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