Transcript Novel Diagnostics and Treatments of AKI

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 AKI
KDIGO
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 < 0.3 ml/kg per hr for > 24 hrs
mg/dl or Initiation of Dialysis
Or 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
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Predict and Diagnose AKI
Identify Location of Injury
Identify Type and Etiology of Injury
Predict Outcomes
Biomarkers of AKI
Functional 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
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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
Cystatin C
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Found in all nucleated cells
Freely filtered
Not protein bound
Not normally secreted in urine
Competes with albumin for
endocytic reabsorbtion
- Analysis affected by:
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DM
Corticosteroids
Hyperthyroidism
Elevated Bilirubin
Inflammation
Charlton et al. NDT ( 2014) 0:1-11
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
Molnar et al. CJASN 2012;7:1749-1760
Age > 2 years
Zappitelli et al. CJASN;2012;7:1761-1769
N-Acetyl-β-D-Glucose Amidase
NAG
• 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
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
Charlton et al. NDT ( 2014) 0:1-11
Parikh et al. CJASN 2013; 8:1079-1088
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 ?
Charlton et al. NDT ( 2014) 0:1-11
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
IL-18
• Levels ↑2x in AKI
• Source:
– Proximal tubular cell
Charlton et al. NDT ( 2014) 0:1-11
Urinary IL-18 In AKI
Parikh et al, Am J. Kid Dis. 2004, 43: 405-414
Liver Fatty Acid –Binding Protein
L-FABP
• Increased 4 hours after
ischemic injury from cardiac
surgery
Charlton et al. NDT ( 2014) 0:1-11
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
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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
Dialysis Free Rate
Sezai et al, JACC . 2011Vol 58 (9):897-203
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