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
•
•
•
•
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
•
•
•
•
•
•
•
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
-
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
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
•
•
•
•
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