ( 2014) 0:1-11
IL-18
• Levels ↑2x in AKI• Source:
– Proximal tubular cell
Urinary IL-18 In AKI
Parikh et al, Am J. Kid Dis. 2004, 43: 405-414
Charlton et al. NDT ( 2014) 0:1-11
Liver Fatty Acid –Binding ProteinL-FABP
• Increased 4 hours after ischemic injury from cardiac surgery
Urinary FABP and NAG as Predictors of AKI Following Cardiac Surgery
Katagiri et al. Ann of thoracic Surgery 2012;93:577-583
Treatment Trials
• Dopamine for prevention of delayed graft function
• N-accetycysteine to prevent RCIN• Chloride-poor IV fluids in ICU• ANP to prevent AKI
Dopamine For Delayed Graft Function
• Randomized, Open label, Multicenter• 264 Deceased Donors• Dopamine at 4 micrograms/Kg/min• Outcome: Need for Dialysis
Dopamine For Prevention of Delayed Graft Function
Schnuelle et al. JAMA. 2009 Vol 302(10):1067-1075
Dopamine For Prevention of Delayed Graft Function
Schnuelle et al. JAMA. 2009 Vol 302(10):1067-1075
Treatment Trials
• Dopamine for prevention of delayed graft function
• N-accetycysteine to prevent RCIN• Chloride-poor IV fluids in ICU• ANP to prevent AKI
N-acetylcysteine To Prevent RCIN
• 180 patients with GFR < 60 ml/min having PCI• Randomized, placebo controlled , double blind• NAC 2000 mg/day or 3 days vs palcebo
N-accetycysteine to prevent RCIN
Miner, et al Am Heart Journal 2004;148:690-695
N-accetycysteine to prevent RCIN
NAC Placebo P Value
Death, MI, Dialysis, Hospitalization, n (%) 23 (24.2) 18 21.2) NS
Death, n %) 4 (4.2) 3 (3.5) NS
Non fatal MI, n( %) 6 (6.3) 4 (4.7) NS
Need for Dialysis, n (%) 1(1.1) 1 (1) NS
Repeat Hospitalizations, n (%) 13 (13.7) 13 (15.3) NS
Miner, et al Am Heart Journal 2004;148:690-695
Treatment Trials
• Dopamine for prevention of delayed graft function
• N-accetycysteine to prevent RCIN• Chloride-poor IV fluids in ICU• ANP to prevent AKI
Is Chloride Bad in Intravenous fluids ?
• Normal saline has 40% higher Chloride than plasma
• High Serum Chloride Associated with Renal vasoconstriction and decreased GFR
• Normal Saline also associated with “ dilutional” metabolic acidosis
Chloride Liberal vs Chloride Restrictive IVF Administration
• 1533 patients admitted to ICU• NS vs Lactate (Chloride 109nmol), Balanced
Buffered soln ( Chloride 98 mmol)• Outcome: AKI
Chloride –Liberal Vs Restricted Chloride i.v. Fluid in ICU Patients
Development of Stage 2 or 3 AKI
Yunos et al. JAMA 2012; 308 (15): 1576-1572
Chloride –Liberal Vs Restricted Chloride i.v. Fluid in ICU Patients
Need for RRT in ICU
Yunos et al. JAMA 2012; 308 (15): 1576-1572
Treatment Trials
• Dopamine for prevention of delayed graft function
• N-accetycysteine to prevent RCIN• Chloride-poor IV fluids in ICU• ANP to prevent AKI ( NU-HIT Trial)
ANP Nu-HIT Trial
• RCT 303 patients with CKD undergoing CABG• Intervention hANP vs Placebo• Outcome: postoperative AKI
hANP During CABG for CKD
Sezai et al, JACC . 2011Vol 58 (9):897-203
Dialysis Free Rate
Summary
• Clinical use of biomarkers for early diagnosis of AKI is promising but awaits prospective clinical trials .
• While several trials have demonstrated the ability to reduce AKI in randomized trials only hANP has demonstrated ability to reduce AKI and decrease risk of CKD and Dialysis