The 2012 KDIGO guidelines on Acute Kidney Injury-

Is there a need for an update and have the

guidelines improved AKI prognosis?

Norbert Lameire, MD,PhD

Em prof of Medicine and Nephrology

University Hospital

Gent, Belgium

Stuttgart, February 24, 2018

A selection of remaining uncertainties in AKI

• Is all AKI equal? Should management be individualized on a better phenotyping of AKI by etiology, severity of injury, and ability to recover? Can we predict/detect AKI early enough to modify outcome? Should biomarkers be incorporated in the diagnosis and result in earlier intervention and improvement of prognosis?

• What determines the long-term outcome of AKI?

• How can recovery be defined and can it be optimized?

• How do we optimize RRT and what parameters can be used for correct timing for initiation and stopping RRT? Does RRT modality affect long-term outcome?

AKI Syndromes

• Sepsis-associated AKI • Nephrotoxic AKI • Cardiorenal syndrome • Hepato-renal syndrome • Cardiac surgery-associated AKI • Acute interstitial nephritis • Glomerulonephritis/Vasculitis/ microangiopathy • Obstructive AKI • Abdominal compartment syndrome • Rhabdomyolysis

Strength of recommendations and level of evidence of the 2012 KDIGO Clinical Practice Guidelines

for AKI

Total number of recommendations: 87

KDIGO definition and classification of AKI

A hypothetical example of real-time GFR and SCr values before and during an episode of AKI.

Thomas et al, Kidney International (2015) 87, 62–73

Hospital mortality in different creatinine trajectories in hospital acquired AKI

THA-AKI: IRA hôpital assocée transitoire; 2HA-AKI transient hospital associated AKI ;IRA qui après résolution est suivie d’une nouvelle rechute

Warnock et al, Nephron 2015;131:227–236

18%

5%

1,7% Hospital mortality

12%

Potential SCr trajectories and AKI misclassification

KD Liu et al, Kidney International Reports (2018) 3, 205–215

Classes of biomarkers in AKI Class of biomarker Biomarker

Inflammatory Proinflammatory cytokines (IL 6, IL 18), Neutrophil gelatinase-associated lipocalin (NGAL)

Cell injury L-fatty acid binding protein (L-FABP), KIM-1, sodium/hydrogen exchanger-3 (NHE-3) and Netrin-1;

Cell cycle markers urinary tissue inhibitor of metalloproteinases-2 (TIMP-2) and insulin- like growth factor-binding protein 7 (IGFBP7)

Functional Cystatin C

AKI- a continuum?

Vaidya et al, Annu. Rev. Pharmacol. Toxicol. 2008, 48:17.1–17.

Structural

Early detection of AKI (left) and prediction of AKI recovery (right) with cell cycle biomarkers after post cardiac surgery

AKI

Non-AKI

Meersch et al, PLoS ONE 9(3), 2014

TMP2xIGFBP7

NGAL

Identification of clinically relevant structural kidney damage using biomarkers. Concurrent use of intrinsic kidney injury biomarkers and serum creatinine-based estimation of glomerular filtration rate (GFR) identifies at least 4 clinically relevant categories differentiating prerenal declines in GFR without structural injury and structural injury by biomarker positivity with or without changes in serum creatinine.

Phenotyping AKI with biomarkers and SCr

Huen, Parikh Am J Physiol Renal Physiol 309: F406–F413, 2015.

?

Preventive strategy performed in high risk cardiac surgery AKI patients

Meersch et al, Int Care Med 43(11):1551-1561, 2017

Application of the “KDIGO care bundle” reduced overall AKI at 72 h from 71% to 55.1% and the rates of moderate-to-severe AKI from 44.9% to 29.7%.

(Pulse contour cardiac output)

Peak post-operative urine biomarkers are not independently associated with the outcome of AKI post cardiac surgery Peak post-operative plasma biomarkers are independently associated with CV events and mortality,

Parikh et al, J Am Soc Nephrol 28(12):3699-3707, 2017

Performance of SCr and Kidney Injury Biomarkers for Diagnosing Histologic Acute Tubular Injury Association of donor characteristics with 6-month recipient eGFR.

NS

Moledina et al Am J Kidney Dis. 2017;70(6):807-816

Ad

just

ed

6m

– R

eci

pin

et e

GFR

(9

5%

CI)

Principle of an electronic early alert system for AKI

Haase M, et al, Electronic alerts for acute kidney injury—a systematic review. Dtsch Arztebl Int 2017; 114: 1–8.

