ASN BOARD REVIEW 2014

AKI Pathogenesis, Diagnosis, Biomarkers and Risk Assessment

Anupam Agarwal, MD

Division of Nephrology

University of Alabama at Birmingham

Outline

• Pathogenesis of Acute Kidney Injury and Repair• Prerenal and Ischemic AKI• Sepsis• Toxin

• Pathogenesis of AKI in the Elderly• Definition, Incidence• Diagnosis, Biomarkers• Clinical Risk Assessment of AKI

TubulesApoptosisNecrosisMitochondrial dysfunctionBack-leakDetachmentObstruction

Systemic factorsProinflammatory cytokinesAntiinflammatory cytokines

VasculatureVasoconstrictionFocal IschemiaVasodilationThrombosisCoagulationInflammationPluggingNo ReflowIntermittent flow

MicroenvironmentInnate immunityAdaptive immunityParacrine factorsAutocrine factors

Pathogenesis of AKIAKI

Biophysical Basis of Decreased GFR

Prowle, J. R. et al. Nat. Rev. Nephrol.;6(2):107-15

Effect of Ischemia on Regional Blood and Medullary PO2

0

20

40

60

80

100

Re

lati

ve

Blo

od

Flo

w

Cortex Outer medulla

Innermedulla

Pre-ischemia

Postischemia

P.O.A. Hellberg, et.al. Kidney Int. 40:625,1991

95

50

20

15

10

Renal Artery

50

10

8

O2 Diffusion

PO2, mm Hg

Cortex

Inner Cortex

Medulla

Renal Vein

Pathogenesis of AKI

PGC

PreRenal AKI

RC Blantz 53:512-523, 1998

Intrarenal Mechanisms for Autoregulation of the Glomerular Filtration Rate

Abuelo JG. N Engl J Med 2007;357:797-805.

NSAIDS ACEI/ARB

M. Epstein Am J. Med: 49: 175-185, 1970

HRS: antemortem HRS: postmortem

Hepatorenal Syndrome Severe Vasoconstriction

Cirrhosis

Portal Hypertension and Splanchnic Arterial Vasodilation

Impaired effective arterial blood volume

Low Arterial Pressure

Activation of Vasoconstrictor System

Renal Vasoconstriction

HEPATORENAL SYNDROME

Abnormal DistributionOf Blood Volume

Cirrhotic Cardiomyopathy

Low SVR Cardiac Preload

Intrahepatic Resistance Splanchnic Vasodilators

IntraabdominalCompartment Syndrome

Ridings, et al 1995Pickhardt et al. 1999

Patel et al 2007

Hemodynamic effect of IAH

Ca

rdia

c In

de

x (L

/min

/m2)

Abdominal Pressure (mmHg above baseline)

Wed

ge

Pre

ssu

re (

mm

Hg

)

Physiologic Sequelae

• Elevated intra-abdominal pressure causes:• Compression of renal

veins and IVC• Reduced cardiac output

to kidneys• Renal failure,

oliguria/anuria

The Result:• Reduced blood flow to

kidney• Renal congestion and

edema• Decreased glomerular

filtration rate (GFR) • Acute tubular necrosis

(ATN)

Adapted from Bonventre and Weinberg

JASN 14:2199-2210, 2003 Courtesy of Bruce Molitoris

Ischemia

Continued Ischemia

DECREASED GFR

Acute Tubular Injury

ApoptosisNecrosis

Tubular ObstructionBackleak

MicrovascularInjury

VasoconstrictionLeukocyte Adhesion

↑ Permeability

MicrovascularCongestion

Innate Immunity

Inflammation

DAMPSImmune Cells

Cytokines

EndotheliumMicrovascular endothelial injury and dysfunction during IRI

Ischemia

Endothelial Cell activation, Dysfunction, 

Injury and/or Detachment

Impaired VasodilationCoagulation

Leukocyte Adhesion

Capillary Obstruction and Continued Ischemia

Extension of ARF

Inflammation

TA Sutton, CJ Fisher, BA Molitoris Kidney Int (2002) 62, 1539–15490

Microvascular Blood Flow at 24h Post Ischemia Effect of sTM

sTM treatedSaline treated

Blood Flow velocity (µm/sec)

253.36+/-95.01 786.75 +/- 280.75 *

Early Pathogenic Mechanisms of AKIEndothelial, Epithelial, Immune Cells and Interstitium

Sharfuddin, A. A. & Molitoris, B. A. (2011) Nat. Rev. Nephrol.

