novel diagnostics and treatments of aki

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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 Presentation

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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

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