acute renal injury: what now?

Acute Renal Injury:

What Now?

Patricia F. Kao, MD MS

Assistant Professor

Department of Nephrology and Hypertenstion

Department of Physiological Sciences

Eastern Virginia Medical School

Disclosures

I have no Conflict of Interests to

Disclose

Learning Objectives

By the end of this lecture, you

should:

Understand controversies in the evaluation

and management of acute kidney injury

Terminology

Acute Kidney Injury

(AKI)?

Terminology

For the remainder of this lecture, I will use the

term “Acute Kidney Injury”, abbreviated as

(AKI), which is currently the most widely

accepted term used by the nephrology

community.

Brief Outline – Acute Kidney Injury

Epidemiology

Definitions and classification of AKI

Diagnosis and Evaluation

Treatment and Management of AKI

The focus for this talk will be on advances

and controversies over the last 2 decades

in each of these areas, rather than a

comprehensive review

Epidemiology

From: Hsu et al.

Kidney Int. 2007;72(2):208–212

vol 1 Figure 5.2 Unadjusted rates of first hospitalization with AKI for Medicare patients aged 66+ by age and year, 2003-2012

Vol 1, CKD, Ch 5 9

vol 1 Figure 5.4 Unadjusted rates of first hospitalization with AKI for Medicare patients aged 66+ by CKD, DM and year, 2003-2012

Vol 1, CKD, Ch 5 10

Epidemiology of AKI

Most epidemiologic studies have shown an

increase in the annual incidence of AKI over

the last 2 decades, however the actual

incidence rates of AKI reported are anywhere

from 1%-25% of critically ill patients

(Chertow et al, 1998; de Mendonca et al,

2000)

Epidemiology of AKI

The wide range of data reported is likely

due to differences in:

the criteria used to dx AKI (different laboratory

criteria, classification systems, and ICD-9

codes)

heterogeneity in the etiology of AKI

characteristics of the study populations

This creates significant challenges in

comparing trials of prevention and therapy

Epidemiology of AKI

Regardless of disparate incidence rates in the

literature, there is a change in the paradigm

of AKI. Whereas it was previously thought

that AKI and CKD were separate entities, it is

now understood that:

AKI is a major risk factor for chronic kidney

disease (CKD)

Significant increase in the long-term risk of CKD

and ESRD following AKI, even after initial

recovery of renal function

AKI is an independent risk factor for mortality

From: The 2012 Kidney Disease: Improving Global Outcomes

(KDIGO) Clinical Practice Guideline for acute kidney injury (AKI)

vol 1 Figure 5.7 Cumulative probability of a recurrent AKI hospitalization within two years of live discharge from first AKI hospitalization in 2010 for Medicare patients aged 66+

Vol 1, CKD, Ch 5 15

vol 1 Figure 5.13 Renal status one year following discharge from AKI hospitalization in 2010-2011, among surviving Medicare patients aged 66+ without kidney disease prior to AKI hospitalization, by CKD stage and ESRD status

Vol 1, CKD, Ch 5 16

Ishani A et al. J Am Soc Nephrol 2009

N= 233.803

Acute kidney injury increases risk of ESRD among elderly

Ishani A et al. J Am Soc Nephrol 2009

AKI and Mortality Rates

Xue et al. published a study in 2006

showing:

In-hospital mortality rates of:

33% in AKI pts requiring dialysis

27.5% in AKI pts not requiring dialysis

4.6% in pts with no AKI

90-day mortality rates of:

44.8% in AKI pts requiring dialysis

40.3% in AKI pts not requiring dialysis

12.1% in pts with no AKI

Chertow et al, JASN

16:3365-70; 2005

•AKI (Δ in SCr >0.5)

•Age (per 10 yr)

•CKD

•CV dis.

•Respiratory dis

•GI dis.

•Cancer

•Infection

6.5

1.7

2.5

1.5

3

2.4

2.9

7.5

<0.0001

<0.0001

<0.0001

<0.04

<0.0001

<0.001

<0.0001

<0.0001

Brigham and Women’s, 9210 adults Multivariable Odds Ratio for Death

Chertow et al, 2005

AKI and Mortality Rates

Definition and Classification

Traditional Definition of AKI in the

Clinical Setting

“A sudden, sustained, and usually

reversible decrease in renal function

occurring over a period of hours to

days”

Definition of AKI in the Clinical

Setting

Clinicians broadly detect a decrease

in renal function by:

an increase in serum creatinine, or

a decrease in urine output

Typically divide AKI into:

Oliguric – urine output < 400-500 ml/24 hrs

Anuric – urine output < 50-100 ml/24 hrs

Definition of AKI in the Literature

Over the last few decades, more than 35 different definitions have been used to define AKI in the literature

The Acute Dialysis Quality Initiative (ADQI) recognized the need to standardize the definition of AKI, both for scientific and clinical use.