Comparison of clinical outcomes between the usual care and alert groups-Korean study

Park et al, Am J Kidney Dis ,71(1):9-19. 2018

Current strategies for preventing AKI

• Hemodynamic management to prevent septic AKI • Unknown exact mean arterial pressure and perfusion

targets • Restricted fluid strategies? • Protocolized fluid and hemodynamic strategies?

• Hemodynamic management to prevent surgical AKI • Perioperative hemodynamic optimization? • Targets unknown

• Pharmacological and non-pharmacological strategies

• Avoidance of nephrotoxins

Pickkers et al , Intensive Care Med (2017) 43:1198–1209

Inidividualized goal-directed hemodynamic therapy of the macro-and microcirculation in sepsis

Saugel et al, SHOCK, 43 : 522-529, 2015

Management of septic shock should be based on both global hemodynamic parameters and tools that reflect tissue perfusion

Ait-Oufella et al, Curr Opin Crit Care 2015, 21:271–275

SDF: side stream dark field

Sublingual microperfusion in sepsis

Trzeciak et al, Ann Emerg Med. 2007;49:88-98

Dogma’s and traditional views on the long term prognosis of AKI survivors in the 1960-2000 years

• The mortality risks are mainly determined by the clinical

context • In contrast with chronic kidney diseases is AKI in principle

a reversible disease • The majority of AKI patients will return to the same renal

function as before the AKI episode • An old adagium : « if the patients survive, so will their

kidneys »

AKI stage and duration are independently associated wtih CV events or death in post cardiac surgery AKI

Parikh et al, J Am Soc Nephrol 28: 3699–3707, 2017

Evolution of long term mortality in community acquired AKI

Sawhney et al Am J Kidney Dis. 69(1):18-28, 2016

Grampian population,

Silver et al, J Am Soc Nephrol 29: ccc–ccc, 2018

Cumulative incidence of mortality causes 1 year after hospital discharge post AKI-

population-based study of residents in Ontario 2003-2013

Total mortality: 28%

Total AKI: 212969 Total discharged : 156690

Silver et al, J Am Soc Nephrol 29: ccc–ccc, 2018

Post AKI cumulative mortality incidence and mortality causes in the year after hospital discharge

population-based study of residents in Ontario 2003-2013

The interrelation between AKI-CKD-AKI

Liu et al, Curr Opin Nephrol Hypertens 18:241–245, 2009

Only knowledge of basal renal function and pre AKI functional profile allow accurate determination of impact of AKI on the

post AKI functional profile

Difficulties to detect persistent kidney dysfunction after AKI in critically ill patients. Serum creatinine

(log scale) in 221 hospitalizations with 3-12 mth FU

Prowle et al, Clin J Am Soc Nephrol 9: 1015–1023, 2014

Definitions and epidemiology of early or late reversal and functional recovery of AKI in ICU

Kellum et al, Am J Respir Crit Care Med 195, 784–791, 2017

AKI stage 2/3

Recovery: reversibility at hospital discharge

Reversal: return to non AKI stage

ICU population

5 profiles

Different types of recovery after AKI-survival to death or RRT

Kellum et al , Am J Respir Crit Care Med 195, 784–791, 2017

Development of CKD stage 3 or higher by 1 year after discharge according to AKI recovery pattern

Heung et al, Am J Kidney Dis. 67(5):742-752, 2016

Cumulative incidence of de novo CKD after recovered hospital –acquired AKI among patients

with normal baseline GFR

De novo CKD: occurrence of ≥ 2 eGFR values <59 ml/min 1.73m2, separated in time by at least 90 but no more than 365 days.

Recovery :‘eGFR value within at least 90% of baseline eGFR occurring within 90 days of AKI

Bucaloiu et al, Kidney Int (2012) 81, 477–485;

Three-year outcomes after AKI: results of a prospective parallel group cohort study

60.7±21 mL/min/1.73 m2

68.4±21 mL/min/1.73 m2

control

AKI

Horne KL, et al. BMJ Open 2017;7:e015316

71±28

mL/min/1.73 m2

68 ±19 mL/min/1.73m²

At 3 years, the number of AKI patients with CKD progression was 30 (24.6%), compared with 10 (7.5%) of the non-exposed group, p<0.001.

CKD progression: a decrease in eGFR of ≥25% associated with a decline in eGFR stage.