J. V. Bonventre and L. Yang J. Clin Invest. 2011;121(11):4210–4221.

Injury and Repair in Ischemic Acute Kidney Injury Human Acute Kidney InjuryBackleak

TS Olsen, HS Olsen, HE Hansen Vichows Arch 1985, 406:75

Regenerating Cell NonReplacement Site

DEAD CELLS, GRANULAR CASTS, REGENERATING EPITHELIUM

Courtesy of MA Venkatachalam

Outline

• Pathogenesis of Acute Kidney Injury and Repair• Prerenal and Ischemic AKI

• Sepsis

• Toxin

• Definition, Incidence

• Diagnosis, Biomarkers

• Clinical Risk Assessment of AKI

Sepsis Related AKI

Mechanisms

• Pro-inflammatory State

• Systemic Vasodilation

• Impaired Microcirculation

• Cytokine mediated cell injury

(Schrier, RW, NEJM, 2004)

Hyperdynamic Circulation in Experimental Septic AKI: Systemic Parameters

C Langenberg…R Bellomo, Kidney Int (2006) 69, 1996–2002

MAP HR

CO TPCConductance

Ecoli Ecoli

C Langenberg…R Bellomo, Kidney Int (2006) 69, 1996–2002

Hyperdynamic Circulation in Experimental Septic AKI: Renal Parameters

E Coli

Hyperemic AKI: Loss of glomerular filtration pressure

• Septic AKI may represent a unique form of AKI: hyperemic AKI. 

• GFR is determined by glomerular filtration pressure. 

• If afferent arteriole dilates and the efferent arteriole dilates even more, RBF will markedly increase, yet pressure within the glomerulus will fall. GFR will also decrease.

Sepsis is a Disorder of the Microcirculation

Trzeciak S et al. Acad Emerg Med 2008; 15:399-413

PO2

Outline

• Pathogenesis of Acute Kidney Injury and Repair• Prerenal and Ischemic AKI• Sepsis• Toxin

• Pathogenesis of AKI in the Elderly• Definition, Incidence• Diagnosis, Biomarkers• Clinical Risk Assessment of AKI

Site Specificity of Common Nephrotoxins

V.S. Vaidya, J.V. BonventreComprehensive Toxicology2010, Pages 197–211

TMACalcineurin Inh

ClopidogrelCocaine

MitomycinQuinine

Proximal Tubule InjuryAcyclovirAminoglycosidesCadmiumCidofovirCisplatinFoscarnetLeadMercuric chloride

HemodynamicsACEI/ARBAmpho BCalcineurin inhDiureticsNSAIDSContrast

Distal Tubule InjuryAmpho BCalcineurin inhLithiumSulfadiazine

Tubular ObstructionAcyclovirIndinavirMethotrexateSulfonamides

Interstitial NephritisAllopurinolAristolochic acidCephalosporinsCiprofloxacinDiureticsNSAIDSPenicillinsPhenytoinPPIs

Aminoglycosides

• GFR is not apparent until 7‐10 days after initiating therapy.

• Occurs in setting of hypotension, prerenal

azotemia other nephrotoxins

• UNa>20 meq/L, FENA>2

• Usually reversible

• Risk factors: prolonged treatment,  volume 

depletion, preexisting renal disease, hypokalemia, 

old age, other nephrotoxins

• Monitor drug levels and creatinine every 2‐3 days

Aminoglycoside binds to the anionic phospholipid of the PTC, it is transferred to the transmembrane protein megalinand endocytosed

Megalin-expressed in the renal proximal tubules, podocytes and ciliary and inner ear epithelium

After endocytosis, endosomes -accumulate in organelles such as the mitochondria and the nucleus- disrupting in mitochondrial function

1.Nagai J; Takano M. Drug Metab Pharmacokinet. 2004 Jun;19(3):159-702.Ford DM et al. Am J Physiol. 1994 Jan;266(1 Pt 1):C52-73.Sandoval RM; Molitoris BA, Am J Physiol Renal Physiol. 2004 Apr;286(4):F617-24.