In 2004, a workgroup from the ADQI published the RIFLE critera in Critical Care

***Note that increases in SCreat are in comparison with the

patient’s baseline creatinine ***

RIFLE Classification of AKI

Strengths Limitations

Valid tool for determining the

incidence of AKI

Baseline serum creatinine is

necessary

Monitoring progression of AKI

severity in the hospital

Subject to limitations of creatinine-

based measurement

RIFLE classes strongly associated

with increased lengths of stay, RRT

requirement, renal recovery,

discharge from hospital

Measuring urine output can be

technically difficult out of ICU setting

and may be affected by

pharmacologic agents

GFR measurements (such as MDRD

eGFR) only valid in steady-state, not

in AKI

AKIN Criteria

In 2007, the Acute Kidney Injury Network

working group published the AKIN

classification system in Critical Care

Dx of AKI only considered after

Achieving an adequate status of hydration

Excluding urinary obstruction

relies on ∆ in SCr, not ∆GFR

baseline SCr not necessary, can use at

least 2 SCr values obtained within a period

of 48hrs to obtain an increase in absolute

SCr

RIFLE vs AKIN

AKIN recognizes that:

even small increases in SCr are associated with a

poor outcome

baseline SCr often not available, and “back-

calculating” baseline creatinine using the MDRD

with eGFR of 75 is subject to significant error

there is extreme variability of resources and

indications to start RRT in different countries and

hospital

From: KDIGO 2012 Clinical Practice Guidelines for AKI

RIFLE vs AKIN

So which classification system should we

use?...

KDIGO

The Kidney Disease Improving Global

Outcomes work group (KDIGO)

published Clinical Practice Guideline

for acute kidney injury (AKI) in 2012

Proposes a classification system that

combines the RIFLE and AKIN criteria

KDIGO Guidelines for AKI

2.1.1: AKI is defined as any of the

following (Not Graded):

Increase in SCr by ≥0.3 mg/dl (≥ 26.5

mmol/l) 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/h for 6 hours.

The Dx of AKI must be established using

this criteria before staging

KDIGO Classification for AKI Stage Serum creatinine Urine output

1 1.5-1.9 × baseline OR

≥ 0.3 mg/dL

<0.5 ml/kg/hr for 6-12 hrs

2

2.0 - 2.9× baseline

<0.5 ml/kg/hr ≥ 12 hrs

3 3.0 times baseline OR

increase in Cr to ≥4.0 mg/dL OR

Initiation of RRT

<0.3 ml/kg/hr ≥ 24 hrs OR

Anuria ≥ 12 hrs

***Note: To reach stage 3 by the criteria SCr ≥ 4.0, the patient must first achieve the creatinine-based change specified in the KDIGO definition of AKI.

Diagnosis and Evaluation

Hou SH, Bushinsky DA, Wish JB. Am J Med 1983; 74: 243-8.

Nash K, Hafeez A, Hou S. Am J Kidney Dis. 2002; 39: 930-6.

Kaufman J, Dhakal M, Patel B, Et al. Am J Kidney Dis 1991; 17: 191-8.

Lameire N et al. (2006) The changing epidemiology of acute renal failure Nat Clin Pract Neprol 2: 364–377 doi:10.1038/ncpneph0218

Figure 2 Percentage distribution of causes of acute renal failure in (A) non-ICU

and (B) ICU settings

Modified with permission from Liano F et al. (1998) The spectrum of acute renal failure in the intensive care unit

compared with that seen in other settings. The Madrid Acute Renal Failure Study Group.

Kidney Int Suppl 66: S16–S24. © (1998) Nature Publishing Group.

“Standard” Initial Diagnostic

Evaluation of AKI

Serum Urine Other

creatinine Urinalysis Post-void residual

BUN Microscopy for RBC’s,

WBC’s, casts

Foley catheterization

Potassium Eosinophils Renal Ultrasound

Phosphorus Electrolytes (Na,

creatinine, and Urea

nitrogen) to calculate

FeNa and FeUN

CO2

Calcium

Pitfalls of Fractional Excretion

of Sodium (FeNa) Pre-existing CKD: FeNa 2-3 even without tubular

injury

Poor sensitivity with diuretics use (use Fractional Excretion of Urea Nitrogen instead)