Cumulative incidences of subsequent renal progression (solid line) for those with (red) and without (blue) an AKI admission in 2003, grouped by 1 year post-episode eGFR and accounting for the competing risk of death

(dashed line) – Grampian study population

Sawhney et al Kidney Int 2017 92(2):440-452.

Long-term survival and renal outcome in a prospective single center study

Schiffl et al, Clin Kidney J (2012) 5: 297–302

“Absolute” or “conventional” parameters for initiating RRT in AKI

Parameter Definition

Hyperkalemia Serum K > 6.5 mmol/L or raidly rising or refractory to standard supportive medical therapy

Metabolic acidosis pH ≤ 7.15

Uremia Urea > 36 mmol/L (equals BUN ~ 100 mg/dl; blood urea = 216 mg/dl)

Anuria/Oliguria Urine output < 0.3 ml/kg.hr for ≥ 24 hrs or anuria for ≥ 12 hrs

Fluid overload Pulmonary edema not responding to diuretics and defined by the presence of all of the following factors: > 10% fluid accumulation ( cumulative fluid balance/

baseline weight > 10%) urine output < 0.5 ml/kg/hr for ≥ 12 hours and severily impaired oxygenation (Pa O2/Fi O2 < 200 as

indicated by respiratory Sequential Organ Failure Assessment (SOFA) score ≥ 3

Differences in design and outcomes between the ELAIN and AKIKI trials

Bagshaw, Wald, Nature Reviews in Nephrol 2016

Advantages and shortcomings of earlier RRT initiation in AKI Advantages Shortcomings

More effective reversal of volume expansion, particularly in diuretic-resistant patients Better control of electrolyte and acid base status Pro active clearance of toxic low and middle molecular weight solutes Avoidance of AKI-related emergencies, (eg cardiac dysrhythmias related to hyperkalemia

Exposure to complications associated with supplemental vascular access (both at time of insertion and therafter- infections, thrombosis, emboli,…)

Exposure to complications associated with RRT (e.g. intradialytic hypotension, dysrhythmias, clearance of antibiotics- hypokalemia, hypoglycemia…..)

Higher cost, especially if patient was destined to recover kidney function

Adapted from Wald, Bagshaw, Semin Nephrol 36:78-84, 2016

Recovery from AKI at 90 days (A) and 1 yr (B)-impact of RRT modality

Liang et al, Clin J Am Soc Nephrol 11: 30–38, 2016

Referral to nephrologist after AKI

Siew et al ,J Am Soc Nephrol 23: 305-312, 2012

Mortalité pendant le FU d’ un an: 22%. L’incidence cumulative d’adressage au nephrologue avant décès, commençement de dialyse, ou amélioration de la function rénale était 8,5%

Survival during FU by specialty of severe AKI adult patients in Ontario

Harel et al, Kidney Intl (2013) 83, 901–908

Disparity between opinions of nephrologists and actual practices in the FU of post AKI patients (Ontario)

Karsanji et al, Clin J Am Soc Nephrol. 2017 Nov 7;12(11):1753-1761

87%

27%

Role of nephrologists in FU of post AKI patient Nephrological

aspects Cardiovascular

aspects Patient’s advocate

FU of Serum Creatinine FU of hypertension Avoiding of potentionally nephrotoxic drugs and interventions

FU of proteinuria Monitoring cholesterol Education of patients and families

Metabolic control Control of circulating volume

Education of non-nephrological specialists

Treatment of renal anemia

Adaptation of drug dosing

Education of general practitioners

Prevention of new AKI episodes

Reinstitution of previously administered drugs (aspirin, statins, ACE, ARBS

Preparation of chronic RRT

Silver, Siew Adv Chronic Kidney Dis. 2017;24(4):246-252)

Performance of SCr and Kidney Injury Biomarkers for Diagnosing Histologic Acute Tubular Injury Association of donor characteristics with 6-month recipient eGFR.

NS

Moledina et al Am J Kidney Dis. 2017;70(6):807-816

Pt 1

Pt 2

Estimating Kinetic GFR when the SCr Is Changing Acutely

Chen S J Am Soc Nephrol 24: 877–888, 2013

Incidence and stages of AKI in hospitalized patients according to the RIFLE,AKIN, KDIGO, and

Creat Kinetics definition

Zeng et al, Clin J Am Soc Nephrol 9: 12–20, 2014.