J.M. Lopez-Nova et al, Kidney Int 79:33, 2011

Aminoglycoside Nephrotoxicity Aminoglycoside Nephrotoxicity

Myeloid bodies

Sodium Diatrizoate-ionic monomer(1500-1800 mosm/kg)

Iohexol-nonionic monomer(780 mosm/kg)

Iodixanol-nonionic dimer(290 mosm/kg)

Structure of Contrast Media

Adapted from C.M. Sandler N.Engl.J.Med 348:551, 2003

Contrast Media-Nephrotoxicity

Contrast Media

Blood Flow OxygenDelivery

OxygenConsumption

Renal Medullary Hypoxia

SystemicHypoxemiaBlood viscosity

PGE2 EndothelinANP VasopressinAdo PGI2

Osmotic Load

Direct Cellular Toxicity

modified from Rudnick et. al. Seminars in Nephrology 17:15-26, 1997

Pathogenesis of CIAKI

Calvin, A. D. et al. (2010) Contrast-induced acute kidney injury and diabetic nephropathyNat. Rev. Nephrol. doi:10.1038/nrneph.2010.116 J. Cerdá et al. Clin J Am Soc Nephrol 3: 881-886, 2008

Progession of AKI to CKD/ESRD

.Loss of Peritubular Capillaries Lead to Chronic Hypoxia

• Decreased oxygen diffusion from peritubular capillaries to tubular and interstitial cells• Stagnation of peritubular capillary blood flow • Decreased peritubular capillary blood flow as a result of imbalance of vasoactive substances• Inappropriate energy usage as a result of uncoupling of mitochondrial respiration induced by oxidative stress• Increased metabolic demands of tubular cells • Decreased oxygen delivery as a result of anemia

Nangaku M JASN 2006;17:17-25

MSCs Repair Kidney

Florian E. Tögel & Christof Westenfelder Nature Reviews Nephrology 6, 179-183 (March 2010)

What is the origin of myofibroblasts in the kidney?

10%

5%

60%

30%

VS LeBleau…R. Kalluri et al. Nature Medicine 19, 1047–1053 (2013)

Molecular Mechanisms of FibrosisCell Cycle and Epigenetic Modification

T.A.Wynn Nature Medicine 16, 523–525 (2010); L. Yang Nature Med 16:535-543, 2010W. Bechtel Nature Med 16:544-550, 2010

Rasal 1

RAS inactivation

Cell Proliferation

HypermethylationRasal 1

RAS activation

Cell Proliferation

Outline

• Pathogenesis of Acute Kidney Injury and Repair• Prerenal and Ischemic AKI• Sepsis• Toxin

• Pathogenesis of AKI in the Elderly• Definition, Incidence• Diagnosis, Biomarkers• Clinical Risk Assessment of AKI

Population incidence of dialysis-requiring AKI in the United States by age groups from 2000 to 2009

Hsu R K et al. JASN 2013;24:37-42

AKI Susceptibility in Elderly

Anderson S et al. JASN 2011;22:28-38

Prevention of AKI in elderly depends on awareness of reduced GFR

• Age dependent decline in GFR; worse with clinical risk factors

• CKD is risk factor for AKI

• Prevention depends on awareness of reduced GFR in elderly despite normal creatinine

M. C. Odden et al. Nephrol Dial Transplant (2010) 25(2): 463‐469 Redrawn from USRDS 2009, P. Eggers

Senile NephrosclerosisAmong 1,203 living kidney donors

AD Rule et al. Nephron Physiol. 2011 August; 119(Suppl 1): p6–p11.