Picture might be muddied by recent Na-containing IV fluid administration

Etiologies of FeNa < 1% OTHER than pre-renal azotemia

hepatorenal syndrome

contrast nephropathy

rhabdomyolysis

acute glomerulonephritis

early obstructive uropathy

Pitfalls of Serum Creatinine

“Creatinine” comes from the Greek word

κρέας, or “flesh”

It is a reflection of muscle mass

Significant factor in:

obese or malnourished patients

Amputees

Weight lifters and other athletes

Acutely ill patients

Cancer patients

Childhood Actor Gary

Coleman 4’8” NBA player Sean Elliot 6’8”


Creatinine is not only freely filtered at the

glomerulus, but is is also secreted in the

proximal tubule

In AKI, although glomerular filtration of

creatinine may decrease, there is an initial

increase in tubular secretion (if there is

enough intact tubular function)

This often results in “lag time” between the

actual decline in GFR and a measurable

increase in serum creatinine


By the time the serum creatinine has

started to rise, there is likely already

significant renal injury

The lag time can make it difficult to

pinpoint the “offending” insult

chronologically and to initiate any

preventive measures

MDRD eGFR

Another common error in the diagnosis

and management of AKI is the use of

the MDRD eGFR in this setting

The automated eGFR reported by

laboratories is based on the 4-variable

MDRD equation (age, gender, race,

serum creatinine)

MDRD eGFR

eGFR, therefore, is subject to the same

errors as using serum creatinine in the

setting of AKI

The MDRD equation was developed in a

population of patients with known CKD,

and was not intended for use in AKI, nor

has it been validated in this setting

MDRD is only valid in steady-state

MDRD eGFR and medication

dosing Guidelines for renal dosing of medications

were established in the 1990’s using the

Cockroft-Gault Equation for CrCl, not MDRD

eGFR

Neither Cockroft-Gault, no MDRD are valid in

the acute, non-steady state setting

Clinical judgement must be used in renal

dosing meds based on eGFR or Crcl,

balancing mediction toxicity with risks

associated with underdosage

“The Search for a Kidney Troponin”

Other potential markers besides

creatinine…

Urine and Plasma Neutrophil Gelatinase-associated

lipocalin (NGAL)

Kidney injury molecule 1 (KIM-1)

Cystatin C

Urine IL-18

Liver-type fatty acid-binding protein (L-FABP)

“The Search for a Kidney Troponin”

The Translational Research Investigating Biomarker

Endpoints in AKI (TRIBE-AKI) failed to show troponin-

like diagnostic performance of any of these markers

The SAPPHIRE study validated 2 new novel biomarkers

Tissue inhibitor of metalloproteinase-2 (TIMP-2)

IGF-binding protein 7 (IGFBP7)

The product of these two markers predicted the onset of severe

AKI (defined as KDIGO stage 2 or 3) within 12 hrs with

significantly greater accuracy than NCAL, KIM-1, IL-18, L-FABP,

or cystatin C

Further investigation is needed to define their role in the clinical

setting

Treatment and Management

KDIGO Guidelines for AKI

Treatment and Management

To date, there are no evidenced-

based treatments for AKI

Likely due to:

Variability in etiologies of AKI

Inconsistent definitions of AKI in the

literature

Heterogeneity in the co-morbidities and

concurrent illnesses of the patients

Management of In-Hospital AKI

To date, the literature has not conclusively

demonstrated any significant benefit in the

use of:

low dose dopamine

Fenoldapam

loop diuretics (may be useful only if pt is volume

overload)

early initiation of hemodialysis or continuous renal

replacement therapy in AKI

Management – IV Fluid of

choice in AKI

KDIGO Clinical Practice Guidelines:

3.1.1: In the absence of hemorrhagic shock, we

suggest using isotonic crystalloids rather than

colloids (albumin or starches) as initial

management for expansion of intravascular volume

in patients at risk for AKI or with AKI. (2B)

3.1.2: We recommend the use of vasopressors in

conjunction with fluids in patients with vasomotor

shock with, or at risk for, AKI. (1C)

Teaching. Discovering. Caring.™

The scientific community has made great strides in defining and classifying AKI

There are multiple guidelines for the diagnosis, treatment, and management of AKI

However, neither the classification system or the guidelines have been widely accepted in clinical practice


Be aware of the pitfalls associated with creatinine based measurements of renal function and using MDRD eGFR in AKI

Multiple biomarkers have been identified that have helped characterize AKI and may be eventually be useful in the diagnosis of AKI


Although the nephrology community has gained a better understanding for AKI and the associated risks, there have not been any significant advances in treatment or prevention…this is the next step

acute renal injury: what now?

Documents