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