GlomerulosclerosisTubular atrophyInterstitial fibrosis >5%Arteriosclerosis

20 yo kidney donor

70 yo kidney donor

Renal Reserve in Elderly

GF

R m

l/min

0

50

100

150

200

250

Young Old Oldest Old

Baseline

Meat Meal

Renal Reserve

CG Musso et al. Int Urol Nephrol (2011) 43:253–256

Pathogenesis of AKI Key Points

• Ischemic, septic or toxin induced AKI often occur concomitantly

• Ischemic AKI results is a summation of events that involve capillary endothelium, tubular epithelial cells, and inflammatory cells and humoral mediators (cytokines and chemokines).

• Nephrotoxins-site specificity

• Sepsis models of AKI • Pro-inflammatory cytokines due to host response.

• Disorder of microcirculation

• AKI in aging• Due to comorbid factors (heart failure, diabetes) and

• Due to noncomorbid factors that relate to age related changes in kidney function.

• Due in part to decrease in renal reserve

• Chronic medullary hypoxia and activation of myofibroblasts are thought to contribute to mechanisms by which AKI leads to CKD.

Pathogenesis of AKI: Key Points: Update

• Role of mesenchymal stem cells –• i) Immediate effects ameliorate injury (paracrine)

• ii) late effects in recovery (“homing”)

• Single episode of kidney injury triggers long-term changes to structure & function.

• Epithelial regeneration leads to repair and fibroblast/pericyte proliferation leads to fibrosis.

Outline

• Pathogenesis of Acute Kidney Injury and Repair• Prerenal and Ischemic AKI• Sepsis• Toxin

• Pathogenesis of AKI in the Elderly• Definition, Incidence• Diagnosis, Biomarkers• Clinical Risk Assessment of AKI

Population incidence of dialysis-requiring AKI in the United States by sex from

2000 to 2009

Hsu R K et al. JASN 2013;24:37-42

Overall

Gender

Age

Over 30 definitions of AKI/ ARF exist in the literature

1. Creat ∆ 0.1 mg/dL2. Creat increase >0.5 mg/dL3. Creat>= 0.5 mg/dL4. Creat >= 1.7 mg/dL5. Creat >= 1.5 mg/dL6. Creat >= 2 mg/dL7. Creat>= 2.1 mg/dL and x 28. Creat >= 177µmol/L ∆>62µmol/L9. Creat > 200µmol/L (2.36 mg/dL)10. Creat> 3.2 mg/dL or x 211. Creat>5 mg/dL or K > 5.512. RIFLE13. Creat increase >= 25%14. Creat increase >= 50%15. Creat increase >= 100%16. ∆Cr72h >0µmol/L17. ∆Cr72h >25µmol/L18. ∆Cr72h >44µmol/L

19.∆Cr72h >50µmol/L20.∆Cr72h >100µmol/L21.Cockcroft-Gault Cr Cl < 30 mL/min22.Cockcroft-Gault Cr Cl 30–60 mL/min23.∆Cockcroft-Gault72hr <0%24.∆Cockcroft-Gault72hr <-15%25.∆Cockcroft-Gault72hr <-25%26.∆Cockcroft-Gault72hr <-50%27.MDRD: 50% change in GFR28.UO <100 q 8hr29.U α1-microglob30.U β2- microglobulin31.U N-acetyl- β-D-glucosaminidase32.U gluthation transferase-π33.U gluthation transferase- α34.NGAL35.RRT36.…

ADQI Rifle Criteria – Consensus Definition

BellomoetalCritCare2004www.ADQI.net

Mortality Risk in Hospitalized Patients

0.0

5.0

10.0

15.0

20.0

Mu

ltiv

ari

ab

le O

R

↑SCr↑SCr> 0.3 > 0.5 > 1.0 > 2.0

mg/dLChertow et al, JASN 16: 3365-3370, 2005Chertow et al, JASN 16: 3365-3370, 2005

R (I)

I (II)

F (III)

Increased SCr x1.5OR > 0.3 mg/dL

UO < .3ml/kg/hx 24 hr or Anuria x 12 hrs

UO < .5ml/kg/hx 12 hr

UO < .5ml/kg/hx 6 hr

Increased SCr x2

Increase SCr x3or SCr 4mg/dl

(Acute rise of 0.5 mg/dl)

HighSensitivity

HighSpecificity

RRT Started

Modifications proposed by AKINAmsterdam, 2005

R (I)

I (II)

F (III)

Criterion must be reached within 48hr

AKIN Criteria (Rifle V2.0)

Riskvs Non-AKI

Injuryvs Non-AKI

Failurevs Non-AKI

1 102.4 4.2 6.4Relative Risk

Increase in All-Cause Mortality with worse RIFLE Class

n=71,527

Ricci et al KI 2008

KDIGO Definition of AKI

• Increase in SCr by ≥0.3 mg/dl within 48 hours; or

• Increase in SCr to ≥1.5 times baseline, which is known or presumed to have occurred within the prior 7 days; or

• Urine volume <0.5 ml/kg/hour for 6 hours.

Baseline Day 1 Day 2 Day 3 Day 7 RIFLE AKIN

0.4 0.5 0.6 0.7 0.4 YES NO

1.0 1.1 1.3 1.2 1.0 NO YES

Examples

5 Problems (at least) with Serum CreatinineRIFLE/AKIN/KDIGO-Creatinine based

1. Not sensitive: There is lot of cellular injury that does not affect (GFR)/creatinine

2. Not Specific: Creatinine can increase without kidney injury (pre-renal state)

3. Delayed: The rise is serum creatinine is delayed by 2-3 days

4. Fluid therapy may dilute serum creatining delaying diagnosis

5. Inter-laboratory variation in measuring creatinine, and bilirubin and other compounds interfere with the colorimetric modified Jaffe assay hence affect serum creatinine levels.

Serum Creatinine and GFR In AKI

Muscle mass

Protein metabolism

Serum creatinine

Renal excretion

Tubular excretion Filtration (GFR)

Drugs Nonlinear

Nutrition Infection

Edema

Volume of distribution

Star RA, Kidney Int, 1998

Definition and Incidence:Summary• RIFLE or AKIN Definitions

• Increase in stage associated with increase in mortality

• Both have important limitations

• KDIGO Definition• Consensus definition- Combines RIFLE and AKIN into a single

definition

• Limitations-number of limitations

Need to integrate biomarkers of injury

Outline

•Pathogenesis of Acute Kidney Injury

•Definition, Incidence

•Diagnosis, Biomarkers

•Clinical Risk Assessment of AKI

Primary and Secondary PreventionRisk Profiling and Biomarkers

High riskHigh risk Prerenal AKIPrerenal AKI AKIAKI

Therapeutic Window

Glomerular Filtration Rate

Sensitive Biomarkers Creatinine

Jo, S.K. M.H. Rosner and M.D. Okusa, Clin. J. Am. Soc. Nephrol. 2: 356 – 365, 2007.

Primary Prevention

Secondary Prevention

What Can An Ideal AKI Biomarker Teach Us?

• Predict and diagnose AKI early (before increase inserum creatinine)

• Identify the primary location of injury (proximal tubule,distal tubule, interstitium)

• Pinpoint the type (pre-renal, AKI, CKD), duration andseverity of kidney injury

• Identify the etiology of AKI (ischemic, septic, toxic,combination)

• Predict clinical outcomes (dialysis, death, length of stay)

• Monitor response to intervention and treatment

• Expedite the drug development process (safety)

Prasad Devarajan: Biomarkers in Acute Kidney Injury :Search for a Serum Creatinine Surrogate

Biomarkers after AKIEarly Detection

Idealized

SCr

IL-18

NGAL

L-FABP

Kim-1

Value of Damage BiomarkersDifferential Diagnosis of AKI

Urinary NGAL Serum Creatinine

TK. Nicholas et al. Ann Intern Med. 2008;148:810-819

635 patients admitted to the hospital with AKI, prerenal azotemia, CKD, or normal kidney function. • RIFLE criteria for AKI used. • At a cutoff value of 130 g/g creatinine, sensitivity and specificity of NGAL for detecting acute injury were

0.900 (95% CI, 0.73 to 0.98) and 0.995 (CI, 0.990 to 1.00),

Combined use of damage biomarkers and functionalbiomarkers Predicts clinical events

Clinical events (initiation of dialysis or in-hospital mortality)

T.K. Nicholas, et al. J Am Coll Cardiol. 2012 January 17; 59(3): 246–255

NGAL KIM-1

Diagnosis of AKI: Combination of Functional and Damage Markers

Dublin, Ireland, August 30th-September 1st, 2011

ZH Endre et al Contrib Nephrol. 2013;182:30-44

RenaStickPoint of Care Testing for AKI

V.S. Vaidya…J. V. Bonventre, et al.Kidney International (2009) 76, 108–114

Timing in Secondary PreventionEarlyARF Study

• Double-blind placebo-controlled trial -early treatment with erythropoietin (E) could prevent the development of AKI in ICU setting.

• Urinary levels of two biomarkers, γ-GT and AP (46.3) triggered randomization to either placebo or two doses of E

• Primary outcome of relative average plasma creatinine increase from baseline over 4 to 7 days.

• Of 529 patients, 162 were randomized within an 3.5 h of a positive sample.

• Early intervention with high-dose erythropoietin did not alter the outcome.

ZH Endre, et al,Kidney Int. (2010) 77, 1020–10301 hr 12 hr 7 d24 hr

RandomizationAv 3.5 h

Placebo or E

randomization

Thresholds for Detection of AKICaveats?

No AKI

AKI

No AKI

AKI

No AKI

AKI

No AKI

AKI

Healthy Adult Adult with CKD?? Pediatric Elderly Adult??

L-FABP, KIM-1, and IL-18Surgery, contrast-induced AKI, sepsis and critical illness.

What are the cut points for:

Urine microscopy in early diagnosis of AKI

• 267 hospitalized patients with a diagnosis of AKI.

• Findings on urine microscopy led change in the initial diagnosis of

• PRA to ATN in 27 patients (23%)

• ATN to PRA in 15 patients (14%)•

MA Perazella et al. Clin J Am Soc Nephrol 3: 1615-1619, 2008

Biomarkers: Summary

Biomarkers – General

• Transition from discovery to validation to clinical use: IL-18; Cystatin

C; KIM -1; NAG

• Combination of “functional” and “damage” biomarkers

• Optimal “context specific” cut-points for the diagnosis of AKI need to be developed for L-FABP, KIM-1, and IL-18 and other

Biomarkers - Older patients• The use of serum creatinine is the current gold standard but its

use necessitates a clear understanding of its limitations especially the older population

• Validation of lead biomarkers need testing in the older population• L-FABP, KIM-1, and IL-18 and others

• Cut-points need to be identified in the older population

Outline

•Pathogenesis of Acute Kidney Injury

•Definition, Incidence

•Diagnosis, Biomarkers

•Clinical Risk Assessment of AKI

Exposure

GFR

Damage

Acu

te K

idn

ey

Inju

ryNormal

Co-morbidities

Demographics

Medications

Su

scep

tib

ilit

y

ESRD/Death

CKD

Recovery

Ou

tco

mes

Inte

rven

tio

n

Before Exposure

After Exposure

During Development of AKI

After Recovery from AKI

Risk Assessment

Adapted from KDIGO; appendix C, Kidney Int. 2012

Pre-Exposure Risk Factors

Shared Susceptibility Factors

Dehydration

Hypoalbuminemia

Advanced Age

Female Gender

Black race?

Previous AKI

Chronic Co-morbidities

CKD

Diabetes Mellitus

Heart Disease

Pulmonary

Multiple myeloma

Acoholism

Preexposure medications

Medications

NSAIDs

ACEI/ARBs

Statins?

Pre

-Exp

osu

re R

isk

Fac

tors

Risk Prediction for RCIN

Hypotension

IABP

CHF

Age>75

Diabetes

Contrast volume

Cr>1.5 mg/dl

eGFR<60 ml/min/1.73 m2

Mehran et al. JACC 2004;44:1393‐1399

Risk Factors

RiskScore

Risk ofRCIN

Risk ofDialysis

≤ 5 7.5% 0.04%

6‐10 14% 0.12%

11‐16 26.1% 1.09%

≥ 16 57.3% ≤12.6%

5

5

5

4

3

1 for each 100ml

4

2 for 40‐604 for 20‐405 for <20

Score

5,561 pts in development set2,786 pts in the validation set

Risk Assessment of ARF Post CABG (1992‐2002)                       

Minimum score, 0 Maximum score, 17 

Risk factors Score

Female gender 1

Congestive heart failure 1

Left ventricular ejection fraction <35%

1

Preoperative use of IABP 2

COPD 1

Insulin-requiring diabetes 1

Previous cardiac surgery 1

Emergency surgery 2

Valve surgery only (reference to CABG)

1

CABG + valve (reference to CABG)

2

Other cardiac surgeries 2

Preoperative creatinine 1.2 to <2.1 mg/dl (reference to 1.2)

2

Preoperative creatinine 2.1 (reference to 1.2)

5

C. Thakar J. Am Soc. Nephrol 16:162-168, 2005

Risk Factors for AKI: Importance of CKDKaiser Permanente Northern California

≥ 60 Reference30-44

15-29

Diabetes Mellitus

45-59

Documented Proteinuria

Diagnosed Hypertension

BaselineGFR

<15

C.Y. Hsu…GM. Chertow…and AS Go Kidney Int. 74, 101–107, 2008

Unadjusted Odds ratio

1,746 hospitalized AKI-D and 600,820 hospitalized with no AKI

Hyperglycemia increases AKI Risk

Van den Berghe, JASN, March 08

Proteinuria increases AKI Risk

T. Huang, et al. JASN Jan 1, 2011 22: 156-163

Obesity and Risk of Acute Kidney Injury Following Cardiac Surgery

F. T. Billings IV et al. JASN 23:1221-1228, 2012

• Examined body mass relationship between BMI and AKI in 445 patients undergoing cardiac surgery.

• Higher BMI –independently associated with increased odds of AKI

• 26.5% increase per 5 kg/m2 (4.3-53.4%; P-0.02).

• Baseline and intraop F2-isoprostane, and intraop PAI-1 independently predicted AKI

• Obesity independently predicts AKI after cardiac surgery in part through oxidative stress.

Predictive and intraoperative Risk Assessment

Demirjian S, et al. AJKD; 59(3): 382-9, 2012.

Non Dialysis AKI Associates with Increased Long Term Mortality

• .

J-P Lafrance and D. R. Miller J Am Soc Nephrol 21:435-42, 2010

Clinical Risk Assessment: Summary

• Understanding individual risk factors may help in preventing AKI

• Interaction of susceptibility of AKI and type/extent of exposure that determines risk of occurrence of AKI

• Susceptibility factors may be modified• Exposures can be avoided or tailored to reduce risk

• Most patients are seen after exposure-still opportunity for risk assessment – closer monitoring, general support measures

• AKI-recovery may lead to CKD/ESRD• Post AKI monitoring and transition of care is important

Cirrhotic Cardiomyopathy

• 50 ys ago Kowalski and Abel described hyperdynamiccirculation in cirrhotic patients

• Gould 1969 demonstrated cardiac contractile response was depressed in alcoholic cirrhosis, confirmed in several other studies (alcoholic cirrhosis)….alcohol cardiomyopathy?

• Depressed cardiac function due to cirrhosis• -adrenergic receptor density of lymphocytes of patients

• Animal studies confirmed

• Nonalcoholic cirrhosis with blunted cardiac inotropic and chronotropic response to exercise, drugs, hemorrhage, surgery and stress.

• Conduction abnormalities